SEMINARS I N NEUROLOGY-VOLUME

12, NO. 1 MARCH 1992

Neuromuscular Complications of Human Immunodeficiency Virus Infection

Table 1. Neuromuscular Complications of Early studies describing the neurologic compliHIV Infection cations of acquired immunodeficiency syndrome (AIDS) included primary diseases of peripheral Peripheral Neuropathy Distal symmetrical polyneuropathy nerve and muscle among these disorder^.'.^ HowIdiopathic ever, these neuromuscular diseases are often overNeurotoxic shadowed by lesions of the central nervous system Vitamin B,, deficiency Inflammatory demyelinating polyneuropathy such as toxoplasmosis, lymphoma, and dementia. Mononeuropathy multiplex Furthermore, multiple lesions of the neuraxis may Progressive polyradiculopathy coexist in an individual patient, causing the often Autonomic neuropathy Motor neuron disease (?) subtle signs of neuromuscular diseases to be overSensory neuropathy (?) looked. Weakness and weight loss in a patient with Myopathy AIDS are often attributed to the ravages of chronic HIV-associated myopathy Zidovudine myopathy disease, or to human immunodeficiency virus HIV wasting syndrome (HIV) wasting syndrome. However, neuromuscular investigation of these patients may reveal myopathy or peripheral neuropathy, often treatable. During the past 5 years, considerable advances PREVALENCE OF NEUROMUSCULAR have been made in the understanding of the neuDISORDERS I N HUMAN romu'scular complications of HIV i n f e ~ t i o n . ~In - ' ~ IMMUNODEFICIENCY VIRUS INFECTION this article, I shall review the spectrum of periphEarly retrospective reports indicated that the eral 2europathies and myopathies that occur in patients with HIV infection. These are summarized in prevalence of neuromuscular disorders in HIV inTable 1. The major forms of peripheral neurop- fection is about 5 to 20%."4 Janssen et all1 elicited of neuropathy from 35% of homosexual athy include distal symmetrical p ~ l y n e u r o p a t h y , ~ . symptoms ~.~ men with lymphadenopathy syndrome. As the deinflammatory demyelinating p~lyneuropathy,~.~ gree of immunosuppression from HIV advances mononeuropathy r n ~ l t i p l e x , ' polyradiculopa~~~~ thy,16,17 and autonomic n e ~ r o p a t h y . l * The . ~ ~ ad- further the prevalence of neuromuscular disorders verse neuromuscular effects of the antiviral agents appears to increase. So et all2diagnosed distal sym2'3'-dideoxyinosine (ddI),20,2Ldideoxycytidine metrical polyneuropathy (DSP) in 13 of 40 consec(ddC),22.23 and z i d o v ~ d i n e ~(ZDV, ~ , ' ~ also known as utive patients with AIDS. The yield of abnormaliAZT), as well as the role of vitamin BIZdefi~iency,'~ ties is increased by laboratory and pathologic will be discussed. The clinical, laboratory, and studies, which often detect subclinical neuromuspathologic features of these disorders are pre- cular pathologic changes. Comi et all3 detected absented, as well as etiologic mechanisms and thera- normalities by means of nerve conduction studies (NCS) or electromyography (EMG) in 11 of 15 papeutic results.

Departments of Neurology and Clinical Neurophysiology. Mount Sinai Medical Center, New York, New York This work was supported in part by grants from the National Institute of Allergy and Infectious Diseases (U01-A1-72667), the National Institute of Neurological Disorders and Stroke (NS28630OlAl), and the National Center for Research Resources (5M01 RR00071) Requests for reprints: Dr. Simpson, Department of Clinical Neurophysiology, Box 1052, Mount Sinai Hospital, New York, NY 10029 Copyright O 1992 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.

Downloaded by: National University of Singapore. Copyrighted material.

Davzd M. Simpson, M.D.

