Quarterly Journal of Medicine, New Series 68, No. 257, pp. 665-677, September 1988

The Neurology of Human ImmunodeficiencyVirus Infection

DALE E. BREDESEN, ROBERT M. LEVY* and MARK L. ROSENBLUMt

From the Departments of Neurology and *Neurosurgery, University of CaliforniaSchool of Medicine, San Francisco, California; and "[Departments of Neurosurgeryand Physiology, Northwestern University Medical Center, Chicago, Illinois

SUMMARY

HIV-infected patients are at markedly increased risk for neurological dysfunction, which mayoccur at any level of the neuraxis (see Table 1). The most common syndromes - AIDS dementiacomplex, vacuolar myelopathy, and possibly distal symmetric peripheral neuropathy - appear tobe related to HTV infection within the nervous system, rather than due to the immunoincompe-tence caused by HIV. However, the mechanism(s) by which HIV causes these syndromes, e.g.,infecting neurons or oligodendroglia directly, interfering with neurotrophic factors, effectingtoxic monokine production, etc., is unknown. Early, albeit incomplete, success with azido-thymidine is encouraging.

Less commonly, neurological syndromes may be secondary to the immunoincompetenceproduced by HIV. Many different etiologies - most of which are treatable - have been encoun-tered, but a few of these (cerebral toxoplasmosis, cryptococcal meningitis, primary CNS lym-phoma, and progressive multifocal leukoencephalopathy) are responsible for most of theopportunistic complications. Marked differences in symptoms and signs between AIDS patientsand immunologically normal patients may complicate recognition of some of these diseases (e.g.,herpes simplex encephalitis).

Finally, some HIV-associated syndromes, e.g., inflammatory demyelinating polyradi-culoneuropathy and retinal raicrovasculopathy, are of unknown etiology.

INTRODUCTION

The human immunodeficiency virus (HIV) is a nononcogenic retrovirus from the subfamilyLentiviridae. Neurological dysfunction is frequently prominent in patients infected with HIV.At least 40 per cent of patients with the acquired immune deficiency syndrome (AIDS) manifestneurological symptoms [1-3], and sensitive neuropsychological tests disclose abnormalities inabout 75 per cent [4, 5]. Furthermore, 10 per cent of patients have neurological dysfunction asthe first manifestation of AIDS [6, 7]. Post-mortem examinations of patients with AIDSdisclose central nervous system (CNS) abnormalities in 70 to 80 per cent [1]. The prevalence ofperipheral nervous system abnormalities is approximately 35 per cent [8].

The incidence of neurological dysfunction in patients with AIDS-related complex is 35 to 50per cent [4]. How frequently patients who are seropositive, but have neither AIDS-relatedcomplex nor AIDS, are neurologically symptomatic, is controversial: in one study, 44 per cent

© Oxford University Press 1988

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TABLE 1. AlDS-related central nervous system diseases

Primary viral (HIV) syndromesHIV encephalopathyAtypical aseptic meningitisVacuolar myelopathy

Opportunistic viral illnessesCytomegalovirusHerpes simplex virus, types I and IIHerpes varicella zosterPapovavirus (progressive multifocal leukoencephalopathy)Adenovirus type 2

Non-viral infectionsToxoplasma gondiiCryptococcus neoformansCandida albicansAspergillus fumigatusCoccidioides immitisMucormycosisRhizopus speciesAcremonium alabamensisHistoplasma capsulatwnMycobacterium hominis tuberculosisMycobacterium avium-intracellulareListeria monocytogenesNocardia asteroides

NeoplasmsPrimary CNS lymphomaMetastatic systemic lymphomaMetastatic Kaposi's sarcoma

CerebrovascularInfarctionHemorrhageVasculitis

Complications of systemic AIDS therapy

of such patients scored in the mildly abnormal range on neuropsychological tests [4], but inanother study, such patients were indistinguishable from controls [9].

