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Acute autonomic and sensory neuropathy after interferon α-2b therapy for chronic hepatitis C
  1. T IRIOKA,
  2. M YAMADA,
  3. M YAMAWAKI,
  4. Y SAITO,
  5. H MIZUSAWA
  1. Department of Neurology and Neurological Science
  2. Graduate School of Medicine
  3. Tokyo Medical and Dental University
  4. 1–5–45 Yushima Bunkyo-ku
  5. Tokyo 113–8519, Japan
  6. Department of Neurology
  7. Kanazawa University School of Medicine, Japan
  8. Department of Internal Medicine, Social Insurance Chuo General Hospital, Japan
  1. Dr T Irioka irioka{at}tc4.so-net.ne.jp
  1. M YAMADA
  1. Department of Neurology and Neurological Science
  2. Graduate School of Medicine
  3. Tokyo Medical and Dental University
  4. 1–5–45 Yushima Bunkyo-ku
  5. Tokyo 113–8519, Japan
  6. Department of Neurology
  7. Kanazawa University School of Medicine, Japan
  8. Department of Internal Medicine, Social Insurance Chuo General Hospital, Japan
  1. Dr T Irioka irioka{at}tc4.so-net.ne.jp
  1. H MIURA
  1. Department of Neurology and Neurological Science
  2. Graduate School of Medicine
  3. Tokyo Medical and Dental University
  4. 1–5–45 Yushima Bunkyo-ku
  5. Tokyo 113–8519, Japan
  6. Department of Neurology
  7. Kanazawa University School of Medicine, Japan
  8. Department of Internal Medicine, Social Insurance Chuo General Hospital, Japan
  1. Dr T Irioka irioka{at}tc4.so-net.ne.jp

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Acute autonomic and sensory neuropathy (AASN) is a disorder characterised by acute autonomic and sensory nerve dysfunctions, and well preserved motor nerve function.1 Although the pathomechanism of AASN is not clear, autonomic and sensory ganglion neuron cell bodies may be the main target of the immune mediated process underlying AASN.2 On the other hand, patients treated with interferon may develop neurological complications including neuropathy.3 We report the first case of AASN which can be associated with interferon α-2b therapy for chronic hepatitis C.

A 57 year old Japanese man with chronic hepatitis C had been treated with interferon α-2b since June 1998. On 3 September, a skin eruption abruptly emerged on his chest and rapidly spread over his whole body. There was no history of exposure to toxins and drugs other than the interferon. The interferon therapy was stopped on 7 September; after a total dose of 390 000 000 units. The skin eruption gradually resolved, but 1 week later, numbness appeared in his limbs. Subsequently he became unable to walk and stand. Further, he developed urinary overflow incontinence and bowel distension. He was then transfered to our neurology department on 2 October.

Physical examination disclosed orthostatic hypotension without secondary tachycardia (120/60 mm Hg lying, 85/52 mm Hg sitting, fixed pulse rate 60 bpm) and paralytic ileus. He was catheterised for incontinence. He was drowsy. The pupils were anisocoric although they reacted promptly to light. Other cranial nerves were unremarkable. Muscle strength and bulk were normal. Deep tendon reflexes were generally absent. There were no pathological reflexes. Light touch, pain, and temperature sensations were impaired moderately over the trunk, more so in his limbs. Vibration and joint sensations were impaired severely in the same distribution, and lost in his fingers, knees, ankles, and toes. Sensory ataxia and pseudoathetosis in his fingers were noted.

Routine laboratory examinations were normal except for hyponatraemia due to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) (plasma sodium 124 mEq/l, urinary sodium 182 mEq/l, plasma osmolarity 262 mOsmol/l, urine osmolarity 775 mOsmol/l, vasopressin 1.86 pg/ml; and normal renal, thyroid, and adrenal function). Liver function was normal, and blood hepatitis C virus RNA was negative. Immunoglobulins and complements were normal. Cryoglobulin, M-protein, antinuclear antibody, and anti-SS-A/-B antibodies were negative. We examined various antiviral antibodies (coxsackie viruses, herpes simplex virus, varicella zoster virus, cytomegalovirus, Epstein-Barr virus, measles, rubella, mumps, adenovirus, and influenza A and B) in the serum or CSF, but they showed no remarkable change. Several tumour markers in the serum also showed no particular change. Serum IgG class anti-GQ1b antibody was present with low titre as demonstrated by enzyme linked immunosorbent assay (ELISA). Immunohistochemistry using frozen sections of rat cerebral cortex, cerebellum, spinal cord, and dorsal root ganglion showed no antineuronal antibody in the serum from the patient, although the serum from a patient with anti-Hu antibody positive paraneoplastic syndrome showed positive reactions with these neurons (data not shown). ELISA for anti-Hu antibody was negative in the serum and CSF. His CSF showed an increased protein concentration (159 mg/dl) without pleocytosis but no oligoclonal bands.

