®

NEUROLOGY BOARD REVIEW MANUAL

STATEMENT OF
EDITORIAL PURPOSE
Approach to the Evaluation
The Hospital Physician Neurology Board Review
Manual is a study guide for residents and
of Encephalopathy
practicing physicians preparing for board
examinations in neurology. Each manual Editor:
reviews a topic essential to the current prac- Catherine Gallagher, MD
tice of neurology.
Assistant Professor of Neurology, University of Wisconsin Movement Dis-
PUBLISHING STAFF orders Program, Staff Physician, Middleton VA Hospital, Madison, WI
PRESIDENT, GROUP PUBLISHER
Bruce M. White
Contributors:
Andrew S. Kayser, MD, PhD
EDITORIAL DIRECTOR
Debra Dreger Fellow in Neurology, Memory and Aging Center, University of
California at San Francisco, San Francisco, CA
ASSOCIATE EDITOR
Rita E. Gould Alireza Atri, MD, PhD
EDITORIAL ASSISTANT Instructor in Neurology, Harvard Medical School, Assistant in Neurology,
Farrawh Charles
Memory Disorders Unit, Massachusetts General Hospital, Boston, MA
EXECUTIVE VICE PRESIDENT
Barbara T. White
EXECUTIVE DIRECTOR
OF OPERATIONS Table of Contents
Jean M. Gaul
PRODUCTION DIRECTOR
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Suzanne S. Banish
PRODUCTION ASSISTANT Distinguishing Encephalopathy from Other Disorders . . . 2
Kathryn K. Johnson
Case 1: A 51-Year-Old Liver Transplant Patient with
ADVERTISING/PROJECT MANAGER
Patricia Payne Castle
Subacute Episodic Confusion. . . . . . . . . . . . . . . . . . . . . . 3
SALES & MARKETING MANAGER Case 2: A 57-Year-Old Patient with a 1-Week History of
Deborah D. Chavis Headache and Personality Changes . . . . . . . . . . . . . . . . . 9

NOTE FROM THE PUBLISHER:

Case 3: A 50-Year-Old Patient with Progressive Mutism
This publication has been developed without Over a Month. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
involvement of or review by the American
Board of Psychiatry and Neurology. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Endorsed by the
Association for Hospital
Medical Education Cover Illustration by Kathryn K . Johnson
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www.turner - white.com Neurology Volume 9, Part 4 1

 NEUROLOGY BOARD REVIEW MANUAL
Approach to the Evaluation of
Encephalopathy
Andrew S. Kayser, MD, PhD, and Alireza Atri, MD, PhD
INTRODUCTION
A request for the evaluation of a patient with altered
mental status, and with encephalopathy/delirium in
particular, is one of the most common reasons for a neu-
rology consultation. Because a broad range of condi-
tions can result in this clinical presentation—from pri-
mary neurologic disorders (seizure, stroke) to systemic
diseases (urinary tract infection, hyponatremia)—the
challenge is to identify the most likely cause or causes.
The neurologist must be able to quickly clarify the
nature of the cognitive change, prioritize the diagnostic
possibilities, decide on an expeditious work-up, and
start appropriate therapy, as early treatment is critical for
many of these conditions (eg, prompt administration of
intravenous antibiotics for meningococcal meningitis).
This manual begins with an overview of the features
that allow one to distinguish encephalopathy from
other disorders, primarily dementia, and continues
with 3 cases illustrating the evaluation of encephalopa-
thy. The cases are intended to provide an introduction
to the work-up of altered mental status and, more
specifically, to emphasize the steps that facilitate timely
evaluation and treatment.
DISTINGUISHING ENCEPHALOPATHY FROM
OTHER DISORDERS
CHARACTERIZING THE COGNITIVE CHANGE
Distinguishing the nature of the cognitive change is
essential in directing the subsequent work-up. This step
requires characterizing the time course of the altered
mental status as acute, subacute, or chronic and as
monophasic or multiphasic (ie, single or multiple epi-
sodes), and determining whether generalized cortical
dysfunction is accompanied by focal neurologic signs
and symptoms.
The neurologist’s use of the term altered mental sta-
2 Hospital Physician Board Review Manual
tus is generally synonymous with encephalopathy and con-
forms, in broad terms, with the psychiatrist’s (Diagnostic
and Statistical Manual of Mental Disorders IV ) definition of
delirium (ie, a disturbance of consciousness that devel-
ops over hours to days and that is accompanied by a
change in cognition that cannot be better accounted
for by a preexisting or evolving dementia). Enceph-
alopathy, therefore, is a generalized cortical dysfunction
characterized by an acute-to-subacute course (ie, hours
to days), prominent fluctuations in the level of con-
sciousness, poor attention, frequent hallucinations and
delusions, and changes in the level of psychomotor
activity (generally increased but at times decreased).
Dementia is more often characterized by chronicity, a
normal level of consciousness, relatively normal psycho-
motor activity, better preservation of attention, and,
usually, less frequent hallucinations and delusions until
late in the course of the illness.1 Clearly, distinguishing
the nature of the illness has implications for the ur-
gency of treatment, which is much less in the case of a
chronic, slowly progressive disease such as dementia.
Of course, one must be wary of delirium complicat-
ing the course of dementia. Various studies estimate the
prevalence of delirium in community-dwelling and hos-
pitalized patients with dementia to be from 22% to
89%.2 Moreover, changes over the course of minutes to
hours can occasionally be inherent to a dementing ill-
ness. For example, patients with dementia with Lewy
bodies are known to have prominent fluctuations in
awareness (attention/vigilance) and vivid visual halluci-
nations during the day.3 Even more importantly, one
should be aware of focal deficits that can sometimes be
mistaken for encephalopathic changes. Patients with
embolic distal left middle cerebral artery (MCA) distri-
bution strokes, for example, can be erroneously classi-
fied as “demented” when their “cognitive difficulties”
are primarily limited to their language,4 and patients
with right MCA/parietal strokes can occasionally pre-
sent primarily with agitation.5 Once a decision is
reached as to the presence of an encephalopathy, fur-
ther assessment can begin accordingly.
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 Approach to the Evaluation of Encephalopathy
• Which of the following is not a risk factor for enceph-
alopathy?
A) Increasing age
B) Female gender
C) Use of multiple medications
D) Visual or auditory impairment
E) Comorbid physical illness
ASSESSING RISK FACTORS FOR ENCEPHALOPATHY
At times, encephalopathy risk factors and precipi-
tants can overlap, and the independence of various risk
factors can blur. For example, there is some controver-
sy as to whether the documented risk factor of older age
can be fully disentangled from the confounder of phys-
ical frailty. Nonetheless, Inouye et al6 found that among
hospitalized patients aged 70 years or older, use of mul-
tiple medications, visual or auditory impairment, and
physical comorbidities all predisposed to delirium. Of
the 5 factors mentioned in the question, only female
gender does not appear to play a role; if anything, male
gender increases a patient’s risk, as described in a meta-
analysis of hospitalized elderly patients by Elie et al.7
While emphasizing significant methodologic problems
with the studies reviewed, these authors also found evi-
dence of increased risk for delirium in patients with a
history of alcohol abuse or depression. Other risk fac-
tors most certainly exist. Meagher1 includes social isola-
tion, a change to a novel (often, hospital) environment,
use of psychoactive medications, the perioperative peri-
od following an emergent or prolonged procedure, and
a history of previous encephalopathy.
Efforts have been made to prevent delirium in at-
risk patients by proactively modifying the environment.
