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Because of the high concentrations of gamma-aminobutyric acid (GABA) in the cerebellar cortex and nuclei, an attempt was made to enhance GABAergic transmission in patients with cerebellar disease. Maximum tolerated doses of sodium valproate, a drug which inhibits the degradation of GABA, failed to influence cerebellar deficits in a double blind crossover study on six patients.
In humans, inability to stand and walk is the most limiting of motor disabilities. In humans, upright stance and gait is the most sensitive indicator of cerebellar disease. From animal and human studies, much has been learned about how the cerebellum coordinates normal movement, and how it may play roles in normal motor adaptation and learning. Much of this work suggests that different parts of the cerebellum control stance and gait in different ways, and differently located lesions cause different deficits. What is not known is whether the cerebellum can compensate for stance and gait disorders caused by lesions in other parts of the nervous system, or whether one part of the cerebellum can compensate for deficits caused by lesion of another part. These issues have become increasingly important in rehabilitation research and practice.
Glutamate dehydrogenase (GDH) activity was measured in leukocytes from 88 patients with various types of degenerative neurological disorders affecting primarily the cerebellum and/or the basal ganglia, and 26 healthy control subjects. Twelve patients with slowly progressive multiple-system atrophic disorders were found to have a partial deficiency of this enzyme (52% of control level). The majority of these patients evidenced a constellation of neurological findings consistent with the diagnosis of olivopontocerebellar atrophy, although others were atypical in their neurological manifestations. Thus, GDH-deficient patients were encountered with predominantly extrapyramidal manifestations (atypical Parkinson's disease), cerebellar dysfunction with peripheral neuropathy, or anterior horn cell signs, suggesting that a pleomorphic phenotypic expression of the enzymatic deficiency may occur. Seven cases of GDH deficiency were familial and 5 were sporadic. The former patient group consisted of siblings of either sex, but no parents or offspring were affected. The genetic pattern of the disorder is compatible with autosomal recessive inheritance. Patients with dominantly inherited olivopontocerebellar atrophy or other types of cerebellar or basal ganglia degenerative neurological disorders showed normal GDH activity. Leukocyte GDH was fractionated into "particulate-heat labile" and "soluble-heat stable" components. In the patients the decrease in activity was limited to the "particulate-heat labile" component. A genetic mutation of a GDH "isoenzyme" may occur in some patients with multiple-system degeneration.
In an attempt to provide a common denominator for cognitive deficits observed in cerebellar patients, it has been suggested that they might be secondary to impaired control of attention, a 'dysmetria of attention', conceptually analogous to motor dysmetria. Albeit appealing and quite influential, the concept of attentional dysmetria as a consequence of cerebellar disease remains controversial. In an attempt to test this concept in a direct way, we compared the performance of patients with cerebellar disorders to that of normal controls on tasks requiring either overt or covert shifts of spatial attention. In the first experiment, visually guided saccades, i.e. overt shifts of spatial attention, were elicited. In the second experiment, covert shifts of attention were evoked by the need to discriminate the orientation of a Landolt C observed during controlled fixation and presented in the same locations as the saccade targets in the previous experiment. The allocation of attention was assessed by comparing acuity thresholds determined with and without spatial cueing. The patients exhibited dysmetric saccades as reflected by larger absolute position errors or a higher number of corrective saccades compared to controls. In contrast, the ability to shift attention covertly was unimpaired in the patients, as indicated by a robust improvement in visual acuity induced by spatial cueing which did not differ from the one observed in the controls and which was independent of the range of SOAs (stimulus onset asynchronies) tested. Finally, the individual amount of saccadic dysmetria did not correlate with the individual performance in the covert attentional paradigm. In summary, we conclude that the contributions of the cerebellum to attention are confined to overt manifestations based on goal-directed eye movements.
