[Skip to Content]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 54.167.149.128. Please contact the publisher to request reinstatement.
Sign In
Individual Sign In
Create an Account
Institutional Sign In
OpenAthens Shibboleth
[Skip to Content Landing]
Observation
May 2005

Brachial Amyotrophic Diplegia in a Patient With Human Immunodeficiency Virus InfectionWidening the Spectrum of Motor Neuron Diseases Occurring With the Human Immunodeficiency Virus

Author Affiliations

Author Affiliations: Departments of Neurology (Drs Berger and Espinosa) and Internal Medicine (Dr Berger), University of Kentucky College of Medicine, Lexington; and Department of Neurology, Ohio State University, Columbus (Dr Kissel).

Arch Neurol. 2005;62(5):817-823. doi:10.1001/archneur.62.5.817
Abstract

Although amyotrophic lateral sclerosis and progressive spinal muscular atrophy have been recognized to occur in association with human immunodeficiency virus infection, to our knowledge, brachial amyotrophic diplegia, a form of segmental motor neuron disease, has not been previously reported. Brachial amyotrophic diplegia results in severe lower motor neuron weakness and atrophy of the upper extremities in the absence of bulbar or lower extremity involvement, pyramidal features, bowel and bladder incontinence, and sensory loss. We describe a human immunodeficiency virus–seropositive man without severe immunosuppression or prior AIDS-defining illnesses who had brachial amyotrophic diplegia. This disorder may represent one end of a spectrum of motor neuron diseases occurring with this retrovirus infection.

Motor neuron disease associated with human immunodeficiency virus (HIV) infection was first reported in 1985,1 4 years after the initial description of AIDS. Clinical patterns of HIV-associated motor neuron disease may mirror those of amyotrophic lateral sclerosis (ALS)15 or progressive spinal muscular atrophy (PSMA).611 However, to our knowledge, a segmental form of PSMA referred to as brachial amyotrophic diplegia (BAD) has not been previously described in association with HIV infection. This disorder is a form of neurogenic “man-in-the-barrel” syndrome in which severe bilateral upper extremity weakness is unaccompanied by bulbar lower extremity or pyramidal abnormalities.12 When associated with motor neuron disease, it has also been referred to as the flail arm syndrome13 and the hanging arm syndrome.14 BAD is classified as a form of segmental lower motor neuron disease.15 While a similar clinical phenotype of bilateral upper extremity weakness may occur following cerebral,1621 brainstem,2224 cervical spinal cord,2528 or bilateral brachial plexus insult,29,30 these may be distinguished from BAD by clinical presentation and radiographic and electrophysiological studies.12 Furthermore, the lack of involvement of bulbar and lower extremity muscles, the absence of pyramidal signs, and the long survival with this disorder distinguish it from ALS.12,15 We describe an HIV-seropositive man presenting with progressive upper extremity weakness that developed in the absence of a detectable viral load or any preceding AIDS-related complications.

REPORT of A Case

This 35-year-old man was first aware of a slowly progressive weakness of the right shoulder in June 2000 when he noted difficulty lifting heavy objects above his head with his right arm. The symptoms in his right arm progressed, and by June 2001, a similar weakness had developed in the left shoulder. Weakness and wasting were progressive in both upper extremities and in his chest muscles in the ensuing months. He denied speech or swallowing difficulties, leg weakness, sphincter disturbances, fasciculations, or stiffness. He reported rare mild cramps in his right medial plantar muscles.

In February 2001, laboratory testing revealed that he was HIV seropositive by enzyme-linked immunosorbent assay and Western blot analysis. At that time, his CD4 cell count was 244/μL and his HIV viral load was 8315 copies per milliliter. He started antiretroviral combination therapy, including zidovudine, lamivudine, and abacavir succinate (Trizivir) in August 2001, and by September 2001, his CD4 cell count was 377/μL and the HIV viral load was undetectable. His medical history was remarkable for diabetes mellitus diagnosed at the age of 14 years, which had been complicated by diabetic retinopathy requiring a right eye vitrectomy in 1998, diabetic peripheral neuropathy, and mild diabetic nephropathy with nonnephrotic proteinuria. The development of severe weakness of his upper extremities ultimately precluded self-injection of insulin, and an insulin pump was inserted. There was no family history of neuromuscular disorders.

