1574 PART 5 Infectious Diseases

surprisingly rare, especially given the increased incidence of staphylococcal bacteremias seen in this population. When septic arthritis has

been reported, it has usually been due to Staphylococcus aureus, systemic fungal infection with C. neoformans, Sporothrix schenckii, or H.

capsulatum or to systemic mycobacterial infection with M. tuberculosis,

M. haemophilum, M. avium, or M. kansasii.

Patients with HIV infection treated with ART have been found to

have an increased incidence of osteonecrosis or avascular necrosis

of the hip and shoulders. In a study of asymptomatic patients, 4.4%

were found to have evidence of osteonecrosis on MRI. While precise

cause-and-effect relationships have been difficult to establish, this

complication has been associated with the use of lipid-lowering agents,

systemic glucocorticoids, and testosterone; bodybuilding exercise;

alcohol consumption; and the presence of anticardiolipin antibodies.

Osteoporosis has been reported in 7% of women with HIV infection,

with 41% of women demonstrating some degree of osteopenia. Several

studies have documented decreases in bone mineral density of 2–6%

in the first 2 years following the initiation of ART. This may be particularly apparent with tenofovir-containing regimens.

Immune Reconstitution Inflammatory Syndrome (IRIS)

Following the initiation of effective ART, a paradoxical worsening of

preexisting, untreated, or partially treated opportunistic infections may

be noted. One may also see exacerbations of pre-existing autoimmune

conditions or the development of new autoimmune conditions following the initiation of antiretrovirals (Table 202-12). IRIS related to a

known pre-existing infection or neoplasm is referred to as paradoxical

IRIS, while IRIS associated with a previously undiagnosed condition

is referred to as unmasking IRIS. The term immune reconstitution

disease (IRD) is sometimes used to distinguish IRIS manifestations

related to opportunistic diseases from IRIS manifestations related to

autoimmune diseases. IRD is particularly common in patients with

underlying untreated mycobacterial or fungal infections. Some form

of IRIS is seen in 10–30% of patients following the initiation of ART,

depending on the clinical setting, and is most common in patients

starting therapy with CD4+ T-cell counts <50 cells/μL who have a precipitous drop in HIV RNA levels following the initiation of ART. Signs

and symptoms may appear anywhere from 2 weeks to 2 years after the

initiation of ART and can include localized lymphadenitis, prolonged

fever, pulmonary infiltrates, hepatitis, increased intracranial pressure,

uveitis, sarcoidosis, and Graves’ disease. The clinical course can be

protracted, and severe cases can be fatal. The underlying mechanism

appears to be related to a phenomenon similar to type IV hypersensitivity reactions and reflects the immediate improvements in immune

function that occur as levels of HIV RNA drop and the immunosuppressive effects of HIV infection are controlled. In severe cases, the use

of immunosuppressive drugs such as glucocorticoids may be required

to blunt the inflammatory component of these reactions while specific

antimicrobial therapy takes effect.

Diseases of the Hematopoietic System Disorders of the

hematopoietic system including lymphadenopathy, anemia, leukopenia, and/or thrombocytopenia are common throughout the course

of HIV infection and may be the direct result of HIV, manifestations

of secondary infections and neoplasms, or side effects of therapy

(Table  202-13). Direct histologic examination and culture of lymph

node or bone marrow tissue are often diagnostic. A significant percentage of bone marrow aspirates from patients with HIV infection have

been reported to contain lymphoid aggregates, the precise significance

of which is unknown. Initiation of ART will lead to reversal of most

hematologic complications that are the direct result of HIV infection.

Some patients, otherwise asymptomatic, may develop persistent

generalized lymphadenopathy as an early clinical manifestation of HIV

infection. This condition is defined as the presence of enlarged lymph

nodes (>1 cm) in two or more extrainguinal sites for >3 months without an obvious cause. The lymphadenopathy is due to marked follicular

hyperplasia in the node in response to HIV infection. The nodes are

generally discrete and freely movable. This feature of HIV disease

may be seen at any point in the spectrum of immune dysfunction and

is not associated with an increased likelihood of developing AIDS.

Paradoxically, a loss in lymphadenopathy or a decrease in lymph node

size outside the setting of ART may be a prognostic marker of disease

progression. In patients with CD4+ T-cell counts >200/μL, the differential diagnosis of lymphadenopathy includes TB, KS, Castleman’s

disease, and lymphoma. In patients with more advanced disease,

lymphadenopathy may also be due to atypical mycobacterial infection,

toxoplasmosis, systemic fungal infection, or bacillary angiomatosis.

