HIV- and HTLV-1 associated neurological manifestations



HIV-associated vacuolar myelopathy: Clinical symptoms usually develop late in the course of HIV infection with slowly progressive weakness of the lower extremities, gait abnormalities, sensory disturbance in lower limbs, impotence, urinary frequency and urgency. It leads to progressive spastic paraparesis and loss of sphincter control. The diagnosis is one of exclusion. The disorder can be associated with dementia and peripheral polyneuropathy. Antiretroviral drugs have no proven efficacy with regard to prevention or improvement of symptoms. The disorder appears to be associated with an abnormality of vitamin B12-dependent transmethylation pathway. Other causes of HIV-associated myelopathy are HTLV-1, TB, herpes zoster, syphilis and bilharziasis.


HIV-associated dementia: Develops in 15 -20% of cases with advanced disease. It is the leading cause of dementia in the young. Risk factors for HIV dementia are CD4<200 cells/mL, history of drug abuse, anemia and low body weight. Required for the diagnosis are the following: HIV-1 seropositivity; history of progressive frontal cognitive/behavioral decline with apathy, inattention, memory loss, impaired concentration, bradyphrenia and social withdrawal; diffuse CNS signs on neurological examination (slowed rapid eye movements, hyperreflexia and release signs); neuropsychological assessment with at least two areas of impairment (frontal, motor speed and non-verbal memory); CSF analysis are consistent with aseptic meningitis but should exclude neurosyphilis and cryptococcal meningitis; MRI shows diffuse cerebral atrophy with ill-defined white matter hyperintensities, exclusion of opportunistic infections; absence of intoxication, psychiatric illness, metabolic or opportunistic infections. High titers of CSF HIV-1 antibodies may be detected. There is a direct correlation between the CSF viral load and the degree of cognitive impairment. In patients with asymptomatic HIV-1 infection, neurophysiologic tests may be the most sensitive indicators of subclinical neurologic impairment.


Primary CNS lymphoma: They constitute 1 - 6% of malignant tumors of the CNS and occur in 50% of patients with AIDS. Other conditions that predispose to primary CNS lymphoma e.g. as ataxia-telangiectasia (Louis-Barr syndrome). Certain infections of the cerebellum e.g. EBV, HIV and human herpes virus 8 have been associated with primary lymphoma of the CNS. Most primary CNS lymphoma are of B-cell origin. Immunocompetent patients commonly present in the 6th or 7th decade of life with an intracranial mass. Since leptomeningeal involvement occurs in only 40% of cases CSF is abnormal in one third of cases with lymphocytic pleocytosis. CSF EBV PCR is sensitive (100%) and specific (99%) for establishing the diagnosis. MRI reveals multiple lesions in 60% of cases, and the lesions, which are homogeneously enhanced on T1 images, are isointense on T2 images. They tend to appear in the white matter adjacent to an ependymal surface. MRI lesions are most commonly found in the cerebral hemispheres, corpus callosum and basal ganglia. Although most lesions are found adjacent to the CSF space, leptomeningeal spread on MRI is uncommon. Necrosis and edema can be found and makes the differential diagnosis with malignant glioma and metastases sometimes difficult. T-cell lymphoma are usually found infratentorial. A dramatic response to high-dose corticosteroids often distinguishes CNS lymphoma from other malignant tumors. Survival rate for T-cell lymphomas is 42% at 2 years.


HIV-associated distal sensory polyneuropathy: 35% of patients with advanced AIDS suffer from this type of predominantly sensory, symmetric polyneuropathy. The initial symptoms vary from mild to painful paresthesias in the feet to disabling dysesthesias. Ankle jerks are lost, vibration and pain/temperature sensation may be decreased in the feet. NCVs show reduced or absent SNAPs. CD+4 lymphocyte count and viral load are predictors of this type of polyneuropathy. The use of dideoxynucleosides antiretroviral zalcitabine, didanosine and stavudine is associated with a toxic neuropathy clinically similar to HIV-associated distal sensory polyneuropathy. The latter tends to be explosive in onset, affects the lower limbs leaving the hands uninvolved, is dosage dependent and develops on average 8 weeks after the start of high-dose treatment. Recovery is seen after withdrawal of the treatment. This type of polyneuropathy should be differentiated from HIV-associated vasculitic neuropathy. Most of these patients have evidence of opportunistic infections (e.g. CMV).


HIV-associated GBS: The clinical appearance of this type of GBS is almost similar to the classical GBS, except for the progression of the weakness which may be longer than in the typical cases of GBS (> 2-4 weeks). GBS develops usually in the early stages of HIV infection or may precede HIV seroconversion. CSF pleocytosis (20-50 cells) are a common finding.


HIV-associated CIDP: This type of neuropathy typically develops early in the stages of HIV infection and may precede seroconversion. CSF may show elevated protein with pleocytosis.


HIV-associated mononeuritis multiplex


HIV-associated CMV polyradiculoneuropathy:  This occurs in patients with established HIV infection. The disorder is subacute and presents with severe back pain radiating to the lower limbs, sacral sensory loss and acute urinary retention and progresses to flaccid paraparesis within a few weeks. It presents either as symmetric polyneuropathy or polyradiculoneuropathy. Other patients develop rapidly progressive mononeuropathy multiplex affecting the limbs with painful paresthesias and disabling dysesthesias. CSF shows high nucleated cell count (>1000 cells/ml), elevated protein and reduced glucose. CMV may be cultured from the CSF or found by PCR. MRI shows prominent contrast enhancement of cauda equina. Nerve biopsy may confirm the diagnosis. The prognosis is bad without therapy.