NEUROMUSCULAR C O M P L I C A T I O N S ~ I M P ~ O N

The major pathologic finding in peripheral nerves of patients with DSP is distal axonal degeneration, with loss of myelinated and unmyelinated fiber^.^'-^^ In some specimens, perivascular mononuclear inflammatory infiltrates have also been pre~ent.~' The cause of DSP is unknown. A direct viral etiology has been suggested by several authors. Ho et a133reported positive cultures for HIV in sural nerve homogenates of several patients. However, it DISTAL SYMMETRICAL POLYNEUROPATHY is not clear which cells were affected and whether these patients had DSP or some other form Distal symmetrical polyneuropathy (DSP) is of peripheral neuropathy. Immunohistochemical the most common form of peripheral neuropathy stains for HIV have been negative in peripheral that occurs in AIDS, particularly in advanced nerve^."^^' Fuller et a13" have suggested that cytostages of disease. Clinical symptoms and signs of megalovirus (CMV) may have a causal role in DSP. DSP may be elicited in approximately 18% of Nine of their 12 patients with DSP had concurrent, AIDS patients,' whereas electrophysiologic abnor- systemic CMV infection, such as retinitis or gasmalities indicating DSP are present in about 35%.12 troenteritis. Grafe and Wiley3' have localized CMV Pathologic evidence of DSP is present in almost all in peripheral nerve of some patients with periphAIDS patients who have undergone sural nerve bi- eral ne~ropathy,~' although the clinical classificaopsy or autopsy.27 tion of these patients was not clear. At present, the The earliest clinical symptom of most patients evidence to support a direct viral pathogenesis of with DSP is paresthesias or burning pain in the DSP is not compelling, although further work, apfeet.'-" Examination at this time generally reveals plying newer techniques of viral localization, is stocking and glove sensory loss and diminished an- necessary. kle reflexes. Involvement of the upper extremities There have been no specific therapies availand symptomatic weakness may occur later in the able to treat DSP associated with AIDS effectively. course of the disease. The natural history of DSP The response to antiviral therapy has been disapis variable. Although some patients may present pointing, although no controlled trials have'been with advanced DSP, particularly when they are performed. Symptomatic relief of pain with tricyseverely immunosuppressed, the progression of clic antidepressants, carbemazapine, o r topical cap-' The coexist- saicin may be offered." symptoms is generally insidio~s.l-~.'~ ence of dementia, myelopathy, or myopathy with DSP complicates the clinical diagnosis of this disorder.l.12 INFLAMMATORY DEMYELINATING POLYNEUROPATHY The laboratory study that is most useful in establishing the diagnosis of DSP is electrodiagnostic Inflammatory demyelinating polyneuropathy examination. Reduction of the amplitudes of sensory nerve action potentials, particularly of the (IDP) appears to be less common than DSP in HIVsural nerve, and abnormalities in F waves are the infected patients. However, in the population of all earliest NCS abnorma1ities.l~"Later in the course patients with IDP, HIV infection plays a prominent of disease, EMG may reveal evidence of denerva- role. The incidence of HIV seropositivity is signiftion in distal muscle groups. These abnormalities icantly elevated in hospitalized patients with IDP.7 are indicative of distal ("dying back") axonal poly- This point is especially important to consider, since most HIV-infected patients with IDP are not neuropathy. The results of other laboratory studies are known to be HIV seropositive at the onset of neugenerally unremarkable. Other causes of DSP, rologic ~yrnptoms.~ HIV-infected patients with IDP present with such as diabetes mellitus, vasculitis, and alcoholism should be excluded. DSP associated with vitamin clinical features similar to those who do not have B,, deficiency and neurotoxic drugs is discussed HIV i n f e ~ t i o nT. ~h e temporal profile of IDP may later in this article. '~xaminationof cerebrospinal be acute, as in Guillain-BarrC syndrome; chronic; fluid (CSF) may reveal abnormalities, such as a or relapsing. Progressive weakness of the limbs mild mononuclear pleocytosis or slight elevation of is the cardinal clinical feature, whereas sensory protein. However, these findings are nonspecific, symptoms are less prominent. Neurologic examisince they are also commonly present in asymp- nation generally reveals diffuse weakness, areflexia, and only minor sensory impairment. tomatic HIV-infected patient^.'^

Downloaded by: National University of Singapore. Copyrighted material.

tients with AIDS.I3 In these subjects, three of six nerve biopsies revealed axonal neuropathy, and four of seven muscle biopsies indicated myopathy. Although these data suggest that neuromuscular disorders are common in patients with HIV infection, estimates of their incidence and prevalence await the performance of large prospective studies.