While indicated in patients with CD4+ T-cell counts <200/μL, lymph

node biopsy is not indicated in patients with early-stage disease unless

there are signs and symptoms of systemic illness, such as fever and

weight loss, or unless the nodes begin to enlarge, become fixed, or

coalesce. Monoclonal gammopathy of unknown significance (MGUS)

(Chap.  107), defined as the presence of a serum monoclonal IgG,

IgA, or IgM in the absence of a clear cause, has been reported in 3%

of patients with HIV infection. The overall clinical significance of this

finding in patients with HIV infection is unclear, although it has been

associated with other viral infections, non-Hodgkin’s lymphoma, and

plasma cell malignancy.

Anemia is the most common hematologic abnormality in

HIV-infected patients and, in the absence of a specific treatable cause,

is independently associated with a poor prognosis. While generally

mild, anemia can be quite severe and require chronic blood transfusions. Among the specific reversible causes of anemia in the setting

of HIV infection are drug toxicity, systemic fungal and mycobacterial

infections, nutritional deficiencies, and parvovirus B19 infections.

The antiretroviral zidovudine may block erythroid maturation prior

to its effects on other marrow elements. A characteristic feature of

zidovudine therapy is an elevated mean corpuscular volume (MCV).

Another drug used in patients with HIV infection that has a selective

effect on the erythroid series is dapsone. This drug can cause a serious

hemolytic anemia in patients who are deficient in glucose-6-phosphate

dehydrogenase and can create a functional anemia in others through

induction of methemoglobinemia. Folate levels are usually normal in

HIV-infected individuals; however, vitamin B12 levels may be depressed

as a consequence of achlorhydria or malabsorption. True autoimmune

hemolytic anemia is rare, although ~20% of patients with HIV infection may have a positive direct antiglobulin test as a consequence of

polyclonal B-cell activation. Infection with parvovirus B19 may also

TABLE 202-12 Characteristics of Immune Reconstitution

Inflammatory Syndrome (IRIS)

Paradoxical worsening of an existing clinical condition or abrupt appearance of

a new clinical finding (unmasking) is seen following the initiation of antiretroviral

therapy

Occurs weeks to months following the initiation of antiretroviral therapy

Is most common in patients starting therapy with a CD4+ T-cell count <50/μL who

experience a precipitous drop in viral load

Is frequently seen in the setting of tuberculosis; particularly when cART is

starting soon after initiation of anti-TB therapy

Can be fatal

TABLE 202-13 Causes of Bone Marrow Suppression in Patients with

HIV Infection

HIV infection Medications

Mycobacterial infections Zidovudine

Fungal infections Dapsone

B19 parvovirus infection Trimethoprim/sulfamethoxazole

Lymphoma Pyrimethamine

5-Flucytosine

Ganciclovir

Interferon α

Trimetrexate

Foscarnet

1575CHAPTER 202 Human Immunodeficiency Virus Disease: AIDS and Related Disorders

cause anemia. It is important to recognize this possibility given the

fact that it responds well to treatment with IVIg. Erythropoietin levels

in patients with HIV infection and anemia are generally lower than

expected given the degree of anemia. Treatment with erythropoietin

may result in an increase in hemoglobin levels. An exception to this

is a subset of patients with zidovudine-associated anemia in whom

erythropoietin levels may be quite high.

During the course of HIV infection, neutropenia may be seen in

approximately half of patients. In most instances it is mild; however,

it can be severe and can put patients at risk of spontaneous bacterial

infections. This is most frequently seen in patients with severely

advanced HIV disease and in patients receiving any of a number of

potentially myelosuppressive therapies. In the setting of neutropenia,

diseases that are not commonly seen in HIV-infected patients, such as

aspergillosis or mucormycosis, may occur. Both granulocyte colonystimulating factor (G-CSF) and GM-CSF increase neutrophil counts in

patients with HIV infection regardless of the cause of the neutropenia.

Earlier concerns about the potential of these agents to also increase

levels of HIV were not confirmed in controlled clinical trials.

Thrombocytopenia may be an early consequence of HIV infection.

