Postgraduate Medical Journal (1988) 64, 180-187

Review Article

Neurological complications of human immunodeficiencyvirus infection

Peter G.E. KennedyGlasgow University Department of Neurology, Institute of Neurological Sciences, Southern General Hospital,Glasgow G51 4TF, UK.

Summary: The protean neurological manifestations of human immunodeficiency virus (HIV)infection are reviewed. Both the central nervous system and peripheral nervous system may beaffected and many of the complications may occur in individuals with acquired immunodeficiencysyndrome (AIDS)-related complex, or who are seropositive for HIV alone as well as those with theestablished AIDS syndrome. Specific therapy is available for certain of these neurological conditions,but the clinical course in others is untreatable and progressive. Although it seems likely that thepathogenesis of some of these syndromes such as the AIDS-dementia complex are due to the directeffect of HIV on the nervous system, in others the neurological injury probably occurs as aconsequence of the immunosuppression which HIV induces, or immune-mediated mechanisms.

Introduction

Human immunodeficiency virus (HIV) is thecausative retroviral agent of the acquired immuno-deficiency syndrome (AIDS). Previously known aslymphadenopathy-associated virus (LAV)1 orhuman T-lymphotropic virus III (HTLV-III)2, theterm HIV has now gained widespread acceptance.Neurological involvement in AIDS is common. Inearly studies from New York and San Francisco itappeared that 30-40% of patients with AIDSbecame neurologically symptomatic during theirillness,3'4 and approximately 10% of patientspresented with neurological symptoms.4 However,neuropathological evidence of involvement of thecentral nervous system (CNS) has indicated that55-80% of patients dying with AIDS havepathological abnormalities in their CNS.4'5'6 Morerecent clinical studies have indicated that neuro-logical involvement in AIDS is indeed morecommon than previously thought with two-thirds ofpatients having some kind of neurologicalabnormality, in particular evidence of the AIDS-dementia complex.7 The estimated percentage ofpatients with CNS involvement depends also on theseverity of the symptoms. For example, as many as90% of individuals probably have evidence of the

AIDS-dementia complex if only mildly affectedpatients are included.7 Our own experience inGlasgow (Kennedy et al., in preparation) is inagreement with a high incidence of neurologicalcomplications, and the picture will become clearerwith time and when more autopsy examinations arecarried out on patients dying with AIDS.The spectrum of neurological disease occurring

in AIDS patients is very wide. The CNS is mostfrequently affected but a number of peripheralnervous system (PNS) syndromes have also beenrecognized. There appear to be at least two generalpathogenetic mechanisms of infectious disease of theCNS in AIDS, namely, direct involvement of HIVin some conditions, and in others opportunisticinfections with organisms that do not usually causedisease in normal immunocompetent individualsoccur. These organisms appear to become patho-genic in AIDS patients as a result of the immuno-suppressive state which the virus induces. HIVcauses a severe defect in cell-mediated immunemechanisms through its selective infection of the Thelper lymphocyte population8 which plays acentral role in the immune response. These twomechanisms of neurological damage are notmutually exclusive and in some cases both HIV andopportunistic organisms such as cytomegalovirus(CMV) may be pathogenic. In other cases morethan one opportunistic infection, e.g., CMV and

© The Fellowship of Postgraduate Medicine, 1988

Correspondence: Professor P.G.E. Kennedy, M.D., Ph.D.,M.R.C.P.Accepted: 15 October 1987

NEUROLOGICAL COMPLICATIONS OF HIV INFECTION 181

herpes simplex virus (HSV) may operate.9 Anadditional factor which has emerged over the lastfew years is that CNS and PNS complications mayoccur not only in patients with full-blown AIDSbut also in those with the AIDS-related complex(ARC), or even asymptomatic individuals who areonly seropositive for HIV.10'11 The long-termprognosis of such patients remains to be seen butboth host and viral factors must almost certainlyinteract to produce these heterogeneous patterns ofdisease.The following account will provide an overview

of the neurological complications seen in AIDSpatients and will not be limited to infections,although infectious agents including HIV actingdirectly by itself may well prove eventually to beimplicated in virtually all of these nervous systemmanifestations. Emphasis will be placed on themore common conditions such as the AIDS-dementia complex. The complications will beconsidered under four broad groups: (a) infectionsof the CNS, (b) neoplasms, (c) vascular disturbancesand (d) PNS complications.

