43 HIV: neurological disorders

HIV enters the central nervous system (CNS) soon after 1° infection, either carried by infected mononuclear cells or by cell-free transfer across the blood–brain barrier. Infected monocytes then differentiate into macrophages, and produce virions that can infect astrocytes and microglia (brain macrophages). Neurons are not infected, but they are lost and become dysfunctional in HIV brain disease.

Neurological disease is common and may be the presenting clinical syndrome in 30% of HIV infections occurring at any stage, but most often presents following seroconversion or with severe immunodeficiency. Neurological features have been reported in 40–70% of patients with AIDS, ↑ to 90% at postmortem examination (Box 43.1). Abnormal cerebrospinal fluid (CSF) findings including ↑ lymphocytes, protein, immunoglobulin, and oligoclonal bands may be found in patients with no neurological symptoms or signs. The presence or absence of neurological disease is independent of CSF viral load.

Mechanisms of CNS injury and the spectrum of neurological disease vary with the stage of HIV infection and the degree of immune deficiency.

HAART has changed the epidemiology of the neurological manifestations of HIV resulting in ↓ CNS OIs, ↓ incidence of HIV dementia complex, and improved prognosis for some infections which were previously difficult to treat, such as progressive multifocal leukoencephalopathy (PML). However, there has been ↑ occurrence of drug induced CNS and peripheral nerve disease.

Prior to HAART dementia was a common cause of morbidity and mortality, seen in up to 50% of patients before death. Pathogenesis may include altered cytokine levels, free radicals, and the neurotoxic effects of gp120. Histological abnormalities include perivascular infiltrates, microglial nodules, multinuclear giant cells, and pruning of dendritic processes in the white matter and subcortical grey matter with relative sparing of the cortex.

Poor concentration, impaired short-term memory, and slowed thought and reaction times. Clumsiness and gait disturbance may follow with corticospinal tract abnormalities. Psychiatric illness and personality change may also be presenting features. Depression, effects of substance abuse, cerebrovascular disease, and neurosyphilis should be excluded.

MRI (preferred option) or CT brain scan reveal cerebral atrophy with abnormality of the periventricular white matter. Neuropsychological examination reveals ↓ thought processes and ↓ short-term memory. CSF should be examined to exclude other pathologies and OIs. Electro-encephalogram (EEG) may reveal encephalopathic changes. Blood and CSF serological tests for syphilis should be carried out and vitamin B₁₂ deficiency excluded. Other conditions such as CNS infections (TB, toxoplasmosis, cytomegalovirus encephalitis), PML, lymphoma, and toxic metabolic states (e.g. alcoholism, adverse medication effects, drug interaction, recreational drug use) should be excluded as dictated by the clinical presentation.

HAART, if possible including zidovudine (proven efficacy) or other drugs that cross the blood–brain barrier, can produce marked improvement in intellectual function and return to independent living. The patient may require psychological and social support.

Varicella zoster virus (VZV) is a rare cause of meningoencephalitis and is seen when CD4 count <50 cell/μL. It is due to direct CNS infection rather than reactivation of dormant virus as is the case with shingles. The pathological process is large- and small-vessel vaculopathy leading to ischaemic and demyelinating lesions. 33–50% of patients do not have the typical rash. CT or MRI may show necrotizing encephalitis and help differentiate from toxoplasmosis and PML, but changes are not specific. CSF should be examined by PCR (highly sensitive and specific). Treatment with aciclovir 10mg/kg 8 hourly should be given for at least 14 days.

CMV encephalitis occurs in advanced immunodeficiency and may be suspected when there is evidence of CMV disease in other organs or blood and CSF PCR is positive. Herpes simplex virus (HSV) is an uncommon cause but diagnosis should be considered in patients with meningo-encephalitis, aseptic meningitis, myelitis, or polyradiculitis. DNA detection in the CSF is very useful because of its high sensitivity and specificity.