VOLUME 12, NUMBER 1

MARCH 1992

Electrophysiologic evidence of primary deMONONEUROPATHY MULTIPLEX myelination is helpful in the diagnosis of IDP. Nerve conduction abnormalities supportive of priIsolated or multifocal cranial or peripheral mary demyelination include marked slowing of neuropathies may occur in the course of HIV inconduction velocities, temporal dispersion, con- fection. Two patterns have been observed. T h e duction block, and marked abnormalities in late re- first generally appears early in HIV infection and sponses.' In some patients, evidence of an axonal has a relatively limited distribution of peripheral neuropathy may also be present. This generally in- nerve inv~lvement.'~~ For example, an isolated fadicates a poorer prognosis. cial or radial nerve palsy may occur. T h e second T h e CSF of patients with IDP and HIV infec- form of multifocal neuropathy occurs in advanced tion usually reveals a mild mononuclear pleocyto- AIDS and is often associated with fever and casis, in the range of 20 to 50 cells.' Although this chexia." Progressive neuropathy usually develops finding is nonspecific, since it is also commonly and may lead to debilitating weakness. present in asymptomatic HIV-infected ~ a t i e n t s , ' ~ 'I'he clinical features of mononeuropathy multhe presence of CSF pleocytosis in a patient with tiplex (MM) may overlap those of DSP or IDP, parIDP should alert the clinician to the possibility of ticularly when peripheral nerve lesions become HIV infection. diffuse and confluent. Electrodiagnostic studies The pathogenesis of IDP in HIV infection are helpful in distinguishing these disorders. T h e may be immune-mediated,%4".' as is proposed in characteristic findings in MM are multifocal and HIV-negative IDP." Although direct support for asymmetrical axonal lesions, as is evident from rethis mechanism is scarce, other autoimmune dis- duced amplitude of motor and sensory nerve poorders, vitiligdb and thrombocytopenic purpura,"' tentials and evidence of denervation on EMG. CSF generally reveals a mild mononuclear pleocytosis, do occur in HIV-infected patients. T h e clinical course of IDP in HIV-infected as in other HIV-positive patients. CSF cultures and patients has been described in relatively few pa- cytology should be performed to exclude cryptotients. Cornblath et a17 reported that three pa- coccal meningitis, syphilis, and lymphoma. Nerve biopsies of patients with MM have retients with Guillain-BarrC syndrome did poorly in spite of therapy, whereas those with chronic vealed at least three patterns. T h e first, generally or relapsing disease responded to plasmapheresis seen in patients early in disease, is axonal degenor corticosteroids. T h e role of these and other eration with mild epineurial and endoneurial intreatments, such as high-dose intravenous immu- flammatory infiltrates.Vn rarer cases, we and noglobulin, will have to be determined by con- othersl%ave observed necrotizing vasculitis of peripheral nerve (Fig. l ) . Finally, in some patients trolled studies.

36

Figure 1. Mononeuritis multiplex. Acute intramural and perivascular arteritis in epineurium of sural nerve biopsy. (Toluidine blue-stained semithin plastic section, final magnification on print, x185.) (From Simpson and O l n e ~Re.~~ printed with permission.)

Downloaded by: National University of Singapore. Copyrighted material.

SEMINARS IN NEUROLOGY

15.3"

T h e clinical course of patients with MM is variable, and may be related in large part to the stage of immunosuppression. In patients with early HIV infection, M M of limited distribution often remits spontaneously if the initial diagnostic evaluation does not reveal a specific cause. In patients with advanced immunosuppression, or with more extensive peripheral nerve involvement, CMV should be considered to be a potential pathogen. CSF analysis and nerve biopsy may identify evidence of CMV. Said et all5 have reported that patients in whom CMV was identified in peripheral nerve respond to ganciclovir therapy. These authors suggested that even in the absence of direct evidence of CMV infection in such patients, an empirical course of ganciclovir may be warranted.

PROGRESSIVE POLYRADICULOPATHY T h e syndrome of progressive polyradiculopathy (PP) associated with AIDS was first reported by Eidelberg et a1 in 1986.8Since then, there has been increased recognition of this disorder, with emphasis on its potential response to specific therapy.17.4"Mostpatients with PP have severe immunosuppression, with extremely low CD4-lymphocyte counts. There is often a history of other opportunistic infections, including CMV pneumonitis, gastroenteritis, or r e t i n i t i ~ . ~ . ~ ~ . ~ "

The initial clinical symptoms of PP are lower extremity and sacral paresthesias, followed by rapidly progressive weakness and sphincter disturbances. Examination reveals flaccid paraparesis, lower extremity areflexia, urinary retention, and variable sensory loss. .The upper extremities may be unaffected or involved late in the course. This disease is usually rapidly fatal if untreated. In one series, the mean duration of illness from onset to death was 6 weeks.17 'The CSF findings in PD are distinctive: there is marked polymorphonuclear pleocytosis, in contrast to other HIV-related peripheral neuropathies, in which only a mild mononuclear pleocytosis is f o ~ n d . ~ . 'CMV ~ . ~ " has been identified in CSF in most reported cases by various techniques, including culture, immunohistochemistry, in situ hybridization, and ~ y t o l o g y . ~ Postmor~~~~' tem studies have revealed extensive inflammatory necrosis of lumbar nerve roots, associated with specific CMV inclusions in endoneurial inflammatory cells, Schwann cells, and endothelial cells (Fig. 2).X.'7.4" Ganciclovir, an antiviral agent used to treat CMV retinitis and gastroenteritis, may effectively treat PP associated with AIDS. In several series dramatic improvement has been reported in most patients who were treated with g a n c i ~ l o v i r . ~ ~ ~ ~ " However, the authors have stressed that patients must be treated early, perhaps within 24 to 48 hours of presentation. In patients with long-standing neurologic deficits, a poor therapeutic response to ganciclovir has been o b ~ e r v e d .It~ ~is , ~ ~

Figure 2. CMVpolyradiculitis. Acute necrotizing inflammation in dorsal root. Typical intranuclear inclusions and cytomegalic changes abound. Autopsy specimen. (Parafin section, hematoxylin and eosin stain; final magnification on print, x740.) (From Simpson and O l n e ~Reprinted .~~ with permission.)