Infections of the CNS (Table I)AIDS-dementia complexSince the early AIDS cases were first encountered ithad been recognized that affected patients werefrequently slow mentally and had difficulty concen-trating. These symptoms usually heralded aprogressive dementia which was initially called'subacute encephalitis'4 but has recently been

Table I Neurological complications of HIV infection-CNS complications

(a) InfectionsAIDS-dementia complexCMV encephalitisHSV and VZV encephalitisCerebral toxoplasmosisProgressive multifocal leukoencephalopathyVacuolar myelopathy and myelitisAseptic meningitisFungal infectionsMycobacterial infectionsTreponema infectionCMV retinitis

(b) NeoplasmsPrimary CNS lymphomaSystemic CNS lymphomaKaposi's sarcoma

(c) VascularCerebral haemorrhageCerebral infarction

termed the 'AIDS-dementia complex'.'0 This is nowrecognized as being the commonest neurologicalmanifestation of AIDS occurring in at least twothirds of affected patients,7 and, as has beenindicated above, the true incidence may be verymuch greater if mild cases are included. Moreover,nearly 25% of cases with this condition occur inpatients with seropositivity for HIV alone or ARCbefore the full-blown AIDS syndrome develops.10The syndrome is usually progressive over a

period of months and the initial complaints are oflethargy, difficulty with concentration and memorydisturbance. A confusional state including organicpsychosis may develop and personality change withgeneral apathy may also be evident. Motor featuresmay develop early or later in the illness. The latterinclude weakness, ataxia, tremor, impaired ocularmotility and myoclonus;7 seizures may also occur.A variety of signs may be detected, slurring ofmotor and verbal responses, hyper-reflexia, frontallobe release signs and the neuropsychologicalfeatures of a subcortical dementia being the typicalfindings.7 The clinical course is usually relentless,resulting in increasing dementia until the patient isbed-bound and incontinent. Some of the earliersigns, e.g., frontal lobe abnormalities, may be subtleand only detected if specifically looked for(Kennedy et al., in preparation7). In children withAIDS the progressive encephalopathy may becharacterized by loss of motor milestones orintellectual abilities, secondary microcephaly,seizures and myoclonus. 2, 3

Neurological investigations may reveal a varietyof abnormalities. The cerebrospinal fluid (CSF)usually shows non-specific features such as a mildpleocytosis and raised protein. HIV has beenisolated from the CSF of both patients with theAIDS-dementia complex and those with other CNSsyndromes,l4 and locally synthesized HIV-specificIgG has been detected in the CSF in suchpatients.15 Computed tomographic (CT) scanningin the AIDS-dementia complex usually showscortical atrophy with consequent enlargement ofthe ventricles,10 sometimes associated with basalganglion calcification in children.12 In our ownexperience (Kennedy et al. in preparation) and thatof others7 the atrophic changes seen on CTscanning may occur at an early stage of thedementia. Magnetic resonance imaging (MRI)abnormalities consisting of white matter attenuationhave also been demonstrated in these patients.7

Characteristic pathological findings in patientswho have died with the AIDS-dementia complexinclude diffuse small areas of focal perivasculardemyelination in white matter,3 diffuse microglialnodules in grey and white matter,4"6 reactive

182 P.G.E. KENNEDY

astrocytosis,4 focal or diffuse white mattervacuolation7 and accumulation of perivascularmacrophages.4"7