Neurological dysfunction associated with human immunodeficiency virus infection mayoccur at any level of the neuraxis. Dementia is the most common syndrome, but involvement ofperipheral nerve, spinal cord, or posterior fossa may also occur. The disease processes fall intothree categories: primary diseases, due to HIV within the nervous system; opportunisticprocesses, due to the immunodeficiency of HIV; and diseases of unknown etiology, many ofwhich appear to be 'autoimmune'. It should be added that, in this review, HIV refers to HIV-1.A more recently described virus, HIV-2, may also cause AIDS (to date, almost exclusively inAfrican patients), but at this time, too few patients with AIDS caused by HIV-2 have beenthoroughly evaluated to determine whether or not HIV-2 is associated with the same neurologi-cal syndromes as is HIV-1.

PRIMARY INVOLVEMENT OF THE NERVOUS SYSTEM BY HTV

AIDS dementia complex

AIDS dementia complex is the most common neurological syndrome in HIV-infected patients.Approximately two-thirds of patients with AIDS become demented [2, 4, 5], most of these

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because of AIDS dementia complex. For the following reasons, it has been suggested thatAIDS dementia complex is due to direct effects of HIV within the CNS: (a) AIDS dementiacomplex appears to be unique to HIV-infected patients [2]; (b) HIV DNA, RNA, protein, andvirions are demonstrable much more frequently in the brains of patients with AIDS dementiacomplex than in AIDS patients without AIDS dementia complex [2,10]; (c) animal models oflentiviral disease (in which secondary pathogens are absent) include prominent encephalopa-thies [11]. However, it is noteworthy that in only one-third of patients with AIDS dementiacomplex is HIV demonstrable by Southern transfer detection of integrated viral DNAsequences or by immunoperoxidase detection of viral antigens [2, 10]. These same patientsdemonstrate multinucleated giant cells in the CNS, and these cells, thought to be of macro-phage origin, harbor the vast majority of the HIV in the brain. Endothelial cells [12], andperhaps oligodendroglia, may contain HIV as well. Glial and neuroblastoma cell lines areinfectable [13], but astrocytes and neurons have not been shown to be infected in vivo.

Thus, the majority of patients with AIDS dementia complex do not have demonstrable HIVin the CNS. Despite this, the distribution of the pathological changes other than the multinucle-ated cells i.e., pallor of the white matter, astrocytosis (primarily in the white matter), andmicroglial nodules, is similar in the two groups [2]. It is possible that the group withoutdemonstrable HIV simply has fewer, and less focally concentrated, viral genomes within theCNS. Alternately, AIDS dementia complex may be secondary to the immunological reactionto central or systemic HIV. Finally, AIDS dementia complex may actually be due to a different,unidentified pathogen.

The primary manifestation of AIDS dementia complex is dementia of a subcortical type [5].Early difficulties with concentration and memory are followed by apparent apathy and socialwithdrawal, which may be mistaken for depression. Abulia is often striking. Organic psychosis,mania, or catatonia may occasionally be presenting symptoms [1, 14].

In addition to dementia, the neurological examination may disclose mild bilateral pyramidalsigns, grasp and snout reflexes, gait apraxia, tremor, and myoclonus. Incontinence usuallyoccurs late in the disease, which is progressive over several months. However, AIDS dementiacomplex may present acutely following psychoactive drugs, infections, or other stresses. In suchcases, obtaining a careful history from the patient's friends or relatives usually reveals that theonset was not truly acute.

Neuropsychological assessment demonstrates decreased attention and concentration, as wellas verbal and motor slowing with unimpaired naming and vocabulary skills [2]. Cranial com-puted tomography usually shows increased ventricular and sulcal size suggestive of cerebralatrophy, and may show generally hypodense white matter. Magnetic resonance imaging oftenshows a diffuse or multifocal increase in T2-weighted signal in the white matter, especiallyfrontally.

There may be non-specific changes in the CSF, with mildly elevated protein concentration inabout two-thirds of patients and a mononuclear pleocytosis in one-quarter. Culture of HIVfrom the cerebrospinal fluid is not specific for AIDS dementia complex, nor is the finding ofintrathecal synthesis of antibodies to HIV [15,16]. Both of these findings may be present in theabsence of neurological symptoms. Presence of HIV antigen (p24) does appear to correlatewith progressive dementia.