In their study of hospitalized elderly patients, Inouye
et al6 specifically targeted issues of preexisting cognitive
impairment, sleep deprivation, immobility, visual im-
pairment, auditory impairment, and dehydration.
Many of the interventions were intuitive: nighttime and
early morning blood draws and medications were
moved to minimize sleep disruption, cerumen disim-
paction and portable amplifying devices were employed
to reduce hearing difficulties, and early mobilization
protocols were implemented. These straightforward
risk-reduction strategies lowered the incidence of delir-
ium to 9.9% in the intervention group versus 15.0% in
the control group. Control of such risk factors, howev-
er, should not distract one from searching for an etiol-
ogy in an already encephalopathic patient.
NARROWING THE DIFFERENTIAL
When evaluating the patient with encephalopathy/
delirium, coming prepared with a broad differential
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Table. Mnemonic for Potential Causes of
Encephalopathy/Delirium
I Infections (central nervous system: meningitis/
encephalitis; systemic: urinary tract infection,
pneumonia, endocarditis, sepsis)
T Trauma, tumor/paraneoplastic
S Stroke, seizure, (p)sychiatric
D Drugs (intoxication or withdrawal), degenerative
(decompensated dementia)
E Electrolytes, endocrine
L Low glucose, leukoencephalopathy
I Inflammatory (eg, acute disseminated encephalomyelitis)
R Rheumatologic (eg, vasculitis)
I Intracranial pressure
U Uremia
M Metabolic (hypoxia, hyperglycemia, hyperammonemia),
malnutrition, mitochondrial
diagnosis is extremely helpful in defining the range of
possible etiologies. Of course, simply hearing the pre-
senting complaint will allow one to narrow down this
list of possibilities significantly. Nonetheless, having a
systematic approach ensures that no potential diagnosis
is missed. One useful mnemonic is shown in the Table.
In the first case, we apply such as systematic approach to
a patient in whom multiple processes may be at work.
CASE 1: A 51-YEAR-OLD LIVER TRANSPLANT
PATIENT WITH SUBACUTE EPISODIC
CONFUSION
INITIAL PRESENTATION
A 51-year-old right-handed man who received an
orthotopic liver transplant 1 year prior is admitted to
the transplant service for evaluation of episodes of con-
fusion over the past month. The inpatient neurology
consult service is called to evaluate the patient on the
day after admission.
Although the patient cannot recall all the episodes,
he reports that they usually occur in the evening and
consist of him asking his wife “stupid questions.” On 2
occasions, he has taken all the medications from his pill-
box at a single time, not realizing until later that he
should not have done so. The patient is unclear whether
the episodes last seconds, minutes, or hours, and his wife
is not currently available. Nonetheless, she has not told
Neurology Volume 9, Part 4 3
 Approach to the Evaluation of Encephalopathy
him nor has he noticed that these spells are ac-
companied by loss of consciousness, shaking, tongue bit-
ing, or urinary incontinence. The patient’s only previ-
ous history of altered awareness was before his liver
transplantation, when he reports, “My ammonia was
high.” He began escitalopram for depression 1 month
ago but denies any changes in his methadone dosing
(for chronic abdominal pain). Review of systems also
reveals 4 weeks of drenching night sweats and 2 weeks of
a warm, erythematous papule on his right calf.
• This patient’s presenting complaint and history thus
far suggest several diagnostic possibilities. Of the
following, which is least likely?
A) Medication effect (eg, serotonin syndrome)
B) Hepatic encephalopathy
C) Meningoencephalitis
D) Transient ischemic attack (TIA)
E) Seizure
This case illustrates one of the first issues in charac-
terizing the cognitive change: defining the time course
of illness. Although critical details about this patient’s
cognitive change are missing, what has been reported
thus far—multiple episodes of confusion (“stupid ques-
tions”) over approximately 1 month, generally occur-
ring in the evenings, with partial recall and without
other obvious clinical signs—suggests an episodic pro-
cess that is not rapidly progressive. In this case, the dif-
ferential diagnosis should be shaped by the fact that the
illness is subacute and multiphasic. We will broaden our
differential slightly, given the vagaries of the history, but
our best guesses will be guided by these constraints.
One other prominent feature of this patient’s histo-
ry is that he is unable to characterize the episodes of
confusion. By the very nature of their illness (ie, the
accompanying inattention and alteration in conscious-
ness), encephalopathic patients are rarely able to give a
complete history. Interestingly, infrequent reports de-
scribe encephalopathic patients who are able to de-
scribe their experiences while altered.8 Such reports
clearly indicate misperceptions and delusions. Whether
a patient’s self-reported descriptions are helpful in the
work-up of the problem is less clear, although certainly
they should be taken seriously in defining the nature of
the disturbance. More importantly, they highlight how
the report of an outside observer, whether a family
member or health care professional, can be extremely
valuable and why the interaction with the patient
should consist of clear, directed language in an opti-
mized environment (eg, with adequate lighting, with
the patient’s hearing aids/glasses in place).
4 Hospital Physician Board Review Manual
In this case, seizure is a definite diagnostic possibility.
The lack of shaking and tongue biting would not be suf-
ficient to rule out this diagnosis; partial complex seizures
are one very frequent seizure type in which observers
often notice only a brief lack of responsiveness. Menin-
goencephalitis should always be considered in transplant
recipients or other immunocompromised patients.
Although the prolonged time course of this patient’s
symptoms would be highly inconsistent with acute bacte-
rial meningitis, fungal or atypical meningoencephalitis
(eg, cryptococcal meningitis) can present insidiously,
even in patients without known risk factors, and should
never be overlooked.9 In a patient with a liver transplant,
poor function of the transplanted organ should be con-
sidered. Although this patient has not had previous epi-
sodes of rejection, his transplant history raises the outside
possibility of changes in liver function that, if not directly
responsible for a metabolic abnormality (eg, hyperam-
monemia), might alter the metabolism of his medica-
tions. In that context, the fact that his altered mental sta-
tus coincides with initiation of escitalopram use suggests
that drug interactions (although escitalopram has few),
altered drug metabolism, or an independent effect
(eg, serotonin syndrome10) should be evaluated.
The least likely possibility for this patient’s mental
status change is TIA. Clarification of the history would
be important, but the events sound stereotyped and
multiple. The history we have so far suggests distal left
MCA dysfunction, given the impairment of speech con-
tent rather than articulation and the lack of prominent
motor deficits. If the symptoms truly represented TIA,
they would be extremely unlikely to be embolic, as it is
exceedingly rare that recurrent emboli (even from a
source more distal than the heart, such as the carotid
artery) would involve the same distal vessel. One possi-
bility would be a flow-limiting atherothrombotic lesion,
but as more and more episodes occur, the likelihood
that they represent TIAs without leading to a subse-
quent stroke significantly declines.11 Finally, the phe-
nomenon of transient global amnesia deserves men-
tion. This syndrome consists of an acute, primarily
anterograde amnesia (persisting for 1–24 hours), in
which patients frequently ask the same questions
over and over but do not lose consciousness or self-
awareness.12 While the origin of the syndrome is un-
clear (migrainous, epileptic, and ischemic etiologies
have all been suggested), the recurrence rate is low
(2.5% annually in 1 study13), and the risk of subsequent
vascular events is small as compared with TIA. Even
without a good description of the events in this case, the
multiple episodes argue somewhat strongly against TIA.
