The Acquired Immunodeficiency

Syndrome (AIDS)
In 1981, physicians became aware of the frequent occurrence of
otherwise rare opportunistic infections and neoplasmsnotably
Pneumocystis carinii pneumonia and Kaposi sarcomain otherwise
healthy young homosexual men. The study of these patients led to
the recognition of a new viral disease, AIDS. In 1983, Montagnier
and his colleagues isolated a retrovirus from a homosexual patient
with lymphadenopathy and named it lymphadenopathy-associated
virus (LAV). Shortly thereafter, Gallo and associates described a
retrovirus in the blood of AIDS patients, which they called human
T-cell lymphotropic virus (now HTLV-III). These two viruses,
LAV and HTLV-III, were shown to be identical, and an international
commission changed the name to human immunodeficiency virus
(HIV)sometimes referred to as HIV-1 to separate it from a similar
virus (HIV-2)associated with AIDS predominantly in West Africa
and elsewhere in persons of West African origin.
HIV infection is characterized by an acquired and usually profound
depression of cell-mediated immunity, as manifest by cutaneous
anergy, lymphopenia, reversal of the T-helper/T-suppressor
cell ratiomore accurately, CD4_/CD8_ lymphocytes, as a result
of reduction in CD4_ cellsand depressed in vitro lymphoproliferative
response to various antigens and mitogens. It is this
failure of immune function that explains the development of a wide
range of opportunistic infections and unusual neoplasms. Virtually
all organ systems are vulnerable, including all parts of the CNS,
the peripheral nerves and roots, and muscle. Moreover, the nervous
system is susceptible not only to diseases that are due to immunosuppression
but also to the AIDS virus infection per se.
Epidemiology In a span of 25 years, HIV infection and AIDS
have spread worldwide, attaining immense pandemic proportions.
At the time of this writing it was estimated by the World Health
Organization (WHO)that approximately 34 million adults were
infected worldwide and that about 850,000 adults in the United
States were seropositive for the virus. By all accounts, the incidence
will continue to increase in the immediate future. Particularly startling
are the statistics from sub-Saharan Africa and Southeast Asia,
where the WHO estimated that about 25,000,000 adults, or almost
9 percent of the adult population, were infected. In some areas of
East Africa, 30 percent of adults are infected with the virus.
In the United States, AIDS affects mainly homosexual and
bisexual males (53 percent of all cases)and male and female drug
users (30 percent). Somewhat less than 3 percent of patients at risk
are hemophiliacs and others who receive infected blood or blood
products, and the disease has occurred in infants born of mothers
with AIDS. Moreover, this virus may be transmitted by asymptomatic
and still immunologically competent mothers to their offspring.
Spread of the disease by heterosexual contact accounts for

about 5 percent of cases, but this number is gradually increasing,

partly through the activities of intravenous drug users. (By contrast,
an estimated 80 percent of African AIDS patients acquire their
disease through heterosexual contact.)
Clinical Features Infection with HIV produces a spectrum of
disorders, ranging from clinically inevident seroconversion to
widespread lymphadenopathy and other relatively benign systemic
manifestations ranging from diarrhea, malaise, and weight loss (the
so-called AIDS-related complex, or ARC)and to full-blown AIDS,
which comprises the direct effects of the virus on all organ systems
as well as the complicating effects of a multiplicity of parasitic,
fungal, viral, and bacterial infections and a number of neoplasms
(all of which require cell-mediated immunity for containment). Until
the recent advent of multiple antiviral drug therapy, once the
manifestations of AIDS had become established, one-half of the
patients died by 1 year and most by 3 years. Clinically, neurologic
abnormalities were noted in only about one-third of patients with
AIDS, but at autopsy the nervous system is affected in nearly all
of them. The infections and neoplastic lesions of the nervous system
that complicate AIDS are listed in Table 33-2. Details of their
pathology are to be found in the articles by Sharer and by Bell.
It has already been mentioned that HIV infection may present
as an acute asymptomatic meningitis, with a mild lymphocytic
pleocytosis and modest elevation of CSF protein. The acute illness
may also take the form of a meningoencephalitis or even a myelopathy
or neuropathy (see below). Most patients recover from the
initial acute neurologic illnesses; the relationship to AIDS may pass
unrecognized, since these illnesses are quite nonspecific clinically
and may precede seroconversion. Once seroconversion has occurred,
the patient becomes vulnerable to all the late complications
of HIV infection. In adults, the interval between infection and the
development of clinical AIDS ranges from several months to 15
years or even longer (the mean latency is 8 to 10 years and 1 year
or less in infants). It is believed that practically all seropositive
individuals will sooner or later develop AIDS, although new drugs
are constantly lengthening the latent period.
AIDS Dementia Complex In the later stages of HIV infection,
the commonest neurologic complication is a subacute or chronic
HIV encephalitis presenting as a form of dementia; formerly it was
called AIDS encephalopathy or encephalitis, but it is now generally
referred to as the AIDS dementia complex, or ADC (Navia and
Price). It has been estimated that only 3 percent of AIDS cases
Table 33-2
Neurologic complications in patients infected with HIV
Brain
Predominantly nonfocal
AIDS dementia complex (subacute/chronic HIV

