Antibodies to Ma2 were originally described in men with testicular cancer and paraneoplastic limbic-brain stem dysfunction.1 Tumour expression of immunoreactive Ma proteins in some of these patients suggests that these antigens, which are widely distributed in normal human brain, are targets of autoimmunity in paraneoplasia. We report on a female patient with brain stem encephalitis, serum anti-Ma2 antibodies, and adenocarcinoma of the lung, and describe the associated tumour and brain immunopathology. Case historyA 77 year old woman with a 50 pack-year smoking history presented in February 1999 with a 2 month history of progressive unsteadiness of gait and slurring of speech. Left facial weakness and dysphagia had developed in the 3 weeks before admission.Examination showed an alert and oriented patient with no cognitive dysfunction. A slurring dysarthria was evident. The eye movements were conjugate. There was gaze evoked right beating nystagmus and mild slowing of horizontal saccades. Vertical eye movements were intact. The vestibulo-ocular reflex (VOR) was preserved, but there was bilateral failure of suppression of the VOR. There was mild lower facial weakness on the left. There were no appendicular cerebellar signs but marked ataxia of gait rendered the patient unable to walk without assistance. Muscle bulk, tone, power, reflexes, plantar responses, and sensation were normal.Investigations showed hyponatraemia (124 mmol/l) and a urine osmolality of 542 mmol/l, consistent with inappropriate antidiuretic hormone secretion. The serum contained an antinuclear antibody (ANA) with a titre>2560 and a speckled pattern on immunofluorescence. Anti-dsDNA was not detected by radioimmunoassay. A T2 weighted MR of the brain showed asymmetric scattered high signal intensity lesions in the pons, left middle and superior cerebellar peduncles, and the basal ganglia and internal capsule regions bilaterally (fig 1). A lumbar puncture yielded clear CSF under normal pressure containing 4×10 6 /l lymphocytes, 0.83 g/l protein, and no detectable oligoclonal bands. No malignant cells were identified on CSF cytological examination. Chest radiography showed a small ill defined left upper lobe lesion and chest CT confirmed the presence of a 1.8 cm left upper lobe mass. A fine needle aspiration and core biopsy of the lesion yielded pulmonary alveolar tissue only, and no malignant cells. Investigation for the presence of antineuronal nuclear antibodies by immunofluorescence on monkey cerebellum was confounded by the presence of the high titre antinuclear antibody. A preliminary diagnosis of paraneoplastic brain stem encephalitis was made; however, specific therapy, in particular resection of the undiagnosed pulmonary lesion, was deferred after discussion with the family.
In addition to expanding the range of PRNP mutations associated with human prion diseases, we believe this case is important for the following reasons. First, from an epidemiological perspective, the avoidance of occasional incorrect classification of patients manifesting neurodegenerative disorders that may have a genetic basis requires systematic genotyping, particularly when there are uncertainties regarding the family history. Second, the incidence of spongiform encephalopathy in elderly patients beyond the typical age range may be underestimated and does not preclude a genetic basis. Finally, as a corollary, this case highlights problematic issues in human transmissible spongiform encephalopathies, as illustrated by disease penetrance and age of onset in genotype-phenotype correlations.
SUMMARY Two female siblings were born with an hydranencephalic‐hydrocephalic syndrome, following pregnancies complicated by hydramnios. No environmental factors such as infections, drugs or metabolic disorders were noted during either pregnancy. Neuropathological studies revealed identical changes in each case. The characteristic feature of the pathology was a proliferative vasculopathy throughout the central nervous system, which apparently caused focal ischaemic lesions and progressive destruction of CNS tissue. The defect probably is inherited as an autosomal recessive trait. RÉSUMÉ Deux soeurs sont nées avec un syndrome hydranencéphalique hydrocéphalique, à la suite de grossesses compliquées par hydramnios. Aucun facteur d'environment tels qu'infection, médication ou désordes métaboliques n'ont été notes durant l'une ou l'autre grossesse. Les études neuropathologiques ont montré des modifications identiques dans chaque cas. L'aspect pathologique caractéristique était une vasculopathie proliferative tout au long du nervax ayant apparemment entrainé des lesions ischémiques locales et une destruction progressive du tissu nerveux. II s'agit probablement d'une anomalie déréditaire se transmettant selon le type autosomal récessif. ZUSAMMENFASSUNG Zwei weibliche Geschwister wurden nach einer durch ein Hydramnion komplizierten Geburt mit einem hydranencephalen‐hydrocephalen Syndrom geboren. Bei keiner Schwangerschaft wurden umweltbedingte Faktoren wie Infektionen, Drogen oder metabolische Erkrankungen festgestellt. Neuropathologische Untersuchungen ergaben bei den Fällen identische Veränderungen. Die charakteristischen Veränderungen waren eine proliferative Vaskulopathie im Bereich der Neuraxis, durch die offenbar fokale ischämische Läsionen und eine progressive Zerstörung von Hirngewebe verursacht wurden. Die Mißbildung wird wahrscheinlich autosomal rezessiv vererbt. RESUMEN Dos hermanas nacieron con un sindrome hidranencefálico‐hidrocefálico, despué de gestaciones complicadas con hidramnios. En ninguna de las gestaciones se registraron factores ambientales tales como infecciones, färmacos o enfermedades metabólicas. Los estudios neuropatológicos revelaron cambios idénticos en ambos casos. La caracteristica de la patologia era una vasculopatia proliferativa a lo largo del neuroeje que aparentemente causaba lesiones focales isquémicas y una destrucción progresiva del tejido de SNC.
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