This patient’s history thus far raises other diagnostic
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 Approach to the Evaluation of Encephalopathy
possibilities not listed in the question. Infections out-
side the central nervous system (CNS), such as cellulitis
or reactivated tuberculosis, could easily be present
(note the history of drenching night sweats), with sec-
ondary effects on cognition. To help narrow the possi-
bilities and to determine whether additional diagnoses
should be considered, we need more history.
PAST MEDICAL HISTORY
The patient’s past medical history confirms that he
underwent orthotopic liver transplantation 1 year prior
for sequelae of hepatitis C virus (HCV) infection and
alcohol abuse. Post-transplantation complications
include malnutrition multiple episodes of upper gas-
trointestinal bleeding, esophageal candidiasis leading
to gastrostomy tube placement, methicillin-resistant
Staphylococcus aureus peritonitis, and possible recent re-
currence of his HCV infection. The patient’s history
also is significant for a left-sided Bell’s palsy, with a sin-
gle recurrence 20 years ago; peripheral neuropathy;
chronic abdominal pain requiring methadone; and loss
of hearing in the left ear after a “high fever as a child.”
• Which of the following diagnostic possibilities is
least likely given the additional history?
A) Alcohol withdrawal
B) Recurrent peritonitis
C) Herpes encephalitis
D) Wernicke’s encephalopathy
E) Altered glucose metabolism
As with many transplant patients, this patient has
experienced several infectious complications of im-
munosuppression as well as many of those associated
with liver disease. Recurrent peritonitis is a possibility,
although the patient does not complain of abdominal
pain and the 1-month time frame seems long; one
would expect an untreated bacterial infection in an
immunocompromised patient to have progressed sig-
nificantly within a much shorter time period.
Alcohol withdrawal is a definite possibility; it is im-
portant to clarify the timing of the patient’s last drink,
if any, and to discuss the possibility of recent use with his
wife. In this context as well as that of past malnutrition,
Wernicke’s encephalopathy should be considered. Thi-
amine deficiency, whether a result of extremely poor
intake due to alcoholism or to malnutrition from other
causes, could be exacerbated by glucose loads.14 If pres-
ent on examination, the triad of altered mental status,
ophthalmoparesis, and gait ataxia would argue strongly
for this diagnosis. However, if the patient is still using a
gastrostomy tube for feeding supplements, this diagno-
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sis might be less likely because most supplements con-
tain thiamine.
Altered glucose metabolism (hyper- or hypogly-
cemia) itself could be an issue, especially if steroids are
part of the patient’s immunosuppressive regimen
and/or hepatic glycogen metabolism is compromised.
However, the latter would generally be present only in
acute liver failure, which is extremely unlikely here.
Finally, perhaps the most serious but least likely pos-
sibility suggested by this patient’s past medical history is
herpes encephalitis. This disease can have a highly var-
ied clinical presentation; along with fever, it can mani-
fest as anything from focal neurologic deficits (aphasia,
cranial nerve palsies, and others) to neurobehavioral
abnormalities, to a depressed level of consciousness.15
Given the prolonged time course of symptoms and the
lack of any symptoms that implicate herpes simplex
virus (HSV) encephalitis, this diagnosis seems quite
unlikely.
MEDICATION HISTORY
The patient’s medication regimen is complex. As an
outpatient, he most recently has taken esomeprazole
40 mg once daily (qd), bupropion 100 mg twice daily
(bid), dronabinol 5 mg bid, atovaquone 1500 mg qd,
ondansetron 4 mg as needed for nausea, metoclopra-
mide 10 mg bid, cyclosporine 150 mg bid, methadone,
erythropoietin, escitalopram, and granulocyte colony-
stimulating factor (G-CSF), although recent use of
G-CSF is unclear. After admission, his medication regi-
men was changed to esomeprazole 40 mg qd, metoclo-
pramide 10 mg bid, methadone 5 mg in the morning/
2.5 mg in the evening, erythropoietin, valganciclovir
900 mg bid, dronabinol 5 mg bid, cefazolin 1 mg intra-
venously 3 times daily (tid), tacrolimus 1 mg bid, spi-
ronolactone 25 mg qd, megestrol acetate 200 mg tid,
aripiprazole 2.5 mg qd, lorazepam 0.5 mg at bedtime,
ribavirin 600 mg/400 mg, peginterferon alfa-2a 180 mg
once weekly, atovaquone 1500 mg qd, ethacrynic acid,
and tamsulosin. He notes that sulfa drugs cause a rash.
• Of this patient’s many current and recent medica-
tions, which is least likely to have an effect on his cog-
nition?
A) Cyclosporine
B) Esomeprazole
C) Bupropion
D) Methadone
E) Aripiprazole
F) Lorazepam
Although the duration of this patient’s cyclosporine
Neurology Volume 9, Part 4 5
 Approach to the Evaluation of Encephalopathy
use is unclear, he has likely been taking cyclosporine or
a similar immunosuppressant since just prior to his liver
transplantation. Thus, cyclosporine-related side effects
may potentially be at play, as this medication has been
associated with confusion, cortical blindness, and sei-
zures16 as well as with systemic complications. The con-
sulting team has apparently considered these potential
complications of cyclosporine and held it temporarily,
pending results of a work-up. Bupropion has been asso-
ciated with seizures.17 As an opiate, methadone has been
associated with depression of consciousness; similarly,
benzodiazepine use can be a double-edged sword. Lo-
razepam is frequently prescribed for its anxiolytic and
sedative properties, as with this patient; however, it can
also exacerbate encephalopathy.18 Aripiprazole, as with
many psychoactive medications, can have adverse effects
on cognition (see page 13 for further discussion of atypical
neuroleptic agents in the management of encephalopathy.) The
least likely drug to affect this patient’s cognition is
esomeprazole. This drug has been associated with head-
ache, but related drugs (eg, omeprazole) have only
extremely rarely been associated with delirium.19 A spe-
cial note should also be made of medications with anti-
cholinergic properties. Because such drugs have a ten-
dency to exacerbate or provoke encephalopathy,18
efforts should be made to reduce or eliminate them
from an at-risk patient’s medication list.
FURTHER HISTORY AND PHYSICAL EXAMINATION
On further review of systems, the patient reports no
fevers or chills, no recent weight loss, no shortness of
breath, no chest pain or pressure, no muscle aches or
joint pains, and no rash. He denies any alcohol use, and
his chart reveals no evidence of recent alcohol use. He
also denies the use of illicit drugs. The patient reports
that he quit smoking cigarettes 2 years ago. He is mar-
ried and monogamous with his wife. He denies any
recent travel and has only a healthy dog in the house.
He graduated from high school and worked for most of
his adult life as a hairdresser, but he retired for medical
reasons 1 year prior to his liver transplantation.
On physical examination, temperature is 99.4°F
(37.4°C), blood pressure is 140/74 mm Hg, pulse is
77 bpm, respiratory rate is 12 breaths/min, and oxygen
saturation is between 98% and 100% on room air. Gen-
eral examination is notable for a thin, pleasant man with
clear lungs, a regular heart rate without murmurs, and
no evidence of photo/phonophobia or meningismus.
Abdominal examination reveals a diffusely and mildly
tender abdomen with a chevron scar as well as a gastros-
tomy tube, but there is no distention, no hepatomegaly,
no rebound tenderness, and no cervical/axillary/
6 Hospital Physician Board Review Manual
inguinal lymphadenopathy. There is a 2-cm indurated,
mildly erythematous area on his right calf.
• Which of the following diagnoses is least supported
by the above findings?