37

Downloaded by: National University of Singapore. Copyrighted material.

with multifocal neuropathy and advanced AIDS, CMV inclusions have been identified in peripheral

SEMINARS I N NEUROLOGY

PERIPHERAL NEUROPATHY ASSOCIATED WITH EXPOSURE TO NEUROTOXINS A variety of agents employed in the treatment of HIV-related diseases may induce peripheral neuropathy. These include well-known neurotoxins, such as isoniazid and vincristine, which are employed as a therapy for Kaposi's sarcoma. The dideoxynucleoside analogues ddI and ddC are becoming increasingly important as antiviral agents in HIV disease. However, Phase I studies have demonstrated peripheral neuropathy to be their major dose-limiting side effect."'-'Y The clinical and laboratory features of this disorder are similar to those of DSP in general (discussed before). Clinical symptoms generally improve after withdrawal of the offending drug, although a "coasting period" of persistent symptoms may last for 4 to 8 weeks. It is possible that different dosing schedules of these agents,'"." or alternation with ZDV, may reduce neurotoxicity.

AUTONOMIC NEUROPATHY Autonomic symptoms that may occur in patients with HIV infection include orthostatic hypotension, syncope, impotence, and diarrhea.4'.42 Patients with advanced HIV disease and those with other neurologic signs are at highest risk for autonomic i n ~ o l v e m e n tAutonomic .~~ impairment may result from a number of factors, including drugs and central or peripheral nervous system dysfunction. Autonomic function testing may be helpful in diagnosing these disorders. In 10 patients with HIV infection, Cohen and Laudenslagen4' found abnormal heart rate responses to provocative tests in eight, and absent quantitative submotor axon reflex tests in four." Chirnelli et al" reported an anatomic site of pathologic alteration that may be responsible for autonomic impairment. They observed marked abnormalities in the cervical sympathetic ganglia in six AIDS patient^.^" Treatment of autonomic disorders includes removal of the offending drugs, fluid management, and antiarrhythmic agents. 38

PERIPHERAL NEUROPATHY ASSOCIATED WITH VITAMIN BIPDEFICIENCY Kieburtz et a1" have reported the association of vitamin El, deficiency with peripheral neuropathy and myelopathy in HIV-infected patients. In that series, 29% of patients with DSP and 67% of patients with DSP and myelopathy had vitamin BIZ deficiency, as evident from low serum levels or impaired absorption. T h e majority of patients with DSP and B,, deficiency had rapid improvement in their symptoms following parenteral B,, repletion. The role of B12 deficiency and therapy in DSP associated with AIDS may be established in large prospective studies.

MOTOR NEURON DISEASE There have been only rare reports of motor neuron disease (MND) in HIV-infected patients, raising doubts whether there is a true association.44.45 In the one patient described in detail, clinical and pathologic features were atypical for MND. We have seen one patient with the unusual combination of amyotrophic lateral sclerosis, HIV infection, and an elevated titer of anti-asialo-GM1 antibody. This case is particularly interesting in light of the recent speculation that MND may be mediated by immunologic mechanisms.

SENSORY NEUROPATHY Several HIV-infected patients have developed progressive sensory n e ~ r o p a t h y . ~ ~ l e c t r o p h ~ s i o logic and pathologic features indicated primary involverncnt of the sensory ganglion cell, with associated distal and proximal degeneration. The pathogenesis of this syndrome and its relationship to HIV infection are unclear.

HUMAN IMMUNODEFICIENCY VIRUSASSOCIATED MYOPATHY Snider et all reported myopathy as a complication of AIDS in 1983. Relatively few cases of this disorder were reported over the next several years."."' It became apparent that laboratory and pathologic features of this syndrome were atypical '~or muscle for classic p o l y m y o ~ i t i s . ~ ~ ~example, biopsies often showed sparse or absent inflammatory infiltrates, as well as unusual inclusions.

Downloaded by: National University of Singapore. Copyrighted material.

possible that alternative agents, such as foscarnet or the addition of intravenous immunoglobulin, may offer added benefit. 'These agents are being studied in multicentered controlled trials, such as those being conducted by the AIDS Clinical Trials Group (ACTG).

