(What Do I Do Now - ) Sara C. LaHue, Morris Levin - Emergency Neurology (What Do I Do Now - ) - Oxford University Press (2021)

ADVANCE PRAISE FOR EMERGENCY NEUROLOGY, SECOND EDITION
“Emergency Neurology provides practical guidance to approaching both

common as well as newly described neurological syndromes. With illus-
trative cases, key points, and useful tables, each chapter addresses common
diagnostic and therapeutic dilemmas in a brief, engaging, and high impact
format. Emergency Neurology is a useful resource for clinicians at all levels
of training and experience in neurology.”
—John Probasco, MD, Vice Chair for Quality,
Safety, and Service, Department of Neurology,
Johns Hopkins University School of Medicine,
Baltimore, Maryland
“Now more than ever, hospital neurologists must be nimble and integra-
tive in responding to complex consultations and urgent cases as their scope
of practice continues to expand rapidly. In this Second Edition of Emergency
Neurology, LaHue and Levin offer nuanced yet pragmatic approaches filled
with clinical pearls relevant to trainees and seasoned clinicians alike. This
book will get you into the mindset of a modern neurohospitalist and will
surely improve your practice.”
—Joshua P. Klein, MD, PhD, Vice Chair, Clinical Affairs,
and Chief, Division of Hospital Neurology,
Department of Neurology, Brigham and
Women’s Hospital, Boston, Massachusetts
“This book makes it easy to grasp collection of critical issues pertinent

to approaching a clinic, hospitalized patient, curbside consult, morning
report, or clinic conference. The text is loaded with logical, stepwise
approaches to differential diagnosis, gently guiding the reader on how
to proceed in the golden hours of neurological emergencies. Ample updates
sprinkled throughout the text span the breadth of topics with significant
advances in recent years—comprehensive, easy on the eyes, and an essential
guide for every clinician.”
—Vineeta Singh, MD, Professor of Neurology,
University of California, San Francisco
What Do I Do Now?
S E R I E S C O -E D ITORS-I N-C HIE F
Lawrence C. Newman, MD
Director of the Headache Division
Professor of Neurology
New York University Langone
New York, New York
Morris Levin, MD
Director of the Headache Center
Professor of Neurology
University of California, San Francisco
San Francisco, California
OT H E R VO L U M E S IN T HE SE RIE S
Headache and Facial Pain

Epilepsy
Pain
Emergency Neurology
Neuroinfections
Neurogenetics
Neurotology
Pediatric Neurology
Neurocritical Care
Stroke
Peripheral Nerve and Muscle Disease
Cerebrovascular Disease
Movement Disorders
Women’s Neurology
Neuroimmunology
Neuro-Ophthalmology
Concussion
Emergency
Neurology
SECOND EDITION
Sara C. LaHue, MD
Assistant Professor of Clinical Neurology
Department of Neurology
University of California
San Francisco, CA, USA
Morris Levin, MD
Professor
Department of Neurology
University of California
1
1
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Library of Congress Cataloging-in-Publication Data
Names: LaHue, Sara C., author. | Levin, Morris, 1955–author.
Title: Emergency neurology /Sara C. LaHue, Morris Levin.
Other titles: What do I do now?
Description: 2nd edition. | New York, NY : Oxford University Press, [2021] |
Series: What do I do now | Morris Levin’s name appears first on previous edition. |
Includes bibliographical references and index.
Identifiers: LCCN 2020020672 (print) | LCCN 2020020673 (ebook) |
ISBN 9780190064303 (paperback) | ISBN 9780190064327 (epub) |
ISBN 9780190064334 (online)
Subjects: MESH: Central Nervous System Diseases | Emergencies | Case Reports
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DOI: 10.1093/med/9780190064303.001.0001
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Contents
Preface vii
Acknowledgments ix
SECTION 1 DIAGNOSTIC DILEMMAS
1 Neurological Deficits Following Carotid Endarterectomy 3
2 Prolonged Migraine Aura 7
3 Acute Generalized Weakness 13
4 Syncope 17
5 Monocular Visual Loss 23
6 Thunderclap Headache 29
7 Generalized Convulsive Status Epilepticus 35
8 Hospital-Acquired Delirium 41
9 Coma with Fever 47
10 Refractory Vertigo 53
11 Febrile Dystonia 59
12 Myelopathy 65
13 Neurologic Complications of Immune Checkpoint Inhibitors 73
14 Cauda Equina Syndrome 77
15 Intracranial Mass in a Person with HIV 83
16 Rapidly Progressive Dementia 91
17 Functional Hemiparesis 97
18 Acute Myopathy 103

SECTION 2 TREATMENT DILEMMAS
19 Cardioembolic Stroke with Contraindications to

Anticoagulation 111
20 Recurring Transient Ischemic Attack 117
21 Acute Neuralgia 123

22 Intractable Migraine 129
23 Intracerebral Hemorrhage on Anticoagulation 135
24 First Seizure 141
25 Acute Stroke Up to 24 Hours 147
26 Acute Cervical Radiculopathy 153
27 Post-Cardiac Arrest Management 157
28 Myasthenic Crisis 163
29 Encephalopathy and Seizure After Transplant 169
30 Nonepileptic Spells 175
31 Migraine in a Pregnant Patient 179
SECTION 3 PEDIATRIC DILEMMAS
32 Acute Migraine in a Child 189
33 Febrile Seizure 193
34 Acute Ataxia in a Child 197
35 Concussion in an Adolescent 203
36 Acute Stroke in an Adolescent 209
Index 213
vi Contents
Preface
Some of the most exciting recent developments in neurology have occurred

in the management of neurologic emergencies. This case-based second edi-
tion of Emergency Neurology features 13 new chapters as well as signifi-
cant updates to chapters that appeared in the first edition and that provide
practical approaches incorporating these clinical advances. The topics in-
clude acute stroke management and stroke prevention, status epilepticus,
neurologic toxicities from cancer immunotherapy, newly appreciated au-
toimmune and paraneoplastic diseases, the prevention and management of
delirium, and many others.
“Can I tell you about a new case?” is a common refrain among medical
colleagues who strive to learn from each other and from our patients. Sharing
cases serves as an internal check to our personal systematic approaches to
the management of various diseases and are a delightfully interactive way
to stay up to date in medicine. A number of clinical presentations that we
see lead to diagnostic or therapeutic impasses (i.e., “What do I do now?”).
We have tried to identify important examples and sort through them in
a comprehensive but practical way. Our point of view is often that of an
attendee at a morning rounds discussion, starting with key details of a rel-
evant case, followed by a pragmatic discussion of the differential diagnosis,
testing options, and management strategies.
This book is for clinicians at all levels of training and in all fields of med-
icine who treat patients with urgent or emergent neurological illnesses. This
book can serve as a reference for common clinical questions or a focused
primer to prepare the busy consultant for a number of eventualities on
service. We hope that sharing our passion for caring for patients suffering
from neurologic emergencies deepens your knowledge and clinical practice.
Sara C. LaHue, MD
Morris Levin, MD
Acknowledgments
As clinicians everywhere know, the management of each case is a team ef-

fort. It is no less true for texts like this one, and we have a number of people
to thank for their assistance. First, we would like to express our sincere ap-
preciation to our partners who put up with less support and time from us
during the writing and editing of Emergency Neurology. There were also a
number of colleagues at the University of California San Francisco (UCSF)
who generously offered suggestions, answered questions, and supported this
effort. We would like to express our gratitude to the UCSF Neurohospitalist
Division faculty, who are each national leaders in the care of patients with
complex and urgent neurological illnesses and are also exceptional teachers.
UCSF is a very special medical institution, with seemingly an international
expert in virtually every subject we wanted to be accurate about. We remain
indebted to all of our colleagues here in the Neurology Department, and
we could not think of more knowledgeable team to be part of. Any errors
are ours, through misinterpretation or asking the wrong questions of them.
Several editors at Oxford University Press helped on this project, including
Jordan McAndrew and Craig Panner—many thanks to you all for being pa-
tient with us and alternately pushing us when that was needed. Finally, we
would like to thank each other for the careful reading and editing of each
other’s chapters before we sent them in to Oxford University Press. Thanks
Mo, thanks Sara!
Sara C. LaHue
Morris Levin
Emergency
Neurology
SECTION 1
Diagnostic Dilemmas
1 Neurological Deficits
Following Carotid
Endarterectomy
A 68-year-old man who presented 6 days
ago with transient language difficulty was
found to have high-grade left internal carotid
stenosis and then underwent left carotid
endarterectomy (CAE) 3 days ago. Today he
awoke with numbness in his right arm, which
has persisted all morning. He also complains of
a mild generalized headache. His wife called 911,
and you are now seeing him the ER. Vital signs
are normal, HEENT exams are normal, lungs
are clear, and cardiac exam is normal. Neck
is supple, and the endarterectomy incision is
healing well. However, there is a bruit over this
carotid. On neurological exam, his mental state,
cranial nerves, strength, and coordination are all
intact, but there does seem to be numbness over
the entire right arm. CT scan without contrast is
normal.
What do you do now?
3
V irtually every clinician treating adults knows that carotid endarterec-
tomy (CEA) has been proven effective for treatment of symptomatic
carotid stenosis. Fewer, however, have seen complications and feel com-
fortable dealing with them. It turns out that perioperative mortality can
be as high as 3%, even at experienced centers. All of the usual potential
postsurgical adverse consequences can occur in these patients. Wound de-
hiscence and infection are very rare. The most common adverse sequelae
include myocardial infarction, transient ischemic attack (TIA)/ stroke,
hyperperfusion syndrome (HPS), neck region nerve injury, and parotitis.
Stroke in the perioperative period can result from a number of contributing
causes including platelet aggregation and thrombosis formation, plaque
emboli, carotid dissection, and relatively low cerebral arterial perfusion
pressure. The etiology of TIA or stroke must be assessed in order to choose
the appropriate treatment.
After symptoms that could relate to carotid disease develop, the first
step—and one which must be done quickly—is to rule out intracranial
hemorrhage with head CT scan and then, if negative, to get a reliable visu-
alization of the carotid artery over its cervical and intracranial course. This is
best done via intraarterial angiography to detect flow-limiting dissection or
thrombosis. CT angiography is often quicker and nearly as useful. If either
is found, anti-coagulation had traditionally been the treatment of choice.
High-quality duplex ultrasound evaluation can be helpful to confirm good
flow through the proximal carotid and is used as a first step by some teams.
Some surgeons favor surgical re-exploration if complications happen very
early, with percutaneous carotid angioplasty with direct stenting. Many case
reports document remission of neurological symptoms if stenting is done
quickly, and several case series comparing stenting to surgical re-exploration
attest to this.
Intraarterial thrombolytic therapy, in highly selected cases, may be
another treatment option in patients with a postoperative thrombotic
stroke suggested by arteriography. The rationale for the administration of
tissue-type plasminogen activator (tPA) for these patients is based on its
proven success in acute stroke, but there is no clear evidence to support
its use here.
4 WHAT DO I DO NOW? Section 1: Diagnostic Dilemmas

Myocardial infarction can occur after CEA, with incidence as high as
2%. Risk factors include older age, preexisting coronary artery disease, and
peripheral arterial disease. Headaches are not uncommon after CEA and are
often benign, but a severe headache should definitely prompt immediate
medical attention. Contralateral stroke after CEA is rare but does occur,
often for unclear reasons.
An important syndrome to exclude is HPS, which can produce three
characteristic conditions: (1) persistent headache, (2) intracerebral hemor-
rhage, or (3) focal seizures. This last can involve significant post-seizure
(“Todds”) paralysis which can be misleading. HPS tends to occur 3–10 days
following endarterectomy. The etiology of the HPS is thought to be caused
by some degree of cerebral autoregulation breakdown due to the large
change in flow. HPS seems to be more likely with high-grade (>80%) pre-
operative carotid occlusion and in patients with recent stroke. It might be
difficult to differentiate hyperperfusion consequences from peri-or postop-
erative stroke. Head CT and MRI with T2 or FLAIR sequences typically
show cerebral edema with or without intracerebral hemorrhage. Transcranial
Doppler testing can reveal cerebral hyperperfusion in some cases. Strict
control of systemic hypertension (systolic pressure <150 mmHg) is the best
way to treat HPS and may require intravenous antihypertensives. Generally,
the lability in postoperative blood pressure (BP) tends to resolve in the first
24 hours.
Since cranial nerves can be damaged during the operative procedure,
this cause of neurological deficits must also be excluded if cranial nerve
symptoms and signs tend to predominate (unlike the presenting case).
Nerves at risk include (1) vagus nerve, which, if damaged, can lead to vocal
cord paralysis; (2) portions of the facial nerve, leading to an asymmetric
smile; (3) glossopharyngeal nerve which can lead to carotid sinus dysfunc-
tion, and, finally, (4) the hypoglossal nerve, which may result in dysarthria,
and tongue deviation to the side of injury on examination. Nerve damage
is generally due to traction, but intraoperative transection is also possible.
The most reliable predictor of cranial nerve injury during endarterectomy
is surgery duration, with a very low likelihood of cranial nerve damage in
patients for whom OR time was less than 2 hours.
1. Neurological Deficits Following Carotid Endarterectomy 5

KEY POINTS TO REMEMBER
• CAE is generally safe but postoperative complications include

stroke and hyperperfusion syndrome.
• In patients who develop focal deficits in the perioperative
period, immediate CT of the head is recommended to exclude
hemorrhage.
• Vascular imaging is essential to determine the presence of
thrombosis or dissection of the carotid artery.
• Assessment of intracranial arterial blood flow is important in
determining the presence of the hyperperfusion syndrome.
• Management of arterial BP is crucial if hyperperfusion
syndrome is suspected.
Further Reading
Adhiyaman V, Alexander S. Cerebral hyperperfusion syndrome following carotid
endarterectomy. Q J Med. 2007;100:239–244.
Anzuini A, Briguori C, Roubin G, Rosanio S, et al. Emergency stenting to treat
neurological complications occurring after carotid endarterectomy. J Am Coll
Cardiol. 2001;37:2074–2079.
Clouse WD, Ergul EA, Patel VI, Lancaster RT, LaMuraglia GM, Cambria RP, Conrad
MF. Characterization of perioperative contralateral stroke after carotid
endarterectomy. J Vasc Surg. 2017;66(5):1450–1456.
Farooq MU, Goshgarian C, Min J, Gorelick PB. Pathophysiology and management of
reperfusion injury and hyperperfusion syndrome after carotid endarterectomy
and carotid artery stenting. Exp Translational Stroke Med. 2016;8(1):7.
Flanigan DP, Flanigan ME, Dorne AL, et al. Long-term results of 442 consecutive,
standardized carotid endarterectomy procedures in standard-risk and high-risk
patients. J Vasc Surg. 2007;46:876.
Tu J, Wang S, Huo Z, Wu R, Yao C, Wang S. Repeated carotid endarterectomy
versus carotid artery stenting for patients with carotid restenosis after carotid
endarterectomy: Systematic review and meta-analysis. Surgery. 2015;57(6):1166–
1173. doi:10.1016/j.surg.2015.02.005

2 Prolonged Migraine Aura
A 34-year-old woman, with a history of migraine
attacks with aura, describes to the ER physician
a typical migraine attack yesterday with
scintillations and vision loss in the “left eye.”
She states that the headache abated with oral
sumatriptan but the visual symptoms have not.
The longest her migraine aura has lasted in the
past is approximately 60 minutes. She feels
anxious and a bit confused, but mental status
testing is normal. Funduscopy is normal, and the
ophthalmology consultant has excluded ocular
disease. There does seem to be a left visual field
deficit involving both upper and lower visual
quadrants, but it tends to fluctuate. Cranial
nerve exam is otherwise normal. Motor exam is
normal. Sensory exam is generally normal, but
there may be some diminution to light touch and
vibration in the left arm and trunk. Coordination
is intact; gait seems limited by vision. Routine
labs are normal. CT of the head with and without
contrast is normal.
What do you do now?
7
T his patient has relatively typical migraine aura symptoms (visual and
sensory) but of atypical duration. The International Classification of
Headache Disorders, 3rd edition (International Headache Society [ICHD]
2018) defines prolonged migraine aura as lasting more than 1 week without
radiographic evidence of infarction. A second entity, migrainous stroke is de-
fined as “one or more aura symptoms [which] persisting for >60 minutes”
and where “Neuroimaging demonstrates ischaemic infarction in a relevant
area” (see Boxes 2.1 and 2.2). Thus, our patient fits neither definition. An
important deciding diagnostic test is MRI with diffusion-weighted imaging
(DWI). If this is positive, it is very possible that a migrainous stroke has
occurred. Migraine itself is a mild risk factor for stroke, particularly in cer-
tain populations, most notably young women. This increased stroke risk
is primarily limited to patients who experience migraine auras, although
migraine without aura carries an overall mild increased risk of stroke as
well. An unanswered question is whether a longer than average duration
of aura symptoms magnifies the risk. Also unanswered, and of great in-
terest, is the question of stroke pathophysiology in migraine. Presumably
this is related either to some migraine-induced circulatory compromise or
hypermetabolic “exhaustion” of normal perfusion, leading to relative is-
chemia to one or more brain regions.
But if the MRI is negative, there are still two important imperatives: (1)
to continue to investigate possible causes of ischemia or other possible
causes of prolonged aura-like symptoms and (2) to attempt to curtail
BOX 2.1 International Classification of Headache Disorders, 3rd

Edition: Persistent aura without infarction. Aura symptoms persisting
for 1 week or more without evidence of infarction on neuroimaging
Diagnostic criteria:
A. Aura fulfilling criterion B
B. Occurring in a patient with 1.2 Migraine with aura and typical of
previous auras except that one or more aura symptoms persists for
≥1 week
C. Neuroimaging shows no evidence of infarction
D. Not better accounted for by another ICHD-3 diagnosis

BOX 2.2 International Classification of Headache Disorders, 3rd
Edition: Migrainous infarction. One or more migrainous aura
symptoms associated with an ischemic brain lesion in appropriate
territory demonstrated by neuroimaging
A. A migraine attack fulfilling criteria B and C
B. Occurring in a patient with 1.2 Migraine with aura and typical of
previous attacks except that one or more aura symptoms persists
for >60 minutes
C. Neuroimaging demonstrates ischemic infarction in a relevant area
the aura. There are a number of conditions which may mimic prolonged
auras including occipital lobe epilepsy, vertebrobasilar transient ischemic
attacks, cerebral venous thrombosis, reversible cerebral vasoconstriction
syndrome (RCVS), carotid or vertebral artery dissection, cerebral vascu-
litis, and hematological diseases causing “sludging.” Mitochondrial en-
cephalopathy, lactic acidosis, and stroke-like episodes syndrome (MELAS)
and cerebral autosomal dominant arteriopathy with subcortical infarcts
and leukoencephalopathy (CADASIL) are two other possibilities which
MRI should exclude. CT angiography may be necessary in cases of pro-
longed aura to exclude vasculitis and RCVS. Imaging of the neck vessels
with CT angiography (CTA) or MR angiography (MRA) may also be ap-
propriate. EEG is very useful not only in excluding ongoing epileptic ac-
tivity, but also to corroborate neurophysiological alterations in the cortex
corresponding to the patient’s symptoms. In the presenting patient, one
would suspect to see some altered electrophysiological activity in right pos-
terior derivations.
Persistent aura symptoms are rare but well-documented. They are often
bilateral and may actually last for months or years. The 1-week minimum
required by the ICHD is based on the opinion of experts, and solid evidence
supporting this timing has not really be presented. Similarly, there are no
clear treatment guidelines for patients suffering from prolonged migraine
auras. Historically, despite a lack of evidence of real benefit, inhalation
2. Prolonged Migraine Aura 9
therapy with 10% carbon dioxide and 90% oxygen, amyl nitrate or isopro-
terenol, and sublingual nifedipine have been used based on the theory that
migrainous auras were the result of prolonged vasoconstriction. And recent
studies of patients with prolonged migraine aura have found areas of cortical
hypoperfusion corresponding to the region of aura symptoms. However, it
seems that this is the result of a decreased metabolic demand rather than
an ischemic mechanism, so presumably there is ongoing cortical spreading
depression in these patients which might respond to a different therapeutic
approach. Hence, a number of agents have been tried including magnesium
sulfate, prochlorperazine, divalproex, acetazolamide, verapamil, flunarizine,
lamotrigine, gabapentin, and memantine. Intravenous magnesium sulfate is
probably a good place to start due to its relative safety, followed by intrave-
nous divalproex. Selected patients with persistent aura have responded to
occipital nerve blocks.
So, in summary, with prolonged migraine aura it is imperative to look
further for evidence of cerebral ischemia and other causes of focal neu-
rological deficits, which can then be explored and managed. If there is no
stroke on MRI DWI images, prolonged aura is the best diagnosis. There are
several options for treating the aura in hopes of curtailing it but no clear
guidelines. Unfortunately, little is known currently about the etiology, risk
factors, prognosis, and best treatments in prolonged migraine aura. Clearly,
this presentation is concerning to patients, so migraine preventive strategies
should be optimized.
• Migraine auras typically develop over 5–20 minutes and resolve

within 1 hour or less.
• When aura lasts beyond 1 hour, investigation into other possible
causes of focal neurological deficits should be considered.
• MRI with DWI should be abnormal in migrainous infarction, and
MR or CT imaging along with EEG can generally rule out other
pathological causes.

• Treatments which have helped some patients to halt prolonged
auras include magnesium sulfate, divalproex, oxygen, and
verapimil.
Further Reading
Cuadrado ML, Aledo-Serrano Á, López-Ruiz P, Gutiérrez-Viedma Á, Fernández C, Orviz
A, Arias JA. Greater occipital nerve block for the acute treatment of prolonged or
persistent migraine aura. Cephalalgia. 2017; 37(8):812–818.
Headache Classification Committee of the International Headache Society.
International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018;
38:1–211.
Hu X, Zhou Y, Zhao H, Peng C. Migraine and the risk of stroke: an updated meta-
analysis of prospective cohort studies. Neurological Sciences. 2017; 38(1):33–40.
Viana M, Sances G, Linde M, Nappi G, Khaliq F, Goadsby PJ, Tassorelli C. Prolonged
migraine aura: new insights from a prospective diary-aided study. J Headache
pain. 2018;19(1):77.
2. Prolonged Migraine Aura 11
3 Acute Generalized Weakness
In the ED, a 28-year-old man complains of
bilateral leg weakness for the past day and a
half. He thinks it is due to a strenuous soccer
match 2 days ago but feels that things seem
to be worsening. He denies headache, visual
problems, and any difficulty swallowing or
breathing, but he also complains about some
pain in his posterior thighs and back. He has
had no bladder or bowel incontinence. He had
a “cold” 2 weeks ago. He has been diagnosed
with bipolar disorder and obsessive compulsive
disorder and has been taking a combination of
sodium divalproex and sertraline over the past
6 months. He also admits to frequent marijuana
use and “some” alcohol use. An emergency
medicine resident has examined this patient and
found an entirely normal neurological exam. You
repeat the exam and find that when asked to sit
and stand, the patient has unexpected difficulty,
and there is some impairment in gait. General
exam is normal; there is no rash.
What do you do now?
13
W hile this case sounds like a standard presentation for Guillain-Barré
syndrome (GBS, aka acute inflammatory demyelinating polyneu-
ropathy), there are a few odd details. Against the diagnosis of GBS might be
the normal reflexes, sparing of the upper extremities and face, and proximal
location. On the other hand, GBS often begins with leg weakness, and,
even though distal sensory complaints are the rule, many patients do com-
plain of back pain. Reflexes, and upper body strength, may be normal for
the first several days in GBS. Since the pathophysiology of GBS is thought
to be an autoimmune attack on peripheral nerve myelin resulting from ac-
tivation by an infectious agent (e.g., Campylobacter, Mycoplasma, and re-
cently, Zika virus) with similar antigenic epitopes, a recent infection may
be an important clue. Yet many patients with GBS cannot recall recent
infections and conversely, the incidence of recent “colds” in the general
population can be high.
Other possibilities for progressive weakness include myasthenia
gravis, tick paralysis, Lyme neuropathy, HIV polyradiculoneuropathy,
hypercalcemia, hypokalemia, hypothyroidism, heavy metal intoxication,
drug toxicity, botulism, polymyositis, polio (highly unlikely in North
America and Europe), and upper spinal cord lesions (see Box 3.1 for a more
complete list).
Myasthenia rarely begins in the proximal lower extremities, and there
is no history of instigators of a myasthenic syndrome in this patient.
Botulism symptoms usually include blurred vision, nausea, abdominal
pain (with ingestion), malaise, and/or dry mouth. Polymyositis should
be apparent on lab testing (creatine kinase [CK], erythrocyte sedimen-
tation rate [ESR], CBC). Electrolyte abnormalities can easily be ruled
out, as can thyroid abnormalities and HIV infection. The patient was not
taking medications known to cause generalized weakness. Lead neurop-
athy usually begins in the arms, and intoxication with arsenic and thal-
lium usually causes GI symptoms as well. Porphyria can be ruled out with
the absence of porphobilinogen on urinalysis. Lyme disease can indeed
cause a polyradiculitis, and the pathognomonic bull’s-eye rash may have
been missed, but cranial nerve palsies are much more common. Also, CSF
pleocytosis is seen. Tick paralysis is, however, a real possibility as he has
been exposed to the common causes—wood ticks and dog ticks. The pre-
sentation is similar to GBS, but CSF protein concentration should be

BOX 3.1 Differential diagnosis of generalized weakness
Guillain-Barré syndrome
Myasthenia gravis
Myasthenia syndrome (e.g., aminoglycoside-induced)
Tick paralysis
Lyme neuropathy
HIV polyradiculoneuropathy
Hypercalcemia
Hypokalemia
Hypothyroidism
Heavy metal intoxication (arsenic, lead, thallium)
Medication (isoniazid [INH], vinca compounds, dapsone,
nitrofurantoin)
Botulism
Sarcoidosis
Polymyositis
Polio
Porphyria
Spinal cord lesions
normal. Tick paralysis is caused by a toxin that seems to interfere with ace-
tylcholine release at the neuromuscular junction and abates soon after the
tick is removed. Therefore, a search for ticks is recommended, including
the hair.
A common question is how far to proceed in searching for a spinal cord
lesion in a patient like this one. After all, he did play a highly physical sport
the day symptoms began. The lack of reflex change and bowel/bladder dys-
function argues against this etiology, but it is difficult to be sure in these
cases. Given the absence of arm weakness, at minimum a thoracic spine
MRI should be obtained, though some may argue for a complete spinal
MRI. A key test in this case is lumbar puncture to see if CSF protein is
high. Unfortunately, in the first week of GBS, around one-third of patients
have normal CSF. Neurophysiological testing is also helpful, though usually
more fruitful within a week or two of symptom onset, specifically showing
3. Acute Generalized Weakness 15

slowed motor conduction along with absent F and H waves. Serologic
testing for anti-ganglioside antibodies associated with GBS and its variants
should be considered.
So, despite a high clinical suspicion for the diagnosis of GBS, a number
of mimics exist, and workup needs to be thorough. Admission to the hos-
pital for further investigation, treatment, and monitoring is generally most
efficient and safe. Respiratory power should be monitored frequently with
forced vital capacity (FVC) and mean inspiratory force (MIF), with a low
threshold to consider elective intubation. If testing is confirmatory of GBS,
IVIg administration is generally begun unless symptoms are extremely
mild. Plasma exchange is an alternative but since it is more difficult and
less available, IVIg has largely replaced it for the treatment of GBS in many
institutions. Prognosis is generally very good for recovery, although the ma-
jority of patients will have some residual motor deficits.
• Acute Guillain-Barré syndrome may present in atypical fashion,

without clear history of antecedent infection.
• The differential diagnosis in acute diffuse weakness is large,
with a number of entities producing similar symptomatology.
• A good initial workup should include thorough metabolic
screening as well as CSF analysis.
• Spinal imaging should be done early if there is any suspicion of
myelopathy.
Further Reading
Fahoum F, Drory V, Issakov J, Neufeld MY. Neurosarcoidosis presenting as Guillain-
Barre-like syndrome: a case report and review of the literature. J Clin Neuromusc
Dis. 2009;11:35–43.
Krishnan AV, Lin CS, Reddel SW, Mcgrath R, Kiernan MC. Conduction block and
impaired axonal function in tick paralysis. Muscle & Nerve. 2009;40:358–362.
Wijdicks EF, Klein CJ. Guillain-Barre syndrome. Mayo Clinic Proc. 2017;92:467–479.

4 Syncope
A 78-year-old woman had an episode of loss of
consciousness at home yesterday afternoon.
She admitted this to her daughter this morning
when asked about the cut on her head. She later
admitted to several (“maybe half a dozen?”)
previous episodes of loss of consciousness,
some of which led to falls, over the past 3–
4 years. She feels fine now, although she is
anxious. She denies incontinence of urine or
feces. She did experience a mild headache when
recovering from her syncopal attack yesterday,
but “it’s gone now.” Her medical history includes
mild COPD and controlled hypertension. Her
blood pressure now is 148/78, does not drop
significantly on sitting or standing, and her pulse
is 88 and regular. Respirations are 14 per minute,
and she is afebrile. Neurological exam is intact
including mental status, cranial nerves, strength,
reflexes, coordination, and gait. She asks you
why this happened and worries about the
possibility of it happening again, “maybe even
when I am driving!”
What do you do now?
17
T he conscious patient reporting syncope is one of the most frequent
triggers for both neurological and cardiological consultation in the ED.
The first step is to determine if, in fact, this was actual syncope (brief loss
of consciousness). Some patients will ultimately be found to have had tran-
sient loss of vision, lightheadedness (presyncope), or transient confusion. If
there was a transient loss of consciousness, and this can be corroborated by
witnesses or perhaps by evidence of trauma sustained due a fall which often
accompanies syncope, the next step is to attempt to discover clues to the
cause of the loss of consciousness. Box 4.1 lists causes of loss of conscious-
ness which include those due to reduced cardiac output.
BOX 4.1 Causes of brief loss of consciousness
Cardiac arrhythmia
Myocardial infarction
Pericarditis or cardiac tamponade
Cardiomyopathy
Aortic stenosis
Mitral valve stenosis or prolapse or atrial myxoma
Dissecting aortic aneurysm
Orthostatic hypotension
Carotid sinus syncope
Vasovagal syncope
Pneumothorax
Pulmonary stenosis
Pulmonary hypertension
Pulmonary embolus
Basilar artery occlusion
Stroke
Subclavian steal syndrome
Intracerebral or subarachnoid hemorrhage
Hypoglycemia
Anemia
Hypoxemia
Hypercarbia
Psychogenic

Important historical features to obtain include information about pro-
vocative factors: after standing, after exercise, while overheated, in the
bathroom, after eating, with stress or intense emotion, or following neck
position changes. Associated symptoms to list include changes in thinking,
nausea, palpitations, shortness of breath, chest pain, and incontinence.
A thorough list of medications should be obtained, and a urine toxicology
screen is not a bad idea. Electrocardiography is essential, and a plain CT
scan of the head is generally necessary, particularly if there is any suspicion
of head injury.
In the presenting case stroke is unlikely as neurological exam is normal,
and hemorrhage has been ruled out by a negative CT of the head. Posterior
cerebral circulation occlusive disease is possible but is unlikely in the ab-
sence of typical accompanying symptoms such as vertigo, imbalance, dysar-
thria, facial numbness, and visual loss. MRI of the brain as well as vascular
imaging (either MR or CT angiography) can help to exclude this.
Intermittent arrhythmias which reduce cardiac output can be occult but
cardiac rhythm monitoring, via inpatient telemetry or portable monitoring
systems, generally clarifies the presence of this as a cause. Blood pressure
(BP) should be checked in both arms to investigate the possibility of subcla-
vian stenosis/coarctation leading perhaps to subclavian steal. A strong clue
to this pathophysiology is instigation of syncopal sensations by exercising
the ipsilateral arm, promoting “stealing” of blood from the brain via the
vertebral artery to supply the arm. Chest x-ray and echocardiography will
help to rule out pericarditis, tamponade, mitral valve, aortic valve or atrial
pathology, and cardiomyopathy. Hypotension, venous engorgement, weak
pulse, and findings on cardiac auscultation might also be present with car-
diac disease.
Orthostatic hypotension (OH) should be relatively straightforward to
rule out. A drop in diastolic pressure of more than 10 mm Hg, or systolic
of 20 mm Hg, when the patient sits or stands up, is diagnostic. If ortho-
static tachycardia occurs, one suspects hypovolemia; if not, there may be an
element of dysautonomia. The potential causes of OH include drug effects
(anticholinergics, dopaminergics, and diuretics), autonomic neuropathies
(e.g., diabetes or amyloid neuropathy), Parkinson’s disease and “Parkinson-
plus” syndromes (including multisystem atrophy), hypovolemia, and
anemia. If OH is identified, these possibilities should all be investigated.
4. Syncope 19
Vasovagal syncope, also referred to as neurocardiogenic syncope, is caused
by a relative surge in parasympathetic activity precipitated by emotional
stress, fear, excessive coughing, pain, or, in some cases, urination (micturi-
tion syncope). Bradycardia and hypotension lead to brain hypoperfusion.
Premonitory symptoms can include diaphoresis, pallor, and nausea. This
may be the most common cause of syncope and is essentially a diagnosis
of exclusion until the patient notices a pattern of recurrence in similar
situations. When vasovagal syncope results from autonomic hypersensi-
tivity to position changes, it begins to resemble orthostatic hypotension.
Using a tilt table to incline the patient during monitoring for BP and pulse
rate can be diagnostic. Treatment includes avoidance of triggers, volume
expansion tactics, and medications.
Chest or abdominal pain and/or dyspnea should be present to at least
some degree in myocardial infarction, pneumothorax, dissecting aortic an-
eurysm, and pulmonary embolism. Measuring levels of cardiac enzymes
should be considered. Anemia, hypoxemia, hypercarbia, and other meta-
bolic disturbances can be easily ruled out with routine labs and pulse ox-
imetry. Carotid sinus syncope occurs when the carotid sinus is compressed
by a tight collar, a seat belt, backpack strap, or other source of external
pressure. This results in vagal stimulation leading to bradycardia and vaso-
dilation with resulting systemic hypotension.
Seizures, when generalized, usually cause loss of consciousness or at least
a period of unresponsiveness to one’s environment. A key to the diagnosis
here is postictal alteration in mentation, consciousness, or other neurolog-
ical function. Patients tend to recover pretty quickly after cardiovascular
syncope, but much less so following generalized seizures. Other impor-
tant clues are witnesses’ reports of sustained motor movements, evidence
of tongue biting, and incontinence. Interestingly, causes of syncope which
involve some degree of cerebral hypoxia can cause tonic-clonic movements
briefly, mimicking epileptic seizures.
Drug intoxication is always a possibility although a classic syncopal
event is unlikely. Still, drug screening must be considered. Psychogenic
syncope is seen in patients with depression, anxiety, and panic. Vasovagal
mechanisms, hyperventilation, or somatization may be the proximate cause
in these patients.

So, there are a number of possibilities here, including several relatively
unlikely neurological ones. The neurologist who can reason through these
cases and offer advice other than “order an EEG” will be much respected
and appreciated.
KEY POINT S TO REMEMBER
• Syncope can result from many causes including cardiovascular,

pulmonary, metabolic, neurological, and psychogenic.
• Careful general, cardiac, pulmonary, neurological history and
exams are essential, including careful assessment of pulse and
BP bilaterally and in different positions.
• Laboratory investigation should include metabolic and
hematological panels, and cardiac enzymes. ECG, chest x-ray,
EEG, echocardiography, and cardiac monitoring should be part
of the investigation as well as CT of the head, particularly if
there is any suspicion of head injury.
• Cerebrovascular imaging of the head and neck should likewise
be considered in cases of syncope accompanied by any focal
neurological deficits.
Further Reading
Chen-Scarabelli C, Scarabelli TM. Neurocardiogenic syncope. BMJ. 2004;329:336–341.
Moya A, Sutton R, Ammirati F, et al. Guidelines for the diagnosis and management of
syncope. Eur Heart J. 2009;30:2631–2671.
Serrano LA, Hess EP, Bellolio MF, et al. Accuracy and quality of clinical decision
rules for syncope in the emergency department: a systematic review and meta-
analysis. Ann Emerg Med. 2010;56:362–373.
4. Syncope 21
5 Monocular Visual Loss
A 46-year-old laboratory tech is seen for acute
visual loss in the right eye. She states that vision
seemed normal yesterday, and she did not even
notice it today until she tried closing her left eye.
She has had no recent infection or trauma. She
is on no daily medication. She denies pain in the
eye and headache. General exam is normal: vital
signs are normal; neck is supple; lungs, heart
and abdomen are normal; there is no skin rash.
Ocular exam is normal, without papilledema,
but pupillary reactivity to light on the right
shows a relative afferent pupillary defect (RAPD).
Neurological exam otherwise normal. Routine
labs are normal.
What do you do now?
23
A cute vision loss is a daunting presentation. Rapid identification of
the cause and speedy corrective measures are imperative. Fortunately
for neurologists, the answers are usually clarified by ophthalmologists, but
a common reason for consultation arises when “ocular causes have been
ruled out.”
The differential diagnosis of acute monocular vision loss can be divided
into the following categories (beginning with the most peripheral and
moving more centrally): (1) opacities in the cornea, lens, or vitreous humor;
(2) retinal disease; (3) retinal or eye ischemia; (4) optic nerve disease (is-
chemic, compressive, or demyelinating); (5) pathology of the chiasm; and
(6) conversion, factitious disorder, or malingering.
Ocular opacities like corneal edema or vitreous hemorrhage generally do
not cause a Marcus Gunn pupil (relative afferent pupillary defect—RAPD)
even with dramatic visual blurring or loss. They are generally painless.
Funduscopic exam is generally diagnostic when done by an ophthalmol-
ogist. Iritis and uveitis can obscure vision due to localized edema, but eye
pain and obvious ocular inflammation generally lead these patients to where
they need to be: into the hands of an ophthalmologist. Acute retinal detach-
ment is usually painless and begins with some degree of vitreous detachment
with patients complaining of “floaters.” Retinal detachment may eventually
cause a deafferented pupil, but generally not initially. Complaints usually
begin with peripheral field loss. Regular funduscopic exam is often negative
although occasionally one can see the classic white “billowing” retinal sepa-
ration. A dilated eye exam by an ophthalmologist is usually diagnostic.
Ischemia of the retina can arise in the setting of several different disease
states. Amaurosis fugax (transient loss of vision in one eye) occurs usu-
ally in the form of a “shade coming down” then receding. This generally
arises as the result of atherosclerotic or thrombotic emboli to the central
retinal artery or one of its retinal branches from a diseased carotid artery.
Occasionally one can see small atheromatous or calcific fragments in ret-
inal arteries on funduscopic exam. If the embolus becomes lodged long
enough, retinal ischemic injury can occur, leading to permanent visual im-
pairment. Retinal artery occlusion may cause deafferentation. Funduscopic
exam usually reveals an area of pallor on the retina with a red macula due
to its thinner epithelium. There is little or no effective treatment for this

condition although hydration, assurance of optimal carotid system perfu-
sion, and perhaps ocular massage may help. Searching for the specific eti-
ology and treatment of it is of course imperative in hopes of preventing
further brain ischemia. More proximal embolic or atheromatous occlusion
of the ophthalmic artery may also cause monocular vision loss and can, like
strokes elsewhere, occur on the basis of cardiac, paradoxical, or arterial em-
bolization; arterial thrombosis; or atherosclerotic narrowing.
Central retinal vein occlusion (RVO) is another fairly frequent cause
of acute monocular vision loss and is generally diagnosed funduscopically
by seeing multiple retinal hemorrhages and papilledema. The vision loss is
often not as severe as that resulting from arterial occlusion. Despite many
proposed interventions, there are no treatments proven to reopen occluded
retinal veins. Management is directed at secondary complications of RVO
that affect vision, including macular edema, retinal neovascularization, and
anterior segment neovascularization. Temporal arteritis (TA; giant cell ar-
teritis) affects the temporal artery and extradural portions of the carotid
and vertebral arteries. This includes the ophthalmic artery so visual loss can
occur as a result of resulting ischemia to the retina and/or optic nerve. TA
usually presents with severe headache and often polymyalgia rheumatica
(manifested by diffuse aching, muscle stiffness, and flu-like symptoms), and
occasionally one can detect a tender temporal artery. By the time vision
has been impaired, it is probably too late to save what has been lost but
rapid treatment with intravenous steroids can prevent further loss. Retinal
vasculitis can also produce monocular visual impairment and is diagnosed
with dilated funduscopic exam and flourescein angiography. The condi-
tion is usually painless. Etiology is often not discovered, but management
consists of searching for systemic causes of vasculitis and treatment with
immunosuppressants.
Anterior ischemic optic neuropathy (AION) is due to ischemia and gen-
erally occurs in patients with diabetes, hypertension, or lupus. Papilledema
is often seen. Treatment is aimed at the underlying disease(s), and patients
often improve. Alternatively, the rarer posterior ischemic optic neuropathy
(PION) does not produce papilledema. It may be due to vasculitis, as can
AION, and the diagnosis is usually made by exclusion of other causes. Both
AION and PION can be caused by TA.
5. Monocular Visual  Loss 25

Optic neuritis (ON) due to acute demyelination is often painful and
usually causes a deafferentated pupil early, along with the vision loss.
Papilledema is seen when the inflammation is close to the retina, but when
it is retrobulbar, diagnosis rests on clinical suspicion along with brain MRI
findings, and enhanced MRI can reveal optic nerve inflammation. Standard
treatment is methylprednisolone. ON can be seen as an isolated syndrome
(although there is a significant chance of developing MS), as an exacer-
bation of MS, or as the presentation of one of the neuromyelitis optica
spectrum disorders (NMOSD) as opposed to just NMO, which includes
autoimmune diseases with antibodies to aquaporin-4 (AQP4) and my-
elin oligodendrocyte glycoprotein (MOG). Leber optic neuropathy is
inherited mitochondrially and can lead to unilateral optic neuropathy ei-
ther subacutely or acutely. Subsequent involvement of the other eye is the
rule. There is no treatment known.
Mass lesions or infections affecting the optic nerve in the orbit or in the
region of the optic foramen generally progress more slowly with gradual
visual impairment over weeks or longer. Involvement of the optic chiasm
by neoplastic and infectious diseases does not lead to monocular vision loss
but rather bitemporal or homonymous field deficits.
Conversion disorder may cause monocular blindness, but it is more
often binocular and can be detected fairly easily by normal pupillary reac-
tivity, normal optokinetic strip testing, and normal visual evoked potentials.
Similarly, visual loss due to malingering or factitious disorder is suggested
by these findings on examination. Clinical suspicion arises when secondary
gain is present.
Diagnostic workup, once thorough ophthalmological examination has
been done and found to be normal, should include complete blood count,
erythrocyte sedimentation rate (ESR), C-reactive protein, antinuclear an-
tibody, hemoglobin A1C, brain MRI with contrast, dedicated carotid im-
aging, and echocardiogram. If suspicion for demyelinating disease is high,
NMO, AQP4, and MOG antibodies should be checked. If the diagnosis
is not clear, Lyme titer, HIV screen, lumbar puncture with CSF exam to
include protein, glucose, fungal and TB stains, and cultures, oligoclonal,
bands and IgG index should be done.

