THE NEUROLOGY OF HIV INFECTION

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1 THE NEUROLOGY OF HIV INFECTION CLINICAL See end of artile for authors affiliations Correspondene to: Dr Hadi Manji, The Mortimer Market Clini, Capper Street, off Tottenham Court Road, London NW1, UK; S H Manji, R Miller J Neurol Neurosurg Psyhiatry 2004; 75(Suppl I):i29 i35. doi: /jnnp ine the onset of the AIDS pandemi in 1981, infetion with the human immunodefiieny virus (HIV) has spread exponentially throughout the world with urrently an estimated 40 million adults and hildren affeted. Worldwide there are approximately new infetions per day. Every day 8000 HIV infeted patients die. In the UK, there are urrently about individuals living with HIV/AIDS. Sine the introdution of highly ative anti-retroviral therapy (HAART), in ommunities where this is available, HIV/AIDS has beome a hroni disorder with dramati redutions in mortality and morbidity both from the effets of HIV itself as well as from opportunisti infetions and tumours. In the UK, the liniian will enounter two broad groups of patients. The first group omprises individuals who have been infeted with HIV for a number of years and are reeiving HAART. This group is omposed largely of homosexual men and those who aquired their infetion in the UK. The seond group onsists of patients who present with opportunisti infetions and tumours and who have late stage HIV infetion. This is a situation that was previously enountered in the late 1980s and early 1990s. This ohort largely onsists of men and women infeted by heterosexual interourse outside Europe. AND PRACTICAL ASPECTS HIV is neuro-invasive (with invasion ourring early in the ourse of the infetion), neurovirulent (ausing a neuropathy, myopathy, myelopathy, and dementia), but it is not espeially neurotrophi. The virus is rarely isolated from neurones either in the peripheral or entral nervous system. Produtive infetion is usually found within the assoiated inflammatory infiltrate, predominantly marophages. Sine all areas of the neuro-axis in an HIV infeted individual may be affeted by different aetiologial agents, the linial assessment of this group of patients may be more omplex than assessment of the immune ompetent patient the priniple of Oam s Razor may not be appliable (table 1). Furthermore, dual infetions frequently o-exist in the immunosuppressed population and this must be borne in mind when following up patients and in assessing a treatment response. For example, one study from Kenya showed that additional infetion ourred in 18% of ases of tuberulous meningitis. A symptomati glandular fever-like syndrome ours in up to 70% of ases at HIV seroonversion. In 10% this may be assoiated with neurologial symptoms and signs for example, an asepti meningitis, enephalitis, aute disseminated enephalomyelitis, transverse myelitis, polymyositis, brahial neuritis or a auda equina syndrome. Guillain Barré syndrome has been desribed at seroonversion and also during the asymptomati immunoompetent phase of HIV infetion; however, whereas usually CSF examination shows evidene of ytoalbuminaemi dissoiation, in HIV infeted individuals, there is a pleoytosis. During the asymptomati phase of HIV infetion, when there is no linially apparent immunosuppression, there is no evidene of neurologial ompromise either in the entral (CNS) or peripheral nervous systems. This has been determined by a number of large ohort studies using linial, neurophysiologial, neuropsyhologial, and magneti resonane imaging (MRI) methods of assessment. However, before the introdution of HAART, in up to 5% of ases HIV dementia was the AIDS defining illness; thus HIV infetion should be onsidered in any patient, espeially below the age of 50 years, presenting with ognitive dysfuntion. HIV infetion should also enter in the differential diagnosis of young stroke sine it may be assoiated with a vasulitis or a thrombophilli state with detetable antiardiolipin antibodies and lupus antioagulant. There may be lues to underlying HIV infetion that will be found on areful general history and examination pyrexia of unknown origin (PUO), unexplained weight loss or diarrhoea, generalised lymphadenopathy, oral hairy leuoplakia, oral andidiasis, seborrhoei dermatitis, mollusum ontagiosum, Kaposi s saroma (whih may only be present on the hard palate), or i29 J Neurol Neurosurg Psyhiatry: first published as /jnnp on 20 February Downloaded from on 3 November 2018 by guest. Proteted by opyright.

