Human Immunodeficiency Virus-Associated Peripheral Neuropathies
2006; Elsevier BV; Volume: 81; Issue: 2 Linguagem: Inglês
10.4065/81.2.213
ISSN1942-5546
AutoresSérgio Ferrari, Sandro Vento, Salvatore Monaco, Tiziana Cavallaro, Francesca Cainelli, Nicolo’ Rizzuto, Zelalem Temesgen,
Tópico(s)Pain Mechanisms and Treatments
ResumoPeripheral neuropathy has emerged as the most common neurologic complication of human immunodeficiency virus (HIV) infection. It will continue to play an important role in HIV infection given the fact that HIV-infected individuals are living longer, are at risk of long-term metabolic complications, and face an increasing exposure to potentially neurotoxic antiretroviral drugs. We review the various types of peripheral neuropathy that have been associated with HIV infection, including distal symmetrical polyneuropathy, toxic neuropathy from antiretroviral drugs, diffuse infiltrative lymphocytosis syndrome, inflammatory demyelinating polyneuropathies, multifocal mononeuropathies, and progressive polyradiculopathy. Peripheral neuropathy has emerged as the most common neurologic complication of human immunodeficiency virus (HIV) infection. It will continue to play an important role in HIV infection given the fact that HIV-infected individuals are living longer, are at risk of long-term metabolic complications, and face an increasing exposure to potentially neurotoxic antiretroviral drugs. We review the various types of peripheral neuropathy that have been associated with HIV infection, including distal symmetrical polyneuropathy, toxic neuropathy from antiretroviral drugs, diffuse infiltrative lymphocytosis syndrome, inflammatory demyelinating polyneuropathies, multifocal mononeuropathies, and progressive polyradiculopathy. The availability of potent antiretroviral drugs and their use in 3 or more combination regimens, highly active antiretroviral therapy (HAART), have led to a substantial decline in the morbidity and mortality associated with human immunodeficiency virus (HIV) infection.1Palella Jr, FJ Delaney KM Moorman AC HIV Outpatient Study Investigators et al.Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection.N Engl J Med. 1998; 338: 853-860Crossref PubMed Scopus (8510) Google Scholar Although a similar overall decline has occurred in the incidence and prevalence of central nervous system complications,2Manji H Neuropathy in HIV infection.Curr Opin Neurol. 2000; 13: 589-592Crossref PubMed Scopus (34) Google Scholar, 3Manji H Miller R The neurology of HIV infection.J Neurol Neurosurg Psychiatry. 2004; 75: i29-i35Crossref PubMed Google Scholar peripheral neuropathy (PN) continues to be a common neurologic complication at every stage of HIV infection. The spectrum of peripheral involvement in HIV infection includes distal symmetrical polyneuropathy (DSP), toxic neuropathy from antiretroviral drugs, diffuse infiltrative lymphocytosis syndrome (DILS), inflammatory demyelinating polyneuropathies (IDPs), multifocal mononeuropathies, and progressive polyradiculopathy. Diagnosis and treatment of PN in the HAART era represent a challenge even for expert neurologists and consultants in infectious diseases because of the overlap of clinical symptoms, complexity of treatment choices, and a possible abnormal presentation of symptoms of PN during immune reconstitution, when the CD4 T-lymphocyte count is rising.3Manji H Miller R The neurology of HIV infection.J Neurol Neurosurg Psychiatry. 2004; 75: i29-i35Crossref PubMed Google Scholar In this review, we discuss the various types of PNs associated with HIV infection, including their clinical presentation, pathogenesis, and treatment. Data for this review were identified by searches of the MEDLINE database for articles published in the English-language literature since 1966 using HIV, peripheral neuropathy, polyneuropathy, distal symmetrical polyneuropathy, inflammatory demyelinating polyneuropathy, mononeuropathy, and polyradiculopathy as keywords or text words. When applicable, we reviewed references cited in relevant reports and studies. We also included relevant microscopy and electron microscopy images from our own files. Distal symmetrical polyneuropathy is the most frequent form of neuropathy in HIV-1 infection. It is detected by clinical examination in 30% of infected patients4So YT Holtzman DM Abrams DI Olney RK Peripheral neuropathy associated with acquired immunodeficency syndrome: prevalence and clinical features from a population-based survey.Arch Neurol. 1988; 45: 945-948Crossref PubMed Scopus (189) Google Scholar and in almost 100% of cases at autopsy examination of individuals with acquired immunodeficiency syndrome (AIDS).5Griffin JW Crawford TO Tyor WR et al.Predominantly sensory neuropathy in AIDS: distal axonal degeneration and unmyelinated fiber loss [abstract].Neurology. 