Neurologic Complications of HIV Infection

History• In 1985 –virus isolated from CSF, brain, spinal

cord, peripheral nerves of patients with AIDS. • virus, pleocytosis, and elevated

immunoglobulins in the CSF of 2/3 after seroconversion

• central nervous system was infected both early and asymptomatically

General Mechanisms

– direct neurotoxicity due to the neurotrophic nature of the virus

– autoimmune disease due to immune dysregulation

– opportunistic infections– cerebrovascular complications, neoplasms, side

effects of retroviral therapy– malnutrition and vitamin deficiencies

• HAART tx lead to almost 50% decrease in incidence of HIV dementia

• Infected macrophages carry HIV into the nervous system

• HIV-related neurologic disease becomes obvious after the development of AIDS (CD4 <200)

• 90% of infected individuals manifesting some form of neurologic involvement by the time of death

Brain Primary HIV and autoimmune• HIV-associated dementia or encephalopathy (children)• Demyelinating syndromes• Parkinsonism and other movement disorders• Sleep disordersNeurologic opportunistic processes • Toxoplasmosis encephalitis, progressive multifocal

leukoencephalopathy• Cytomegalovirus and varicella zoster virus encephalitis• Fungal: aspergillus, mucormycosis, histoplasmosis• Bacterial: tuberculosis, syphilis• Neoplasm: primary central nervous system lymphomaMedications • Neuroleptic sensitivity

Meninges

Primary HIV and autoimmune • Acute aseptic or chronic meningitisNeurologic opportunistic processes • Cryptococcal meningitis• Bacterial: tuberculosis, syphilis• Neoplasm: lymphomatous meningitis

Spinal cord

Primary HIV and autoimmune • Vacuolar myelopathyNeurologic opportunistic processes • Herpesviruses: varicella zoster virus,

cytomegalovirus, Herpes simplex virus• Bacterial: syphilis, tuberculosis• Neoplasm: metastatic lymphoma

Root and plexus

Neurologic opportunistic processes• Cytomegalovirus polyradiculitis, syphilis,

tuberculosis• Neoplasm: lymphomatous meningitis

Nerve Primary HIV and autoimmune

• Distal symmetrical polyneuropathy• Diffuse infiltrative lymphomatosis syndrome• Acute and chronic inflammatory demyelinating polyneuropathies• Mononeuritis multiplex• Motor neuron diseaseNeurologic opportunistic processes • Cytomegalovirus mononeuritis multiplex• Varicella zoster virus (multidermatomal)Medications • Nucleosides: didanosine, zalcitabine, stavudine, Dapsone,

metronidazole, isoniazid, pyridoxine, vincristine

Muscle

Primary HIV and autoimmune• Inflammatory myopathyNeurologic opportunistic processes • ToxoplasmosisMedications • Zidovudine, trimethoprim-sulfamethoxazole• Statins

• New-onset neurologic complications often are superimposed on an ongoing process with a different etiology

• The first consideration must be the stage of systemic HIV infection, which influences both the risk of neurologic disease as well as possible etiologies

• Risk depends CD4 count, past and current exposure to infectious agents, HAART agents, use of antibacterial prophylaxis

• CD4 count provides critical information to guide evaluation

CD4 Cell Count: >500/mm3

Infectious complications• Acute retroviral syndrome Noninfectious complications• Acute inflammatory demyelinating

polyneuropathy • Mononeuritis multiplex• Aseptic meningitis• HIV-associated headache

CD4 Cell Count: <200/mm3

Infectious complications• Cytomegalovirus encephalitis and polyradiculitis• Progressive multifocal• Leukoencephalopathy (PML)• Toxoplasmosis encephalitis• Cryptococcosis meningitisNoninfectious complications • HIV-associated dementia• HIV-associated polymyositis • Vacuolar myelopathy• Distal sensory polyneuropathy• Diffuse infiltrative lymphomatosis syndrome

CD4 Cell Count: 200 to 500/mm3

Infectious complications• Herpes zoster (multidermatomal)• Tuberculous meningitis • NeurosyphilisNoninfectious complications• Mononeuritis multiplex• AZT-induced myopathy• HIV-associated headache• Motor neuron disease

HIV Dementia• Prevalence of 5% to 20% among untreated

AIDS patients and an annual incidence of 7% per year

• Is an AIDS-defining illness • Subcortical dementia - clinical triad

progressive motor (tremor, gait instability, and loss of fine motor control), cognitive (mental slowing, forgetfulness, and impaired concentration) and behavioral (mania, apathy, emotional lability) abnormalities

HIV Dementia• Must be discriminated from other causes of

cognitive impairment. • Must always consider opportunistic infections• Primary CNS lymphoma can also present in

later stages of AIDS • Multi-infarct or vascular dementia may be

considered in particular cases• Vasculitis secondary to infection or illicit drug

use may rarely be found.

HIV Dementia

• Illicit drugs, alcohol, or prescription drugs may account for cognitive difficulties

• Depression should also be excluded/treated• Always r/o encephalopathy (delirium)• Causes of dementia in the general population

may need to be considered, which will likely become a larger issue as the HIV-infected population ages

HIV Dementia• Cerebral and basal ganglia atrophy and diffuse

WM hyperintensities on T2• MRS - diminished NAA = neuronal injury• Neuropsych testing with HIV dementia scale• MRS identifies higher Cho/Cr in the basal ganglia,

with reduced NAA/Cr and higher MI/Cr in frontal white matter, confirming a subcortical predominance

• Continuous arterial spin labeled MRI shows decrease in both caudate blood flow and volume

HIV Dementia• Leads to a significant increase in the overall

morbidity due to AIDS. • Increased number of hospitalizations, increased

duration of hospital stays, and decreased life expectancy as compared to patients with

• Average life span may be as low as 6 mo unless HAART is administered.

• With HAART impairment can be reversed to some extent and the likelihood of survival greatly improved

HIV Dementia• CSF typically demonstrates a mild pleocytosis +/- protein elevation• HIV-1 antigen, intrathecal production of anti–HIV-1 antibodies,

presence of oligoclonal bands and presence of cytokines• CSF viral RNA levels correlate with severity of cognitive impairment • EEG - diffuse slowing of background rhythms but lacks specificity in

the diagnosis of HIV-associated dementia or minor cognitive and motor disorder.

• CSF interleukin-18 levels may be useful in the detection of HIV-positive patients with opportunistic infections, being elevated in this patient population but not elevated in HIV-positive or HIV-associated dementia patients.

• Serum interleukin-18 levels are elevated in HIV-positive or HIV-associated dementia patients but not in HIV patients with opportunistic infections or HIV-negative controls