VOLUME 12, NUMBER 1 MARCH 1992

NEUROMUSCULAR COMPLICATIONS-SIMPSON

CLINICAL FEATURES

In contrast to the other neuromuscular syndromes, which appear to occur selectively at certain stages of HIV infection, myopathy may occur early or late in the course of disease.47In some patients, myopathy may be the initial manifestation of HIV infection." The typical presenting clinical symptom is progressive proximal muscle weakness. Myalgia, which is most prominent in the thighs after exertion, is considerably more common in this ~~,~~ disorder than in classic p o l y m y o ~ i t i s . Progressive weight loss frequently accompanies muscle weakness. 'This may be diagnosed nonspecifically as AIDS-wasting syndrome, a disorder that may result from numerous nutritional and catabolic factors and is often present in terminally ill AIDS patients. However, in patients without alternative factors to explain progressive weakness and weight loss, myopathy may occasionally be diagnosed and successfully treated.49 Neurologic examination reveals generalized proximal muscle weakness, with prominent involvement of neck and hip flexors. Lesions of the nervous system may coexist in the patient, complicating the clinical diagnosis of myopathy. T h e weakness generally progresses over months, and, if untreated, may produce significant disability.

LABORATORY FEATURES

T h e most sensitive serologic marker in HIVassociated myopathy is serum creatine kinase ( C K ) . ~ " ' ~ 4 ~ o w e vthe e r ,CK level may vary over a wide range and does not correlate with the degree of weakness. Furthermore, some patients with biopsy-proven myopathy have normal CK levels.47In these and other cases, needle EMG is a particularly helpful supplementary study. EMG reveals brief, low amplitude polyphasic motor units that recruit with full interference patterns. Abnormal irritative activity indicating active denervation is also commonly present. Studying the iliopsoas muscle has a particularly high yield in revealing abnormalities. In over half of our patients with myopathy, NCS have revealed an associated peripheral neuropathy.47 PATHOLOGIC FEATURES

Muscle biopsy remains the "gold standard" in . ~ ~ has the diagnosis of all forms of m y ~ p a t h yThere been a spectrum of pathologic findings reported in HIV-associated myopathy. T h e most characteristic feature, in our experience, has been noninflammatory scattered myofiber d e g e n e r a t i ~ n ~(Fig. ~.~" 3). In fewer than 50% of biopsies are there significant interstitial inflammatory infiltrates, such as those present in most cases of p o l y m y o ~ i t i s . ~ ~ . ~ ~ , ~ ~ ) These inflammatory cells have been characterized as CD8 + cells and activated macrophages. Unusual myofiber inclusions that occur in HIV-associated

Figure 3. HIV-associated myopathy. Twelve scattered atrophic myofibers display coarse granular sarcoplasmic staining without ragged red accumulations, necrosis, or associated interstitial inflammatory infiltrates. (Cryostat section, modified trichrome stain; final print magnification, x185.)

Downloaded by: National University of Singapore. Copyrighted material.

Although the pathogenesis of this disease is unknown, we prefer the more descriptive term HIVassociated myopathy for this syndrome.

SEMINARS IN NEUROLOGY

PATHOGENESIS

HIV-associated myopathy does not appear to be a direct result of HIV infection. We and others have been unable to localize HIV within myofibers by immunohistochemistry or in situ hybridizat i ~ n . "However, ~~ other investigators have localized HIV antigens in cells of the monocyte-macrophage lines in the inter~titium."~~ It is possible that HIV infection incites an immune response, which then causes myofiber damage. Other factors, such as cytokines, may also mediate pathologic processes in muscle. Cachectin (tumor necrosis factor), which is one such cytokine, causes cachexia when injected into laboratory animal^.^' Cachectin is also elevated in patients with AIDS and AIDS-related complex (ARC).5" Its role in HIV-associated myopathy is under investigation. ROLE OF ZZDOVUDINE IN MYOPATHY