encephalitis)
Acute HIV-related encephalitis
Cytomegalovirus encephalitis
Varicella zoster virus encephalitis
Herpes simplex virus encephalitis
Metabolic encephalopathies
Predominantly focal
Cerebral toxoplasmosis
Primary CNS lymphoma
Progressive multifocal leukoencephalopathy
Cryptococcoma
Brain abscess/tuberculoma
Neurosyphilis (meningovascular)
Cerebrovascular disordersnotably nonbacterial endocarditis,
cerebral hemorrhages associated with thrombocytopenia, and
vasculitis
Spinal cord
Vacuolar myelopathy
Herpes simplex or zoster myelitis
Meninges
Aseptic meningitis (HIV)
Cryptococcal meningitis
Tuberculous meningitis
Syphilitic meningitis
Metastatic lymphomatous meningitis
Peripheral nerve and root
Infectious
Herpes zoster
Cytomegalovirus lumbar polyradiculopathy, virus- or
immune-related
Acute and chronic inflammatory HIV polyneuritis
Mononeuritis multiplex
Sensorimotor demyelinating polyneuropathy
Distal painful sensory polyneuritis
Diffuse infiltrative lymphocytic syndrome (DILS)
Muscle
Polymyositis and other myopathies (including drug-induced)
SOURCE: Adapted by permission from Brew B, Sidtis J, Petito DK, Price RW: The
neurologic complications of AIDS and human immunodeficiency virus infection,
in Plum F (ed), Advances in Contemporary Neurology. Philadelphia, Davis, 1988,
chap 1.
present in this manner, but the frequency is far higher, close to twothirds,
after the constitutional symptoms and opportunistic infections
of AIDS are established. In children with AIDS, dementia is
more common than all opportunistic infections, over 60 percent of
children eventually being affected.
This disorder takes the form of a slowly or rapidly progressive
dementia (loss of retentive memory, inattentiveness, language disorder,

and apathy)accompanied by abnormalities of motor function.

Patients complain of being unable to follow conversations,
taking longer to complete daily tasks, and becoming forgetful.
Inco-ordination of the limbs, ataxia of gait, and impairment of
smooth pursuit and saccadic eye movements are usually early accompaniments
of the dementia. Heightened tendon reflexes, Babinski
signs, grasp and suck reflexes, weakness of the legs progressing
to paraplegia, bladder and bowel incontinence reflecting
spinal cord or cerebral involvement, and abulia or mutism are
prominent in the later stages of the disease. In the untreated case,
the dementia evolves relatively rapidly, over a period of weeks or
months; survival after the onset of dementia is generally 3 to 6
months but may be considerably longer. Tests of psychomotor
speed seem to be most sensitive in the early stages of dementia
(e.g., trail-making, pegboard, and symbol-digit testing).
Epstein and colleagues have described a similar disorder in
children, who develop a progressive encephalopathy as the primary
manifestation of AIDS. The disease in children is characterized by
an impairment of cognitive functions and spastic weakness and
secondarily by impairment of brain growth.
The CSF in patients with AIDS dementia (but lacking other
manifestations of AIDS)may be normal or show only a slight elevation
of protein content and, less frequently, a mild lymphocytosis.
HIV can be isolated from the CSF. In the CT scan there is
widening of the sulci and enlargement of the ventricles; MRI may
show patchy but confluent or diffuse white matter changes with illdefined
margins (Fig. 33-2). These findings are particularly useful
in diagnosis, although CMV infection of the brain in AIDS patients
produces a similar MRI appearance, as described further on.
The pathologic basis of the dementia appears to be a diffuse
and multifocal rarefaction of the cerebral white matter, accompanied
by scanty perivascular infiltrates of lymphocytes and clusters
of a few foamy macrophages, microglial nodules, and multinucleated
giant cells (Navia et al). Evidence of CMV infection may be
added, but accumulating virologic evidence indicates that the AIDS
dementia complex is due to direct infection with HIV. Which of
these changes, or the cortical atrophy, correspond most closely to
the presence and severity of dementia has not been settled. The
pathologic changes in AIDS dementia are actually not as uniform
as portrayed here. In one group of patients, there is a diffuse pallor
of the cerebral white matter, most obvious with myelin stains, accompanied
by reactive astrocytes and macrophages; the myelin pallor
seems to reflect a breakdown of the blood-brain barrier. In another
form of this process, referred to as diffuse poliodystrophy,
there is widespread astrocytosis and microglial activation in the