Unlike other OIs, the prevalence of PML has not significantly declined with HAART. It is a demyelinating disease caused by reactivation of the JC (John Cunningham) papovavirus (polyomavirus) and occurs in 4–8% of patients with advanced HIV infection. Fulminant disease with dementia and coma can occur, but the usual picture is of subacute or chronic progressive disease with focal deficits. These include personality change, aphasia, hemiparesis, dizziness, gait disturbance, visual field defects, and seizures. CT or MRI scans usually reveal lesions (single or multiple) without mass effect in the white matter, particularly in the parieto-occipital region (Plate 20). CSF CJ PCR is +ve in ~60% of cases and ↑ CJ VL associated with poorer prognosis.

Prognosis is poor, especially without HAART. HAART leads to significant improvement in ~10%, but 33% still die within 2 years. Some individuals, especially those with very low CD4 counts, can develop IRIS with worsening of PML or new-onset PML after the initiation of HAART. Treatment trials with cidofovir, interferon α, and topotecan were inconclusive.

The most common cause of mass lesions in HIV prior to the introduction of 1° PCP prophylaxis which has ↓ incidence. Results from reactivation of a previously acquired infection when CD4 declines (<200 cells/μL). All patients should be tested for toxoplasma IgG. If −ve should be advised to eat meat only if well cooked, avoid cats and dogs, and wash hands carefully after gardening or contact with excrement.

Typically includes confusion, headache, personality change, hemiparesis, focal sensory disturbances, fits, and fever.

MRI or CT scanning reveal ring-enhancing lesions, usually multiple, particularly in the cortex and deep grey matter. The differential diagnosis, particularly if lesions are single, includes 1° cerebral lymphoma, cryptococcal cerebritis, and tuberculomas. CSF changes are non-specific. Positive toxoplasma IgG in 90%. CSF PCR is helpful if +ve (sensitivity 50%, specificity 100%).

Standard therapy for cerebral toxoplasmosis is sulfadiazine 100mg/kg/day in divided doses and pyrimethamine 200mg loading dose followed by 50–100mg/day with folinic acid to reduce bone marrow toxicity. High-dose clindamycin 1.2g IV four times daily if allergic to sulfonamide. Neuro-imaging should be repeated after 2 weeks followed by brain biopsy to exclude other pathologies if no improvement. Secondary prophylaxis should be given until immune reconstitution with HAART (CD4 >200 cells/μL for >6 months). Primary prophylaxis as for PCP.

Cryptococcus neoformans (an encapsulated yeast)—most common fungal pathogen in the CNS. Usually when CD4 <100 cells/μL.

Usually as subacute meningitis (but symptoms may initially be surprisingly mild) with headache and fever. Evidence of meningism occurs in only 30%. A high index of suspicion must be maintained to avoid delays in diagnosis. Other presentations include acute confusional state and cranial nerve palsies.

CSF pressures can be markedly raised but pleocytosis may be absent and protein and sugar levels normal. The organism may be visualized by India ink staining but this is relatively insensitive. Mainstay of diagnosis is detection of CSF and serum cryptococcal antigen, which is highly sensitive. Neuro-imaging is usually normal but cryptococcomas can occur, usually in the basal ganglia.

Daily lumbar punctures may be required until CSF pressures normalize to avoid cranial nerve lesions. If CSF pressure does not ↓ with LPs, a lumbar drain may be used. Antifungal therapy with IV amphotericin β 1mg/kg/day IV in combination with flucytosine 100mg/kg/day or liposomal amphotericin 3mg/kg/day plus flucytosine for 2 weeks followed by fluconazole 400mg daily. A test dose of amphotericin 25mg should be given before commencing full therapy to detect hypersensitivity. Renal function should be monitored. Ongoing suppressive therapy with fluconazole (superior to itraconazole) is required to minimize significant relapse rates. Continue until immune reconstitution is achieved with HAART.

Most commonly presents at seroconversion but may be recurrent or become chronic. Usually presents with headache. Cranial nerve palsies and altered mental state can occur. Lumbar puncture, following neuro-imaging when focal deficits are present, needed to exclude other pathologies. Mildly ↑ CSF lymphocyte counts and protein level with normal glucose are typical findings.