2 i30 Table 1 Common neurologial ompliations of HIV-1 infetion Due to HIV Distal sensory peripheral neuropathy (DSPN) HIV dementia (HAD) Vauolar myelopathy (usually in assoiation with HAD) HIV polymyositis Opportunisti infetions Toxoplasmosis Cryptooal meningitis Tuberulosis meningitis, absesses, tuberuloma Cytomegalovirus (CMV) enephalitis, retinitis, lumbar polyradiulopathy, vasuliti peripheral neuropathy Progressive multifoal leuoenephalopathy (PML) Tumours Primary CNS lymphoma Metastati systemi lymphoma Drug related ompliations Peripheral neuropathy aused by ddi, ddc and d4t; isoniazid Myopathy (zidovudine) otton wool spots on fundosopy. Investigations may show an unexplained thrombo- or lymphopaenia, or an elevated erythroyte sedimentation rate due to the polylonal hypergammaglobulinaemia assoiated with HIV infetion. Brain imaging studies may reveal unexplained erebral atrophy. Cerebrospinal examination may be abnormal even in asymptomati HIV infeted patients. A mild erebrospinal fluid (CSF) pleoytosis, an elevated CSF protein, and oligolonal bands an all be found in suh patients. On the other hand, as a result of HIV indued immunosuppression, the CSF ytohemial parameters may be entirely normal. The diagnosis of meningiti and enephaliti disorders therefore relies on speifi tests on CSF suh as the detetion of ryptooal antigen (by latex agglutination CrAg) for ryptooal Table 2 Infetion Drug treatment regimens for the ommon CNS infetions Toxoplasmosis Aute phase (for 6 weeks) First line treatment: Pyrimethamine loading dose (100 mg orally for 3 days, then 75 mg/day) Sulfadiazine 6 8 g/day orally/iv Folini aid 15 mg/day Seond line treatment: Clindamyin mg/day by mouth/iv instead of sulfadiazine Maintenane treatment Pyrimethamine mg/day Sulfadiazine 2 4 g/day Folini aid 10 mg/day Clindamyin 600 mg/day instead of sulfadiazine Cryptooal meningitis Aute phase treatment for 4 6 weeks or until CSF ulture negative Amphoteriin B mg/kg/day (via entral line) Fluytosine mg/kg/day orally In milder ases Fluonazole 400 mg iv/orally Maintenane treatment Fluonazole mg/day orally meningitis or CSF VDRL (venereal disease researh laboratory) in suspeted neurosyphilis (a negative test does not exlude the diagnosis, whereas a non-reative CSF-FTA (fluoresent treponemal antibody) does exlude ative infetion). Before HAART, the CD4 ount was a useful guide in attempting to determine the speifi aetiologies of the opportunisti infetions and tumours. For example, toxoplasmosis and ryptooal meningitis our with CD4 ounts below 200 ells/mm 3 ; CMV retinitis, enephalitis, and polyradiulopathy our with CD4 ounts, 50 ells/mm 3. Following institution of HAART, there is usually a rise in peripheral blood CD4 ounts, although these ells may not all be fully funtional (sine some of the antigen speifi lones are lost). HAART has led to a number of ompliations hitherto not enountered in HIV mediine. These inlude immune reonstitution inflammatory syndrome (IRIS) whih has been defined as a paradoxial deterioration in linial status attributable to reovery of the immune system. Clinially, within a few weeks of starting treatment there may be an exaerbation or an unusual manifestation of a speifi infetion. Neurologial reonstitution syndromes desribed inlude progressive multifoal leuoenephalopathy (PML), ryptooal meningitis, and ytomegalovirus (CMV) syndromes suh as enephalitis and retinitis. More reently, a rare, severe leuoenephalopathy has been desribed in patients who failed treatment with HAART. MANAGEMENT OF MASS LESIONS In the ontext of signifiant immunosuppression (CD4,200/ mm 3 ), the most ommon auses of mass lesions are toxoplasmosis, primary CNS lymphoma (PCNSL), and tuberulous granulomata or tuberulous absesses (fig 1). Although brain biopsy remains the gold standard, with inreasing experiene standard management protools have been developed. An Side effets Marrow suppression Rash, nephrotoxiity, marrow suppression Rash, diarrhoea Nephrotoxiity, anaemia, hepatitis, marrow suppression Rash, hepatitis Stopping maintenane may be onsidered if after HAART is started the CD4 ount remains above 200/mm 3 for over four months. J Neurol Neurosurg Psyhiatry: first published as /jnnp on 20 February Downloaded from on 3 November 2018 by guest. Proteted by opyright.

