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S t a t u s i n H I V-I n f e c t e d
Patients
a,b, a,b,c
Emily L. Ho, MD, PhD *, Cheryl A. Jay, MD
KEYWORDS
Human immunodeficiency virus AIDS Altered mental status
Central nervous system infection
EPIDEMIOLOGY
Before ART became the standard of HIV care in high-income countries, approximately
half of HIV-infected patients developed symptomatic central or peripheral nervous
system disease, with neuropathology observed in nearly all individuals dying with
HIV/acquired immunodeficiency syndrome (AIDS).5,6 Since the advent of ART, the
incidence of dementia, the major cerebral OIs (cryptococcal meningitis, toxoplas-
mosis, progressive multifocal leukoencephalopathy [PML]), and primary CNS
lymphoma (PCNSL) has fallen.3,7,8 HIV-associated dementia is also less common
and more indolent in patients on ART.3,9 In the United States, fewer patients now
Funding support: Emily L. Ho has received a Clinical Research Training Fellowship from the
American Academy of Neurology.
a
Department of Neurology, University of California San Francisco, San Francisco, CA, USA
b
Department of Neurology, 4M62, San Francisco General Hospital, 1001 Potrero Avenue, San
Francisco, CA 94110, USA
c
Positive Health Program, San Francisco General Hospital, 1001 Potrero Avenue, San Francisco,
CA 94110, USA
* Corresponding author. Department of Neurology, 4M62, San Francisco General Hospital, 1001
Potrero Avenue, San Francisco, CA 94110.
E-mail address: Emily.Ho@ucsf.edu
develop the mutism, quadriparesis, and incontinence that were common with late-
stage infection in the early years of the AIDS epidemic.
In approximately 25% of patients, the first weeks and months after initiation of ART
may be complicated by the immune reconstitution inflammatory syndrome (IRIS), with
paradoxic worsening of previously diagnosed or subclinical OIs or the development of
autoimmune disorders.10 IRIS affects most organ systems, including the brain.
Patients with tuberculosis may be at particular risk of IRIS, and tuberculous meningitis
and tuberculoma associated with initiation of ART have been reported. Clinical
exacerbation of cryptococcal meningitis, worsening PML, and rapidly progressive
dementia in the setting of immune reconstitution has also been described.4 The clin-
ical spectrum of IRIS is not yet fully defined, and should be considered when patients
develop AMS in the first weeks and months after starting ART.
Patients with HIV are at increased risk for substance abuse, affective disorders, and
psychosis.2 Injection drug users with HIV remain at risk for the neurologic sequelae of
endocarditis, including brain abscess, meningitis, ischemic stroke from septic embo-
lism, and hemorrhagic stroke from mycotic aneurysm rupture. Patients coinfected
with hepatitis C are at risk for cognitive impairment even in the absence of cirrhosis
and portal hypertension.11 In addition, HIV-infected patients who use cocaine or meth-
amphetamine are at risk for seizures and ischemic and hemorrhagic stroke.
Medications used to treat HIV disease or associated conditions may also contribute to
AMS. Antiretroviral agents, particularly the nonnucleoside reverse transcriptase inhibitor
(NNRTI) efavirenz, can cause cerebral side effects, including psychiatric syndromes, as
can the myriad other drugs used to treat HIV/AIDS and comorbid medical conditions.2
Finally, as a multisystem illness, HIV infection can cause AMS even without primary
neurologic, psychiatric, or medication-associated illness. For example, patients with
HIV-associated nephropathy are subject to the neurologic complications of uremia,
including encephalopathy. Septic patients may present with AMS in the absence of
CNS infection.
CLINICAL FEATURES
As for any patient presenting to the emergency department (ED) with AMS, important
elements of the history include the temporal progression of symptoms, drug use
(prescription, over-the-counter, illicit), trauma, focal symptoms (aphasia, neglect,
hemianopsia, hemiparesis, hemisensory loss), seizures, and symptoms suggesting
increased intracranial pressure (ICP) (Box 1 and Table 1). Additional important details
in the HIV-infected patient include recent and nadir CD4 count, viral load and, for
patients on ART, the specific regimen and the duration of therapy. Regardless of treat-
ment history, patients with CD4 counts less than 200 cells/mm3 are at highest risk for
cerebral OIs, primary CNS lymphoma, and HIV-associated dementia.1,3,5,8,9 Patients
with prior cerebral toxoplasmosis or cryptococcal meningitis require secondary
prophylaxis unless ART increases the CD4 count to greater than 200 cells/mm3 for
6 months.7 Clinicians should have a high index of suspicion for relapse in an altered
patient with a history of cerebral OIs.