HTLV-1 associated myelopathy (tropical spastic paraparesis): Endemic areas for HTLV-1 occurrence include the Caribbean (3-4% seropositive), north to equatorial Africa, and southwest Japan. In general, 9% of iv drug users and 0.025% blood donors are seropositive. The median time to seroconversion is 51 days following exposure (packed red cells, whole blood, and platelet fractions to a lesser extent fresh-frozen plasma). Transmission by sexual contact occurs at rates of approximately 5% in females married to infected males and approximately 1 % in males married to infected females. Symptoms typically become evident during the 4th and 5th decades of life. This chronic or subacute disorder develops in 1-2 % of HTLV-1 seropositive patients and is clinically characterized by prominent weakness in proximal lower extremities with pyramidal signs (slowly progressive spastic paraparesis), loss of vibration sense and proprioception, urinary bladder dysfunction, impotence and low back pain. In some patients muscle wasting and fasciculations are found. Very commonly, patients with HTLV-1 associated myelopathy develop polymyositis (85% IgG anti-HTLV-1 antibodies). Other coexisting disorders are: peripheral demyelinating or axonal polyneuropathy, polyradiculopathy, cranial neuropathies (optic atrophy and deafness), meningitis, cerebellar ataxia and encephalopathy. The diagnosis is one of exclusion (MS, compressive lesions, neoplasms, vascular malformations, infectious and parainfectious conditions, MND and PLS). MRI shows multiple foci of signal abnormality in T2 weighted images of spinal cord and sometimes brain similar to that of MS. CSF shows elevated protein, oligoclonal bands and mild lymphocytic pleocytosis. Detection of HTLV-1 specific antibodies in blood and CSF is supportive of the diagnosis. Confirmation of positive serologic studies may be accomplished by PCR amplification of proviral DNA fragments from infected lymphocytes or HLTV-1 DNA in CSF (sensitivity 93%, specificity 85%). The combination of all these investigations provides a sensitivity of 96% and specificity of 100%. However since up to 98% of the HTLV-1 virus infected patients are asymptomatic the interpretation of the results need to fit the clinical picture. Fewer than 2% of HTLV-1 seropositive patients develop other inflammatory conditions, including uveitis, dermatitis, polymyositis, HTLV-1 associated arthropathy and Sjögren syndrome. About 95% of HTLV-1 seropositive patients appear to be asymptomatic carriers. Intrathecal hydrocortisone, intravenous high-dose methylprednisolone, and interferon-a have all been tried with variable results.


HTLV-1 polymyositis: Any patient with HTLV-1 associated myelopathy presenting with subacute or progressive exacerbation of weakness or abnormal serum CK levels should be suspected of polymyositis. Deterioration of strength in proximal muscles are hinting towards this type of polymyositis. CK levels may be increased are normal. EMG may show a myopathic pattern or can be normal. Biopsy will ultimately settle the issue.


Zidovudine-induced myopathy: This myopathy starts about 1 year after the start of zidovudine therapy and is clinically associated with myalgia and weakness. Serum CK levels are high. Biopsy is essential. The myopathy is reversible and recovery is expected over 2 months. The disease needs to be differentiated from HIV-associated polymyositis.


CMV encephalitis: This infection presents often as ventriculitis in patients with AIDS or post-organ transplantation and is not necessarily preceded by CMV retinitis. The clinical features include subacute or chronic delirium, seizures, cranial neuropathies, and nystagmus. Neuroimaging may show ventricular enlargement and enhancement of periventricular white matter (“owl eyes” sign on FLAIR). Possible differential diagnosis of lesions with periventricular enhancement (and/or calcifications) includes toxoplasmosis, rubella and herpes simplex virus infections (ToRCH infections). CSF analysis shows increased protein and variable pleocytosis (mononuclear cells). Detection of CMV DNA by PCR is the diagnostic test of choice (95% sensitivity and 99% specificity). The same “owl eyes” may be found on pathologic examination (intranuclear and intracytoplasmic inclusions of CMV particles. The prognosis is generally bad. Necrotizing ventriculoencephalitis is a rapidly fatal form of CMV encephalitis.


HIV-related CNS infections: Most of these infections occur when CD4 counts are <200 cells/mL. Toxoplasmosis encephalitis complain of headache, fever, confusion and seizures. Serum anti-toxoplasma IgG is usually positive. PCR detection of toxoplasma in CSF is not sensitive enough. Brain MRI shows single or multiple lesions located at the hemispheric gray-white junction, in the deep white matter, or in the basal ganglia. Thallium SPECT may be useful to differentiate between toxoplasma and CNS lymphoma. A presumptive diagnosis can be made by response to pyrimethamine and sulfadiazine (clinical improvement within 1-2 weeks and radiologically within 2-3 weeks). Brian biopsy may be considered if there is no response to the treatment. Neurosyphilis can present in its different forms. Diagnosis of neurosyphilis should be made by means of FTA-ABS and excludes equivocal cases. Other infections associated with HIV include, trypanozoma cruzi, acanthamoeba, pneumocystis carinii, PMFLE, listeria, salmonella, nocardia and histoplasma.