Approximately 3% of patients with untreated HIV infection and CD4+

T-cell counts ≥400/μL have platelet counts <150,000/μL. For untreated

patients with CD4+ T-cell counts <400/μL, this incidence increases to

10%. Thrombocytopenia is more common in patients with hepatitis C

co-infection, cirrhosis, and/or ongoing high-level HIV replication.

Thrombocytopenia is rarely a serious clinical problem in patients with

HIV infection and generally responds well to successful ART. Clinically, it resembles the thrombocytopenia seen in patients with idiopathic thrombocytopenic purpura (Chap. 111). Immune complexes

containing anti-gp120 antibodies and anti-anti-gp120 antibodies have

been noted in the circulation and on the surface of platelets in patients

with HIV infection. Patients with HIV infection have also been noted

to have a platelet-specific antibody directed toward a 25-kDa component of the surface of the platelet. Other data suggest that the thrombocytopenia in patients with HIV infection may be due to a direct effect

of HIV on megakaryocytes. Whatever the cause, it is very clear that the

most effective medical approach to this problem has been the use of

ART. For patients with platelet counts <20,000/μL, a more aggressive

approach combining IVIg or anti-Rh Ig for an immediate response and

ART for a more lasting response is appropriate. Rituximab has been

used with some success in otherwise refractory cases. Splenectomy is a

rarely needed option and is reserved for patients refractory to medical

management. Because of the risk of serious infection with encapsulated

organisms, all patients with HIV infection about to undergo splenectomy should be immunized with vaccines to prevent disease from

S.  pneumoniae, N. meningitidis, and H. influenzae type b. It should

be noted that, in addition to causing an increase in the platelet count,

removal of the spleen will result in an increase in the peripheral blood

lymphocyte count, making CD4+ T-cell counts unreliable markers of

immunocompetence. In this setting, the clinician should rely on the

CD4+ T-cell percentage for making diagnostic decisions with respect

to the likelihood of opportunistic infections. A CD4+ T-cell percentage

of 15 is approximately equivalent to a CD4+ T-cell count of 200/μL.

In patients with early HIV infection, thrombocytopenia has also been

reported as a consequence of classic thrombotic thrombocytopenic

purpura (Chap. 111). This clinical syndrome, consisting of fever,

thrombocytopenia, hemolytic anemia, and neurologic and renal dysfunction, is a rare complication of early HIV infection. As in other settings, the appropriate management is the use of salicylates and plasma

exchange. Other causes of thrombocytopenia include lymphoma,

mycobacterial infections, and fungal infections.

The incidence of venous thromboembolic disease such as deep-vein

thrombosis or pulmonary embolus is approximately 1% per year in

patients with HIV infection. This is approximately 10 times higher

than that seen in an age-matched population. Factors associated with

an increased risk of clinical thrombosis include age >45, history of an

opportunistic infection, lower CD4 count, and estrogen use. Abnormalities of the coagulation cascade, including decreased protein S activity,

increases in factor VIII, anticardiolipin antibodies, PAR-1 expression

on T cells, or lupus-like anticoagulant, have been reported in more than

50% of patients with HIV infection. The clinical significance of this

increased propensity toward thromboembolic disease is likely reflected

in the observation that elevations in d-dimer are strongly associated

with all-cause mortality in patients with HIV infection (Table 202-9).

Dermatologic Diseases Dermatologic problems occur in >90%

of patients with HIV infection. From the macular, roseola-like rash

seen with the acute seroconversion syndrome to extensive end-stage

KS, cutaneous manifestations of HIV disease can be seen throughout

the course of HIV infection. Among the more common nonneoplastic problems are seborrheic dermatitis, folliculitis, and opportunistic

infections. Extrapulmonary pneumocystosis may cause a necrotizing

vasculitis. Neoplastic conditions are covered in a separate section

below.

Seborrheic dermatitis occurs in 3% of the general population and

in up to 50% of patients with HIV infection. Seborrheic dermatitis

increases in prevalence and severity as the CD4+ T-cell count declines.

In HIV-infected patients, seborrheic dermatitis may be aggravated by

concomitant infection with Pityrosporum, a yeastlike fungus; use of

topical antifungal agents has been recommended in cases refractory to

standard topical treatment.

