Confirmation of the SCA-2 locus as an alternative locus for dominantly inherited spinocerebellar ataxias and refinement of the candidate region.

The autosomal dominant spinocerebellar ataxias (SCAs) are a clinically heterogeneous group of neurodegenerative diseases. To date, two SCA loci have been identified-one locus (SCA-1) on the short arm of chromosome 6 and the second locus (SCA-2) on the long arm of chromosome 12. We have studied two large kindreds from different ethnic backgrounds, segregating an autosomal dominant form of SCA. A total of 207 living individuals, including 50 affected, were examined, and blood was collected. We performed linkage analysis using anonymous DNA markers which flank the two previously described loci. Our results demonstrate that the two kindreds, one Austrian-Canadian and one French-Canadian, are linked to SCA-2 (chromosome 12q). Multipoint linkage analysis places the SCA-2 locus within a region of approximately 16 cM between the microsatellites D12S58 and D12S84/D12S105 (odds ratio 2,371:1 in favor of this position). We show that the SCA-2 locus is not a private gene and represents an alternative SCA locus.

Parieto-cerebellar loop impairment in ataxic hemiparesis: proposed pathophysiology based on an analysis of cerebral blood flow.

Sixteen stroke patients suffering from ataxic hemiparesis syndrome were studied with regional cerebral blood flow measured by 133-Xenon inhalation technique (12 patients) and by SPECT (HMPAO) (9 patients). The causative lesions (hematoma in 7 and infarct in 9), unilateral in 15 patients and bilateral in 1, were located in the posterior two-thirds of the corona radiata, thalamo-capsular and subthalamus regions, or cerebral peduncle. Ataxia of the cerebellar type was unilateral in 15 patients and bilateral in 1 with similar, deep, bilateral causative lesions. Four patients presented some characteristics of proprioceptive ataxia (mixed ataxia). Associated cognitive disturbances were present in 9 patients and absent in 7. Eleven of the 12 subjects studied by 133-Xenon inhalation technique showed limited centro-parietal hypoperfusion, mainly in the inferior parietal lobule, ipsilateral to the causative lesion and bilaterally in the patient with bilateral lesions and ataxia. Ipsilateral hypoperfusion was confirmed in 7/9 patients studied by SPECT, which also demonstrated contralateral cerebellar hypoperfusion in 4 patients. These findings suggest that ataxic hemiparesis syndrome results from functional depression (diaschisis) consequent to the interruption at many levels of an "inferior parietal associative cortex-cerebellar anterior lobe" circuit.

Progressive focal degenerative disease of the posterior associative cortex.

A 72-year-old man developed a very progressive neuropsychologic deficit 6 years ago, beginning with isolated visual topographic memory disturbances and visuo-constructive apraxia without additional manifestations of dementia. The syndrome worsened thereafter with the emergence of visual agnosia, simultagnosia, psychic paralysis of gaze, auditivo-verbal agnosia, and recently an amnestic syndrome with confabulation and confusion (at the end of 1989). CT scans, which remained unchanged over the years, showed mild, focal atrophic changes revealed by dilatation of the right occipital horn. His angiograms were normal. Two SPECT studies (with HMPAO measurements), performed 6 years from the onset, detected marked hypoperfusion in both parieto-occipital regions, mainly on the right side. Progressive focal degenerative disease without dementia is a relatively new syndrome, especially in cases with progressive aphasia. As noted in our patient, progressive disturbances initially localized in the right parieto-occipital region followed by posterior bilobar degeneration (pronounced on the right side) without dementia until late in the course may represent another exceptionally reported characteristic of this new syndrome. It is suggested that this variant of the Mesulam syndrome is more likely explained by progressive atrophy of the Alzheimer type.

[Cerebral crossed diaschisis caused by cerebellar lesion: role of the cerebellum in mental functions]. / Diaschisis cérébral croisé par lésion cérébelleuse: rôle du cervelet dans les fonctions mentales.

In 3 patients with a stroke limited to the posterior fossa, regional cerebral blood Flows were measured by the 133 Xe inhalation method (the first two cases) or by the SPECT with HMPAO method (the third case). The first patient had a median and paramedian hematoma of the left cerebellar hemisphere and the left dorsolateral portion of the pons. Remote cerebral hypoperfusion, measured 3 months later, was observed in both frontal premotor regions (but more marked in the right hemisphere) and in a circumscribed area of the right temporal region. The second patient had a right-sided ischaemic lesion of the anterior cerebellar lobe and the mesencephalic tectum. Contralateral parietal and rolandic hypoperfusion, measured 7 weeks after the stroke, was observed. The third patient had on old infarct of the right cerebellar hemisphere. The SPECT, measured 17 years later, showed a left fronto-parieto-temporal hypoperfusion and the absence of perfusion in the right cerebellar hemisphere. Preliminary data of neuropsychological assessment in our patients disclosed impairment in visuo-spatial and constructive organization, memory and learning compatible with the published findings in some patients and animals with predominantly cerebellar damage. These interesting findings should be confirmed in a large number of patients with age, sex, and sociocultural matched controls. In the absence of supratentorial insult, and during the hemodynamical stable phase, crossed cerebello-cerebral diaschisis is suggested in our 3 patients. Although it is too early to draw definite conclusions, our findings may: (1) confirm the functional interconnections between the cerebellum and the cerebrum in man and (2) provide functional basis for the behavioral function impairment reported in patients with cerebellar insult. Further rCBF, metabolism, and pathologic studies on this subject are required to elucidate this issue.