A physical examination performed in April 2003 showed a slender man, weighing 55.8 kg. His cognition, language, and speech were normal. The result of a cranial nerve examination was normal. There was dramatic wasting of the muscles of the shoulder girdle and upper extremity and to a lesser extent the muscles of the forearms, hands, chest, and thorax (Figure). The scapulae were winged. Coarse fasciculations were observed in multiple muscles in the upper extremity and over the chest. His abdominal muscles were preserved. No spasticity was evident. Upper extremity strength was graded as trace in both deltoids, 2 of 5 in the right biceps and brachioradialis, 3 of 5 in the left biceps and brachioradialis, 4 of 5 in both triceps, and 4 of 5 at the wrist extensors and flexors, although the extensors were weaker. His interossei and other intrinsic hand muscles were mildly weak. Wasting in the lower extremities was confined to both extensor digitorum brevis muscles, greater on the left, which was associated with weakness of toe extension. Otherwise, strength in his lower extremities was preserved. Muscle stretch reflexes were graded as absent at the right biceps and brachioradialis, +1 at the right triceps, trace at the left biceps and brachioradialis, +1 at the left triceps, +2 at both knee jerks, and trace at the ankles. There was no Hoffmann or Babinski sign, and his jaw jerk was normal. His gait was normal. Pinprick and temperature sensation were diminished to the lower third of the calves. Vibratory and position sense was diminished in a stocking distribution in the distal lower extremities, and the Romberg sign was positive.

Figure.
 Profound wasting of the muscles of the upper extremities and chest is evident.

Profound wasting of the muscles of the upper extremities and chest is evident.

The result of magnetic resonance imaging of the cervical spine was normal, with minimal degenerative changes of the spine. With the exception of a mildly increased creatine kinase level (3.86 × 105 U/L), the results of hematologic and other laboratory studies, including erythrocyte sedimentation rate, rheumatoid factor, antinuclear antibody, tests for hereditary neuropathy with liability to pressure palsies, and antibodies to GM1 and myelin-associated glycoprotein, were negative or normal. The complete blood cell count revealed a hemoglobin level of 12.3 g/dL, a hematocrit of 36%, and a white blood cell count of 6500/μL, with a normal differential. The vitamin B12level was 528 pg/mL (390 pmol/L). Cerebrospinal fluid analysis showed 3/μL leukocytes, 0 erythrocytes, a glucose level of 115 mg/dL (6.38 mmol/L), a protein level of 5.5 × 10−2 g/dL, negative microbiological study results, including those for the VDRL test and cryptococcal antigen, normal cytologic test results, a normal IgG index, and 7 oligoclonal bands (attributed to HIV infection). Cerebrospinal fluid HIV viral assays were not performed. Electrophysiological studies performed on February 20, 2001, showed evidence of active and chronic denervation bilaterally of muscles innervated by C5 through the middle thoracic nerve roots by electromyography. The result of needle electromyography of the lower extremities was normal, with the exception of the observation of long-duration large-amplitude motor unit action potentials, fibrillation potentials, and mildly reduced recruitment in the muscles supplied by the superficial and deep peroneal nerves. Nerve conduction studies in the legs revealed sensory amplitudes all greater than 60% of the lower limit of normal for our laboratory, with preserved conduction velocities. Motor conductions were all greater than the 90th percentile of the lower limit of normal, with normal amplitudes. The changes overall were compatible with a mild to moderate distal sensorimotor polyneuropathy with predominantly axonal features. The findings on the nerve conduction study were complex and believed to be most consistent with diabetic peripheral neuropathy, a right peroneal neuropathy, and bilateral mild ulnar nerve entrapments at the elbow.

A trial of intravenous immunoglobulin was initiated in October 2003 without any improvement. Through January 2004, there was neither significant progression of his weakness nor development of any cranial nerve abnormalities or weakness, cramps, or fasciculations of the lower extremities.