Electroencephalography is rarely helpful in the diagnosis of AIDS dementia complex. In onestudy, there were no changes that permitted the distinction of this dementia complex from otherdementing disorders.

Diagnosis is usually made by the combination of compatible history, examination, andradiological studies; and by ruling out other causes of dementia. Prognosis is very poor withouttreatment, but improvement with azidothymidine (zidovudine) has been achieved clinically,

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neuropsychologically, and radiographically [17]. However, at this time, partial, rather thancomplete, recovery appears to be the rule.

HIV meningoencephalitis

A less common syndrome due to HIV is meningitis or meningoencephalitis. This was originallytermed 'atypical aseptic meningitis' [18] before the discovery of HIV, since the cerebrospinalfluid suggests aseptic meningitis while the clinical syndrome includes recurrence, chronicity,long tract signs, and cranial neuropathies. It is now clear that this syndrome is associated withseroconversion [19], but may appear later as well.

Vacuolar myelopathy

Vacuolar myelopathy accounts for most of the cases of myelopathy in patients with AIDS. Inone series, it was present in about one-half of demented patients with AIDS, but in only 8 percent of non-demented AIDS patients [2]. This correlation, and the culture of HIV fromaffected but not unaffected regions of the spinal cord, suggest to some that vacuolar myelopa-thy is a result of direct infection of the spinal cord by HIV.

Symptoms of vacuolar myelopathy are usually subacute to chronic, and reflect the pathologi-cal predilection for posterior and lateral columns. There is usually no accompanying back pain,tenderness, or radiculopathy. There is no effective treatment, but evaluation of the efficacy ofazidothymidine (zidovudine) is incomplete - one reported patient failed to improve with acourse of azidothymidine that was cut short because of side effects.

Acute myelopathy, occurring at the time of seroconversion to HIV, has been reported [20]but is uncommon.

OPPORTUNISTIC PROCESSES

Cerebral toxoplasmosis

Cerebral toxoplasmosis and cryptococcal meningitis are the most common non-viral oppor-tunistic pathogens in the CNS of AIDS patients, each occurring in about 5 per cent of suchpatients [7]. Frequently, cerebral toxoplasmosis is the presenting syndrome leading to thediagnosis of AIDS.

Presentation is usually as a subacute alteration in cognition and consciousness. In contrast toAIDS dementia complex, the level of consciousness is frequently affected early. Headache,hemiparesis, and seizures occur frequently. Less frequent accompaniments include ataxia,incontinence, hemisensory deficit, cranial nerve paresis, aphasia, anisocoria, pain, hemianop-sia, diplopia, dysarthria, and photophobia.

Cranial computed tomography is abnormal in approximately 90 per cent of cases. Typically,there are multiple bilateral ring-enhancing lesions which involve the basal ganglia or the gray-white junction, or both. However, scans may be normal.

Magnetic resonance imaging is more sensitive than computed tomography, and nearly alwaysshows multiple lesions. The lesions usually appear as areas of increased signal intensity onT2-weighted images.

Neither the CT nor the MRI appearance of cerebral toxoplasmosis is pathognomonic.Diagnosis may be established by cerebral biopsy, since serological tests for toxoplasmosis areunreliable in patients with AIDS. Recently, intrathecal synthesis of antibodies specific forToxoplasma gondii has been demonstrated in patients with cerebral toxoplasmosis; however,the sensitivity of this test was only 70 per cent in one reported study [21]. Thus, because of the

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large number of patients affected and the rapid response of cerebral toxoplasmosis to antibio-tics, a diagnostic and therapeutic trial of sulfadiazine and pyrimethamine is recommended forneurologically stable patients. This often obviates the need for biopsy. Following three weeksof treatment, radiological studies are repeated. If any lesion has improved, antitoxoplasmosistherapy should be continued for the life of the patient. If any lesion does not improve, biopsyshould be considered. These two possibilities are not mutually exclusive - in some patients,some but not all lesions respond, and in such cases, multiple processes are usually found.Finally, if corticosteroid is given concomitantly with the sulfadiazine and pyrimethamine, thereliability of the diagnostic and therapeutic trial is reduced, since a non-specific decrease inedema surrounding any lesion may be mistaken for a specific response to antibiotic.