Remote effect of deep-seated vascular brain lesions on cerebral blood flow.

We measured regional cerebral blood flow using the xenon-133 inhalation method, at approximately 1 month after onset, in 60 stroke patients who had no evidence of major carotid artery stenosis or occlusion. Their single lesions (43 infarcts and 17 hematomas) were located in the capsulothalamolenticular region, sparing the cortex. Hemispheric mean cerebral blood flow was reduced on the side of the lesion in 25 patients and on both sides in 20. Regional hypoperfusion was observed in 46 patients (ipsilaterally in 34, bilaterally in 10, and contralaterally in two). Regional hypoperfusion was observed most frequently in the frontal lobe, particularly in the motor and premotor cortices of the prerolandic area. The 46 patients with regional hypoperfusion were compared with the 14 patients without regional hypoperfusion, considering the size and location of the lesion as well as the functional and analytic motor performances. As a rule, the lesion was slightly smaller and more posterior and the functional (p less than 0.001) and analytic (p less than 0.05) motor performances were significantly better in the 14 patients without regional hypoperfusion. Since the xenon-133 inhalation method examines cortical blood flow, we can attribute blood flow reductions resulting from deep-seated lesions to a functional depression akin to diaschisis. Interpretation of the clinical consequences and pathogenesis of this phenomenon requires further sequential and pathologic studies.

Pathogenesis of aphasia in deep-seated lesions: likely role of cortical diaschisis.

In order to study the pathophysiology of language disorders due to deep-seated left-hemisphere lesions not involving the cortex, a population of 43 right-handed stroke patients (29 aphasic) presenting with such lesions was studied clinically and by regional cerebral blood flow measurements (two-dimensional xenon-133 inhalation method). Most of the patients were studied sequentially between the 1st and 3rd months after stroke. Cortical diaschisis did not account for the whole clinical picture: the remote effect on the cortex could explain the occurrence of aphasia and its severity but not the type of aphasia. Furthermore, the clinical improvement observed in most cases was not accompanied by the disappearance of the diaschisis.

Role of the cerebellum in complex human behavior.

Thirty-three outpatient epileptics with normal CT scans (group 1) and 31 patients with cerebellar and brain stem (CBS) atrophy (group 2) were randomly included in this study. There were no significant statistical differences between the groups with regard to age, education, and number of grand mal and other seizures. Statistical analyses showed that group 2 had a longer history of epilepsy with a consequently longer duration of phenytoin (PHT) consumption. Neuropsychological assessment revealed lower performance by this group on the following measures: full I.Q. scale, verbal I.Q. scale, performance I.Q. scale, information, arithmetic, block design, object assembly, digit symbol, Stroop test forms I and II, the B-M dexterity test, and the simple visual and auditory reaction time. No significant differences were observed between the two groups for the remaining 5 subtests from the WAIS scale, for the immediate recall and the delayed recall subtests belonging to Wechsler memory scale as well as for visual and auditory movement time. Analysis of the composite scores of neuropsychological performance showed that the cerebellum interferes with the following complex behavioral functions: (i) visuo-spatial organization for a concrete task, a function related to the cerebello-parietal loops' (ii) planning and programming of daily activities, a function related to the cerebello-frontal loops; and (iii) the speed of information processing, a mainly subcortical function.

Cerebellar atrophy in epileptic patients.

High-resolution CT scans of the brain and posterior fossa were performed on 106 phenytoin (PHT)-treated epileptics, 28 de novo epileptics and 43 control subjects. A higher incidence of cerebellar and brainstem (CBS) atrophy was observed in chronic PHT- or PHT+ phenobarbital-treated epileptics compared to the two other groups. Some control subjects and de novo epileptics presented mild CBS atrophy, whereas moderate to severe atrophy was noted exclusively in chronically-treated patients. In attempting to delineate the etiology of CBS atrophy, epileptic patients were divided in three groups: 55 subjects with normal CT scans, 30 with both cerebral and CBS atrophy, and 49 with pure CBS atrophy. Their ages, length of illness, number of generalized seizures, number of other seizures, and amount of PHT received during their lifetime were assessed. Statistical analysis revealed that posterior fossa atrophy in epileptics was significantly correlated with both the length of the illness and the amount of PHT ingested during the patient's lifetime. The number of seizures appears to not be related to CBS atrophy.

Electromyographic studies of congenital mirror movements.

We studied two patients with congenital mirror movements. In one, the movements were associated with impaired sensation and a cervicodorsal meningocele. In the other, no abnormality of the nervous system was found. In an EMG study, the normal temporal characteristics, response latency, duration, and amount of EMG on the normal and mirror sides suggest that similar motor commands are responsible for both voluntary and mirror movements.

Reversible chronic cerebellar ataxia after phenytoin intoxication: possible role of cerebellum in cognitive thought.

Reversible chronic cerebellar ataxia followed phenytoin treatment in two epileptic women. Cerebellar ataxia in both patients and axonal polyneuropathy in one patient were improved after administration of thiamine alone or with folate. In one patient, some specific behavioral functions improved. However, recovery could have been spontaneous.