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INFECTION

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`HIV-ASSOCIATED NEUROCOGNITIVE

DISORDERS

Human immunodeficiency virus (HIV-1) infection of the brain can produce a range of HIV-associated neurocogni- tive disorders. These include asymptomatic neurocogni-

tive impairment (demonstrable only by cognitive testing), minor neurocognitive disorder (mild to moderate cogni-

tive and functional impairment), and HIV-associated

dementia (moderate to severe cognitive and functional

impairment). The incidence of HIV-associated dementia has declined since the introduction of combination antiret- roviral therapy, but its prevalence has increased as patients live longer. Risk factors include intravenous drug use, female gender, and increased age.

A. Pathogenesis

HIV-associated dementia results from invasion of the brain by blood-borne macrophage-tropic retrovirus, which infects macrophages, microglia, and astrocytes, but not neurons. The virus appears to reach the CNS early in the course of systemic HIV-1 infection, but may remain latent and asymptomatic for years. Alternatively it can produce transient symptomatic HIV-1 meningitis (see Chapter 4, Confusional States). Proposed mechanisms of pathogene- sis include neurotoxic effects of viral proteins, and cyto- kines, chemokines and other soluble factors released by inflammatory cells.

B. Pathology

The brain in HIV-associated dementia shows perivascular infiltration by macrophages, multinucleated giant cells, and astrogliosis, which affect the basal ganglia, subcortical white matter, thalamus, and brainstem. Neuronal loss may be noted in basal ganglia and frontal and temporal cortex. The spinal cord may also be affected by a vacuolar myelopathy.

C. Clinical Findings

The onset of HIV-associated dementia is usually insidious and is associated with cognitive, behavioral, and motor deficits. These include memory loss, apathy, difficulty with reading and writing, gait disorder, and tremor. Cortical deficits such as impaired executive function and learning and parkinsonian features have also become common with antiretroviral treatment. Examination may show primitive reflexes, hyperreflexia, extensor plantar responses, and cerebellar ataxia.

D. Investigative Studies

There is no definitive laboratory test for HIV-associated dementia. CSF may show mild to moderate elevation of protein (≤200 mg/dL), modest, usually mononuclear pleo- cytosis (≤50 cells/μL), and oligoclonal bands. MRI shows cortical and subcortical atrophy with diffuse signal abnor- malities in subcortical white matter (Figure 5-14) and is useful for excluding other HIV-related neuropathologic processes, such as opportunistic infection.

E. Treatment

Patients with HIV-associated cognitive disorders should receive combination antiretroviral therapy as described for HIV-1 meningitis in Chapter 4, Confusional States.

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▲

▲_{Figure 5-14. T2-weighted MRI in HIV-associated}

dementia, showing increased signal intensity (arrows) in subcortical white matter.

F. Prognosis

The course may be relatively static, steadily progressive, or acutely exacerbated by concurrent disease. With combina- tion antiretroviral treatment, median survival has been extended from a few months to several years.

Zhou L, Saksena NK. HIV associated neurocognitive disorders. Infect Dis Rep. 2013;5(suppl 1):38-50.

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`Neurosyphilis

Syphilis is caused by Treponema pallidum transmitted by sexual contact, which results in infection in approximately one-third of encounters with infected individuals. Dementia from neurosyphilis (general paresis) was com- mon in the prepenicillin era but is now rare.

A. Clinical Findings

1. Primary syphilis is characterized by local skin lesions (chancres) that usually appear within 1 month of expo- sure. Hematogenous spread of T. pallidum produces symptoms and signs of secondary syphilis, including fever, skin rash, alopecia, anogenital skin lesions, and ulceration of mucous membranes, within 1 to 6 months. Neurologic symptoms are uncommon. Meningeal syphi-

lis, the earliest form of symptomatic neurosyphilis, occurs

2 to 12 months after primary infection, and is associated with headache, stiff neck, nausea and vomiting, and cra- nial nerve (especially II, VII, or VIII) involvement.

Meningovascular syphilis is seen 4 to 7 years into the

course of the disease and usually presents with transient ischemic attacks or stroke (see Chapter 13, Stroke). 2. Late (parenchymatous) neurosyphilis produces the

syndromes of general paresis and tabes dorsalis, which can occur separately or together (taboparesis); either one can occur in combination with optic atrophy.

General paresis is a chronic meningoencephalitis

caused by active spirochetal infection. Onset is with gradual memory loss or altered affect, personality, or behavior. This is followed by global intellectual deterio- ration with grandiosity, depression, psychosis, and focal weakness. Terminal features include incontinence, sei- zures, or strokes. Neurologic examination may show tremor of the face and tongue, paucity of facial expres- sion, dysarthria, and pyramidal signs. Taboparesis is the coexistence of tabes dorsalis (see Chapter 10, Sensory Disorders) with general paresis. Signs and symptoms of tabes dorsalis include Argyll Robertson pupils (see Chapter 7, Neuro-Ophthalmic Disorders), lancinating (stabbing) pains, areflexia, posterior col- umn sensory deficits with sensory ataxia and Romberg sign, incontinence, impotence, Charcot (hypertrophic) joints, and genu recurvatum (hyperextended knees). Optic atrophy may also be present.

B. Investigative Studies

Treponemal serologic blood tests (fluorescent treponemal antibody absorbed [FTA-ABS] or microhemagglutination- Treponema pallidum [MHATP]) are reactive in almost all patients with active neurosyphilis, but non-treponemal blood tests (Venereal Disease Research Laboratory [VDRL] or rapid plasma reagin [RPR]) can be negative; therefore, a treponemal blood test should be obtained in all suspected cases. If this is nonreactive, neurosyphilis is effectively excluded; if it is reactive, lumbar puncture should be per- formed to confirm the diagnosis of neurosyphilis and provide a baseline CSF profile against which to gauge the efficacy of subsequent treatment. The CSF in active neuro- syphilis shows a lymphocytic pleocytosis and reactive non- treponemal CSF serology (eg, VDRL), except in early meningeal and meningovascular syphilis and end-stage tabes dorsalis. Other CSF abnormalities include protein elevation, increased γ-globulin, and the presence of oligo- clonal bands. The MRI in general paresis may show unilat- eral or bilateral medial temporal lobe T2 high-intensity abnormalities with or without associated atrophy.

C. Treatment

General paresis is treated as described for syphilitic men- ingitis earlier (see Chapter 4, Confusional States). Transient fever and leukocytosis may occur shortly after therapy is

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return to normal within 6 months requires retreatment.

D. Prognosis

General paresis may improve or stabilize after treatment, but in some cases it continues to worsen. Patients with persistently reactive CSF serologic tests but no pleocytosis are unlikely to respond to penicillin therapy but are usually treated nevertheless.

Zhang HL, Lin LR, Liu GL, et al. Clinical spectrum of neuro- syphilis among HIV-negative patients in the modern era. Dermatology. 2013;226:148-156.

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