A touch preparation for histological examination [22] is usually diagnostic, but occasionallymay yield falsely positive or falsely negative results. The former may be due to the misin-terpretation of nuclear debris in lymphomas as Toxoplasma gondii organisms; further confu-sion may arise from the reactive lymphocytes seen with toxoplasmosis, which may appearneoplastic. The latter may arise from a dearth of organisms within the biopsy. Thus, two moresensitive and specific tests may be required - the peroxidase-antiperoxidase technique [23] andthe electron microscopic technique [24].

The neurological prognosis for AIDS patients with cerebral toxoplasmosis is good, andnearly all patients respond to antibiotics; however, other opportunistic infections often super-vene, and death frequently occurs within two to six months of the diagnosis of cerebraltoxoplasmosis.

Cryptococcal meningitis

Meningoencephalitis due to Cryptococcus neoformans occurs in approximately 5 per cent ofAIDS patients [7]. Typically, it is a subacute illness, and its symptoms include headache,alterations in consciousness or cognition, neck stiffness, fever, nausea and vomiting, andsometimes seizures. Focal findings other than cranial neuropathy are uncommon.

CT scans are usually normal, but about 10 per cent of patients have cryptococcomas.Hydrocephalus may also be noted. Lumbar puncture is the diagnostic procedure of choice.However, cerebrospinal fluid protein and glucose concentrations, and cell count are all withinthe normal range in 20 per cent of patients. Therefore, India ink staining, which is positive in 70to 80 per cent of cases [25], or preferably the cryptococcal antigen test, which is positive in 95per cent of cases, should be done on each diagnostic lumbar puncture performed on patientswith AIDS or suspected AIDS.

Treatment with amphotericin B and flucytosine is recommended. However, about one-thirdof patients require discontinuation of flucytosine because of side effects such as leukopenia,thrombocytopenia, or elevated serum concentrations of hepatic enzymes. The role of treat-ment via an Ommaya reservoir is unknown.

Initial response to treatment tends to be good. However, relapse is common, and thereforecontinued treatment with weekly doses of amphotericin B is recommended. This has beenshown to decrease the frequency of relapse; none the less, other opportunistic infectionsfrequently occur, and most patients die within three to six months.

Primary central nervous system lymphoma

Lymphomatous involvement of the CNS in patients with AIDS may be due to primary ormetastatic lymphoma. In the former case, the tumor is of the B-cell type. One or a fewintraparenchymal lesions are typical, although diffuse infiltrating tumor occasionally is seen.

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AIDS patients with primary CNS lymphoma usually present with alterations in conscious-ness or cognition, hemiparesis or aphasia (40 per cent), seizures (10 to 15 per cent), or cranialneuropathies (5 to 10 per cent). Thus, primary CNS lymphoma may be difficult to distinguishfrom cerebral toxoplasmosis. CT and MRI scans may also fail to distinguish between the two.

The most reliable distinguishing feature, excluding histological differences, is the lack ofresponse of lymphoma to a course of sulfadiazine and pyrimethamine. Of course, concomitantcorticosteroids may render this method of distinction unreliable. Even interpretation of biopsyresults may be difficult, since bizarre, reactive lymphocytes are frequently encountered withtoxoplasmosis. Lymphocyte typing is helpful in such cases.

Whole-brain radiation is recommended for patients with primary CNS lymphoma; the role ofadjuvant chemotherapy is undefined. Regression of these radiosensitive tumors is the rule.Prognosis in early studies was extremely poor, but is improving, possibly because of earlierdiagnosis and treatment. Survival for more than one year may occur, but it is usually less thansix months.

Metastatic lymphoma

Less commonly, systemic (usually non-Hodgkin's) lymphoma may lead to neurological dys-function in AIDS patients. In such cases, the neurological syndrome usually results frommeningeal or skull base involvement rather than intraparenchymal growth. Cranial neuropathyand headache are common. Epidural compression of the spinal cord or cauda equina mayoccur.

Diagnosis is made by cytological examination of the cerebrospinal fluid. This reveals malig-nant cells in about 70 per cent of cases. Treatment is with intrathecal chemotherapeutic agents,usually methotrexate, arabinosyl cytosine or both. If compressive myelopathy is present,radiation therapy and corticosteroids should be employed.