3 Figure 1 Management of mass lesions (CD4 ount, 200/mm 3 ). overall assessment using data from serologial and radiologial investigations may help in differentiating between the possible aetiologies. The ountry of origin may also be helpful, partiularly with respet to the likelihood of tuberulosis and to a lesser extent toxoplasmosis. However, even in areas where tuberulosis is endemi, the most ommon ause of a mass lesion(s) is toxoplasmosis. See table 2 for the drug treatment regimens for toxoplasmosis. Toxoplasma serology In HIV, toxoplasmosis is almost always a reativation and serology is positive in 85% of ases. Seronegative ases our as a result of loss of antibody with inreasing immunosuppression or rarely a primary infetion. The prevalene of previous exposure in a population varies worldwide and reflets dietary habits with respet to eating underooked meat in Frane. 90% ompared to 35% in the UK. Radiologial studies Toxoplasmosis usually auses multiple lesions loated at the grey/white interfae or involves the basal ganglia. A single lesion on MRI is more likely to be due to PCNSL as is a lesion adjaent to the ventriles (fig 2). Tuberulous absesses have similar imaging appearanes to toxoplasmosis, whereas tuberulomata tend to be smaller lesions with less mass effet (fig 3) The hest x ray is abnormal in up to 60% of ases with CNS tuberulosis. PML does not produe mass effet. i31 J Neurol Neurosurg Psyhiatry: first published as /jnnp on 20 February Downloaded from on 3 November 2018 by guest. Proteted by opyright.

4 i32 Figure 2 Primary CNS lymphoma (PCNSL): single lesion adjaent to the lateral ventrile. Thallium SPECT sans Thallium SPECT (single photon emission omputed tomography) sans may help differentiate between absesses and lymphoma there is inreased uptake in the latter but false negatives and positives our. CSF examination Lumbar punture is usually ontraindiated in most patients with lesions ausing mass effet. However, if there are no ontraindiations, CSF studies are useful in the diagnosis of PCNSL. The detetion of Epstein-Barr virus (EBV) by polymerase hain reation (PCR) is diagnosti as this tumour Table 3 Prognosti markers for ryptooal meningitis Abnormal mental status CSF opening pressure.25 m CSF CSF ryptooal antigen titre.1:1024 CSF white ell ount,20 ells/ml Extra-neural ulture of ryptoous is EBV driven ; PCR for Myobaterium tuberulosis is positive in 60% of tuberulous absesses, and granulomata may our in assoiation with a tuberulous meningitis. CRYPTOCOCCAL MENINGITIS Before the introdution of HAART, meningitis aused by Cryptoous neoformans was a ommon ompliation in patients with CD4 ounts below 100/mm 3. This ubiquitous organism is partiularly found in the exreta of pigeons. Pulmonary infetion, usually asymptomati, ours by inhalation followed by haematogenous spread to the meninges. Patients present with a short history of headahe, fever, nausea, and vomiting. Only one third of patients will have the lassi features of meningism photophobia, nek stiffness, and a positive Kernig s sign. The threshold for performing brain imaging studies followed by CSF examination should be low in HIV infeted patients presenting with non-speifi symptoms suh as mild headahe. In 20% of ases there may be evidene of extraneurologial involvement with diffuse pulmonary infiltrates, lobar onsolidation or avitating lesions on hest x ray, skin lesions (small papules whih may resemble mollusum ontagiosum), and infetion of the urinary trat. Brain imaging is usually normal but may reveal hydroephalus, ryptooomas or basal meningeal enhanement. At lumbar punture, CSF pressure is frequently elevated. In most ases there is a moderate mononulear ell pleoytosis, an elevated protein, and a low gluose. In 25% of ases, the CSF may be normal. The diagnosis is established by the identifiation of India ink positive hyphae in 75% and the detetion of ryptooal antigen in 95% of ases. J Neurol Neurosurg Psyhiatry: first published as /jnnp on 20 February Downloaded from on 3 November 2018 by guest. Proteted by opyright. Figure 3 A small ring enhaning lesion is more suggestive of a tuberuloma, as seen on this ontrast enhaned oronal MRI. Figure 4 Progressive multifoal leuoenephalopathy: T1 weighted oronal MRI showing a low attenuation lesion in the white matter of the left erebellar hemisphere.