1991; 41 (Abstract 900S.): 374Google Scholar In one study, DSP showed a significant decline in prevalence from 42.5% in 1995-1996 to 34.4% in 1997-1998.6Maschke M Kastrup O Esser S Ross B Hengge U Hufnagel A Incidence and prevalence of neurological disorders associated with HIV since the introduction of highly active antiretroviral therapy (HAART).J Neurol Neurosurg Psychiatry. 2000; 69: 376-380Crossref PubMed Scopus (248) Google Scholar In contrast, the prevalence of suspected drug-induced polyneuropathy increased to 31% compared with 20% in 1995-1996. Moreover, after the introduction of HAART, DSP was not associated with increased HIV-1 load or decreased CD4 T-cell count.7Morgello S Estanislao L Simpson D Manhattan HIV Brain Bank et al.HIV-associated distal sensory polyneuropathy in the era of highly active antiretroviral therapy: the Manhattan HIV Brain Bank.Arch Neurol. 2004; 61: 546-551Crossref PubMed Scopus (168) Google Scholar In a recent HIV-1 outpatient cohort study, 13.1% of 2515 patients received a clinical diagnosis of DSP,8Lichtenstein KA Armon C Baron A Moorman AC Wood KC Holmberg SD HIV Outpatient Study Investigators Modification of the incidence of drug-associated symmetrical peripheral neuropathy by host and disease factors in the HIV outpatient study cohort.Clin Infect Dis. 2005; 40: 148-157Crossref PubMed Scopus (123) Google Scholar with a decreasing incidence after the introduction of HAART. The risk of developing DSP increased during the initial period of drug therapy, especially when therapy was started in patients with low CD4 lymphocyte counts (50-90 cells/μL) and higher HIV-1 load ( 200/μL). This study also showed that cerebrospinal fluid pleocytosis was not always present in HIV-1-associated acute IDP. Recurrence of acute IDP and evolution to chronic IDP were observed in 3 of these 10 patients. Neurophysiologic examination shows slow conduction, increase in distal motor latencies, increase of F-wave latency, and partial conduction blocks outside entrapment sites, suggesting demyelinating neuropathy. High protein content and, at variance with non-HIV-1-associated IDPs (in which the lymphocyte count is always >10 cells/μL), mild lymphocytic pleocytosis are present in the spinal fluid.31Cornblath DR McArthur JC Kennedy PG Witte AS Griffin JW Inflammatory demyelinating peripheral neuropathies associated with human T-cell lymphotropic virus type III infection.Ann Neurol. 1987; 21: 32-40Crossref PubMed Scopus (295) Google Scholar Pathologic examination of peripheral nerves in chronic IDP shows segmental demyelination with onion bulb formations, macrophage activation and infiltration by mononuclear cells of nerve fascicles, and endoneurial edema. Treatment options for HIV-associated acute and chronic IDPs are similar to those used in HIV-negative persons. The treatment response also appears to be similar, although data from large series and controlled trials are lacking. Treatment of acute IDP includes high-dose intravenous immunoglobulins or plasmapheresis. The course of chronic IDP generally improves with oral prednisone; high-dose immunoglobulins or plasmapheresis is used for recurrences.36Cornblath DR Treatment of the neuromuscular complications of human immunodeficiency virus infection.Ann Neurol. 1988; 23: S88-S91Crossref PubMed Scopus (44) Google Scholar, 37Snider WD Simpson DM Nielsen S Gold JW Metroka CE Posner JB Neurological complications of acquired immune deficiency syndrome: analysis of 50 patients.Ann Neurol. 1983; 14: 403-418Crossref PubMed Scopus (1074) Google Scholar Mononeuritis multiplex is a rare complication that occurs in either early or late stages of HIV-1 infection.38So YT Olney RK The natural history of mononeuropathy multiplex and simplex in patients with HIV infection [abstract].Neurology. 1991; 41 (Abstract 902S.): 375PubMed Google Scholar When mononeuritis multiplex occurs early in HIV-1 infection, it is often the result of a self-limited dysimmune neuropathy or vasculitis. In patients with long-standing HIV-1 infection and CD4 cell counts less than 50/μL, an association with cytomegalovirus (CMV) infection has frequently been noted. Mononeuritis multiplex has also been associated with varicella zoster39Said G Lacroix C Chemouilli P et al.Cytomegalovirus neuropathy in acquired immunodeficiency syndrome: a clinical and pathological study.Ann Neurol. 