Earlier studies suggested that CMV may be thecausative agent of the syndrome in view of thecharacteristic histopathology,4.16 the isolation ofCMV from some of the patients' brains4 and thedemonstration of CMV antigens in brain tissue.13Although it is possible that a true CMVencephalitis may indeed occur in AIDS, it nowseems likely that the AIDS-dementia complexresults from the direct effect of HIV in the brain.The initial convincing evidence for this view wasprovided by a study which used Southern blottinganalysis and in situ molecular hybridization todemonstrate the presence of HIV DNA in thebrains of five patients; viral-specific RNA was alsodetected in four of these individuals.17 Thesefindings have now been corroborated by severalother studies. For example, HIV has been isolatedfrom the CSF and a variety of neural tissues suchas brain from AIDS patients with neurologicalinvolvement including those with dementia.1'4'8 Inaddition, the presence of HIV nucleic acidsequences and proteins has been confirmed in thebrains of these patients using in situ hybridizationand immunocytochemistry.'9 The viral genome waslocalized mainly in capillary endothelial cells,mononuclear inflammatory cells and giant cells.Very recently, the presence of HIV proteins in thesebrains has been confirmed using immunocyto-chemistry.20 Although there is some evidence thatHIV may be present in some glial cells andneurones,19,20 the evidence for this is notunequivocal. Although the virus is clearly present inmacrophages, in the author's opinion the preciseglial cell localization of HIV has yet to bedetermined convincingly. It should also be borne inmind that the dementia may be a consequence of aninfection with more than one virus and both HIVand CMV (or another virus) may be actingsynergistically to produce the neurological disease.By contrast, a condition in AIDS which has beenshown unequivocally to be due to CMV is CMVchorioretinitis leading to blindness in many cases.21A recent study has suggested a further possiblemechanism of HIV-mediated neurological disease inthat non-cytocidal natural variants of HIV havebeen isolated from four patients with AIDS andCNS manifestations.22 Most of the HIV isolatesfrom end-stage AIDS, however, have been cytocidalto T4 cells. The authors have therefore suggestedthat the neurological disorders may result from thenon-cytocidal HIV variants causing metabolicabnormalities of neural cells rather than directneural cell killing. There is no specific treatment for

the AIDS-dementia complex although it is possiblethat it may respond to drugs currently beingevaluated in AIDS patients such as azido-thymidine.23

Encephalitis due to herpesviruses

Encephalitis due to both HSV and varicella-zostervirus (VZV) have been described in patients withAIDS. VZV infections are well-known to occur withincreased frequency in immunocompromisedindividuals,24 and encephalitis and arteritis due toVZV may rarely occur in AIDS patients.3'4'7Although HSV encephalitis has been described inthese patients4'25 this is a rare occurrence. Mostcases have been due to HSV-1 encephalitis aswould be expected since HSV-2 usually causesencephalitis only in neonates. However, brainbiopsy-proven encephalitis due to HSV-2 in twohomosexual men with persistent lymphadenopathyhas been described.26 This is perhaps not surprisingin view of the increased incidence of HSV-2encephalitis in immunosuppressed patients. Theclinical picture of HSV encephalitis in AIDS issimilar to that occurring in immunocompetentindividuals and specific treatment should be givenwith intravenous acyclovir.

Spinal cord and meningeal conditions

A vacuolar myelopathy occurring in 20 out of 89consecutive patients with AIDS has beendescribed,27 and it is now clear that about one thirdof all adult individuals with AIDS have thiscomplication.28 The clinical presentation ischaracterized by spastic paraparesis, ataxia andsphincter disturbance, and dementia is present inmany cases. Indeed this myelopathy may be part ofthe AIDS-dementia complex although its preciserelation to the latter entity is not certain.7 Theredoes not seem to be a correlation between theincidence and severity of the dementia and themyelopathy.27 There is a very typical pathologicalpicture consisting of symmetrical vacuolation in theposterior and lateral columns of the spinal cord,mainly in the thoracic segments. Some patients alsohave similar vacuolation within the brain. Electronmicroscopic analysis has demonstrated swellingwithin myelin sheaths which appeared to lead to thevacuolar changes. Some of the vacuoles containedlipid-laden macrophages. The aetiology of thiscondition is not known. The pathological changesare similar in many respects to those seen insubacute combined degeneration of the cord due toB12 and folate deficiency. However, there areclinical differences between the two groups of

NEUROLOGICAL COMPLICATIONS OF HIV INFECTION 183

patients and the serum B12 levels are normal in theAIDS patients with the syndrome.27 Whether HIVis directly involved in the pathogenesis of themyelopathy is unknown.

Spinal cord degeneration in an individual withAIDS was also described by other authors29 andthis patient may have had the same condition.Symmetrical degenerative spongy changes anddemyelination were seen in the lateral and anteriorpyramidal tracts and the posterior columns, andscattered microglial nodules were seen in the spinalcord and brain. The aetiology of this condition was,again, unclear.