COMMENT

Motor neuron disease with HIV infection may appear in several forms. A summary of previously reported cases of motor neuron disease complicating HIV infection and a summary of our patient are included in the Table. Motor neuron disease with HIV infection may be indistinguishable from classic ALS, resulting in an inexorably progressive disorder of upper and lower motor neurons.15 Alternatively, progressive lower motor neuron disease affecting bulbar and extremity muscles may occur in the absence of upper motor neuron findings consistent with PSMA.611 Other disorders occurring with HIV infection that mimic motor neuron disease include chronic inflammatory polyradiculoneuropathy,34 axonal motor polyradiculoneuropathy,32 and multifocal motor neuropathy with anti-GM1 antibodies.33 While progressive lower motor neuron weakness is seen with these disorders, the slow tempo of our patient’s illness would be distinctly unusual for chronic inflammatory polyradiculoneuropathy and multifocal motor neuropathy, and its severity and distribution inconsistent with HIV-associated axonal motor polyradiculoneuropathy.

Table. 
 Summary of Cases of Motor Neuron Disease Heralding HIV Infection Table. Summary of Cases of Motor Neuron Disease Heralding HIV Infection
Summary of Cases of Motor Neuron Disease Heralding HIV Infection Table. Summary of Cases of Motor Neuron Disease Heralding HIV Infection

Our patient had focal weakness of the right upper extremity that progressed to involve the left upper extremity during the ensuing year. The weakness and wasting have remained confined to a few myotomes of the cervical and upper thoracic region. There has been neither involvement of bulbar muscles nor progressive weakness of his lower extremities. The lower extremity findings of distal sensory loss, depressed ankle jerks, and distal wasting and weakness are the consequence of his concomitant diabetic peripheral neuropathy and mild entrapment neuropathies. Therefore, we believe that profound weakness and wasting of his upper extremities are consistent with BAD.

Diabetes may result in brachial and lumbosacral plexopathies, resulting in a disorder referred to as diabetic radiculoplexus neuropathy (or diabetic amyotrophy) that may mimic the disorder observed in our patient.35 This disorder, however, affects the lumbosacral plexus in most cases, and upper extremity involvement is uncommon.36,37 In addition, patients with brachial diabetic radiculoplexus neuropathy typically have unilateral weakness that progresses more rapidly than in our patient with preceding weight loss, severe pain, and sensory and autonomic abnormalities.35 Because none of these features was present in our patient, we think this an unlikely cause of our patient’s disorder.

Motor neuron disease occurring in association with HIV infection has been attributed to direct damage to the motor neurons by HIV, neurotoxic HIV viral proteins, cytokines and chemokines arising consequent to HIV infection, and opportunistic viruses that directly attack motor neurons.32 The prototypical virally mediated motor neuron disease is poliomyelitis36; however, it is clinically quite distinct from the inherited and idiopathic forms of motor neuron disease. Flaccid paralysis has been reported with various viruses in the Enterovirus genus.36 Recently, French investigators have found the nucleic acid of enteric cytopathogenic human orphan virus, an enterovirus, in the neuronal cell bodies within the gray matter of the spinal cord of 88% of patients with ALS, suggesting a possible association between this enterovirus and ALS.37 However, poliovirus and other enteroviruses, when associated with weakness, are typically characterized by an acute febrile illness followed by a flaccid paralysis of 1 or more limbs.36 Whether HIV infection itself or an accompanying, currently unrecognized, opportunistic infection is responsible for the motor neuron findings in HIV-infected persons with motor neuron disease or whether it is unrelated to HIV infection remains to be determined. Findings of reverse transcriptase,38 antibodies directed to human retroviral antigens,39 an association of human T-lymphotropic virus I with clinical and pathological features consistent with ALS,40,41 amplification of human T-lymphotropic virus tax/rex,39 animal models of retrovirus-induced motor neuron disease,42,43 and the presence of PSMA and ALS in HIV infection suggest that HIV infection is causative or contributory.