1991; 29: 139-146Crossref PubMed Scopus (123) Google Scholar and hepatitis C infections.40Caniatti LM. Tugnoli V. Eleopra R. Tralli G. Bassi R. De Grandis D. Cryoglobulinemic neuropathy related to hepatitis C virus infection: clinical, laboratory and neurophysiological study.J Peripher Nerv Syst. 1996; 1: 131-138PubMed Google Scholar The clinical setting of mononeuritis multiplex is characterized by symptoms and signs of sensory involvement, with numbness and tingling in distribution of one peripheral nerve trunk. Sequential sensory and motor involvement of other noncontiguous nerves evolves over days and weeks. The initial multifocal and random neurologic features may progress to symmetrical neuropathy. Some patients with vasculitis present at onset with distal symmetrical neuropathy. The diagnosis of mononeuritis multiplex is supported by electrophysiologic examination that reveals a multifocal pattern of reduction in evoked sensory and motor compound muscle action potential amplitudes. Virtually every pattern of vasculitis of small, medium, and large vessels has been encountered in HIV-1 infection.41Chetty R Vasculitides associated with HIV infection.J Clin Pathol. 2001; 54: 275-278Crossref PubMed Scopus (170) Google Scholar Vasculitis of the peripheral nerve can occur either as an isolated process or, more commonly, as a manifestation of a systemic disease. Vasculitis of the peripheral nerve is arare event in HIV-1-infected patients, occurring in 0.3% to 1.0% of patients with AIDS.42Fuller GN Jacobs JM Guiloff RJ Nature and incidence of peripheral nerve syndromes in HIV infection.J Neurol Neurosurg Psychiatry. 1993; 56: 372-381Crossref PubMed Scopus (104) Google Scholar In contrast to the situation in the pre-HAART era, vasculitic damage in the peripheral nervous system may now present with clinical features of DSP.43Bradley WG Verma A Painful vasculitic neuropathy in HIV-infection: relief of pain with prednisone therapy.Neurology. 1996; 47: 1446-1451Crossref PubMed Scopus (45) Google Scholar, 44Ferrari S Lanzafame M Faggian F et al.Painful neuropathy vasculitis in 2 patients with long-standing human immunodeficiency virus-1 infection.Scand J Infect Dis. 2004; 36: 392-393Crossref PubMed Scopus (7) Google Scholar Peripheral nerve examination shows variable loss of myelinated axons and ongoing axonal degeneration with focal distribution in different fascicles. Perivascular inflammatory cell infiltration (Figure 1) and fibrinoid necrosis of small epineural blood vessels are observed. Vasculitis is treated with corticosteroids or intravenous immunoglobulin.44Ferrari S Lanzafame M Faggian F et al.Painful neuropathy vasculitis in 2 patients with long-standing human immunodeficiency virus-1 infection.Scand J Infect Dis. 2004; 36: 392-393Crossref PubMed Scopus (7) Google Scholar Cytomegalovirus disease is a recognized opportunistic infection in HIV-infected patients with low CD4 cell counts(>50 cells/μL). The spectrum of CMV disease in HIV-infected patients includes retinitis, gastrointestinal involvement, hepatitis, pneumonia, epididymitis, cervicitis, adrenalitis, and pancreatitis. Central nervous system and peripheral nerves may also be infected with CMV; when the peripheral nerve is affected, the clinical pattern may be mononeuritis multiplex, polyradiculopathy, or a mixture of 2 patterns.35Brannagan III, TH Zhou Y HIV-associated Guillain-Barré syndrome.J Neurol Sci. 2003; 208: 39-42Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar Electrodiagnostic findings confirm a multifocal nerve involvement. Peripheral biopsy specimen of the affected nerve shows an infiltrate of polymorphonuclear cells harboring CMV in nerve fascicles (Figure 2) and CMV-infected endoneurial cells that contain viral inclusions (Figure 3). Treatment consists of the antiviral drugs ganciclovir, foscarnet, and cidofovir.FIGURE 3Cytomegalovirus particles (arrows) in cytoplasm of endoneurial cell (electron micrography, original magnification ×37,500).View Large Image Figure ViewerDownload (PPT) Progressive polyradiculopathy is an uncommon but well-described complication of HIV infection. No accurate estimates exist of the incidence of progressive polyradiculopathy associated with HIV infection. Fuller et al42Fuller GN Jacobs JM Guiloff RJ Nature and incidence of peripheral nerve syndromes in HIV infection.J Neurol Neurosurg Psychiatry. 1993; 56: 372-381Crossref PubMed Scopus (104) Google Scholar identified 54 patients (approximately 4%) with peripheral nerve syndromes among a cohort of 1500 HIV-infected patients followed up for 15 months before the introduction of HAART. Only 2 patients (0.1%) had progressive polyradiculopathy. The incidence of HIV-associated progressive polyradiculopathy is thought to have declined in the era of HAART. However, no reliable and specific estimates are available. Maschke et al6Maschke M Kastrup O Esser S Ross B Hengge U Hufnagel A Incidence and prevalence of neurological disorders associated with HIV since the int
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