40

In 1988, Bessen et a154 reported on four patients who developed myopathy while being treated with ZDV. Strength of three of them improved after ZDV withdrawal. It is of interest that these authors had not observed myopathy in this population prior to the use of ZDV, in spite of reports of myopathy by Simpson and Bender47and by other^^.^.^^ prior to the use of ZDV. There have been several small case series of patients with myopathy attributed to ZDV the rap^.^^.^^ T h e clinical presentation of myopathy in ZDV-treated patients is indistinguishable from that of patients who are not receiving ZDV. In some series, the diagnosis appears to have been based in large part on histologic findings of mitochondrial abnormalities in ~ ~ . ~ ~ relatively few pamuscle b i o p s i e ~ . However, tients with myopathy who were not treated with ZDV were investigated. A majority of patients in these series were reported to improve following ZDV withdrawal, although some also received other therapies, such as predni~one.'~ Other investigators have questioned the role of ZDV in producing myopathy. Sharpton reported that 8 of 20 patients treated with ZDV developed an elevated CK Only one patient had significant weakness. ZDV was continued at the same dose and symptoms either resolved or remained stable in all subjects. A significant percent-

age of our patients with HIV-associated myopathy have never received ZDV.47The clinical, laboratory, and pathologic features of myopathy in patients were similar, whether or not ZDV therapy was given. In the majority of patients in whom ZDV was withdrawn, no significant improvement in strength occurred, although C K levels occasionally fell. The basis for the different results reported between these series is unclear. Decisions concerning the appropriate management of HIV-associated myopathy in patients receiving ZDV await controlled clinical trials, which are presently under way. THERAPY

HIV-associated myopathy is generally a progressive disorder, although spontaneous remissions may Although corticosteroids may increase the risk of opportunistic infections in HIV-infected patient^,^' we47and othersz4have not observed significant complications with steroid therapy. However, these risks have not been examined in controlled trials. Therefore we have reserved prednisone therapy for patients with progressive and debilitating weakness, who do not have active systemic infections.

SUMMARY As the lifespan of patients with HIV infection is prolonged with more ecfective antiviral therapies, the prevalence of neuromuscular disorders is likely to increase. The understanding of the pathogenesis and optimal therapy of these illnesses has advanced during the past 5 years. However, there are still significant gaps in our knowledge. It is important that neurologists remain at the forefront of investigation and treatment of these complex disorders. ACKNOWLEDGMENT

I thank Dr. David Wolfe for pathologic specimens, a n d Cicely Corbett f o r technical assistance. Emile Godfrey, RD, a n d o u r Neuromuscular Fellows assisted i n t h e care o f these patients.

REFERENCES 1. Snider WD, Simpson DM, Nielsen S, et al. Neurological complications of acquired immune deficiency syndrome: analysis of 50 patients. Ann Neurol 1983; 14:403-18 2. Levy RM, Bredesen DE, Rosenblum ML. Neurological manifestations of the acquired immunodeficiency syndrome (AIDS): experience at UCSF and review of the literature. J Neurosurg 1985;62:475-95 3. Dalakas MC, Pezeshkpour GH. Neuromuscular diseases

Downloaded by: National University of Singapore. Copyrighted material.

myopathy include nemaline rods and cytoplasmic b o d i e ~ . " ~Dalakas ~ ~ ~ " et aP4 have reported the presence of "ragged red fibers," indicative of abnormal mitochondria, in patients treated with ZDV (discussed later). In contrast, we have observed electron microscopic evidence of mitochondrial abnormalities in biopsies of patients with HIV-associated myopathy, regardless of ZDV therapy, but have not identified classic ragged red fiber^.^"

VOLUME 12, NUMBER 1 MARCH 1992

4. 5. 6. 7.

8. 9. 10. I I.

12.

IS. 14. 15.

16. 17. 18. 19. 20.

2 1.

22.

23. 24. 25. 26.