5 Figure 5 Progressive multifoal leuoenephalopathy: T2 weighted axial MRI showing a high signal lesion within the white matter of the left erebellar hemisphere. A number of prognosti markers have been identified (table 3). For drug treatment regimens see table 2. A ompliation that needs lose vigilane is the development of raised intraranial pressure, unrelated to hydroephalus, aompanied by loss of vision. This should be managed by repeated lumbar punture with high volume CSF removal and, when indiated, the plaement of a lumbar or ventriular drain. Aetozolamide, but not ortiosteroids, has a signifiant adjuntive role. PROGRESSIVE MULTIFOCAL LEUCOENCEPHALOPATHY PML is aused by the reativation of the Jamestown Canyon virus (JCV), a ommon polyoma virus, whih infets 75% of the general population. It is usually a mild hildhood respiratory trat infetion. Cell mediated immunity is the hief predisposing fator for the development of PML, and before the AIDS epidemi was generally enountered in patients with lymphoproliferative disorders or those treated with immunosuppressive drugs for example post-transplant surgery and saroidosis. Abbreviations CMV: ytomegalovirus CNS: entral nervous system CT: omputed tomography EBV: Epstein-Barr virus DSPN: distal sensory peripheral neuropathy HAART: highly ative anti-retroviral therapy HAD: HIV dementia HIV: human immunodefiieny virus JCV: Jamestown Canyon virus MRI: magneti resonane imaging NCT: nerve ondution tests NRTI: nuleoside reverse transriptase inhibitor PCNSL: primary CNS lymphoma PCR: polymerase hain reation PML: progressive multifoal leuoenephalopathy Neurology of HIV infetion: key points Neurologial ompliations are seen at all stages of HIV infetion Many of the neurologial ompliations of HIV are treatable Oam s Razor does not apply in assessment of HIV patients Highly ative anti-retroviral therapy has substantially altered the patterns of neurologial disease in patients with HIV HIV indued immunosuppression urrently aounts for 85% of ases of PML. Before HAART, 5% of AIDS patients developed PML with CD4 ounts usually below 100/mm 3. After HAART, although the inidene of most neurologial ompliations suh as HIV dementia have delined, it is not lear whether there has been a similar redution in PML. However, it does seem that PML is more prevalent in HIV infetion than expeted underlying reasons may be related to inreased ativation of JCV by the HIV proteins. The pathologial hanges result from repliation of the virus within the oligodendroytes, ausing lysis and demyelination. It is unlear whether PML within the CNS results from reativation of the virus following immunosuppression or is aused by invasion of the CNS by infeted lymphoytes from the peripheral irulation. The linial presentation is subaute with a progressive hemiparesis, hemianopia or ataxia. Cognitive dysfuntion usually ours with foal neurologial signs. Cortial involvement may oasionally result in dysphasia and seizures. By ontrast with other more ommon auses of foal intraranial lesions in HIV infeted patients suh as toxoplasmosis, there are usually no symptoms or signs of systemi infetion or raised intraranial pressure. Cranial omputed tomography (CT) shows hypodense lesions. Typially, MRI shows large single or multiple lesions involving white matter, with salloping at the grey/white interfae. The parieto-oipital and frontal lobes are most ommonly affeted. The affeted areas are low signal on T1 weighted images (fig 4) and hyperintense on T2 weighted sequenes (fig 5). This may help distinguish PML from HIV dementia. There is no mass effet. Some ontrast enhanement may be seen whih has been identified as a good prognosti marker. Until reently the diagnosis was only possible by brain biopsy with the histologial demonstration of demyelination, enlarged oligodendroyte nulei with JCV inlusion partiles and bizarre enlarged astroytes. It is now possible to isolate JCV-DNA in the CSF by PCR with a sensitivity of 75% and almost omplete speifiity. It may be neessary to repeat the CSF examination in PCR negative ases (raising the yield to 85%) before onsidering stereotati brain biopsy. The treatment of PML in patients with HIV is two pronged: improving the underlying immunosuppression with HAART, and anti-jcv therapy. Institution of the former has resulted in fourfold prolongation of survival, with patients neurologial status stabilising or even improving. A number of drugs have been shown to have anti-jcv ativity and have been tried with variable suess. Cytosine arabinoside (AraC) given intravenously or intratheally onfers no signifiant benefit. The use of a interferon was prompted by its antiviral and immune enhaning effet in a i33 J Neurol Neurosurg Psyhiatry: first published as /jnnp on 20 February Downloaded from on 3 November 2018 by guest. Proteted by opyright.