• Ophthalmological evaluation is critical in acute monocular

visual loss and should include a dilated funduscopic exam (prior
to which careful pupillary testing should be done).
• When ophthalmological causes of monocular blindness have
been excluded, retinal ischemia, ischemic optic neuritis, and
demyelinating optic neuritis must be considered.
• Diagnostic testing should include brain and vascular imaging,
ESR, and possibly lumbar puncture.
Further Reading
Abbatemarco JR, Patell R, Buccola J, Willis MA. Acute monocular vision loss: don’t
lose sight of the differential. Clev Clin J Med. 2017;84(10):779.
Vortmann M, Schneider JI. Acute monocular visual loss. Emerg Med Clin N Am.
2008;26:73–96.
Ward TN, Levin M. Headache in giant cell arteritis and other arteritides. Neurol Sci.
2005;26(Suppl 2):s134–s137.
Zhang LY, Zhang J, Kim RK, et al. Risk of acute ischemic stroke in patients with
monocular vision loss of vascular etiology. J Neuro-Ophthal. 2018;38(3):328–333.
5. Monocular Visual  Loss 27

6 Thunderclap Headache
A 42-year-old man rapidly developed a severe
headache while biking up a challenging hill. He
had to get off his bike, and then he called 911,
which led to his arrival in the ED by ambulance.
He told the ED staff that he has never had
headaches and that this one “made me see
stars.” Pain continues for the next 2 hours
along with some blurred vision. General and
neurological exams are normal. Neck is supple
and funduscopic exam is normal. CT of the head
and lumbar puncture (LP) have been done and
are negative.
What do you do now?
29
T his is, of course, the famous “thunderclap headache.” Most patients
will seek attention, and some will turn out to have one of the scarier
conditions that are known to cause sudden severe headaches, such as
intracerebral hemorrhage or subarachnoid hemorrhage, which are identified
with CT and LP (see Box 6.1). Seeing “stars” and complaining of persis-
tent visual difficulties are clues that there may indeed be an underlying sec-
ondary cause of headache here. So—what is a wise course of action when this
initial workup is negative? One problem is that several causes of thunder-
clap headache are identifiable only with more advanced imaging. Cerebral
venous thrombosis is one example, since standard MRI imaging may fail
to identify even large thrombi in cerebral veins. MR or CT venography,
however is almost always diagnostic. The syndrome of reversible cerebral
vasoconstriction syndrome (RCVS), also known as Call-Fleming syndrome,
often presents as sudden or severe headache and only later with neurolog-
ical deficits. Unlike CNS vasculitis, CSF in RCVS is generally normal, and
BOX 6.1 Causes of sudden (thunderclap) headache
• Acute hypertension
• Carotid or vertebral artery dissection
• Cerebral vasculitis
• Cerebral venous thrombosis
• Hypertensive, lobar, or pituitary intracranial hemorrhage
• Intracranial hypotension
• Primary thunderclap headache
• Reversible cerebral vasoconstriction syndrome (RCVS)
• Sphenoid sinusitis
• Subarachnoid hemorrhage or “aneurysmal leak” (sentinel headache)
Rarer causes
• Aqueductal stenosis
• Cardiac cephalalgia
• Colloid cyst of the third ventricle
• Giant cell arteritis
• Ischemic stroke

MRI is often normal as well. The hallmark is the finding of segmental ar-
terial narrowing seen on angiography. Fortunately, CT angiography seems
to be almost as useful as standard intraarterial angiography. Interestingly,
RCVS often becomes symptomatic (with severe headache) after vigorous
exercise and this may well be the explanation for this patient’s presentation.
To complicate matters, RCVS may lead to focal subarachnoid bleeding (per-
haps the most common cause of acute severe headaches in these patients),
which can lead to a fruitless quest for a ruptured aneurysm. While in most
cases RCVS is a self-limited disorder, it may progress, and calcium channel
blockers are often used in some centers to prevent stroke.
Carotid or vertebral arterial dissection can present with acute severe
headache, without other neurological symptoms. Again, vascular imaging,
including the proximal segments of these vessels, is required for exclusion
of dissection. Sphenoid sinusitis may also present as sudden diffuse head
pain, and, while it may be missed on CT, MRI is generally quite adequate
to diagnose it. Spontaneous intracranial hypotension, generally diagnosed
by the patient’s complaint of significant worsening of pain upon sitting
or standing and improvement with reclining, may present with thunder-
clap headache. Exertional headaches are generally short-lived, but exercise-
induced migraine may persist, similar to regular migraine, for hours to even
days. Likewise, orgasmic headache, thought to represent a benign primary
headache type, can persist and mimic serious vascular causes. A key distin-
guishing feature, of course, is that these follow a pattern—stereotypic recur-
ring sudden or at least rapidly building global headaches at or near the time
of orgasm—clearly not the cause in our case. And finally, there is a primary
benign headache condition termed “primary thunderclap headache,” which
is obviously a diagnosis of exclusion. Rare causes are possible, including
third ventricular colloid cysts, giant cell arteritis, pheochromocytoma, and
cardiac cephalgia due to an as yet unclear pain referral phenomenon from
ischemic myocardium.
But have we really excluded an aneurysm as an underlying cause of this
patient’s severe acute headache? Head CT imaging resolution is generally
considered adequate to detect subarachnoid blood (Figure 6.1). But some
reports suggest that there are between 1% and 5% false negatives. Hence,
the need for LP. But this, too, has a finite false-positive rate, particularly
if the hemorrhage was recent, deep, and limited. There have been several
6. Thunderclap Headache 31
(a)
(b)
FIGURE 6.1 CT scan of a patient with subarachnoid hemorrhage (a) Axial view without contrast
showing the presence of blood in the cerebral subarachnoid systems and (b) Axial view after
contrast showing a basilar tip aneurysm.
reports of patients with unruptured aneurysms, or aneurysms which have
“leaked,” and produced thunderclap headaches (the so-called sentinel head-
ache) without producing bloody CSF. MRI is generally very sensitive to
even small amounts of subarachnoid blood, undetectable by CT or in the
CSF sample. But high-resolution cerebrovascular imaging is necessary to
exclude the possibility of an unruptured aneurysm. The mechanism un-
derlying acute headache with unruptured aneurysm is not clear, but some
have postulated stretching of the nociceptive receptors in the aneurysmal
wall as causal. The International Classification of Headache Disorders also
included unruptured arteriovenous malformation as a cause of headache,
but these are generally not thunderclap in presentation.
So, what is the most parsimonious workup for thunderclap headache
once CT and LP have been negative? A brain MRI to rule out recent hem-
orrhage, MRA of the cerebral vessels to investigate for aneurysm (or AVM)
and segmental arterial narrowing, MRA of the cervical vessels to look for
dissection and an MR venogram to rule out CVT would be a very thorough
approach. MR angiography may not be as sensitive as CT angiography for
detecting berry aneurysms, so the latter or a conventional intraarterial dye
angiogram should be considered.
If all serious causes of thunderclap headache are ruled out, primary thun-
derclap headache may be the diagnosis although it must be viewed with
suspicion. Indomethacin may relieve this type of headache, but opioids may
be necessary.
• Sudden severe headache is a potential emergency and

should be evaluated with CT and, if negative, LP to rule out
hemorrhage.
• There are several diagnostic possibilities for thunderclap
headache that may not be diagnosed with CT, LP, or even MRI,
including cerebral arteritis, cerebral venous thrombosis, RCVS
and cervical arterial dissection.
• Primary thunderclap headache, thought to be a primary
headache disorder, may be the underlying diagnosis but must
be a diagnosis of exclusion.
6. Thunderclap Headache 33
Further Reading
Barritt A, Miller S, Davagnanam I, Matharu M. Rapid diagnosis vital in thunderclap
headache. Practitioner. 2016;260(1792):23–28.
Day JW, Raskin NH. Thunderclap headache: symptom of unruptured cerebral
aneurysm. Lancet 1986;2(8518):1247–1248.
Ducros A, Wolff V. The typical thunderclap headache of reversible cerebral
vasoconstriction syndrome and its various triggers. Headache.
2016;56(4):657–673.
Kowalski RG, Claassen J, Kreiter KT, et al. Initial misdiagnosis and outcome after
subarachnoid hemorrhage. JAMA. 2004;291:866–869.
Singhal AB. Diagnostic challenges in RCVS, PACNS, and other cerebral
arteriopathies. Cephalalgia. 2011;31:1067–1070.

7 Generalized Convulsive
Status Epilepticus
A 45-year-old woman with a history of traumatic
brain injury and alcohol use disorder was
brought to an outside hospital by paramedics
after having a witnessed seizure in the
supermarket. She had a second seizure that
was described as “generalized” en route to the
hospital, and so she received midazolam 10 mg
IM. She had a third generalized seizure in the
outside hospital ED, and so she was intubated
and loaded with fosphenytoin IV. Her vital signs
were notable for a temperature of 100.2°F, blood
pressure of 85/50, heart rate of 110, oxygenating
well. Her exam was limited as she received
paralytics in order to be intubated, but her pupils
were reactive and symmetric to light; she was
not following commands prior to intubation.
Given concern for meningoencephalitis she was
started on meningeal-dosed antibiotics. She
underwent a head CT that showed a subdural
hemorrhage; vessel imaging was unremarkable.
She is transferred to your hospital for continuous
EEG monitoring.
What do you do now?
35
G eneralized convulsive status epilepticus (GCSE) is a neurological
emergency with high morbidity and mortality. While the duration
of seizure activity that defines GCSE has changed over time, it is clear that
the sooner the seizure activity is stopped, the better the prognosis. The hip-
pocampus is particularly sensitive to prolonged generalized seizure activity.
For this reason, it is more practical to recommend prompt treatment for sei-
zure activity lasting for at least 5 minutes, or two or more sequential seizures
without full recovery of consciousness between seizures.
General support must include close scrutiny of airway, breathing, and
circulation and monitoring of temperature as many patients in GCSE can
become hyperthermic, leading to secondary brain injury (see Box 7.1).
Acidosis usually occurs but resolves with termination of the seizure. Cardiac
arrhythmias can also occur.
The most common cause of GCSE is discontinuation of medications,
but new exacerbating factors must always be ruled out. Therefore, it is
important to search for infection, including meningitis or encephalitis;
metabolic derangements including aberrancies in levels of sodium (low),
glucose (high/low), calcium (low), and magnesium (low); hepatic and renal
BOX 7.1 An approach to status epilepticus
1. Assess airway, breathing, and circulation

Obtain finger-stick glucose: if glucose < 60 mg/dL then give
thiamine 200 mg IV followed by D50W IV.
Start IV with normal saline and obtain labs (CBC, BMP, Mg/Ca,
LFTs, AED levels, ABG, toxicology screen).
2. Lorazepam 4 mg IV (2 mg/min) or midazolam 5–10 mg IM.
Repeat benzodiazepine after 5–10 minutes if needed.
3. Give one of the following:
• Fosphenytoin (20 mgPE/kg, maximum 1,500 mgPE)
• Valproate (40 mg/kg, maximum 3,000 mg)
• Levetiracetam (60 mg/kg, maximum 4,500 mg)
Begin EEG monitoring if patient does not awaken or if anticipate
escalation to continuous IV therapy.
4. Intubate and proceed to use of anesthetics.

dysfunction; drug toxicity (e.g., cocaine, amphetamines); ethanol or barbi-
turate withdrawal; hypoxia; and focal intracranial processes like ischemic
or hemorrhagic stroke; subarachnoid or subdural hemorrhage (as seen in
this case, see Figure 7.1); traumatic brain injury; or mass lesion. Convulsive
movements can be observed in patients with basilar artery occlusions and
so vigilance for this mimic is crucial.
Initial workup is done simultaneously with administration of antiepileptic
drugs (AEDs) and should generally include an ABG, comprehensive met-
abolic panel, complete blood count, drug screen, urinalysis, and CT of the
head. A lumbar puncture should be considered if this is a first seizure, first
episode of GCSE, there is evidence of fever, or suspicion for subarachnoid
hemorrhage. Complications from prolonged convulsive seizure should also
be assessed, such as aspiration using chest x-ray, and rhabdomyolysis using
serum creatine kinase.
In addition to providing rapid treatment, it will be important to
make sure the patient is medically stable, and to ensure airway patency.
FIGURE 7.1 Noncontrast CT of the head showing acute-on-chronic right holohemispheric

subdural hematoma with leftward midline shift.
7. Generalized Convulsive Status Epilepticus 37

Lorazepam 4 mg IV or midazolam IM (5 mg for patients 13–40 kg, and
10 mg for patients >40 kg) can be given acutely. There are now three AEDs
shown to have similar efficacy for status epilepticus based on results from
the Established Status Epilepticus Treatment Trial (ESETT). These AEDs
are fosphenytoin (20 mgPE/kg, maximum 1,500 mgPE), valproate (40 mg/
kg, maximum 3,000 mg), or levetiracetam (60 mg/kg, maximum 4,500
mg). The appropriate dose of these medications can be remembered by the
20-40-60 rule. The recommended loading dose of levetiracetam for GCSE
is quite high, and so an alternate AED should be considered if the patient
has renal impairment. If available, fosphenytoin is preferred to phenytoin
as it can be administered faster and does not carry the risk of “purple-glove
syndrome.”
A finger stick glucose should be obtained quickly, and if glucose is lower
than 60 mg/dL give thiamine 200 mg IV followed by D50W IV. If the pa-
tient is on INH or hydralazine, administer pyridoxine (vitamin B6) 5 g IV
over 5 minutes, then repeat 30 minutes later.
If seizures continue, intubation should be considered given the likely
need to escalate to anesthetics. It is reasonable to escalate to an anesthetic
rather than additional trials of second-line AEDs. Advocate for short-acting
paralytics if intubation is necessary to limit its impact on the neurological
(a) (b)
FIGURE 7.2 MRI of the brain showing signal abnormalities in the bilateral hippocampi (a) and right
thalamus (b) likely due to postictal state.

exam. If available, EEG monitoring should be sought if seizure activity
returns when sedatives are paused, or if there is a need to escalate contin-
uous IV therapy. If EEG monitoring is not available, transfer to a facility
that can provide continuous EEG monitoring should be attempted. MRI
can also be helpful with identifying an underlying cause, and may also re-
veal post-ictal changes (Figure 7.2).
• Prompt treatment for GCSE is necessary for any seizure lasting

at least 5 minutes or when there is an incomplete return to
baseline between seizures.
• Control of seizures must be achieved as quickly as possible,
along with a search for causes including meningitis, stroke/
hemorrhage, drug intoxication/withdrawal, metabolic
derangements or head trauma.
• It is important to not underdose benzodiazepines if someone is
in GCSE.
• There is a choice of three AEDs to load for GCSE: fosphenytoin
(20 mgPE/kg, maximum 1,500 mgPE), valproate (40 mg/kg,
maximum 3,000 mg), or levetiracetam (60 mg/kg, maximum
4,500 mg).
• General medical monitoring for hyperthermia, hypertension,
hypoxia, renal dysfunction, electrolyte imbalance, and
arrhythmia must occur simultaneously with treatment of GCSE.
Further Reading
Betjemann JP, Lowenstein DH. Status epilepticus in adults. Lancet Neurol. Jun
2015;14(6):615–624.
Kapur J, Elm J, Chamberlain JM, et al. Randomized trial of three anticonvulsant
medications for status epilepticus. N Engl J Med. 2019;381(22):2103–2113.
doi:10.1056/NEJMoa1905795
Silbergleit R, Durkalski V, Lowenstein D, et al. Intramuscular versus intravenous
therapy for prehospital status epilepticus. N Engl J Med. 2012;366(7):591–600.
doi:10.1056/NEJMoa1107494
7. Generalized Convulsive Status Epilepticus 39

8 Hospital-Acquired Delirium
A 72-year-old man with a history of a left frontal
glioblastoma multiforme (GBM) had a witnessed
generalized seizure shortly after dinner. He
received midazolam by the paramedics and
stopped seizing. On arrival to the ED, his
blood pressure (BP) was 141/75, heart rate 105
and regular, and he was afebrile. His general
examination revealed a laceration on the lateral
aspect of his tongue. His neurological exam
showed intact orientation but impaired naming
and bilateral hearing impairment, as well as
mild right face and hand weakness. A head
CT showed increased edema around the GBM
without hemorrhage. He received a levetiracetam
load and dexamethasone. He was admitted
to the hospital and stayed awake much of the
night. He pulled at his IV, so limb restraints were
placed. On hospital day 2, he said the year was
“1953.” That evening, he asked his wife to take
their dog out for a bathroom break and gestured
to the corner.
What do you do now?
41
T here are many reasons why someone may become confused in the hos-
pital. While confusion may seem innocuous, serious illness may un-
derlie it. It is important to start with an assessment of the patient’s airway,
breathing, and circulation. Check vital signs, looking for abnormalities in
BP and pulse (elevated or depressed), oxygen saturation, and temperature.
Vital signs may point toward dehydration, hypertensive emergency, hypox-
emia, or infection. A finger-stick glucose can be helpful to rule out hypo-
glycemia. If the patient is hypoglycemic, give thiamine prior to dextrose to
avoid possible precipitation of Wernicke’s encephalopathy. Review hospital
medications, paying particular attention to anticholinergic medications,
benzodiazepines, opioids, cefepime or other antibiotics, and steroids. If the
patient is somnolent and there is recent opiate use, consider a naloxone trial
(1–2 amps IV or IM every 5 minutes). If altered mental status develops
within a few days of admission, compare inpatient medications with home
medications to check for possible withdrawal, especially if the patient pre-
viously took benzodiazepines, opioids, or baclofen.
The bedside general physical examination should focus on screening
for infectious signs, such as heart murmur, respiratory difficulty, and skin
lesions/rashes. Meningismus should be looked for, though development of
a new central nervous system infection during hospitalization is rare unless
the altered mental status was present on admission or the patient has had
neurosurgery or is immunocompromised.
The neurological exam can also help narrow the differential. The exam
should include detailed mental status testing, especially attention (such as
digit span forward and backward). Testing of language fluency, naming,
repetition, and comprehension may point toward a receptive aphasia caused
by a vascular or structural cause, which can be easily mistaken for “confu-
sion” if the deficit is isolated to language without obvious motor deficits.
The development of neglect is also a reason for altered mental status and
should be checked. Pupil abnormalities can suggest a structural or toxic
etiology. Cranial nerve dysfunction can suggest brainstem involvement or
a process in the subarachnoid space. In addition to strength testing, which
can indicate a hemispheric abnormality, it can also be helpful to assess
for abnormal tone, involuntary movements, and any evidence of seizure-
like activity. Sensory testing is often challenging and primarily consists of
assessing the patient’s response to noxious stimulation. Coordination can be

estimated by watching the patient reach for objects if unable to follow more
complex commands. Gait should only be assessed if safe to do so.
Serum testing should include a complete metabolic panel, CBC, thy-
roid studies, and ammonia. These studies may point toward underlying
electrolyte disturbances, infection, dehydration, uremic or hepatic enceph-
alopathy, hypoxia, or hypercarbia. Urinalysis, urine culture and urine tox-
icology should also be obtained. Chest x-ray can uncover a lung infection.
A head CT should be considered as several vascular disorders could cause
confusion, including ischemic stroke, subdural hemorrhage, subarachnoid
hemorrhage, and intracerebral hemorrhage. Even in a patient without a
neurological history, a head CT or brain MRI may be warranted if there is
no obvious abnormality on initial testing or if the examination uncovers a
focal finding. If the mental status continues to fluctuate, an EEG may be
needed to rule out nonconvulsive status epilepticus. It is also reasonable to
empirically treat for Wernicke’s encephalopathy with thiamine 500 mg IV
every 8 hours for 3 days, followed by 100 mg/d orally.
In this patient, his lab testing showed a leukocytosis, which was ulti-
mately explained by his steroid use rather than infection. On head CT, the
edema around his GBM was mildly improved, as expected with the steroid
use. Given his recent seizure, an EEG was obtained, which did not show
any further seizures. He was ultimately diagnosed with delirium.
Delirium is an acute change in mental status, characterized by
fluctuations in attention and cognition. Delirium is common in the hos-
pital and can affect 10% of general medical admissions and 80% of in-
tensive care unit admissions. While delirium may indicate an underlying
life-threatening illness, delirium itself is a serious condition that is associ-
ated with several poor clinical outcomes. Even when correcting for illness
severity, delirious patients are more likely to stay in the hospital longer, be
discharged to nursing homes, and have a higher rate of mortality: two-fold
higher than adults who do not develop delirium. The development of de-
lirium is also an independent risk factor for the development of new func-
tional and cognitive decline.
While delirious patients can become agitated (hyperactive delirium),
they may also become more lethargic or withdrawn (hypoactive delirium)
or show a combination of features (mixed); hypoactive delirium is more
likely to be missed.
8. Hospital-Acquired Delirium 43
While antipsychotics, such as Seroquel, were once routinely given to
delirious patients, this is no longer recommended unless the patient is a
danger to self or others. Rather, the underlying cause of delirium should
first be identified. While there are nonmodifiable risk factors for delirium,
such as advanced age and cognitive impairment, many other risk factors can
be corrected. For instance, hearing or vision impairment can be improved
with pocket amplifiers and ensuring glasses are always accessible. If pos-
sible, having a family member or a friend at the bedside can help with
reorientation and engagement. Immobilization can be corrected by using a
safety attendant rather than physical restraints, and tethers, such as urinary
catheters—which also carry an infection risk—should be discontinued as
soon as possible. Reviewing medications and discontinuing the unneces-
sary ones can ameliorate polypharmacy. Underlying infection and meta-
bolic derangements should be identified and treated. Adequate sleep is very
important but often difficult to achieve in the hospital. Normalization of
sleep-wake cycle can make a difference for both prevention and treatment
of delirium, and so it is worth reducing the frequency of vital sign checks
(if safe to do so), providing ear plugs and an eye mask, and using mela-
tonin (3–10 mg) at night, ensuring pain and nausea are controlled, as well
as getting adequate light exposure and avoiding napping during the day
(Box 8.1).
BOX 8.1 Approach to hospital-acquired delirium
Step 1: Assess airway, breathing, circulation, vital signs, blood glucose.

Consider naloxone.
Step 2: Review medications and infection risk factors. Identify signs
of infection on exam, perform attention tasks, and look for any
focal finding on the neurologic exam.
Obtain BMP, Ca/Mg/Phos, CBC, LFTs, ammonia, VBG, blood
cultures, UA, Utox, CXR, EKG.
Step 3: If no obvious cause identified, consider head imaging, EEG,
lumbar puncture.
Step 4: If no obvious cause identified, consider thyroid function tests,
morning cortisol, vitamin B12, ESR, ANA.

• Do not use antipsychotics unless the patient is a danger to self

or others.
• There is no harm to giving thiamine 500 mg IV every 8 hours
for 3 days to someone who is confused if there is concern
for Wernicke’s, especially if there is a history of alcohol use,
malnutrition, or malabsorption.
• Review medications for unnecessary medications as well as
benzodiazepines, opiates, and anticholinergics.
• If appropriate, try to normalize sleep-wake cycles by limiting
overnight checks and encouraging activity during the day.
Further Reading
Brown EG, Douglas VC. Moving beyond metabolic encephalopathy: an
update on delirium prevention, workup, and management. Semin Neurol.
2015;35(6):646–655.
Ely EW, Shintani A, Truman B, et al. Delirium as a predictor of mortality
in mechanically ventilated patients in the intensive care unit. JAMA.
2004;291(14):1753–1762.
Inouye SK, van Dyck CH, Alessi CA, Balkin S, Siegal AP, Horwitz RI. Clarifying
confusion: the confusion assessment method. A new method for detection of
delirium. Ann Intern Med. 1990;113(12):941–948.
8. Hospital-Acquired Delirium 45
9 Coma with Fever
A 32-year-old man is brought to the hospital
when he becomes confused and agitated
following a recent camping trip. His temperature
is 102°F, blood pressure 104/60 mm Hg, and
pulse rate 102. Breathing is regular at a rate of
14. His neck is stiff in flexion/extension but not
in rotation. Cardiac auscultation reveals only a
soft midsystolic murmur. There is no rash. He is
agitated but gradually becomes less responsive.
Pupils are 4 mm and react to light equally.
Corneal reflexes are intact. Oculocephalic reflex
is present. His extremities move sluggishly
in response to painful stimulation with some
suggestion of decreased power in his right leg.
Electrocardiogram is normal. Chest x-ray has not
been done yet. Blood count reveals WBC 14,000,
RBC 39,000, and electrolytes are normal. Lactate
is 4.8. He has been given glucose and naloxone
with no response. You are consulted to come and
do a lumbar puncture (LP) as the ED staff has
tried and failed.
What do you do now?
47
T his seriously ill—perhaps even fatally ill—patient requires quick diag-
nostic and treatment decision-making. The questions you began con-
sidering even on the way to the ED were whether further delay in obtaining
CSF is allowable and whether a dangerous mass lesion might be hiding
intracranially. The two are connected because puncturing the dura in a pa-
tient with increased intracranial pressure, particularly if asymmetrical, as in
the case of a temporal mass lesion, could lead to transtentorial herniation,
clinical worsening, and even death. So, a head CT is warranted immediately
if an LP is needed (which is certainly the case here; see Box 9.1). But there
has already been delay and waiting for the CT will add further delay. So, the
first step is to lessen the danger here: starting broad-coverage antimicrobial
therapy immediately, in addition to steroids, in order to at least begin
treating what might be a life-threatening meningitis or encephalitis. Once
this is started, proceeding to head CT in a brisk fashion, followed by LP,
will be possible. There are several blood tests to keep in mind, including
obtaining a CBC, lactate, HIV, and blood cultures. Blood cultures can
aid in the diagnosis in a majority of cases and should be obtained before
antibiotics are started.
Interestingly, what we were taught in medical school about the nature of
meningismus is correct: stiffness in flexion-extension is indicative of menin-
geal irritation; stiffness in rotation is not. Therefore, this patient clearly has
meningismus. Meningitis can be caused by a number of organisms in this
age group, and, surprisingly, the relative probability of various organisms
has changed somewhat over the past few years, probably as a result of the
H. influenza and S. pneumoniae vaccines. For example, gram- negative
BOX 9.1 When to obtain a head CT before LP

Age >60 years
History of central nervous system disease
Immunocompromised
New-onset seizure within the past week
Altered mental status or coma
Optic disc edema
Focal neurologic deficit

bacteria and Staphylococcus have overtaken Streptococcus in some areas as the
most common cause.
Despite advances in antibiotic choices and early diagnosis, approximately
10–20% of adults with meningitis will die from it and another similar frac-
tion will have significant morbidity from it. Initial choices in antibiotic
therapy should consist of ceftriaxone (2 g IV every 12 hours), vancomycin
(1 g IV every eight hours if <65 kg or 1.5 g IV every eight hours if >65 kg),
and acyclovir 10 mg/kg every eight hours with the possible addition of
ampicillin 2 g IV every four hours if Listeria monocytogenes is suspected
(e.g., in older or immune-compromised patients). There is growing resist-
ance to even these antibiotics, however, which unfortunately makes culture
results even more important. Nosocomial causes of meningitis, as well as
suspected meningitis after penetrating head injury, lead to different etiolog-
ical considerations, which is not an issue with this case.
The addition of corticosteroids before or with initial antibiotics in the
management of strongly suspected bacterial meningitis is generally done at
a high dose as soon as possible, despite some conflicting evidence of effi-
cacy. A common approach is to use dexamethasone 0.15 mg/kg every six
hours IV for 4 days.
The suppressed mental status in this patient is concerning, and so a head
CT should be expedited. If possible, CT with contrast can be helpful as it
increases the sensitivity for identifying meningeal and intraparenchymal in-
volvement. Cerebral edema may occur in bacterial meningitis, which may
cause elevated intracranial pressure and/or hydrocephalus. Certain bacteria,
especially S. pneumoniae, can lead to vascular complications such as arte-
rial and venous thrombi. For this reason, it is important to also obtain CT
angiography and CT venography of the brain when getting the screening
head CT.
Measuring an opening pressure with the LP can be helpful if this is ab-
normally elevated. Legs should be straightened prior to measuring the pres-
sure as bent legs can falsely elevate it.
There should be a Gram stain and culture performed on the CSF. In the
presenting case, if this patient does have bacterial meningitis, there may be
a problem in identifying the causative organism in culture since antibiotics
were begun before CSF obtained. This is another reason why drawing
blood cultures before starting antibiotics is so important. Fortunately, for
9. Coma with  Fever 49

most bacterial causes of meningitis, cultures will be positive even after
antibiotics are started. This is less true for Neisseria, but for all bacterial
causes, Gram stain data will be abnormal for many hours, and neutrophil-
prominent pleocytosis will persist as well. Low glucose and high protein
will likewise be present for some time after treatment is begun (Table 9.1).
If lab evaluation is equivocal, polymerase chain reaction (PCR) testing for
common causal organisms may be obtained. Herpes simplex virus 1 and 2
PCR should always be done if there is any chance of viral encephalitis, in
addition to varicella zoster virus PCR, IgG, and IgM. It is also reasonable
to test for fungi, such as Cryptococcus, in the CSF and serum. This patient
should also be investigated for other infectious diseases, depending on what
is endemic to the area or recent travel history, and head MRI, MR angiog-
raphy (to assess for possible vasculopathy), and MR venography (to exclude
cerebral venous thrombosis) should be considered.
TABLE 9.1 CSF patterns in meningitis of various etiologies
Pathogen CSF differential CSF CSF protein

glucose
Bacterial PMNs (may be Low High

lymphocytic if
partially treated)
Viral Lymphocytic (PMNs Normal Normal/

may present acutely) High
Mycobacterial Lymphocytic Low High
Fungal Lymphocytic (some Low Normal/

may be more High
monocytic)
CNS lymphoma, Abnormal cells, Normal/ High

carcinomatous mononuclear Low
T. solium, C. immitis, Eosinophils

Angiostrongyluscantonensis,
Gnathostoma, hardware
CMV, EBV, enterovirus, Atypical lymphocytes

VZV, WNV

Patients with suspected bacterial meningitis should be placed in respi-
ratory isolation for the first day of treatment if possible until the organism
is identified. Patients with meningococcal meningitis should remain on
droplet precautions for at least 24 hours after antibiotics are begun, al-
though specific guidelines vary by hospital. Pneumococcal and viral causes
do not require isolation. Meningococcal meningitis contacts should be
treated prophylactically once the organism is identified depending on local
policy.
There are several complications to remain vigilant for if your patient
is not improving. Meningitis may result in hydrocephalus due to reduced
CSF absorption, or cerebral edema, which may require placement of an
extraventricular drain or use of hyperosmolar agents like mannitol or
hypertonic saline. Lack of source control may cause worsening, and so
a search for a parameningeal focus, such as an epidural abscess, may be
warranted. These patients are also at increased risk for seizure, including
nonconvulsive status epilepticus, so EEG should be considered if mental
status remains poor.
• Bacterial meningitis must be treated with a broad-coverage

antibiotic regimen as soon as possible to prevent morbidity and
mortality, even if this means treating prior to obtaining CSF.
• Bacterial blood cultures should be obtained before giving
antibiotics.
• CSF Gram stain and white blood cell results remain abnormal
for many hours following the initiation of antibiotics.
• Corticosteroids have been shown to be effective in reducing
rates of hearing loss and neurological complications in patients
with meningitis due to S. pneumoniae and should be given in
addition to antibiotics.
• Bacterial meningitis may lead to arterial and venous clots, and
so vessel imaging should be obtained for any focal neurologic
exam finding or suppressed mental status.
9. Coma with  Fever 51

Further Reading
Durand ML, Calderwood SB, Weber DJ, Miller SI, Southwick, Caviness VS, Swartz
MN. Acute bacterial meningitis in adults: a review of 493 episodes. N Engl J Med.
1993;328:21–28.
Hasbun R, Abrahams J, Jekel J, et al. Computed tomography of the head
before lumbar puncture in adults with suspected meningitis. N Engl J Med.
2001;345(24):1727–1733.
Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of
bacterial meningitis. Clin Infect Dis. 2004;39(9):1267–1284.

