International Cooperative Ataxia Rating Scale for pharmacological assessment of the cerebellar syndrome. The Ataxia Neuropharmacology Committee of the World Federation of Neurology.

Despite the involvement of cerebellar ataxia in a large variety of conditions and its frequent association with other neurological symptoms, the quantification of the specific core of the cerebellar syndrome is possible and useful in Neurology. Recent studies have shown that cerebellar ataxia might be sensitive to various types of pharmacological agents, but the scales used for assessment were all different. With the long-term goal of double-blind controlled trials-multicentric and international-an ad hoc Committee of the World Federation of Neurology has worked to propose a one-hundred-point semi-quantitative International Cooperative Ataxia Rating Scale (ICARS). The scale proposed involves a compartimentalized quantification of postural and stance disorders, limb ataxia, dysarthria and oculomotor disorders, in order that a subscore concerning these symptoms may be separately studied. The weight of each symptomatologic compartment has been carefully designed. The members of the Committee agreed upon precise definitions of the tests, to minimize interobserver variations. The validation of this scale is in progress.

Bilateral ptosis due to mesencephalic lesions with relative preservation of ocular motility.

Three cases of bilateral ptosis with relatively normal ocular motility are presented. In two of the patients, neuroimaging demonstrated lesions in the region of the third cranial nerve subnuclei. These unusual clinical presentations are due to isolated involvement of the central caudal nucleus supplying the bilateral levator muscles, with, virtually complete sparing of other third cranial nerve structures.

Intrafamilial variability in Machado-Joseph disease.

Dominantly inherited ataxias resulting from different gene mutations are difficult to distinguish based on clinical phenotypes. We believe the phenotypic variability within families can be a clue to clinical diagnosis. We illustrate the range of phenotypes extending from levodopa-responsive extrapyramidal disease to more purely ataxic syndromes seen in two families with molecularly proven Machado-Joseph disease.

Decreased parvalbumin immunoreactivity in surviving Purkinje cells of patients with spinocerebellar ataxia-1.

The distribution of two calcium-binding proteins, calbindin D28k (CaBP) and parvalbumin (PV), was investigated by immunohistochemistry in the brains of three individuals dying of nonneurologic illness and three patients with spinocerebellar ataxia-1 (SCA-1). SCA-1 has recently been proven to be due to an unstable CAG repeat mutation on chromosome 6. In the cerebellum of control individuals the Purkinje cells showed strong immunoreactivity to CaBP. Other cells were CaBP-negative. Parvalbumin was highly localized to Purkinje, basket, stellate, and Golgi cells. All surviving Purkinje cells in SCA-1 were strongly immunoreactive to CaBP. The number of PV-immunoreactive Purkinje cells was markedly reduced in SCA-1. In addition, there was a significant decrease in the intensity of PV immunostaining within the individual Purkinje cells compared with controls. However, in the hippocampus, temporal cortex, and lateral geniculate scattered PV-positive neurons were seen in SCA-1 patients, similar to those in controls. The present results suggest that the decreased PV-immunoreactivity in the surviving Purkinje cells in SCA-1 may reflect biochemical alterations preceding Purkinje cell degeneration.

Dominantly inherited cerebello-olivary atrophy is not due to a mutation at the spinocerebellar ataxia-I, Machado-Joseph disease, or Dentato-Rubro-Pallido-Luysian atrophy locus.

The dominantly inherited ataxias are characterized both by phenotypic variability (phenotypic heterogeneity) within the same genotype and overlapping phenotypes from different genotypes (genotypic heterogeneity). Therefore it is important to characterize specific clinical-neuropathologic phenotypes as precisely as possible at the genetic level. We describe a family with dominantly inherited ataxia of late adult onset with relatively "pure" cerebellar signs. Neuropathologic examination in two individuals from this family revealed findings consistent with cerebello-olivary atrophy, suggesting that this neuropathologic phenotype many run true within f families. Mutations at the spinocerebellar ataxia-I, Machado-Joseph disease, and dentatorubropallidoluysian atrophy loci were excluded by direct DNA analysis on the leukocytes of one living affected member. Thus we provide evidence that these mutations are not responsible for this particular phenotype of dominantly inherited ataxia.

Hereditary adult-onset Alexander's disease with palatal myoclonus, spastic paraparesis, and cerebellar ataxia.

