Clinical Neurology and Neurosurgery 111 (2009) 193–195
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Case report
Neuralgic amyotrophy associated with hepatitis E virus Farina Fong a,∗ , Memon Illahi b,1 a b
106 Woodford Avenue, Gants Hill, Ilford, Essex IG2 6XB, United Kingdom Emergency Care Centre, Kent & Canterbury Hospital, Ethelbert Road, Canterbury, Kent CT1 3NG, United Kingdom
a r t i c l e
i n f o
Article history: Received 18 March 2008 Received in revised form 28 August 2008 Accepted 4 September 2008 Keywords: Neuralgic amyotrophy Parsonage–Turner syndrome Brachial plexus neuropathy Hepatitis E
a b s t r a c t Neuralgic amyotrophy (NA) is characterised by neuropathic pain and patchy paresis of the upper or lower limbs, usually involving the upper and middle trunks of the brachial plexus. The aetiology of NA is varied, with precipitating factors that include trauma, surgery, pregnancy, inoculations and infections. Deranged liver enzymes have been noted in previous NA reports but no cause identified. We describe a case of bilateral NA in a 53-year-old man who presented with peripheral neuropathy and isolated derangement of liver enzymes. Serology was positive for hepatitis E infection and negative for other infections previously described to be associated with NA. The diagnosis was supported by electrophysiological findings. This case report suggests that hepatitis E is a potential cause of NA that had not previously been described in the literature, and further supports a proposed immune pathogenesis underlying the condition. © 2008 Elsevier B.V. All rights reserved.
1. Introduction
2. Case report
Neuralgic amyotrophy (NA) is a form of peripheral neuropathy characterised by neuropathic pain and patchy paresis of the upper limbs, usually involving the upper and middle trunks of the brachial plexus. NA typically manifests initially with pain, with subsequent weakness and atrophy of affected muscles. The incidence of idiopathic NA is 2–3/100,000 per year [1]. First described in the nineteenth century, the publication of the first large case series of 136 patients in 1948 coined its eponymous name, Parsonage–Turner syndrome [2]. Precipitating causes of NA include trauma, surgery, inoculations and various infections, although the pathophysiology behind its development remains unclear. Hepatitis E is an enterically transmitted virus prominent in the developing world, responsible for both sporadic and endemic hepatitis. It was first characterised in patients with serological markers distinct from hepatitis A or B virus, and became known as nonA, non-B hepatitis [3]. The course of illness is usually self-limiting with no reports of chronic hepatitis E infection. In addition, to our knowledge, there has not been any documented neurological complications or peripheral neuropathy arising subsequent to hepatitis E infection.
A 53-year-old ecologist presented to the Emergency Department with onset of bilateral shoulder pain radiating to the chest. He had returned from a trip to Equador 4 weeks prior to presentation. He had no past medical history, previous surgery to the shoulder or neck or history or trauma. He did not have any flulike or coryzal symptoms. He reported minimal alcoholic intake. Systemic examination including neurological examination was normal. Investigations revealed no evidence of systemic infection; the plasma leukocyte count and inflammatory markers were within normal limits (white cell count 4.7 × 109 L−1 , CRP 7 mg/L). However, liver function tests were substantially deranged (bilirubin 20 mol/L, alanine transaminase (ALT) 2547 units/L, alkaline phosphatase (ALP) 247 units/L). At 2-week follow-up, the patient was still experiencing mild bilateral shoulder pain. However, systemic and neurological examinations remained normal. Laboratory tests showed an improvement in his hepatic function (ALT 297, ALP 147) with no other abnormal parameters. An abdominal ultrasound was normal. Autoantibody screen and hepatitis A, B and C serology were negative. In addition, heterophile antibody test (Paul–Bunnell), Borrelia burgdorferi, Treponema pallidum and human T-cell lymphotrophic viral antibodies were negative. Hepatitis E serology was positive (anti-hepatitis E IgM antibody). It is feasible that the patient had acquired hepatitis E infection through faecal–oral transmission during his trip to Equador. Approximately 6 weeks after initial presentation, the patient’s pain had resolved. However, he had developed weakness in his right
∗ Corresponding author. Tel.: +44 20 8550 2298. E-mail addresses:
[email protected] (F. Fong),
[email protected] (M. Illahi). 1 Tel: 44 1227 766 877x74696; fax: +44 1227 864 251. 0303-8467/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.clineuro.2008.09.005
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F. Fong, M. Illahi / Clinical Neurology and Neurosurgery 111 (2009) 193–195
shoulder and an area of sensory loss over his right radial forearm and hand, and left upper arm. Systemic examination and cranial nerve functions were normal. There were no supraclavicular or axillary masses. Neurological examination revealed winging of his right scapula. Fasciculations of his right serratus anterior muscle were visible on attempting to abduct his shoulder (MRC grade 2/5) and lateral rotation was limited to 60◦ (MRC grade 3/5). All reflexes in the right arm were absent. In addition, there was an area of numbness over the C5 dermatome of the right arm and in the distribution of the lateral brachial cutaneous nerve of the left arm. A magnetic resonance imaging scan of the cervical spine showed bulging of the intervertebral disc at the level of C6/C7 but no evidence of nerve root compression. The cord signal was normal. Electrophysiological studies (electromyography and nerve conduction tests) were performed 3 months after initial presentation due to waiting times, although ideally the studies could have been performed at 6 weeks or earlier. Electromyography revealed patchy denervation affecting the right serratus anterior and right supraspinatus muscles, with mild spontaneous fibrillation potentials, positive sharp waves and a moderately reduced interference pattern. The mean duration and amplitude of motor unit potentials were normal. No abnormalities were present in any other muscles. Nerve conduction velocities, the amplitude and area of compound muscle action potentials were normal. However, the sensory amplitude potentials of the median and ulnar nerves both hands were poor compared with the sural nerves. The results supported a diagnosis of bilateral NA. The patient received rehabilitative physiotherapy to facilitate neural regeneration. His neurological function normalised on 2-year follow-up with no residual motor deficit.