Evidence of autonomic dysfunction can be found at various stages of HIV infection. Measurement of pulse rate variation in response to standing, deep breathing, Valsalva manoeuvre, and cold exposure reveal autonomic dysfunction in ~15%. Frequency related to the level of immune function but, unlike sensory neuropathy, not the use of nucleoside reverse transcriptase inhibitors. Symptomatic autonomic neuropathy occurs in advanced immunodeficiency and may result in severe postural hypotension and syncope. Cardiac denervation may lead to serious cardiac dysrhythmias. Those developing postural dizziness or syncope should have postural blood pressure recordings, tests of autonomic function, and assessment of sodium intake. Adrenal insufficiency should be excluded by carrying out a short Synacthen^® test. Therapy with mineralocorticoid (fludrocortisone 50–200mcg daily), sodium supplements, compression stockings, and α-adrenergic agents, such as midodrine, may reduce postural blood pressure falls and alleviate symptoms. There may be improvement in autonomic function with HAART.

Post-mortem studies have shown vacuolar myelopathy in up to 30% but clinically it is far less common. Pathological mechanisms are probably the same as in HIV dementia complex. It is often associated with dementia but may be isolated when the clinical picture mimics that of vitamin B₁₂ deficiency spinal cord disease.

Typically with subacute progressive motor and sensory deficits with paraesthesiae, but brisk tendon reflexes. Uncharacteristic findings may occur if there is concomitant peripheral neuropathy or other cause.

Investigations should include measurement of vitamin B₁₂ level and radiological imaging to exclude structural lesions. Areas of ↑ T2 signal may occasionally be seen on MRI scan. CSF may be normal or show only non-specific abnormalities such as low-level pleocytosis or mildly ↑ protein levels.

Spasticity may require anti-spasmodic therapy such as baclofen 10–30mg three times daily and dysasthesia may require amitriptyline or gabapentin. Physiotherapy and occupational therapy input may be valuable. Improvements in function may occur with HAART.

In patients from areas of significant risk for human T lymphotropic virus type I (HTLV1) infection, such as Japan, the Caribbean, and parts of Central and Latin America, subacute myelopathy may result from HTLV1 infection and anti-HTLV1 antibodies should be assayed.

Acute spinal cord disease may occasionally occur as a seroconversion event. Other important causes are spinal cord compression from lympho-matous metastases, tuberculous or bacterial abscesses, and acute infections with VZV.

Typically rapidly developing neurological deficit, such as leg weakness and sphincter disturbance, with evidence of a sensory level.

Emergency investigation required with spinal MRI or CT. In the absence of compression CSF and/or biopsy of compressive lesion, patient should be examined for evidence of infectious and neoplastic causes including viral PCR and cytology.

Supportive with specific treatment directed at the identified cause.

May occur at any stage of HIV infection with a typical distribution and course. Atypical multi-dermatomal involvement, viraemic dissemination of lesions, and recurrences more common as CD4 counts ↓.

Frequently prodromal pain of dermatomal distribution followed by an erythematous maculopapular eruption evolving into vesicles which then pustulate and crust. Bullous haemorrhagic and necrotic lesions may occur. Lesions will be at various stages at any one time. Pain during the acute phase can be severe, and disabling post-herpetic neuralgia may follow.

Clinical picture is usually characteristic. Varicella zoster virus (VZV) can be detected in vesicular fluid by immunofluorescence.

Pain often does not respond well to conventional analgesics and adjuvants. Amitriptyline 25–150mg/day or gabapentin up to 2.4g/day in divided doses may be required. Begin antiviral therapy with IV aciclovir 10mg/kg 8 hourly as early as possible (most effective within 24 hours but useful even if given later in immunocompromised) and switch to oral famciclovir 500mg three times daily or valaciclovir 1g three times daily when lesions cease to progress for a total course of at least 7 days or until all lesions have dried and crusted. Ophthalmology review if ophthalmic branch of trigeminal nerve affected (forehead and inside of nose).