A) Hypertensive encephalopathy
B) Meningoencephalitis
C) Alcohol withdrawal
D) Systemic infection
E) Medication side effect
Hypertensive encephalopathy is a diagnostic possi-
bility, given this patient’s cyclosporine use. However,
this diagnosis depends not on the absolute value of the
blood pressure but on the difference in blood pressure
relative to baseline. In a study by Hinchey et al,20 in
which most patients experiencing blood pressure in-
creases were peripartum, immunosuppressed, or renal-
ly impaired, 1 patient experienced symptoms at a sys-
tolic pressure of “only” 150 mm Hg. Thus, to rule in a
diagnosis of hypertensive encephalopathy, we need to
review this patient’s previous blood pressures.
Meningoencephalitis, perhaps nonbacterial, also is a
possibility. The patient currently has only 1 component of
the classic tetrad of fever, headache, meningismus, and
altered mental status; the presence of just 1 of these key
clinical features would be a rare finding in community-
acquired acute bacterial meningitis (only 4% in 1 study21).
However, with an atypical or nonbacterial meningitis or in
the setting of immunosuppression, it is not clear that
these statistics would apply.
For similar reasons, we have yet to rule out infection
outside the CNS. This patient’s abdomen is mildly con-
cerning as is the indurated area on his right calf. Medi-
cation side effect also cannot be excluded without a
neurologic examination, especially since memory impair-
ments exacerbated by anticholinergic medications can be
present without overt systemic manifestations. However,
there is currently no good evidence for alcohol withdraw-
al. Evidence of recent use, and other criteria for the
diagnosis—autonomic hyperactivity, insomnia, nausea/
vomiting, and anxiety as well as hallucinations, psy-
chomotor agitation, increased hand tremor, and general-
ized tonic-clonic seizures22—have not been identified.
Clearly, information from the neurologic examination is
needed to narrow the diagnostic possibilities.
NEUROLOGIC EXAMINATION
Cognitive Examination
On cognitive examination, the patient is alert and
oriented to time, place, and context; interactive; ap-
propriate; and follows all commands. He names the
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 Approach to the Evaluation of Encephalopathy
months of the year backward and is able to perform ser-
ial 7s through 65 with one self-corrected error. His
speech is fluent without paraphasic errors; he names
wholes and parts, repeats, and follows 3-step, midline-
crossing commands easily. There is no evidence of
neglect with confrontational visual field testing. Clock
draw is intact. The patient is not apraxic. He names 14
“F” words with one neologism (“fortuitive”) in 60 sec-
onds and 22 animals in 60 seconds. He denies halluci-
nations.
• Which of the following accompaniments of enceph-
alopathy are revealed in the cognitive evaluation of
this patient?
A) Waxing and waning alertness
B) Inattention
C) Psychomotor slowing or agitation
D) Perceptual distortions
E) None of the above
Clearly, alertness was not an issue during the cogni-
tive evaluation, as evidenced by the patient’s ability to
comply with all tasks. Attention, as frequently assessed
by working memory tasks (eg, serial 7s, naming the
months of the year backward), was also not an issue,
despite the fact that inattention (by definition) is often
one of the most prominent abnormalities to emerge in
the history and examination of an encephalopathic
patient. Inattention would also be implied by a lack of
orientation to time and date, both of which require fre-
quent updating. However, the patient had minimal dif-
ficulties with the orientation questions. There is likewise
no clear evidence for psychomotor changes or percep-
tual distortions (visual hallucinations being a particu-
larly prominent form).
Although the best answer is “none of the above,” one
trap to avoid is the assumption that because an alter-
ation in mental status is not currently present, it never was
present. Encephalopathic states often produce marked
fluctuations in the level of consciousness and mental
acuity. The existence of “sundowning,” in which pa-
tients with baseline cognitive impairment appear well
during the day but become delirious in the evening,23 is
an example of a more stimulus-sensitive fluctuation in
mental status. Once again, questioning other health
care providers and family members who have seen the
patient recently can often provide valuable information
in this regard.
Elemental Neurologic Examination
On the elemental neurologic examination, pupils
are equally round and reactive, without evidence of
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papilledema on funduscopic examination, and visual
fields are full. There is some saccadic intrusion on eye
movement testing but no limitations in excursion.
Facial sensation is intact; a left facial droop that includes
the forehead is easily visible. Weber lateralizes to the
right and Rinne is positive on the left, confirming the
existence of left sensorineural hearing loss revealed in
the past medical history. Voice and palatal movement
are normal. The tongue is tremulous but midline. On
motor examination, bulk is diffusely decreased but tone
is normal. There is a bilateral action tremor but no
asterixis. Strength is full throughout. Reflexes including
the jaw jerk are 3+, except at the ankles, where they are
2+. Plantar responses are flexor bilaterally. Cold sensa-
tion is decreased to the mid-shin bilaterally, but other
modalities are intact throughout. Tests of coordination
and gait are normal.
• Which of the following diagnoses is least likely based
on the elemental examination?
A) Hepatic encephalopathy
B) Serotonin syndrome
C) Stroke
D) Uremia
E) Seizure
The elemental examination of the patient is inter-
esting and reveals clear abnormalities, but the question
is whether any of the findings suggest a new pathophys-
iologic process. Based on the patient’s history, the left
facial droop and left hearing loss have been present for
many years, and his peripheral neuropathy has been
documented. Potentially new findings are the tremu-
lousness of his tongue, his bilateral action tremor, and a
possible mild hyperreflexia. There is consequently no
clear evidence for a new focal lesion, and thus, of the
choices listed, the possibility of a stroke is the least like-
ly. One must be cautious of the fact that right MCA
strokes can occasionally present only as symptoms of
agitation.5 However, this patient’s impairment of
speech content rather than articulation and lack of
prominent motor deficits would, if anything, argue for
left MCA distribution ischemia. The patient’s general-
ized findings would not rule out any of the other diag-
nostic possibilities listed, although they do not argue
strongly for or against seizure.
Special note of the serotonin syndrome should be
made, especially since the patient’s cognitive changes
began about the same time he initiated escitalopram (a
selective serotonin reuptake inhibitor). Serotonin syn-
drome is a toxic hyperserotonergic state that occurs as
a result of excess agonism of serotonergic receptors.10
Neurology Volume 9, Part 4 7
 Approach to the Evaluation of Encephalopathy
The syndrome is potentially life-threatening and char-
acterized in its mild form by motor signs (tremor,
hyperreflexia), autonomic signs (tachycardia, diaphor-
esis), and mild encephalopathy. It can progress, how-
ever, to manifest as a range of findings including hyper-
thermia, clonus, and increased muscle tone; shock; or
even death. Serotonin syndrome requires a certain
index of clinical suspicion, as there are no confirmato-
ry laboratory tests. This patient presents with findings
suggestive of the syndrome (ie, hyperreflexia, tremor),
although alternative explanations do exist (eg, tremor
may be due to cyclosporine use).
• Which of the following tests would be least helpful in
the initial diagnostic work-up of this patient?