3. Discussion This patient had NA because of his clinical presentation with a characteristic patchy peripheral neuropathy involving the brachial plexus that was confirmed with electrophysiological testing. The diagnosis of NA is based on clinical findings and is supported by nerve conduction studies and electromyography. However, factors such as the time of testing, the patchy distribution and varying degree of neural damage may influence the results and thus be inconclusive or yield false-negative results [5]. Important differential diagnoses include cervical radiculopathy and peripheral nerve lesions. Magnetic resonance imaging of the shoulder has recently been explored as a useful adjuvant investigation that can detect atrophy and muscle involvement in involved regions [6], although it may not identify NA confined to the middle or lower trunks of the brachial plexus. NA represents a heterogeneous clinical syndrome, illustrated by Van Alfen and Van Engelen in their case-series analysis of 246 cases [4]. It occurs more commonly in males than females at a mean age of 41 years. Motor symptoms usually dominate the clinical picture with the development of muscular atrophy. Most reports detail that patients with NA slowly recover normal function without intervention. However, more recent publications suggest that approximately a third of patients suffer from chronic pain and that a majority of patients have persisting functional deficits more than 6 years after initial presentation [4]. To date, interventions such as electrotherapy and corticosteroids have no proven effect in improving the clinical course of the condition [7] although a corticosteroid trial is currently underway. The aetiology of NA is varied. Underlying causes can be generally categorised by a dichotomy into hereditary and acquired forms. Of the acquired form of NA, various precipitants have been identified that include trauma, surgery, inoculations [8], infection and preg-
nancy [9]. Precipitating infections include influenza [10], infectious mononucleosis [11], B. burgdorferi [12] and parvovirus [13]. To our knowledge, an association with hepatitis E virus has not been reported in the literature, although a similar case of brachial paresis complicating acute non-A, non-B hepatitis in a parenteral drug user was described in 1984 [14]. Unfortunately, the infection was not specifically identified to be hepatitis E. Interestingly, a false positive result to T. pallidum was noted in this case (T. pallidum is a known cause of infectious myelopathies) that may occur with autoimmune diseases and certain infections, e.g. atypical mycobacteria. The authors postulated an immune-mediated mechanism for the development of neuropathy. Hepatitis E infection presents clinically after an incubation period of approximately 8–10 weeks. Similar to other hepatitis viruses, infection may be asymptomatic, or classically manifest with jaundice and non-specific symptoms (such as abdominal pain, nausea, vomiting, fevers and arthralgia). Serum bilirubin is variably elevated with a significant rise in serum ALT (most marked in the second to third weeks after inoculation). In this case, the patient was asymptomatic and exhibited a similar pattern on liver function tests. The course of infection is usually self-limiting and resolves within 1–4 weeks, with laboratory values normalising by 6 weeks in most cases, as was noted in our patient. Serum hepatitis E virus antibodies are detected before or at the time of the ALT peak [16]. A small proportion of patients develop severe fulminant hepatitis, with a mortality of 0.5–4% [16]. There have been no reports to date of hepatitis E associated with neurological complications. Infection may lead to the development of NA through an autoimmune-mediated process that destroys neural tissue or via a parainfectious mechanism. Sierra et al. noted that patients with NA had decreased levels of serum CD3+ and CD8+ lymphocytes, an increased ratio of CD4+ to CD8+ T cells, and their lymphocytes exhibited increased blastogenic activity in the presence of brachial plexus nerve extracts [15]. This pattern is similar to that seen in other disorders of immune regulation, such as multiple sclerosis, Guillain–Barre syndrome, idiopathic polyneuritis and recurrent Bell’s palsy. Autoimmune dysfunction can occur in chronic active hepatitis and may reflect an immune-mediated