Folliculitis is among the most prevalent dermatologic disorders in

patients with HIV infection and is seen in ~20% of patients. It is more

common in patients with CD4+ T-cell counts <200 cells/μL. Pruritic

papular eruption is one of the most common pruritic rashes in patients

with HIV infection. It appears as multiple papules on the face, trunk,

and extensor surfaces and may improve with ART. Eosinophilic pustular

folliculitis is a rare form of folliculitis that is seen with increased frequency in patients with HIV infection. It presents as multiple, urticarial

perifollicular papules that may coalesce into plaque-like lesions. Skin

biopsy reveals an eosinophilic infiltrate of the hair follicle, which in

certain cases has been associated with the presence of a mite. Patients

typically have an elevated serum IgE level and may respond to treatment with topical anthelmintics. Pruritus is a common symptom in

patients with HIV infection and can lead to prurigo nodularis. Patients

with HIV infection have also been reported to develop a severe form of

Norwegian scabies with hyperkeratotic psoriasiform lesions.

Both psoriasis and ichthyosis, although they are not reported to be

increased in frequency, may be particularly severe when they occur in

patients with HIV infection. Preexisting psoriasis may become guttate

in appearance and more refractory to treatment in the setting of HIV

infection.

Reactivation herpes zoster (shingles) is seen in 10–20% of patients

with HIV infection. This reactivation syndrome of varicella-zoster

virus indicates a modest decline in immune function and may be the

first indication of clinical immunodeficiency. In one series, patients

who developed shingles did so an average of 5 years after HIV infection. In a cohort of patients with HIV infection and localized zoster,

the subsequent rate of the development of AIDS was 1% per month.

In that study, AIDS was more likely to develop if the outbreak of

zoster was associated with severe pain, extensive skin involvement,

or involvement of cranial or cervical dermatomes. The clinical manifestations of reactivation zoster in HIV-infected patients, although

indicative of immunologic compromise, are not as severe as those seen

in other immunodeficient conditions. Thus, while lesions may extend

over several dermatomes, involve the spinal cord, and/or be associated

with frank cutaneous dissemination, visceral involvement has not been

reported. In contrast to patients without a known underlying immunodeficiency state, patients with HIV infection tend to have recurrences

of shingles with a relapse rate of ~20%. Valacyclovir, acyclovir, or famciclovir is the treatment of choice. Foscarnet may be of value in patients

with acyclovir-resistant virus.

Infection with herpes simplex virus in HIV-infected individuals is

associated with recurrent orolabial, genital, and perianal lesions as part

of recurrent reactivation syndromes (Chap. 187). As HIV disease progresses and the CD4+ T-cell count declines, these infections become

more frequent and severe. Lesions often appear as beefy red, are exquisitely painful, and tend to occur high in the gluteal cleft (Fig. 202-37).

1576 PART 5 Infectious Diseases

Perirectal HSV may be associated with proctitis and anal fissures. HSV

should be high in the differential diagnosis of any HIV-infected patient

with a poorly healing, painful perirectal lesion. In addition to recurrent mucosal ulcers, recurrent HSV infection in the form of herpetic

whitlow can be a problem in patients with HIV infection, presenting

with painful vesicles or extensive cutaneous erosion. Valacyclovir,

acyclovir, or famciclovir is the treatment of choice in these settings. It

is noteworthy that even subclinical reactivation of herpes simplex may

be associated with increases in plasma HIV RNA levels.

Diffuse skin eruptions due to Molluscum contagiosum may be seen

in patients with advanced HIV infection. These flesh-colored, umbilicated lesions resemble those of Penicillium marnefei or Cryptococcosis. They tend to regress with effective ART and can also be treated

with local therapy. Similarly, condyloma acuminatum lesions may be

more severe and more widely distributed in patients with low CD4+

T-cell counts. Imiquimod cream may be helpful in some cases. Atypical mycobacterial infections may present as erythematous cutaneous

nodules, as may fungal infections, Bartonella, Acanthamoeba, and KS.

Cutaneous infections with Aspergillus have been noted at the site of IV

catheter placement.

The skin of patients with HIV infection is often a target organ for

drug reactions (Chap. 56). Although most skin reactions are mild

and not necessarily an indication to discontinue therapy, patients may

have particularly severe cutaneous reactions, including erythroderma,

Stevens-Johnson syndrome, and toxic epidermal necrolysis, as a reaction

to drugs—particularly sulfa drugs, nonnucleoside reverse transcriptase

inhibitors, abacavir, amprenavir, darunavir, fosamprenavir, and tipranavir. Similarly, patients with HIV infection are often quite photosensitive and burn easily following exposure to sunlight or as a side effect

of radiation therapy (Chap. 57).