associated with human immunodeficiency virus infection. Ann Neurol 1988;23(suppl):S38-48 Parry (;.I. Peripheral neuropathies associated with human immunodeficiency virus infection. Ann Neurol 1988;23(suppl):S49-53 Cornblath DR. Treatment of the neuromuscular complications of human immunodeficiency virus infection. Ann Neurol 1988;23(suppl):S88-91 1.ipkin WI, Parry G, Kiprov D, Abrams D. Inflammatory neuropathy in homosexual men with lymphadenopathy. Neurology 1985;35: 1479-83 Cornblath DR, McArthur J C , Kennedy PGE, et al. Inflammatory demyelinating peripheral neuropathies associated with human T-cell lymphotropic virus type 111 infection. Ann Neurol 1987;21:32-40 Eidelberg I), Sotrel A, Vogel H, et al. Progressive polyradiculopathy in acquired immune deficiency syndrome. Neurology 1986;36:9 12-6 Dalakas MC, Pezenshkpour G H , Gravell M, Sever JL. Polymyositis associated with AIDS retrovirus. JAMA 1986;256:238 1-3 Stern R, G o l d J , DiCarol EF. Myopathy complicating the acquired immune deficiency syndrome. Muscle Nerve 1987;10:313-22 Janssen US, Saykin AJ, Kaplan JE. Neurological complications of H I V infection in patients with lymphadenopathy syndrome. Ann Neurol 1988;23:49-55 So YT, Holtzman DM, Abrams Dl, et al. Peripheral neuropathy associated with acquired immunodeficiency syndrome: prevalence and clinical features from a population-based survey. Arch Neurol 1988;45:945-8 Corni G, Magdalin S, Galardi J , et al. Subclinical neuromuscular involvement in AIDS. (Abstr.) Muscle Nerve 1986;9:665 Gherardi R, Lebargy F, Gaulard P, et al. Necrotizing vasculitis and H I V replication in peripheral nerves. (Letter.) N Engl J Med 1989;321:685-6 Said G, Lacroix C, Chemouilli P, et al. Cytomegalovirus neuropathy in acquired immunodeficiency syndrome: a clinical and pathological study. Ann Neurol 1991; 29: 139-46 Behar R, Wiley C, McCutchan JA. Cytomegalovirus polyradiculopathy in AIDS. Neurology 1987;37:557-61 Miller KG, Storey JR, Greco CM. Ganciclovir in the treatment of progressive AIDS-related polyradiculopathy. Neurology 1990;40:569-74 Freeman R, Roberts M, Friedman L, Braodbridge C. Autonomic function and human immunodeficiency virus infection. Neurology 1990;40:575-80 Cohen JA, Laudenslager M. Autonomic nervous system involvement in patients with human immunodeficiency virus infection. Neurology 1989;39: 11 11-2 Lambert JS, Seidlin M, Reichman RC, et al. 2',3'-Dideoxyinosine ( d d l ) in patients with the acquired immunodeficiency syndrome o r AIDS-related complex. N Engl J Med 1990;322: 1330-40 Cooley TP, Kunches LM, Saunders CA, et al. Once-daily administration of 2',3'-dideoxyinosine ( d d l ) in patients with the acquired immunodeficiency syndrome o r AIDS-related complex. N Engl J Med 1990;322: 1340-5 Dubinsky RM, Yarchoan R, Dalakas M, et al. Reversible axonal neuropathy from the treatment of AIDS and related disorders with 2',3'dideoxycytidine (ddC). Muscle Nerve 1989; 12:856-60 Arezzo.1, Schaumburg H H , Schroeder C, et al. d d C neuropathy: an animal model in the cynomolgus monkey. (Abstr.) Neurology 1990;40(suppl 1):428-9 Dalakas M, Illa I, Pezeshkpour G H , et al. Mitochondria1 myopathy caused by long-term zidovudine therapy. N Engl J Med 1990;322: 1098-105 Simpson DM. Myopathy associated with HIV infection but not with zidovudine. (Letter.) Ann Intern Med 1988; 108:842 Kieburtz KD, Giang DW, Schiffer RB, et al. Abnormal vitamin B12 metabolism in H I V infection: association

27.

28.

29. 30. 31. 32.

33.

34. 35.

36. 37. 38. 39.

40.

4 1. 42. 43.

44. 45. 46.

47. 48. 49.