Brain and spinal MRI were normal. Whole body CT examination; colon fibroscopy and a 67Ga-citrate scintigram showed no malignancy.

On neurophysiological studies, an EEG showed delta bursts in all leads. Motor conduction velocity and amplitude of compound muscle action potentials in the right median, ulnar, and posterior tibial nerves were within the normal range. By contrast, sensory nerve action potentials (SNAPs) could not be elicited in right median and sural nerves. In the right ulnar nerve, amplitude of SNAPs was markedly decreased (5 μV) with preservation of sensory conduction velocity (53.3 m/s). A needle EMG gave normal results. Sympathetic skin response could not be elicited in the upper and lower limbs. The coefficient of variation of R-R intervals on ECG was decreased (1.17% at rest; mean value and lower limit in the 50s age group 2.80, 1.41).

The sural nerve biopsy disclosed marked axonal degeneration with a significant decrease of both myelinated (1359/mm2) and unmyelinated fibres (13 791/mm2) (figure). There was no inflammatory cell infiltration or vasculitis.

Pathological findings in the sural nerve. (A) Histologically, most of the myelinated fibres show formation of myelin ovoids indicating active axonal degeneration, which is also present in the teased fibre preparations (B). (C) The unmyelinated fibres are also affected showing swelling of the axons (arrows). ((A) epon embedded section stained with toluidine blue; bar=20 μm; (B) teased fibre, bar=100 μm; (C) electron micrograph; bar=2 μm).

The patient was treated with plasmapheresis (3000 ml×3) beginning on 6 October. Soon after the plasmapheresis, joint sensation in his fingers was slightly improved and anisocoria disappeared. Plasma sodium concentration, the patient's level of consciousness, and the EEG were subsequently normalised. After the plasmapheresis, he was treated with steroids (methylprednisolone (1000 mg intravenously), for the first 3 days, and then prednisone (60 mg orally), followed by a gradual taper). This did not further improve his symptoms; severe sensory impairment, orthostatic hypotension, and constipation persisted 3 months after the onset of the disorder.

Our patient presented with acute onset of sensory impairment, autonomic dysfunctions, selective impairment of sensory and autonomic nerves in electrophysiological studies, and a raised CSF protein concentration. These clinical features are compatible with a diagnosis of AASN. In addition, our patient showed SIADH and consciousness disturbance suggestive of involvement of the CNS.4

In AASN, episodes of infection before the onset are often seen, suggesting that preceding infection may induce the immune mediated process leading to AASN. Pavesi et al described a patient with Coxsackie B virus infection complicated by an acute autonomic and sensory neuropathy.5In their patient, diffuse mucosal and c utaneous erythema preceded neurological complications. Our patient also presented a cutaneous lesion followed by an autonomic and sensory neuropathy. However, serum and CSF studies for antiviral antibodies showed no evidence for any viral infection.

Peripheral neuropathy is a rare neurological side effect of interferon. There have been reports of multiple mononeuropathy, acute motor or sensorimotor axonal polyneuropathy, and cranial nerve palsies. Although the pathomechanism underlying peripheral neuropathy associated with interferon is unknown, immunomodulatory effects of interferon may cause disorders of the peripheral nervous system.3

In our patient, AASN developed after the interferon therapy with an increased protein concentration in the CSF, and plasmapheresis seemed to result in slight improvement and prevention of the disease progression. This is the first report suggesting association of interferon and AASN. We suggest that interferon may induce an immune mediateddamage to the autonomic and sensory ganglion neurons leading to clinical manifestation of AASN.

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