Progressive multifocal leukoencephalopathy

Approximately 0.5 to 1.0 per cent of AIDS patients develop progressive multifocal leukoen-cephalopathy [7]. The presentation and course are similar to those in other immuno-compromised patients. Characteristically, cranial CT scans show multiple white matter lesions,often posteriorly disposed, with well-defined borders, no mass effect, and no enhancement [3].However, we have encountered single lesions also involving gray matter. There is no effectivetreatment for progressive multifocal leukoencephalopathy, and survival is usually less thanthree months.

Cytomegalovirus infections

Four herpesviruses have been implicated in neurological syndromes occurring in AIDSpatients: cytomegalovirus, herpes simplex virus, varicella-zoster virus, and Epstein-Barr virus.

Cytomegalovirus in these patients has been associated with encephalitis, retinitis, andprogressive polyradiculopathy. Whether or not cytomegalovirus plays a primary role in thepathogenesis of these syndromes has been called into question. For example, in one study [26],characteristic cytomegaloviral inclusions were found in 31 per cent of demented AIDS patients,but also in 13 per cent of non-demented patients, and did not correlate with the white matterpallor that was found in all of the demented patients (and, to a milder degree, in three-quartersof the non-demented patients). It has been suggested that cytomegalovirus may play a role as an

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adjuvant in the development of HIV-related syndromes. The ubiquity of cytomegalovirus inthe AIDS population and its ability to induce immunosuppression make this theory plausible.

Cases in which cytomegalovirus is associated with AIDS dementia complex areindistinguishable clinically from other cases of AIDS dementia complex. Virus may occa-sionally be recovered from the cerebrospinal fluid. Cranial CT scans may show periventricularenhancement compatible with ventriculitis, but are often normal or suggestive of cerebralatrophy. There is no effective treatment, but the success of dihydroxypropoxymethyl guaninein arresting progression of cytomegalovirus retinitis is promising.

Progressive polyradiculopathy, a distinctive clinical syndrome that may manifest as aradiculopathy or a radiculomyelopathy, usually occurs in patients with AIDS. It usually beginswith leg weakness, often asymmetrical, and progresses cephalad over several weeks. Sensoryloss is less prominent, but also spreads rostrally. Urinary retention is typical.

The cerebrospinal fluid characteristically shows hypoglycorrhachia in addition to poly-morphonuclear pleocytosis and elevated protein concentration. Cytomegalovirus or, less com-monly, herpes simplex virus may be cultured from the cerebrospinal fluid.

Nerve conduction studies and F responses are usually normal early, but later the size ofcompound muscle potentials is reduced. The electromyogram shows a reduced recruitmentpattern early, and abnormal spontaneous activity later.

Pathological and virological results implicate cytomegalovirus as the etiologic agent in thissyndrome; in some cases, herpes simplex virus may be involved. In one treated case, no benefitwas noted from acyclovir, plasmapheresis, or dihydroxy prqpoxymethyl guanine, despite aconcomitant arrest in cytomegalovirus retinitis. The prognosis is very poor. However, wehave observed seropositive, non-AIDS patients with a transient, usually mild, sacral myelo-radiculitis, some with perianal herpetic rashes. Thus, it is possible that progressive poly-radiculopathy represents the more severe end of a spectrum of radicular involvement by virusesof the herpes family in patients with HIV infection.

Herpes simplex virus infections

Herpes simplex types I and II are associated with encephalitis and myelitis (or radiculomyelitis)in HIV-infected patients. Differences in focality, severity, and viral type occur betweenimmunocompetent patients and HIV infected patients. In AIDS patients, herpes simplex type Ior II may lead to diffuse, rather than focal, encephalitis, or even encephalomyelitis. Conver-sely, type II virus, which is rarely associated with focal encephalitis in immunocompetentpatients, has been recovered from patients with HIV-related generalized lymphadenopathyand focal, temporal encephalitis typical of that associated with type I virus. Chronic mildencephalitis or even subclinical encephalitis may occur. The rapidity of the disease and theseverity of the inflammation correlate with the degree of immunocompetence.

