(What Do I Do Now - ) Sara C. LaHue, Morris Levin - Emergency Neurology (What Do I Do Now - ) - Oxford University Press (2021)
(What Do I Do Now - ) Sara C. LaHue, Morris Levin - Emergency Neurology (What Do I Do Now - ) - Oxford University Press (2021)
“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
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
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
San Francisco, CA, USA
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
Classification: LCC RC350.7 (print) | LCC RC350.7 (ebook) | NLM WL 301 |
DDC 616.8/0425—dc23
LC record available at https://lccn.loc.gov/2020020672
LC ebook record available at https://lccn.loc.gov/2020020673
DOI: 10.1093/med/9780190064303.001.0001
This material is not intended to be, and should not be considered, a substitute for medical or
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Printed by Marquis, Canada
Contents
Preface vii
Acknowledgments ix
4 Syncope 17
6 Thunderclap Headache 29
8 Hospital-Acquired Delirium 41
10 Refractory Vertigo 53
11 Febrile Dystonia 59
12 Myelopathy 65
17 Functional Hemiparesis 97
Index 213
vi Contents
Preface
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.
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.
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
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
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
Diagnostic criteria:
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
D. Not better accounted for by another ICHD-3 diagnosis
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.
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.
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
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
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.
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.
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
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.
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.
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
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.
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
• 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
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.
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.
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
(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.
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
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
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).
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.
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
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
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.
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.
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
Delirium + + + +
Fever + + + +
Autonomic + + + +
dysfunction
Nausea/ +
Vomiting
Rigidity + ++ + +
Myoclonus +
Tremor +
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.
- 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
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.
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.
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
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.
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
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.
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
Toxoplasmosis
Primary CNS lymphoma
Tuberculomas
Abscess
Cryptococcoma
Syphilitic gumma
Acute neurocystercosis
Steroids may eliminate contrast enhancement of a lesion.
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.
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.
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
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
Caspr2 Thymoma
DPPX Unknown
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.
97
BOX 17.1 Conversion disorder (functional neurological symptom
disorder)
Diagnostic criteria
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
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.
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.
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
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.
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.
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.
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
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
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.
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
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
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.
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:
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.
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,
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.
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
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
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.
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.
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
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.
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,
Further Reading
Mehren C, Wanke-Jellinek L. Posterior foraminotomy for lateral cervical disc
herniation. Eur Spine J. 2019;28(1):1–2.
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
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.
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%
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.
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.
(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.
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.
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
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
Ketorolac D
Hydromorphone C
Morphine C
Metoclopramide B Unlikely
Promethazine C None
Prochlorperazine C None
Chlorpromazine C None
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.
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.
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
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.
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.
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.
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
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
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.
(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.
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
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,
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.
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.
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
224 Index