10 Refractory Vertigo
A 65-year-old woman is seen in the ED for severe
dizziness for the past 3 days. She relates brief
milder episodes of this in the past. She has
vomited, has a mild headache posteriorly, and
states she is unable to walk. She endorses a
sensation of “things moving” and not knowing
“which way is up.” She denies vision changes,
trouble speaking, sensory changes, and
weakness. Her medical history is remarkable for
hypertension and pre-diabetes. She had migraine
headaches in her 20s. General exam is normal.
Neurological exam is remarkable for midposition
poorly reactive pupils and horizontal nystagmus,
worse on gaze to the left. Her speech is slightly
dysarthric. Strength is normal. Reflexes are
diffusely diminished. Touch and proprioception
are slightly reduced in her feet. Gait is unsteady,
but base is not widened. CT scan of the head
reveals some cortical atrophy and subtle white
matter changes bilaterally.
What do you do now?
53
S orting out the patient with “dizziness” can be tricky. The first step in
evaluating these patients is to distinguish between the major symptoms
which can lead a patient to complain of dizziness: (1) vertigo, (2) lighthead-
edness and (3) disequilibrium. This can be more difficult than expected
since these perceptions do overlap, and particularly if your patient has any
degree of mental fogginess or anxiety (not uncommon). And of course,
there are a number of patients who use the word “dizzy” to refer to other
perceptions like confusion, visual change, clumsiness or even anxiety.
Patients using the words “unbalanced”, “wobbly”, and “unsteady” are
generally describing disequilibrium, which usually implicates cerebellar,
cortico-cerebellar connections, or dorsal column sensory dysfunction. CT
scan of the head is a good initial step here, to rule out brainstem or cer-
ebellar hemorrhage. An acute brainstem or cerebellar stroke will not be
seen, so MRI is necessary to discover this. Generally, cerebrovascular causes
of vertigo or imbalance will be accompanied by other signs of ischemia.
A common cerebrovascular cause of vertigo is the Wallenberg syndrome,
due to lateral medullary ischemia, which can consist of dysphagia, slurred
speech, ataxia, ipsilateral facial sensation loss, contralateral body sensation
loss, vertigo, nystagmus, Horner’s syndrome, and diplopia. In some cases,
ataxia and vertigo do predominate. A special case, vertebral dissection, can
lead to ischemia of the brainstem with prominent balance issues, along with
headache which tends to be posterior in location but may radiate anteriorly
as well.
Lightheadedness is usually the term patients choose to describe
presyncope, which is generally related to some reduction in cerebral perfu-
sion. This can be due to any number of conditions from dehydration to a
serious cardiovascular condition (see Chapter 9 - Syncope). Workup should
begin with a thorough cardiovascular exam and an ECG. More lengthy
cardiac monitoring, echocardiography, and imaging of the cervical arteries
with CT or MRI angiography may be necessary as well. Tilt table testing
may be indicated if autonomic instability is suspected.
Patients who describe a sensation of movement are probably feeling ver-
tiginous, which implicates a lesion or lesions in labyrinths, vestibular nerves,
or vestibular brainstem centers. Nausea is usually an accompaniment.
Vestibular neuronitis or “labyrinthitis”, thought to be a self-limited viral or
otherwise inflammatory reaction in the labyrinthine system, is a common

cause of vertigo at all ages. Bacterial infections of the middle ear can also lead
to vertigo along with hearing changes. Benign positional vertigo, thought
to be due to otolith formation within the semicircular canals, should not be
prolonged as in this patient and positional triggering is usually described by
the patient. In all of these cases of so-called “peripheral” vertigo (stemming
from labyrinthine or vestibular nerve pathology) imaging will be negative
but the Dix-Hallpike maneuver should be positive with induction of severe
vertigo (and probably nausea) when the extended head is turned to the side
of the dysfunctional inner ear in the supine position. In addition, nystagmus
(generally horizontal or diagonal, not vertical) is brought on by this ma-
neuver, but this can vary.
Meniere’s disease, thought to result from chronic excess endolymph in
inner ear structures, is eventually accompanied by hearing loss and/or tin-
nitus, but may not yet be present initially. Perilymph fistula also generally
involves a hearing loss, and there is almost always a history of a prior inci-
dent like weightlifting, barotrauma, scuba diving, or forceful nose-blowing.
Meningeal infection or inflammation is usually suggested by meningismus,
headache, other cranial neuropathies. Superior semicircular canal dehis-
cence can cause new and persistent vertigo, with clues to diagnosis in-
cluding sound induced vertigo, hyperacusis and vertigo.
In migraine-related vertigo—aka vestibular migraine (VM)—there is
usually a history of migraine, or at least a strong family history, coupling
of symptoms with headache at least some of the time, and response to mi-
graine abortive medications (like triptans). The mechanism of vertigo in mi-
graine may relate to the many interconnections between vestibular and head
pain networks or perhaps to the overall sensory “disintegration” postulated
in migraine. There is some belief in a form of VM that generally is inde-
pendent of head pain and can occur episodically on its own. A relatively
new entity—persistent postural perceptual vertigo PPPV—is currently not well
understood but is diagnosed when the following triad is present: persistent
subjective non-rotational vertigo or dizziness, hypersensitivity to motion
stimuli (self or surroundings), and difficulties with visual tasks. Typically,
these patients have normal clinical balance tests, and there are no vestibular
tests which diagnose them with accuracy. The mechanism of PPPV is unclear
but seems to be based on multisensory dysfunction in integrating vestibular,
visual and motion stimuli in the CNS.
10. Refractory Vertigo 55

Psychogenic vertigo does occur, but one might expect an absence of
nystagmus and other neurological signs and a history of phobias or
panic attacks. A number of medications can produce vertigo including
antiarrhythmics, antihypertensives, antihistamines, amphetamines, anti
microbials, digoxin, muscle relaxants, bladder control anticholinergics,
lithium, and antiparkinson medications.
Vestibular nerve involvement may be due to a mass in the
cerebellopontine angle or an infectious/inflammatory process in the suba-
rachnoid space affecting the acoustic nerve. Hence MRI and lumbar punc-
ture are indicated if suspicion is high, particularly if other focal findings
are seen on exam such as cranial neuropathies. Lyme titer, angiotensin
converting enzyme level, and VDRL are all worth considering in these
cases. Electronystagmography may eventually confirm a labyrinthine cause
of vertigo, but even then, cerebrovascular etiology is not entirely ruled out
since small vessel embolization (to the internal auditory artery, or vestib-
ular artery) or other occlusive pathophysiology can lead to similar results
with essentially isolated vertigo.
A helpful diagnostic exercise can be to try to determine whether vertigo
is “peripheral” (due to labyrinthine or vestibular nerve dysfunction) or “cen-
tral” (brainstem or cerebral causes). Much study has been devoted to making
this determination, but it remains challenging. Kattah et al. in 2009 found
that a battery of three bedside tests had good accuracy in differentiating pos-
terior circulation stroke from peripheral vestibulopathy, details of which are
outlined in their article in the suggested reading list at the end of this chapter.
(Box 10.1 provides a full list of the causes of isolated vertigo.)
This patient seems to have isolated new onset vertigo, with similar episodes
in the past. Her accompanying symptoms and signs of nausea and walking
difficulty seem attributable to the vertigo itself. The pupillary unreactivity is
probably related to cataract surgery, and the distal sensation loss may very well
be due to diabetic peripheral neuropathy. So, a labyrinthine cause of vertigo,
such as vestibular neuronitis or a central cause, particularly vestibular mi-
graine, are both high on the list. But she has risk factors for stroke and is in an
age group where this is more probable—so she should probably be admitted
at least for observation while workup is pending. One should be prepared for

BOX 10.1 Causes of isolated vertigo
Labyrinthine or vestibular nerve dysfunction:

Benign Positional Vertigo
Medication effect – aspirin, nonsteroidal anti-inflammatory drugs,
phenytoin, aminoglycosides
Vestibular neuronitis/Labyrinthitis
Meniere’s disease
Post-traumatic vertigo
Cogan’s syndrome – Autoimmune disease of inner ear
Arnold Chiari syndrome
Neurosyphilis – labyrinth infection, meningitis, arteritis
Intralabyrinthine hemorrhage (leukemia, trauma)
Sarcoidosis
Perilymph fistula
Meningitis – Carcinomatous, TB, fungal, bacterial
Ramsay Hunt syndrome (Zoster infection of Geniculate ganglion)
Labyrinthine ischemia
CNS causes
Brainstem or cerebellopontine region tumor
Brainstem or cerebellar ischemia
Brainstem AVM
Complex partial seizures
Migraine
MS – brainstem plaque
Brainstem neoplasm
Hyperventilation
Hypothyroidism
Hypoglycemia
Carcinoid syndrome
Cardiac arrhythmia
Pheochromocytoma
Phobic vertigo
a negative workup however, since cerebrovascular causes of isolated vertigo
are actually infrequent.
Despite the cause, vertigo can be treated with anticholinergics or
antihistamines reasonably well. Many patients find oral or parenteral
hydroxyzine 25–50 mg to be helpful, and for severe vertigo, transdermal sco-
polamine is often very effective. Vertigo and associated nausea or vomiting
can be treated with a neuroleptic class antiemetic such as promethazine 25 mg
IV. Benzodiazepine medication such as lorazepam 1–2 mg IV is quite helpful
acutely. Although systemic corticosteroids have been recommended as a treat-
ment for vestibular neuritis, there is insufficient evidence. If migrainous ver-
tigo is suspected, a trial of a triptan (if cerebro- and cardiovascular disease has
been ruled out) may be very useful. And perhaps preventive meds such as a
beta blocker, tricyclic antidepressant, or topiramate might be of use.
• “Dizziness” can indicate any of several different states including

vertigo, imbalance, and lightheadedness, with significant
perceptual overlap.
• In patients who have risk factors for cardiovascular and
cerebrovascular disease, an initial CT scan, and later MRI, cerebral
vascular imaging, and echocardiography are probably indicated.
• Vertigo when accompanied by cranial neuropathies should
prompt LP, after head imaging, if there are no contraindications.
• Significant lightheadedness with or without syncope should
lead to cardiac evaluation.
Further Reading
Grad A, Baloh RW. Vertigo of vascular origin: clinical and electronystagmographic
features in 84 cases. Arch Neurol. 1989;46:281–284.
Huang TC, Wang SJ, Kheradman A. Vestibular migraine: an update on current
understanding and future directions. Cephalalgia. 2020;40:107–121.
Kattah JC, Talkad AV, Wang DZ, et al. HINTS to diagnose stroke in the acute vestibular
syndrome. Stroke. 2009;40:3504–3510.
Kerber KA, Brown DL, Lisabeth LD, et al. Stroke among patients with dizziness,
vertigo, and imbalance in the emergency department: a population-based study.
Stroke. 2006;37:2484–2487.

11 Febrile Dystonia
A 35-year-old man was brought to the ED
from a drug and alcohol rehabilitation facility
because of abnormal movements and a change
in behavior. He carries the diagnoses of bipolar
affective disorder and alcohol/sedative use
disorder. His current medication list includes
fluoxetine, olanzapine, and nortriptyline. His
temperature is 40oC and his blood pressure is
160/100. He is tachycardic at 120. Mental status is
initially remarkable for some mild agitation, but,
over time, he becomes somnolent. Neurological
exam reveals a mild action tremor, occasional
myoclonic jerks in his lower extremities,
hyperactive muscle stretch reflexes, ankle
clonus, and diffusely increased muscle tone.
White blood cell count is normal at 10,000.
Creatine kinase (CK) is mildly elevated at 550 U/
L. Chemistry panel is otherwise normal. Urine
toxicology is pending.
What do you do now?
59
T he initial step in patients with fever and altered mental status is to
rule out life-threatening CNS infection. After plain CT is negative
for a mass lesion or hemorrhage, lumbar puncture (LP) will help to rule
out meningitis and encephalitis. There are occasional cases of viral en-
cephalitis with benign CSF, and if suspicion is high, initiating antiviral
therapy while awaiting polymerase chain reaction (PCR) testing results
for herpes simplex virus (HSV) and varicella zoster virus (VZV) might
be reasonable. Status epilepticus is another possibility here but is unlikely
with his relatively preserved mental status exam (EEG may be necessary
when there is a question). Once workup has ruled these out, a number of
possibilities present themselves here, each requiring a different manage-
ment approach.
His medication regimen suggests the possibility of a drug-induced syn-
drome such as neuroleptic malignant syndrome (NMS), serotonin syn-
drome (SS), or anticholinergic toxicity. And just because he is in a rehab
center, it should not be assumed that he is not intoxicated or withdrawing
from a substance. Alcohol withdrawal in particular can mimic many
medication-induced symptoms. Urine toxicology will exclude substance
intoxication but not a withdrawal syndrome. A vague history concerning
medications and doses adds to the challenge, of course, and one must al-
ways consider that patients have used higher doses than prescribed and the
possibility of other drug use. Drugs like cocaine and amphetamines (in-
cluding methylenedioxymethamphetamine [MDMA]) can produce an en-
cephalopathy, though fever and myoclonus is not typical.
Neuroleptic medications can induce several neurological syndromes:
(1) acute dystonia, (2) akathisia, (3) oculogyric crisis, (4) parkinsonism,
(5) tardive dyskinesia, and (6) NMS. This patient’s presentation is in
some ways typical for NMS—encephalopathy, hyperthermia, muscle
rigidity, tachycardia—but the CK level is not as high as is typical in
NMS. This patient could be early in the development of the NMS syn-
drome, so CK should be rechecked. It is not unreasonable to begin
treatment presumptively in suspicious cases. Treatment consists of
cooling, dantrolene sodium (a direct acting muscle relaxant) 1–2 mg/kg
IV, repeated every few hours, and bromocriptine 2.5–10 mg three times
a day. Volume depletion must be corrected with IV fluids. Hypotension

may also respond to fluid boluses. Cooling methods include cooling
blankets, ice packs, cold IV fluids, and antipyretics. When rhabdomyol-
ysis occurs, hydration and alkalinization of the urine with sodium bicar-
bonate is essential in hopes of preventing renal failure. Benzodiazepines
can also help reduce muscle rigidity. Prognosis in NMS was said to be
poor in the past, but, more recently, with proper care, at least 90% of
patients will survive.
The viral encephalitis of rabies resembles NMS a bit more than does
HSV or the other viral encephalitides. Patients can present with the “fu-
rious” form with fever, agitation, motor hyperactivity, hallucinosis, con-
fusion, and, ultimately, seizures and coma. There can be calm (lucid)
periods. Rigidity is unlikely, although sometimes there can be motor weak-
ness. While it is uncommon to contract rabies from an infected human,
precautions must be observed if it is suspected.
Anti-NMDA receptor encephalitis can present with abnormal move
ments (generally seizures at some point) and fever, and it is diagnosed with
autoantibody testing from blood and CSF samples.
Malignant hyperthermia is a genetic disorder resulting from ryanodine
receptor mutations, which presents with fever, rigidity, tremors, agitated de-
lirium, and hallucinosis, and progresses to stupor and coma. It is generally
provoked by inhalational anesthetics and/or depolarizing muscle relaxants.
Treatment consists of cooling, dantrolene sodium 1–2 mg/kg IV, in repeated
doses, and bicarbonate to normalize metabolic acidosis. Arrhythmias must
be treated and electrolyte imbalances corrected. It can be difficult to differ-
entiate from NMS, so history is crucial.
Overdose with anticholinergic medication including cyclic anti
depressants and antihistamines can present with febrile encephalopathy.
The presentation can include fever, tachycardia, hypotension, encephalop-
athy, and muscle rigidity. Skin is usually dry, and the patient has mydriasis.
Serotonin syndrome (SS), due usually to additive effects of multiple se-
rotonergic medications, seems the most likely diagnosis here. SS is usu-
ally accompanied by hyperreflexia, as opposed to the hyporeflexia seen
with NMS. Also, patients with SS typically have a normal WBC count.
Medications that may contribute to excessive serotonin effect via various
mechanisms include tricyclic antidepressants, selective serotonin reuptake
11. Febrile Dystonia 61

BOX 11.1 Differential diagnosis hyperthermia with delirium
Meningitis: Generally bacterial

Viral encephalitis, especially HSV
Rabies
Malignant hyperthermia
Neuroleptic malignant syndrome
Serotonin syndrome
Anticholinegic medication overdose
Status epilepticus
Drug overdose: Cocaine, amphetamines
Drug, ethanol withdrawal
inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs),

buspirone, the serotonin- 3 receptor antagonists (e.g., ondansetron),
dextromethorphan, carbamazepine, valproate, cyclobenzaprine, meto
clopramide, tramadol, monoamine oxidase inhibitors (MAOIs), ergot
derivatives (including LSD), and lithium.
Treatment of SS should, of course, include discontinuation of all seroto-
nergic agents. In mild cases, symptoms resolve within a day or two at most.
Cooling agents, antihypertensives, nasal oxygen, and benzodiazepines can
all be helpful. Those with severe symptoms, including autonomic insta-
bility not responsive to initial therapies, may warrant treatment with the
serotonin blocker cyproheptadine. Patients who are severely hyperthermic
or agitated might need endotracheal intubation to support respiration and
to protect their airway as the serotonin effect wanes.
The diagnosis in cases of delirium with hyperthermia, like the one
presenting here, can be challenging, with overlapping symptoms and signs
seen in several conditions (Box 11.1 and Table 11.1). A menu of testing
includes CT of the head, LP with CSF analysis including viral PCR testing,
EEG, CBC, full chemistry panel, toxicology screen, urine myoglobin, lac-
tate and CK levels, arterial blood gases, and blood cultures.

TABLE 11.1 Comparison of presentation in serotonin syndrome (SS),
neuroleptic malignant syndrome (NMS), malignant hyperthermia, and
anticholinergic overdose
Symptom/ Serotonin NMS Malignant Anticholinergic

sign syndrome hyperthermia toxicity
Delirium + + + +
Fever + + + +
Autonomic + + + +
dysfunction
Pupils Dilated Dilated
Nausea/ +
Vomiting
Rigidity + ++ + +
Reflexes Increased Decreased Decreased
Myoclonus +
Tremor +
CK Increased High High
Treatment Benzodiazepine, Bromocriptine, Dantrolene

cyproheptadine, dantrolene,
antihistamine benzodiazepine
• Febrile encephalopathy is a dire emergency that requires a

speedy workup and possibly empiric antibiotic treatment while
diagnostic tests are pending.
• Muscle rigidity, sympathetic lability, high CK and febrile
encephalopathy, in the context of dopamine antagonist use or
dopamine agonist withdrawal, are suggestive of NMS.
• Myoclonic jerks and hyperreflexia are more typical of SS.
11. Febrile Dystonia 63

Further Reading
Ables AZ, Nagubilli R. Prevention, recognition, and management of serotonin
syndrome. Am Fam Physician. 2010;1;81:1139–1142.
Broderick ED, Crosby B. Anticholinergic toxicity. 2018;StatPearls [Internet].
Gillman KP. Triptans, serotonin agonists, and serotonin syndrome (serotonin
toxicity): a review. Headache: The Journal of Head and Face Pain,
2010;50:264–272.
Turner AH, Kim JJ, McCarron RM, Nguyen CT. Differentiating serotonin syndrome
and neuroleptic malignant syndrome. Current Psychiatry. 2016;18:30–36.
Werneke U, Jamshidi F, Taylor D, et al. Conundrums in neurology: diagnosing
serotonin syndrome: a metaanalysis of cases. BMC Neurol. 2016;16:97.

12 Myelopathy
A 70-year-old painter with history of metastatic
colon cancer presents with progressive
weakness and numbness in his hands over
the course of a week. He reports difficulty with
holding paint brushes and yesterday recognized
a new imbalance and weakness in his legs. He
denies incontinence or constipation. His vital
signs are unremarkable with a blood pressure
of 130/70 and heart rate of 70; he is afebrile. He
appears well on his general physical exam. His
mental status is intact, and he has no cranial
nerve deficits. His finger taps are slowed
bilaterally; his foot taps are also mildly slowed.
He has reduced vibration in the feet but no clear
sensory level to pinprick. He is hyperreflexic in
the legs. He underwent an MRI of the cervical
spine showing a long segment of abnormal
signal in the cervical cord as well as an area with
contrast enhancement.
What do you do now?
65
A detailed history is helpful here as we think about localization and
cause. First, clarify the onset of symptoms. Weakness that occurs
acutely may be due to structural diseases of the spinal cord or vascular
causes (e.g., ischemic stroke, hemorrhage). Subacute myelopathy is more
likely to be due to infection or autoimmune/inflammatory diseases or
tumors. Subacute to chronic myelopathies may be due to neurodegenerative
diseases, infections such as HIV or human T-lymphotropic virus (HTLV),
metabolic derangements, or insidious compression from a structural cause.
Is the weakness static, relapsing, or progressive? Are there any predisposing
factors, such as trauma, recent illness, or toxic exposures? Determining if
there is additional involvement of the face, arms, bowel/bladder function,
or asymmetrical weakness can aid with localization. In addition to weak-
ness, is there pain or numbness, and if so, where?
The localization of bilateral leg weakness is broad. Before focusing on
the spinal cord, it is a helpful exercise to think of all the other possibilities.
Another CNS cause is from a rare variant of the anterior cerebral artery
(ACA), called the azygos ACA. Diseases affecting multiple nerve roots
(polyradiculopathy), including at the level of the cauda equina (cauda
equina syndrome), may result in bilateral leg weakness. Bilateral lumbosacral
plexopathy, such as from diabetic amyotrophy, may have pain, muscle at-
rophy, and weakness. Diseases that affect multiple peripheral nerves, such
as Guillain-Barré syndrome, can cause bilateral leg weakness that is often
asymmetrical. A variety of diseases (e.g., myasthenia gravis, botulism) can
affect the neuromuscular junction, which can cause bilateral leg weakness
but may also affect bulbar musculature, too. Last, diseases that affect the
muscle, such as inclusion body myositis, are more likely to affect the prox-
imal musculature of the leg.
The first goal for any suspected myelopathy is to rule out a com-
pressive cause, which may require urgent surgical treatment (Box 12.1).
Compression can be due to trauma, degenerative spine disease, infection
(e.g., epidural abscess, tuberculosis infection of the vertebral bodies), neo-
plasm (e.g., meningioma, metastasis), or other abnormalities within the ep-
idural space, such as lipomatosis or hemorrhage. Identifying the presence of
a compression often requires imaging, preferably MRI. Flexion-extension
x-rays also allow for detection of dynamic instability of the vertebral bodies.

BOX 12.1 Compressive myelopathy causes
- Trauma
- Degenerative spine disease
- Infection
• Epidural abscess, TB of the vertebral bodies
- Neoplastic
• Meningioma, metastasis
- Other
• Fatty infiltration of the epidural space (lipomatosis), hemorrhage
Noncompressive myelopathy causes
- Noninflammatory
• Neoplastic
• Lymphoma, glioma
• Toxic/Metabolic
• Intrathecal chemotherapy, post-radiation
• Vitamin/mineral deficiency: vitamin B12, vitamin E, copper
• Vascular
• Ischemic stroke, AVM, dAVF
• Genetic
• Friedreich ataxia, hereditary spastic paraplegia,
adrenoleukodystrophy spinocerebellar ataxia, amyotrophic lateral
sclerosis
- Inflammatory
• Autoimmune/demyelinating
• CNS: MS, NMO, MOG
• Systemic: SLE, Sjögren’s, sarcoidosis, vasculitis
• Infectious
• Bacterial: TB, Syphilis
• Viral: Herpes viruses (HSV, VZV, EBV, CMV), HIV, HTLV;
Enterovirus, WNV
• Parasitic: Schistosoma
• Paraneoplastic
• Anti-Hu, anti-CRMP5, anti-amphiphysin
Noncompressive myelopathy can be neoplastic, vascular, toxic/meta-
bolic, genetic, or inflammatory. Neoplastic causes include lymphoma as
well as primary spinal cord tumors such as a glioma. Vascular causes include
ischemic infarcts, such as to the anterior spinal artery, leading to an ante-
rior cord syndrome (deficits in motor and spinothalamic tract but preserva-
tion of dorsal column function) or the presence of a vascular malformation,
such as arteriovenous malformation (AVM) or dural arteriovenous fistula
(dAVF). Spinal dAVF are especially important to have on the differential
for an older man with a slowly progressive myelopathy—carefully look at
the MRI for the presence of flow voids.
The identification of a toxic/metabolic etiology can be aided by a thor-
ough history, including medications, prior surgeries (e.g., gastric bypass),
and health-related behaviors, such as the use of nitrous oxide canister
“whippits”. Intrathecal chemotherapy may be a toxic source of myelopathy.
Exposure of the spinal cord to radiation may produce early delayed (within
6 months) or delayed (years later) radiation myelopathy. Metabolic causes
include vitamin B12 deficiency, functional vitamin B12 deficiency due to
nitrous oxide exposure, vitamin E deficiency, or copper deficiency (which
can be from zinc excess: watch out for denture cream!). Decompression
sickness, a complication of scuba diving, can result immediately or within
days of ascent, often affecting the thoracic cord.
There are several genetic disorders associated with myelopathy, including
Friedreich ataxia, hereditary spastic paraplegia, and adrenoleukodystrophy.
Spinocerebellar ataxia is an autosomal dominant disease that may fea-
ture myelopathy in addition to ataxia. Amyotrophic lateral sclerosis usu-
ally has mixed upper and lower motor neuron signs but can present with
myelopathy.
The main categories of inflammatory myelopathy (myelitis) are auto-
immune/demyelinating, infectious, and paraneoplastic. There are several
autoimmune diseases that affect the CNS. These include multiple sclerosis,
neuromyelitis optica spectrum disorder (NMOSD), and myelin oligoden-
drocyte glycoprotein antibody (anti-MOG). Clues for NMOSD include
the presence of a longitudinally extensive spinal cord lesion that extends
for at least three vertebral segments. The presence of NMO-IgG in serum
is supportive of this diagnosis. CSF may feature a neutrophilic pleocytosis,
and oligoclonal bands are often absent. Anti-MOG can be distinguished

from NMOSD as these cases are more likely to present with simultaneous
bilateral optic neuritis and have fewer relapses, and the spinal cord lesions
may be more likely to occur in the lower regions of the spinal cord. The
presence of MOG-IgG is supportive.
Systemic autoimmune diseases that can result in myelopathy include sys-
temic lupus erythematous, sarcoidosis, Sjögren’s syndrome, and vasculitis.
There are several infectious causes of noncompressive myelitis. Viruses
are the most common pathogen and include the herpes viruses (herpes
simplex virus, varicella zoster virus, Epstein Barr virus, and human cyto-
megalovirus), hepatitis C virus, HIV-associated vacuolar myelopathy, and
HTLV-I. Certain viruses can also affect the anterior horn cells resulting in
flaccid weakness and absent reflexes. These viruses include enteroviruses
(e.g., poliovirus, coxsackie virus) and the flaviviruses (e.g., West Nile virus
and Japanese encephalitis virus). In addition to causing a compressive mye-
lopathy (Pott’s disease), tuberculosis can cause tuberculomas that also cause
myelopathy. Syphilis primarily affects the dorsal columns. The parasite
Schistosoma more often affects the thoracic spinal cord and can result in
symptoms of transverse myelitis; here, CSF may show a pleocytosis with
eosinophilia.
While rarer, there are paraneoplastic causes for myelopathy. These are
thought to be due to an autoimmune reaction to an antigen shared by a
tumor. The most common example is anti-Hu, which is associated with
breast and lung cancers. Antibodies to amphiphysin, collapsin response-
mediator protein-5 (CRMP5), and glutamic acid decarboxylase (GAD)
may also present with myelopathy.
So many things can result in myelopathy! How to narrow the differ-
ential? After obtaining a detailed history and physical exam, spinal cord
imaging is the next step, such as an MRI with and without contrast (see
Figures 12.1 and 12.2). Presence of a sensory level can help guide which
spinal cord segment should be imaged first. It is also reasonable to obtain
an MRI of the brain if there is any possibility that the localization is not
specific to the spinal cord. If there is concern for a vascular malformation,
then a conventional angiogram will be needed for diagnosis and treatment.
Otherwise, if trying to determine if the myelopathy is inflammatory or
noninflammatory, serum studies assessing for the causes outlined earlier, as
well as CSF sampling, is necessary.
12. Myelopathy 69
FIGURE 12.1 MRI of the cervical spine showing a long segment hyperintense intramedullary
central cervical cord lesion.
FIGURE 12.2 MRI of the same cervical spine lesion as in Figure 12.1, but with enhancement.
While carrying out the diagnostic work-up, it is important to remember
management of complications that can arise from myelopathy, such as
checking a post-void residual to assess for urinary retention, and DVT pro-
phylaxis if mobility is limited.
• If someone presents with a myelopathy, the first goal is to

determine if it is from a compression to the spinal cord.
• Flexion-extension x-rays can help identify dynamic instability
that may result in intermittent cord compression.
• Once compression is ruled out, consider differentiating
inflammatory from noninflammatory causes of myelopathy,
which often requires CSF analysis.
• Remain vigilant for vascular causes of myelopathy, including the
presence of a spinal dural arteriovenous fistula.
Further Reading
Barreras P, Fitzgerald KC, Mealy MA, et al. Clinical biomarkers differentiate myelitis
from vascular and other causes of myelopathy. Neurology. 2018;90(1):e12–e21.
Cho TA, Bhattacharyya S. Approach to myelopathy. Continuum (Minneap Minn).
2018;24(2, Spinal Cord Disorders):386–406.
Graber JJ, Nolan CP. Myelopathies in patients with cancer. Arch Neurol.
2010;67(3):298–304.
12. Myelopathy 71
13 Neurologic Complications
of Immune Checkpoint
Inhibitors
A 43-year-old man is admitted for aspiration
pneumonia. He has a history of nasopharyngeal
carcinoma treated with radiation, chemotherapy,
and resection. He started pembrolizumab several
months ago without progression of his cancer.
On admission, he required 3 L oxygen via nasal
cannula but had otherwise normal vital signs.
He now complains of difficulty keeping his
head up. His voice has become quieter, and he
has difficulty swallowing. He denies diplopia
but endorses generalized weakness. When
you examine him in the afternoon, his mental
status is normal. His speech is hypophonic and
dysarthric. Pupils are symmetric and reactive.
There is bilateral ptosis that worsens with
sustained upgaze. Extraocular movements
are full. There is weakness of neck flexion and
deltoids; the remainder of the muscle groups are
full strength. Sensation and reflexes are intact
throughout. When you examine him the next
morning, his ptosis is improved, and his voice is
clearer.
What do you do now?
73
T he neurologic exam of this patient features several findings that are
suspicious for a process beyond local involvement of the cancer. The
combination of ocular, bulbar, neck, and proximal limb weakness may
localize to the subarachnoid space affecting multiple roots, the neuromus-
cular junction, or muscles. The fluctuation of the weakness and absence
of sensory deficits is most concerning for a neuromuscular junction dis-
order, such as myasthenia gravis. This patient’s chest pain and dyspnea
may be from a concomitant myocarditis or myositis affecting the muscles
of respiration.
One key piece of history is the use of pembrolizumab, an immune
checkpoint inhibitor (ICPi). Initially approved for metastatic melanoma,
ICPis are increasingly used for the treatment of many types of cancers.
ICPis are monoclonal antibodies that block the checkpoint pathways that
normally dampen the immune system, enabling T-cells to attack cancer
cells. The current FDA-approved ICPis fall into three classes: anti-CTLA-
4 (ipilimumab), anti-PD-1 (nivolumab, pembrolizumab), and anti-PDL-1
(atezolizumab, avelumab, durvalumab).
While a groundbreaking cancer treatment, inhibition of immune
checkpoints can lead to immune-related adverse events (irAEs) that can af-
fect any organ system and are more common when ICPis from different
classes are used in combination. While irAEs are more likely to develop 8–
12 weeks from treatment start, they can be idiosyncratic to the start of the
drug. Neurologic irAEs occur in approximately 1–4% of patients treated
with ICPis and affect the peripheral nervous system twice as often as the
central nervous system. Examples of irAEs include encephalitis; aseptic
meningitis; transverse myelitis; axonal or demyelinating neuropathy af-
fecting motor, sensory, or autonomic nerves; disorders of the neuromus-
cular junction, such as myasthenia gravis or Lambert-Eaton myasthenic
syndrome (LEMS); and myositis.
The severity of irAEs, distinguished by toxicity “grades,” is variable.
While rare, neurologic irAEs have a higher risk of fatality than other
irAEs. For this reason, it is important to be vigilant for such complications
when caring for a patient exposed to one of these medications. While the
reason for these complications is not fully understood, possibilities include
increased T-cell activity against both cancerous and host tissue, increased
levels of preexisting autoantibodies, and heightened inflammation. The

most comprehensive guidelines on the management of irAEs were published
by the American Society of Clinical Oncology.
Symptoms of myasthenia gravis in the setting of ICPi use may overlap
with myositis, myocarditis, or thyroiditis. The workup includes pulmonary
function testing, especially forced vital capacity (FVC) and mean inspiratory
force (MIF), and several blood tests, including creatinine kinase, thyroid-
stimulating hormone (TSH), and free T4, as well as acetylcholine receptor
(AChR) and antistriated muscle antibodies. If AChR antibodies are neg-
ative, muscle-specific kinase and lipoprotein-related 4 (LRP4) antibodies
can also be obtained. Voltage-gated calcium channel antibodies can assist
with diagnosis of LEMS. An ECG and troponin should be obtained to
screen for myocarditis, and, if positive, a cardiology consultation and ad-
ditional cardiac testing is advised. If myositis is suspected, liver enzymes,
rheumatologic serologies, and a myositis antibody panel (including anti-
HMG-CoA, see Chapter 18) should be tested.
Electrodiagnostic studies are recommended in these cases, including
nerve conduction study (NCS) and electromyography (EMG) to evaluate
for neuropathy or myopathy, as well as including neuromuscular junction
testing with repetitive stimulation or single-fiber EMG. These studies are
important because AChR antibodies can be nonspecific, and the absence of
antibodies associated with myasthenia gravis does not exclude myasthenia
gravis. Due to the indiscriminate nature of irAEs, electrodiagnostic studies
can also help tease out if there are multiple overlapping processes (e.g.,
coexisting myasthenia gravis and myositis). MRI with and without contrast
of the brain and/or spine can be considered depending on clinical suspicion
and exam.
The management of ICPi-associated myasthenia gravis is guided by
symptom severity and may include holding/discontinuing ICPi and starting
corticosteroids. High-dose steroids may worsen symptoms in those with
myasthenia gravis, and it is not known if this is also true for ICPi-associated
myasthenia gravis, so caution is recommended. IVIg or plasma exchange
should be started in patients with an incomplete response to steroids or
with severe symptoms. It is not known if immunomodulatory therapies also
counteract the treatment on the cancer itself. ICPi-associated myasthenia
gravis may be monophasic and so long-term use of a steroid-sparing immu-
nosuppressant may not be warranted.
13. Neurologic Complications of Immune Checkpoint Inhibitors 75

In addition, pyridostigmine 30 mg orally three times a day can be tri-
aled, with up-titration to 120 mg orally four times day. Rehab services,
such as speech, occupational, and physical therapy should be engaged,
and swallowing function should be assessed. Medications that can worsen
myasthenia gravis, such as beta-blockers and aminoglycosides, should be
avoided.
• Immune checkpoint inhibitors can cause a variety of neurologic

immune-related adverse events that affect the central and
peripheral nervous systems.
• Immune-related adverse events may overlap with each other
(e.g., concurrent myasthenia gravis and myositis).
• The timing of immune-related adverse events can be
idiosyncratic with administration of the drug.
Further Reading
Brahmer JR, Lacchetti C, Thompson JA. Management of immune-related adverse
events in patients treated with immune checkpoint inhibitor therapy: American
Society of Clinical Oncology Clinical Practice Guideline summary. J Oncol Pract.
2018;14(4):247–249.
Guidon AC. Lambert-Eaton Myasthenic syndrome, botulism, and immune
checkpoint inhibitor-related myasthenia gravis. Continuum (Minneap Minn).
2019;25(6):1785–1806.
Wang DY, Salem JE, Cohen JV, et al. Fatal toxic effects associated with immune
checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol.
2018;4(12):1721–1728.

14 Cauda Equina Syndrome
A 55-year-old man with a history of hypertension
presents to the ED with acute lower back pain
after falling from the top of a ladder while
attaching Halloween decorations to his home. He
denies head trauma or loss of consciousness. He
could walk following the injury but experienced
severe pain shooting down his right buttock. On
arrival, his blood pressure is 130/70, his heart
rate is 90, and he is afebrile. His neurologic exam
shows intact mental status and cranial nerves
and normal strength in the arms and legs except
for the right leg, where effort is limited by pain.
Both of you are surprised when you perform
your sensory examination as he lacks sensation
in the perianal area; his rectal tone is also low.
Concerned, you obtain a bladder scan that
shows 500 mL of retained urine after he attempts
to void. An MRI reveals lumbar disc compression
on the cauda equina.
What do you do now?
77
T he possibility of cauda equina syndrome strikes fear into many
practitioners, often because of its variable presentation as well as the
need for urgent neuroimaging and treatment. The cauda equina, from the
Latin “horse’s tail,” is the collection of nerve roots that includes L2 through
L5, S1 through S5, and the coccygeal nerves. These nerve roots serve a va-
riety of functions including lower extremity strength (L2 through S2) and
sensation (L2 through S3), and perineal (S2 through S4) and coccygeal
sensation (S4 through S5, coccygeal). Sacral portions of the cauda equina
also mediate bladder function and external anal sphincter control. The
most caudal end of the spinal cord is a cone-shaped region named the conus
medullaris, which most commonly terminates at the L1–L2 disc level.
Due to their proximity, it is not always possible to differentiate a
conus medullaris lesion from a process affecting the cauda equina. Conus
medullaris lesions are more likely to have early bowel, bladder, and sexual
dysfunction, which tend to be less pronounced in cauda equina lesions,
as well as nonradicular back pain as opposed to radicular pain. Conus
medullaris lesions are more likely to result in mild but symmetric leg weak-
ness, whereas cauda equina lesions are more likely to result in asymmetric
leg weakness, as seen with nerve root involvement. However, weakness may
not be present in cauda equina syndrome—for example, in the setting of a
central disc herniation that affects lower sacral or coccygeal nerve roots—so
do not be falsely reassured if weakness is absent. Regardless, the presence of
these symptoms warrants an urgent investigation, as discussed here.
Similarly, it can be challenging to differentiate cauda equina syndrome
from a myelopathy or polyradiculoneuropathy. Features that may point
toward cauda equina syndrome include a normal neurologic exam of the
arms, absence of a cervical or thoracic sensory level, proximal leg weakness,
reduced sensation in the legs or perineal region (“saddle anesthesia”), or
reduced reflexes in the lower limbs. Reflexes include the patellar, Achilles
tendon, anal wink, and bulbocavernosus reflexes. Early bladder impair-
ment is often characterized by urinary retention, which may later become
overflow incontinence. While often not elicited, it is also important to ask
about the presence of sexual dysfunction, which can also be seen with cauda
equina syndrome.
The causes of cauda equina syndrome are often divided into discogenic
and nondiscogenic categories, but it can be helpful to instead think of

FIGURE 14.1 MRI of the lumbar spine showing a large, expansile destructive mass at
approximately L4 resulting in severe canal stenosis and obliteration of the CSF space within the
thecal sac.
compressive and noncompressive causes. These can be quickly delineated

by the presence of a compression on MRI of the lumbosacral spine with and
without contrast (see Figures 14.1 and 14.2). Compression may be caused
by vertebral disc disease including disc herniation, vertebral body collapse,
trauma, tumor, or focal infection, such as an epidural abscess. Intervertebral
disc herniation is the most common cause of cauda equina syndrome. The
most common tumors that affect the cauda equina are metastases, nerve
sheath tumors, and ependymomas. Additional masses include epidural
lipomatosis and epidural hematomas. Neoplastic or infectious infiltration
of the vertebral bodies may lead to instability and compression.
While less common, noncompressive causes of cauda equina syn-
drome include inflammatory/ autoimmune, infectious, and neoplastic
processes. Acute inflammatory demyelinating polyneuropathy may cause
14. Cauda Equina Syndrome 79

FIGURE 14.2 MRI of same lumbar spine mass, but with avid enhancement.
inflammation of the cauda equina, as can sarcoidosis, which can be

visualized as nerve root enhancement on MRI with contrast. Inflammation
of the arachnoid—arachnoiditis—may also present as cauda equina syn-
drome. Many infections can affect the cauda equina, especially viruses such
as the herpes viruses (herpes simplex virus, varicella zoster virus, Epstein-
Barr virus, and human cytomegalovirus), and bacterial infections, including
Lyme disease and tuberculosis. Leptomeningeal metastases (carcinomatous
meningitis) may also affect the cauda equina nerve roots.
Once cauda equina syndrome is suspected, urgent neuroimaging should
be obtained. Plain radiographs may show a fracture, but ultimately an
MRI is required to guide management. If an MRI cannot be obtained,
then a CT myelogram should be considered. Compressive cauda equina
syndrome requires urgent surgical management, especially in patients
with a rapid onset of symptoms. If a noncompressive cause is suspected,

electromyography can confirm this localization, though this may be falsely
negative acutely. An LP looking for infectious and neoplastic etiologies
will be helpful. Systemic imaging, including a PET, may also be helpful in
order to identify additional areas of infection or neoplasm. Treatment of
noncompressive cauda equina syndrome is specific to the underlying cause,
• Identifying cauda equina syndrome can be challenging,

so maintain a high level of suspicion for this neurologic
emergency.
• Symptoms can include sciatica, urinary/bowel impairment, back
pain (with or without radicular symptoms), perineal anesthesia,
and impaired sexual function.
• Urgent neuroimaging is crucial, preferably with MRI.
• Urgent consultation for surgical decompression should be
sought in these cases.
Further Reading
Bennett SJ, Katzman GL, Roos RP, Mehta AS, Ali S. Neoplastic cauda equina
syndrome: a neuroimaging-based review. Pract Neurol. 2016;16(1):35–41.
Lavy C, James A, Wilson-MacDonald J, Fairbank J. Cauda equina syndrome. BMJ.
2009;338:b936.
Todd NV, Dickson RA. Standards of care in cauda equina syndrome. Br J Neurosurg.
2016;30(5):518–522.
14. Cauda Equina Syndrome 81

15 Intracranial Mass in a
Person with HIV
A 40-year-old woman with a history of AIDS
not on antiretrovirals (ARVs) (CD4 45, viral load
>300,000) presented to the ED for generalized
weakness, including progressive leg weakness
over several weeks, headache, and confusion.
She does not smoke tobacco or drink alcohol.
General exam is notable for being ill-appearing,
normotensive, and afebrile. Mental status exam
is notable for somnolence but arouses briefly
to voice, is oriented to hospital and city, and
is able to follow one-step commands but falls
asleep between them, requiring prompting. The
remainder of the neurological exam is notable
for right arm drift and symmetric 2+ reflexes;
otherwise, her exam is limited by her mental
status. A head CT reveals multifocal hypodense
areas which are clearly enhancing on MRI.
What do you do now?
83
T he differential diagnosis of a focal mass (either single or several) differs for
patients with normal immune function and those with a compromised
immune system, as in this patient. In patients who are immunocompe-
tent, the differential includes infection, such as bacterial or parasitic causes
like cysticercosis if there is a history of living in or travel to an endemic
area, autoimmune disorders (e.g., multiple sclerosis, sarcoid), or neoplastic
causes (primary or metastatic). In patients with HIV or AIDS, those on
chemotherapy, transplant patients, or those immunosuppressed from other
causes, the list should also include fungal abscess (like Cryptococcus), lym-
phoma, Mycobacterium tuberculosis (TB), Toxoplasma gondii, and Nocardia
(see Box 15.1). Progressive multifocal leukoencephalopathy (PML) may
also take the form of an apparent mass lesion in these patients. Clinical
presentation does not help narrow the list very much, as most can pre-
sent with headache, focal findings, and either seizures or depression of con-
sciousness. Geographic location or exposure to foreign location may also be
informative.
The CD4 count can guide the differential in patients with HIV. If the
CD4 count is greater than 500/μL, the list of causes will be similar to im-
munocompetent patients. In patients with a CD4 count from 200 to 500/
μL, focal brain lesions are less common than neuromuscular disorders (acute
inflammatory demyelinating polyneuropathy, mononeuritis multiplex, pe-
ripheral neuropathy). A person meets criteria for AIDS with a CD4 count
of less than 200/μL, which is when opportunistic infections (OIs) become
most likely, including Toxoplasma gondii, Cryptococcus, and PML.
Imaging characteristics can be very helpful. The initial scan for a patient
in the ED is likely going to be a head CT. This is especially important if
BOX 15.1 Susceptibility for neurological disease based on CD4 count
CD4 <400: Mononeuritis multiplex, Guillain-Barré syndrome,

autoimmune conditions, peripheral neuropathy, syphilis
CD4 <200: Toxoplasma gondii, Cryptococcus, progressive multifocal
leukoencephalopathy (PML), IRIS if recently started ARVs
CD4 <100: Primary CNS lymphoma, CMV, CNS TB, and all of
the above

BOX 15.2 Differential for CNS lesions with mass effect
Toxoplasmosis
Primary CNS lymphoma
Tuberculomas
Abscess
Cryptococcoma
Syphilitic gumma
Acute neurocystercosis
Steroids may eliminate contrast enhancement of a lesion.
a lumbar puncture (LP) is planned in order to assess for herniation risk.