These variations must be kept in mind during evaluation of HIV-infected patients withencephalitis. If herpes simplex encephalitis is suspected, diagnosis is best made by brain biopsy.Electroencephalography may be helpful in suggesting the diagnosis if the characteristic pseudo-periodic slow or sharp and slow complexes at 1-4 s intervals, most conspicuous over thetemporal lobes are present. However, we have seen these EEG findings in the focal, but not yetin the diffuse, cases. Culture of CSF may be slightly more productive in these patients than inimmunocompetent patients, but is certainly not sensitive enough to replace brain biopsy.Furthermore, the usual inflammatory changes may be absent in patients with chronic, mildencephalitis.

Prognosis for patients treated with acyclovir is incompletely characterized, since so few of thepatients with non-localized disease have been treated.

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Varicella-zoster virus infections

Varicella-zoster virus is associated with several neurological syndromes, both in immunocom-petent and immunoincompetent patients. These include, among others, radiculitis, myelitis,encephalitis, cranial neuropathies, leukoencephalopathy, and cerebral vasculitis. There is noqualitative difference in these syndromes as reported for the two patient groups, but patientswith AIDS appear to develop such complications of varicella-zoster infection more frequently[27].

Definitive diagnosis of varicella-zoster related neurological syndromes may be difficult.Temporal association with a zoster rash is presumptive evidence, but may be misleading in apatient group in which multiple pathogens are common. Futhermore, the syndromes may bedelayed or recurrent. Elevated antibody titers in CSF have been reported. Culture from CSF ishelpful, but may not be sensitive. Histopathological findings of Cowdry type A intranuclearinclusions or of herpesvirus-like particles by electron microscopy, have also been reported, aswell as immunoperoxidase staining and hybridization to Southern transfers.

Treatment is with acyclovir, and has been recommended by some for all HIV-infectedpatients [27]. In AIDS patients, the prognosis is poor, and progressive disease is common. InHIV-infected patients with greater immunocompetence, recovery (often, with future recur-rence) is more common.

Epstein—Barr virus

Several neurological syndromes are associated with Epstein-Barr virus infection, includingencephalitis, acute cerebellar ataxia, transverse myelitis, ascending myelitis, and acute psycho-sis. To date, however, the only Epstein-Barr virus related neurological syndromes described inAIDS patients have been primary CNS lymphoma and systemic (Burkitt's-like) lymphoma withmeningeal or extradural involvement.

Meningovascular syphilis

Patients in a high risk group for HIV are also at high risk for syphilis, but it is unclear whetherinfection with HIV is itself an independent risk factor. It has been suggested that HIV infectionleads to neurosyphilis at a higher frequency and with greater resistance to treatment. Althoughthis may well prove to be true, this conclusion has been criticized for lack of adequatesupportive data. None the less, it is prudent to evaluate all HIV-infected patients for syphilis; toperform lumbar puncture on those with syphilis and on those with undiagnosed neurologicalsymptoms; and to treat those with neurosyphilis (latent or symptomatic) with high-doseintravenous penicillin.

Other causes of neurological dysfunction

There are many other diseases associated with neurological dysfunction in HIV-infectedpatients, all less common than those detailed above.

Mycobacterium tuberculosis, Mycobacterium avium-intracellulare, and Mycobacterium kan-sasii are included in this group. Tuberculomas and tuberculous meningitis in this patientpopulation are associated almost exclusively with Haitian origin or intravenous drug use.Patients with Mycobacterium avium-intracellulare intracerebrally nearly always have dissemi-nated infection. Clinical presentation in these latter cases is usually as an encephalopathy orencephalitis, but rarely have other pathogens (especially HIV) been ruled out.

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Kaposi's sarcoma rarely metastasizes to the brain, but when it does, usually causes hemor-rhagic lesions. We have observed acute, transient symptoms following chemotherapy andhemorrhage, as well as more chronic symptoms.

Fungi other than Cryptococcus neoformans may affect the brain in HIV-infected patients.Usually these patients are severely systemically ill. Candida albicans brain abscess or micro-abscesses may occur, especially with fungemia. Rarely Aspergillus fumigatus may producebrain abscess or meningitis. Treatment usually requires surgical excision, and the prognosis ispoor.