A) Complete blood count (CBC) and chemistry
panel
B) Blood cultures, urinalysis with culture, and
chest radiograph
C) Electroencephalogram (EEG)
D) Magnetic resonance imaging/magnetic reso-
nance angiography (MRI/MRA) of the brain
E) Coagulation studies, liver function tests, and
ammonia level
F) Cyclosporine level
G) Lumbar puncture
H) Fine needle aspiration (FNA) of the skin lesion
As always, appropriate testing depends on the prior-
itized differential diagnosis. Evidence from the pa-
tient’s history and physical and neurologic examina-
tions suggests a subacute process with episodic/
multiphasic alteration in awareness (not currently pres-
ent on examination) that is without clear focal mani-
festations. The patient does manifest a bilateral action
tremor and a mild hyperreflexia. Currently, the diag-
nostic possibilities include a metabolic process such as
systemic or localized infection (night sweats would sug-
gest the need to test for tuberculosis), hyperammone-
mia, an electrolyte disturbance (perhaps secondary to
cyclosporine-induced renal dysfunction), or a medica-
tion side effect. Seizure remains a possibility. Vitamin
deficiency (thiamine, vitamin B12) could possibly be
contributory.
To address these possibilities, we would need a CBC
and chemistry panel, liver function tests including co-
agulation studies, ammonia levels, routine infectious
screening (blood cultures, urinalysis with culture, chest
radiograph), and a cyclosporine level. FNA of the skin
lesion would be a significant consideration, and EEG
would be useful to screen for a seizure focus. Although
8 Hospital Physician Board Review Manual
some might hesitate to order a lumbar puncture, ce-
rebrospinal fluid (CSF) culture would be useful—
particularly in an immunocompromised patient—to
rule out subacute nonbacterial meningitis (especially a
mycobacterial or cryptococcal infection) presenting
atypically. Of the studies listed, the least useful initial
test would be MRI/MRA of the brain. We currently
have several diagnostic possibilities to explain a mild
encephalopathy, and the lack of focal findings argues
against such possibilities as a stroke or tumor. If the
patient’s condition should worsen, the need for brain
imaging would need to be re-evaluated.
DIAGNOSIS AND CASE CONCLUSION
The transplant team orders many of the studies
requested by the neurology consultants for the initial
work-up of the patient (ie, CBC and chemistry panel,
liver function tests, coagulation studies, cyclosporine lev-
els, urinalysis with culture, chest radiograph). The leuko-
cyte count is low at 2.4 × 109/L (normal, 4.5–11.0 ×
109/L) but with a normal differential. The mean cell vol-
ume is elevated at 106 µm3 (normal, 80–96 µm3). Elec-
trolytes are normal, although blood urea nitrogen and
creatinine levels are mildly elevated at 38 mg/dL (nor-
mal, 11–23 mg/dL) and 1.4 mg/dL (normal, 0.6–
1.3 mg/dL), respectively. Glucose level is normal. Liver
function tests show elevations of aspartate transaminase
(75 U/L [normal, 1–36 U/L]), alanine transaminase
(76 U/L [normal, 1–45 U/L]), total bilirubin
(1.2 mg/dL [normal, 0.3–1.1 mg/dL), and alkaline
phosphatase (461 U/L [normal, 35–150 U/L]). Albu-
min is mildly decreased at 3.2 g/dL (normal, 3.3–
5.2 g/dL). Cyclosporine level is below the reference
therapeutic range. Urinalysis results and chest radio-
graph are unremarkable. Blood cultures, an EEG, and
ammonia and vitamin B12 levels are ordered and the pa-
tient is started on thiamine, folate, and a multivitamin.
The patient and his family refuse lumbar puncture.
The next day, the ammonia level returns at 116 µmol/L
(normal < 50 µmol/L), and the vitamin B12 level is low
at 175 pg/mL (normal > 200 pg/mL). The patient is
started on lactulose and high-dose oral vitamin B12 sup-
plementation. Additionally, he and his wife opt to dis-
continue escitalopram under regular monitoring by his
primary care physician. The EEG is not performed.
FNA of his leg lesion reveals no evidence of cellulitis or
infectious organisms such as mycobacteria. Further
work-up of his elevated ammonia level by the primary
team does not reveal any evidence of new liver patholo-
gy (rejection or infection). Over the next 6 months, the
patient has no further episodes.
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 Approach to the Evaluation of Encephalopathy
SUMMARY
The diagnostic work-up in this case revealed multi-
ple and confluent causes for the patient’s alteration in
mental status. Mild liver dysfunction leading to hyper-
ammonemia as well as the possible contributions of
mild vitamin B12 deficiency and escitalopram use were
enough to lead to a mild encephalopathy, which re-
solved with appropriate therapy. Fortunately, the pa-
tient was sufficiently stable that there was time to obtain
the results of multiple studies prior to initiating the
appropriate therapy. Nonetheless, one should always
briefly consider acute possibilities that require immedi-
ate treatment. As previously discussed, emergent issues
such as stroke, ongoing seizure, bacterial meningitis,
and hypertensive encephalopathy should all be consid-
ered, even if only briefly. In the next case, similar con-
siderations will hold, although the management deci-
sions will be more acute.
CASE 2: A 57-YEAR-OLD PATIENT WITH A
1-WEEK HISTORY OF HEADACHE AND
PERSONALITY CHANGES
INITIAL PRESENTATION
A 57-year-old right-handed woman is brought to the
emergency department (ED) by her daughter for eval-
uation of confusion. The patient had been well until
1 week prior, at which time she developed a dull bi-
frontal headache, rhinorrhea, and nasal congestion. At
a medical walk-in clinic, a chest radiograph identified a
left lower lobe infiltrate, and the patient was prescribed
a short course of azithromycin. Despite treatment, her
condition did not improve. The patient began to com-
plain not only of ongoing headache and respiratory
symptoms, but also of “odd smells.” Additionally, her
daughter felt that her mother’s personality had become
more irritable and impulsive. The patient was brought
in for re-evaluation when she became persistently
“sleepier.” Neurology consultation is requested.
• This patient’s presenting complaint and history thus
far suggest a number of diagnostic possibilities. Of
the following, which is least likely?
A) Brain tumor
B) Frequent seizures
C) Viral encephalitis
D) Stroke
E) Vasculitis
F) Paraneoplastic syndrome
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Obviously, a great deal of background information
about this patient’s condition has yet to be revealed, but
the history so far is notable for the development of
headache and subsequent progression of irritability,
somnolence, and possibly parosmia over approximately
1 week. This constellation of symptoms, particularly
personality changes and parosmia, is concerning for
temporal lobe pathology. A brain tumor is possible;
while one often expects symptomatic tumors to present
more indolently, at times even stroke-like symptoms are
recognized as a presenting feature. In a study of 224
patients admitted to Johns Hopkins over the course of
1 year and discharged with a diagnosis of brain tumor,
4.9% were initially thought to have had a stroke; gener-
ally, these patients were older and were subsequently
diagnosed with a glioblastoma multiforme.24
The case patient’s headache has yet to be character-
ized. However, if it were worse in the morning and bet-
ter with standing or sitting, the presence of concomi-
tant raised intracranial pressure or hydrocephalus
should be considered. Frequent seizures are also plau-
sible, since headache is an atypical presentation of idio-
pathic temporal lobe epilepsy. However, the diagnosis
of seizure is only a beginning, and further work-up to
determine the cause of seizure would be necessary. The
patient’s symptoms do fit quite well with a viral en-
cephalitis. Common forms, such as herpes encephalitis,
can present over days with personality changes,
headache, and focal neurologic signs.15 Vasculitis, how-
ever, is also a possibility. Headache is common in vas-
culitides that affect the CNS, and focal signs would
depend on the location of the inflammatory lesions.25
In contrast, a paraneoplastic syndrome such as limbic
encephalitis would be expected to develop over a slow-
er time course; however, presentations after days can
sometimes be seen.26 Considering all of the patient’s
known symptoms, the least likely explanation is stroke.