Remember, head CT must be done before LP if the patient is immuno-
compromised, older than 60 years, comatose, altered or with focal deficits,
has a history of CNS disease, is presenting with a new seizure, or there
is another reason to suspect a mass. Opening pressure measurement can
be very helpful because an elevated opening pressure may point toward
fungal infection (e.g., Cryptococcus). If the patient is known to have HIV,
it is helpful to obtain the head CT with and without contrast to assess for
enhancement. The head CT can also reveal calcification, which may be
present in neurocysticercosis infection. However, MRI with and without
contrast tends to be the most helpful, especially if a brain biopsy is ulti-
mately warranted.
Intracranial lesions can be categorized by whether they are focal or diffuse,
with or without mass effect (see Boxes 15.2 and 15.3). Focal lesions with
mass effect include cerebral toxoplasmosis and primary CNS lymphoma,
which can be challenging to distinguish on imaging alone. Cerebral toxo-
plasmosis tends to result in multiple lesions, especially in the basal ganglia
BOX 15.3 Differential for CNS lesions without mass effect
Progressive multifocal leukoencephalopathy (PML)

CMV
HIV encephalopathy
15. Intracranial Mass in a Person with HIV 85

or gray–white junction, with ring or nodular enhancement and necrosis
in the center, where as CNS lymphoma is more likely to be a single lesion
with solid enhancement and restricted diffusion on diffusion-weighted im-
aging (DWI). Brain abscesses are thick-walled, with wall enhancement and
significant edema. PML tends to be a focal lesion without mass effect, with
abnormalities in the white matter extending to subcortical U fibers; these
very rarely enhance, whereas cerebral tuberculoma may appear as variably
enhancing small nodules without edema. Recent steroid use may eliminate
any contrast enhancement and so imaging should be interpreted with this
in mind.
But these characteristics are often not specific enough to help the ED
physician or neurologist map out a definitive course for diagnosis and
treatment. What are the best steps here? Large lesions with mass effect
threatening herniation should signal the need for open biopsy with decom-
pression. If this is not the case, the diagnosis may be made with serologic
or CSF testing or systemic imaging, before pursuing biopsy. In addition to
sending serologies and cultures, metagenomic next-generation sequencing
and universal polymerase chain reaction (PCR) should be sent, especially
if an infectious pathogen remains elusive. A detailed ophthalmology assess-
ment can also be high yielding as it may show lymphoma, ocular toxoplas-
mosis, or CMV retinitis.
For CNS toxoplasmosis, serum Toxoplasma IgG is often positive, al-
though it can be falsely negative. Consistent brain imaging and positive
Toxoplasma IgG has a 90% predictive value for CNS toxoplasmosis, and
so empiric treatment should be considered in those cases (see Figures 15.1
and 15.2). CNS Cryptococcus can be diagnosed with serum cryptococcal an-
tigen (CrAg), which is very sensitive and specific in immunocompromised
patients (but not adequate if immunocompromised). If PML is suspected,
a positive CSF JC virus PCR can confirm the diagnosis. However, given
variable sensitivity of this test, a negative CSF JC virus PCR despite clin-
ical suspicion warrants brain biopsy for definitive diagnosis. Positive CSF
Epstein-Barr virus (EBV) PCR may point toward primary CNS lymphoma.
CSF cytology and flow cytometry can be helpful with diagnosis of lym-
phoma, but for increased sensitivity three separate LPs are recommended.
The risks of LP in a patient with intracranial masses are significant, how-
ever, and CSF samples in many of the infectious processes may yield only

(a) (b)
FIGURE 15.1 MRI of the brain with innumerable peripherally enhancing lesions in the
supratentorial and infratentorial brain, some with vasogenic edema.
(a) (b)
(c) (d)
FIGURE 15.2 MRI of the brain with interval decrease in size and number of enhancing lesions as
seen on DWI (a), ADC (b), T2 FLAIR (c), and gadolinium enhanced (d).
nonspecific pleocytosis and increased CSF protein. However, metagenomic
sequencing and universal PCR may increase the yield. Blood cultures for
bacteria and fungus and a search for an infectious source in the sinuses, ears,
mouth and teeth, and heart should be done.
Systemic imaging may reveal other affected areas that can provide
clues. Chest radiography can help to exclude tuberculosis, and, espe-
cially in smokers, it may reveal lung neoplasms. Concomitant pulmonary
infection in an immunocompromised patient also raises concern for
nocardiosis as a cause for brain abscess, which is treated with trimethoprim-
sulfamethoxazole and can be missed with typical empiric antibiotics. PET
CT may reveal more accessible lesions that are amenable to biopsy and
should be considered before pursuing brain biopsy. PET and single posi-
tron emission CT (SPECT) can help to distinguish CNS lymphoma from
other causes, as lymphoma tends to reveal hypermetabolic features whereas
infections, including PML, are relatively hypometabolic.
If initial blood, spinal fluid, and imaging does not narrow a diagnosis,
and whole-body PET is negative, stereotactic brain biopsy can be considered
if the lesion is in a reasonable location. Areas of enhancement should be
prioritized when deciding on a biopsy target. Empiric treatment of an in-
fectious cause, such as toxoplasmosis, should result in a repeat MRI 2 weeks
later to assess for improvement. Empiric steroid therapy might be tempting,
and while it may improve symptoms or make the MRI look better, this does
not help diagnosis and may delay definitive treatment if the lesion is pri-
mary CNS lymphoma—its use should be discouraged.
No algorithm is perfect, so clinical judgment and discussion with
patients is crucial. And finally, of course, this patient needs to be treated for
HIV infection with antiretrovirals—watching closely for the development
of immune reconstitution inflammatory syndrome (IRIS)—and have her
leukocyte counts and general health closely monitored.

• An updated CD4 count can help narrow the differential.

• In addition to sending serologies and cultures, metagenomic
next-generation sequencing and universal PCR should be sent,
especially if concerned for an infectious pathogen.
• Toxoplasmosis is a common infectious cause of intracranial
mass lesions; however, a number of other infectious, neoplastic,
and other processes may present in this way.
• Neuroimaging, especially MRI with contrast, can help to
distinguish between some of these conditions.
• If the diagnosis is elusive, biopsy is recommended. Sometimes
an alternate biopsy target can be found on whole-body PET CT
before pursuing brain biopsy.
Further Reading
American Academy of Neurology Quality Standards Committee. Evaluation and
management of intracranial mass lesions in AIDS. Neurology. 1998;50:21–26.
Antinori A, Ammassari A, De Luca A, et al. Diagnosis of AIDS-related focal brain
lesions: a decision-making analysis based on clinical and neuroradiologic
characteristics combined with polymerase chain reaction assays in CSF.
Neurology. 1997;48:687–694.
Antinori A, Ammassari A, Luzzati R, et al. Role of brain biopsy in the management of
focal brain lesions in HIV-infected patients. Gruppo Italiano Cooperativo AIDS &
Tumori. Neurology. 2000;54:993.
Marra CM. Central nervous system infection with Toxoplasma gondii. Handb Clin
Neurol. 2018;152:117–122.
Stenzel W, Pels H, Staib P, et al. Concomitant manifestation of primary CNS
lymphoma and Toxoplasma encephalitis in a patient with AIDS. J Neurol.
2004;251:764.
15. Intracranial Mass in a Person with HIV 89

16 Rapidly Progressive
Dementia
You are asked to consult on a 46-year-old
woman on the inpatient psychiatric service to
“rule out frontotemporal dementia.” For the past
several months she has been “acting strangely,”
seeming depressed, anhedonic, and apathetic.
She is single, having lived alone for 12 years
after a difficult divorce. Medical history includes
chronic depression and migraine headaches.
Current medications include citalopram and
clonazepam, which seemed to improve her mood
and behavior. However, over the past several
days, she has worsened and is distinctly less
involved with her care team who are diagnosing
a form of catatonic psychosis. Vital signs have
been stable. She is afebrile. Neck is supple, and
general exams have been normal. She tends to
assume a fetal position but relaxes intermittently
with good limb movements, and she is able to
answer some questions. Facial movements are
symmetric, motor tone is diffusely increased,
and reflexes are brisk with Babinski signs
bilaterally.
What do you do now?
91
T his alarming case seems psychiatric but is unexpectedly not responding
at all to medications. That has appropriately raised red flags to the psy-
chiatry team. In addition, the hyperreflexia and dyskinetic movements are
suggestive of neurological disease. History here is so sparse that it is impor-
tant not to make too many assumptions about the timing of her symptoma-
tology: it could be chronic or subacute, and things seemingly are worsening.
The search for treatable neurological disease is paramount, and the best
next intervention would be to obtain head imaging, followed by a lumbar
puncture. Following this, an EEG would be ideal not only to investigate
the possibility of seizures, but also to search for clues of focal or generalized
cortical or subcortical dysfunction (Box 16.1).
Possibilities here include rapid dementia and relatively slow enceph-
alitis or encephalopathy. This patient’s presentation is reminiscent of
frontotemporal dementia (FTD), in particular the semantic variant pri-
mary progressive aphasia form. However, the course here seems much more
BOX 16.1 Differential diagnosis in subacute encephalopathy
Multi-infarct dementia
Primary CNS angiopathy
Cerebral amyloid angiopathy
Lyme disease
HIV dementia
Neurosyphilis
Whipple’s disease
Wernicke encephalopathy
Vitamin B12 deficiency
Hepatic encephalopathy
Porphyria
Autoimmune encephalitis (paraneoplastic encephalitis; limbic
encephalitis)
Medication effects
Creuzfeld-Jacob disease
Frontotemporal dementia
Lewy body dementia

rapidly progressive than FTD, although a fuller history could, of course,
provide clues to a longer progression.
The motor changes and subacute presentation can suggest encephalitis,
though not typical of common viral encephalitides like herpes simplex or
zoster encephalitis (or Eastern and Western Equine, West Nile, and other
less common encephalitides), which are much more rapidly progressive and
manifest with early headache and altered consciousness and cognition. Also,
MRI typically will show parenchymal abnormalities once the course of the
disease has progressed. Herpes zoster encephalitis can sometimes progress
more slowly. For example, there are a number of reports of this more suba-
cute presentation in patients with AIDS. Metabolic encephalopathies seem
unlikely here with normal lab values. Syphilitic meningoencephalitis is pos-
sible, even though risk factors are not apparent and VDRL was normal.
Lyme disease, ehrlichiosis, and cat-scratch fever are also said to sometimes
cause a slowly progressive encephalopathy, but the prominent behavioral
features in our case with a paucity of exam findings suggest an autoimmune
encephalitis (AE).
Anti-
NMDA- receptor encephalitis is an often paraneoplastic au-
toimmune attack on NMDA receptors in the brain, generally affects
younger patients, and initially presents with altered behavior, progressing
to worsening mental status, catatonia, and focal neurological deficits in-
cluding aphasia, weakness, ataxia, and eventually seizures and coma. High
rates of co-occurring tumors, particularly teratomas that contain NMDA
receptors, suggest that an autoimmune response develops. But no tumors
are ever found in many patients. MRI can be normal, as are routine labs
and inflammatory markers such as ESR and CRP. EEG can reveal slowing
and epileptiform discharges. CSF usually reveals lymphocytic pleocytosis,
elevated protein with normal glucose, elevated IgG index, and unique
oligoclonal bands. Diagnosis can be made with identification of NMDAR
antibody in serum or CSF, and often it is tested in both specimens. In
female-bodied individuals, it is important to search for an ovarian tera-
toma with use of ultrasound or MRI and to rescreen if initially negative
(Table 16.1).
AMPA receptor encephalitis seems also to usually result from
paraneoplastic autoimmune activity, and, like NMDAR encephalitis, most
patients will ultimately be found to have a solid organ tumor. Clinical
16. Rapidly Progressive Dementia 93

TABLE 16.1 Tumors associated with autoimmune encephalopathy
NMDA receptor Ovarian or mediastinal teratoma
AMPA receptor Lung, breast cancer, thymoma
Hu Small cell lung cancer (SCLC), neuroendocrine

tumors
Yo Ovarian cancer, breast cancer
CV2/CRMP5 SCLC, thymoma
Ri SCLC, breast cancer, gynecologic cancer
Ma2 Testicular, breast, lung, stomach cancer
Amphiphysin SCLC, breast cancer
Recoverin SCLC, Non-SCLC
LGI1 Thymoma, thyroid cancer, lung cancer, renal cell

cancer
Caspr2 Thymoma
GABA B receptor SCLC
GABA A receptor Thymoma, Hodgkin’s lymphoma, multiple myeloma
MGluR5 Hodgkin’s lymphoma
DPPX Unknown
Glycine receptor Thymoma, lymphoma, breast cancer
symptoms share characteristics with NMDAR encephalitis, with altered

behavior and thinking initially (which usually leads to psychiatric evalua-
tion) followed by focal neurologic deficits such as aphasia, paresis, ataxia,
and later catatonia, seizures, and coma. Hyperreflexia, Babinski reflexes,
and posturing are often seen.
Management of AE relies on early diagnosis and immunomodulation as
soon as infectious etiologies are ruled out. Antibody screening is wise as is
polymerase chain reaction (PCR) testing for all possible infectious agents
including herpes simplex and zoster. A search for a tumor which might be
the etiologic source is essential, as resection and treatment can lead to re-
covery with no other intervention.

A number of interventions for the management of AE have been
promoted including corticosteroids, plasma exchange, IVIg, rituximab, and
cyclophosphamide. Currently there is not a consensus on which should
be employed first or the duration of therapy. Prognosis is generally good
if treatment is begun relatively soon after the disease becomes apparent.
Our presenting case has progressed, and the ultimate outcome is not clear.
Even when treatment is successful, relapses can occur, sometimes months
or years later.
• AEs often present with psychiatric symptoms, although

they may progress to more overt neurological presentations
including focal seizures, paresis, and depressed consciousness.
• Lab testing and imaging can be normal in AEs, and CSF analysis
is essential to rule out treatable infectious encephalitis and to
confirm the immunological etiology.
• Specific treatment of AE is debatable, but plasma exchange,
IVIG, or immune modulators are the mainstay of treatment,
with relative good prognosis possible with reasonably early
treatment.
Further Reading
Budhram A, Silverman M, Burneo JG. Neurosyphilis mimicking autoimmune
encephalitis in a 52-year-old man. CMAJ. 2017;189(29):E962–E965.
Dalmau J, Armangué T, Planagumà J, et al. An update on anti-NMDA receptor
encephalitis for neurologists and psychiatrists: mechanisms and models. Lancet
Neurol. 2019;18:1045–1057.
Olney NT, Spina S, Miller BL. Frontotemporal dementia. Neurol Clin.
2017;35(2):339–374.
16. Rapidly Progressive Dementia 95

17 Functional Hemiparesis
A 45-year-old man began noticing weakness on
his right side 2 days ago, gradually worsening.
He denies previous symptoms of weakness
and has had no recent trauma. General exam
is normal. A screening mental status exam is
normal. Cranial nerves all seem to be normal
except for numbness to touch on the right side
of his face, normalizing at the midline. He has
“give-way weakness” in all muscles of the
right arm and leg. Hoover’s sign is positive
(lack of left hip extensor muscle activity when
asked lift his right leg). Muscle tone is normal,
reflexes are all in the 2+ range, and there are no
abnormal motor movements. Gait fluctuates;
you note dramatic wavering and near falling
when supporting some weight on the right leg.
Sensation to touch and temperature is reduced
in the right arm and leg, and there is numbness
on the right side of his trunk normalizing at the
midline. CT scan of the head is normal. Basic
labs are also normal.
What do you do now?
97
BOX 17.1 Conversion disorder (functional neurological symptom
disorder)
Diagnostic criteria
A. One or more symptoms of altered voluntary motor or sensory

function
B. Clinical findings provide evidence of incompatibility between the
symptom and recognized neurological or medical conditions
C. The symptom or deficit is not better explained by another medical
or mental disorder
D. The symptom of deficit causes clinically significant distress or
impairment in social, occupational, or other important areas of
functioning or warrants medical evaluation
From American Psychiatric Association, Diagnostic and Statistical Manual
of Mental Disorders (5th ed.).
T his patient seems to be suffering from a conversion disorder (CD; a

functional neurological symptom disorder), now classified as one of
the somatic symptoms and related disorders in the Diagnostic and Statistical
Manual of Mental Disorders of the American Psychiatric Association, Fifth
Edition (DSM-5) (Box 17.1). This group of disorders was formerly known
as somatoform disorders and are also known as functional disorders, implying
normal neurological function with overlying disability of unknown cause,
presumably psychogenic. CD has been explained in different ways but is
generally presumed to be the result of significant unresolved psychological
factors, particularly trauma, and can be viewed as adaptive. Symptoms of
CD commonly include weakness/paralysis, involuntary movements, sen-
sory losses, ataxia, visual dysfunction, nonepileptic seizures (psychogenic
nonepileptic spells [PNES]), and other alterations in consciousness (see
Box 17.2).
Diagnosis of CD must be made carefully in order to avoid missing
neurological disease. A careful exam with clear documentation is essential
as multiple exams over time can be decisive. While many features of the
neurological exam depend on reliable patient cooperation, there are some

BOX 17.2 Signs of conversion disorder
Weakness does not follow corticospinal, myotomal, or peripheral

nerve pattern
Normal reflexes, tone, and posture with paralysis
Variable resistance over time
Variable resistance against variable force
Give-way weakness, especially against very light force
Drift without pronation
Observe inadvertent movements awake (perhaps with distraction)
and asleep
Hoover’s sign in someone with asymmetric weakness
Reverse hands/fingers with strength testing
Vibration and other sensation loss splitting the midline
Nonanatomic distribution of sensory loss
Astasia abasia
elements that can objectively provide evidence for CD. In cases of motor
dysfunction, suggestive clues for CD include the presence of “give-way”
weakness (initial full-power on manual testing, followed by relaxation),
fluctuation in power over a short period of time, inconsistency of strength
testing when done in different ways (such as our patient with plantarflexion),
and patterns of weakness that cannot be explained anatomically. Normal
reflexes and lack of abnormal postures or tone differences are all clues as
well. On exam of pronator drift, falling of the arm without pronation can
be seen. Another clue to non-neurological paralysis is “Hoover’s sign,” a lack
of contralateral hip extension (by the otherwise strong leg) to support the
“weak” hip flexion; however, this is only helpful with unilateral weakness as
hip extension must be possible with the contralateral, strong leg. Moving
of the paralyzed limb during sleep, if observed, constitutes good evidence
of CD. Another good way to induce movement in the weak limb is to have
the patient cross fingers or hands and rapidly ask for right and left actions.
Clues to functional sensory loss include nonanatomical presentations such
as facial numbness including the angle of the jaw (C2) in otherwise trigem-
inal region of facial numbness; facial numbness stopping at the hairline (V1
17. Functional Hemiparesis 99

extends to vertex); sensory loss stopping at wrist, elbow, shoulder, knee, or
groin; and “midline-splitting” sensory loss, as in our patient. Vision loss
can be circumvented by asking the patient to do something that requires
good vision or watching them do very poorly at something (like fingertip
touching) that requires proprioception but not vision. Functional move-
ment disorders such as tremors or more dramatic dyskinetic movements
tend to vary with situation and with suggestibility and distraction. Unusual
gaits appearing extremely unstable but without falling (“astasia-abasia”) can
be seen. Mental status is not particularly telling in CD, and in particular,
the famous la belle indifference (unconcerned demeanor) is overrated as a
diagnostic feature of CD.
Managing functional neurological illness is challenging even when other
neurological conditions have been reliably ruled out. It is important to re-
member that the symptoms manifested by patients with CD are quite real
to them and a source of distress and disability. Many treatment approaches
have been promoted, including cognitive therapy, physical therapy, and
psychoactive medications. Most would now agree that a direct confron-
tational approach in the acute setting is generally not fruitful. Rather, a
compassionate, non-judgmental discussion of higher-level brain “software”
problems as causal in the condition will set the stage for gradual improve-
ment with physical and psychotherapeutic interventions. As patients with
CD may have underlying psychiatric illness, asking about suicidal ideation
is important.
A related disorder, also in the DSM-5’s Somatic Symptom chapter, is
factitious disorder, which consists of “falsification” of signs and symptoms
with the purpose of deception. Unlike CD, the patient is well aware of
the pretense. It is distinguished from malingering (though closer than to
CD) in that the benefit to the patient is more obscure. A typical example
is the patient with a functional neurological presentation for whom the
“sick role” is beneficial on a social/psychological level but without clear gain
(such as financial gains or freedom from prosecution). These distinctions
are often complex, but important, as approaches to CD, factitious disorder,
and malingering will be different.
Another related disorder, somatic symptom disorder, is generally not
a presenting factor in emergency settings but can certainly complicate
neurological presentations in the ED. This condition is characterized by
10 0 WHAT DO I DO NOW? Section 1: Diagnostic Dilemmas

multiple concurrent distressing symptoms including pain, nausea, dizzi-
ness, and fatigue. There are often underlying medical illnesses which serve
to heighten the patient’s vigilance and awareness of somatic complaints.
The patient tends to be highly anxious and worried about their symptoms
as compared with patients with CD, and they are often very resistant to
approaches consisting of reassurance.
• CD (functional neurological symptom disorder) simulates

neurological disease but can generally be distinguished with
careful observation, neurological exam, and testing.
• Typical presentations of CD include motor weakness, movement
abnormalities, ataxia, sensory changes, alterations in
consciousness, and spells concerning for seizure.
• Management of CD centers around appropriate testing and
sharing reassuring normal test results with the patient, followed
by a plan for treatment, often involving cognitive and behavioral
techniques, with predicted gradual improvement and even
resolution of symptoms.
• Factitious disorder and malingering are distinguished from CD
by the patient’s conscious effort to deceive.
Further Reading
American Psychiatric Association. Somatic symptom and related disorders. In
Diagnostic and statistical manual of mental disorders (DSM-5). Washington,
DC: American Psychiatric Association Publishing; 2013: 309–327.
Daum C, Hubschmid M, Aybek S. The value of “positive” clinical signs for weakness,
sensory and gait disorders in conversion disorder: a systematic and narrative
review. J Neurol Neurosurg Psychiatry. 2014;85(2):180–190.
Richardson M, Isbister G, Nicholson B. A novel treatment protocol (nocebo
hypothesis cognitive behavioural therapy; NH-CBT) for functional neurological
symptom disorder/conversion disorder: a retrospective consecutive case series.
Behav Cogn Psychother. 2018;46(4):497–503.
Stone J, Edwards M. Trick or treat? Showing patients with functional (psychogenic)
motor symptoms their physical signs. Neurology. 2012;79(3):282–284.
17. Functional Hemiparesis 101

18 Acute Myopathy
A 70-year-old man with diabetes and
hyperlipidemia presents with difficulty
swallowing. Two weeks ago, he noticed leg
weakness, and then arm weakness, especially in
his deltoids. One week ago, he developed double
vision; 4 days ago, he choked when drinking
liquids. Vital signs show a heart rate 104, blood
pressure 142/80, and oxygen saturation 97% on
room air. Exam is notable for normal mental
status; speaking in full sentences; with reactive
pupils; full extraocular muscles; and bifacial,
tongue, and neck flexion weakness, as well
as weakness in his proximal arms and legs.
There are no muscle fasciculations. Sensation is
intact. Reflexes are present except at the ankles.
Labs include normal chemistries and CBC, mild
transaminitis, creatine kinase (CK) 4,500, and
negative troponin. He has no family history of a
neuromuscular disease.
What do you do now?
103
B efore considering the localization for these symptoms, it is important
to recognize potential life-threatening clues on this exam. Neck flexion
weakness is a good surrogate for diaphragmatic weakness and should raise
concern for respiratory insufficiency. For this reason, bedside respiratory
function tests are recommended. It is especially helpful to ask respiratory
therapy to measure the functional vital capacity (FVC) and maximal inspir-
atory force (MIF). One can anticipate need for intubation for FVC <15–20
cc/kg (or <1 liter), MIF ≤25 cm H2O (where approximately −50 cm H2O
is normal), or for rapid worsening. In the acute period, MIF and FVC can
be measured multiple times a day to assess for crucial changes. While less
precise, respiratory capacity can also be assessed and trended by asking the
patient to count out loud as quickly as possible using one breath (normal
is approximately 40). Importantly, while these patients should have pulse
oximetry monitoring because oxygen saturation can be falsely reassuring.
In neuromuscular respiratory weakness, hypercarbia often occurs before
hypoxemia, and so once the pulse oximeter starts beeping, your patient is
already in crisis.
What might cause this patient’s constellation of symptoms? The lack of
upper motor neuron features makes brain or spinal cord involvement less
likely. Normal sensation and overall intact reflexes make nerve root and
nerve far less likely. There is no history of fluctuating weakness, but the
bulbar symptoms and limb weakness may be consistent with a neuromus-
cular junction process. However, the most likely localization, given pre-
served sensation, muscle soreness, proximal muscle weakness, and elevated
creatine kinase, is muscle (Box 18.1).
Myopathies can be caused by a multitude of factors, including
medications, systemic disease (e.g., HIV), genetic disorders, and inflam-
matory diseases. If suspicious for a myopathy, the CK can help narrow the
differential. Elevated CK may be found in toxic myopathies, inflamma-
tory myopathies (synonym: myositis), and infection-related myopathies.
A normal or low CK can be seen with endocrine myopathy (e.g., thyroid
disease), critical illness myopathy, and some congenital myopathies. While
inflammatory myopathies usually present with high CK, the CK may re-
turn to normal if partially treated, so inquiring about recent steroid use is
crucial.

BOX 18.1 Causes of myopathy
Inflammatory
- Antisynthetase syndrome
- Dermatomyositis
- Immune-mediated necrotizing myopathy
- Inclusion body myositis
- Overlap syndromes: Lupus, Sjögren’s syndrome, scleroderma
- Vasculitis
Noninflammatory
- Toxic: HMG-CoA reductase inhibitors, corticosteroids, alcohol
- Electrolyte: Hypokalemia, hypophosphatemia, hypocalcemia
- Infectious: Bacterial (e.g., Lyme), viral (e.g., HIV, CMV, EBV),
fungal, parasitic (e.g., toxoplasmosis, trichinosis)
- Rhabdomyolysis: Seizure, crush/trauma, hyperthermia
- Inherited: Muscular dystrophy, acid maltase deficiency
The time course can also help narrow the differential. Rapidly progressive
myopathies, especially with elevated CK, are more likely to be a toxic myop-
athy, such as due to a drug. One of the most important drug classes to consider
are statins, which can cause a toxic myopathy, especially in older individuals
and when used in combination with drugs that affect statin metabolism (e.g.,
cytochrome P450 inhibitors), or cause an immune-mediated necrotizing my-
opathy as described below. Other key drugs to ask about if considering a toxic
myopathy are amiodarone, colchicine, corticosteroids, ethanol, fibrates, and
zidovudine, though the list of possible drugs is extensive and so obtaining a
full and accurate medication history (including supplements) is crucial. The
treatment of a toxic myopathy is removal of the drug.
There is a growing recognition of immune-mediated myopathies. This
class of myopathy can be distinguished from other types of myopathy based
on biopsy characteristics. Biopsy can be helpful since an antibody cannot
always be identified, and this type of myopathy is often treatable. The most
common inflammatory myopathies are immune- mediated necrotizing
myopathies, dermatomyositis, antisynthetase syndrome, and inclusion
body myositis. These subtypes are associated with specific antibodies that
18. Acute Myopathy 105

are helpful to identify as they can predict the development of extramuscular
disease, including dermatologic, cardiac, and pulmonary complications,
and even malignancies.
Immune-mediated necrotizing myopathies feature severe, often acute
proximal muscle weakness. The two main antibodies associated with this
type of myopathy are anti-HMG-CoA and anti-SRP, though no antibody
is identified in a large fraction of cases. In addition to a toxic myopathy,
statins can cause an immune-mediated necrotizing myopathy due to the
presence of an antibody against HMG-CoA reductase, though up to a third
of patients with this antibody have no known statin exposure. The treat-
ment of immune-mediated necrotizing myopathy is immunomodulatory
therapy, including high- dose corticosteroids and often steroid- sparing
immunosuppressive agents. There is rarely extramuscular involvement in
immune-mediated necrotizing myopathy.
Dermatomyositis is often characterized by subacute proximal muscle
weakness and rash. This rash is erythematous and involves photosensitive
areas of the face including eyelids (heliotrope), shoulders, and extensor
surfaces of the joints. In addition to skin, there can also be cardiac involve-
ment resulting in cardiac arrhythmias, heart failure, or myocarditis, as well
as the development of interstitial lung disease. Dermatomyositis is associ-
ated with malignancy.
Antisynthetase syndrome is associated with antibodies to aminoacyl
transfer RNA synthetases and these are associated with an array of clinical
features, including diseases of the heart and lungs. These patients can de-
velop similar skin findings as in dermatomyositis. The presence of an anti-
antisynthetase antibody with evidence of collagen disease (e.g., systemic
lupus erythematosus) is also classified as an overlap myositis.
Inclusion body myositis is distinct in that it is slowly progressive and
tends to affect the deep finger flexors and quadriceps. While the other in-
flammatory myopathies are generally responsive to immunotherapy, inclu-
sion body myositis is not.
Consider sending a myositis panel to test for known antibodies associated
with inflammatory myopathies prior to starting any immunomodulatory
therapy because treatment can result in false negatives. Identification of an
antibody can guide the need for searching for concomitant extramuscular

disease. Of note, despite increasing recognition, most panels do not include
anti-HMG-CoA and so this must be sent separately.
Nerve conduction study (NCS) and electromyography (EMG) can assist
with confirming the diagnosis of myopathy and with identifying potential
muscle targets for biopsy. A muscle biopsy is often more helpful when the
CK is elevated than when it is normal.
In addition to identification and treatment of the myopathy, it is im-
portant to also remember the downstream complications of myopathy,
like myoglobinuria resulting in acute kidney injury and deconditioning
requiring assistance from rehabilitative services.
The patient described here was confirmed to have a myopathy on NCS/
EMG. His statin was stopped on admission. He tested positive for anti-
HMG-CoA. He received pulse steroids and intravenous immunoglobulin
with excellent clinical response.
• Neck flexion strength is an important surrogate for respiratory

muscle strength.
• Neuromuscular respiratory weakness causes hypercarbia before
hypoxemia.
• Myopathies can be associated with high and normal/low
creatinine kinase, which can help inform the differential.
• Toxic myopathy is the most common cause of acute myopathies
that predominantly affect proximal muscles. A thorough review
of recent medications, including supplements, is required.
• Inflammatory myopathy (myositis) can be associated with
extramuscular diseases that can affect the skin, heart, and lungs,
as well as be associated with malignancy.
• Statins can cause both a toxic myopathy and an immune-
mediated necrotizing myopathy (anti-HMG-CoA).
• Consider sending a myositis antibody panel, as well as anti-
HMG-CoA, before starting immunomodulatory therapy.
Identification of an antibody can help guide workup of
associated diseases and direct treatment.
18. Acute Myopathy 107

Further Reading
Goyal NA. Immune-mediated myopathies. Continuum (Minneap Minn).
2019;25(6):1564–1585.
Schmidt J. Current classification and management of inflammatory myopathies. J
Neuromuscul Dis. 2018;5(2):109–129.

SECTION 2
Treatment Dilemmas
19 Cardioembolic Stroke
with Contraindications
to Anticoagulation
A 74-year-old man with chronic atrial fibrillation
was directed to discontinue warfarin therapy
3 months ago when he was found to have
significant iron deficiency anemia with blood in
the stool but negative endoscopic and radiologic
workup of his GI tract. Last week he had a
transient left visual field loss, and this morning,
about 8 hours prior to presenting to the ED, he
noticed difficulty with speech after getting out
of the shower. In the remote past he had a left
cerebellar stroke which led to transient ataxia
and vertigo, at which time the atrial fibrillation
was discovered. Today, his heart rate is irregular
at approximately 76 beats per minute, atrial
fibrillation is identified on ECG, and blood
pressure (BP) is 134/76 mm Hg. General exam
is normal, but on neurological exam there is
some difficulty with naming low-frequency
objects, and fluency is reduced. Basic labs are
normal, including coagulation studies. CT today
reveals the old cerebellar stroke and a question
of attenuation changes in the cortex near the left
Sylvian fissure but is otherwise normal.
What do you do now?
111
T his patient is likely having recurrent cerebral ischemic events, prob-
ably occurring due to cardiac thromboemboli. After confirming
this, your next thought should be about ways to prevent further strokes.
Anticoagulation is appropriate but there are understandable concerns. First
is the fact that this patient was felt to be a risk for serious GI bleeding.
The second is that there is likely to be a new area of infarction, which
can undergo hemorrhagic conversion, which is more likely if the patient is
anticoagulated. He is out of the window for tissue plasminogen activator
(tPA). So it is time to assess the risk of anticoagulation versus the risk of a
new cardioembolic event while keeping his unique risk factors for bleeding
in mind.
First, let’s tackle the GI bleeding issue. His blood count is normal and
there is no active GI bleeding; his previous GI workup was negative. The
ideal timing to restart anticoagulation remains poorly characterized. For
patients with a high risk of ischemic stroke from atrial fibrillation estimated
with a CHA2DS2-VASc Score and low risk of rebleeding, resumption of
anticoagulation can be considered within a few days (Table 19.1). Patients
with a higher risk of bleeding but lower risk of thromboembolism may ben-
efit from a more delayed start. Hematocrit should be followed closely, and
the patient should remain vigilant for evidence of rebleeding.
TABLE 19.1 CHA2DS2-VASc score calculation
Category +0 Points +1 Point +2 Points
Age (years) < 65 65–74 ≥ 75
Sex Male Female –
Congestive heart failure history No Yes –
Hypertension history No Yes –
Stroke/TIA/thromboembolism history No – Yes
Vascular disease history No Yes –
Diabetes history No Yes –

Score 0: “low” risk, may not require anticoagulation
Score 1: “low-moderate” risk, consider antiplatelet or anticoagulation
Score 2: “moderate-high” risk, consider anticoagulation
112 WHAT DO I DO NOW? Section 2: Treatment Dilemmas

What about the risk of converting an ischemic infarction into a hemor-
rhagic one? Evidence is controversial here, too. The size of the acute infarction
is probably important (i.e., a large infarction is more likely to bleed). Avoiding
very high spikes in BP and careful monitoring of coagulation studies will
bias the odds against intracerebral hemorrhage. On the other hand, acutely
lowering BP in acute stroke can lead to extension of the infarctions so the risk
must be balanced. MRI can help estimate the size of the stroke and can also
detect even small amounts of bleeding, which could inform anticoagulation
decisions. But, back to the original question: Will the reduction in risk of re-
current infarction be outweighed by the risk of hemorrhagic conversion and
resulting morbidity and mortality risks? It turns out that the risks tend to
balance out pretty closely. Thus, evidence here is mixed.
Is there any advantage to using low-molecular weight heparin (LMWH)?
No; in fact, there are disadvantages. The half-life of LMWH is long, and
it is inactivated by protamine to a much lesser extent. Therefore, if there
is a bleeding complication, heparin is easier to reverse. Also, its activity
is not assessable by partial thromboplastin time (PTT), so the degree of
anticoagulation is generally inferred. And it is expensive (Table 19.2).
So, what to do in terms of attempting to prevent recurrent cerebral is-
chemia in this patient? Since evidence does not really help, this becomes
a clinical judgment problem. But, you are not alone. This patient and his
family can and should be enlisted to weigh the pros and cons. What they
need to know is that the next stroke can be devastating, but that it is im-
possible to know when or if this will happen. Echocardiography can help
by ruling out an intracardiac thrombus, but of course this is just a snap-
shot, and thrombi can begin to form at any time. The chances of recur-
rent stroke happening are generally below 5% in the first several days, so
odds are good that this will not occur while they are weighing the options
acutely. MRI can help by delineating the size of the stroke. Perhaps it is
small but with a penumbra of impending ischemia, therefore less likely
to bleed than a large area of infarcted tissue. If the patient and family opt
to avoid anticoagulation, this decision can be reassessed over the next
few days. Cardiological consultation about acute and long-term plans for
dealing with the atrial fibrillation with medication, cardioversion, or abla-
tion therapy might help but the success rate of these interventions has not
been high enough to obviate the need for anticoagulation.
19. Cardioembolic Stroke with Contraindications to Anticoagulation 113

TABLE 19.2 Comparison of oral anticoagulants for stroke prophylaxis in patients
with nonvalvular atrial fibrillation
Anticoagulant Warfarin Apixaban (Eliquis) Dabigatran Rivaroxaban

(Pradaxa) (Xarelto)
Mechanism Vitamin K Selective direct Competitive Selective

antagonist factor Xa inhibitor direct direct factor
thrombin Xa inhibitor
inhibitor
Routine level Variable: None None None

monitoring semi-weekly
to monthly
Dosing Per pharmacist Twice daily Twice daily Nightly

frequency
Dosing No renal dose Dose adjustment Dose Dose

considera adjustment. based on age, adjustment adjustment
tions weight, and/or renal based on based on
function renal function renal function
Antidote 10 mg vitamin Andexanet alfa Idarucizumab Andexanet

K IV and (AndexXa) (Praxbind) alfa (AndexXa)
four-factor
prothrombin
complex
concentrate (if
not available,
use fresh
frozen plasma).
Comparison ARISTOTLE: Superior RELY: Superior ROCKET-

with warfarin to warfarin to warfarin in AF: Non-
for stroke intention-to- inferior to
prevention treat analysis warfarin.
• Both systemic bleeding and intracerebral bleeding risks must

be considered before starting anticoagulation in the acute post-
stroke setting.
• MRI of the brain and echocardiography can help the
neurologist and patient weigh the risks and benefits of starting
anticoagulation.