with neurological dysfunction. Arch Neurol 1991; 48:312-4 Griffin JW, Crawford T O , Tyor WR, et al. Predominantly sensory neuropathy in AIDS: distal axonal degeneration a n d unmyelinated fiber loss. (Abstr.) Neurology l 9 9 l ; 4 l ( s u p p l 1):374 McArthur JC, Cohen BA, Farzedegan H , et al. Cerebrospinal fluid abnormalities in homosexual men with and without neuropsychiatric findings. Ann Neurol 1988; 23(suppl):534-7 So Y T , Holtzman DM, Abrams DI, Olney RK. Peripheral neuropathy associated with AIDS. Arch Neurol 1988; 45:945-8 Mah V, Vartavarian LM, Akers MA, Vinters H . Abnormalities of peripheral nerve in patients with HIV infection. Ann Neurol 1988;24:7 13-7 d e la Monte SM, Gabuzda I>H, H o D, Brown RH, et al. Peripheral neuropathy in the acquired immunodeficiency syndrome. Ann Neurol 1988;23:485-92 Grafe MR. Wiley CA. Spinal cord and peripheral nerve pathology in AIDS: the roles of cytomegalovirus and human immunodeficiency virus. Ann Neurol 1989; 25:561-6 H o DD, Roata T R , Schooley KI-, et al. Isolation of HTLV111 from CSF and neural tissues of patients with neurological syndromes related to the acquired immunodeficiency syndrome. N Engl J Med 1985;313:1493 Fuller GN, Jacobs J M , Guiloff RJ. Association of painful peripheral neuropathy in AIDS with cytomegalovirus infection. Lancet 1989; 1:937-41 Arnason BGW. Inflammatory polyradiculoneuropathies. In: Dyck PJ, Thomas PK, Lambert EH, eds. Peripheral neuropathy. Philadelphia: W.B. Saunders, 1975: 11 10-49 Duic M, Rapini R, Hoots WK, Mansell PW. HIV associated vitiligo: expression of autoimmunity with immunodeficiency. J Am Acad of Dermatol 1987; 17:656-62 Walsh C, Krigel R, Lennett EW, Karpatkin S. Thrombocytopenia in homosexual patients. Ann Intern Med 1985; 103:542-45 So YT, Olney RK. T h e natural history of mononeuritis nlultiplex a n d simplex in HIV infection. (Abstr.) Neurology 199 1;4l(suppl 1):375 S n ~ a l lPM, McPahaul LW, Sooy CD, et al. Cytorrz!galovirus infection of the laryngeal nerve presenting as hoarseness in patients with acquired immunodeficiency syndrome. JAMA 1989;86: 108-10 d e Gans .J, Portegies P, Tiessens G, et al. Therapy for cytomegalovirus polyradiculopathy in patients with AIDS: treatment with ganciclovir. AIDS 1990;4:421-5 Lin-Greenberg P, Taneja-Uppal N. Dysautonomia and infection with the human immunodeficiency virus. (Letter.) Ann Intern Med 1987;106:167 Cohen JA, Laudenslagen M. Autonomic nervous system involvement in patients with human immunodeficiency virus infection. Neurology 1989;39: 1 11 1-2 Chimelli L, Scaravilli F. Morphological changes in the autonomic nervous system of patients with AIDS. (Abstr.) Proceedings of the Seventh International Conference on Neuroscience of HIV Infection, Padova, Italy 1991;89 Hoffman PM, Feistaff BW, Giron CT, et al. Isolation of LAVIHTLV-3 from a patient with amyotrophic lateral sclerosis. (Letter.) N Engl J Med 1985;313:324-5 Verma RK, Ziegler DK, Kepes JJ. HIV-related neuromuscular syndrome simulating motor neuron disease. Neurology 1990;40:544-6 Elder G, Dalakas M, Pezeshkpour G, et al. Ataxic neuropathy d u e to ganglioneuritis after probable acute human immunodeficiency virus infection. Lancet 1986; ii: 1275-6 Simpson DM, Bender AN. HIV-associated myopathy: analysis of 11 patients. Ann Neurol 1988;24:70-84 Bohan A, Peter J B . Polymyositis and dermatomyositis Part 1. N Engl J Med 1975;292:344-7 Simpson DM, Bender AN, Farraye J , et al. H I V wasting

Downloaded by: National University of Singapore. Copyrighted material.

NEUROMUSCULAR COMPLICATIONS-SIMPSON

41

SEMINARS IN NEUROLOGY VOLUME 12, NUMBER 1 MARCH 1992

51.

52. 53. 54.

55. Chalmers AC, Greco CM, Miller RM. Prognosis in AZT myopathy. Neurology 1991;41:1181-4 56. Mhiri C, Baudrimont M, Bonne G, et al. Zidovudine myopathy: A distinctive clinical disorder associated with mitochondria1 dysfunction. Ann Neurol 1991;29:606-14 57. Sharpton T. Polymyositis during zidovudine therapy. (Abstr.) Proceedings of the Fifth International Conference on AIDS 1989:341 58. Shafer RW, Offit K, Macris NT, et al. Possible risk of steroid administration in patients at risk for AIDS. Lancet 1985; 1:934-5 59. Simpson DM, Olney RK. Peripheral neuropathies associated with HIV infection. Neurol Clin 1992; 10:(in press)

Downloaded by: National University of Singapore. Copyrighted material.

50.

syndrome may represent a treatable myopathy. Neurology 1990;40:535-8 Wolfe D, Simpson D. Myopathology of HIV infection. (Abstr.) J Neuropathol Exp Neurol 1990;49:352 Chad DA, Smith TW, Blumenfeld A, et al. HIV-associated myopathy: immunochemical identification of an HIV antigen (GP41) in muscle macrophages. Ann Neurol 1990;28:579-82 Bentler B, Cerami A. Cachectin: more than a tumor necrosis factor. N Engl J Med 1987;316:479-85 Lahdevirta J, Maury C, Teppo A-M, Repo H. Elevated levels of circulating cachectin/tumor necrosis factor in patients with AIDS. Am J Med 1988;85:289-91 Bessen LJ, Greene JB, Louie E, et al. Severe polymyositislike syndrome associated with zidovudine therapy of AIDS and ARC. (Letter.) N Engl J Med 1988;318:708

Neuromuscular complications of human immunodeficiency virus infection.

As the lifespan of patients with HIV infection is prolonged with more effective antiviral therapies, the prevalence of neuromuscular disorders is like...
855KB Sizes 0 Downloads 0 Views