Stroke would be expected to result in a sudden change
rather than in an evolution of changes over 1 week and
is also not usually associated with positive symptoms
such as “odd smells.”
FURTHER HISTORY
Further history and review of systems (via the pa-
tient’s daughter) reveal that the headache was holo-
cephalic and without clear positional or diurnal varia-
tion. There was also no past history of headache. At no
point did the patient complain of visual changes, verti-
go, word-finding difficulty, dysarthria, dysphagia, inco-
ordination, focal weakness, or focal sensory changes.
Aside from the respiratory symptoms described in the
Neurology Volume 9, Part 4 9
 Approach to the Evaluation of Encephalopathy
initial history, the patient has no systemic complaints.
Past medical history is significant only for chronic bron-
chitis attributed to a 25 pack-year history of tobacco
use. Aside from her recent course of azithromycin, the
patient’s only medication is occasional naproxen. She
has no known drug allergies.
The daughter reports that her mother has not traveled
recently or mentioned recent insect bites. The patient’s
mother died of lung cancer related to tobacco use at age
76 years; her father died of cardiac causes at age 78 years.
Her 2 siblings suffer from hypertension and diet-
controlled diabetes but are otherwise healthy. Her 3 adult
daughters are healthy. The patient is a homemaker.
• Is this further history helpful in identifying a specif-
ic etiology?
On the whole, the further history from the daughter
provides little useful information to help explain the
patient’s clinical presentation. It is unclear how we
would relate the patient’s tobacco use directly to her
current symptoms, although it certainly is associated
with increased rates of stroke and small cell lung cancer
(the latter of which has been associated with anti-Hu
antibodies and related paraneoplastic syndromes,
including limbic encephalitis26). The medication histo-
ry reveals only intermittent naproxen use. While non-
steroidal anti-inflammatory drugs (NSAIDs) such as
naproxen can be responsible for cases of aseptic menin-
gitis,27 perhaps even more so in patients with lupus (see
discussion in Ostensen and Villiger28), it would be rela-
tively difficult to envisage a scenario in which occasion-
al naproxen accounted for the current presentation.
A SUDDEN CHANGE
While the neurologist is speaking to the daughter in
the waiting room, the patient experiences a seizure.
The neurologist is called emergently, but by the time he
arrives the movements have stopped and the patient is
being intubated. As described by the ED staff, during
the episode the patient became unresponsive and start-
ed picking at her clothes with her left hand. Her head
turned to the left, and she then shook all her limbs for
approximately 20 seconds.
• Which of the following is not a cause of seizure?
A) Brain tumor
B) Viral encephalitis
C) Large-vessel stroke
D) Vasculitis
E) Paraneoplastic syndrome
F) Toxic leukoencephalopathy
10 Hospital Physician Board Review Manual
The least likely cause of a seizure in this case would
be a toxic leukoencephalopathy (for a review, see Filley
et al29); disorders that disrupt white matter tracts but
preserve cortical architecture are unlikely to produce
seizures. The other etiologies listed are all potentially
epileptogenic. In a study of 50 patients with paraneo-
plastic limbic encephalitis, exactly half suffered from
seizures at some point during the course of their ill-
ness.26 In an analysis of 474 stroke patients, 4.4% pre-
sented with a convulsion.30 Pace et al31 found that in 119
consecutive patients with supratentorial gliomas, 62
(52%) presented with seizures. Herpes encephalitis, the
most common viral encephalitis, presents quite com-
monly with seizures because of its predilection for the
temporal lobe. One recent study of 32 Middle-Eastern
encephalitis patients who were HSV-1 positive by CSF
polymerase chain reaction (PCR) assay reported that 24
(75%) suffered from seizures.32 Finally, vasculitis is a het-
erogeneous disorder, and seizure frequency likely
varies. However, multiple vasculitides share an associa-
tion with seizure.25 Thus, seizure excludes very few of
the potential diagnoses. Examination, even of an intu-
bated patient, will be critical.
POST-SEIZURE PHYSICAL AND NEUROLOGIC
EXAMINATIONS
Shortly after intubation, the patient’s temperature is
102.5°F (39.2°C), blood pressure is 148/82 mm Hg,
pulse is 115 bpm, respiratory rate is 12 breaths/min on
assist-control ventilation, and oxygen saturation is
100%. She has been administered 2 mg of lorazepam in
addition to the short-acting paralytics and sedatives used
in the intubation. Neck examination is complicated by
the presence of the endotracheal tube; meningismus is
difficult to evaluate. Examination of the ears does not
reveal any effusion; tympanic light reflex appears nor-
mal. Lungs are clear to auscultation, and cardiac exami-
nation is notable for tachycardia and a 2/6 mid-systolic
murmur. Abdomen is soft, and extremities do not reveal
any rash, splinter hemorrhages, or petechiae.
On neurologic examination, the patient grimaces to
sternal rub but does not open her eyes. Pupils are
equally round and reactive to light; there is no clear
papilledema on funduscopic examination. There is a
mild right gaze preference, but oculocephalic reflex is
intact bilaterally. Corneal reflex is intact. There is a mild
left facial droop that appears to spare the forehead. The
patient withdraws purposefully to noxious stimuli on
the right but is more sluggish with her left arm and leg.
Reflexes are 1+ on the right and 2+ on the left; the
planter reflex is equivocal bilaterally.
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 Approach to the Evaluation of Encephalopathy
• Which of the following therapies would be least crit-
ical to start empirically?
A) Ceftriaxone
B) Vancomycin
C) Ampicillin
D) Acyclovir
E) Dexamethasone
F) Acetaminophen
G) Phenytoin
The physical and neurologic examination has helped
to narrow the differential diagnosis in this case. The
presence of fever necessitates evaluation of infection. In
addition to investigating for encephalitis and/or menin-
gitis, other infectious etiologies such as bacterial endo-
carditis, brain abscess, and septic central venous throm-
bosis should be considered. Moreover, the presence of
fever to 102.5°F (39.2°C) argues against a paraneoplas-
tic syndrome, brain tumor, or stroke. Another diagnosis
that commonly enters the differential—acute dissemi-
nated encephalomyelitis—would be less likely in the
presence of fever, which typically precedes rather than
accompanies the illness but can be present in fulminant
cases.33 Finally, the newly discovered focal symptoms
(ie, mild right-sided gaze preference, left-sided hemi-
paresis) argue for involvement of the right frontopari-
etal cortex and/or the right corticospinal tract above the
level of the facial nucleus. In conjunction with the tem-
poral lobe pathology suggested by the history, our suspi-
cion of a more widespread, predominantly right hemi-
spheric process is raised.
While further tests are considered, the patient clearly
should be treated empirically for the most likely and the
most concerning possibilities. In this case, the fever and
concern for meningoencephalitis strongly suggest that
empiric antibiotic therapy and antipyretics (eg, aceta-
minophen) should be administered emergently. Ceftri-
axone, vancomycin, and ampicillin are very appropriate
antibiotic choices; ampicillin in particular will treat Lis-
teria monocytogenes, which should always be considered in
the elderly and the potentially immunocompromised.
The possibility of herpes encephalitis, especially given
symptoms referable to the temporal lobe, should be cov-
ered with intravenous acyclovir. Phenytoin is also a very
reasonable drug in this instance. While it is well known
that single idiopathic seizures may not need to be treat-
ed, the more obviously appropriate consideration is
whether the inciting factors that precipitated the seizure
remain present. In this case, the fever and focal signs
argue that those inciting factors remain.