Usually occurs in patients with advanced HIV disease. Typical presentation is with subacute onset of multifocal or asymmetric sensory deficits. Nerve conduction studies show demyelination and axonal loss. May be associated with cytomegalovirus (CMV) infection in advanced immunodeficiency. Differential diagnosis includes nerve compression in severe wasting syndrome, neoplastic infiltration, and neurotropic viral infections (e.g. VZV). Consider treatment with ganciclovir or foscarnet if circumstantial evidence of CMV infection (e.g. positive blood PCR).

The toxicity of therapeutic drugs, notably didanosine, zalcitabine, and stavudine, is responsible for ↑ proportion of neuropathy.

Occurs in ~35% of patients with advanced HIV disease. ~15% of those with asymptomatic HIV infection have abnormal nerve conduction studies. Typical symptoms are tingling, numbness, and burning pain beginning in the toes or plantar surfaces, often ascending over time. Involvement of hands is rare. Examination shows ↓ ankle jerks, vibration sense, appreciation of temperature, and fine touch. Unexpectedly brisk reflexes should raise the question of additional spinal cord or brain disease. Differential diagnosis includes effects of alcohol, drug toxicity, and vitamin deficiency. Treatment is directed towards controlling neuropathic pain with drugs, such as amitriptyline 25–150mg daily or gabapentin starting at 300mg 8 hourly and titrating to a maximum of 2.4g daily.

May occur with seroconversion or during late stages of HIV infection. Manifestations as in non-HIV status with progressive symmetric weakness in the limbs and loss of tendon jerks, but CSF pleocytosis may occur. Treatment is immunoglobulin 400mg/kg/day for 5 days or plasmapheresis up to six exchanges over 2 weeks. Patients with the chronic form may need monthly cycles of treatment until stabilization.

Caused by CMV infection in patients with CD4 counts <50cells/μL. Evidence of CMV disease elsewhere. Bilateral leg weakness progresses over several weeks, sometimes to flaccid paraplegia. Sphincter disturbance is common and sensory loss combined with painful dys-aesthesia is usual. Sensory symptoms differentiate this from myopathy, and sphincter disturbance with sparing of the upper limbs distinguishes it from other forms of neuropathy. Cord compression should be excluded by imaging. CSF usually has a cell count >500 × 10⁶/L with 40–50% neutrophils, ↑ protein content, and low glucose. CSF PCR for CMV is positive and the patient should be treated with ganciclovir or foscarnet.

Strokes and transient ischaemic attacks are reported in 0.5–8% of HIV-infected patients. Prevention should include attention to vascular risk factors such as smoking, hypertension, and hyperlipidaemia. Cocaine use and alcoholic binges may lead to thrombotic strokes. Embolic strokes may result from cardiac or carotid artery disease. Cardiogenic emboli may result from infective or non-infective endocarditis following myo-cardial infarction or from dysrhythmias. Cerebral vasculitis, particularly due to VZV or syphilis, may cause cerebral thrombosis. The hyper-coagulable state that may occur with HIV may contribute. Haemorrhage may complicate VZV cerebral vasculitis and thrombocytopenia, rarely due to metastatic Kaposi’s sarcoma or as a result of an incidental cerebral aneurysm.

Can affect most parts of the nervous system ( Chapter 6, Clinical features—late syphilis p. 118).

Kaposi’s sarcoma, although the most common systemic neoplasm in HIV infection, rarely involves the nervous system. The CNS may be invaded by non-Hodgkin’s lymphoma, leading to malignant meningitis and compressive symptoms requiring intrathecal cytotoxic therapy and radio-therapy. 1° cerebral lymphoma occurs in patients with advanced immunodeficiency and presents with confusion, lethargy, personality change, focal neurological deficits, seizures, ataxia, and aphasia. On MRI or CT scanning lesions are ring-enhancing, and about 50% are associated with cerebral oedema and mass effect. The finding of a single lesion favours the diagnosis of lymphoma over cerebral toxoplasmosis. +ve EBV PCR is suggestive but not diagnostic of 1° cerebral lymphoma. Treatment for toxoplasma empirically may be considered with brain biopsy if no clinical response after 2 weeks. Cerebral radiotherapy may improve survival. Prognosis very poor with 3 months median survival.