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Miller-Fisher syndrome and Hodgkin’s disease
  1. E Rubio-Nazabal,
  2. J Marey-Lopez,
  3. J P Torres-Carrete,
  4. P Alvarez-Perez,
  5. P Rey Del Corral
  1. Departments of Neurology and Haematology, Hospital Juan Canalejo, La Coruña, Spain
  1. Correspondence to:
 Dr E Rubio-Nazabal, Servicio de Neurología, Hospital Juan Canalejo, As Xubias sn, 15006 La Coruña, Spain;

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Miller-Fisher syndrome (MFS) is a rare clinical entity classically regarded as a variant of Guillain-Barré syndrome (GBS) and characterised by the clinical triad of ophthalmoplegia, ataxia and areflexia.1 In MFS, paralysis is restricted to extraocular and occasionally other craniobulbar muscles. We report on a patient with a relapsing Hodgkin’s disease who developed MFS. Conventional immunosuppressive and intravenous immunoglobulin treatments improved the neurological deficits.

This 27 year old white man who had an eight year history of Hodgkin’s disease (type mixed cellularity, pathological stage IVB) had been receiving a salvage ESHAP regimen (etoposide VP-16 68 mg/day, methylprednisolone 500 mg/day, and cisplatin 42.5 mg/day for four days and cytosinearabinoside 3.4 g/day on the fifth day) since the first disease relapse four months before admission. He was admitted to the hospital for constitutional symptoms (39°C fever, recurrent night sweats, fatigue, malaise, and weakness). There was no history of infection. General examination was unremarkable except for bilateral inguinal adenopathy (1.5 × 1.5 cm). Haemoglobin concentration was 63 g/l, packed cell volume 17.8%, platelet count 89 × 109/l, white cell count 3.34 × 109/l (neutrophils 2.42 × 109/l), and lactate dehydrogenase 461 U/l. Results of the following investigations were normal: glucose, cholesterol, triglycerides, and ions; renal, liver, and thyroid function tests; vitamin B12 and folic acid; and tests for Campylobacter jejuni, herpes simplex virus, herpes zoster virus, cytomegalovirus, Epstein-Barr virus, Streptococcus pyogenes, Borrelia sp, syphilis, and cerebrospinal fluid parameters.

Staging evaluation included negative computed tomography of the chest. Computed tomography of the abdomen showed para-aortic nodal enlargement and normal sized spleen. Bone marrow examination found histological evidence of Hodgkin’s disease. Therefore, a diagnosis of relapsing Hodgkin’s disease was considered.

Before starting a cycle of ESHAP chemotherapy, the patient complained of bilateral horizontal diplopia, photophobia, dysphonia, and gait instability. Neurological function was assessed at that time, eight days after admission. Examination of the cranial nerves found a left sided ptosis with a total bilateral external ophthalmoplegia and fixed dilated pupils. The patient’s pupillary response to a 0.05% solution of pilocarpine showed increased sensitivity consistent with a postganglionic parasympathetic lesion. (Oculomotor nerves are among the few myelinated fibres of the postganglionic nervous system and this patient likely had dysfunction in these fibres similar to that observed in the other peripheral nerves. Pupillary abnormalities are encountered in about half of patients with MFS.2) There was dysphonia, mild dysphagia, and peripheral seventh nerve palsy. Examination of the peripheral nervous system showed loss of deep tendon reflexes. His muscle strength was normal, and pinprick, touch, position, and vibratory sensation were not impaired. There was obvious ataxia in all four limbs. He could walk with assistance and tandem gait was impossible. His cerebrospinal fluid protein concentration was 0.79 g/l with 2 lymphocytes/mm3. Cerebrospinal fluid culture and cytological studies showed only normal lymphocytes. Subsequent investigations found increased IgG ganglioside antibodies to GQ1b glycolipids (titre of 4900). Standard delayed hypersensitive skin tests were performed to purified protein derivative of tuberculin (intermediate strength), Candida albicans, mumps, tricophyton, and streptokinase/streptodornase, showing failure to elicit a response to any skin test antigens. Serum immunoglobulin concentrations were increased (IgG: 19 g/l, normal 10.51 ± 2.9, IgA: 4.8 g/l, normal 1.65 ± 0.8).

Gadolinium enhanced magnetic resonance imaging of the head showed no abnormalities. There was neurophysiological evidence of an axonal sensory neuropathy (sensory conduction in the right sural and median nerves was absent; the right median motor compound muscle action potential was 7.1 mV with a conduction velocity of 41.5 m/s). F wave latencies from the right posterior tibial, right common peroneal, right median, and ulnar nerves were minimally prolonged two days after onset but were within normal limits by three months. The patient presented moderate reduction of facial compound muscle action potential amplitude (right amplitude: 1.5 mV, left amplitude: 1.3 mV, right latency: 3 ms, left latency: 3.2 ms). Blink reflex R1 latencies were mildly prolonged (right: 13.9 ms, left: 14 ms). Blink R2 response latencies were normal (right: 30 ms, left: 29 ms). Masseter reflex was normal. The amplitude of the distal sensory evoked response was greatly reduced (upper extremity somatosensory evoked potentials to median nerve stimulation at the wrist). Brainstem auditory evoked potentials were normal. Intravenous immunoglobulin was given for five days at a dosage of 0.4 g/kg/day, starting 24 hours after the onset of neurological symptoms. He gradually improved over the next two weeks. A follow up examination by the time of discharge four weeks after the onset found nearly complete clinical recovery from the ataxia and occasional diplopia but the tendon reflexes were still hypoactive. Three months later, neurological examination and lumbar puncture results were normal, all electrophysiological parameters were normalised, and IgG antibody titres to GQ1b were not detectable.

In Hodgkin’s disease, the incidence of polyneuropathy is about the same as for the reticuloses in general—that is, approximately 1 or 2%.3 The major clinical picture of this patient was acute ataxia, ophthalmoplegia, and areflexia associated with increased cerebrospinal fluid protein and high titres of antibodies to the GQ1b ganglioside in the context of relapsing Hodgkin’s disease, which suggests an autoimmune mediated neurological disorder. To our knowledge this is the first report on a patient with MFS evolving during a relapse of Hodgkin’s disease. GBS and MFS occur in relation with conditions marked by partial immunosuppression, such as systemic lupus erythematosus, pregnancy, postoperative states, and a host of viral infections.3 Such situations are commonplace, and yet only a tiny proportion is complicated by GBS or MFS. This suggests that a special set of circumstances must prevail for MFS and GBS to occur. Viewed this way, not only are MFS and GBS disorders that can occur in the presence of partial immunosuppression, but also the immunosuppression may be involved in the pathogenesis of the syndromes. One must ask how an autoimmune, possibly cell mediated reaction can occur in an immunosuppressed patient. Animal models such as the NZB mouse show that depression of cell mediated immunity and the T cell system is associated with an increase in autoantibodies and autoimmune diseases, even though this increase is more often humorally mediated.4,5. Lisak et al3 described three patients with GBS and Hodgkin’s disease, postulating that selective depression of cell mediated immunity from whatever cause may allow the development of an immune reaction, either humoral, cellular, or both, directed against peripheral nervous system antigens.

The development of MFS in the context of relapsing Hodgkin’s disease, together with the improvement of this syndrome after tumour treatment and intravenous immunoglobulins, supports the theory that partial immunosuppression and the presence of IgG anti-GQ1b are possible pathogenic mechanisms.

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  • Competing interests: none declared

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