The use of dexamethasone is perhaps the most con-
troversial in this case. In adults, dexamethasone has
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been shown to be beneficial in the treatment of acute
bacterial meningitis, particularly due to Streptococcus
pneumoniae 34 and Mycobacteria tuberculosis,35 and should
be started at the time of the first antibiotic dose. In this
case, however, the concern for other infections, such as
bacterial endocarditis, argues against corticosteroid
use. Our leading diagnosis, herpes encephalitis, has
not (yet) been shown to benefit from acute steroid
treatment, although steroid use has been suggested
when early edema is present.36 We will thus obtain fur-
ther information before considering dexamethasone
in this case.
• Of the following tests and procedures, which would
be least urgent in this case?
A) Lumbar puncture
B) Blood cultures
C) CBC and chemistry panel
D) EEG
E) MRI of the brain
F) Computed tomography (CT) of the head
With our differential heavily focused on infectious
etiologies, lumbar puncture should be performed as
expeditiously as possible, with the caveat that the focal
findings and poor examination argue for a screening
CT of the head to first rule out the possibility of hydro-
cephalus or mass effect—both of which would be con-
traindications to lumbar puncture. CBC, chemistry
panel, and blood cultures are all critical to evaluate for
the extent and severity of an infectious process. Given
the focal findings referable to the right hemisphere,
MRI of the brain with and without gadolinium would
be the best approach to evaluate the nature of the cere-
bral pathology. While helpful, the EEG is not critical
immediately, unless the patient remains sedated and
our ability to monitor potentially ongoing seizure activ-
ity is compromised.
DIAGNOSTIC WORK-UP
The ED physicians note the neurologist’s recom-
mendations and quickly obtain many of the requested
studies. The CBC is notable only for a borderline leuko-
cyte count of 11.0 × 109/L (the upper cutoff on the lab-
oratory reference scale). Screening chemistries are all
within normal limits. CT of the head does not reveal
any evidence of hydrocephalus. Blood samples are
drawn and sent for culture.
A lumbar puncture is performed. The CSF is clear
and colorless, with a glucose of 62 mg/dL (normal,
50–75 mg/dL) and protein of 72 mg/dL (normal,
10–40 mg/dL). No red cells are present, but 17 white
Neurology Volume 9, Part 4 11
 Approach to the Evaluation of Encephalopathy
Figure. Magnetic resonance imaging scan of the brain with fluid-
attenuation, inversion recovery (FLAIR) sequence obtained from
the patient in case 2. Note the increased signal intensity in the
right temporal lobe involving both gray and white matter.
cells per high power field are seen, 97% of which are
lymphocytes. Gram stain reveals no organisms.
MRI of the brain with and without gadolinium is
obtained. A representative fluid-attenuation, inversion
recovery (FLAIR) sequence reveals increased signal in-
tensity in the right temporal lobe that extends upward
into the right frontal lobe (Figure).
• Based on the CSF and imaging results, what is the
leading diagnosis?
A) Acute bacterial meningitis
B) NSAID-associated meningitis
C) Herpes encephalitis
D) Bacterial endocarditis complicated by stroke
E) Brain abscess
Given the entire constellation of signs, symptoms,
and laboratory findings, the leading diagnosis is a viral
encephalitis. The most common of these and the most
treatable (with acyclovir) remains herpes encephalitis,
which is the most likely cause in this case. This patient’s
acute-to-subacute onset accompanied by fever, enceph-
alopathy, and focal neurologic findings referable to the
temporal lobe are classic for HSV encephalitis.15 As
described in Chaudhuri and Kennedy’s37 discussion of
Kennedy’s 1988 retrospective study of 46 cases (29 con-
firmed by isolation of HSV from the brain), presenting
symptoms include “a history of a prodromal influenza-
12 Hospital Physician Board Review Manual
like illness (48%), rapid onset of headache, clouding of
consciousness and confusion (52%), meningism (65%),
raised intracranial pressure (33%), deep coma (35%),
mutism or aphasia (46%), focal neurologic signs (89%),
and seizures (61%).” The MRI scan documents the
classic finding of increased T2-weighted (in this case,
FLAIR) signal in the temporal lobe. As an aside, it
should be borne in mind that other viral encephalitides
exist, as do treatments for them, including cytomegalo-
virus encephalitis (gancyclovir and foscarnet), varicella
zoster virus encephalitis (acyclovir), and enteroviral en-
cephalitis (pleconaril, currently under investigation).
Thus, thinking broadly is important.37
The CSF lymphocytosis argues against acute bacter-
ial meningitis, which would be associated with the
presence of polymorphonuclear leukocytes. Bacterial
endocarditis would not typically be associated with evi-
dence of infection in the CSF. NSAID-associated
meningitis, while it could be consistent with the CSF
results in isolation, would not explain the MRI find-
ings. Brain abscess, whose associated CSF findings
would be dependent on both the organism and the
extent of communication with the CSF space, also
would not be consistent with the MRI scan; one would
expect to see a localized collection (or collections)
with ring enhancement following administration of
contrast rather than the relatively diffuse signal hyper-
intensity seen here.
DIAGNOSIS AND INITIAL MANAGEMENT
HSV PCR assay subsequently returns a positive re-
sult, and the patient is started on a 21-day course of
intravenous acyclovir. Over the next 3 to 4 days, her con-
dition stabilizes, and she is successfully weaned off the
ventilator. However, she subsequently becomes some-
what agitated, moaning and reaching for her central
line and other tubing. The team asks the neurologist
for help with symptomatic management.
• Which of the following interventions is least likely to
be efficacious?
A) Haloperidol
B) Environmental cues
C) Lorazepam
D) Olanzapine
E) Clonidine
Few randomized controlled trials (RCTs) of sympto-
matic management of encephalopathy have been con-
ducted. In a recent meta-analysis, Weber and col-
leagues38 reported that there is very little good evidence
to guide management; this finding was confirmed by a
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 Approach to the Evaluation of Encephalopathy
Cochrane review of delirium in patients with pre-existing
cognitive impairment.39 In an RCT by Cole and col-
leagues,40 227 patients were randomized to usual care or
to consultation and follow-up with a study nurse and
either a geriatrician or psychiatrist. These specialists
could implement their own recommendations; no treat-
ment medications were specified, although the nursing
staff used a checklist to make environmental, cognitive,
and activity recommendations. Improvement was de-
fined as “an increase in the Mini-Mental State Examina-
tion (MMSE) score of 2 or more points, with no decrease
below baseline plus 2 points, or no decrease below a base-
line MMSE score of 27.” By this measure, there was no
significant difference in the percentage of improvement
between study groups (48% in the intervention group
versus 45% in the usual care group). In a smaller study of
31 hospitalized AIDS patients, Breitbart and colleagues41
found that haloperidol and chlorpromazine but not
lorazepam were efficacious in treating symptoms of de-
lirium, as assessed by improvements on the Delirium
Rating Scale. Other studies have suggested efficacy for
the atypical antipsychotics olanzapine and risperidone as
well as for the antidepressant mianserin (not available in
the United States).38 In a consensus statement of the
American Psychiatric Association, the authors emphasize
use of haloperidol for its lack of anticholinergic side
effects, lower incidence of extrapyramidal side effects,
and lower likelihood of sedation and hypotension rela-
tive to other neuroleptics.42 The guidelines also note the
possible utility of atypical antipsychotics, and they sug-
gest reserving benzodiazepine treatment for alcohol or
sedative-hypnotic withdrawal and for adjunctive treat-
ment in patients who cannot tolerate effective doses of
antipsychotics. Clonidine is least likely to be helpful as a
treatment for agitation in this case.