Inflammatory conditions of the spinal cord andmeninges are also well-described in AIDS. Forexample, aseptic meningitis is a recognized featurewhich may occur at the time of HIV sero-conversion. The aseptic meningitis in AIDS presentsin a different clinical way from the AIDS-dementiacomplex.4 Fever, headache and meningism aretypical and the attacks tend to be self-limiting orrecurrent; CMV has been isolated from the CSF ofat least one case with this condition.4

Ascending myelitis has also been described inAIDS patients. For example, a case of AIDS withKaposi's sarcoma and disseminated CMV infectionwho also developed a progressive necrotizingascending myelitis has been reported.10 Both CMVand HSV-2 were isolated from multiple sitesthroughout the nervous system and CMV was alsocultured from the CSF. The myelitis waspresumably due to one or both of these viruses. Atleast two other cases appear to have had myelitis,4and VZV is probably also capable of causing a viralmyelitic syndrome.7

Progressive multifocal leukoencephalopathy (PML)PML30 is a rare but well-recognized opportunisticCNS infection caused by a papovavirus, usually JCvirus31 but in two cases the SV40 virus32 has beenimplicated. PML occurs in immunosuppressedindividuals with defective cell-mediated immunitysuch as those with Hodgkin's disease and/or whoare receiving immunosuppressive drugs. PML isnow well-established as an unusual complication ofAIDS, 2% of such patients showing the neuropatho-logical changes of PML at post-mortem.5'7 Severalcases with the typical clinical features of thiscondition have now been described. The clinicalpresentation of PML is characteristic and consistsof a steadily progressive illness with mentaldeterioration and a wide variety of focal distur-bances such as blindness, aphasia, hemiparesis,sensory impairment and ataxia.4'7 Most patients diewithin months of the onset.

Investigations in PML are also characteristic, theCT scan usually showing single or, more commonly,multiple low-density lesions in white matter. Asmight be expected from its greater sensitivity MRIscanning is particularly useful in detecting suchlesions at an early stage of the illness.7 The CSF isgenerally normal but the EEG is usually abnormal.The typical pathological findings consist of focalareas of demyelination, absence of inflammatoryreaction, enlarged bizarre shaped astrocytes andpapovavirus particles within enlarged oligodendro-cytes demonstrable by electron microscopy.33 Bycontrast, neurones appear to be unaffected by thedisease process on the basis of morphology. There isno specific treatment for PML although bothadenine arabinoside34 and cytosine arabinoside3have been given to some patients without markedeffect.

Cerebral toxoplasmosis

Toxoplasmosis results from infection with theprotozoan parasite Toxoplasma gondii and is one ofthe commonest opportunistic infections in AIDSpatients, being the most frequent cause of focalneurological disease. Indeed, toxoplasmosis is themost frequent cause of CNS disease in HaitianAIDS patients35 and accounts for 10-15% ofneurological complications in AIDS overall.28However, this high incidence has not been found inall series, one recording, for example, only one caseout of 29 studied at post-mortem.6 The reasons forsuch marked discrepancies are not clear but mustrelate at least in part to geographical differences.The clinical picture may be variable in terms of

onset, severity and symptomatology. The typicalpresentation is with focal deficits and alteredmentation and consciousness. Seizures are commonand may be a presenting feature in about 15% ofcases.4 Both fever and headache are common andrarely cerebellar and brain stem involvement maybe evident.7CSF analysis in these patients may show non-

specific pleocytosis and elevation of protein levels.Serological tests for toxoplasma IgG are generallyunreliable and are not really helpful in diagnosis.False-negative results are well-recognized and IgMtoxoplasma titres may be negative in patients withcerebral toxoplasmosis complicating AIDS.4'35 BothCT scanning and MRI are extremely useful indiagnosis and typically reveal single or multiplecontrast-enhancing ring lesions. The lesions have aspecial tendency to occur in deep grey matterstructures.3 Less frequently non-enhancing orhomogeneously-enhancing lesions may be seen orthe CT scan may be normal.3'4'7'36 In all these

184 P.G.E. KENNEDY

cases differentiation from other causes of focal braindisease such as cerebral lymphoma must be made.MRI appears to be more sensitive than CT indetecting the presence and nature of toxoplasmosislesions.4'7