For patients recently started on ART, additional diagnostic considerations include
medication side effects (eg, efavirenz) or IRIS.2,4,9,10 Patients with CD4 counts of
more than 200 cells/mm3 may be at risk for the major HIV-related brain disorders if
treatment was begun within the past 6 months or if there is evidence of treatment
failure, such as falling CD4 count, rising viral load, or both.
It is important to remember that the immune dysfunction that predisposes HIV-
infected patients to cerebral infections also masks the signs and symptoms
Altered Mental Status in HIV-Infected Patients 313
Box 1
Key elements of the history
Table 1
Differential diagnosis of AMS in the HIV high-risk population
Box 2
Key points in recognizing subtle CNS infections in advanced HIV disease
DIFFERENTIAL DIAGNOSIS
Focal Cerebral Dysfunction
Patients with signs or symptoms suggesting lateralized brain disturbance (Table 2)
may have AMS by several mechanisms, more than one of which can coexist in a given
patient. Brainstem or cerebellar lesions may impair level of alertness early. Patients
with solitary hemispheric lesions are awake unless there is significant mass effect,
concomitant meningitis, or toxic-metabolic encephalopathy. Dominant hemisphere
lesions cause aphasia (often with associated right homonymous hemianopsia, hemi-
paresis, or hemisensory loss) and nondominant hemisphere processes cause neglect
or inattention with left-sided visual, motor, or sensory dysfunction. Patients with old
focal brain lesions, such as prior trauma, stroke, tumor, or infection, may experience
a worsening of stable focal deficits in the setting of drug intoxication, metabolic
derangement, meningitis, or seizure. In general, CNS OIs and primary CNS lymphoma
are more common in patients with CD4 counts less than 200 cells/mm3, whereas cere-
brovascular disease (which may complicate CNS infection, particularly tuberculosis
[TB] or syphilitic meningitis) is more common in HIV-infected patients with focal
cerebral deficit at higher CD4 counts.12
Initial evaluation proceeds as for any patient with AMS, with particular attention to
evidence of increased ICP, first-time seizure, trauma, or focal cerebral deficit
(Table 4). Appropriate laboratory studies include electrolytes, blood urea nitrogen
Table 2
Clinical features: focal cerebral dysfunction in HIV/AIDS
Abbreviations: CSF, cerebrospinal fluid; CMV, cytomegalovirus; EBV, Epstein-Barr virus; TB, tuberculosis; VZV, varicella-zoster virus.
315
316 Ho & Jay
Table 3
Clinical features: diffuse cerebral dysfunction in HIV/AIDS
(BUN) and creatinine, liver function tests, complete blood count (CBC), prothrombin
time, and toxicology screen.
Although magnetic resonance imaging (MRI) is more sensitive for many HIV-related
cerebral disorders, multidetector computed tomographic (CT) scanners are preferable
for agitated and otherwise unstable patients. If there are contraindications to iodinated
Table 4
Selected HIV-related brain disorders: neuroimaging, CSF
Cerebral toxoplasmosis Toxoplasma IgG positive: serologic screening is part of routine HIV care, so results may be available in the medical
record of patients with an established HIV diagnosis
CT/MRI (see Fig. 1): ring-enhancing lesions with marked surrounding edema in basal ganglia or cortical/subcortical
junction
Enhancing lesions with negative Toxoplasma serology are more likely to be other infectious cause or primary CNS
lymphoma
LP may be contraindicated, depending on imaging results: elevated protein, normal glucose, lymphocytic/monocytic
pleocytosis; Toxoplasma antibodies usually not done routinely in CSF
PCNSL CT/MRI (see Fig. 2): Homogeneously enhancing lesion or lesions in periventricular regions or corpus callosum, with mild
to moderate surrounding edema
LP may be contraindicated, depending on imaging results: elevated protein, normal glucose (unless associated
lymphomatous meningitis, in which case glucose may be low), lymphocytic pleocytosis, sometimes with positive EBV
PCR or more rarely cytology
PML CT/MRI (see Fig. 3): Nonenhancing, asymmetric white matter lesion or lesions, often in parietal or occipital white
matter, without surrounding edema in most patients. May be confused with ischemic stroke—sparing of gray matter in
Abbreviations: AFB, acid-fast bacillus; CT, computed tomography; LP, lumbar puncture; MRI, magnetic resonance imaging; PCR, polymerase chain reaction; VDRL,
Venereal Disease Research Laboratory test.