Cerebral mucormycosis is associated with HIV infection in intravenous drug users; we havealso encountered it in a child with AIDS. The prognosis is very poor.

Intracranial infections due to Coccidioides immitis, Histoplasma capsulatum, andAcremonium alabamensis have also been reported.

Bacterial meningitides and brain abscesses are uncommon in HIV-infected patients. Listeriamonocytogenes may produce meningitis or brain abscess. Treatment with high-dose intra-venous penicillin or ampicillin is recommended [25].

Rarely Nocardia species produce CNS mass lesions in the presence of pulmonary disease.Recommended treatment consists of surgical excision followed by at least six months oftreatment with a combination of trimethoprim and sulfamethoxazole [25].

Escherichia coli meningoencephalitis has been reported without further clinical description.Finally, the parasite Acanthamoeba culbertsoni has been discovered in brain abscesses in at

least one AIDS patient.

HIV-ASSOCIATED SYNDROMES OF UNKNOWN ETIOLOGY

Peripheral neuropathies

At every level of the peripheral nervous system, abnormalities in patients with HIV infectionhave been described [28]. However, excluding vincristine neuropathy and zoster radiculitis,nearly every patient has one of four readily distinguishable syndromes: distal symmetricalperipheral neuropathy, inflammatory demyelinating polyradiculoneuropathy, mononeuro-pathy multiplex, or progressive polyradiculopathy. These are compared in Table 2.

TABLE 2. The major peripheral neuropathic syndromes in HIV-infected patients

Patients with

MotorSensoryCranial neuropathyUrinary retentionCSF

White bloodcells

ProteinGlucose

Distalsymmetricperipheralneuropathy

AIDS

++ + +--Normal

Inflammatorydemyelinatingpolyradiculo-neuropathy

AIDS-relatedcomplex+ + +++-

Mono

HighNormal

Mononeuro-pathymultiplex

AIDS-relatedcomplex+ ++ ++ + +-

Mono

HighNormal

Progressivepolyradiculo-neuropathy

AIDS

+ + ++Late+ + +

Poly

HighLow

Mono=monoclear pleocytosis; poly=polymorphonuclear pleocytosis.

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Distal symmetrical peripheral neuropathy

This is the most common syndrome of peripheral nervous system disease in AIDS patients.Symptoms and signs, which are often mild and chronically progressive, include hypesthesia,paresthesia, sensory ataxia, weakness and hypoactive deep tendon reflexes. Pain is infrequent.Sensory function is usually affected more than motor, and although complaints referable to theautonomic nervous system have rarely been recorded, dysautonomia may occur.

Electrophysiological findings are compatible with an axonal process. Cerebrospinal fluid isusually normal unless other processes such as toxoplasmosis co-exist.

Nerve biopsy may be normal, or may show axonal loss with absent or minimal inflammationand demyelination. Azidothymidine (also called zidovudine) has produced improvement insome patients [29] but not in others [30]. Otherwise, treatment is symptomatic, and includesamitriptyline or other non-steroidal agents for pain, and ankle-foot orthoses for foot drop.Plasmapheresis is ineffective.

Inflammatory demyelinating polyradiculoneuropathy

In HIV-infected patients, inflammatory demyelinating polyradiculoneuropathy may be acute,subacute or chronic [28]. In contrast to distal symmetrical peripheral neuropathy, inflamma-tory demyelinating polyradiculoneuropathy usually occurs in seropositive patients withoutAIDS. It usually produces more severe motor than sensory symptoms. Tendon reflexes areusually absent or markedly hypoactive throughout. Sensory symptoms are usually mild anddistal, affecting larger fiber modalities out of proportion to small. Unlike in the Guillain—Barresyndrome, autonomic symptoms are usually absent.

Cerebrospinal fluid usually demonstrates elevation of protein concentration and cell count.Nerve conduction velocity measurements show patchy, marked slowing, as well as delayed orabsent F responses. Conduction block and dispersion are common. The electromyogTam maybe free of abnormal spontaneous activity, but usually shows fibrillations and positive waves.Thus, this syndrome in HIV-infected patients is usually not purely demyelinating in nature.