• Unless there is a contraindication, an antiplatelet should be
started and then switched to anticoagulation when appropriate.
• If anticoagulation is begun in the acute post-stroke setting, strict
control of BP and close monitoring of bleeding parameters is
essential.
Further Reading
Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with
atrial fibrillation. N Engl J Med. Sep 17 2009;361(12):1139–1151.
Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients
with atrial fibrillation. N Engl J Med. Sep 15 2011;365(11):981–992.
Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the prevention of stroke in
patients with stroke and transient ischemic attack: a guideline for healthcare
professionals from the American Heart Association/American Stroke Association.
Stroke. Jul 2014;45(7):2160–2236.
Paciaroni M, Agnelli G, Falocci N, et al. Early recurrence and cerebral bleeding in
patients with acute ischemic stroke and atrial fibrillation: effect of anticoagulation
and its timing: the RAF Study. Stroke. Aug 2015;46(8):2175–2182.
Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular
atrial fibrillation. N Engl J Med. Sep 8 2011;365(10):883–891.
Sacchetti DC, Furie KL, Yaghi S. Cardioembolic stroke: mechanisms and therapeutics.
Semin Neurol. Jun 2017;37(3):326–338.
Witt DM, Delate T, Garcia DA, et al. Risk of thromboembolism, recurrent hemorrhage,
and death after warfarin therapy interruption for gastrointestinal tract bleeding.
Arch Intern Med. Oct 22 2012;172(19):1484–1491.
19. Cardioembolic Stroke with Contraindications to Anticoagulation 115

20 Recurring Transient
Ischemic Attack
A 73-year-old man was noted by his wife to
abruptly slur his speech and complain of right
arm clumsiness earlier this evening, which
resolved within minutes. These symptoms
recurred several hours later, this time lasting for
10 minutes, before completely resolving again.
He is now in the ED despite his unwillingness to
have medical care and admits that symptoms
like today’s have bothered him in the past. He
denies head pain, chest pain, and shortness of
breath. Medical history is only remarkable for
hypertension that has been well controlled. He
has no other neurological history. His general
exam is normal except for cataracts. His blood
pressure (BP) is 128/67, heart rate is 78 and
regular, and there are no cardiac murmurs. His
neurological exam is normal. A noncontrast
CT scan of the head shows some mild cortical
atrophy but is otherwise unremarkable. He has
made it clear that he intends to go home.
What do you do now?
117
T his presentation is most likely to be the result of recurrent transient
ischemia to the brain. The localization is probably the subcortical left
frontal region since the arm and articulatory muscles seem most affected.
For this reason, there is a suspicion of left middle cerebral artery (MCA)
involvement. However, the lack of cognitive/dysphasic symptoms might
suggest posterior circulation. Upper and lower limbs should be equally
affected when pathological processes affect the corticospinal tract in the
brainstem, but this rule is not entirely reliable. Could this presentation re-
flect nonischemic CNS dysfunction? Acephalgic migraine (migraine aura
without headache) can occur in his age group, but very rarely in patients
without a history of migraine. A seizure affecting the motor cortex can af-
fect articulation and limb strength, so this is another possibility. However,
migraine auras and focal seizures are generally manifested by “positive
phenomena”: in the case of migraine, by paresthesias, visual images, and
scotomata; in the case of focal seizures, by dystonic or clonic activity rather
than by weakness. It is possible that observers did not note a focal sei-
zure, with subsequent Todd’s paralysis mimicking the weakness of a tran-
sient ischemic attack (TIA). Another possibility is so-called recrudescence
of symptoms from an old stroke on the basis of infectious, metabolic, or
hypoperfusion conditions. In the presenting case, the CT does not reveal a
prior stroke, and so this is less likely. The diagnosis of TIA is a clinical one.
Given the risk of subsequent completed infarct, it is prudent to take such
symptoms seriously.
If this patient’s recurrent symptoms do indeed stem from focal ischemia,
what are the possible etiologies? Cardiogenic or artery-to-artery emboliza-
tion is certainly possible, but the stereotypic manifestations in this patient
are rather convincing for small vessel stenosis. The noncontrast CT scan
ruled out hemorrhage as a cause. Workup to help determine etiology and
stratify risk of subsequent stroke is paramount, which may require admis-
sion to the hospital for expedited testing. Stroke risk following a TIA can be
stratified using the ABCD2 score, which can help triage who would benefit
from admission (score of ≥4) or who could receive urgent completion of
outpatient studies within 24−72 hours (Table 20.1).
Helpful labs include a comprehensive metabolic profile, coagulation
studies, hemoglobin A1c, and lipid panel. Testing for a hypercoagulable
state can also be considered if there is clinical concern, though some studies

TABLE 20.1 ABCD2 score
Category +0 Points +1 Point +2 Points
Age ≥60 years No Yes –
Initial SBP ≥140 or No Yes –

DBP ≥90
Clinical features Other Speech Unilateral

of TIA symptoms disturbance weakness
(no weakness)
Symptom duration <10 10–59 ≥60

(minutes)
Diabetes history No Yes –
may be falsely elevated in the acute setting. A urinalysis or chest x-ray can
be obtained if there is concern for recrudescence in the setting of infection
(e.g., urinary tract infection or pneumonia, respectively), and a urine toxi-
cology screen can help reveal additional stroke risk factors (e.g., stimulant
use). An ECG should be performed to assess for atrial fibrillation. While in
the hospital, the patient should be placed on telemetry and receive a 30-day
cardiac monitor on discharge to screen for atrial fibrillation. The patient
should also undergo a transthoracic echocardiogram (TTE) to evaluate for
intracardiac thrombus, valvular disease, and the efficiency of the heart in
case reduced cardiac outflow might contribute to this patient’s symptoms.
Obtaining a saline contrast “bubble” study with the TTE remains a topic of
debate and should be reserved for those who may be candidates for closure
of a patent foramen ovale if found.
This patient already underwent a noncontrast CT scan of his head, which
can help assess for blood but does not provide information on the vessels of
the head or neck. A CT angiogram of the head and neck extending to the
aortic arch can show vessel stenosis or dissection. MR angiography (MRA)
with gadolinium is an alternative; if the patient cannot receive gadolinium,
an MRA can be performed without gadolinium using a “time of flight”
sequence. Alternatively, neck vessel patency can be assessed with bilateral
carotid ultrasound, but this excludes the intracranial vasculature.
Primary stroke prevention is the next consideration. A daily aspirin
should be started. There are a few scenarios where dual antiplatelet therapy
20. Recurring Transient Ischemic  Attack 119

(DAPT) should be considered. Patients with TIA or minor stroke—without
upcoming surgery or reason for anticoagulation—are recommended to
start DAPT. One approach is to start aspirin (81 mg/d) plus clopidogrel
(600 mg loading dose, followed by 75 mg/d) for 21 days, with antiplatelet
monotherapy thereafter. It is also recommended to start a high-dose statin
with goal LDL of less than 70 mmol/L. Anticoagulation should be discussed
if the patient is found to have atrial fibrillation on cardiac monitoring.
Normotension should be targeted—though an exception is stated later—
and blood glucose should stay within a normal range.
If the patient is determined to have symptomatic carotid stenosis (ste-
nosis >70%), urgent treatment is recommended within the same hospital-
ization given the high risk of recurrent stroke. The CREST study looked
at treatment of carotid stenosis by stenting (CAS) or carotid endarterec-
tomy (CEA). Here, individual outcomes revealed a twofold higher risk of
perioperative stroke with CAS compared with CEA, whereas CEA yielded
a twofold higher risk of perioperative myocardial infarction. Several factors
must be considered when deciding on the appropriate treatment, including
the patient’s medical comorbidities, age, gender, and life expectancy, as well
as the degree and location of the stenosis.
If a focally stenotic MCA or MCA branch consistent with this patient’s
symptomatology is identified, treatment must focus on management of
hypertension and any other possible risk factors including statin treat-
ment of hyperlipidemia. However, maintenance of adequate BP may be
the most helpful intervention aimed at preventing permanent ischemic
damage to the territory supplied by the focally stenotic artery in the short
term. This quandary is usually approached carefully by allowing BP to
remain elevated to 220 mm Hg, with gradual reduction in the setting
of neurologic exam checks. For symptomatic intracranial atherosclerosis,
the SAMMPRIS trial demonstrated that maximal medical therapy, in-
cluding DAPT with aspirin and clopidogrel for 90 days, was superior to
stenting for secondary prevention of stroke. Following the 90-day pe-
riod, antiplatelet monotherapy is continued. Endovascular stenting of in-
tracranial vessels is not recommended. More aggressive antithrombotic
therapy with warfarin has not proved any better than aspirin so should
not be used.

Last, this is an opportunity to review lifestyle choices, such as encour-
aging cardiovascular exercise and cessation of tobacco products, if appli-
cable. Stroke teaching and precautions should also be provided before
discharge.
• Recurrent transient neurological symptoms are best regarded

as a warning for impending cerebral ischemic damage unless
proved otherwise.
• Cerebral ischemia tends to produce “negative phenomena,”
whereas migraine and focal epilepsy more “positive
symptomatology.”
• TIAs should warrant a search for the contributing arterial causes
as well as risk factors for stroke, including consideration of a 30-
day cardiac monitor.
• Select patients with TIA or minor stroke are recommended to
start DAPT for 21 days, followed by antiplatelet monotherapy
thereafter . Patients with symptomatic intracranial
atherosclerosis are recommended to use DAPT for 90 days.
Further Reading
Castel J, Mlynash M, Lee K, et al. Agreement regarding diagnosis of transient
ischemic attack fairly low among stroke-trained neurologists. Stroke.
2010;41:1367–1370.
Chimowitz MI, Lynn MJ, Derdeyn CP, et al. Stenting versus aggressive
medical therapy for intracranial arterial stenosis. N Engl J Med. Sep 15
2011;365(11):993–1003.
Gladstone DJ, Spring M, Dorian P, et al. Atrial fibrillation in patients with cryptogenic
stroke. N Engl J Med. Jun 26 2014;370(26):2467–2477.
Johnston SC, Rothwell PM, Nguyen-Huynh MN, et al. Validation and refinement of
scores to predict very early stroke risk after transient ischaemic attack. Lancet.
Jan 27 2007;369(9558):283–292.
Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the prevention of stroke in
patients with stroke and transient ischemic attack: a guideline for healthcare
professionals from the American Heart Association/American Stroke Association.
Stroke. 2014;45(7):2160–2236.
20. Recurring Transient Ischemic  Attack 121

21 Acute Neuralgia
A 65-year-old man is seen in the ED for
excruciating right facial pain which has been
bothering him for the past several weeks, but
which escalated dramatically this morning. The
most painful territory is in the right preauricular
and lower cheek areas, and he is moaning and
in tears due to its severity and incessancy.
Pain feels “electrical” and “burning.” He denies
headache or pain anywhere else, and has
had no changes in vision, muscle strength or
coordination. He denies recent rashes or other
recent illnesses. CT scan of the head is normal
as is routine blood testing. Neurological exam
is remarkable only for some hearing loss
bilaterally and reduction in reflexes diffusely. He
is resistant to any touching of the face because it
exacerbates the pain, but there is no tenderness
over the mastoid or areas outside the painful
region. There are no skin changes noted.
What do you do now?
123
T his patient probably has a typical case of trigeminal neuralgia (TN),
which has become intractable. Pain can mount to such an extent
that some patients become suicidal. Fortunately, there are some useful
strategies acutely, but first, steps should be taken to rule out other causes
of his pain.
TN is considered a “primary neuralgia,” implying that it is not due
to some underlying pathological process. This is, of course, not true, as
it is probably the result of some insult to the trigeminal nerve or nu-
cleus that has not been fully characterized. Many believe most cases of
TN to be the result of compression of the proximal trigeminal nerve
by an artery, often the superior cerebellar artery. At any rate, it is your
responsibility to exclude other causes. Meningeal inflammatory/infec-
tious processes, tumors, aneurysms, and abscesses can cause irritation
of the trigeminal nerve, and a multiple sclerosis (MS) plaque near the
root entry zone in the pons can also produce secondary trigeminal neu-
ralgic syndromes. Herpetic infection of the nerve as well as post-herpetic
neuralgia can be the cause. Inflammatory, infectious, thrombotic, gran-
ulomatous, neoplastic, and vascular lesions in the cavernous sinus can
also cause a TN picture. In these cases, only the first two divisions of the
trigeminal are involved at most, since the third division, the mandib-
ular branch, does not pass through the cavernous sinus. Cluster head-
ache, paroxysmal hemicrania (PH), and the syndrome of short-lasting
unilateral neuralgiform headache (SUN) can all lead to pain that can be
mistaken for TN. Cluster headaches are generally much longer than the
lancinations of TN, PH and SUN headaches. PH and SUN headaches
are shorter, but all three of these primary headache disorders are asso-
ciated with autonomic features like tearing, rhinorrhea, and nasal con-
gestion ipsilateral to the pain, which are not present with the presenting
case. Infection or neoplastic disease in the sinus, orbit, ear or mouth can
also mimic TN (Box 21.1).
A good workup for suspected TN would include brain MRI with and
without contrast to exclude MS, brainstem region masses or infection, and
cavernous sinus region lesions. MR angiography can be helpful to identify
vascular compression of the nerve. Lumbar puncture might be indicated,
particularly if there are other cranial nerves involved, to rule out an infec-
tious, inflammatory, or neoplastic process. A search for herpetic lesions or

BOX 21.1 Differential diagnosis of trigeminal neuralgia
Cavernous sinus syndromes

Cluster headache
Paroxysmal hemicranias
Short-lasting unilateral neuralgiform headaches
Hemifacial spasm
Migraine headache
Post-herpetic neuralgia
Subarachnoid hemorrhage
Sinus, ocular, or otic pathology
Herpetic and post-herpetic neuralgia
Multiple sclerosis
Chronic meningeal infection/inflammation (Lyme, TB, sarcoidosis)
scars might be revealing. And a very good head and neck exam should be
done to exclude an otic, orbital, or sinus lesion or infection.
Most patients with TN can get good, long-lasting relief with judicious
use of antineuralgia medication such as carbamazepine, oxcarbazepine,
gabapentin, amitriptyline, or baclofen, as well as a number of second-line
prophylactic medications, including lamotrigine, pregabalin, and phen-
ytoin. The use of botulinum toxin type A injected in the region of the
greatest pain has been used effectively in some cases as well. Trigeminal
nerve decompression is often recommended when imaging reveals vascular
compression of the nerve. For intractable cases, ablative procedures of the
trigeminal nerve or Gasserian ganglion (including gamma knife procedures)
have been successful in some cases, though potential adverse effects, such as
worsening pain due to denervation, must be considered.
However, the problem confronting you is how to stop this man’s excru-
ciating pain as soon as possible. Intravenous phenytoin has been helpful for
a number of patients at a dose of 15 mg/kg infused slowly, with care taken
to avoid extravascular injection as this can be highly toxic to dermal tissues
(leading in some cases to the “purple glove syndrome”). Fosphenytoin is
safer and, while costlier, is equally effective. Intravenous lidocaine can also
be useful in a dose up to 5 mg per kilogram of body weight in 250 mL of
21. Acute Neuralgia 125

5% dextrose solution over 1 hour. Standard cardiac monitoring is advis-
able as lidocaine can induce arrhythmia. Occipital nerve blocks with lido-
caine or bupivacaine have helped some patients acutely. Other parenteral
anticonvulsants have been tried in the acute setting, including levetiracetam.
Neuroleptic antiemetics have also been helpful for selected patients in ex-
cruciating pain from TN. Chlorpromazine, for example, at a dose of 25–50
mg IV given carefully with diphenhydramine to prevent dystonic reaction,
seems to be effective in acute exacerbations of TN. This can be very sedating,
so patients must be watched carefully after administration. Finally, there are
reports of benefit from a number of other interventions including ocular
topical anesthetic (when pain seems greatest in the ophthalmic division),
sumatriptan given subcutaneously, and intravenous infusion of magnesium
sulfate in the 1–3 g range. Here, too, cardiac monitoring may be wise.
TN typically produces lancinating pain and can be triggered by touch,
as in this patient. The usual areas of pain fall into the maxillary and man-
dibular regions of the face (served by the lower two divisions of the trigem-
inal nerve). Patients may be seen to have contractions of their face on the
side of pain (hence the synonym for TN: tic dolouroux). This is not to be
confused with hemifacial spasm, thought to be due to irritation of the fa-
cial nerve. But some patients complain of more aching type pain without
the other features of TN. This has been termed “atypical facial pain” and
carried the connotation of psychogenic etiology. It seems much more likely
that it is simply a different manifestation of the same process—trigeminal
irritation—and the search for secondary causes and successful treatment is
very similar.
For those interested in the classification of neuropathic pain subtypes,
the International Classification of Headache Disorders approach may help,
in which consistent categories are used for neuropathic pain involving the
face or head. According to this approach, neuralgia is used to describe
primarily lancinating pain derived from a pathological process affecting
the nerve, and painful neuropathy is used to describe pain that is generally
continuous with evidence of a sensory deficit on exam (Box 21.2). This
classification is generalizable to other neuralgias. Likewise, the acute and
prophylactic treatment described earlier tends to be effective for other neu-
ropathic pain conditions such as glossopharyngeal neuralgia and occipital
neuralgia.

BOX 21.2 International Classification of Headache Disorders (3rd ed.)
Classification of trigeminal nerve pain

13.1 Pain attributed to a lesion or disease of the trigeminal nerve
13.1.1 Trigeminal neuralgia
13.1.1.1 Classical trigeminal neuralgia (due to vascular
compression)
13.1.1.2 Secondary trigeminal neuralgia (MS, masses, etc.)
13.1.1.3 Idiopathic trigeminal neuralgia
13.1.2 Painful trigeminal neuropathy
13.1.2.1 Painful trigeminal neuropathy attributed to
herpes zoster
13.1.2.2 Trigeminal post-herpetic neuralgia
13.1.2.3 Painful post-traumatic trigeminal neuropathy
13.1.2.4 Painful trigeminal neuropathy attributed to
other disorder
13.1.2.5 Idiopathic painful trigeminal neuropathy
• Acute exacerbations of TN can be excruciating and even lead to

suicidality.
• Prophylactic pharmacological treatment of TN is generally very
effective.
• There are several options for acute treatment of exacerbations,
with guidelines now available for guidance.
• Atypical facial pain is a somewhat perjorative term that probably
represents an overlap syndrome with many features of TN.
Further Reading
Bendtsen L, Zakrzewska JM, Abbott J, et al. European Academy of Neurology
guideline on trigeminal neuralgia. Eur J Neurol. 2019;26(6):831–849.
Cruccu G, Gronseth G, Alksne J, et al. AAN-EFNS guidelines on trigeminal neuralgia
management. Eur J Neurol. 2008;15:1013–1028.
Headache Classification Committee of the International Headache Society (IHS).
The International Classification of Headache Disorders (3rd ed.). Cephalalgia.
2018;38:1–211.
21. Acute Neuralgia 127

Moore D, Chong MS, Shetty A, Zakrzewska, JM. A systematic review of rescue
analgesic strategies in acute exacerbations of primary trigeminal neuralgia. Br J
Anaesth. 2019;123(2):e385–e396.
Newman JW, Blunck JR, Fields RK, Croom JE. Fosphenytoin-induced purple glove
syndrome: a case report. Clin Neurol Neurosurg. 2017;160:50–53.

22 Intractable Migraine
A 32-year-old woman with a several year history
of migraine is being seen in the ED for a severe
headache which has failed to respond to IM
ketorolac 60 mg, prochlorperazine 25 mg IM and
lorazepam 4 mg IM. She tried sumatriptan PO
at home last night, which was ineffective. She
states that the pain is unbearable and beseeches
you to “just give me a shot of morphine!” You
see that her last ED visit for headache occurred 2
weeks ago and that she has had 9 visits to the ED
in the last 6 months. She also complains of some
nausea, severe photo- and phono-phobia, and
some mild vertigo. She is taking amitriptyline
100 mg qhs, topiramate 100 mg bid, propranolol
80 mg bid, and clonazepam 2 mg qhs. She also
takes sumatriptan, hydrocodone and butalbital
as well as an assortment of over-the-counter
analgesics regularly. She has a normal general
exam, a supple neck, and no neurological
findings. Funduscopic exam is also normal.
CT of the head is normal.
What do you do now?
129
T here is no emergency room physician who cannot recall many patients
whose presentation was nearly identical to this patient’s. The headache
is most likely migraine, fitting the diagnosis of “status migrainosus” (Box
22.1), but making sure to rule out secondary causes of headaches is im-
perative. Intracranial by mass, hemorrhage, meningitis, encephalitis, hy-
drocephalus, and abscess are all highly unlikely with a normal exam. But
cervical arterial dissection, vasculitis, reversible cerebral vasoconstriction
syndrome, toxicity or metabolic derangement, cerebral venous thrombosis,
and an array of less common causes of headache must be considered. A way
to quickly decide whether to embark on a workup for these is to ask the
following questions:
• Was the headache onset sudden (thunderclap)?

• Is this a new headache or a change from the old headache pattern?
• Is there fever, significant hypertension, or neck stiffness?
• Is there any finding on neurological exam including cognitive
dysfunction?
• Is this headache occurring in the setting of systemic illness (e.g., AIDS,
cancer)?
BOX 22.1 International Classification of Headache Disorders criteria

for status migrainosus
1.4.1 Status migrainosus

Description: A debilitating migraine attack lasting for more than
72 hours
A. A headache attack fulfilling criteria B and C
B. Occurring in a patient with 1.1 Migraine without aura and/or 1.2
Migraine with aura, and typical of previous attacks except for its
duration and severity
C. Both of the following characteristics:
1. unremitting for >72 hours
2. pain and/or associated symptoms are debilitating

Generally, the answer to all of these is No. But if any of these “red flags”
are present, imaging of the head, lumbar puncture, cerebrovascular im-
aging, and extensive metabolic screening may be indicated.
If this is indeed simply another migraine, why is it so unresponsive to
medication, and why is she having to come to the ED so often despite
prophylactic medication and appropriate acute headache medication?
Unfortunately, the medications are most likely contributing to this patient’s
problems. When migraine patients overuse analgesic and/ or migraine-
abortive medications, headache frequency may increase via an as yet poorly
understood mechanism. Previously termed “analgesic rebound,” this condi-
tion is referred to as medication overuse headache (MOH), and it is very chal-
lenging to treat. It is also difficult to diagnose with certainty since there are
certainly patients who developed frequent migraine attacks prior to using
acute medications frequently—thus the medication use is a result not a
cause of the frequent headaches.
In patients with MOH, there is poor response to acute treatments, even
those that were once useful. And when they try to discontinue their acute
“rescue meds,” pain worsens and they tend to give up. These patients also
tend to lose responsiveness to prophylactic medications. The frequency and
doses of the analgesic/abortive medications needed to produce this syn-
drome probably varies from patient to patient and with different acute
medications, but usage on 3 days per week or more is generally thought to
be enough to cause MOH (Box 22.2).
So, an apparently unsolvable problem confronts the medical team here.
Fortunately, there are some reasonably good options for immediate control of
pain that will not escalate the problem of medication overuse. Ketorolac was a
good choice but was not effective, possibly because of the frequent use of OTC
medications in the NSAID category. Another option is intravenous valproate
which is given as a 500–1,000 mg bolus. Intravenous magnesium sulfate is
another option and is given in doses of 1 g up to 5 g total as slow IV push.
Intravenous dihydroergotamine (DHE) 1 mg is another option although
should not be given in close temporal proximity to a triptan, as vasoconstric-
tive effects can be additive. Greater occipital nerve blocks seem to be very
helpful for some patients, although the mechanism is not well understood.
Intravenous neuroleptic medication can be extremely useful for acute re-
fractory migraine. A good choice is prochlorperazine 10 mg. Because of the
22. Intractable Migraine 131

BOX 22.2 Range of medication overuse headache causes
8.2 Medication-overuse headache (MOH): Headache on 15 or

more days per month in the setting of chronic overuse of acute
medications (generally >10 per month usage, but >15 days/
month for NSAIDs)
8.2.1 Ergotamine-overuse headache
8.2.2 Triptan-overuse headache
8.2.3 Non-opioid analgesic-overuse headache
8.2.3.1 Paracetamol (acetaminophen)-overuse headache
8.2.3.2 Non-steroidal anti-inflammatory drug (NSAID)-
overuse headache
8.2.4 Opioid-overuse headache
8.2.5 Combination-analgesic-overuse headache
8.2.6 Medication-overuse headache attributed to multiple drug
classes not individually overused
8.2.7 Medication-overuse headache attributed to unspecified or
unverified overuse of multiple drug classes
From International Classification of Headache Disorders (3rd ed.).
risk of dystonia, this is often administered with diphenhydramine 25 mg

intravenously. Finally, parenteral corticosteroids, either as a one-time dose
or followed by a tapering oral dose over several days can break a cycle of mi-
graine, though there tends to be some delay after initial dosing. This might
consist of 1,000 mg of methylprednisolone or 6–8 mg of dexamethasone.
The evidence for acute relief of migraine with steroids is weak but it does
seem that they can effectively prevent recurrence of the headache when used
in addition to other interventions.
Opioids are to be avoided. While they can certainly relieve pain, the effect
is temporary, and large doses are generally required, leading to significant
sedation. Plus, opioids will just amplify the medication overuse condition.
Patients who have had opioid treatment in the past may remember the
gratifying relief of pain (and perhaps euphoria) and ask for it again. This is
interpreted as illicit drug-seeking, but rather, it may be better framed as ap-
propriate protective behavior. Nonetheless, the request for opioids is to be

countered with clear explanations regarding why they are not indicated. If all
approaches fail, the patient can be admitted and treated more aggressively, per-
haps with a course of intravenous DHE infusions or parenteral neuroleptics.
Some or all of the above are usually successful in alleviating the patient’s
headache or at least significantly reducing its severity. But the problem of
headache recurrence, very likely in the setting of medication overuse, re-
mains. Patients like this must be enlisted in the fight to limit acute pain
medications, and it may be reasonable to refer them to a headache specialist
who can simplify and adjust the prophylactic program and help to design a
multimodal treatment plan.
• Even patients with a known headache disorder must be

thoughtfully evaluated for the presence of a new secondary
cause when presenting to the ED with intractable pain.
• There are a number of parenteral pharmacological choices for
acute migraine treatment including ketorolac, DHE, magnesium,
valproate, neuroleptics, and corticosteroids.
• Occipital nerve blocks may be a useful addition to the treatment
options.
• Medication overuse may complicate the picture of acute
refractory migraine and must be addressed.
Further Reading
Friedman BW. Review: phenothiazines relieve acute migraine headaches in the ED
and are better than other active agents for some outcomes. Ann Intern Med.
2010;152:JC4–JC11.
Katsarava Z, Holle D, Diener H-C. Medication overuse headache. Curr Neurol
Neurosci Rep. 2009; 9:115–119.
Marmura MJ, Silberstein SD, Schwedt TJ. The acute treatment of migraine in
adults: the American Headache Society Evidence assessment of migraine
pharmacotherapies. Headache. 2015;55(1):3–20.
Singh A, Alter HJ, Zaia B. Does the addition of dexamethasone to standard therapy
for acute migraine headache decrease the incidence of recurrent headache for
patients treated in the emergency department? A meta-analysis and systematic
review of the literature. Acad Emerg Med. 2008;15(12):1223–1233.
22. Intractable Migraine 133

23 Intracerebral Hemorrhage
on Anticoagulation
A 66-year-old man with a history of atrial
fibrillation and myocardial infarction complicated
by heart failure was admitted to the hospital for
ventricular assist device placement, now on a
therapeutic heparin infusion. His hospital course
was also complicated by acute on chronic renal
failure, requiring continuous renal replacement
therapy. While working with physical therapy he
is noted to be newly confused and not moving
his right side. A stroke alert is called. His vital
signs include a blood pressure (BP) of 90/50,
pulse 95. His finger-stick blood glucose is 110.
His pupils are symmetric and reactive. His NIH
Stroke Scale is 24, notable for global aphasia,
left gaze preference, right field cut, right facial
weakness, right hemiparesis, and sensory
loss. He is emergently intubated for airway
protection and taken for a noncontrast head CT,
which shows a large left frontal intracerebral
hemorrhage (ICH) with midline shift.
What do you do now?
135
E ven before the head CT is obtained, there is high concern for an ICH
given his rapid clinical deterioration, his focal neurologic deficits on
exam, and the important history of concurrent anticoagulation use. ICH
carries a high rate of disability and mortality, and patients with ICH are
at risk of early decompensation from hematoma expansion, so it is impor-
tant to act quickly. In these situations, there are several things to keep in
mind before the patient leaves the unit for head imaging. The first thing is
to ensure that the patient is stable enough to go to the CT scanner, which
includes lying flat for several minutes. If intubation is indicated, try to ob-
tain a rapid neurologic exam prior to the use of paralytics in order to guide
initial management.
Depending on the patient’s history, exam, and clinical circumstance,
it may be reasonable to begin treatment for increased intracranial pres-
sure prior to obtaining the head CT, as discussed later. In addition to a
noncontrast head CT (see Figures 23.1 and 23.2), which will quickly pro-
vide information on the presence of blood or cerebral edema, it is often
helpful to also obtain a CT angiogram (CTA) of the brain. The CTA will
help determine whether the ICH is from a vascular cause, like an aneu-
rysm or vascular malformation. For example, hemorrhage involving the syl-
vian fissure is often aneurysmal in origin. Contrast enhancement within
the ICH (“spot sign”) may indicate active bleeding. CT venogram (CTV)
should also be considered as a significant minority of venous occlusions
present with hemorrhage.
ICH is often complicated by increased intracranial pressure (ICP), which
requires emergent identification and treatment. Management of increased
ICP centers on the Monroe-Kelli doctrine, which states that any sudden
change in volume of the different intracranial compartments—broadly
speaking, parenchyma, blood, and CSF—will result in increased ICP due
to the fixed volume of the skull. Immediate steps can be taken at the bed-
side, including elevating the head of the bed and ensuring the head is mid-
line, to encourage venous return. Temporary hyperventilation (PaCO2 goal
of 30–35 mm Hg) with gradual reversal, either through bag-masking or
intubation, leads to arterial vasoconstriction and so lowers cerebral blood
volume and ICP. If possible, a reduction in positive end-expiratory pres-
sure (PEEP) can reduce intrathoracic pressure, facilitating venous return.
Hyperosmolar therapy, either with mannitol or hypertonic (23.4%) saline,

FIGURE 23.1 Noncontrast CT of the head showing large left frontal parenchymal hematoma
with mass effect.
can be given. At this time, there is no clear evidence of superiority of one

agent over the other and so the choice is often determined by accessibility
and expediency. Serum sodium and osmolality should be trended with a
goal of hypernatremia (serum sodium approximately 145–155 mEq/L)
and hyperosmolality (300–320 mosmol/kg). Hypotonic fluids should be
avoided.
Any coagulopathy in someone with ICH should be emergently reversed,
if the benefits outweigh the risks. Coagulopathy may be iatrogenic, he-
reditary, or acquired from a systemic process (e.g., malignancy, uremia).
For patients on an unfractionated heparin infusion, IV protamine sulfate
can be given for reversal, with a dose based on the amount of heparin re-
ceived and the timing of its last administration. For patients on warfarin,
the INR will serve as a guide for reversal with a goal of INR lower than 1.5.
If the anticoagulation is iatrogenic, is important to keep in mind the reason
for starting it in the first place and what the risks of reversal may be, but
expedited reversal remains paramount.
23. Intracerebral Hemorrhage on Anticoagulation 137

FIGURE 23.2 CT of the same left frontal parenchymal hematoma with interval expansion
6 hours later.
In order to reverse vitamin K antagonist (e.g., warfarin), an INR

will serve as the guide for four-factor prothrombin complex concen-
trate (PCC) administration, which is favored over fresh frozen plasma.
Vitamin K 10 mg IV should also be provided over 30 minutes with close
monitoring, given risk for anaphylaxis. Direct oral anticoagulants have
several benefits over warfarin as anticoagulants but are more challenging
to reverse. If the last dose was given within 2 hours, activated charcoal
can be given to reduce absorption. The reversal agent for dabigatran
is idarucizumab. The reversal agent for apixaban and rivaroxaban is
andexanet alfa.
If a patient is receiving tissue plasminogen activator (tPA) and
experiences an acute neurologic decline, a stat noncontrast head CT should
be obtained to assess for hemorrhage. In patients with suspected hemor-
rhage, the tPA infusion should be stopped. Treatment options in this sce-
nario include cryoprecipitate 10 units or the use of antifibrinolytic agents,
such as aminocaproic acid or transexamic acid.

Platelet transfusions may be helpful if the patient is thrombocytopenic
(platelet <100,000/μL). However, platelet transfusions are not indicated—
and may even be harmful—if the goal is to “reverse” recent antiplatelet use,
as shown in the PATCH trial.
Neurosurgical colleagues should also be consulted immediately. Rapid
correction of a coagulopathy will also prevent delay of surgical intervention if
needed. An external ventricular drain (EVD; also known as ventriculostomy
or extraventricular drain) should be considered if there is hydrocephalus
or significant intraventricular hemorrhage from a supratentorial hemor-
rhage. Decompressive hemicraniectomy should be discussed for large ICH,
especially cerebellar hemorrhages larger than 3 cm, as these increase the
risk of brainstem compression and ventricular obstruction leading to acute
hydrocephalus.
The management of refractory elevated ICP centers on the reduction of
brain metabolism and improved ventilator synchrony with the use of seda-
tion and paralytics.
Unlike this scenario, intraparenchymal hemorrhage is often accompanied
by hypertension because of uncontrolled chronic hypertension as a cause
for the hemorrhage or as a stress response. In severe cases, hypertension is
accompanied by bradycardia and irregular breathing, which is the Cushing
response seen with increased intracranial pressure. Common areas of hem-
orrhage seen with hypertensive bleeds are the basal ganglia, thalamus, pons,
and cerebellum. When faced with a hypertensive patient, current evidence
suggests that a rapid reduction in BP can reduce the risk of hematoma ex-
pansion and improve outcomes. The BP target is an area of controversy.
Recent guidelines recommend that if the systolic BP (SBP) is between 150
and 220 mm Hg and there is no contraindication to acute BP treatment,
then acute lowering to SBP 140 mm Hg is safe and can improve functional
outcome. The choice of antihypertensive is also important as venodilators
may increase ICP. Overaggressive BP reduction, below the recommended
target, can result in ischemia and increased edema, especially in patients
with a long-standing history of hypertension.
Clinical seizures should be treated with antiepileptics. However, in
nontraumatic ICH, there are no data to support the use of prophylactic
antiepileptics. Similarly, there is no evidence to support steroid use for ce-
rebral edema in these cases.
23. Intracerebral Hemorrhage on Anticoagulation 139

Even before the patient is stabilized, prognostication of neurologic out-
come will likely come up. The latest American Heart Association/American
Stroke Association (AHA/ASA) guidelines caution providing early prog-
nostication because current models are insufficient. For this reason, these
guidelines encourage early aggressive care and postponement of a new do-
not-resuscitate (DNR) order until at least the second full hospitalization day.
• In addition to a noncontrast head CT, consider the use of vessel

imaging (arterial and venous) to assess for alternate etiologies
of hemorrhage.
• Treatment of coagulopathy is specific to the underlying
cause. Platelets are not indicated unless the patient is
thrombocytopenic (platelet <100,000/μL).
• Be on the lookout for signs of increased ICP and treat
expeditiously.
• An external ventricular drain may be needed if there is
significant intraventricular blood or hydrocephalus.
Further Reading
Baharoglu MI, Cordonnier C, Al-Shahi Salman R, et al. Platelet transfusion versus
standard care after acute stroke due to spontaneous cerebral haemorrhage
associated with antiplatelet therapy (PATCH): a randomised, open-label, phase 3
trial. Lancet. 2016;387(10038):2605–2613.
Hemphill JC, 3rd, Greenberg SM, Anderson CS, et al. Guidelines for the Management
of Spontaneous Intracerebral Hemorrhage: A Guideline for Healthcare
Professionals From the American Heart Association/American Stroke Association.
Stroke. 2015;46(7):2032–2060.
Witt DM, Nieuwlaat R, Clark NP, et al. American Society of Hematology 2018
guidelines for management of venous thromboembolism: optimal management
of anticoagulation therapy. Blood Adv. 2018;2(22):3257–3291.

24 First Seizure
A 42-year-old man was seen earlier today to
“look off into space” and, within a few minutes,
was observed to have a generalized rhythmic
shaking of his legs and arms. He had urinary
incontinence. He has had no recent illnesses
or medical symptoms. He has been working a
second job lately—and sleeping less—due to
financial need. He has no history of seizures
or stroke. CT of the head was normal as was a
lumbar puncture. He is very anxious. Vital signs
are normal except for tachycardia at 110. Blood
count reveals a WBC of 12,000, but RBC count,
hematocrit, and hemoglobin are normal as are
serum chemistries. Full neurological exam is
entirely normal.
What do you do now?
141
T he first question in a patient with a first-time seizure-like spell is: “Is
this epileptic?” It certainly sounds like it here, but it is important to
remember that there a number of conditions which can mimic seizures in-
cluding movement disorders, TIA, syncope, psychiatric conditions, and mi-
graine. None of these seems likely here.
When patients do not recover from their seizure completely, have a
prolonged postictal period (more than a couple of hours), have multiple
seizures, are sick medically, or have an unstable/unsupervised home life,
hospitalization is warranted. This patient, who apparently has none of these
complicating issues, will probably be anxious to return home, which is not
unreasonable. But the neurologist, who may never see this patient again,
has a responsibility to attempt to predict the future here and do everything
possible to rule out treatable causes of seizures and prevent their recurrence.
The WBC elevation is entirely expected, as generalized seizures lead to
WBC demargination and spuriously increased WBC counts, but infections
should be considered. Other etiological factors should be entertained such
as intracranial mass lesions, meningitis, encephalitis, electrolyte imbalance
(such as hyponatremia, hyper-or hypoglycmeia, hypomagnesemia, or hy-
pocalcemia), medication side effects (opioids, antidepressants), intoxication
(particularly with stimulants), or withdrawal (see Box 24.1). Here, again,
none of these seems likely. Sleep deprivation is likely to have contributed.
Autoimmune diseases of the brain, genetic diseases, perinatal cortical injury,
and the remote effects of brain trauma are possibilities. To be certain no
causative factors have been missed, the patient should have an MRI of the
brain with and without contrast and an EEG with provocative maneuvers
like photic stimulation and hyperventilation. Both of these can generally be
done safely during the subsequent several days on an outpatient basis. After
normal CT imaging of the brain, lumbar puncture is warranted in patients
with fever, meningismus, or focality on neurological exam, including per-
sistent alteration in mental status.
The decision about starting anticonvulsant medication in a patient who
had a first seizure revolves around the risk of seizure recurrence, which
is probably around 30% in the next 5 years, but changes depending on
risk factors. One risk factor for seizure recurrence is partial onset—and
here there seems to have been complex partial seizure activity (impaired
awareness) followed by secondary generalization. Other risk factors are the

BOX 24.1 Causes of first-time seizures
Intracranial neoplasm
Subdural hematoma
Cerebral infarction
Intracerebral hemorrhage
Cerebral venous thrombosis
Cerebral vasculitis
Meningitis
Encephalitis
Brain abscess
Electrolyte imbalance (such as hyponatremia, hypomagnesemia,
hypocalcemia, hypoglycemia or hyperglycemia, uremia)
Medication side effects (opioids, antidepressants)
Drug intoxication (amphetamines, cocaine)
Drug withdrawal (barbiturates, benzodiazepines)
Ethanol withdrawal
Perinatal cortical injury
Posttraumatic cortical injury
Inherited metabolic diseases
presence of focal neurological deficits on exam, the presence of epileptiform

activity on EEG, and brain CT or MRI abnormalities. With normal MRI,
the risk of a recurrence after the first seizure goes down to about 30%.
Unprovoked seizures are more likely than provoked seizures to recur, but
the nature of provocation is probably important. Unprovoked seizures will
have highest recurrence in the first 2 years, and early antiseizure treatment
is felt to be important.
Other considerations are, of course, the relative risks and benefits of an-
ticonvulsant medication for the particular patient. The risk of antiseizure
drug adverse effects is high—up to around 30%, though most of these are
mild and reversible. Some neurologists ask patients about their lifestyle risks
(i.e., the consequences of a seizure recurrence). For example, a seizure recur-
rence in a long-distance truck driver might be of more concern than in an of-
fice worker. However, any generalized seizure is potentially life-threatening,
24. First Seizure 143

particularly if it should happen while the patient is driving, on a stairway,
etc. Therefore, the decision is individual and should be made as a team with
input from the patient, family, and neurologist. Often, if workup is entirely
normal, instituting anticonvulsant therapy is done with the plan of tapering
and stopping medication within a year if seizures have not recurred and
EEG remains normal. This might be reasonable here. Equally reasonable,
if the patient wishes, the decision can be postponed until the EEG and
further brain imaging has been done. And it is not unreasonable to simply
choose to adjust lifestyle to raise the seizure “threshold” and avoid taking
anticonvulsants entirely for the time being. For this patient this would in-
volve assuring adequate sleep, avoiding intoxicants like ethanol, and prob-
ably looking into stress-reducing tactics including personal counseling.
Most neurologists would agree that anticonvulsant treatment is indicated
after two seizures as recurrence risk is significantly higher after two or more
unprovoked seizures than after just one, rising to 70% even in patients with
normal brain MRI scans.
The best choice in anticonvulsant medication for a first-time generalized
seizure is not clear. Several studies have attempted to compare the available
anticonvulsants on the basis of effectiveness and tolerance, but different
results seem to surface. All antiepileptic drugs can potentially have fairly sig-
nificant side effects, and many alter hepatic metabolic activity. Some should
be titrated upward slowly, which will lead to a delay in attaining therapeutic
levels. Serum drug concentrations can be useful with some anticonvulsants
but not all.
Since little is yet known about this patient’s seizure type other than it be-
came generalized, a good choice might be to begin with a medication that
is good for seizures with an unknown classification. It is essential to know
and share with patients the common adverse effects of the AEDs you are
considering and what monitoring lab tests will be necessary.
It is worth letting patients know that around 10% of people will have
one seizure, about 1% have epilepsy (more than two unprovoked seizures),
but, having had one seizure, there is a higher risk of having a second seizure.