6 i34 Table 4 Drug HAART related drug toxiities Nuleoside reverse transriptase inhibitors (NRTIs) Class assoiated Drug speifi Zidovudine Stavudine (d4t) Zalitabine (ddc) Didanosine (ddi) Lamivudine (3TC) Non-NRTIs Efavirenz Nevirapine Protease inhibitors Class assoiated Drug speifi Nefinavir Indinivir Ritonivir Amprenivir Lopinivir pre-haart retrospetive open labelled observational study. About one third of patients showed some neurologial benefit with some also showing radiologial improvement. The anti-cmv drug idofovir used in onjuntion with HAART has shown, in a number of small studies, inreased neurologial improvement or stability when ompared to HAART alone. There was also faster learane of the virus from the CSF. However, others have failed to onfirm this finding. Cidofovir has a number of serious side effets: nephrotoxiity due to a dose dependent renal tubular aidosis, neutropenia, and oular hypotonia. The results of larger, better ontrolled studies are awaited. A number of other drugs that are also urrently undergoing study inlude topotean and hlorpromazine, both of whih suppress repliation of JCV in vitro. HIV DEMENTIA Prior to HAART, HIV developed in 20% of patients with AIDS. The risk fators identified inluded low CD4 ount, high plasma viral load, older age group, intravenous drug use, female sex, and onstitutional symptoms suh as anaemia. Sine HAART, the inidene of HAD has been redued by 50% although the prevalene has inreased as a result of improved survival. The linial features of HIV dementia (HAD) in the early stages may be mild with symptoms of poor onentration, mental slowing, and apathy whih may mimi depression. Later on, as the syndrome progresses, more speifi ognitive hanges develop with memory loss and personality hange assoiated with motor and sphinter diffiulties as a result of an assoiated vauolar myelopathy. Examination may show impaired saadi eye movements, generalised hyperreflexia, and erebellar and frontal release signs. Investigations are indiated to exlude other auses MRI typially shows evidene of atrophy and diffuse white matter signal hanges. The CSF shows non-speifi ytohemial abnormalities but must be examined for onditions suh as neurosyphilis, CMV, and PML. The CSF viral load orrelates with severity of the dementia. However, this test is not sensitive enough for diagnosti purposes. Neuropsyhologial assessment typially shows abnormalities in the following ognitive domains: psyhomotor speed, Toxiity Lati aidosis, hepati steatosis, lipodystrophy Myelosuppression, myopathy Peripheral neuropathy Peripheral neuropathy Peripheral neuropathy, panreatitis? Neuropathy Dysphoria, mood hanges, vivid dreams, hyperholesterolaemia Hepatitis, Stevens-Johnson syndrome Lipodystrophy, hyperlipidaemia, diabetes Diarrhoea Nephrolithiasis Perioral dysaesthesia, flushing, diarrhoea, hyperuriaemia Diarrhoea Diarrhoea attention, frontal lobe funtion, and verbal and non-verbal memory. Pre-HAART, the mean survival rate for patients with HAD was one year. Sine HAART, most patients stabilise or improve. Although there are onerns as to whether the various antiretroviral drugs atually ross the blood brain barrier, no speifi HAART regimen has been shown to be superior in the management of HAD. Adjuvant treatments suh as selegine and memantine are under trial. PERIPHERAL NERVE COMPLICATIONS Whereas there has been a deline in other neurologial ompliations, the inidene and prevalene of peripheral neuropathy has inreased as a result of inreased longevity and the use of neurotoxi antiretroviral therapies. The most ommon peripheral nerve disorder enountered due to HIV is a distal sensory peripheral neuropathy (DSPN). The prevalene rate pre-haart was estimated to be around 35% and at neropsy, 95% of patients had sural nerve pathologial abnormalities. Risk fators for the development of DSPN inlude higher HIV viral load and lower CD4 ounts. Patients with other neuropathi risk fators suh as diabetes, exess alohol intake, and geneti neuropathies may be more liable to develop the ompliation. The presentation is with painful, numb feet. A signifiant proportion of patients omplain of hyperpathia. There is little or no weakness and the upper limbs are usually not involved. Abnormal neurologial signs inlude depressed or absent reflexes and impaired sensation to pain and temperature harateristi of a small fibre neuropathy. Nerve ondution tests (NCT) may be normal or show mild axonal abnormalities. Thermal thresholds are abnormal. Sine linially DSPN is reasonably well defined further investigations are usually not neessary. It seems prudent to hek a random blood gluose and a vitamin B12 value. In ases where on examination there are signs of signifiant weakness suh as a foot drop or presene of prominent upper limb involvement NCT and nerve biopsy should be onsidered to exlude vasulitis, demyelinating neuropathies, and lymphomatous infiltration. J Neurol Neurosurg Psyhiatry: first published as /jnnp on 20 February Downloaded from on 3 November 2018 by guest. Proteted by opyright.