Treatment with plasmapheresis is very successful when demyelination predominates overaxonal loss. Prednisone is often ineffective, and its decrease of cellular immune function is apotential concern. Spontaneous improvement may occur [28].

Mononeuropathy multiplex

Mononeuropathy multiplex occurs in a similar patient group to that of inflammatorydemyelinating polyradiculoneuropathy. Its hallmark is the rapid development of sensory ormotor loss (or both) in the distribution of one or more peripheral nerves, nerve roots, nervetrunks, or cranial nerves.

The cerebrospinal fluid is usually inflammatory, with a mononuclear pleocytosis and oligo-clonal bands. Electromyography and nerve conduction studies usually show changes suggestiveof comined axonal loss and demyelination. Sural nerve biopsy may be normal or may showaxonal degeneration, segmental demyelination, endoneurial edema and inflammatory cells inthe endoneurium and epineurium. Vasculitis is seen occasionally.

Plasmapheresis may lead to improvement.

Etiological considerations

The etiology (or etiologies) of these syndromes is unknown. Human immunodeficiency virushas been cultured from nerve in at least one case [19]; however, in-situ hybridization studies in

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cases of inflammatory demyelinating polyradiculoneuropathy have been uniformly negative[28]. No evidence had been obtained for involvement of viruses other than human immunodefi-ciency virus in these three syndromes. Other etiological possibilities include cross-reactiveantibodies to nerve or myelin, and antagonism of a neurotrophic factor such as neuroleukin [31,32].

Cerebrovascular disease

HIV-infected patients have a high rate of cerebrovascular complications; 19 per cent of ourpatients who had post-mortem examination demonstrated such complications [33]. Clinically,12 per cent of patients in one series [3] and 1.6 per cent in another series suffered cerebrovascu-lar complications. Another study found an increased frequency of stroke in AIDS patients, toone hundred times that expected for controls of similar age [34]. It is noteworthy that 89 to 100per cent of AIDS patients who had autopsy had retinal microvasculopathy, the cause of which isunknown.

Although there are many conceivable causes for both hemorrhagic and ischemic complica-tions in AIDS patients, the majority of cases of cerebral infarction remain unexplained, evenafter pathological evaluation [34]. Processes associated with intracerebral, subarachnoid, orsubdural hemorrhage include immune thrombocytopenia, aneurysm, and lymphoma. Hemor-rhage into lymphoma following biopsy of a patient with thrombocytopenia has been reported[3].

Cerebral infarction is more common than intracranial hemorrhage in AIDS patients, andmay take the form of small multifocal infarcts or large infarcts, without apparent predilectionfor one vascular territory. Associated conditions include non-bacterial thrombotic endocar-ditis, hypotension, meningovascular syphilis, cerebral vasculitides (in some cases, associatedwith previous zoster ophthalmicus), fibrinoid vasculopathy, metastatic Kaposi's sarcoma,cryptococcal meningitis, cerebral toxoplasmosis, and lupus anticoagulant. The relationship ofthe underlying condition to the infarct(s) is not always clear.

Laboratory evaluation should include CT scans or MRI, lumbar puncture, angiography (if nomass lesion has been demonstrated), echocardiography, platelet count, Venereal DiseaseResearch Laboratory (VDRL) test, and test for lupus anticoagulant (the partial thrombo-plastin time is usually, but not always, elevated in the presence of lupus anticoagulant).

Treatment is directed at the etiology. For the large number of cases in which no etiology isdiscovered, it is presently unknown if there is a direct role for HIV in pathogenesis (HIVprobably does infect endothelia [35]) and there are no data concerning treatment withazidothymidine, plasmapheresis, or other modalities.

The prognosis is poor unless a specific etiology is discovered and treated. Patients may sufferrecurrent strokes over the span of a few days to months.

ACKNOWLEDGEMENTS

We thank M. Wesley, S. Mahawar, and R. Gupta for assistance with data collection; R. Dixforviral culture studies; R. G. Miller for evaluation of some of the patients with peripheralneuropathies; and R. L. Davis for neuropathological expertise.

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