Based on this, many patients will opt to start an AED, at least for sev-
eral months. Whatever is decided, the patient should be cautioned about
risks of driving, operating machinery, or doing any activity that might be
dangerous to himself or others if he were to have a seizure. You should be
aware of state laws concerning cessation of driving after documented sei-
zure occurrence and counsel the patient about his or her responsibilities
concerning this as well as any requirement for you to notify state motor
vehicle departments.
• First-time seizures should trigger a workup to exclude

intracranial pathology and metabolic causes.
• The acute evaluation of a patient with a first-time seizure should
include CT scan of the brain, and preferably, EEG, as well as full
metabolic evaluation including toxicology.
• LP should be performed if there is concern for meningitis or
encephalitis.
• MRI of the brain should also be completed in the near future.
• The decision to begin seizure prophylaxis depends on
the patient’s risks, preferences, and results of the workup,
particularly MRI and EEG.
Further Reading
Bao EL, Chao LY, Ni P, et al. Antiepileptic drug treatment after an unprovoked first
seizure: a decision analysis. Neurology. 2018;91(15):e1429–e1439.
Bonnet LJ, Shukralla A, Tudur-Smith C, Williamson PR, Marson AG. Seizure
recurrence after antiepileptic drug withdrawal and the implications for
driving: further results from the MRC Antiepileptic Drug Withdrawal Study and a
systematic review. J Neurol Neurosurg Psychiatry. 2011;82:1328–1333.
Faught E. The cost of the second seizure: rethinking the treatment decision. Epilepsy
Curr. 2019;19(2):88–90.
24. First Seizure 145

25 Acute Stroke Up to 24 Hours
A 61-year-old man with untreated hypertension
woke up with difficulty moving his right arm
and difficulty speaking. He went to bed at
approximately 10 pm and awoke to these
symptoms at 6 am. Both symptoms have
persisted. His wife called the paramedics, who
activated a stroke alert in the field. The patient is
alert but is unable to follow verbal commands
or speak. He has decreased movement of the
lower right face and is unable to move his right
arm. Paresis is noted in the right deltoid, triceps,
biceps, wrist extensors, and finger extensors.
The right leg is also weak but not as severely.
Sensation seems intact to noxious stimulation.
His coordination appears intact on the left. CT of
the head is negative, ECG shows sinus rhythm
without any signs of cardiac ischemia. His wife
pleads with you to do something as he is a
carpenter and they are very worried about a
disabling stroke.
What do you do now?
147
A s a neurology trainee, there were few scenarios more disappointing
than determining that someone with an acute stroke was out of the
window for treatment. This was especially true for those who “woke up”
with stroke symptoms and so often fell outside the previously narrow 6-
hour eligibility limit for endovascular thrombectomy. Now, therapeutic
options for acute stroke have expanded in the past few years, rendering
thrombectomy available to more patients than ever before.
There are several key pieces of information that are needed when an acute
stroke is suspected before considering treatment. First you must establish
when the patient was last known to be at his or her neurologic baseline. This
gives the best estimate of when the stroke began and is distinct from when
the patient may have been found down or with a new deficit. Don’t forget
to ask the patient. However, if the patient cannot participate or is aphasic,
this information may need to come from family, friends, or bystanders. Two
large-bore IVs should be placed (these will be needed if antihypertensives,
contrast, or thrombolytics are given). Stat labs should include chemistry,
CBC, and coagulation profiles. A finger-stick glucose is needed to exclude
hypoglycemia (glucose <50) as a stroke mimic. As part of standard protocol,
patients should be weighed, and blood pressure should be controlled to less
than 185/110 if the patient may be eligible for tissue plasminogen activator
(tPA, alteplase), which will be discussed in more detail later.
Keep in mind that all this is occurring while the patient is being examined
using the NIH Stroke Scale (NIHSS). Once the ABCs (airway, breathing,
and circulation) are deemed stable, the patient should go immediately for
a noncontrast head CT, CT angiography (CTA) head/neck, and CT perfu-
sion if available.
The main goal of the noncontrast head CT is to exclude hemorrhage (see
Figure 25.1). Once hemorrhage is excluded, the decision to give or with-
hold tPA should be made. TPA is not FDA-approved for use in the United
States in a stroke of longer than 3 hours duration. However, this window
was widened to 4.5 hours following the third European Cooperative Acute
Stroke Study (ECASS III) that showed a higher percentage of patients with
favorable outcomes if given tPA compared with placebo without difference
in mortality. At the time of this publication, tPA eligibility is based on
time from symptom onset rather than imaging characteristics, though this
is likely to change in future.

FIGURE 25.1 Noncontrast CT of the head with a loss of gray–white matter differentiation in the
left insula, frontal and temporal lobes.
After the noncontrast head CT is obtained and the tPA decision is made,
obtain the CTA head and neck to look for a large vessel occlusion. Unless
clearly contraindicated, we do not wait for the creatinine to return before
completing the CTA. If available, it is also important to obtain CT per-
fusion, which helps to differentiate brain tissue at risk (penumbra) from
infarcted tissue (infarct core) (see Figures 25.2). The DAWN and DEFUSE-
3 trials demonstrated efficacy of thrombectomy in patients with proximal
anterior circulation occlusion up to 24 hours from symptom onset based
on clinical and imaging criteria—specifically, finding patients with a large
amount of tissue at risk (penumbra) but with a small infarct core.
Endovascular therapy should be pursued, regardless of whether tPA
is given, for all acute ischemic strokes with distal inferior cerebral artery
(ICA) or proximal middle (MCA) or anterior (ACA) occlusions. The deci-
sion to provide tPA is independent of the decision for thrombectomy, and
vice versa. Symptomatic basilar thrombosis should almost always receive
endovascular therapy. The efficacy of endovascular therapy was confirmed
25. Acute Stroke Up to 24 Hours 149

(a) (b) (c)
FIGURE 25.2 (a) Perfusion imaging of same lesion showing increased mean transit time.
(b) Perfusion imaging of same lesion showing decreased cerebral blood flow. (c) Perfusion imaging
of same lesion showing relatively preserved cerebral blood volume.
with the release of four pivotal randomized controlled trials (MR CLEAN,
ESCAPE, EXTEND- IA, and SWIFT PRIME) that demonstrated
improved functional outcomes at 90 days. Patients with a large-vessel oc-
clusion should be transferred to the nearest center offering thrombectomy.
In these cases, tPA can be offered prior to transfer if eligible (“drip and
ship”). Optimization of the acute management of ischemic stroke is an area
of neurology that is advancing rapidly and so it is important to remain vig-
ilant for such advances.
• While IV tPA can be offered to select patients up to 4.5 hours

from stroke onset, early administration is better (“time is
brain”).
• Thrombectomy can be offered to select patients with large-
vessel occlusion up to 24 hours from symptom onset.
• Patients who are eligible for IV tPA and thrombectomy should
still receive IV tPA prior to thrombectomy. If the patient must
be transferred to another institution for thrombectomy, tPA can
often be given prior to transfer (“drip and ship”).

Further Reading
Adams, HP, del Zoppo, G, Alberts, MJ. Guidelines for the early management of adults
with ischemic stroke. A guideline from the American Heart Association/American
Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular
Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular
Disease and Quality of Care Outcomes in Research Interdisciplinary Working
Groups. Stroke. 2007;38:1655–1711.
Albers GW, Lansberg MG, Kemp S, et al. A multicenter randomized controlled trial of
endovascular therapy following imaging evaluation for ischemic stroke (DEFUSE
3). Int J Stroke. 2017;12(8):896–905.
Hacke W, Kaste M, Bluhmki E, et al.; ECASS Investigators. Thrombolysis
with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med.
2008;359:1317–1329.
Nogueira RG, Jadhav AP, Haussen DC, et al. Thrombectomy 6 to 24 hours after stroke
with a mismatch between deficit and infarct. N Engl J Med. 2018;378:11–21.
Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the early management
of patients with acute ischemic stroke: 2019 update to the 2018 Guidelines for
the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare
Professionals from the American Heart Association/American Stroke Association.
Stroke. 2019;50(12):e344–e418.
25. Acute Stroke Up to 24 Hours 151

26 Acute Cervical
Radiculopathy
A 52-year-old right-handed man was awakened
by severe right shoulder and medial scapular
pain which did not respond to ibuprofen or
heat. He went to one of his twice weekly martial
arts classes the night before but does not recall
any specific trauma. He recalls similar pain
for short periods in the last few months, but
of much milder intensity. He required 2 mg of
hydromorphone intravenously for relief. He
endorses feeling weak in his legs transiently. He
denies bladder or bowel difficulty. Left biceps
and brachioradialis seem stronger than right.
Right biceps reflex is diminished; otherwise
reflexes are normal and there is no Babinski
reflex. Abdominal reflexes are normal as are
cremasteric reflexes. Gait is normal. Spurling
maneuver seems to duplicate pain on the
right side when looking up and to the right.
Plain x-rays of the neck reveal some “mild
degenerative changes” at C5-6 and C6-7, and
“spine straightening”. Severe pain begins to
reemerge.
What do you do now?
153
T his patient’s symptoms seem to emanate from the right C6 spinal
nerve, producing the characteristic shoulder and lateral arm pain.
Presumably this is due to disc rupture on the basis of his recent neck
stress during martial arts training. Interestingly, many patients with C6
radiculopathy seem to upper back or shoulder pain even before neck and
arm pain. The cause of this is unknown but may relate to compression of
the medial branches of the dorsal rami of the spinal nerves. The cervical
spinal nerves originate as the dorsal and ventral roots which merge and
exit at the intervertebral foramen. The spinal nerves of the neck exit the
intervertebral foramen above the numbered cervical vertebrae (thoracic
and lumbar nerves exit the intervertebral below the numbered vertebra).
So here we will be looking for evidence of pathology in the vicinity of the
C5–6 interspace. Cervical spine straightening on plain x-rays is not par-
ticularly helpful, nor is the evidence of early degenerative spine disease.
MRI of the cervical spine will be important to confirm our impression
of disc rupture and to rule out fracture or mass, as well as the presence
of disc fragments in the spinal canal. Electromyography can be helpful
at localizing the site of the pathology, but since it can be falsely normal
acutely and does not provide information on the possible cause, MRI is
actually superior.
Rupture of cervical intervertebral discs is less common than in lumbar
discs, which is interesting because it has been shown that the annulus fi-
brosis in cervical discs is less robust (anatomical cadaver dissection work
by Bogduk). Trauma is usually required but patients often cannot specify
dramatic injuries. In our patient, as is fairly typical, subtle trauma becomes
symptomatic after a bit of a delay, perhaps because the leak of nucleus
pulposis material is gradual. This may underlie our patient’s previous “pre-
monitory” symptoms. Nonetheless, the pain can be intense.
Other than the pain, it is important to try to characterize the clinical
state for a couple of important reasons. First, unlike lumbar disc rupture,
cervical disc rupture carries the risk of spinal cord compression which,
while uncommon, can lead to significant permanent myelopathy. This
patient seemed to have some initial leg weakness but on exam is entirely
free of myelopathic symptoms such as trunk or lower extremity sensation
change, balance issues, and bowel/bladder dysfunction, and he is likewise
not manifesting myelopathic findings such as hyperreflexia, increased tone,

or lower extremity weakness. Intact abdominal reflexes are a nice confirm-
atory finding, as is the cremaster reflex. However, there can be a delay in
myelopathic features, and it is wise to admit these patients for inpatient ob-
servation and surgical decompression in a timely fashion should it become
necessary.
Another reason for a careful exam is to try to accurately gauge motor
weakness in radicular compression. If this is minor, strength and reflexes
tend to improve with conservative management, including physical ther-
apeutic measures and pain control. But if there is significant weakness,
surgical intervention may be appropriate. The surgical treatments include
the anterior approach discectomy with fusion or other spine stabilizing
techniques including implanted “cages.” Posterior approaches, including
endoscopic procedures, are gaining popularity in some areas as they do not
require spine stabilization, but their outcome data are less clear. Epidural
steroid infusion can help modulate pain but these seem not to provide
added long-term benefit. Chiropractic manipulation has not been conclu-
sively shown to help, and there is risk of vertebral artery injury in the high-
speed manipulations practiced by many chiropractors.
• Cervical radiculopathy is often post-traumatic, but the injury can

be relatively innocuous.
• C6 and C7 radicular pain can begin in the upper back and
shoulder.
• Careful examination is essential to rule out myelopathy.
• MRI of the cervical spine is the best confirmatory test and is
important in ruling out impending spinal cord compression,
mass lesions, and spinal canal bone fragments.
• Physical therapy helps the majority of cases, but surgical disc
removal may be necessary, particularly in cases of significant
weakness or severe pain refractory to treatment.
Further Reading
Mehren C, Wanke-Jellinek L. Posterior foraminotomy for lateral cervical disc
herniation. Eur Spine J. 2019;28(1):1–2.
26. Acute Cervical Radiculopathy 155

Mizutamari M, Sei A, Tokiyoshi A, Fujimoto T, Taniwaki T, Togami W, Mizuta
H. Corresponding scapular pain with the nerve root involved in cervical
radiculopathy. J Orthop Surg. 2010;18(3):356–360.
Vleggeert-Lankamp CL, Janssen TM, van Zwet E, Goedmakers CM, Bosscher L,
Peul W, Arts MP. The NECK trial: effectiveness of anterior cervical discectomy
with or without interbody fusion and arthroplasty in the treatment of cervical
disc herniation; a double-blinded randomized controlled trial. Spine J.
2019;19(6):965–975.

27 Post-Cardiac Arrest
Management
A 38-year-old man in excellent health is found
unresponsive by his spouse when he fails to
turn off his morning alarm. Paramedics find
the patient in ventricular fibrillation; he is
subsequently shocked and receives epinephrine
with a conversion to pulseless electrical activity.
The man is shocked again, receives additional
epinephrine, with return of spontaneous
circulation. He is intubated in the field with
paralytics, and total CPR time is approximately
20 minutes. On arrival to the ED, blood pressure
(BP) is 158/98 (without vasopressors), heart rate
is 90, oxygen is 98% ventilated. Neurological
exam is limited by recent use of paralytics;
pupils are 3 mm and reactive bilaterally. Labs are
notable for WBC 20, lactate 7, and venous blood
gas with pH 7.2.
What do you do now?
157
A fter stabilization, one of the main decisions to make for this indi-
vidual is whether or not to provide targeted temperature management
(TTM), also known as therapeutic hypothermia or cooling. TTM is cur-
rently the only therapy shown to improve outcomes for hypoxic-ischemic
neurologic injury after cardiac arrest. The randomized controlled trials that
support the use of TTM only included patients with cardiac arrest in the
community, although TTM may also be considered for in-hospital car-
diac arrest. While previously studied in patients with cardiac arrest with
shockable rhythms (ventricular fibrillation or pulseless ventricular tachy-
cardia), there is also growing evidence to support the use of TTM following
nonshockable rhythms (pulseless electrical activity or asystole) as well. For
this reason, the initial cardiac rhythm does not factor into the TTM deci-
sion or subsequent prognostication.
Current guidelines recommend achieving a target temperature of 33–
36°C for 24 hours, followed by 48 hours of normothermia with fever pre-
vention. The goal is to achieve the target temperature as soon as possible.
TTM is only suitable for patients who are not following commands, in-
cluding patients whose exam may be clouded by sedatives and paralytics.
Make your TTM decision based on what you see, not what you think the
patient is capable of doing. Potential contraindications to TTM include
active bleeding (especially at a noncompressible site) or an inability to
maintain SBP at greater than 90 mm Hg with pressors. Acute coronary syn-
drome or planned cardiac interventions, including those that may require
thrombolysis or anticoagulation, are not contraindications. If a patient is
determined to be too unstable for TTM, then it is recommended to at least
avoid fever for protection against neurologic deterioration.
Passive cooling can begin immediately in eligible patients with the use
of surface ice packs and intravenous chilled normal saline. There are several
methods for maintaining hypothermia, and so reference the protocol at
your institution.
The initial neurological exam should focus on mental status, brainstem
reflexes (pupil reactivity, corneal reflex, oculocephalic reflex, presence of
cough and gag), and the best motor response to central and peripheral nox-
ious stimulation.
After stabilization, a noncontrast head CT should be obtained to en-
sure that the cardiac arrest was not caused by an aneurysmal subarachnoid

hemorrhage or other intracranial pathology. It can also be helpful to assess
for presence of cerebral edema (see Figure 27.1), which can affect intracra-
nial pressure management.
During the period of TTM maintenance, there are several aspects to
monitor in addition to the core temperature. Shivering should be treated
as it increases the metabolic rate and may make maintaining the goal tem-
perature challenging. Options for shivering control include buspirone,
meperidine, magnesium sulfate, benzodiazepines, and propofol. If these
medications fail to adequately control shivering, paralysis can be used, but
this significantly limits the exam. The patient should remain NPO and goal
blood glucose is less than 180. Potassium should be replaced only up to 3.4
mEq/L as rewarming can cause rebound hyperkalemia.
Rewarming begins 24 hours from TTM start, not from when goal tem-
perature was reached. Rewarming should occur slowly, with a temperature
increase no greater than 0.5°C per hour, and then maintained at 37°C for
the first 24 hours post-TTM to avoid rebound hyperthermia. Following
FIGURE 27.1 Noncontrast CT of the head showing global cerebral edema.
27. Post-Cardiac Arrest Management 159

the acute period, it is recommended to maintain a core temperature of less
than 37.5°C. Secondary neurologic injury can be avoided by aggressively
treating fever (goal temp < 37.5°C), hypocapnia (goal PaCO2 > 35 mm Hg),
hyperoxemia (goal PaO2 < 200 mm Hg), and treating seizure if present.
If, after rewarming, the patient is following commands, prognosis is
excellent.
However, if the patient remains unresponsive, the question of prognos-
tication arises. Variables used for prognostication should predict with high
specificity who will have an invariably poor prognosis, to make sure that
those who are labeled as having a poor prognosis have no chance of a mean-
ingful recovery.
American Academy of Neurology (AAN) evidence-based algorithm for
prognostication after cardiac arrest is based on data from the pre-TTM era.
For this reason, prognostication using these guidelines must be used with
caution in those who underwent TTM.
No neurologic prognostication should occur until at least 24 hours
post-arrest. In those who undergo TTM, prognostication may take even
longer, since hypothermia can directly affect mental status and the metab-
olism of drugs. Patients who undergo TTM may also receive more sedating
medications than those who are not made hypothermic. It is absolutely
crucial to not rush into prognostication.
The neurologic exam should be performed 72 hours post-arrest, ensuring
sedatives have been discontinued for a sufficient period of time so as to not
affect the examination. The examination should center on the same aspects
listed earlier. In addition, quantitative pupillometry is a helpful tool when
assessing pupillary reactivity.
EEG and SSEPs should be obtained after rewarming, between 24 and 72
hours post-arrest. Some institutions also recommend the use of EEG during
the cooling and rewarming phases. Serum neuron specific enolase (NSE)
can be measured at 48, and 72 hours post-arrest. The 72-hour exam, pres-
ence of myoclonus, NSE levels, EEG characteristics, and SSEP responses
can be combined for multimodal prognostication of poor outcome. It is im-
portant to note that outcome is often described as a Cerebral Performance
Category (CPC) from 1 (normal) to 5 (death). A poor outcome may group
CPC 3–5, where CPC 3 refers to severe disability with dependency, but
with some ability to communicate or even ambulate. For this reason, what

a study labels as a poor outcome may not actually be unacceptable to a
patient or surrogate decision-maker and is a significant limitation in prog-
nostication discussions.
• Patients who do not follow commands after cardiac arrest

should be considered for TTM.
• If eligible, TTM should be initiated on arrival and not delayed for
procedures.
• Shivering and fever should be aggressively treated in order to
reduce metabolic demands.
• No neurologic prognostication should occur until at least
24 hours post-arrest. Prognostication guidelines are largely
based on pre-TTM data. In these studies, definitions of a poor/
unfavorable outcome may differ from what is an acceptable
quality of life to the patient’s previously stated wishes or
determination by decision-makers.
Further Reading
Callaway CW, Soar J, Aibiki M, et al. Part 4: Advanced life support: 2015 International
consensus on cardiopulmonary resuscitation and emergency cardiovascular
care science with treatment recommendations. Circulation. 2015;132(16 Suppl
1):S84–S145.
Geocadin RG, Callaway CW, Fink EL, et al. Standards for studies of neurological
prognostication in comatose survivors of cardiac arrest: a scientific statement
from the American Heart Association. Circulation. 2019;140(9):e517–e542.
Hawkes MA, Rabinstein AA. Neurological prognostication after cardiac arrest in the
era of target temperature management. Curr Neurol Neurosci Rep. 2019;19(2):10.
27. Post-Cardiac Arrest Management 161

28 Myasthenic Crisis
A 60-year-old woman with generalized
myasthenia gravis presents to the ED in
respiratory distress. She takes low-dose
prednisone, pyridostigmine, and azathioprine.
She developed congestion and cough 1 week
ago. When you assess her, her heart rate is 120s,
respiratory rate is 20s, oxygen saturation 88% on
room air. Bedside forced vital capacity (FVC) is
0.6 L, and mean inspiratory force (MIF) is −26 cm
H2O. She is tachypneic, using accessory muscles
for breathing. Her mental status is normal, but
she can only speak a few words at a time. She
has bilateral ptosis and bifacial weakness. Her
speech is hoarse. She can barely lift her head
off the pillow, and she has deltoid weakness;
otherwise strength is full. The remainder of the
neurologic exam is unremarkable. Labs show
normal chemistries and a mild leukocytosis.
Serial venous blood gases show her carbon
dioxide is uptrending. A chest x-ray shows a right
lower lobe opacity concerning for pneumonia.
What do you do now?
163
W hile there are many causes of respiratory distress, neuromuscular
weakness is an important addition to the differential. The pneu-
monia is clearly not helping this patient, but her breathing difficulties are
due to much more than a lung infection.
There are several bedside surrogates for respiratory strength, especially
in patients with neuromuscular weakness, such as from myasthenia gravis.
For example, this patient has difficulty speaking in complete sentences and
she has neck flexion weakness. Neck flexion weakness is a good surrogate
for diaphragmatic weakness. Neck flexion requires the accessory nerve as
well as the cervical nerves arising from C2 and C3. Similarly, the dia-
phragm relies on the phrenic nerve, which arises from a combination of
C3, C4, and C5 nerve fibers—you may recall the rhyme “C3, 4, 5 keeps
the diaphragm alive.” Neck flexion strength is an easy exam maneuver that
can be serially monitored with each intervention. Patients may also exhibit
accessory muscle use or paradoxical abdominal breathing when in respi-
ratory distress. However, increased fatigue can make it difficult for the
patient to adapt in this way, and so its absence can be falsely reassuring to
the medical team.
Not all respiratory failure is due to diaphragmic weakness for patients
with myasthenia gravis. For example, oropharyngeal muscle weakness can
result in dysphagia leading to aspiration or upper airway obstruction.
Bedside respiratory function tests can help quantify the degree of weak-
ness. Specifically, FVC and MIF can help guide the need for intubation.
Intubation can be considered for FVC less than 15–20 cc/kg (or <1 L),
MIF less than −25 cm H2O (where approximately −50 cm H2O is normal),
or for rapid worsening. While less precise, respiratory capacity can also be
assessed by asking the patient to count out loud as quickly as possible using
one breath—here, counting to at least 40 is reassuring. As this patient is un-
able to speak in full sentences, she will likely do very poorly with this test.
Importantly, while these patients should have pulse oximetry monitoring,
oxygen saturation can be falsely reassuring. In neuromuscular respiratory
weakness, hypercarbia often occurs before hypoxemia, and so serial blood
gases should be obtained.
This patient is clearly in a myasthenic crisis, which is a life-threatening
complication of myasthenia gravis marked by acute exacerbation of neuro-
muscular weakness resulting in respiratory failure. An estimated 10–20%

of patients with myasthenia gravis may experience at least one myasthenic
crisis; a similar number of patients may be first diagnosed with myasthenia
gravis during a crisis.
This patient’s examination is very concerning for all of the reasons just
stated. Intubation at this point should be considered given her hypercarbia
and poor respiratory function testing. While myasthenia gravis used to have
a high mortality, ICU management with mechanical ventilation has made
death from myasthenia gravis exceedingly rare.
The triggers for a myasthenic crisis are often physical stressors, such as an
infection, surgery, or pregnancy; the use of a medication that can exacerbate
myasthenia gravis; or the tapering of treatment.
On the differential for respiratory failure in someone with myasthenia
gravis is also cholinergic crisis, which is rare but can occur in patients taking
high doses of pyridostigmine, a cholinesterase inhibitor. Cholinergic crisis
can be distinguished from myasthenic crisis by the presence of pupillary
miosis, excessive salivation, and diarrhea, as well as muscle fasciculations
and cramps.
The management of a myasthenic crisis centers on respiratory support,
including elective intubation if necessary (with avoidance of neuromuscular
blocking agents), emergent use of IVIg or plasma exchange, and identifica-
tion and treatment of the trigger for the crisis. Plasma exchange is thought
to directly remove acetylcholine receptor (AChR) antibodies from circula-
tion, though AChR antibody titers do not correlate with disease severity or
improvement. IVIg can often be provided more expeditiously than plasma
exchange and does not carry the same bleeding risks. Rather, the risks as-
sociated with IVIg include thrombosis, volume overload, acute kidney in-
jury, and anaphylaxis, especially in those who are IgA deficient, and so it is
recommend to test immunoglobulin levels—but not delay treatment while
waiting for these results. Plasma exchange requires the placement of a spe-
cialized central line. Potential risks include hypocalcemia, hypotension, line
infection, and bleeding complications from the loss of fibrinogen, which
requires daily monitoring. Plasma exchange may take effect more quickly
than IVIg; however, there is limited data comparing these two treatments,
and there is no clear benefit of using one over the other with regard to
overall efficacy. Consult your individual hospital policy prior to IVIg or
plasma exchange use.
28. Myasthenic Crisis 165

Acutely, pyridostigmine is often held until respiratory function has
improved as it can increase secretion production.
There is some controversy around the use of glucocorticoids in patients
with myasthenia gravis. The initiation of high-dose glucocorticoids may
result in a worsening of myasthenic symptoms in approximately half of
patients, which may lead to respiratory failure in a minority of these patients.
An example of this is starting high-dose steroids for a chronic obstructive
pulmonary disease exacerbation in someone with myasthenia gravis, who
then develops worsening myasthenic symptoms. Importantly, exacerbation
of neuromuscular weakness is usually delayed, between 5 and 10 days fol-
lowing glucocorticoid initiation, and the effect can last for several days. It
is thought that the risk of worsening once IVIg or plasma exchange has
started is dramatically reduced. If a patient is intubated, then it is reason-
able to initiate high-dose glucocorticoids (e.g., prednisone 60–80 mg/d).
However, if the patient is experiencing worsened myasthenic symptoms but
is not intubated, the risk of high-dose glucocorticoids may be too great, in
which case a low dose can be tried with a very gradual up-titration. If a pa-
tient is started on steroids for an extended period of time, remember to also
start supplementation for vitamin D and calcium, as well as prophylaxis for
Pneumocystis jirovecii pneumonia and gastrointestinal ulcers.
Other immunomodulating, steroid- sparing treatments can be
considered, such as azathioprine and mycophenolate mofetil, but a clinical
response may take several months.
While rapid recognition and treatment has dramatically reduced mor-
tality from myasthenic crisis, prolonged ICU admissions and ventilator
days can result in significant morbidity. Providers should remain vigilant
for common complications such as infection, vascular complications—
including those from treatment— and cardiac complications, such as
arrhythmias. Rehabilitation services should be engaged as soon as feasible.

• Neuromuscular respiratory weakness is usually associated with

hypercarbia before hypoxemia.
• Triggers for a myasthenic crisis are often physical stressors,
such as an infection, surgery, or pregnancy; the use of a
medication that can exacerbate myasthenia gravis; or the
tapering of treatment.
• While rare, consider cholinergic crisis in patients taking high
doses of pyridostigmine who present with miosis, excessive
salivation, diarrhea, muscle fasciculations, and/or cramps.
• In myasthenic crisis, treatment with IVIg or plasma exchange
should begin emergently.
Further Reading
Gajdos P, Chevret S, Clair B, Tranchant C, Chastang C. Clinical trial of plasma
exchange and high-dose intravenous immunoglobulin in myasthenia gravis.
Myasthenia Gravis Clinical Study Group. Ann Neurol. 1997;41(6):789–796.
Gajdos P, Tranchant C, Clair B, et al. Treatment of myasthenia gravis exacerbation
with intravenous immunoglobulin: a randomized double-blind clinical trial. Arch
Neurol. 2005;62(11):1689–1693.
Gummi RR, Kukulka NA, Deroche CB, Govindarajan R. Factors associated with acute
exacerbations of myasthenia gravis. Muscle Nerve. 2019;60(6):693–699.
Sanders DB, Wolfe GI, Benatar M, et al. International consensus guidance
for management of myasthenia gravis: executive summary. Neurology.
2016;87(4):419–425.
28. Myasthenic Crisis 167

29 Encephalopathy and Seizure
After Transplant
A 35-year-old man with a history of hypertension
and end-stage renal disease status post kidney
transplant, on tacrolimus, mycophenolate, and
prednisone, presents to the ED after a witnessed
generalized tonic-clonic seizure. He received
midazolam 5 mg IM by paramedics. In the ED, he
is afebrile, blood pressure 200/100, heart rate 90.
He is postictal but following simple commands,
without clear focality to his exam. A nicardipine
drip is started. He is loaded with fosphenytoin 20
mg/kg IV. His labs show a leukocytosis to 13 and
normal electrolytes. Urine toxicology is negative.
His tacrolimus level is normal. His noncontrast
head CT does not reveal an acute process. He is
started on vancomycin, ceftriaxone, ampicillin,
and acyclovir at meningeal dosing. His lumbar
puncture (LP) has a normal opening pressure, a
WBC count of 2, RBC count of 5, protein 40, and
glucose 81. His EEG is mildly slow and without
epileptiform discharges.
What do you do now?
169
T here are several aspects of this case that should cause concern and
modify the differential diagnosis. One is that this patient recently un-
derwent a solid organ transplant and is taking several immunosuppressant
medications. He had a prodrome of feeling unwell prior to having a seizure.
Last, he was markedly hypertensive on arrival. Once he is stabilized, how do
you sort out what is going on?
First, his hypertension should be emergently corrected. In this patient,
given his calcineurin inhibitor use, hypertension may be a sign of poste-
rior reversible encephalopathy syndrome (PRES). PRES is a syndrome of
varying severities characterized by headache, confusion, visual symptoms,
and seizures with distinct neuroimaging findings often involving edema
of the white matter in the posterior regions of the brain (see Figure 29.1).
PRES is a misnomer as it is not always reversible, not always located in the
posterior part of the brain, and is not isolated to the white matter because
cortical signs and symptoms (e.g., seizure) can occur.
The underlying cause is not known but is likely due to endothelial dys-
function and cerebral autoregulation malfunction. It is associated with
several conditions, including the use of immunosuppressant medications,
eclampsia, and hypertension (see Box 29.1). Similar to PRES, reversible
cerebral vasoconstriction syndrome (RCVS) may also be due to malfunc-
tion of cerebral autoregulation and can be triggered by vasoactive drugs;
however, RCVS is characterized by evidence of arterial construction, unlike
PRES. While several medications are associated with the development of
PRES (Box 29.1), the development of PRES is largely idiosyncratic when it
comes to duration, dose, or drug level. In addition to treating hypertension
and seizure, discontinuation of the immunosuppressive therapy is usually
recommended.
To formulate a differential diagnosis, it can be helpful to identify the
type of transplantation (solid organ or hematopoietic cell), which organ if
a solid organ transplantation was performed, and the time lapsed from the
transplant itself.
Given he is immunosuppressed, he should undergo a noncontrast head
CT prior to his LP. This head CT will help identify cerebral edema or any
unexpected mass lesion. Solid organ transplantation recipients are at risk for
infection, so an LP is crucial here if safe to perform.

(a)
(b)
FIGURE 29.1 MRI of the brain showing parieto-occipital and posterior fossa vasogenic edema
preferentially involving the white matter concerning for posterior reversible encephalopathy
syndrome, shown on axial (a) and sagittal (b) views.
BOX 29.1 Nonexhaustive list of medications and medical conditions
associated with posterior reversible encephalopathy syndrome (PRES)
Medications
- Calcineurin inhibitors: Tacrolimus, sirolimus, cyclosporine
- VEGF inhibitors: Bevacizumab
- Platinum-based agents: Cisplatin
- Tyrosine kinase inhibitors: Sorafenib
- Methotrexate
- Rituximab
- Iodine contrast
Medical conditions
- Hypertension
- Kidney disease
- Preeclampsia/eclampsia
- Transplantation
- Hematologic: Hemolytic uremic syndrome, thrombotic
thrombocytopenic purpura
- Vasculitis
- Sepsis
- Excessive licorice consumption (leading to hypertension)
During the first month post-transplant, these infections are often from
the hospital environment or from the organ itself if the donor had an in-
fection. After discharge, these patients remain at high risk for infection.
These infections represent a wide range of pathogens, including bacteria
such as Nocardia, Listeria, and Mycobacterium tuberculosis; fungi, including
Cryptococcus neoformans and Aspergillus species; viruses, including the varied
herpesviruses; and the parasite Toxoplasma gondii. Particular to this case,
herpesviruses are more often associated with seizure, especially human
herpesviruses 1, 2, and 6.

More than 6 months post- transplant, additional infections should
be considered. JC virus targets oligodendrocytes and causes progressive
multifocal leukoencephalopathy (PML), a complication with high mor-
tality. Epstein- Barr (EBV)- associated diseases include post- transplant
lymphoproliferative disorder. For this reason, it is important to check JC
virus DNA PCR, cytology, and flow cytometry in CSF, in addition to
obtaining an opening pressure.
MRI brain with and without contrast is warranted after the patient is
stabilized. The MRI can provide more detailed information on patterns of
edema or enhancement, which is important for framing the differential and
trending over time.
There are several other conditions to keep in mind. In addition to
chemotherapeutic medications, toxic leukoencephalopathies can occur from
a variety of compounds, including amphetamines, opiates such as heroin
and fentanyl, and carbon monoxide. Delayed leukoencephalopathies can
be seen with radiation and anoxia. Cerebrovascular disorders may mimic
these clinical and radiographic findings, including ischemic arterial and
venous strokes. Malignancies in addition to lymphoma, such as carcino-
matous meningitis and astrocytoma, can be considered. Immune-mediated
demyelinating syndromes are more often seen in the peripheral nervous
system but can also be found centrally.
In this case, PRES is a likely diagnosis. Those who develop seizures in the
setting of PRES are unlikely to develop unprovoked seizures in the long-
term. Antiepileptics can likely be weaned in the subsequent months pro-
vided that seizure precipitants, including hypertension, are avoided.
The prognosis of patients with PRES is overall favorable, especially if
a precipitant is identified and treated. However, it is important to keep in
mind that serious morbidity and even mortality can occur from cerebral
edema. For example, cerebral edema can lead to hydrocephalus or other
cerebrovascular complications, such as stroke. For these reasons, it is impor-
tant to remain vigilant for this entity and not assume a guaranteed benign
“reversible” course.
29. Encephalopathy and Seizure After Transplant 173

• PRES can be caused by several medications used post-

transplant, especially calcineurin inhibitors such as tacrolimus
and cyclosporine, and it is not always associated with a
supratherapeutic drug level.
• PRES can occur at any point post-transplant, and symptoms
can vary.
• Transplant recipients are at high risk for infection, and the
specific risk changes over time.
• PRES may result in marked cerebral edema leading to
hydrocephalus and stroke acutely, and so vigilance for these
complications is paramount.
Further Reading
Datar S, Singh T, Rabinstein AA, Fugate JE, Hocker S. Long-term risk of seizures
and epilepsy in patients with posterior reversible encephalopathy syndrome.
Epilepsia. 2015;56(4):564–568.
Fugate JE, Rabinstein AA. Posterior reversible encephalopathy syndrome: clinical
and radiological manifestations, pathophysiology, and outstanding questions.
Lancet Neurol. 2015;14(9):914–925.
Kumar Y, Drumsta D, Mangla M, et al. Toxins in brain! Magnetic resonance (MR)
imaging of toxic leukoencephalopathy—a pictorial essay. Pol J Radiol.
2017;82:311–319.
Pruitt AA, Graus F, Rosenfeld MR. Neurological complications of solid organ
transplantation. Neurohospitalist. 2013;3(3):152–166.