7 The nuleoside reverse transriptase inhibitors (NRTIs) didanosine (ddi), zalitabine (ddc), and stavudine (d4t) have all been shown to ause a dose dependent peripheral neuropathy (table 4). The assoiation with lamivudine (3TC) is less well doumented. Zidovudine auses a myopathy when used in high doses but does not ause a neuropathy. Mitohondrial toxiity from inhibition of DNA polymerase may be the underlying mehanism for NRTI related side effets. The same mehanism ould also aount for the other side effets with this lass of drug panreatitis, fulminant hepati failure, and lati aidosis. Abnormal fat distribution (lipodystrophy), in whih there is fat wasting around the buttoks, fae, and limbs, and internal visera disposition with distension, is assoiated with both NRTIs and protease inhibitors. The linial presentation of these antiretroviral drug related neuropathies is similar to that seen with DSPN. However, the drug related neuropathies are more likely to be painful, have an abrupt onset, and rapidly progress. After stopping the ulprit antiretroviral drug, there may be a paradoxial worsening of neuropathi symptoms over a period of 4 8 weeks ( oasting ). An improvement of symptoms an be expeted in some but not all as some may be left with the underlying DSPN that has been unmasked by the drug treatment. The risk of neuropathy is inreased when ombinations of drugs are used for example, when hydroxyurea is used to potentiate the antiretroviral effets of ddi and d4t. The risk of isoniazid indued neuropathy is higher when used in ombination with the antiretroviral drugs. As with the treatment of painful sensory neuropathy in general, the management of this group of patients an be diffiult. The development of a painful sensory neuropathy is a signifiant ause of morbidity and poor drug ompliane. If the patient is on one of the three neurotoxi drugs (ddi, ddc or d4t), the issue of stopping the drug needs to be disussed with the patient and their HIV physiian. In pratie, this may be a diffiult deision, espeially if there has been a good virologial response and CD4 has signifiantly risen. Also lowering the dose of an offending drug raises the possibilities of HIV viral resistane. The drugs used in the symptomati treatment of DSPN and the antiretroviral related neuropathies are those used in all painful neuropathies. Gabapentin, whih has been shown to be effetive in diabeti neuropathy, is first line treatment although there are no published data to date in HIV related neuropathies. A starting dose of 300 mg at night an be gradually inreased to 300 mg three times daily. A maximum dose of up to 2.4 g per day should be tried if tolerated. There is no interation with the antiretroviral drugs whih is an important onsideration when introduing any new drug in this group of patients. Lamotrigine has been shown to redue pain sores in a small plaebo ontrolled trial. The starting dose was 25 mg/day for two weeks gradually titrating the dose to 150 mg daily. Other drugs that merit onsideration inlude amitriptyline, starting at 10 mg at night, even though one trial failed to show any group benefit.... Authors affiliations H Manji*, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK R Miller, Royal Free and University College Shool of Mediine, London, UK *Also at the Ipswih Hospital, Ipswih, UK REFERENCES 1 Brew B. HIV neurology. Contemporary Neurology Series. Oxford: Oxford University Press, An exellent referene book for all those involved in the management of HIV/AIDS patients. 2 Seth P, Diaz F, Major E. Advanes in the biology of JC virus and indution of progressive multifoal leuoenephalopathy. J Neurovirol 2003;9: An exellent review of PML whih inludes a summary of the drug treatment trials to date. 3 MArthur JC, Haughey N, Gartner S, et al. Human immunodefiieny virus assoiated dementia: an evolving disease. J Neurovirol 2003;9: An up-to-date review of the subjet by the one of the most ative researh groups in the field in HIV neurology. 4 Keswani S, Pardo CA, Cherry CL, et al. HIV assoiated sensory neuropathies. AIDS 2002;16: An up-to-date review of the most ommon problem in HIV neurology linis. i35 J Neurol Neurosurg Psyhiatry: first published as /jnnp on 20 February Downloaded from opyright. on 3 November 2018 by guest. Proteted by