While the pathogenesis of ALS remains a conundrum, several theories have been proposed. Among the possible mechanisms that are considered are neuronal excitation and free radical generation.44 Both of these mechanisms have also been proposed as pathways to brain neuronal injury in the setting of HIV infection.45 Mitochondria, through several mechanisms, have also been suggested as instrumental in ALS, as in other neurodegenerative disorders.46 A critical role of the mitochondria in neuronal apoptosis has been suggested with neurotoxic HIV proteins, gp120,47 and Tat.48 Some investigators have also advanced a role for autoimmunity in ALS.49,50 Antineuronal antibodies have been demonstrated in HIV infection, and may correlate with the presence of dementia.51,52 Therefore, several proposed pathogenetic mechanisms for ALS may also be operative in HIV-associated central nervous system disease.

In conclusion, motor neuron disease occurs in association with HIV infection. The spectrum of HIV-associated motor neuron disease is broad and includes BAD, PSMA, and ALS. These disorders remain rare, and their underlying pathogenesis is uncertain.

Back to top
Article Information

Correspondence: Joseph R. Berger, MD, Department of Neurology, University of Kentucky College of Medicine, 740 S Limestone St, Lexington, KY 40536-0284 (jrbneuro@uky.edu).

Accepted for Publication: June 16, 2004.

Author Contributions:Study concept and design: Berger and Kissel. Acquisition of data: Berger and Kissel. Analysis and interpretation of data: Berger and Espinosa. Drafting of the manuscript: Berger and Espinosa. Critical revision of the manuscript for important intellectual content: Berger and Kissel. Administrative, technical, and material support: Berger and Espinosa. Study supervision: Berger.