cerebral cortex, with little recognizable neuronal loss. In other patients,

small or large perivascular foci of demyelination, like those
of postinfectious encephalomyelitis, are observed; the nature of this
diffuse lesion is not understood. These forms of pathologic change
may occur singly or together and all correlate poorly with the severity
of the dementia.
AIDS Myelopathy, Peripheral Neuropathy, and Myopathy A
myelopathy, taking the form of a vacuolar degeneration that bears
a striking resemblance to subacute combined degeneration due to
vitamin B12 deficiency, is sometimes associated with the AIDS dementia
complex; or the myelopathy may occur in isolation, as the
leading manifestation of the disease (Petito et al). This disorder of
the spinal cord is discussed further on page 1059.
AIDS may also be complicated by several forms of peripheral
neuropathy. Of 50 such patients reported by Snider and coworkers,
8 had a distal, symmetrical, axonal polyneuropathy, predominantly
sensory and dysesthetic in type. This has been the most common
neuropathic pattern. The HIV virus has been isolated from the peripheral
nerves and ganglia. In fact, this stands as the first proven
viral polyneuritis in man (Zoster being more a ganglionopathy). In
other patients, a painful mononeuropathy multiplex occurs, seemingly

related to a focal vasculitis, or there may be a subacute inflammatory

cauda equina syndrome (a polyradiculitis)that is usually
due to an accompanying CMV infection (Eidelberg et al).
Cornblath and colleagues have documented the occurrence of an
inflammatory demyelinating peripheral neuropathy, of both the
acute (Guillain-Barre)and chronic types, in otherwise asymptomatic
patients with HIV infection. Most of these patients had a
mild pleocytosis in addition to an elevated CSF protein content.
Also, all of the patients with inflammatory demyelinating neuropathy
recoveredeither spontaneously or in response to plasma exchange
suggesting an immunopathogenesis similar to that of the
Guillain-Barre syndrome. Cornblath and associates have suggested
that all patients with inflammatory demyelinating polyneuropathies
should now be tested for the presence of HIV infection, but this is
probably appropriate only in groups of patients or in geographic
areas where the disease is prevalent. Facial palsy is being reported
with increasing frequency as a feature of AIDS; its relationship to
the generalized polyneuritis of AIDS is uncertain.
In the rare complication of AIDS called diffuse infiltrative
lymphocytosis syndrome (DILS), a variety of clinical syndromes
has been described, including all of the usual AIDS polyneuropathies.
Some instances of polyneuropathy in AIDS patients are
probably due to the nutritional depletion that characterizes advanced
stages of the disease and to the effects of therapeutic agents.
These AIDS-related neuropathies are discussed in Chap. 46 and are
well summarized by Wulff and Simpson.
A primary myopathy, taking the form of an inflammatory
polymyositis, has been described in AIDS patients, occurring at
any stage of the disease (Simpson and Bender). In some of these
cases, the myopathy has improved with corticosteroid therapy. The
original anti-AIDS drug, zidovudine (AZT), has been said to cause
a myopathy, probably due to its effect on mitochondria, but some
workers disagree and find almost all such cases to be attributable
to the AIDS virus itself (see page 1203). From listening to the
discussions of our colleagues, it is apparent that this remains an
area of controversy.
Opportunistic Infections and Neoplasms of the CNS in AIDS
In addition to the direct neurologic effects of HIV infection, a variety
of opportunistic disorders, both focal and nonfocal, occur in
such patients, as outlined in Table 33-2. Interestingly, there appears
to be a predilection for certain onesCMV infection, primary Bcell
lymphoma, cryptococcosis, toxoplasmosis, and progressive
multifocal leukoencephalopathy (page 651), in this order of frequency
(Johnson). The focal encephalitis and vasculitis of VZV
infection, considered earlier in this chapter, and unusual types of
tuberculosis and syphilis are other common opportunistic infections
of AIDS. Usually P. carinii infection and Kaposi sarcoma do
not spread to the nervous system.
Toxoplasmosis Of the focal complications, cerebral toxoplasmosis