Of course, these medications are symptomatic treat-
ments that rarely treat the primary cause of the enceph-
alopathy. Every effort should be made to treat the un-
derlying etiology as well as to avoid significant side
effects (especially sedation) that may cloud under-
standing of the evolution of an unknown disease pro-
cess. Losing the ability to follow changes in the neuro-
logic examination for iatrogenic reasons, such as
oversedation, can lead not only to unnecessary testing
but also to missed opportunities to treat incipient ill-
ness. As always, excellent nursing care is extremely
important and can potentially reduce the need for
pharmacologic approaches. Simple interventions to
minimize insomnia and auditory and visual impair-
ment, for example, are low-risk and may help to pro-
vide re-orienting cues.
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FURTHER MANAGEMENT AND CASE CONCLUSION
A low dose of olanzapine coupled with environmen-
tal changes lead to improvements in the patient’s agita-
tion. Over the following months, the patient continues
to recover but sustains significant memory deficits,
some blunting of personality, and a right hemiparesis.
She is readmitted to the inpatient neurology service
once for recurrent seizures despite levetiracetam mono-
therapy and subsequently requires multiple agents to
control her epilepsy.
SUMMARY
Without immediate treatment with acyclovir on her
initial presentation, this patient’s deficits certainly could
have been worse. Unfortunately, she remained impaired
despite maximal initial therapy. In the next case, we pre-
sent yet another instance in which urgent treatment is
essential.
CASE 3: A 50-YEAR-OLD PATIENT WITH
PROGRESSIVE MUTISM OVER A MONTH
INITIAL PRESENTATION
A 50-year-old right-handed woman is brought by
her boyfriend to the ED for evaluation of progressive
cognitive and right arm difficulty over the past month.
The neurology consult team is called to see the patient
shortly after her arrival.
The patient was apparently in her baseline state of
good health until 4 weeks ago, when her car slid on the
ice and she crashed into a retaining wall at low speed.
Her boyfriend, who provides most of the history, re-
ports that the patient “split her upper lip” and was very
upset about the accident but denied loss of conscious-
ness and headache. She refused medical care at that
time. She returned to work as a high school teacher for
2 days but then decided she “couldn’t do it anymore”
and called in sick through the winter break. Her boy-
friend denies that the patient has experienced major
changes in personality or behavior other than being
“more withdrawn and talking less.” He notes that until
recently she was still speaking on the phone every day
with her father.
One week after the accident, the boyfriend noticed
that the patient was using her right arm less around the
house. She continued to bathe, feed herself, and inter-
act with him. Finally, over the past 2 to 3 days, she has
been close to mute, providing only occasional “yes” or
“no” answers when she appears to be emotionally
Neurology Volume 9, Part 4 13
 Approach to the Evaluation of Encephalopathy
aroused. Although it is unclear whether she is reliable,
during the interview the patient does follow commands
and shakes her head to deny headache, blurry vision,
diplopia, vertigo, incoordination, and sensory changes.
There have been no lapses in consciousness.
• Based on this patient’s history, which of the follow-
ing etiologies would be least likely?
A) Subdural hematoma
B) Brain tumor
C) Hypothyroidism
D) Brain abscess
E) Intracerebral hemorrhage
The most striking aspect of this patient’s history is its
neurologic focality. Perhaps related to an episode of
trauma, the patient experienced a 4-week history of
mild behavioral changes and progressive difficulty with
both language production (suggestive of a Broca’s
aphasia) and movement of the right arm. This story
strongly implicates dysfunction of the left frontal lobe.
There is no evidence for encephalopathy in the history.
The patient has been persistently alert, interactive, and
without other markers of encephalopathy (eg, psy-
chomotor retardation, agitation, hallucinations). Thus,
the least likely etiology of those listed is the one that
does not give rise to such strikingly focal findings—
hypothyroidism. Investigation of systemic processes
such as hypothyroidism, uremia, and the like may sub-
sequently be useful but not as primary explanations for
the chief complaint.
PHYSICAL AND NEUROLOGIC EXAMINATIONS
The patient’s vital signs and general examination are
unremarkable. Neurologic examination reveals an
abulic woman who follows 3-step, midline-crossing
commands easily but who is unable to repeat and who
verbalizes only twice (“but,” “no”) during the entire
30-minute clinical examination. Elemental examina-
tion is most notable for bilateral optic disc edema; 4/5
weakness of the right triceps, wrist extensors, and finger
extensors; right-sided hyperreflexia; and a Babinski re-
sponse on the right.
• What is the most important next step in the work-up
of this patient?
A) CT scan of the head
B) Lumbar puncture
C) CBC with differential
D) Carotid ultrasonography
E) EEG
14 Hospital Physician Board Review Manual
This patient’s signs and symptoms, which include a
Broca’s aphasia and right hemiparesis, are strongly sug-
gestive of focal involvement of the left frontal lobe.
Thus, the most important step would be to clarify the
nature of the pathology, which would be best accom-
plished by acquiring an image of the brain. CBC with
differential and carotid ultrasonography may subse-
quently prove to be useful but will not be most reveal-
ing now. Seizure must be considered, and an EEG may
be helpful later, especially if the patient shows episodic
changes in her language function. Lumbar puncture
would be contraindicated by the signs of increased in-
tracranial pressure (bilateral papilledema) found on
examination.
CASE CONCLUSION
One hour later, a CT scan of the head documents a
2.5 cm × 3.5 cm left frontal mass accompanied by dif-
fuse edema. There is obliteration of the left lateral ven-
tricle, subfalcine herniation, and 1.6 cm of midline
shift. The patient is immediately given 10 mg intra-
venous dexamethasone and urgently evaluated by the
neurosurgical service for possible resection of the mass.
SUMMARY
This case emphasizes that evidence of focal neuro-
logic deficits, including mutism, should strongly sug-
gest a diagnosis other than or in addition to en-
cephalopathy.
CONCLUSION
Because the scope of potential causes of enceph-
alopathy is broad and the time for action is frequently
short, following a systematic approach to evaluation is
critical. As should be familiar to physicians from all
fields of medicine, one should quickly clarify the nature
of the cognitive change: Is encephalopathy present?
Are the symptoms acute, subacute, or chronic? Is the
change mono- or multiphasic? Because the cause of
mental status change is often multifactorial, having a
broad initial differential diagnosis helps to ensure that
no possibilities are overlooked. One should then prior-
itize the diagnostic possibilities, with emphasis on the
inclusion or exclusion of emergent or life-threatening
diagnoses. Work-up should be initiated promptly, and
the decision to start the appropriate therapy, possibly
empirically, should be made expeditiously.
Identifying and treating the underlying cause(s) of
the encephalopathy is paramount, but supportive and
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 Approach to the Evaluation of Encephalopathy
symptomatic therapy should also be considered early,
with the important caveat that many of these interven-
tions will (and should) be nonpharmacologic. For
example, measures to reduce insomnia, minimize sen-
sory impairments, encourage as much mobility as is
safe, and encourage contact with familiar objects and
people are potentially quite helpful. Finally, attention to
the patient’s caregivers and family members is extreme-
ly important. Not only are these episodes often fright-
ening for them, but their understanding and help will
be critical for the patient’s care in the future.
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