References
1.
Hoffman  PMFestoff  BWGiron  LT  JrHollenbeck  LCGarruto  RMRuscetti  FW Isolation of LAV/HTLV-III from a patient with amyotrophic lateral sclerosis. N Engl J Med 1985;313324- 325
PubMedArticle
2.
MacGowan  DJScelsa  SNWaldron  M An ALS-like syndrome with new HIV infection and complete response to antiretroviral therapy. Neurology 2001;571094- 1097
PubMedArticle
3.
Moulignier  AMoulonguet  APialoux  GRozenbaum  W Reversible ALS-like disorder in HIV infection. Neurology 2001;57995- 1001
PubMedArticle
4.
Casado  IGomez  MCarmona  CGarcia-Castanon  IMartin  CSanchez  JF Motor neuron disease and HIV [in Spanish]. Rev Neurol 1997;25552- 554
PubMed
5.
Zoccolella  SCarbonara  SMinerva  D  et al.  A case of concomitant amyotrophic lateral sclerosis and HIV infection. Eur J Neurol 2002;9180- 182
PubMedArticle
6.
Nishio  MKoizumi  KMoriwaka  FKoike  TSawada  K Reversal of HIV-associated motor neuron syndrome after highly active antiretroviral therapy. J Neurol 2001;248233- 234
PubMedArticle
7.
Galassi  GGentilini  MFerrari  S  et al.  Motor neuron disease and HIV-1 infection in a 30-year-old HIV-positive heroin abuser: a causal relationship? Clin Neuropathol 1998;17131- 135
PubMed
8.
Sher  JWrzolek  MShnuter  Z Motor neuron disease with AIDS [abstract]. J Neuropathol Exp Neurol 1988;47303
9.
Verma  RKZiegler  DKKepes  JJ HIV-related neuromuscular syndrome simulating motor neuron disease. Neurology 1990;40544- 546
PubMedArticle
10.
Huang  PPChin  RSong  SLasoff  S Lower motor neuron dysfunction associated with human immunodeficiency virus infection. Arch Neurol 1993;501328- 1330
PubMedArticle
11.
Pearl  DNoursadeghi  MManji  HEdwards  SMiller  R Lower motor neuron syndrome and HIV infection [letter]. Sex Transm Infect 2003;79351
PubMedArticle
12.
Katz  JSWolfe  GIAndersson  PB  et al.  Brachial amyotrophic diplegia: a slowly progressive motor neuron disorder. Neurology 1999;531071- 1076
PubMedArticle
13.
Hu  MTEllis  CMAl-Chalabi  ALeigh  PNShaw  CE Flail arm syndrome: a distinctive variant of amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 1998;65950- 951
PubMedArticle
14.
Mulder  DW The clinical syndrome of amyotrophic lateral sclerosis. Mayo Clin Proc 1957;32427- 436
PubMed
15.
Van Den Berg-Vos  RMVan Den Berg  LHVisser  Jde Visser  MFranssen  HWokke  JH The spectrum of lower motor neuron syndromes. J Neurol 2003;2501279- 1292
PubMedArticle
16.
Sage  JIVan Uitert  RL Man-in-the-barrel syndrome. Neurology 1986;361102- 1103
PubMedArticle
17.
Clerget  LLenfant  FRoy  HGiroud  MBen Salem  DFreysz  M Man-in-the-barrel syndrome after hemorrhagic shock. J Trauma 2003;54183- 186
PubMedArticle
18.
Crisostomo  EASuslavich  FJ Man-in-the-barrel syndrome associated with closed head injury. J Neuroimaging 1994;4116- 117
PubMed
19.
Moore  APHumphrey  PR Man-in-the-barrel syndrome caused by cerebral metastases. Neurology 1989;391134- 1135
PubMedArticle
20.
Shaw  PJTharakaram  SMandal  SK Brachial diplegia as a sequel to cardio-respiratory arrest: “man-in-the-barrel syndrome” [letter]. Postgrad Med J 1990;66788
PubMedArticle
21.
Hurley  JPWood  AE Isolated man-in-the-barrel syndrome following cardiac surgery. Thorac Cardiovasc Surg 1993;41252- 254
PubMedArticle
22.
Alberca  RIriarte  LMRasero  PVillalobos  F Brachial diplegia in central pontine myelinolysis. J Neurol 1985;231345- 346
PubMedArticle
23.
Georgiadis  DSchulte-Mattler  WJ Cruciate paralysis or man-in-the-barrel syndrome? report of a case of brachial diplegia. Acta Neurol Scand 2002;105337- 340
PubMedArticle
24.
Strupp  MBruckmann  HHamann  GFBruning  RBrandt  T Simultaneous brachial diplegia and rotational vertigo due to combined spinal anterior and vertebrobasilar embolism. Eur Neurol 2000;43240- 242
PubMedArticle
25.
Berg  DMullges  WKoltzenburg  MBendszus  MReiners  K Man-in-the-barrel syndrome caused by cervical spinal cord infarction. Acta Neurol Scand 1998;97417- 419
PubMedArticle
26.
Renard  JFMassardier  EIasci  L  et al.  Brachial diplegia caused by cervical spinal cord ischemia: a case [in French]. Rev Neurol (Paris) 1997;153690- 693
PubMed
27.
Barbizet  JDegos  JDHurth  MDuval  JAillerie  MA Brachial diplegia due to ischemia of the anterior horns during septicemia caused by Salmonella typhimurium [in French]. Ann Med Interne (Paris) 1974;125191- 194