Treatment of cerebral toxoplasmosis is withpyrimethamine and sulphadiazine which is highlyeffective in many cases. It is important to starttreatment as soon as possible after the clinicaldiagnosis has been made. Marked clinical improve-ment may occur many days prior to resolution ofthe CT appearances7 but the relapse rate is stillhigh. There is no general consensus on the exactrole of brain biopsy in toxoplasmosis. The authorshares the view of some authors7'37 which favoursa therapeutic trial of pyrimethamine andsulphadiazine in these patients while recommendingbiopsy for patients who fail to respond to medicaltherapy or in whom there exists diagnostic doubt.However, other workers have recommended brainbiopsy of all AIDS patients who have such masslesions in view of the unhelpful serology and thefact that more than one infectious intracranialpathology may exist in these patients.4

Fungal infectionsCNS fungal infections with Cryptococcus neoformans,Candida albicans, Aspergillusfumigatus, and Coccidio-mycosis have all been described in patients withAIDS. The most important of these organisms isCryptococcus neoformans which is a frequent fungalinfection of the CNS in immunocompromisedindividuals.4'38 The primary site of infection isusually the lung with subsequent spread via thebloodstream to the CNS.6 Cryptococcal meningitishas been frequently described in patients withAIDS. The presentation is variable and oftensubacute. Typically, there is the development ofmeningitic symptoms and signs or the developmentof raised intracranial pressure. Headache mayprecede the development of clinical signs byweeks.38 Features such as altered consciousness andpersonality, visual loss, seizures, cranial nervepalsies and the development of long tract signsand hydrocephalus may also be apparent.38Intracranial cryptococcoma has also rarely beendescribed in AIDS patients.4'35

Diagnostic studies in suspected cryptococcalmeningitis should always include a chest X-ray butthis is frequently normal. The CT scan may showcerebral atrophy, white matter changes, hydro-cephalus, an intracranial mass, or it may benormal.4'38 The CSF is often normal but it mayshow non-specific changes such as mononuclearpleocytosis, mild protein elevation and depressed

glucose levels. The diagnosis on the CSF may bemade by visualization of the organisms by Indianink staining, by means of culture of the organism,or by demonstration of cryptococcal antigen in theCSF. The latter test utilizes a latex agglutinationprocedure and is of considerable diagnostic value incryptococcal meningitis.39The treatment of cryptococcal meningitis has

usually been with amphotericin B or 5-fluorocytosine and the importance of earlytreatment before the development of major CNScomplications has been emphasized.38'40 In somecases the use of an Ommaya reservoir for directintraventricular administration of drugs has beenadvocated41 but this is not without complications.Hydrocephalus should also be treated if present.The prognosis of cryptococcal meningitis is pooreven after appropriate treatment with reportedmortality rates in the region of 40%.4

Rare cases of Candida albicans infection in AIDSpatients have been described, and both meningitisand brain abscesses may occur.3'42 Cerebral abscessdue to aspergillosis infection has also beenreported.43Other infections

Syphilitic infections due to Treponema pallidumhave been described in AIDS patients and thepresentation may be with meningovascularsyphilis.43 However, it is important to establish thatthe infection is an active one since many AIDSpatients are likely to have had an increased risk ofcontracting a previous and currently inactiveinfection. Patients with AIDS also have anincreased incidence of CNS Mycobacteriumtuberculosis infections, in particular with theatypical Mycobacterium avium intracellulare. Thepresentation may be with tuberculous meningitis or,more rarely, intracerebral tuberculoma.35

Neoplasms (Table I)

The incidence of malignant neoplasms is increasedin patients with AIDS presumably as a result of theimmunocompromised state of these patients. CNSlymphoma is the most frequently describedmalignancy, and a number of cases of primary CNSlymphoma and systemic lymphoma with CNSinvolvement have been described.3'4'43 Primarylymphoma may be discovered at autopsy without ahistory of clinical symptomatology. In symptomaticcases the presentation is variable, although there isa marked tendency for the primary lymphoma toinvolve the brain parenchyma.4 The clinical features