is the most frequent (and treatable; see page 623). In the

autopsy series of AIDS reported by Navia and colleagues, areas of
inflammatory necrosis due to Toxoplasma were found in approximately
13 percent (see Fig. 32-7). Lumbar puncture, contrastenhanced
CT scanning, and MRI are useful in diagnosis. The
spinal fluid usually shows an elevation of protein in the range of
50 to 200 mg/dL, and one-third of patients have a lymphocytic
pleocytosis. Since the disease represents reactivation of a prior
Toxoplasma infection, it is important to identify Toxoplasmaseropositive
patients early in the course of AIDS and to treat them
vigorously with oral pyrimethamine (100 mg initially and then
25 mg daily)and a sulfonamide (4 to 6 g daily in four divided
doses). Curiously, the toxoplasmosis infection, so common in the
brains of AIDS patients, is not a frequent cause of the typical
infestation, namely, myositis. The main clinical problem in reference
to toxoplasmosis in AIDS is its differentiation from cerebral
lymphoma as discussed below and in Chap. 31.
CNS Lymphoma In the Johns Hopkins study (see Johnson),
about 11 percent of AIDS patients developed a primary CNS lymphoma,
which may in some cases be difficult to distinguish from
toxoplasmosis clinically and radiologically. If the cytologic study
of the CSF is negative and there has been no response to antibiotics,
stereotaxic brain biopsy may be necessary for diagnosis. The prognosis
in such patients is considerably less favorable than in nonAIDS patients; the response to radiation therapy, methotrexate, and
corticosteroids is short-lived, and survival is usually measured in
months.
In the face of enhancing focal brain lesions in AIDS, the current
approach is to assume initially the presence of toxoplasmosis,
which is treatable. Antibody tests for toxoplasmosis should be obtained;
the absence of IgG antibodies mandates that treatment be
changed in order to address the problem of brain lymphoma. Also,
if antitoxoplasmal therapy with pyrimethamine and sulfadiazine
fails to reduce the size of the lesions within several weeks, another
cause should be sought, again mainly lymphoma. In those patients
who cannot tolerate the frequent side effects of pyrimethamine or
sulfonamides (rash or thrombocytopenia), clindamycin may be of
value. Recently it has been suggested that thallium isotope singlephoton
emission computed tomography (SPECT)and positron
emission tomography (PET)can reliably exclude lymphoma as the
cause of a mass lesion in the AIDS patient. The less frequent possibilities
of tuberculous or bacterial brain abscess should be kept
in mind if none of the other avenues allow a confident diagnosis.
Cytomegalovirus Among the nonfocal neurologic complications
of AIDS, the most common are CMV and cryptococcal infections.
At autopsy, about one-third of AIDS patients are found to be infected
with CMV. However, the contribution of this infection to the total clinical picture is often
uncertain. Despite this ambiguity,