PubMed
28.
Fuentes  JMVlahovitch  BNegre  C Brachial diplegia of traumatic origin as a result of injuries of the cervical cord [in French]. Neurochirurgie 1984;30165- 170
PubMed
29.
Foncea  NYurrebaso  IGomez Beldarrain  MGarcia-Monco  JC Postoperative bilateral brachial plexopathy mimicking the “man-in-the-barrel” syndrome [in Spanish]. Neurologia 2002;17388- 390
PubMed
30.
Zuin  DRNeme  RVera  J Bilateral braquial plexopathy mimicking the “man-in-the-barrel” syndrome [in Spanish] [letter]. Neurologia 2003;18413
PubMed
31.
Sastre-Garriga  JTintore  MRaguer  NRuiz  IMontalban  XCodina  A Lower motor neuron disease in a HIV-2 infected woman. J Neurol 2000;247718- 719
PubMedArticle
32.
Goldstein  JMAzizi  SABooss  JVollmer  TL Human immunodeficiency virus–associated motor axonal polyradiculoneuropathy. Arch Neurol 1993;501316- 1319
PubMedArticle
33.
Simpson  DMorgello  SCitak  KCorbo  MLatov  N Motor neuron disease associated with HIV-1 and anti–asialo GM1 antibody [abstract]. Muscle Nerve 1994;171091Article
34.
Dalakas  MCCupler  EJ Neuropathies in HIV infection. Baillieres Clin Neurol 1996;5199- 218
PubMed
35.
Dyck  PJWindebank  AJ Diabetic and nondiabetic lumbosacral radiculoplexus neuropathies: new insights into pathophysiology and treatment. Muscle Nerve 2002;25477- 491
PubMedArticle
36.
Ropka  SJubelt  B Enteroviruses.  In: Berger  J, ed. Clinical Neurovirology. New York, NY: Marcel Dekker Inc; 2003:359-377
37.
Berger  MMKopp  NVital  CRedl  BAymard  MLina  B Detection and cellular localization of enterovirus RNA sequences in spinal cord of patients with ALS. Neurology 2000;5420- 25
PubMedArticle
38.
Andrews  WDTuke  PWAl-Chalabi  A  et al.  Detection of reverse transcriptase activity in the serum of patients with motor neurone disease. J Med Virol 2000;61527- 532
PubMedArticle
39.
Westarp  MEFerrante  PPerron  HBartmann  PKornhuber  HH Sporadic ALS/MND: a global neurodegeneration with retroviral involvement? J Neurol Sci 1995;129(suppl)145- 147
PubMedArticle
40.
Kuroda  YSugihara  H Autopsy report of HTLV-I–associated myelopathy presenting with ALS-like manifestations. J Neurol Sci 1991;106199- 205
PubMedArticle
41.
Jubelt  B Viruses and motor neuron diseases. Adv Neurol 1991;56463- 472
PubMed
42.
Jubelt  B Motor neuron diseases and viruses: poliovirus, retroviruses, and lymphomas. Curr Opin Neurol Neurosurg 1992;5655- 658
PubMed
43.
Gardner  MBHenderson  BEOfficer  JE  et al.  A spontaneous lower motor neuron disease apparently caused by indigenous type-C RNA virus in wild mice. J Natl Cancer Inst 1973;511243- 1254
PubMed
44.
Bromberg  MB Pathogenesis of amyotrophic lateral sclerosis: a critical review. Curr Opin Neurol 1999;12581- 588
PubMedArticle
45.
Kaul  MGarden  GALipton  SA Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature 2001;410988- 994
PubMedArticle
46.
Manfredi  GBeal  MF The role of mitochondria in the pathogenesis of neurodegenerative diseases. Brain Pathol 2000;10462- 472
PubMedArticle
47.
Corasaniti  MTTurano  PBilotta  A  et al.  Evidence that increases of mitochondrial immunoreactive IL-1β by HIV-1 gp120 implicate in situ cleavage of pro-IL-1β in the neocortex of rat. J Neurochem 2001;78611- 618
PubMedArticle
48.
Kruman  IINath  AMattson  MP HIV-1 protein Tat induces apoptosis of hippocampal neurons by a mechanism involving caspase activation, calcium overload, and oxidative stress. Exp Neurol 1998;154276- 288
PubMedArticle
49.
Yi  FHLautrette  CVermot-Desroches  C  et al.  In vitro induction of neuronal apoptosis by anti–Fas antibody–containing sera from amyotrophic lateral sclerosis patients. J Neuroimmunol 2000;109211- 220
PubMedArticle
50.
Appel  SHSmith  RGEngelhardt  JIStefani  E Evidence for autoimmunity in amyotrophic lateral sclerosis. J Neurol Sci 1994;124(suppl)14- 19
PubMedArticle
51.
Schutzer  SEBrunner  MFillit  HMBerger  JR Autoimmune markers in HIV-associated dementia. J Neuroimmunol 2003;138156- 161
PubMedArticle
52.
Kumar  MResnick  LLoewenstein  DABerger  JEisdorfer  C Brain-reactive antibodies and the AIDS dementia complex. J Acquir Immune Defic Syndr 1989;2469- 471
PubMed
×