HIV infection and its treatment may be accompanied by cosmetic

changes of the skin that are not of great clinical importance but may

be troubling to patients. Yellowing of the nails and straightening of the

hair, particularly in African-American patients, have been reported as

a consequence of HIV infection. Zidovudine therapy has been associated with elongation of the eyelashes and the development of a bluish

discoloration to the nails, again more common in African-American

patients. Therapy with clofazimine may cause a yellow-orange discoloration of the skin and urine.

Neurologic Diseases Clinical disease of the nervous system

accounts for a significant degree of morbidity in a high percentage of patients with HIV infection (Table 202-14). The neurologic

problems that occur in HIV-infected individuals may be either primary to the pathogenic processes of HIV infection or secondary to

opportunistic infections or neoplasms. Among the more frequent

opportunistic diseases that involve the CNS are toxoplasmosis, cryptococcosis, progressive multifocal leukoencephalopathy, and primary

CNS lymphoma. Other less common problems include mycobacterial

infections; syphilis; and infection with CMV, herpes zoster, HTLV-1,

Trypanosoma cruzi, or Acanthamoeba. Overall, secondary diseases of

the CNS have been reported to occur in approximately one-third of

patients with AIDS. These data antedate the widespread use of ART,

and this frequency is considerably lower in patients with suppressed

viral replication. Primary processes related to HIV infection of the

nervous system are reminiscent of those seen with other lentiviruses,

such as the maedi-visna virus of sheep.

Neurologic problems directly attributable to HIV occur throughout the course of infection and may be inflammatory, demyelinating,

or degenerative in nature. The term HIV-associated neurocognitive

disorders (HAND) is used to describe a spectrum of disorders that

range from asymptomatic neurocognitive impairment (ANI) to minor

neurocognitive disorder (MND) to clinically severe dementia. The

most severe form, HIV-associated dementia (HAD), also referred to as

the AIDS dementia complex, or HIV encephalopathy, is considered an

AIDS-defining illness. Many HIV-infected patients have some neurologic problem during the course of their disease. Even in the setting

of suppressive ART, approximately 50% of HIV-infected individuals

can be shown to have mild to moderate neurocognitive impairment

using sensitive neuropsychiatric testing. As noted in the section

on pathogenesis, damage to the CNS may be a direct result of viral

infection of the CNS macrophages or glial cells or may be secondary

to the release of neurotoxins and potentially toxic cytokines such as

IL-1β, TNF-α, IL-6, and TGF-β. It has been reported that HIV-infected

individuals with the E4 allele for apoE are at increased risk for AIDS

encephalopathy and peripheral neuropathy. Virtually all patients with

HIV infection have some degree of nervous system involvement with

the virus. This is evidenced by the fact that CSF findings are abnormal

in ~90% of untreated patients, even during the asymptomatic phase

of HIV infection. CSF abnormalities include pleocytosis (50–65% of

patients), detection of viral RNA (~75%), elevated CSF protein (35%),

and evidence of intrathecal synthesis of anti-HIV antibodies (90%). It

is important to point out that evidence of infection of the CNS with

HIV does not imply impairment of cognitive function. The neurologic

function of an HIV-infected individual should be considered normal

unless clinical signs and symptoms suggest otherwise.

Aseptic meningitis may occur at any time in the course of HIV

infection; however, it is rare following the development of AIDS. This

suggests that clinical aseptic meningitis in the context of HIV infection

is an immune-mediated disease. In the setting of acute primary infection, patients may experience a syndrome of headache, photophobia,

and meningismus. Rarely, an acute encephalopathy due to encephalitis

may occur. Cranial nerve involvement may be seen, predominantly

cranial nerve VII but occasionally V and/or VIII. CSF findings include

a lymphocytic pleocytosis, elevated protein level, and normal glucose

level. This syndrome, which cannot be clinically differentiated from

other viral meningitides (Chap. 134), usually resolves spontaneously

within 2–4 weeks; however, in some patients, signs and symptoms may

become chronic.