mechanism for the development of NA following hepatitis infection. The presence of circulating serum antibodies to smooth muscle, nuclei and mitochondria may be noted in these patients, and is associated with continuing liver injury [17]. However, it is well-established that hepatitis E is an acute infection with no documented reports of chronicity, and it is questionable whether an acute infection can result in autoimmune dysfunction that may precipitate NA. We cannot exclude the possibility that hepatitis E was a coincidental finding in the diagnosis of NA. The patient did not have any concomitant systemic infection, as evidenced by his asymptomatic presentation and otherwise normal investigations. Furthermore, infections previously reported to be associated with NA were excluded in this patient. Interestingly, in their recent review of the clinical spectrum of NA, van Alfen and van Engelen noted that in 10 of 246 cases, the patients exhibited grossly elevated liver enzymes in a cohort of predominantly male patients with bilateral symptoms and phrenic nerve involvement [4]. Two of the 10 were found to have a previous amoebic abscess and a Ricketsia Conorii infection, respectively. Of the other eight, the pattern of derangement in liver function was variable [18]. Although our patient did not have phrenic nerve involvement, the other features of his presentation are consistent with their described subgroup. They postulated that an uncharacterised preceding infection might have triggered the condition in these patients. Whilst the variable pattern of liver function may indicate different pathogens,
F. Fong, M. Illahi / Clinical Neurology and Neurosurgery 111 (2009) 193–195
infections associated with liver dysfunction may be responsible for triggering NA. Our report suggests that NA is a rare but possible complication of hepatitis E virus that may explain abnormal liver enzymes in some previous reported cases. Conflicts of interest None to declare. Acknowledgement None. References [1] MacDonald BK, Cockerell OC, Sander JW, Shorvon SD. The incidence and lifetime prevalence of neurological disorders in a prospective community-based study in the UK. Brain 2000;123:665–76. [2] Parsonage MJ, Turner JWA. Neuralgic amyotrophy: the shoulder girdle syndrome. Lancet 1948;26:973–8. [3] Feinstone SM, Kapikian AZ, Purcell RH, Alter HJ, Holland PV. Transfusionassociated hepatitis not due to viral hepatitis type A or B. N Engl J Med 1975;292:767–70. [4] van Alfen N, van Engelen GM. The clinical spectrum of neuralgic amotrophy in 246 cases. Brain 2006;129:438–50.
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[5] Miller JD, Pruitt S, McDonald TJ. Acute brachial plexus neuritis: an uncommon cause of shoulder pain. Am Fam Physician 2000;62:2067–72. [6] Gaskin CM, Helms CA. Parsonage–Turner syndrome: MR imaging findings and clinical information of 27 patients. Radiology 2006;168:3920–1. [7] Aymond JK, Golner JL, Hardaker WT. Neuralgic amyotrophy. Orthop Rev 1989;18:1275–9. [8] Kiwit JC. Neuralgic amyotrophy after administration of tetanus toxoid. J Neurol Neurosurg Psychiatry 1984;47:320. [9] Rossi M, Morena M, Zanardi M. Neuropathy of the brachial plexus associated with pregnancy. Report of a case. Recenti Prog Med 1993;84:350–6. [10] Billings R, Grahame R. Neuralgic amyotrophy with hemidiaphragmatic paralysis. Rheumatol Rehabil 1975;14:260–1. [11] Drozdowski W, Baniukiewicz E. Neuralgic amyotrophy as a manifestation of infectious mononucleosis. J Neurol 2002;249:1605–7. [12] Nangaku M, Tamaoka A, Iguchi K, Inoue K, Mannen T. A case of “neuralgica amyotrophy” with elevated serum antibody titer against Borrelia burgdorferi. Rinsho Skinkeigaku 1990;30:84–7. [13] Pellas F. Neuralgic amyotrophy after parvovirus B19 infection. Neurology 1993;342:503–4. [14] Del Giudice G, Galli M, Chemotti M, Gasparro M, Franzetti F, Lazzarin A. Brachial paresis complicating acute non-A, non-B hepatitis. Boll Ist Sieroter Milan 1984;63:499–504. [15] Sierra A, Prat J, Bas J, Romeu A, Montero J, Matos JA, et al. Blood lymphocytes are sensitized to branchial plexus nerves in patients with neuralgic amyotrophy. Acta Neurol Scand 1991;83:183–6. [16] Panda SK, Thakral D, Rehman S. Hepatitis E virus. Rev Med Virol 2007;17:151–80. [17] Zauli D, Cassani F, Bianchi FB. Auto-antibodies in hepatitis C. Biomed Pharmacother 1999;53:234–41. [18] van Alfen N. Personal communication 2008.