NEUROLOGICAL COMPLICATIONS OF HIV INFECTION 185

include encephalopathy with alteration of mentalstatus, headaches, seizures, aphasia and focal limbsigns such as hemiparesis. In addition, single ormultiple cranial neuropathies and intrinsic brainstem syndromes may occur.43 The CT scan is oftenhelpful in diagnosis and may show single ormultiple lesions, but in some cases it may benormal or show only cerebral atrophy. Patho-logically these lymphomas are of the B cell type.44Radiation therapy should be considered in theseindividuals, with reported improvement in somecases.4

Systemic lymphoma in these patients may involvethe CNS through invasion of the brain, meningesor spinal cord, causing cerebral syndromes, cranialneuropathies and/or carcinomatous meningitis, andspinal cord compression respectively. Incarcinomatous meningitis the CSF may be normalor show mild non-specific abnormalities and thediagnosis can sometimes be made by the use ofCSF cytology.43 Both radiation therapy andcytotoxic therapy should be considered in theseindividuals. Although Kaposi's sarcoma is anextremely common malignancy in AIDS, intra-cerebral Kaposi's sarcoma is exceptionally rare withonly two pathologically proven cases having beenreported to date.4

Vascular involvement (Table I)

Cerebrovascular syndromes have been described inpatients with AIDS and these appear to be prim-arily the consequence of other pathologies foundin these cases. For example, cerebral infarcts areknown to occur, secondary to non-bacterial throm-botic endocarditis.3 Intracerebral haemorrhagehas also been described, resulting from haemato-logical abnormalities such as thrombocytopenia orin some cases from CNS lymphoma.3 The possi-bility of meningovascular syphilis as a cause ofcerebrovascular pathology should always be con-sidered in these patients.

PNS complications (Table II)

A variety of PNS syndromes has been described inAIDS patients. A prominent feature is thedevelopment of one of several types of peripheralneuropathy. The most common form is a pro-gressive distal symmetrical sensori-motor neuro-pathy usually occurring late in the disease inpatients with established AIDS.3,7'45 Painfuldysaethesias are common but weakness is notprominent and both demyelinating and axonaldegenerative processes may be apparent.3'45 In thestudy of 12 homosexual patients with ARC, four of

Table II Neurological complications of HIV infection-PNS complications

Distal sensorimotor neuropathyAcute, subacute or chronic demyelinating inflammatory

neuropathiesMononeuritis multiplexHerpes zoster radiculitis and cranial neuropathyMyopathy and polymyositis

whom subsequently developed AIDS, both mono-neuritis multiplex and cranial nerve involvementalso occurred in some cases.45 There is currently nospecific therapy for these neuropathies.

In our own studies of HIV positive patients,several cases with HIV infection alone or ARChave developed inflammatory demyelinatingneuropathies which have either been acute orsubacute with a Guillain-Barre-like syndrome or achronic inflammatory demyelinating neuropathy.1lSome of these patients have subsequently developedfull-blown AIDS. These patients respondedfavourably to plasmapheresis and/or steroid therapyand the prognosis for this type of neuropathyappears to be good, a number of patients havingmade a marked recovery. The aetiology is thoughtto be immune-mediated rather than due to directHIV infection of the nerves. The occurrence of thisneurological complication in patients who do nothave full-blown AIDS is reminiscent of thepresentation of the AIDS-dementia complex andhas important implications for patient diagnosis,screening, handling of body fluids andpathogenesis. "As might be expected from the immuno-

suppression occurring in AIDS patients herpeszoster radiculitis also occurs with increasedfrequency in these individuals. The pattern ofinfection is similar to that occurring in immuno-competent individuals with thoracic segment andtrigeminal nerve involvement being prominent.Cranial neuropathy in AIDS may thus result fromVZV infection although it may also occur inassociation with CMV infection.43 An additionalcomplication of VZV infection in AIDS patients isdissemination of VZV to the bloodstream and CNSas a consequence of the immunosuppressed state.Treatment of VZV infections is with intravenousacyclovir.

Finally it should be mentioned that myopathyappears to be a complication of AIDS infections.For example, in one series3 clinical and patho-logical features consistent with polymyositis with anecrotizing myopathy occurred in one patient. Bothproximal muscle weakness and focal myocarditishave also been described.43'46

186 P.G.E. KENNEDY

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