317
318 Ho & Jay
Fig. 1. Cerebral toxoplasmosis. Head CT pre- (left) and postcontrast (center) from a patient
who presented with headache, speech difficulty, and left arm weakness demonstrated
a ring-enhancing lesion with surrounding edema in the right globus pallidus (and a smaller
lesion in the left temporal lobe not seen on this image). HIV serology came back positive,
with positive Toxoplasma IgG. The patient’s headache and focal deficits resolved with empir-
ical therapy for toxoplasmosis. Repeat postcontrast head CT 2 months later (right) showed
decreased edema and resolution of abnormal enhancement.
Altered Mental Status in HIV-Infected Patients 319
Fig. 2. Primary CNS lymphoma. Head CT pre- (left) and postcontrast (right) from an
untreated AIDS patient who presented with a generalized seizure after a week of dysarthria
and right-sided weakness and numbness demonstrated an intrinsically hyperdense left fron-
toparietal lesion with mass effect and slight homogeneous enhancement. Toxoplasma
serology was negative, and brain biopsy revealed primary CNS lymphoma.
Except for patients with a secure diagnosis of a rapidly reversible and definitively treat-
able toxic-metabolic encephalopathy, such as hypoglycemia or opiate overdose, or
seizure with full recovery (and negative workup), most patients with AMS and HIV
disease require admission. Patients with focal CNS infection, meningitis, or PCNSL
are at risk for seizures and increased ICP, although antiepileptic drugs (AEDs) are
not given as routine prophylaxis without a documented seizure. Elevated ICP may
develop as a consequence of focal or generalized cerebral edema, hydrocephalus,
or both. Patients with meningitis may develop cranial neuropathies, and ischemic
stroke may complicate syphilitic, tuberculous, or acute bacterial meningitis.
320 Ho & Jay
Fig. 3. Progressive multifocal leukoencephalopathy. Brain MRI from an AIDS patient who
presented with mental status change and ataxia showed left basal ganglia (top left) and
left cerebellum (bottom left) lesions without mass effect on FLAIR images. Repeat brain
MRI 2 months later (top right) showed increase in the size of the basal ganglia lesion as
well as interval development of a smaller lesion in the left frontal white matter. T1-
weighted MRI post gadolinium demonstrated no enhancement of the left cerebellar lesion
(bottom right) or the left frontal lobe and basal ganglia lesions (not shown). Positive CSF JC
virus polymerase chain reaction confirmed the diagnosis of progressive multifocal
leukoencephalopathy.
Therapy may not always be started in the acute care setting for HIV-related cerebral
OIs if there is significant diagnostic uncertainty and no indication of neurologic emer-
gency (ie, no increased ICP, seizure, bacterial meningitis, or acute stroke) (Table 5).
Increased ICP is managed in the usual fashion, as is status epilepticus. The recur-
rence risk for seizures in patients with HIV disease appears to be higher than in sero-
negative patients18; hence it is reasonable to consider AED therapy for a single
seizure, in the absence of an obvious reversible toxic-metabolic precipitant such as
withdrawal, cocaine or methamphetamine use, hypoglycemia, hyponatremia, or hypo-
calcemia. That decision is particularly complicated in patients on ART, because first-
line AEDs such as phenytoin and carbamazepine, as hepatic enzyme inducers, have
Altered Mental Status in HIV-Infected Patients 321
Table 5
Initial treatment of selected CNS infections in HIV/AIDS
SUMMARY
Key elements of the history in HIV-infected patients with AMS include recent and nadir
CD4 count, recent viral load, prior neurologic or psychiatric disorders, and detailed
medication history, including antibiotic use and allergies, illicit and other nonpre-
scribed drugs, and composition and duration of ART regimen. AMS in the first weeks
to months of ART may be medication-related if efavirenz is one of the prescribed
drugs, or may be due to an immune reconstitution relapse of tuberculous or crypto-
coccal meningitis or PML. The risk of major cerebral OIs and malignancies is highest
for patients with CD4 counts less than 200 cells/mm3. The absence of headache,
fever, or meningismus should not be used to exclude these diagnoses. Noncontrast
head CT is indicated in the evaluation of AMS in HIV-infected patients; contrast-
enhanced CT should be considered in patients with CD4 counts less than 200
cells/mm3 or symptoms or signs of focal cerebral dysfunction. Cerebral toxoplasmosis
is a common cause of fever and focal cerebral dysfunction in patients with AIDS and
ring-enhancing lesions on neuroimaging studies; Toxoplasma IgG serology is usually
positive. AIDS patients with headache may have cryptococcal meningitis, even with
normal mental status, nonfocal examination, and normal neuroimaging. Serum cryp-
tococcal antigen can help suggest or exclude the diagnosis in patients who refuse
or have other contraindications to LP. Medications should be prescribed carefully
for patients on ART, because of complex drug-drug interactions, particularly for
hepatic enzyme-inducing agents such as rifampin and older antiepileptic drugs.
REFERENCES