certain features have emerged as typical of CMV encephalitis in

the AIDS patient. According to Holland and colleagues, late in the
course of AIDS and usually concurrent with CMV retinitis, the
encephalopathy evolves over 3 to 4 weeks. Its clinical features
include an acute confusional state or delirium combined, in a small
proportion of cases, with cranial nerve signs including ophthalmoparesis,
nystagmus, ptosis, facial nerve palsy, or deafness. In
one of our patients, there were progressive oculomotor palsies that
began with light-fixed pupils. Pathologic specimens and MRI show
the process to be concentrated in the ventricular borders, especially
evident as T2 signal hyperintensity in these regions. It may be seen
to extend more diffusely through the adjacent white matter and be
accompanied by meningeal enhancement by gadolinium in a few
cases. Extensive destructive lesions have also been reported; this
has been true in two of our own cases. Such lesions may be associated
with hemorrhagic changes in the CSF in addition to showing
an inflammatory response. CMV may also produce a painful lumbosacral
polyradiculitis in AIDS.
The diagnosis of CMV infection during life is often difficult.
Cultures of the CSF are usually negative and IgG antibody titers
are nonspecifically elevated. Newer PCR methods may prove useful
here. Where the diagnosis is strongly suspected, treatment with
the antiviral agents ganciclovir and foscarnet has been recommended;
but, as pointed out by Kalayjian and colleagues, the CMV
disease may develop and progress while patients are taking these
medications as a form of maintenance therapy.
Cryptococcal Infection Meningitis with this organism and less
often solitary cryptococcoma are the most frequent fungal complications
of HIV infection. Flagrant symptoms of meningitis or meningoencephalitis
may be lacking, however, and the CSF may show
little abnormality with respect to cells, protein, and glucose. For
these reasons, evidence of cryptococcal infection of the spinal fluid
should be actively sought with India ink preparations, antigen testing,
and fungal cultures. Treatment is along the lines outlined (on
page 621).
Varicella Zoster Cerebral infections with this virus are less common
complications of AIDS, but when they do occur, they tend to
be severe. They take the form of multifocal lesions of the cerebral
white matter, somewhat like those of progressive multifocal leukoencephalopathy,
a cerebral vasculitis with hemiplegia (usually
in association with ophthalmic zoster), or rarely a myelitis. Encephalitis
due to HSV-1 and HSV-2 has also been identified in the
brains of AIDS patients, but the clinical correlates are unclear.
There is no evidence that acyclovir or other antiviral agents are
effective in any of these viral infections. Shingles involving several
contiguous dermatomes is known to occur in AIDS, as in other
immunosuppressed conditions.

Tuberculosis Two particular types of mycobacterial infection

tend to complicate AIDSMycobacterium tuberculosis and Mycobacterium
avium-intracellulare. Tuberculosis predominates
among drug abusers and AIDS patients in underdeveloped countries,
and a higher than usual proportion of these immunosuppressed
individuals develop tuberculous meningitis. Diagnosis and
treatment are along the same lines as in non-AIDS patients (page
612). Atypical mycobacterial infections are usually associated
with other destructive cerebral lesions and respond poorly to therapy.
Neurosyphilis Syphilitic meningitis and meningovascular syphilis
appear to have an increased incidence in AIDS patients. Cell
counts in the CSF are unreliable as signs of luetic activity; diagnosis
depends entirely upon serologic tests. It seems unlikely that
AIDS causes false-positive tests for syphilis, but this remains to be
settled.
Other rare organisms, such as Rochalimaea henselae (formerly
Bartonella), the cause of cat-scratch fever, are found with
unexpectedly high frequencies in AIDS patients and have been implicated
in an encephalopathy. Progressive multifocal leukoencephalopathy,
a viral disease now closely linked with the immunosuppressed
state of AIDS, is discussed further on in this chapter.
Diagnostic Tests for HIV Infection Many screening tests are
now available for the detection of antibodies to HIV. Most of them
are based on an enzyme-linked immunoassay (ELISA or EIA),
which has proved to be highly sensitive. However, there is a small
incidence of false-positive reactions, particularly when these tests
are used to screen persons at low risk for HIV infection. All positive
EIA tests should therefore be repeated.
The Western blot test, which identifies antibodies to specific
viral proteins, is more specific than EIA tests and is used to confirm
a positive screening test. Indeterminate Western blot tests should
be repeated monthly for several months to detect a rising concentration
of antibodies. Newer tests, using purified antigens, are being
developed and should be more specific than those currently available.
Treatment The treatment of HIV infection/AIDS, as is true for
any chronic, life-threatening disease, is difficult. Patients and their
families require counseling and education, and frequently psychologic
support in addition to complex drug regimens. Drug therapy
for HIV infection continues to change rapidly. A combination of
three and sometimes four drugs, including the reverse transcriptase
inhibitors (AZT and 3-TC or lamivudine, which act synergistically
and cross the blood-brain barrier)and the newer protease inhibitors
(such as indinavir)render 90 percent of patients free of detectable
virus for over a year. It is believed that this approach will prolong
survival, but it might be expected also to increase the prevalence
of neurologic complications of AIDS, each of which needs to be
treated as it is recognized. Referral to a specialist or a center devoted

to the management of this disease may be required.