Fungal meningitis is the leading infectious cause of meningitis in

patients with AIDS (Chap. 210). While the vast majority of these are

due to C. neoformans, up to 12% may be due to C. gattii. Cryptococcal

meningitis is the initial AIDS-defining illness in ~2% of patients and

generally occurs in patients with CD4+ T-cell counts <100/μL. Cryptococcal meningitis is particularly common in untreated patients with

AIDS in Africa, occurring in ~5% of patients. Most patients present

with a picture of subacute meningoencephalitis with fever, nausea,

vomiting, altered mental status, headache, and meningeal signs. The

incidence of seizures and focal neurologic deficits is low. The CSF

profile may be normal or may show only modest elevations in WBC

or protein levels and decreases in glucose. The opening pressure in the

CSF is usually elevated. In addition to meningitis, patients may develop

cryptococcomas and cranial nerve involvement. Approximately onethird of patients also have pulmonary disease. Uncommon manifestations of cryptococcal infection include skin lesions that resemble

molluscum contagiosum, lymphadenopathy, palatal and glossal ulcers,

arthritis, gastroenteritis, myocarditis, and prostatitis. The prostate

TABLE 202-14 Neurologic Diseases in Patients with HIV Infection

Opportunistic infections

Toxoplasmosis

Cryptococcosis

 Progressive multifocal

leukoencephalopathy

Cytomegalovirus

Syphilis

Mycobacterium tuberculosis

HTLV-1 infection

Amebiasis

Neoplasms

Primary CNS lymphoma

Kaposi’s sarcoma

HIV-1 infection

Aseptic meningitis

 HIV-associated neurocognitive disorders

(HAND), including HIV encephalopathy/AIDS

dementia complex

Myelopathy

 Vacuolar myelopathy

Pure sensory ataxia

 Paresthesia/dysesthesia

Peripheral neuropathy

 Acute inflammatory demyelinating

polyneuropathy (Guillain-Barré syndrome)

 Chronic inflammatory demyelinating

polyneuropathy (CIDP)

 Mononeuritis multiplex

 Distal symmetric polyneuropathy

Myopathy

1577CHAPTER 202 Human Immunodeficiency Virus Disease: AIDS and Related Disorders

gland may serve as a reservoir for smoldering cryptococcal infection.

The diagnosis of cryptococcal meningitis is made by identification of

organisms in spinal fluid with india ink examination or by the detection

of cryptococcal antigen. Blood cultures for fungus are often positive. A

biopsy may be needed to make a diagnosis of CNS cryptococcoma and

to distinguish inadequately treated infection from immune reconstitution syndrome. Initial treatment is with IV amphotericin B 0.7 mg/kg

daily, or liposomal amphotericin 4–6 mg/kg daily, with flucytosine

25 mg/kg qid for at least 2 weeks if possible. Decreases in renal function

in association with amphotericin can lead to increases in flucytosine

levels and subsequent bone marrow suppression. Therapy continues

with amphotericin alone until the CSF culture turns negative followed by fluconazole 400 mg/d PO for 8 weeks, and then fluconazole

200 mg/d until the CD4+ T-cell count has increased to >200 cells/μL

for 6 months in response to ART. Repeated lumbar puncture may be

required to manage increased intracranial pressure. Symptoms may

recur with initiation of ART as an immune reconstitution syndrome

(see above). Other fungi that may cause meningitis in patients with

HIV infection are C. immitis and H. capsulatum. Meningoencephalitis

has also been reported due to Acanthamoeba or Naegleria.

HIV-associated dementia consists of a constellation of signs and

symptoms of CNS disease. While this is generally a late complication

of HIV infection that progresses slowly over months, it can be seen in

patients with CD4+ T-cell counts >350 cells/μL. A major feature of this

entity is the development of dementia, defined as a decline in cognitive ability from a previous level. It may present as impaired ability to

concentrate, increased forgetfulness, difficulty reading, or increased

difficulty performing complex tasks. Initially these symptoms may be

indistinguishable from findings of situational depression or fatigue. In

contrast to “cortical” dementia (such as Alzheimer’s disease), aphasia,

apraxia, and agnosia are uncommon, leading some investigators to

classify HIV encephalopathy as a “subcortical dementia” characterized

by defects in short-term memory and executive function (see below).

In addition to dementia, patients with HIV encephalopathy may also

have motor and behavioral abnormalities. Among the motor problems

are unsteady gait, poor balance, tremor, and difficulty with rapid

alternating movements. Increased tone and deep tendon reflexes may

be found in patients with spinal cord involvement. Late stages may be

complicated by bowel and/or bladder incontinence. Behavioral problems include apathy, irritability, and lack of initiative, with progression

to a vegetative state in some instances. Some patients develop a state

of agitation or mild mania. These changes usually occur without

significant changes in level of alertness. This contrasts with the finding of somnolence in patients with dementia due to toxic/metabolic

encephalopathies.