We describe a progressive neurologic disorder in three sisters characterized clinically by palatal myoclonus, spastic weakness, hyperreflexia, mild cerebellar dysfunction, and ocular motor abnormalities. Postmortem examination of one patient demonstrated widespread Rosenthal fiber deposition associated with demyelination. The father previously was reported to have similar pathologic findings and carried a clinical diagnosis of multiple sclerosis. These clinical and pathologic findings describe a rare familial leukodystrophy that corresponds most closely to cases reported as adult Alexander's disease. Although similar pathologically to the well-characterized infantile variant of Alexander's disease, it is not known whether this adult variant represents the same disease process.

Familial progressive subcortical gliosis.

We report clinical and pathologic findings from two kindreds afflicted with a familial form of progressive subcortical gliosis. The disorder segregated as an autosomal dominant trait. Onset was in the presenium and the course was slowly progressive. Affected individuals initially manifested personality change, degeneration of social ability, disinhibition, psychotic symptoms, memory impairment, or depression. Later, all developed progressive dementia, frequently associated with verbal stereotypy, decreased speech output, echolalia, or manifestations of the human Klüver-Bucy syndrome. Terminal clinical manifestations included profound dementia, frequently with mutism, dysphagia, and extrapyramidal signs. Autopsy of seven end-stage patients revealed generalized cerebral atrophy, predominantly involving the white matter of the frontal and temporal lobes. Microscopically, prominent fibrillary astrocytosis was present in the subcortical white matter and in the subpial and deep layers of the overlying cerebral cortex. These changes were most pronounced in the frontal and temporal lobes, especially in the cingulate gyri and insulae. Mild cortical neuronal loss accompanied the gliosis, but no myelin loss was evident. The claustra and substantia nigra also showed severe astrocytosis and degenerative changes. Amyloid deposits and neuronal cytoskeletal inclusions were absent.

Decreased insulin-like growth factor I-mediated protein tyrosine phosphorylation in human olivopontocerebellar atrophy and lurcher mutant mouse.

We examined insulin-like growth factor I (IGF-I)-dependent phosphorylation and protein tyrosine kinase (PTK) activity in cerebellar cortex of normal humans, patients with olivopontocerebellar atrophy (OPCA) ("C" kindred) and in lurcher mutant mouse, a suggested animal model for OPCA. PTK activity and IGF-I-dependent protein tyrosine phosphorylation was significantly reduced in cerebellar cortex of human OPCA patients as compared to the normal controls. Immunoblot analysis also demonstrated a decrease in cerebellar 80 kDa phosphotyrosine protein in these patients. By autoradiography, IGF-I receptors were localized in the molecular layer of 30-day-old control and lurcher mutant mice cerebella. However, the lurcher mutant mice showed a decrease in [125I]-IGF-I binding in the molecular layer as compared to the littermate controls. The IGF-I receptor autophosphorylation was also markedly reduced in 15-day- and 22-day-old lurcher cerebella. These results suggest that the process of cerebellar degeneration in human OPCA and lurcher mutant mouse may be associated with altered IGF-I receptor binding and protein tyrosine phosphorylation.

Low dose oral methotrexate treatment of multiple sclerosis: a pilot study.

An 18-month double-blind treatment of multiple sclerosis with low dose oral methotrexate showed it to be well tolerated and suggested effectiveness in exacerbating-remitting MS but not in the exacerbating progressive and chronic progressive stages.

Inositol 1,4,5-trisphosphate metabolism in the cerebella of Lurcher mutant mice and patients with olivopontocerebellar atrophy.

We have investigated inositol 1,4,5-trisphosphate (InsP3) metabolism in cerebellar membranes of normal humans and patients with dominant ataxia ('C' kindred), and also in cerebellar microsomes of Lurcher mutant mouse (a suggested model for cerebellar ataxia). Various [3H]InsP3 metabolites formed were separated by HPLC using 3 successive convex gradients of 1.7 M ammonium formate, pH 3.7. [3H]InsP3 metabolism was rapid and in 15- and 45-day-old control mice cerebella about 50% of [3H]InsP3 was metabolized within 20 s. In 15-day-old Lurcher mice the rate of [3H]InsP3 metabolism was significantly low (40% of normal). [3H]InsP3 metabolism was almost absent in 45-day-old Lurcher mice cerebellar microsomes. The decreased [3H]InsP3 metabolism was consistent with decreased recovery of the various inositol polyphosphates formed. Similarly, in cerebellar membranes of human patients with olivopontocerebellar atrophy (OPCA) a significant decrease in [3H]InsP3 metabolism was observed when compared with normal controls. These data suggest that altered phosphoinositide turnover may be associated with the onset of neuronal degeneration in human OPCA.