30 Nonepileptic Spells
A 28-year-old woman is brought to the ED
after a series of “fits” manifested by bilateral
forceful lower extremity shaking movements
and loud verbal outbursts. A friend is with her
and states this has happened in the past “when
doctors changed her epilepsy medicine.” While
you are examining her, she has another spell
with head turning from side to side, cursing,
singing, and bilateral intermittent asynchronous
leg shaking. There is no incontinence, and after
about 3 minutes the patient stops shaking,
looks at you and asks “Did I do it again?” She
is able to converse well but is agitated. Vital
signs are normal. She has several small areas
of ecchymosis. She moves all extremities well
but is a bit dysarthric. General and neurological
exams are otherwise normal.
What do you do now?
175
T his patient’s ictal behavior is decidedly inconsistent with epileptic
seizures: maintenance of consciousness despite bilateral clonic limb
movements, immediate return to full interactive communication after the
event, singing, etc. However, before diagnosing nonepileptic spells, certain
key steps must be taken. Fortunately, most medical systems have ways to
share medical records electronically or at least quickly, and, for this patient,
one suspects that these will be revealing of pertinent history. Metabolic
screening as well as drug screening should be done, and if there are any
neurological deficits, CT of the head should rule out significant intracra-
nial pathology. Here the dysarthria may qualify as a neurologic sign so CT
is probably indicated. Unfortunately, EEG is not particularly helpful unless
another spell happens during recording. This patient apparently carries a
diagnosis of epilepsy, and it is essential to control breakthrough seizures if
they are occurring.
Seizures like this patient exhibits are best termed psychogenic nonepileptic
seizures (PNES) to distinguish them from “organic” nonepileptic seizures,
which refers to conditions like migraine, movement disorders, syncope, and
transient ischemic attacks (TIAs) which can mimic epilepsy. PNESs are
more common than was once thought, although prevalence is difficult to
measure. The condition arises from psychological causes including conver-
sion disorder, factitious disorder, and dissociative disorders. They are often
seen in people who have suffered abuse or trauma. People with PNES are
usually initially misdiagnosed as having epilepsy, and since it is hard to re-
verse that diagnosis, correct identification often takes years. Nonepileptic
spells are not uncommon in patients with epilepsy (a meta-analysis of ob-
servational studies found that approximately 22% of patients with PNES
had comorbid epilepsy, and approximately 12% of patients with epilepsy
had PNES), making the evaluation even more challenging.
Often PNESs manifest with behavior unusual in epileptic seizures, such
as asynchronous limb shaking, laughing, crying, arching of the back, and
awareness of surroundings despite apparent bilateral cerebral discharges.
Self-injury, like tongue biting, which is common in epileptic generalized
motor seizures, is less common, as is incontinence. Triggers for PNES
spells tend to be emotional or situational, and they usually occur in the
presence of others. There is often a history of refractoriness to anticon-
vulsant medications, leading to frequent medication changes. There is also

commonly a history of posttraumatic stress disorder (PTSD) and childhood
sexual and physical abuse.
Diagnosis of PNES rests on video-EEG monitoring which is nearly al-
ways successful (if a spell is observed) in differentiating it from frontal lobe
epilepsy and complex partial seizures which may resemble the behavioral
manifestations of PNES. If this service is unavailable at your institution,
it is important to refer your patient to an epilepsy center that can provide
that. Once the diagnosis of PNES is made, the process of communicating
this to the patient and designing a treatment program begins. This should
be done in a nonjudgmental fashion, framed in a way that does not suggest
that the patient is malingering, since this is usually not the case. Cognitive-
behavioral therapy is reported to be helpful. Selective serotonin reuptake
inhibitor (SSRI) antidepressants have been shown to be helpful in some
patients as well.
When a patient with a known diagnosis of PNES is seen in the ED fol-
lowing a spell or series of spells, the approach can still be problematic. There
are often mixed feelings on the part of the patient’s medical care providers
about the diagnosis, and more often than not, antiepileptic medication has
been continued “just in case.” This does nothing but confuse the patient
and family, and it then falls to the medical team in the ED to try to make
some progress toward appropriate treatment. Again, approaching the diag-
nosis in a nonaccusatory way is essential in order to make any real progress.
Psychiatric consultation should be sought, and obtaining previous video-
EEG data can be very useful as well. It is important to avoid repetition of
diagnostic testing and escalation of antiepileptic medication.
• The diagnosis of PNES is challenging, and patients may be

misdiagnosed with epilepsy for years.
• Clues to the diagnosis of PNES can be found in the ictal
presentation, as well as in the patient’s description of triggers.
• Video-EEG monitoring is generally successful in distinguishing
PNES from epilepsy.
• Communicating the diagnosis to the patient must be done in a
clear and consistent but nonaccusatory way.
30. Nonepileptic Spells 177

Further Reading
Avbersek A, Sisodiya S. Does the primary literature provide support for clinical signs
used to distinguish psychogenic nonepileptic seizures from epileptic seizures? J
Neurol Neurosurg Psychiatry 2010;81:719–725.
Brown RJ, Reuber M. Towards an integrative theory of psychogenic non-epileptic
seizures (PNES). Clin Psychol Rev. 2016;47:55–70.
Carlson P, Perry KN. Psychological interventions for psychogenic non-epileptic
seizures: a meta-analysis. Seizure. 2017;45:142–150.
Carton S, Thompson PJ, Duncan JS. Non-epileptic seizures: patients’
understanding and reaction to the diagnosis and impact on outcome. Seizure.
2003;12(5):287–294.
Kutlubaev MA, Xu Y, Hackett ML, Stone J. Dual diagnosis of epilepsy and
psychogenic nonepileptic seizures: systematic review and meta-analysis of
frequency, correlates, and outcomes. Epilepsy Behav. 2018;89:70–78.
LaFrance WC Jr, Baird GL, et al. Multicenter pilot treatment trial for psychogenic
nonepileptic seizures: a randomized clinical trial. JAMA Psychiatry.
2014;71(9):997–1005.
Reuber M, Fernandez G, Bauer J, et al. Diagnostic delay in psychogenic nonepileptic
seizures. Neurology. 2002;58(3):493–495.

31 Migraine in a Pregnant
Patient
A 26-week pregnant 30-year-old woman with a
long history of migraines is seen in the ED with
2 days of unrelenting diffuse severe headache
pain that came on gradually. The accompanying
nausea has led to incessant vomiting—“there
is nothing left to throw up” she tells the ED
physician. She also describes lightheadedness
and blurred vision but no other neurological
symptoms. She has not had auras. Her
examination is normal, although she is clearly
fatigued. She is taking only perinatal vitamins.
What do you do now?
179
M any women with migraine experience improvement and even re-
mission in their headaches during pregnancy by the time of their
second trimester. This tends to be even more likely in women with
menstrually related migraine attacks. But there are still many women
who experience the opposite trend, with recurring, disabling head pain
and nausea during pregnancy. The first decision in this type of case, of
course, is how seriously to workup the changes in her migraine symptoms,
primarily, the intensity of pain and nausea. Gestational hypertension and
preeclampsia must be ruled out, of course. Of note, there is some evi-
dence that eclampsia occurs more often and earlier in pregnancy in women
with migraine. Elevated blood pressure, proteinuria, and elevated hepatic
enzymes (seen in HELLP syndrome along with anemia and thrombocy-
topenia) are diagnostic. Meningitis or encephalitis are considered with
meningismus, altered mental state, fever, or leukocytosis. Without focal
neurological deficits, an intracranial mass, inflammatory, or infectious
process is unlikely. Cerebral venous thrombosis and idiopathic intracra-
nial hypertension (IIH) are, however, possible, and if clinical suspicion is
high or if there are even subtle neurological findings on exam (optic disc
swelling, dysconjugate gaze, mild mental status alteration, etc.), a head
MRI, MR venogram, and lumbar puncture (LP) would be indicated. The
poorly understood syndrome of “postpartum angiopathy,” also known as
the reversible cerebral vasoconstriction syndrome (RCVS), could be possible
here, which would require imaging of the cerebral vessels and can be ac-
complished with CT angiogram or MR angiogram time-of-flight, as gad-
olinium should be avoided during pregnancy. However, RCVS tends to be
limited to the puerperium or late pregnancy and tends to include recurrent
thunderclap (sudden) headaches and sometimes focal neurological deficits,
none of which is present in this case. Pituitary hemorrhage tends to present
with sudden headache and visual acuity and field deficits, but history can
be vague, and, contrary to previous belief, this is not necessarily limited to
the peripartum period (a case series and literature review by Grandmaison
in 2015 found the median gestational age was in fact 24 weeks). To rule
this out, CT or MRI might be best.
Once secondary causes of acute severe headache are excluded, status
migrainosus is the most likely diagnosis here and constitutes an urgent
management need. If vomiting has led to dehydration, intravenous

rehydration must be done, ideally with a bolus of normal saline to avoid
fetal compromise. While neuroleptic antinauseants are not known to be
safe in pregnancy, it is common practice to use metoclopramide 10 mg,
promethazine 25 mg, or prochlorperazine 10 mg intravenously. These
have the added benefit of reducing headache pain as well as nausea in
many cases. This class of medication can, of course, lead to dystonia or ak-
athisia, appearing generally within minutes after administration. Infusing
diphenhydramine (generally considered safe in pregnancy) 25 mg IV at
least 15 minutes prior to antinauseant use can help to prevent the dystonia,
although it is less effective in akathisa.
Even without preeclampsia, magnesium infusion can be very helpful as
magnesium sulfate at a dose of 1 g slow IV push or dissolved in normal
saline. However, magnesium should be used sparingly as it may increase
the risk of fetal osteopenia. On occasion greater occipital nerve blocks, gen-
erally done bilaterally, can be very helpful for acute migraine, and trigger
point injections can be useful as well, although evidence is lacking for these
interventions. Massage and ice application to the head and neck can be
surprisingly helpful, and, after nausea is controlled, these may suffice along
with rest. But more intensive pharmacotherapy is often needed.
Medication choices in pregnancy are limited. There are some data about
drug safety in pregnancy, but sources of information differ. The US Food
and Drug Administration (FDA) has in the past provided a listing of relative
safety, using five categories A, B, C, D, and X (see Box 31.1). Unfortunately,
very few drugs are in the “safer” categories (A and B) and many drugs
are not rated. Another rating system, the Teratogen Information Service
(TERIS) of the University of Washington also provides risk categories for
many drugs from “no risk” to “high risk.” Unfortunately, many drugs are
rated “undetermined” or “unlikely.” And the FDA and TERIS ratings often
do not concur.
Acetaminophen is in the FDA category B, and, used intravenously in
a dose of 1,000 mg, it can be surprisingly effective even in cases where
oral acetaminophen has been ineffective. Non-steroidal anti-inflammatory
medications are probably best avoided as there is some evidence of fetal risk
in the first and third trimesters. The use of parenteral opioids is controver-
sial. The only opioids which are in category B are oxycodone, butorphanol,
meperidine, and morphine. Morphine is preferred; it has been observed,
31. Migraine in a Pregnant Patient 181

BOX 31.1 US Food and Drug Administration (FDA) pregnancy
risk categories
Category A: Controlled human studies indicate no apparent risk to

fetus. The possibility of harm to the fetus appears remote.
Category B: Either animal studies do not indicate a fetal risk or
animal studies do indicate a teratogenic risk, but well-controlled
human studies have failed to demonstrate the same risk.
Category C: Studies indicate teratogenic or embryocidal risks in
animals, but no controlled studies have been done in women, or
there are no controlled studies in animals or humans.
Category D: Positive evidence of human fetal risk, but in certain
circumstances, the benefits of the drug may outweigh the risk
involved.
Category X: Positive evidence of significant fetal risk, and the risk
clearly outweighs any possible benefit.
however, that after responding to opioid medication, migraine tends to

recur (see Table 31.1 and Box 31.2).
Triptans, particularly sumatriptan, seem to be safe during pregnancy
based on pregnancy registry data, although it is not known with certainty,
and all are category C. Most headache specialists advocate occasional use
of sumatriptan, and in the 6 mg subcutaneous form it can be highly ef-
fective even in status migrainosus. Ergots, including ergotamine and
dihydroergotamine are Category X, due to their effects on implantation of
the embryo, uterine blood flow, and fetal development as well as their ten-
dency to produce uterine contractions.
Of the antiemetics, metoclopramide is in category B; prochlorpera-
zine and promethazine are in category C, but all have been used when
nausea and vomiting lead to dehydration and/or metabolic imbalances in
pregnant women.
Corticosteroid use in pregnancy has been linked to premature birth and
low birth weight, and corticosteroids are Category C. In the ED setting,

TABLE 31.1 Selected medications for acute migraine commonly used
in pregnancy
Medication FDA category TERIS risk rating
Acetaminophen B (oral), C (IV) No risk
Ibuprofen B (D in 3rd trimester) Minimal
Naproxen B (D in 3rd trimester) Undetermined
Ketorolac D
Hydromorphone C
Morphine C
Magnesium sulfate IV B (limited to 5 days to Unlikely

avoid fetal osteopenia)
Metoclopramide B Unlikely
Prednisone C in 1st trimester; less Minimal

clear in 2nd/3rd
trimesters
Promethazine C None
Prochlorperazine C None
Chlorpromazine C None
methylprednisolone 1 g IV can eventually help break a long-lasting mi-

graine and help to prevent recurrence.
After the headache is controlled, it is worth thinking about prophy-
laxis in order to prevent recurrence. Agents such as beta blockers, calcium
channel blockers, and cyclic antidepressants are all Category C agents (ex-
cept for atenolol which is Category D) and may not even be that effec-
tive at preventing migraine during pregnancy. Topiramate is in Category
D. A number of medications used to treat migraine can alter folate metab-
olism so supplementing with 0.4 mg/d folate is advisable when using daily
medications.

BOX 31.2 A stepwise approach to the pregnant patient with acute
severe headache
1. Vital signs, IV hydration, thorough general and neurological exam

including careful mental status and funduscopic exam; CBC,
complete chemistry panel, urinalysis including toxic screen. Try to
create a quiet, dark environment, use cold application and massage
if possible.
2. If HA is new to patient, recent trauma, vital signs are abnormal,
neurological exam is in any way abnormal (or cannot be
completed) or meningismus is present, rule out intracranial
hemorrhage, intracranial hypertension, cerebral venous
thrombosis, infection, and RCVS, with all of the appropriate
following testing: CT or MRI (and perhaps CT or MR
angiography), and lumbar puncture.
3. If workup complete and reassuring, assume migraine, and treat
with diphenhydramine 25 mg IV followed by metoclopramide
10 mg IV.
4. Magnesium sulfate 1 g to be repeated up to 3 more times every 30
min, with cardiac monitoring.
5. Consider IV acetaminophen 1,000 mg IV, sumatriptan 6 mg
subcutaneously, or morphine 1–2 mg IV which can be repeated.
6. Methylprednisolone 1 g IV.
• While migraines improve during pregnancy for most women,

there are many cases of the opposite, sometimes accompanied
by severe nausea and vomiting.
• Suspicion for secondary cause of headaches such as cerebral
venous thrombosis, RCVS, and hemorrhage should be high with
any change in headache pattern, although most headaches will
be benign.

• Nonpharmacological therapy such as massage, local application
of cold, and rest in a quiet dark place can help, particularly after
nausea and dehydration are corrected.
• Pharmaceutical treatment of pain is indicated in severe cases
and can include parenteral magnesium, acetaminophen, and
opioids used cautiously.
Further Reading
Ayer R, Schmutz T, Guechi Y, Ribordy V. Headaches in pregnancy: management in the
emergency department. Revue medicale suisse. 2018;14:1405–1407.
Briggs GB, Freeman RK, Towers CV, Forinash AB. Drugs in Pregnancy and
Lactation: A Reference Guide to Fetal and Neonatal Risk (11th ed.). New York:
Lippincott Williams & Wilkins; 2017.
Sandoe CH, Lay C. Secondary headaches during pregnancy: when to worry. Curr
NeurolNeurosci Rep. 2019;19(6):27.

SECTION 3
Pediatric Dilemmas
32 Acute Migraine in a Child
A 25 kg 9-year-old boy with recurrent migraine
headaches awoke with a particularly severe
headache this morning. He has been vomiting
all morning and has been unresponsive to
oral analgesics and antiemetics. In the ED, IV
ketorolac has been only minimally helpful.
IV prochlorperazine has helped the nausea,
but severe headache persists. General and
neurological exams are normal. CT has not been
done in order to avoid exposure to radiation.
What do you do now?
189
T his boy seems to have a typical case of migraine, which is not un-
common (before puberty, male and female prevalence of migraine
is roughly equal), but the intense severity is unusual. The unremitting
vomiting and intractability of the pain is also a bit unusual but not unheard
of. A thorough neurological examination, including comprehensive mental
status exam, should be performed to make sure there really is no focal def-
icit. If this is normal, then a CT scan is probably not necessary. An MRI
may be worthwhile at some point to exclude an intracranial mass, arteri-
ovenous malformation, or congenital cranial malformations. The general
examination should focus on evidence of trauma, accidental or inflicted, as
well as any signs of infection or general medical issues. Meningismus should
be carefully looked for. It is important to check basic metabolic function
regarding electrolyte balance (especially given the persistent vomiting), glu-
cose level, blood counts, and hepatic and renal function. Ruling out infec-
tion is crucial since urinary, pulmonary, ear, and other infections can induce
severe migraine.
A good first step in treating this boy is to make sure to replace lost fluids
intravenously. This will provide the added benefit of IV access for poten-
tially useful pain-and nausea-relieving medications. Other than the neuro-
leptic/antiemetics, medications that might be useful for the nausea include
ondansetron and hydroxyzine. Ondansetron is available as a sublingual 4
mg or 8 mg wafer that children often tolerate well, although it is not known
to be entirely safe in this patient’s age group. The dose is in the 0.15 mg/
kg range, so 4 mg would be just right. Hydroxyzine is an antihistaminic
which has both antiemetic and analgesic, as well as anxiolytic properties,
and it can be given orally or intravenously in a dosage of approximately
0.25–0.5 mg/kg.
Other than acetaminophen and ibuprofen, there is very little evidence
of safety or efficacy of any acute antimigraine medication. Sumatriptan
and rizatriptan oral tablets and zolmitriptan nasal spray have been studied
in children and seem to be safe and effective. Adverse effects are gener-
ally mild but can include taste disturbance, nasal congestion, dizziness,
fatigue, low energy, nausea, or vomiting. Subcutaneous sumatriptan has
been used successfully in adolescents and children, and there are now lower
dose sumatriptan cartridges—3 mg and 4 mg—which would be appro-
priate for larger children and adolescents. While ergots are not known to
190 WHAT DO I DO NOW? Section 3: Pediatric Dilemmas

be safe in children, dihydroergotamine (DHE) in a dose of approximately
0.25 mg IV for preteens and 0.5–1.0 mg for teens has been used success-
fully. An antinauseant should be used along with DHE since it can be quite
nauseating.
Most children and adolescents will find that the migraine resolves after
sleep. Most of the antinauseants have some soporific effects, which can be
an added benefit. Good choices include promethazine 0.5–1 mg/kg orally
or rectally, or prochlorperazine 0.15 mg/kg in parenteral, rectal, or oral
forms. It is important to remember that dyskinesia can occur; pretreatment
with diphenhydramine tends to prevent this. Akathisia is also possible and
tends to respond to low doses of parenteral benzodiazepines.
Hydroxyzine likewise has a sedative and analgesic effect; it can be useful
in a dose of 0.5–1 mg/kg in oral or parenteral routes. In rare cases, when
none of these seems to work, deeper sedation and analgesia may be needed,
which can be achieved with barbiturates or opioids. If this approach is nec-
essary, it should probably be done on an inpatient basis so that the patient
can be observed carefully.
Most children with severe migraine are to some extent scared or nervous
about the intensity of the acute experiences. A quiet, dark room is essen-
tial for acute treatment to be most effective. Reassurance is essential. More
formal counseling can help, and this also opens the door for subsequent
family counseling that could help to reduce triggers and defuse some of the
drama for all family members that can escalate during the acute attacks.
Medication overuse must be screened for. If headaches are frequent, lead to
frequent ED visits, or lead to missed social or family events, the use of pre-
ventive measures must be considered—and probably a referral to a pediatric
neurologist/headache specialist is warranted.
• With severe migraine in a child, secondary causes must be ruled

out including neurological infections, intracranial mass, and
systemic metabolic or infectious disease.
• There is little evidence to aid in choosing agents for acute
migraine treatment in children.
32. Acute Migraine in a Child 191

• Triptans can be very effective, as can antinauseants and
sedatives.
• Most children with severe recurrent migraine headaches
find them to be emotionally stressful and may benefit from
counseling.
Further Reading
Lewis D, Ashwal S, Hershey A, Hirtz D, Yonker M, Silberstein S. Pharamacological
treatment of migraine headache in children and adolescents: Report of
the American Academy of Neurology Quality Standards Subcommittee
and the Practice Committee of the Child Neurology Society. Neurology.
2004;63:2215–2224.
Linder SL. Subcutaneous sumatriptan in the clinical setting: the first 50 consecutive
patients with acute migraine in a pediatric neurology office practice. Headache.
1996;36(7):419–422.
Oskoui M, Pringsheim T, Holler-Managan Y, et al. Practice guideline update
summary: Acute treatment of migraine in children and adolescents: report of
the Guideline Development, Dissemination, and Implementation Subcommittee
of the American Academy of Neurology and the American Headache Society.
Neurology. 2019;93(11):487–499.
Patniyot IR, Gelfand AA. Acute treatment therapies for pediatric migraine: a
qualitative systematic review. Headache. 2016;56(1):49–70.
Richer LP, Laycock K, Millar K, et al. Treatment of children with migraine in emergency
departments: national practice variation study. Pediatrics. 2010;126:e150–e155.

33 Febrile Seizure
A 3-year-old girl is brought to the ED after having
a generalized seizure in her sleep witnessed by
her mother who is a nurse. She describes diffuse
body stiffening, followed by generalized limb
shaking. The mother relates that her daughter
seemed to stop breathing and looked “cyanotic.”
The seizure lasted approximately 15 minutes
and was followed by mild somnolence which
has persisted now for 1 hour. She recently had
a gastrointestinal viral syndrome with diarrhea
and vomiting, accompanied by fever up to 103oF,
but she has only had “at most” a mild fever
over the past 12 hours, according to the mother.
Now rectal temperature is 100.5oF, the child is
breathing regularly at 12 breaths per minute,
and pulse is 82. She is arousable but sleepy.
She moves all extremities, and there are normal
reflexes.
What do you do now?
193
B enign febrile seizures generally occur in children between 3 months
and 5 years of age. The mechanism is unknown, but predisposing
genetic factors have been postulated because different genetic strains in
animal models have required different temperature thresholds for sei-
zure production. Fever generally needs to be above 102oF in children.
The annual incidence is probably between 5% and 10%. These seizures
are usually single, generalized, and last less than 15 minutes. The child
should be otherwise neurologically healthy and without neurological ab-
normality by examination or by developmental history. If there is any
focality to the seizure, if it is prolonged, or if there are any focal neu-
rological findings on exam, this does not qualify as a “simple febrile sei-
zure” (see Box 33.1).
In this case there are a couple of features that are a bit unsettling.
First, the seizure was rather prolonged. Fifteen minutes is still within the
“simple” febrile seizure window, but it was at the upper limit. The mother
should be a good historian as she is a nurse, but parents may overestimate
the duration of seizures, so the actual duration may have been shorter.
This child may or may not have been febrile at the time, although this is
not clear. But most importantly, she is not returning to completely normal
consciousness. This could be explained, however, by the time of night,
falling in the middle of her normal sleep cycle. The cyanosis is actually
not that uncommon, with some children seemingly becoming apneic for
a short time.
BOX 33.1 Features of “simple” febrile seizures
Febrile at the time of the seizure

Single seizure
Age between 3 months and 5 years
Generalized without evidence of focality
Duration less than 15 minutes
Normal neurological exam
Normal developmental history

The most important question to ask is whether this seizure could be
due to meningitis or encephalitis. Lumbar puncture (LP), while not usually
necessary for simple febrile seizures, would not be a bad idea here. There is
scant risk of causing brain herniation with a nonfocal neurological exam,
but CT of the head could be done to rule out a mass. Since serum glucose
will be drawn to compare with CSF glucose, adding electrolytes, calcium,
and perhaps magnesium and a CBC is probably worth doing even though
this is generally not necessary in patients with benign febrile seizures. LP is
particularly worthwhile in infants between 6 and 12 months of age who pre-
sent with a seizure and fever who have not received the usual Haemophilus
influenzae or Streptococcus pneumoniae immunizations.
Once CNS infection is ruled out, it might be worthwhile searching fur-
ther for a structural cause for the seizure. However, when febrile seizures do
not recur, and if the patient fully awakens with no residual deficits, MRI
scanning of the brain is not considered necessary. EEG might provide some
evidence of an epileptic focus in a few patients with febrile seizures, but it is
probably not indicated for this patient. If she awakens fully, CSF is normal,
and no abnormalities are seen on the basic blood testing, there is also no
reason to admit her to the hospital.
Finally, the questions of future seizure risk and the need for prophylactic
treatment generally arises. Patients with simple febrile seizures have only a
slightly higher risk of recurrent seizures (unless they again occur during a
fever in the right age range) than any other person. Children with “complex
febrile seizures” (not fulfilling the requirements for simple febrile seizures)
are much more likely to have epilepsy later, probably in the 80% range.
Since this patient essentially falls within the benign febrile seizure group,
she should not have a significantly increased risk of seizure occurrence.
Prophylaxis with antiepileptic medication is generally not recommended
for children who have single febrile seizures since the benefit is low and
there are significant side effects to all antiepileptic medications, particularly
cognitive slowing. If the parent’s concern is high, EEG can be helpful in
identifying any potential seizure focus which might suggest prophylactic
treatment.
33. Febrile Seizure 195

• Simple febrile seizures generally do not require lab

investigation.
• If there is any suspicion of meningitis or encephalitis, LP should
be strongly considered.
• Focal seizure activity, prolonged duration of the seizure
(>15 minutes), multiple seizures, older age (>5 years old), or
abnormal neurological exam should prompt a more careful
investigation.
• Prophylaxis is not indicated for single simple febrile seizures.
Further Reading
American Academy of Pediatrics Subcommittee on Febrile Seizures. Febrile
seizures: guideline for the neurodiagnostic evaluation of the child with a simple
febrile seizure: clinical practice guideline. Pediatrics. 2011;127:389–394.
Natsume J, Hamano SI, Iyoda K, et al. New guidelines for management of febrile
seizures in Japan. Brain Dev. 2017;39(1):2–9.
Smith DK, Sadler KP, Benedum M. Febrile seizures: risks, evaluation, and prognosis.
Am Fam Phys. 2019;99(7):445–450.

34 Acute Ataxia in a Child
A 7-year-old girl is brought to the ER by her
mother because of gait difficulty. She had been
well until yesterday, when she began stumbling
while walking; when she tried to play soccer
with her friend, she kept falling. She has no
other symptoms and general exam is normal
with blood pressure 90/60, pulse regular at 76,
respirations 14, and temperature of 98oF. Birth
and past medical history are unremarkable, and
there is no family history of neurological disease.
On neurological exam, mental status is intact.
Cranial nerves are normal except for sustained,
direction-changing horizontal nystagmus and
mild dysarthria that the mother and child
also appreciate. Motor tone and strength are
intact, as is sensation. Reflexes are present and
symmetrical. She has difficulty with gait, truncal
instability, and incoordination of limbs. CT of the
head is entirely normal.
What do you do now?
197
T he examination is primarily concerning for a process affecting the
cerebellum and is notable for both axial and appendicular ataxia.
Differential diagnosis of the acute cerebellar syndrome in children (Box
34.1) includes structural lesions and infectious or postinfectious etiologies,
as well as toxic and metabolic causes.
Structural causes include tumors such as cerebellar astrocytoma or
medulloblastoma, ischemic stroke (such as secondary to a vertebral artery
dissection), or hemorrhage. For this reason, it is important to inquire about
recent head or neck trauma. CT scan of the head should rule most of these,
but MRI with contrast is the preferred imaging test. Vessel imaging of the
BOX 34.1 Causes of acute childhood ataxia
Structural
Brain tumor
Head trauma
Cerebellar ischemic stroke
Cerebellar hemorrhagic stroke
Vertebrobasilar dissection
Cerebellar abscess
Infectious
Meningitis or encephalitis
Cerebellar abscess
Labyrinthitis
Postinfectious or autoimmune
Acute cerebellar ataxia syndrome
Miller Fisher syndrome
Acute disseminated encephalomyelitis
Opsoclonus/myoclonus syndrome
Toxic
Alcohol
Other drugs of abuse
Antiepileptic toxicity, especially phenytoin
Metabolic
Inborn error of metabolism

head and neck should be obtained if a vascular cause is likely. A posterior
fossa mass seems unlikely in this case given the acute nature of this presen-
tation, but a stroke or a mass that bleeds can definitely present acutely.
An abscess is an infectious lesion that can present acutely. Meningitis
and encephalitis must also be considered as these are associated with high
morbidity and mortality, and so CSF should be obtained if there is con-
cern for infection. Cerebellar inflammation (cerebellitis) from an infectious
cause includes Listeria monocytogenes, Lyme disease, Epstein-Barr virus, var-
icella zoster virus and Coxsackie virus. Treatment and recovery depend on
the isolated pathogen. Acute disseminated encephalomyelitis (ADEM) is a
rare cause of ataxia that can also occur following an infection. In addition
to cerebellar ataxia, ADEM may also be associated with multifocal neu-
rological deficits, seizures, or altered mental status. MRI in ADEM should
be abnormal, and CSF will often have a pleocytosis and elevated protein.
It is important to keep in mind that cerebellar edema or a space-occupying
lesion in the posterior fossa is a neurologic emergency. Depending on the
cause, treatment may include steroids and/or surgical decompression. An
external ventricular drain (EVD) must be carefully considered because a
supratentorial EVD placement without infratentorial decompression can
result in upward herniation.
Accidental ingestion of medication such as anticonvulsants can lead to
ataxia, and some detective work along these lines might be fruitful. Toxins
such as ethanol or illicit drugs can also lead to cerebellar dysfunction and
must be excluded with toxicology studies. While this patient does not have
the typical back pain and lower extremity weakness seen in spinal cord
lesions like discitis, myelopathy with sensory and/or motor dysfunction
should be kept in mind as a cause of ataxia, though this would not explain
the bulbar symptoms.
Miller Fisher syndrome, a variant of Guillain-Barré syndrome, may pre-
sent with acute cerebellar symptoms and signs but is often accompanied
by hyporeflexia and ophthalmoplegia. Opsoclonus/myoclonus syndrome
is another possibility, also known as “dancing eyes-dancing feet.” This is
a paraneoplastic autoimmune disorder seen in children with neuroblas-
toma and manifests as migratory myoclonic jerks as dramatic jumping eye
movements (opsoclonus) and ataxia. This patient did have mild nystagmus
but did not have the prerequisite opsoclonic movements or myoclonic
34. Acute Ataxia in a  Child 199

jerks. Acute labyrinthitis can lead to the appearance of ataxia, and children
might not be able to explain that their balance/gait difficulties stem from
vertigo rather than imbalance. However, nausea is usually preeminent, and
children are generally quite distressed with vertigo. Posttraumatic vertigo
may also be considered, and so inquiring about recent head trauma, even
mild, can be helpful.
When other more ominous possibilities are ruled out, acute cerebellar
ataxia syndrome, which is largely postinfectious, is likely. This has been
observed following a number of infections including varicella, Epstein-Barr
virus, mycoplasma, enterovirus, roseola, rubeola, and parvovirus. The syn-
drome is generally seen in children between 2 and 7 years old but has been
reported in older children and adults. It accounts for approximately 40–
50% of the cases of acute ataxia in children. The mechanism is presumably
immune-mediated cerebellar inflammation, and there have also been cases
of acute ataxia in children who have recently had vaccinations. Other than
truncal and limb ataxia with gait difficulty, there are generally no other
accompanying symptoms. Some children have nystagmus, as did this child.
While often a benign, monophasic illness, it is important to remember
that postinfectious cerebellitis can be complicated by significant cerebellar
edema. For this reason, brain imaging should be pursued in any ataxic pa-
tient, and lumbar puncture (LP) should also be considered, especially if the
patient also presents with altered mental status, asymmetric or progressive
neurologic deficits, or headache.
• Acute childhood ataxia is often due to a benign self-limited

postinfectious condition.
• Accurate history is important to assure that the ataxia is acute
rather than gradually progressive and to rule out accidental
ingestions and accompanying symptoms.
• Workup of acute ataxia in a child should include head CT or MRI.
LP should be performed if there is concern for an infectious or
inflammatory cause.
20 0 WHAT DO I DO NOW? Section 3: Pediatric Dilemmas

Further Reading
Salas, AA, Nava, A. Acute cerebellar ataxia in childhood: initial approach in the
emergency department. Emerg Med J. 2010;27:956–957.
Van der Maas, NAT, Vermeer-de Bondt, PE, de Melker, H, Kemmeren, JM. Acute
cerebellar ataxia in the Netherlands: a study on the association with vaccinations
and varicella zoster infection Vaccine. 2009;27:1970–1973.
34. Acute Ataxia in a  Child 201

35 Concussion in
an Adolescent
A 16-year-old boy is brought to the ED by his
soccer coach after an injury during practice 2
hours ago. His head collided with the shoulder
of another player, and the patient was knocked
to the ground. He may have had a brief loss of
consciousness but was able to get up and walk
off the field on his own. He was seen to “wander
around” the sidelines for the next 30 minutes.
General exam including vital signs is normal,
although there seems to be some ecchymosis
and tenderness in the left frontotemporal scalp.
CT of the brain is negative. Mental status exam
is remarkable for some disorientation to date
and time, and poor memory for recent events.
His speech seems a bit slow, but language is
otherwise normal. Cranial nerves, motor tone
and strength, sensation, coordination and
balance are all intact. The coach wants to know
if it is “OK if he plays in the championship game
tomorrow?”.
What do you do now?
203
C oncussion, now also known as “mild traumatic brain injury (mTBI)”
is defined as a change in neuropsychiatric function after a blow to the
head. There need not be a loss of consciousness. Clearly there is a spec-
trum of severity to acute post-head injury syndromes, and many researchers
have attempted to classify these by analyzing symptoms and signs following
injury in an effort to plan best treatment and predict recovery for each
patient. But this has proved difficult, perhaps because of a large range of
individual reactions to brain injury. One conclusion seems clear: even mild
head injuries can lead to lasting sequelae in some people.
It is important to rule out epidural, subdural, and intracerebral hem-
orrhage in these patients as soon as possible (see Figure 35.1). CT is very
sensitive and, as in the presenting case, usually helps to definitively rule
these out. The tenderness over this boy’s frontotemporal scalp is unsettling
because it is the general vicinity of the middle meningeal artery, which is
the most common artery to cause epidural hematoma when lacerated by
fractured skull components. Interestingly, epidural hematomas will often
present with the classic pattern of loss of consciousness, lucid interval, and
then progressive deterioration, so this history is crucial to obtain. Skull
fractures can be missed but must be discovered as they can also lead to the
very serious sequelae of CNS infection, delayed bleeding, and cranial nerve
damage. Raccoon eyes (periorbital ecchymosis), Battle’s sign (ecchymosis
over the mastoid), otorrhea, and rhinorrhea are suggestive signs of basal
skull fracture, but careful review of inferior views on the head CT is also
imperative. And careful assessment of the neurological exam with special
attention to the cranial nerves is essential.
In patients with normal head CT scans, all is still not worry-free.
Petecchial hemorrhaging might have occurred, generally in anterior frontal
and/or anterior temporal regions due to the net result of force vectors
resulting from trauma, and this can progress. When these small areas of
bleeding occur, often not apparent on initial CT scanning, they can later
coalesce and become true cerebral contusions, sometimes 24–48 hours later.
These can then lead to increased intracranial pressure and focal neurological
deficits. Thus, repeating CT scans if patients seem to regress, or even if they
do not clearly recover to their baseline, makes sense, as do a screening blood
count and bleeding parameters in patients who have sustained head injury.

(a)
(b)
FIGURE 35.1 Noncontrast CT of the head of a child following head trauma (a) axial view
revealing multicompartment intracranial parenchymal hemorrhages and left holohemispheric
subdural hematoma with midline shift, (b) Coronal view showing right frontal parenchymal
hemorrhage and left subdural hematoma.
What can be done in the acute period to hasten recovery in cases of
mTBI like this one? This area is hotly debated, and while many feel that
physical and mental rest for some time after injury is essential, there is evi-
dence that this does not provide benefit. There is at this point no evidence
that medication or supplements offer any protection or help.
So, assuming that all of the important workup is negative, can this
young man return to play tomorrow? A consensus statement published
by the British Journal of Sports Medicine suggests that any athlete, 18 and
under, who may have sustained a concussion during sports should not be
allowed to return to activity the same day. In the past this group believed
that it was appropriate for the athlete to return to activity if cleared by a
doctor or certified athletic trainer. The change came since it became clear
that there is no way to make an immediate determination of safety. The
American Academy of Neurology published a position statement in 2013
stating that (1) athletes who have had a concussion of any severity be imme-
diately removed from participation and (2) the concussed athlete not return
to participation until cleared by a physician with training in sports concus-
sion. Numerous researchers have attempted to refine and direct treatment,
return to play guidelines, and prognosis based on symptoms and signs in
patients following concussion, such as amnesia, headache, cognitive dys-
function, balance, etc., but unfortunately these all tend to occur to some
degree and seem not be good predictors of future status. For example, vir-
tually all concussed patients develop some retro-and anterograde amnesia,
much of which resolves.
A number of patients will have persistent symptoms of the “postconcussive
syndrome” which can last for months or even indefinitely, including
headaches, dizziness, cognitive difficulties, sleep abnormalities, fatigue, and
mood disturbances. These symptoms can occur either singly or as the full
syndrome and can become disabling, leading to falling behind in school
and to a great deal of emotional suffering. The cause(s) of these symptoms is
not entirely clear, but this is being actively investigated, in large part due to
the growing numbers of returning soldiers concussed in combat as well as in
noncombat areas and the alarming reports of many athletes suffering long-
term effects of repeated concussions. It is now clear that chronic traumatic
encephalopathy (CTE) is not uncommon after multiple head injuries, even
when there seems to have been reasonably good recovery from each of them.

And it takes little imagination to suspect that a single identified concussion
may actually be the latest in a series.
One tool for understanding the results of TBI is diffusion tensor im-
aging (DTI), which is being used to assess white matter changes, thought
by many to bear the brunt of force vectors delivered to the head. This and
other imaging test results are also being correlated with neuropsychiatric
testing before and after the athletic season in an attempt to quantify cogni-
tive changes. Of course, the athletes who are being tested are often canny
enough to know that if they show a significant drop in cognition over the
season, their coach may be reluctant to play them next year. As a result, pre-
season test scores can be artificially low.
At any rate, this patient certainly cannot go back to the field today.
He may even need to be admitted to the hospital for careful observation
and, if he does not improve, perhaps a repeat CT scan of the head to
ensure that contusions have not formed. If he is entirely back to normal
tomorrow, the question about return to play will be a difficult one. One
important thing to always consider is that a second head injury can be
devastating, for unclear reasons, so to be safe, most would consider this
patient to be best served by some time off contact sports. How long is
not clear.
• Concussion is defined as a change in neuropsychiatric function

after a blow to the head, with or without loss of consciousness.
• Severe sequelae of head injury, such as epidural, subdural, and
intracerebral hematomata must be ruled out acutely.
• Cerebral contusions can be delayed and should be investigated
if the patient does not improve or regresses.
• There is consensus that return to the field the same day after
a sports injury is contraindicated, but the benefit of longer rest
times is not clear.
Further Reading
Giza CC, Kutcher JS, Ashwal S, et al. Summary of evidence-based guideline
update: evaluation and management of concussion in sports: report of the
35. Concussion in an Adolescent 207

Guideline Development Subcommittee of the American Academy of Neurology.
Neurology. 2013;80(24):2250–2257.
Gupta A, Summerville G, Senter C. Treatment of acute sports-related concussion.
Curr Rev Musculoskel Med. 2019;12(2):117–123.
McCrea MA, Nelson LD, Guskiewicz K. Diagnosis and management of acute
concussion. Phys Med Rehabil Clin. 2017;28(2):271–286.
McCerory, P, Meeuwisse, W, Johnston, K, Dvorak, J, Aubry, M, Molloy, M, Cantu, R.
Consensus statement on concussion in sport: the 3rd International Conference
on Concussion in Sport. Br J Sports Med. 2009;43(Suppl I):i76–i84.
Willer BS, Haider MN, Bezherano I, Wilber CG, Mannix R, Kozlowski K, Leddy JJ.
Comparison of rest to aerobic exercise and placebo-like treatment of acute sport-
related concussion in male and female adolescents. Arch Phys Med Rehabil.
2019;100(12):2267–2275.

