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Ovid: Oxford Handbook of Genitourinary Medicine, HIV, and Aids

Editors: Pattman, Richard; Snow, Michael; Handy, Pauline; Sankar, K. Nathan; Elawad, Babiker Title: Oxford Handbook of Genitourinary Medicine, HIV, and Aids, 1st Edition Copyright ©2005 Oxford University Press > Table of Contents > HIV/AIDS > Chapter 43 – HIV: neurological disorders Chapter 43 HIV: neurological disorders P.422
Introduction HIV enters the central nervous system (CNS) soon after 1° infection, carried by infected mononuclear cells or by cell free transfer across the blood brain barrier. Macrophages and microglial cells are the predominant cell types infected and the main sites of HIV replication in the brain. Neurological disease is common and may be the presenting clinical syndrome in 30% of HIV infections occurring at any stage but most often following seroconversion or with severe immunodeficiency. Pre-HAART 10–20% of patients developed cognitive impairment and neurological features were reported in 40–70% of patients with AIDS ↑ to 90% at postmortem examination. Abnormal cerebrospinal fluid (CSF) findings including ↑ lymphocytes, protein, immunoglobulin, and oligoclonal bands may be found in patients with no neurological symptoms or signs. Presence or absence of neurological disease is independent of CSF viral load. Mechanisms of CNS injury and spectrum of neurological disease vary with the stage of HIV infection and the degree of immune deficiency.

  • At seroconversion—viraemia and inflammation resulting from the initial immunological response to HIV infection predominate, inducing aseptic meningitis, meningoencephalitis, ataxic neuropathy, Guillain–Barré syndrome, acute myelopathy, a multiple sclerosis like syndrome, acute brachial neuritis, Bell’s palsy, and acute meningoradiculitis. ▶ Patients presenting with these syndromes should have their HIV risk assessed and be offered HIV screening.
  • During the asymptomatic phase—neurological disease reflects that of the general population.
  • As HIV progresses—altered CNS cytokine production and directneurotoxic effects of HIV components such as gp120 are pathogenic.
  • With immunodeficiency—opportunist infections (OIs)/tumours and complications of treatment predominate.

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 previously difficult-to-treat infections, such as progressive multifocal leukoencephalopathy (PML). However, there has been ↑ occurrence of drug induced CNS and peripheral nerve disease. P.423
HIV-related neurological and neuromuscular disease may present with a number of symptom complexes Headaches. May be an important symptom of neuropathology, such as primary or opportunist meningitis, intracerebral opportunist pathologies, or the side-effects of drugs such as zidovudine or co-trimoxazole. Non-HIV-related problems such as migraine or psychogenic headache may occur. Altered peripheral sensation. May occur with or without motorabnormalities and a significant symptom in peripheral neuropathy. Leg weakness. May result from muscular weakness due to myopathic processes but intrinsic or extrinsic spinal cord disease should be considered and sensory levels searched for. Seizures. ↑ risk. First seizure is a presenting manifestation of an HIV associated disease in ~20% of patients. Seizures may result from:

  • metabolic encephalopathy
  • cerebrovascular disease
  • OIs such as toxoplasmosis, cryptococcosis, and PML
  • CNS lymphomas.

Focal neurological signs and symptoms. Particularly with cerebral toxoplasmosis, 1° cerebral lymphoma, and PML. P.424
Cerebral disorders HIV-associated dementia complex Cognitive impairment usually occurs when CD4 counts are <200cells/µL in patients with systemic symptoms of HIV disease. 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. Presentation: 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. Diagnosis: magnetic resonance imaging (MRI)—preferred option, or computerized tomography (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. Management: 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. Viral encephalitis Varicella zoster virus (VZV) is an important cause of meningoencephalitis which may be complicated by cranial nerve palsies and cerebral vasculitis leading to cerebral infarction. Consider in patients with stroke or transient ischaemic attacks, even in the absence of a vesicular rash. CSF should be examined by PCR and culture for VZV. CT or MRI may show evidence of ischaemia or haemorrhage. 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 are positive. Herpes simplex virus (HSV) is an uncommon cause. Progressive multifocal leukoencephalopathy (PML) Unlike other OIs its prevalence has not significantly declined with HAART. A demyelinating disease caused by the JC polyoma virus and occurs in 4–8% in 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, hemiparesis, dizziness, gait disturbance, visual field defects, and epilepsy. CT or MRI scans usually reveal lesions (single or multiple) in the P.425
white matter, particularly in the parieto-occipital region (Plate 20). Treatment options include immune reconstitution with HAART and specific antiviral therapy with cidofovir (does not alter survival). Cerebral toxoplasmosis (Toxoplasma gondii) The most common cause of mass lesions in HIV prior to the introduction of 1° PCP prophylaxis which has ↓ incidence. Presentation: typically includes confusion, headache, personality change, hemiparesis, focal sensory disturbances, fits, and fever. Diagnosis: 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 serology in 90%. Management: 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 intravenously 4 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. P.426
Meningitis Cryptococcal meningitis Cryptococcus neoformans (an encapsulated yeast)—most common fungal pathogen in the CNS. Presentation: 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. Diagnosis: 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 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. Management: daily lumbar punctures may be required until CSF pressures normalize to avoid cranial nerve lesions. Antifungal therapy with intravenous amphotericin B 1mg/kg/day intravenously 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 is required to minimize significant relapse rates. Continue until immune reconstitution is achieved with HAART. Aseptic meningitis 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. Autonomic neuropathy 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 auto-nomic 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 P.427
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 50–200µg daily), sodium supplements, compression stockings, and alpha-adrenergic agents, such as midodrine, may reduce postural blood pressure falls and alleviate symptoms. There may be improvement in autonomic function with HAART. P.428
Spinal cord disease Vacuolar myelopathy Postmortem 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 and the clinical picture mimics that of a vitamin B12 deficiency spinal cord disease. Presentation: 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. Diagnosis: investigations should include measurement of vitamin B12 level and radiological imaging to exclude structural lesions. Areas of ↑ T2 signal may be seen occasionally on MRI scan. CSF may be normal or show only non-specific abnormalities such as low-level pleocytosis or mildly ↑ protein levels. Management: spasticity may require anti-spasmodic therapy such as baclofen 10–30mg 3 times a day and a dysasthesia may require amitriptyline or gabapentin. Physiotherapy and occupational therapy input may be valuable. Improvements in function may occur with HAART. Human T lymphotropic virus type I associated (HTLV1) myelopathy In patients from areas of significant risk for 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 myelopathy Acute spinal cord disease may occasionally occur as a seroconversion event. Other important causes are spinal cord compression from lymphomatous metastases, tuberculous or bacterial abscesses, and acute infections with VZV. Presentation: Typically rapidly developing neurological deficit, such as leg weakness and sphincter disturbance, with evidence of a sensory level. Diagnosis: emergency investigation required with spinal MRI or CT. In the absence of compression CSF should be examined for evidence of infectious and neoplastic causes including viral PCR and cytology. Management: supportive with specific treatment directed at the identified cause. P.429
P.430
Peripheral nerve disease Neuritis