HIV-associated dementia is the initial AIDS-defining illness in ~3%

of patients with HIV infection and thus only rarely precedes clinical

evidence of immunodeficiency. Clinically significant encephalopathy

eventually develops in ~25% of untreated patients with AIDS. As

immunologic function declines, the risk and severity of HIV-associated

dementia increases. Autopsy series suggest that 80–90% of patients

with HIV infection have histologic evidence of CNS involvement.

Several classification schemes have been developed for grading HIV

encephalopathy; a commonly used clinical staging system is outlined

in Table 202-15.

The precise cause of HIV-associated dementia remains unclear,

although the condition is thought to be a result of a combination of

direct effects of HIV on the CNS and associated immune activation.

HIV has been found in the brains of patients with HIV encephalopathy

by Southern blot, in situ hybridization, PCR, and electron microscopy.

Multinucleated giant cells, macrophages, and microglial cells appear to

be the main cell types harboring virus in the CNS. Histologically, the

major changes are seen in the subcortical areas of the brain and include

pallor and gliosis, multinucleated giant cell encephalitis, and vacuolar

myelopathy. Less commonly, diffuse or focal spongiform changes occur

in the white matter. Areas of the brain involved in motor function,

language, and judgment are most severely affected.

There are no specific criteria for a diagnosis of HIV-associated

dementia, and this syndrome must be differentiated from other

diseases that affect the CNS of HIV-infected patients (Table 202-14).

The diagnosis of dementia depends on demonstrating a decline in cognitive function. This can be accomplished objectively with the use of a

Mini-Mental Status Examination (MMSE) in patients for whom prior

scores are available. For this reason, it is advisable for all patients with a

diagnosis of HIV infection to have a baseline MMSE. However, changes

in MMSE scores may be absent in patients with mild HIV encephalopathy. Imaging studies of the CNS, by either MRI or CT, often

demonstrate evidence of cerebral atrophy (Fig. 202-40). MRI may

also reveal small areas of increased density on T2-weighted images.

Lumbar puncture is an important element of the evaluation of patients

with HIV infection and neurologic abnormalities. It is generally most

helpful in ruling out or making a diagnosis of opportunistic infections.

In HIV encephalopathy, patients may have the nonspecific findings of

an increase in CSF cells and protein level. While HIV RNA can often be

detected in the spinal fluid and HIV can be cultured from the CSF, this

finding is not specific for HIV encephalopathy. There appears to be no

correlation between the presence of HIV in the CSF and the presence of

HIV encephalopathy. Elevated levels of macrophage chemoattractant

protein (MCP-1), β2

-microglobulin, neopterin, and quinolinic acid

(a metabolite of tryptophan reported to cause CNS injury) have been

noted in the CSF of patients with HIV encephalopathy. These findings

TABLE 202-15 Clinical Staging of HAND According to Frascati Criteria

STAGE

NEUROCOGNITIVE

STATUSa FUNCTIONAL STATUSb

Asymptomatic 1 SD below mean in 2

cognitive domains

No impairments in

activities of daily living

Mild neurocognitive

disorder

1 SD below mean in 2

cognitive domains

Impairments in activities

of daily living

HIV-associated dementia 2 SD below mean in 2

cognitive domains

Notable impairments in

activities of daily living

a

Neurocognitive testing should include assessment of at least 5 domains, including

attention-information processing, language, abstraction-executive, complex

perceptual motor skills, memory (including learning and recall), simple motor skills,

or sensory perceptual skills. Appropriate norms must be available to establish

the number of domains in which performance is below 1 SD. b

Functional status

is typically assessed by self-reporting but might be corroborated by a collateral

source. No agreed measures exist for HIV-associated neurocognitive disorder

criteria. Note that, for diagnosis of HIV-associated neurocognitive disorder,

other causes of dementia must be ruled out and potential confounding effects of

substance use or psychiatric illness should be considered.

Source: Adapted from A Antinori et al: Neurology 69:1789, 2007.

FIGURE 202-40 AIDS dementia complex. Postcontrast CT scan through the lateral

ventricles of a 47-year-old man with AIDS, altered mental status, and dementia.

The lateral and third ventricles and the cerebral sulci are abnormally prominent.

Mild white matter hypodensity is seen adjacent to the frontal horns of the lateral

ventricles.