36 Acute Stroke in an
Adolescent
A 17-year-old girl with a history of depression
and prior suicide attempts is brought in by
parents for progressively worsening confusion.
Her parents discovered her that morning, when
they returned from a weekend trip, lying on her
right side on a hard linoleum floor with an empty
Benadryl container nearby. Her blood pressure
is 155/80, heart rate 110 and regular, her breaths
are 20 breaths per minute and shallow. Her ECG
shows a QTc 520. In the ED you notice that her
alertness waxes and wanes, speech is garbled.
Her pupils are dilated and respond symmetrically
to light, and she has blink to threat present
bilaterally. You notice she seems to be moving
her right arm and leg less than her left side. You
wonder if she may have had a stroke, but your
colleague says you are overreacting, that she just
needs to be treated for a drug overdose.
What do you do now?
209
W hile this patient is exhibiting signs of drug toxicity, there are also
focal signs on her exam that are concerning for stroke (e.g., aphasia,
right-sided weakness). Stroke can occur in children and adolescents for the
same major reasons that adults succumb: athero-thrombosis and embolism.
And, although the risks are much lower, stroke in adolescence is not rare
and can occur from a variety of reasons, including hematologic, cardiac,
vascular (both noninflammatory and inflammatory), and genetic etiologies.
A major cause of stroke in children and adolescents is sickle cell di-
sease due to spontaneous thrombosis, which can occur in any cerebral
vessel. Sickle trait does not lead to an increased risk of stroke. A number
of coagulopathies can lead to stroke at young ages including protein C and
S deficiencies, factor V-Leiden deficiency, and others. Leukemia can also
lead to stroke, both from the hypercoagulable state of cancer and from the
abnormal increase of cells in the blood vessels. Neuroblastoma, other child-
hood neoplasms, and inflammatory states such as inflammatory bowel di-
sease, can also cause hypercoagulability which can predispose to arterial or
venous thrombosis.
Congenital heart disease is an important risk factor for stroke in child-
hood. Endocarditis and rheumatic heart disease can increase the risk of clot
formation leading to arterial stroke. A patent foramen ovale (PFO) can lead
to paradoxical embolic events. Those who undergo cardiac surgery are also
at risk of perioperative stroke.
Several noninflammatory vasculopathies may cause pediatric stroke.
Moyamoya disease is a progressive steno-occlusive arteriopathy that affects
the anterior circulation. Arterial dissection of the carotid or vertebral
arteries can occur spontaneously or secondary to trauma or connective
tissue disease. Inflammatory vascular diseases can also lead to stroke, in-
cluding primary CNS vasculitis, Takayasu’s arteritis, polyarteritis nodosa,
and other rheumatologic diseases. Infectious and postinfectious vasculitis
can result in stroke; clues for this risk factor include the presence of pharyn-
gitis, sinusitis, bacterial meningitis, chickenpox, pneumonia, HIV, syphilis,
or tuberculosis. Cerebral venous thrombosis can also arise due to dehydra-
tion; infections of the ears, nose, sinuses, and meninges; and oral estrogen-
containing medications.
Mitochondrial encephalomyopathy, lactic acidosis, and stroke- like
episodes (MELAS) commonly presents in childhood with stroke syndromes,

often accompanied by migraine-like headaches. Cerebral autosomal dom-
inant arteriopathy with subcortical infarcts and leukoencephalopathy
(CADASIL) can present (rarely) in the adolescent age group. Migraine
can lead to persistent motor aura in the hemiplegic variant which exists in
sporadic and familial forms. Partial epilepsy can lead to postictal paralysis
(Todd’s paralysis), which can also mimic stroke.
Signs and symptoms of stroke are similar in adolescents and adults.
This patient had an occlusion of anterior cerebral and middle cerebral
branches. Had she presented acutely, tissue plasminogen activator (tPA)
and endovascular therapy could have been considered. The cause of this
stroke was ultimately found to be a tragic combination of a deep venous
thrombosis and PFO. Clearly there are some childhood strokes that could
benefit from intravenous thrombolysis. The problem, in addition to the
lack of controlled studies of this treatment, is that childhood stroke eti-
ology is more varied than adult stroke, leading to a large number of causes
not expected to benefit from tPA. At this time, management of acute
stroke in pediatric patients is largely based on hospital-specific guidelines.
Additional interventions include good hydration, permissive mild hyper-
tension, and treatment of the underlying mechanism as fast as possible.
If seizure is suspected, EEG should be done to attempt to confirm it, and
anticonvulsants can be started if there is strong suspicion. Anticoagulants
are rarely used. If intracranial pressure (ICP) increases, which can happen in
particularly large strokes, as in adults, ICP monitoring can be very helpful
in directing measures to reduce pressure, such as hyperosmolar therapy
(e.g., mannitol) and even hemicranicetomy. This kind of increase in ICP is
fortunately rare in children. Sickle cell disease is managed by repeat blood
transfusions.
Diagnostic workup should be thorough and include MRI of the head
with DWI and MR venography and MR arteriography of the head and
neck in hopes of localizing the pathology. If a dissection is suspected, a fat
saturation sequence of the neck vessels should be obtained to increase sensi-
tivity of dissection identification. Echocardiogram is essential for ruling out
valvular disease and intracardiac thrombus; this should always be performed
with a saline contrast shunt “bubble” study to assess for both intracardiac
(e.g., PFO) and extracardiac (e.g., pulmonary AV malformation) shunts.
Sickle cell disease should be ruled out, and a coagulation profile should
36. Acute Stroke in an Adolescent 211

be completed including anticardiolipin, lupus anticoagulant, protein C,
protein S, factor V Leiden, fibrinogen, antinuclear antibody, ESR, blood
cultures, toxicology screen, urine amino acids, organic acids and homocys-
teine, lipid panel, basic chemistry panel, blood count, and lactate. Lumbar
puncture is indicated if there is concern for CNS infection or vasculitis.
As with anyone with a stroke, secondary prevention and rehab assess-
ment is crucial. A stroke can be emotionally devastating to any patient, but
especially to children and adolescents, so careful and thorough explanations
and appropriate counseling are both highly important.
• The causes of stroke in childhood and adolescence include

those commonly underlying adult stroke as well as a number
of other diseases, including hypercoagulable disorders and
vascular anomalies.
• Some conditions can mimic stroke including hemiplegic
migraine and postictal paralysis.
• While tPA is probably a useful treatment in many adolescent
strokes, the disparity in causation of childhood/adolescent
stroke makes it difficult to design a protocol.
• Anticoagulation is only indicated in the acute treatment
of stroke in this age group when there is a clear cardiac
thromboembolic source or cerebral venous thrombosis.
Further Reading
Amlie-Lefond C, Benedict S, Bernard T, et al. and the International Paediatric Stroke
Study Investigators. Thrombolysis in children with arterial ischemic stroke: initial
results from the International Paediatric Stroke Study. Stroke. 2007;38:485.
Arnold M, Steinlin M, Baumann A, et al. Thrombolysis in childhood stroke: report of 2
cases and review of the literature. Stroke. 2009;40:801–807
McGlennan C, Ganesan V. Delays in investigation and management of acute arterial
ischaemic stroke in children. Dev Med Child Neurol. 2008;50:537–540.

Index
For the benefit of digital users, indexed terms that span two pages (e.g., 52–53) may, on occasion,
appear on only one of those pages.
ABCD2 score, 118, 119t amyotrophic lateral sclerosis, 68

abscesses, 199 analgesic rebound, 131
acetaminophen, 181–82, 182t, 184t andexanet alfa, 138
acetylcholine receptor (AChR) anesthesia, saddle, 78
antibodies, 165 aneurysms, unruptured, 31–33
acute cerebellar ataxia syndrome, 198, angiography
198t, 200 computed tomography (CT), 119,
acute cervical radiculopathy, 153 136, 148–49
acute childhood ataxia, 197, 198t magnetic resonance (MR), 119
acute disseminated encephalomyelitis anterior cerebral artery (ACA), azygos, 66
(ADEM), 199 anterior cerebral artery (ACA) occlusion
acute generalized weakness, 13 in adolescent, 149f, 150f, 211
acute migraine endovascular therapy, 149–50
in children, 189 anterior cord syndrome, 68
in pregnancy, 181–82, 184t anterior ischemic optic neuropathy
treatment, 133 (AION), 25
acute myopathy, 103 antibody panels, 106–7
acute neuralgia, 123 anticholinergic overdose, 61, 62, 62t
acute refractory migraine, 131–32, 133 anticoagulation
acute stroke acute post-stroke, 114–15
in adolescent, 209 contraindications, 111
up to 24 hours, 147 intracerebral hemorrhage
acute vision loss, 24 on, 135
acyclovir, 49 for stroke in adolescents, 212
adolescents for stroke prevention, 113–15,
acute stroke in, 209 114t, 119–20
concussion in, 203 anticonvulsants, 142–44
migraine in, 191 antidepressants, 61, 177, 183
adverse events, immune-related antiemetics
(irAEs), 74–76 neuroleptic, 125–26
AIDS, 84–85, 86–88 pregnancy risk, 181–82, 183t
altered mental status, 42–43 antiepileptic drugs (AEDs), 143–44
amaurosis fugax, 24–25 adverse effects, 144–45
AMPA receptor encephalitis, 92t, 93–94 categories, 144
amphetamines, 60 “just in case,” 177
amphiphysin, 69 for seizures, 139, 145
ampicillin, 49 for status epilepticus, 38, 39
antifibrinolytic agents, 138 benzodiazepines
antihistamines, 61, 62t for neuroleptic malignant syndrome
anti-HMG-CoA antibody, 106, 107 (NMS), 60–61, 62t
anti-Hu, 69 for serotonin syndrome, 62t
antiplatelets, 119–20, 121 for status epilepticus, 36t, 39
antipsychotics, 44 for vertigo, 57–58
anti-SRP antibody, 106 bilateral leg weakness, 66
antisynthetase syndrome, 106 blood pressure, systolic, 139
antithrombotic therapy, 120 blood pressure control, 148
aortic aneurysm botulism, 14–15, 66
dissecting, 20 brain imaging. see also specific modalities
unruptured, 31–33 indications, 200
apixaban (Eliquis), 113, 114t, 138 post-transplant, 173
arachnoiditis, 79–80 bromocriptine, 62t
arrhythmias, 19, 61 bubble studies, 118–19, 211–12
arteriovenous fistula, dural (dAVF), 68
arteriovenous malformation (AVM), CADASIL (cerebral autosomal dominant
31–33, 68 arteriopathy with subcortical infarcts
aspirin, 119–20 and leukoencephalopathy), 8–9
astasia-abasia, 98–100 Call-Fleming syndrome, 30–31
ataxia, acute childhood, 197, 198t carbamazepine, 144
atenolol, 183 cardiac arrest, 157
atezolizumab, 74 cardioembolic stroke, 111
atherosclerosis, intracranial, 120, 121 carotid arterial dissection, 31
athletes, adolescent, 203 carotid endarterectomy (CEA), 3, 120
atrial fibrillation, nonvalvular, 113, 114t carotid or vertebral artery dissection, 8–9
autoimmune diseases carotid sinus syncope, 20
susceptibility for, based on CD4 count, carotid stenosis, 120
84, 84t cauda equina, 78, 79–80
systemic, 68–69 cauda equina syndrome, 66, 77, 79f, 80f
autoimmune encephalitis (AE), 93, 94–95 CD4 counts, 84, 84t
autoimmune encephalopathy, 92t, 93 ceftriaxone, 49
avelumab, 74 central nervous system (CNS) infection, 60
azathioprine, 166 central nervous system (CNS) lesions,
azygos ACA, 66 85–86, 85t
central retinal vein occlusion, 25
bacterial infections, 79–80 cerebellar hemorrhage, 139
bacterial meningitis, 48t, 49–51 cerebellitis, postinfectious, 200
basal skull fracture, 204 cerebral autosomal dominant arteriopathy
Battle’s sign, 204 with subcortical infarcts and
bedside respiratory function tests, 164 leukoencephalopathy (CADASIL),
la belle indifference, 98–100 8–9, 210–11
benign positional vertigo, 54–55 cerebral contusion, 207
214 Index
cerebral edema, 159f postconcussive syndrome, 206–7
Cerebral Performance Category contusion, cerebral, 207
(CPC), 160–61 conus medullaris, 78
cerebral vasculitis, 8–9 conversion disorder (CD), 26, 176
cerebral venous thrombosis, 8–9, 30–31 diagnostic criteria for, 98–100, 98t, 101
cerebrospinal fluid (CSF), 14–15, 48t, 49–50 management, 100, 101
cervical radiculopathy, acute, 153 signs of, 98, 99t, 101
cervical spine imaging convulsive status epilepticus, generalized,
in myelopathy, 65, 70f, 71 35, 37f
in radiculopathy, 154, 155 cooling
CHA2DS2-VASc Score, 112, 112t passive, 158
children therapeutic, 158
acute ataxia in, 197, 198t corticosteroids
acute migraine in, 189 for meningitis, 49, 51
febrile seizure in, 193 for migraine pain, 131–32, 182–83
risk factors for stroke, 210 pregnancy risk, 182–83
stroke in, 210, 212 Coxsackie virus, 199
chlorpromazine, 125–26, 182t cranial nerve dysfunction, 42–43
cholinergic crisis, 165, 167 cranial nerve injury, 5
chronic traumatic encephalopathy cranial nerve palsy, 14–15
(CTE), 206–7 creatine kinase (CK), 59, 103
clopidogrel, 119–20 crisis, myasthenic, 163
cluster headache, 124 cryoprecipitate, 138
coagulopathy, 139, 140 Cryptococcus
collapsin response-mediator protein-5 diagnosis, 49–50, 86–88
(CRMP5), 69 in HIV or AIDS, 84–85, 86–88
coma, 47 susceptibility for, based on CD4 count,
compressive myelopathy, 66, 67t 84, 84t
computed tomography (CT) CTLA-4, 74
before brain biopsy, 88 Cushing response, 139
in coma with fever, 47–48 cyproheptadine, 62, 62t
indications, 47–48, 50t, 88, 148, 170, 200 cytomegalovirus
before LP, 48, 50t, 170 in cauda equina syndrome, 79–80
single photon emission computed susceptibility for, based on CD4 count,
tomography (SPECT), 88 84, 84t
in stroke up to 24 hours, 148
computed tomography angiography (CTA) dabigatran (Pradaxa), 113, 114t, 138
indications, 136, 148 dancing eyes-dancing feet, 199–200
in recurring TIA, 119 dantrolene sodium
in stroke up to 24 hours, 149 for malignant hyperthermia, 61, 62t
concussion for neuroleptic malignant syndrome
in adolescents, 203 (NMS), 60–61, 62t
definition, 207 decompression sickness, 68
Index 215
deep venous thrombosis, 211 Eliquis (apixaban), 113, 114t
delirium encephalitis
hospital-acquired, 41, 44t AMPA receptor, 92t, 93–94
hyperactive, 43 autoimmune, 93, 95
hyperthermia with, 62, 63t herpes zoster, 93
hypoactive, 43 immune-related, 74
dementia NMDA receptor, 61, 92t, 93
frontotemporal, 91, 92–93 viral, 60, 61
rapidly progressive, 91 encephalopathy
denture cream, 68 autoimmune, 92t, 93
dermatomyositis, 106 chronic traumatic, 206–7
dexamethasone, 49, 131–32 differential diagnosis in, 92, 94t
diagnostic dilemmas, 1 metabolic, 93
diaphragmatic weakness, 104, 164 posterior reversible, 170, 172t, 173–74
diffusion tensor imaging (DTI), 207 and seizure, 169
diffusion-weighted imaging (DWI), 211–12 subacute, 92, 94t
dihydroergotamine (DHE), 131, 190–91 after transplant, 169
diphenhydramine, 125–26, Wernicke’s, 42, 43, 45
131–32, 180–81 endovascular therapy, 149
disc rupture, 154 epilepsy, 8–9, 142, 145
disequilibrium, 54 Epstein-Barr virus (EBV), 79–80, 173, 199
dissecting aortic aneurysm, 20 ergot, 182
Dix-Hallpike maneuver, 54–55 European Cooperative Acute Stroke Study
dizziness, 54, 58 (ECASS III), 148
do-not-resuscitate (DNR) orders, 140 exercise, 121
drug overdose exertional headache, 31
in adolescent, 209 external ventricular drain (EVD), 139,
anticholinergic, 61, 62, 62t 140, 199
differential diagnosis, 14 extraventricular drain, 139
syncopal, 20 eye ischemia, 24
dual antiplatelet therapy (DAPT),
119–20, 121 facial nerve, 5
dural arteriovenous fistula (dAVF), 68 facial pain, atypical, 126, 127
durvalumab, 74 factitious disorder, 100–1, 176
dystonia, febrile, 59 fever
coma with, 47
echocardiography, 113, 211–12 febrile dystonia, 59
transthoracic, 118–19 febrile seizures, 193, 194t
electroencephalography (EEG), 60, treatment, 159–60, 161
160–61 floaters, 24
video-EEG monitoring, 177 folate, 183
electrolyte imbalances, 61 Food and Drug Administration (FDA),
electromyography (EMG), 75, 107, 154 181, 183t
216 Index
fosphenytoin orgasmic, 31
for pain, 125–26 in pregnancy, 181–82, 184t
for status epilepticus, 36t, 38, 39 sentinel, 30t, 31–33
frontotemporal dementia (FTD), 91, 92–93 sudden (thunderclap), 29, 30t
functional disorders, 98, 176 head computed tomography (CT)
functional hemiparesis, 97 in acute ataxia in child, 200
functional vital capacity (FVC), 104, 164 before brain biopsy, 88
fungal meningitis, 48t, 49–50 in coma with fever, 47–48
indications, 47–48, 50t, 88, 148,
gabapentin, 144 170, 200
gadolinium, 119 before LP, 48, 50t, 170
gastrointestinal bleeding, 112 single photon emission computed
GBS. see Guillain-Barré syndrome tomography (SPECT), 88
generalized convulsive status epilepticus in stroke up to 24 hours, 148
(GCSE), 35, 37f heavy metal intoxication, 14–15
generalized weakness HELLP syndrome, 180
acute, 13 hematoma, 37f, 137f, 138f
differential diagnosis, 14, 15t, 16 hematopoietic cell transplant recipients, 170
genetic disorders, 68 hemicrania, paroxysmal, 124
giant cell arteritis, 25 hemiparesis, functional, 97
give-way weakness, 97, 98–100, 129, hemorrhage
153, 203 cerebellar, 139
glucocorticoids, 166 intracerebral, 135, 137f, 138f
glutamic acid decarboxylase (GAD), 69 heparin, low-molecular weight
Guillain-Barré syndrome (GBS) (LMWH), 113
acute, 16 herpes simplex virus (HSV), 60, 79–80
clinical presentation of, 14, 16, 66 herpes zoster encephalitis, 93
management, 16 HIV infection, 14–15, 83
neurophysiological testing for, 15–16 HIV polyradiculoneuropathy, 14–15
pathophysiology, 14 HMG-CoA reductase, 106, 107
susceptibility for, based on CD4 count, Hoover’s sign, 97, 98–100, 129, 153
84, 84t hospital-acquired delirium, 41, 44t
hydrocephalus, 140
Haemophilus influenzae, 48–49 hydromorphone, 182t
headache hydroxyzine, 190, 191
acute severe, 181–82, 184t hyperactive delirium, 43
cluster, 124 hypercalcemia, 14
exertional, 31 hypercarbia, 164
International Classification of Headache hypernatremia, 136–37
Disorders, 8, 8t, 9t, 126–27, 127t, hyperosmolality, 136–37
130, 130t hyperosmolar therapy, 136–37
medication overuse, 131, 132t hyperoxemia, 159–60
migraine, 129, 179 hyperperfusion syndrome (HPS), 4, 5
Index 217
hypertension International Classification of Headache
idiopathic intracranial, 180 Disorders
management, 139 classification of trigeminal nerve pain,
hyperthermia 126–27, 127t
with delirium, 62, 63t criteria for migrainous infarction, 8, 9t
malignant, 61, 62, 62t criteria for prolonged migraine aura, 8, 8t
hypertonic saline, 136–37 criteria for status migrainosus, 130, 130t
hyperventilation, temporary, 136–37 intervertebral disc rupture, 154
hypoactive delirium, 43 intoxication
hypocapnia, 159–60 anticholinergic, 61, 62, 62t
hypoglossal nerve, 5 drug, 14, 20, 209
hypoglycemia, 42–43, 148 heavy metal, 14–15
hypokalemia, 14 intracerebral hemorrhage (ICH), 135
hypotension intracranial atherosclerosis, 120, 121
intracranial, 31 intracranial hypertension, idiopathic, 180
orthostatic, 19 intracranial hypotension, spontaneous, 31
hypothermia, therapeutic, 158 intracranial masses, 83, 87f
hypothyroidism, 14 intracranial pressure (ICP)
increased, 136–37, 139, 140, 211
ibuprofen, 182t monitoring, 211
idarucizumab, 138 intravenous immunoglobulin (IVIg),
idiopathic intracranial hypertension 165–66, 167
(IIH), 180 ipilimumab, 74
imaging, 140. see also specific modalities
immune checkpoint inhibitors JC virus, 173
(ICPis), 73
immune-mediated necrotizing ketorolac, 182t
myopathy, 107
immune reconstitution inflammatory la belle indifference, 98–100
syndrome (IRIS), 84, 84t, 88 labyrinthitis, acute, 199–200
immune-related adverse events lacosamide, 144
(irAEs), 74–76 Lambert-Eaton myasthenic syndrome
inclusion body myositis, 106 (LEMS), 74
infection, post-transplant, 172–73, lamotrigine, 144
174 lead neuropathy, 14–15
inferior cerebral artery (ICA) leg weakness, bilateral, 66
occlusion, 149–50 leukocytosis, 43
inflammatory demyelinating levetiracetam (Keppra)
polyneuropathy. see Guillain-Barré for seizures, 144–45
syndrome (GBS) for status epilepticus, 36t, 38, 39
inflammatory myelopathy, 68–69 lidocaine, 125–26
inflammatory myopathy, 107 lifestyle choices, 121
INR, 137–38 lightheadedness, 54–55, 58
218 Index
Listeria monocytogenes, 49, 199 medication overuse, 131, 133
lorazepam medication overuse headache (MOH),
for status epilepticus, 36t, 38 131, 132t
for vertigo, 57–58 MELAS (mitochondrial encephalopathy,
loss of consciousness, brief, 18, 18t lactic acidosis, and stroke-like episodes
low-molecular weight heparin syndrome), 8–9
(LMWH), 113 melatonin, 44
lumbar puncture (LP) Meniere’s disease, 55
for children, 195 meningismus, 42, 48–49
head CT before, 48, 50t, 170 meningitis, 48–49
indications, 56, 60, 145, 180, 195, 200 aseptic, 74
measuring opening pressure with, 49 bacterial, 48t, 49–51
lumbar spine masses, 79f, 80f carcinomatous, 79–80
Lyme disease, 14–15, 79–80, 199 CSF patterns, 48t, 49–50
Lyme neuropathy, 14–15 meningococcal, 51
lymphoma treatment, 49, 51
diagnosis, 86–88 viral, 48t, 49–51
in HIV or AIDS, 84, 86–88 meningococcal meningitis, 51
susceptibility for, based on CD4 count, meningoencephalitis, syphilitic, 93
84, 84t mental status testing, 42–43
metabolic encephalopathy, 93
magnesium, 131, 181 metabolic myelopathy, 68
magnesium sulfate, 181, 182t, 184t methylprednisolone
magnetic resonance angiography (MRA) for migraine pain, 131–32, 182–83, 184t
with gadolinium, 119 pregnancy risk, 182–83
time-of-flight (TOF) sequence, 119 metoclopramide, 180–81, 182, 182t
magnetic resonance arteriography, 211–12 midazolam, 36t
magnetic resonance imaging (MRI) middle cerebral artery (MCA), 118
in acute ataxia in child, 200 middle cerebral artery (MCA) occlusion
after acute stroke in adolescent, 211–12 in adolescent, 149f, 150f, 211
in ADEM, 199 endovascular therapy, 149–50
of cervical spine, 154, 155 middle cerebral artery (MCA)
after first seizure, 145 stenosis, 120
indications, 145, 200, 211–12 migraine
post-transplant, 173 acephalgic, 118
magnetic resonance venography, 211–12 acute, 189, 133
malignant hyperthermia, 61, 62, 62t acute refractory, 131–32, 133
malingering, 101 in children, 189
mannitol, 136–37 exercise-induced, 31
masses, intracranial, 83 intractable, 129
maximal inspiratory force (MIF), 104 in pregnancy, 179, 182t
MDMA, 60 treatment, 133
mean inspiratory force (MIF), 164 vestibular, 55–56
Index 219
migraine aura neglect, 42–43
prolonged, 7, 8t Neisseria, 49–50
without headache, 118 nerve blocks, occipital, 131, 133
migrainous stroke, 8, 9t nerve conduction study (NCS), 75, 107
mild traumatic brain injury (mTBI), 203 neuralgia
Miller Fisher syndrome, 199–200 acute, 123
mitochondrial encephalopathy, lactic definition, 126–27
acidosis, and stroke-like episodes primary, 124
syndrome (MELAS), 8–9, 210–11 trigeminal, 124–25
mononeuritis multiplex, 84, 84t neurocardiogenic syncope, 20
Monroe-Kelli doctrine, 136–37 neuroleptic malignant syndrome (NMS),
morphine, 182t, 184t 60–61, 62, 62t
Moyamoya disease, 210 neuroleptic medications, 60–61
multiple sclerosis (MS), 26, 68–69 neuromyelitis optica spectrum disorder
myasthenia gravis (NMOSD), 68–69
clinical presentation, 14–15, 66, 164 neuron specific enolase (NSE), 160–61
complications, 163 neuropathic pain, 126–27, 127t
generalized, 163 neuropathy, painful, 126–27, 127t
ICPi-associated, 74–76 NIH Stroke Scale (NIHSS), 148
management, 75–76 nitrous oxide canisters
myasthenic crisis, 163 (whippits), 68
Mycobacterium tuberculosis, 84 nivolumab, 74
mycophenolate mofetil, 166 NMDA receptors, 92t, 93
myelin oligodendrocyte glycoprotein Nocardia, 84
antibody (anti-MOG), 68–69 nonepileptic spells, 175
myelitis, 68–69, 74 nonsteroidal anti-inflammatory
myelopathy, 16, 65, 67t drugs, 181–82
myocardial infarction, 4, 5, 20
myopathy occipital lobe epilepsy, 8–9
acute, 103 occipital nerve blocks, 131, 133
causes, 104, 105t ondansetron, 190
inflammatory, 107 opioids
toxic, 107 avoid use, 132–33
myositis, 106, 107 pregnancy risk, 181–82
myositis antibody panels, 106–7 optic nerve disease, 24, 26
optic neuritis (ON), 26
naloxone trial, 42–43 orgasmic headache, 31
naproxen, 182t orthostatic hypotension, 19
neck flexion strength, 104, 107, 164 overdose
neck region nerve injury, postoperative, 4 anticholinergic, 61, 62, 62t
necrotizing myopathy, immune-mediated, drug, 14, 20, 209
106, 107 heavy metal, 14–15
negative phenomena, 121 oxcarbazepine, 144
220 Index
pain posterior reversible encephalopathy
facial, atypical, 126, 127 syndrome (PRES), 170
neuropathic, 126–27, 127t causes, 174
trigeminal nerve, 126–27, 127t complications, 174
pain management medications and conditions associated
in acute neuralgia, 123 with, 170, 172t
intractable migraine, 129, 131–32 post-transplant, 173, 174
migraine in pregnancy, 179, 184t prognosis, 173
parenchymal hematoma, 137f, 138f postpartum angiopathy, 180
Parkinson-plus syndromes, 19 posttraumatic stress disorder
parotitis, 4 (PTSD), 176–77
paroxysmal hemicrania (PH), 124 postural perceptual vertigo,
partial thromboplastin time (PTT), 113 persistent, 55–56
patent foramen ovale (PFO), 210, 211 Pott’s disease, 69
PD-1, 74 Pradaxa (dabigatran), 113, 114t
PDL-1, 74 prednisone, 166, 182t
pediatric dilemmas, 187 pregnancy
pembrolizumab, 74 acute severe headache in, 181–82, 184t
peripheral neuropathy, 84, 84t medication choices in, 181, 183t
peripheral vertigo, 54–55 migraine in, 179, 182t, 184t
persistent postural perceptual vertigo pregnancy risk categories, 181, 183t
(PPPV), 55–56 primary neuralgia, 124
phenytoin, 125–26, 144 primary thunderclap headache, 31, 33
physical therapy, 155 prochlorperazine
plasma exchange, 165–66, 167 for migraine, 131–32, 180–81
platelet transfusions, 139, 140 for migraine in children and
pleocytosis, CSF, 14–15 adolescents, 191
pneumothorax, 20 for migraine in pregnancy, 182t
polio, 14 pregnancy risk, 182
polymerase chain reaction (PCR) testing, progressive multifocal
49–50, 86 leukoencephalopathy (PML)
polymyositis, 14–15 diagnosis, 86–88
polyradiculitis, 14–15 post-transplant, 173
polyradiculopathy, 66 susceptibility for, based on CD4 count,
porphyria, 14–15 84, 84t
positional vertigo, benign, 54–55 progressive weakness, subacute, 14
positive end-expiratory pressure promethazine
(PEEP), 136–37 for migraine, 180–81
positive phenomena, 118, 121 for migraine in children and
positron emission tomography (PET), 88 adolescents, 191
postconcussive syndrome, 206–7 for migraine in pregnancy, 182t
posterior ischemic optic neuropathy pregnancy risk, 182
(PION), 25 protamine sulfate, 137
Index 221
prothrombin complex concentrate postictal state, 37f
(PCC), 138 prevention of, 145
psychogenic nonepileptic seizures psychogenic nonepileptic, 175
(PNES), 175 recurrence, 142–44
psychogenic syncope, 20 risk factors for recurrence, 142–43
psychogenic vertigo, 56 subclinical, 38–39
pulmonary embolism, 20 threshold for, 143–44
purple-glove syndrome, 38, 125–26 after transplant, 169
pyridostigmine, 76, 166, 167 treatment, 38, 39, 139, 142–43
pyridoxine (vitamin B6), 38 selective serotonin-reuptake inhibitors
(SSRI), 177
rabies, 61 sensory loss, midline-splitting, 98–100
raccoon eyes, 204 sensory testing, 42–43
rescue medications, 131 sentinel headache, 30t, 31–33
respiratory distress, 164 Seroquel, 44
respiratory failure serotonin syndrome (SS), 60, 61–62, 62t
causes, 164 shivering control, 159, 161
differential diagnosis, 165 short-lasting unilateral neuralgiform
respiratory function tests, 164 headache with conjunctival injection
respiratory weakness, 167 and tearing (SUNCT), 124
retinal artery occlusion, 24–25 sickle cell disease, 210, 211–12
retinal detachment, 24 sickle cell trait, 210
retinal ischemia, 24–25 sick role, 100–1
return to play, 206, 207 single photon emission computed
reversible cerebral vasoconstriction tomography (SPECT), 88
syndrome (RCVS), 8–9, 30–31, sinusitis, sphenoid, 31
170, 180 skull fracture, 204
rewarming, 159–60 sleep-wake cycle, 44, 45
rhabdomyolysis, 60–61 smoking cessation, 121
rivaroxaban (Xarelto), 113, 114t, 138 solid organ transplant recipients, 170
somatic symptom disorder, 101
saddle anesthesia, 78 somatoform disorders, 98
saline, hypertonic, 136–37 somatosensory evoked potentials
Schistosoma, 69 (SSEPs), 160–61
seizures spells, nonepileptic, 175
causes, 142, 143t sphenoid sinusitis, 31
in children, 193 spinal cord lesions, 15–16
conditions which mimic, 142 spinal dural arteriovenous fistula, 68
encephalopathy and, 169 spontaneous intracranial hypotension, 31
febrile, 193, 194t sports injury, adolescent, 203
first-time, 141, 143t spot sign, 136
generalized, 20, 143–44 SRP, 106
partial (focal), 144 Staphylococcus, 48–49
222 Index
statins, 107, 119–20 syphilis
status epilepticus susceptibility for, based on CD4 count,
approach to, 36, 36t 84, 84t
generalized convulsive, 35, 37f syphilitic meningoencephalitis, 93
treatment, 38 systolic blood pressure (SBP), 139
status migrainosus
diagnostic criteria for, 130, 130t targeted temperature management (TTM),
in pregnancy, 180–81 158, 159–60, 161
stents, 120 temporal arteritis (TA), 25
stimulants, 60 therapeutic hypothermia or cooling, 158
strength testing, 42–43 thiamine
Streptococcus pneumoniae, 48–49, 51 for status epilepticus, 36t, 38
stroke for Wernicke’s encephalopathy, 43, 45
acute, 147, 209 thrombectomy, 149, 150
in adolescent, 209 thrombocytopenia, 139, 140
anticoagulation acute thrombolytic therapy, 4
post-stroke, 114–15 thunderclap headache, 29, 30t
cardioembolic, 111 tic dolouroux, 126
after CEA, 4–5 tick paralysis, 14–15
in children, 210, 212 time-of-flight (TOF) sequence, 119
“drip and ship” management, 149–50 tissue plasminogen activator (tPA),
migrainous, 8, 9t 112, 138
minor, 121 postoperative, 4
postoperative, 4 for stroke in adolescents, 211, 212
risk factors for, 210 for stroke up to 24 hours, 148, 149–50
signs and symptoms of, 211 Todd’s paralysis, 118, 210–11
up to 24 hours, 147 topiramate, 144–45
stroke mimics, 148, 212 toxic/metabolic myelopathy, 68
stroke prevention toxic myopathy, 107
in nonvalvular atrial fibrillation, toxoplasmosis, 84, 84t, 86–88
113, 114t transient ischemic attack (TIA), 121
primary, 119–20 postoperative, 4
secondary, 120, 121 recurring, 117
stroke risk, 118, 119t stroke risk after, 118
subdural hematoma, 37f vertebrobasilar, 8–9
sudden (thunderclap) headache, 29, 30t transplant recipients
sumatriptan, 184t, 190–91 encephalopathy and seizure in, 169
surgery risk for infection, 172–73, 174
neurological deficits after transthoracic echocardiography
CEA, 3 (TTE), 118–19
postoperative stroke, 4 transverse myelitis, 74
postoperative TIA, 4 traumatic brain injury, mild (mTBI), 203
syncope, 17 treatment dilemmas, 109
Index 223
trigeminal nerve, 5 persistent postural perceptual, 55–56
trigeminal neuralgia (TN), 124–27 psychogenic, 56
classification, 126–27, 127t refractory, 53
differential diagnosis, 124, 125t treatment, 57–58
triptans, 182 vessel imaging, 140. see also specific
tuberculosis (TB) modalities
in cauda equina syndrome, 79–80 vestibular migraine (VM), 55–56
in HIV or AIDS, 84 video-EEG monitoring, 177
susceptibility for, based on CD4 count, viral encephalitis, 60, 61
84, 84t viral meningitis, 48t, 49–51
tumors, 92t, 93 visual loss, monocular, 23
vitamin B6 (pyridoxine), 38
upper spinal cord lesions, 14 vitamin K, 138
vagus nerve, 5 Wallenberg syndrome, 54

valproate warfarin, 113, 114t, 120, 137
for pain, 131 weakness
for seizures, 144–45 diaphragmatic, 104
for status epilepticus, 36t, 38, 39 generalized, 13, 15t
vancomycin, 49 give-way, 97, 98–100, 129, 153,
varicella zoster virus (VZV), 60, 79–80, 199 203
vascular malformations, 68 neck flexion, 104, 164
vasovagal syncope, 20 respiratory, 167
ventriculostomy, 139 subacute progressive, 14
vertebral artery dissection, 8–9, 31, 54 Wernicke’s encephalopathy, 42, 43, 45
vertebrobasilar transient ischemic whippits (nitrous oxide canisters), 68
attack, 8–9 white blood cells (WBCs), 142
vertigo
benign positional, 54–55 Xarelto (rivaroxaban), 113, 114t
causes, 56, 57t
new-onset, 56 zinc excess, 68
peripheral, 54–55 zonisamide, 144–45
224 Index

(What Do I Do Now - ) Sara C. LaHue, Morris Levin - Emergency Neurology (What Do I Do Now - ) - Oxford University Press (2021)

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(What Do I Do Now - ) Sara C. LaHue, Morris Levin - Emergency Neurology (What Do I Do Now - ) - Oxford University Press (2021)

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ADVANCE PRAISE FOR EMERGENCY NEUROLOGY, SECOND EDITION

“Emergency Neurology provides practical guidance to approaching both

“This book makes it easy to grasp collection of critical issues pertinent

S E R I E S C O -​E D ITORS-​I N-​C HIE F

Headache and Facial Pain

SECTION 1 DIAGNOSTIC DILEMMAS

1 Neurological Deficits Following Carotid Endarterectomy 3

2 Prolonged Migraine Aura 7

3 Acute Generalized Weakness 13

5 Monocular Visual Loss 23

7 Generalized Convulsive Status Epilepticus 35

9 Coma with Fever 47

13 Neurologic Complications of Immune Checkpoint Inhibitors 73

14 Cauda Equina Syndrome 77

15 Intracranial Mass in a Person with HIV 83

16 Rapidly Progressive Dementia 91

18 Acute Myopathy 103

19 Cardioembolic Stroke with Contraindications to

20 Recurring Transient Ischemic Attack 117

21 Acute Neuralgia 123

23 Intracerebral Hemorrhage on Anticoagulation 135

24 First Seizure 141

25 Acute Stroke Up to 24 Hours 147

26 Acute Cervical Radiculopathy 153

27 Post-​Cardiac Arrest Management 157

28 Myasthenic Crisis 163

29 Encephalopathy and Seizure After Transplant 169

30 Nonepileptic Spells 175

31 Migraine in a Pregnant Patient 179

SECTION 3 PEDIATRIC DILEMMAS

32 Acute Migraine in a Child 189

33 Febrile Seizure 193

34 Acute Ataxia in a Child 197

35 Concussion in an Adolescent 203

36 Acute Stroke in an Adolescent 209

Some of the most exciting recent developments in neurology have occurred

As clinicians everywhere know, the management of each case is a team ef-

What do you do now?

4 WHAT DO I DO NOW? Section 1: Diagnostic Dilemmas

1. Neurological Deficits Following Carotid Endarterectomy 5

• CAE is generally safe but postoperative complications include

6 WHAT DO I DO NOW? Section 1: Diagnostic Dilemmas

What do you do now?

BOX 2.1 International Classification of Headache Disorders, 3rd

8 WHAT DO I DO NOW? Section 1: Diagnostic Dilemmas

KEY POINTS TO REMEMBER

• Migraine auras typically develop over 5–​20 minutes and resolve

10 WHAT DO I DO NOW? Section 1: Diagnostic Dilemmas

What do you do now?

14 WHAT DO I DO NOW? Section 1: Diagnostic Dilemmas

3. Acute Generalized Weakness 15

KEY POINTS TO REMEMBER

• Acute Guillain-​Barré syndrome may present in atypical fashion,

16 WHAT DO I DO NOW? Section 1: Diagnostic Dilemmas

What do you do now?

BOX 4.1 Causes of brief loss of consciousness

18 WHAT DO I DO NOW? Section 1: Diagnostic Dilemmas

20 WHAT DO I DO NOW? Section 1: Diagnostic Dilemmas

KEY POINT S TO REMEMBER

• Syncope can result from many causes including cardiovascular,

What do you do now?

24 WHAT DO I DO NOW? Section 1: Diagnostic Dilemmas

S E R I E S C O -E D ITORS-I N-C HIE F

27 Post-Cardiac Arrest Management 157

• Migraine auras typically develop over 5–20 minutes and resolve

• Acute Guillain-Barré syndrome may present in atypical fashion,

5. Monocular Visual  Loss 25

5. Monocular Visual  Loss 27

FIGURE 7.1 Noncontrast CT of the head showing acute-on-chronic right holohemispheric

BOX 8.1 Approach to hospital-acquired delirium

9. Coma with  Fever 49

Viral Lymphocytic (PMNs Normal Normal/

Fungal Lymphocytic (some Low Normal/

CNS lymphoma, Abnormal cells, Normal/ High

• Bacterial meningitis must be treated with a broad-coverage

9. Coma with  Fever 51

inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs),

Symptom/ Serotonin NMS Malignant Anticholinergic