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Glutamic acid decarboxylase (GAD) is a major autoantigen in type I diabetes mellitus and stiff-man syndrome. Patients with progressive cerebellar ataxia and GAD autoantibodies (GAD-Abs) have been reported,1,2 and the pathogenetic role for GAD-Abs in suppressing cerebellar γ-aminobutyric-acid (GABA)-ergic transmission has been discussed. We present a woman who eventually developed progressive cerebellar ataxia, but had stroke-like episodes and brain stem involvement during her clinical course.
A 63 year old woman suffered dizziness of sudden onset accompanied by nausea and vomiting. Her physician found horizontal, gaze evoked nystagmus. A few days later, she noticed transient horizontal diplopia, after which spontaneously all her symptoms gradually subsided. Two months later, she experienced intermittent vertigo when she turned her head and then unsteadiness of gait. Her past medical and family histories were unremarkable. On examination, she was fully conscious and had no general physical abnormalities. There was coarse horizontal nystagmus, coarser on the left side. On phonation, her posterior pharyngeal wall shifted rightward, indicating paralysis of the constrictor muscles of the left side of the posterior pharyngeal wall (signe de rideau, Vernet3). She had ataxia in her left arm and leg and walked throwing the left leg outward. Although lesion in the left dorsolateral lower brain stem was suspected, MRI and MR arterial and venous images were unremarkable. A routine blood examination, as well as glucose tolerance and thyroid function tests, detected no abnormalities. CSF analysis was normal with negative oligoclonal IgG bands and a normal IgG index of 0.45. Her condition remained unchanged for six months, after which gait unsteadiness progressed gradually for one month. Thereafter, she had difficulty in speaking and swallowing on waking in the morning. In addition to the signs seen at the first presentation, a neurological examination showed ataxic dysarthria and limb ataxia on both sides. She became dependent on walking aids. The muscular tone of her limbs was decreased but the strength was normal. Tendon reflexes were normal, and plantar responses flexor on both sides. There was neither sensory nor bladder disturbance. Repeat CSF analysis and brain MRI results were normal. An electroencephalogram and nerve conduction studies gave normal results.
Routine haematological and blood chemistry studies, as well as the serum levels of vitamins B1, B12, and E, were normal. Faecal occult blood was negative. Infection by neurotrophic viruses was excluded serologically. Polymerase chain reaction analysis of the CSF for herpes simplex virus types 1 and 2 was negative. Intensive search for gynaecological, breast, or lung cancer, as well as haematological malignancies, including whole body computed tomography, bilateral mammography, and bone and gallium scintigrams produced negative results; anti-Hu and Yo antibodies were negative. Genetic analysis for spinocerebellar ataxia type 6 was negative. Glucose tolerance was impaired, but insulin secretion preserved. The serum GAD-Abs level determined by radioimmunoassay was highly increased at 10 400 U/ml (normal <1.5 U/ml). Evaluation of GAD-Abs from plasma frozen at her first presentation showed a titre of 9830 U/ml. Serum thyroid stimulating hormone was slightly increased, but thyroid hormone levels were normal, indicative of subclinical hypothyroidism associated with autoantibodies to thyroperoxydase and thyroglobulin. Low titre positivities were found for antinuclear, anti-double stranded DNA, anti-parietal cells, and anti-insulin antibodies. CSF GAD-Abs titre was 496 U/ml. Intrathecal GAD-Ab synthesis, calculated by Schüller's formula, gave a ratio of 10.7 for intrathecal GAD-Ab specific activity (ASA)/serum ASA, consistent with positive intrathecal synthesis.1
Her limb and gait ataxia progressed and were overlaid by truncal ataxia within a month. She underwent a five time course of double filtration plasmapheresis that filtered 15 litres of plasma. Immediately after completion of the plasmapheresis course, her GAD-Abs titre decreased to 4700 U/ml, and left posterior pharyngeal wall motion and independent gait returned. Ataxia, however, returned three weeks later and then progressed, accompanied by a gradual rise in GAD-Abs titre. A five day course of intravenous immunoglobulins 0.4 g/kg/day produced no improvement.
The overall clinical picture for this patient, subacutely progressive ataxia, is complicated by acute onset, exacerbations, and such signs of brain stem involvement as hemiparalysis of the posterior pharyngeal wall and asymmetrical coarse nystagmus. Although she does not have type I diabetes mellitus, the high serum GAD-Abs titre, intrathecal GAD-Ab synthesis, and presence of organ specific autoantibodies are comparable to previous findings for patients with progressive cerebellar ataxia and GAD-Abs.1,2 Selective suppression of GABA-ergic transmission by GAD-Abs is a possible cause of SMS, cerebellar ataxia, focal epilepsy, and palatal myoclonus. This mechanism, however, does not explain our patient's paralysis of the pharyngeal constrictor muscles because motoneurons in the nucleus ambiguus receive GABA mediated inhibition.4 As speculated by Honnorat et al,2 high GAD-Abs titre would merely reflect the presence of a more complex immune reaction against the nervous system. In this context, the subacute and atypical presentation of this patient raises the possibility that the GAD-Abs might have been a paraneoplastic phenomenon. Sillevis Smitt et al reported reversible cerebellar ataxia attributable to autoantibodies against a glutamate receptor in two patients with Hodgkin's disease.5 At present, however, follow up examinations of this patient showed no evidence for malignancy. The case of our patient suggests that progressive ataxia with high GAD-Abs titre may present with episodes that resemble multiple sclerosis or recurrent brain stem encephalitis.
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