  • Herpes zoster (shingles)

May occur at any stage of HIV infection with a typical distribution and course. Atypical multidermatomal involvement, viraemic dissemination of lesions, and recurrences more common as CD4 counts ↓. Presentation: 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. Pain during the acute phase can be severe and disabling post-herpetic neuralgia may follow. Diagnosis: clinical picture is usually characteristic. Varicella zoster virus (VZV) can be detected in vesicular fluid by immunofluorescence. Management: 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 intravenous aciclovir 10mg/kg 8 hourly as early as possible and switch to oral famciclovir 500mg 3 times daily or valaciclovir 1g 3 times daily when lesions cease to progress for a total course of at least 7 days or until all lesions have dried and crusted.

  • Mononeuritis multiplex

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). Neuropathy Drug toxicity: the toxicity of therapeutic drugs, notably didanosine, zalcitabine, and stavudine, responsible for ↑ proportion of neuropathy. Distal symmetric polyneuropathy: occurs in ~35% of patients with advanced HIV disease. ~15% of those with asymptomatic HIV infection show abnormal nerve conduction studies. Typical symptoms are tingling, numbness, and burning pain beginning in the toes or plantar surfaces, often ascending over time. 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 the 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. Inflammatory demyelinating neuropathy or Guillain–Barré syndrome: may occur during seroconversion or with changes in immune function. Manifestations as in non-HIV setting with progressive symmetric weakness in the limbs and loss of tendon jerks but CSF pleocytosis may occur. P.431
Treatment is immunoglobulin 400mg/kg/day for 5 days or plasmapheresis, up to 6 exchanges over 2 weeks. Patients with the chronic form may need monthly cycles of treatment until stabilization. Progressive lumbosacral polyradiculopathy: caused by CMV infection in patients with CD4 counts <50cells/µL. Bilateral leg weakness progresses over several weeks, sometimes to flaccid paraplegia. Sphincter disturbance is common and sensory loss combined with painful dysasthesia is usual. Sensory symptoms differentiate this from myopathy, and sphincter disturbance with sparing of the upper limbs distinguish 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 and ↑ protein content. PCR for CMV is positive and the patient should be treated with ganciclovir or foscarnet. Miscellaneous Cerebrovascular disease 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 myocardial infarction or from dysrhythmias. Cerebral vasculitis, particularly due to VZV or syphilis, may cause cerebral thrombosis. The hypercoagulable state that may occur with HIV may contribute. Haemorrhage may complicate VZV cerebral vasculitis, thrombocytopenia, rarely due to metastatic Kaposi’s sarcoma or as a result of an incidental cerebral aneurysm. Neurosyphilis May affect most parts of the nervous system (see p. 96). Neoplastic disease Kaposi’s sarcoma, although the most common systemic neoplasm in HIV infection, rarely involves the nervous system. CNS may be invaded by non-Hodgkin’s lymphoma leading to malignant meningitis and compressive symptoms requiring intrathecal cytotoxic therapy and radiotherapy. 1° cerebral lymphoma occurs in patients with advanced immunodeficiency and presents with confusion, lethargy, personality change, focal neurological deficits, 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. Brain biopsy should be considered and cerebral radiotherapy may improve survival.

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