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Dysarthria due to involvement of the cerebellum represents a facultative symptom of cerebellar disease. The mechanisms by which such dysarthrias are produced are unknown but may result from pathologic involvement of the entire cerebellum. The symptoms of cerebellar dysarthria in children and in adults are described in two case histories. Characteristic speech defects or dysarthrophony occur. In addition to speech pathology, computer tomography of the skull is useful in obtaining both differential diagnosis and an estimate of prognosis. The goal of treatment should be the improvement of muscle defects of tonus and coordination needed for speech, and can employ both physio- and ergotherapy.
The hereditary ataxias, also referred to as the spinocerebellar degenerations, comprise a series of clinical manifestations that include ataxia and dysmetria, resulting from the predominant involvement of the cerebellum and its afferent and efferent pathways. These disorders are system degenerations; many of them are specific entities clearly inherited as autosomal dominant or autosomal recessive traits. Although the clinical manifestations and neuropathologic findings of cerebellar disease dominate the spinocerebellar degenerations, there may also be characteristic changes in the basal ganglia, optic atrophy, retinitis pigmentosa, or peripheral nerve disease. There are many gradations from pure cerebellar manifestations to mixed cerebellar and brain-stem disorders, cerebellar and basal ganglia syndromes, and spinal syndromes or peripheral nerve disease. The clinical picture may be consistent in one family, but sometimes there is a characteristic syndrome in the majority of family members and an entirely different disorder in one or several members.
Hyperventilation can affect nystagmus in patients with vestibular disorders. However, the effects on nystagmus in patients with cerebellar disease have not been systematically studied. Using the magnetic field search coil technique, we studied the effects of hyperventilation on nystagmus in a series of cerebellar patients. In four of eight patients, hyperventilation produced an increase in the slow-phase velocity of downbeat nystagmus. We speculate that this effect may be mediated through metabolic effects on cerebellar calcium channels.
The origin of the generation of saccadic and smooth-pursuit eye movements has not been proved. The goal of the study reported here was to search for the connection of visuooculomotor reactions--saccades and eye-tracking test--with cerebellar damage. Using electronystagmography, we tested 11 patients treated with aminoglycosides because of pneumonia. After a mean of 21 days of pharmacological therapy, a neurological examination revealed cerebellar disability in all cases. On the basis of our previous studies, we suspected cortical Purkinje cell damage. In all tested patients, saccadic movements were disturbed: We observed overshoot, undershoot, and prolonged latencies. In seven patients, eye-tracking test results were not correct: We noted the degradation of the sinusoidal pattern most often. The results pointed to a connection between the generation of these two tested visuooculomotor reactions with cerebellar diseases possibly located in the cortex.
Three patients (two of them siblings) had Leber's congenital amaurosis and cerebellar disease. Despite blindness and severe motor deficits, all three patients have achieved relatively normal intellectual and psychosocial milestones. Computed tomographic scans, performed in two patients, demonstrated hypoplasia of the cerebellar vermis in both. The presence of delayed speech and motor development as well as structural CNS abnormalities in children with Leber's congenital amaurosis does not necessarily imply that severe intellectual impairment will be present.
A 46-year-old man developed sudden dysarthria and atactic gait and was noted to be unable to get up even on the bed about one year prior to his death. By following several days, he started to have scanning speech, nausea, trancal ataxia and dysmetria in succession. The cerebro-spinal fluid yielded moderate pleocytosis. There were no sensory disturbance, pathological reflexes and Romberg's sign. Half a year later, submandibular tumor was noted. The biopsy showed metastatic small cell undifferentiated carcinoma, presumably of pulmonary origin, and paraneoplastic cerebellar degeneration was suspected. He died of bronchopneumonia, superimposed on lung cancer on February 25 in 1979. The necropsy showed a large tumor in the right lung which was histologically verified small cell undifferentiated carcinoma (so-called oat-cell carcinoma). The cerebellum disclosed diffuse cortical atrophy, chiefly of Purkinje cell type. Moderate demyelination with reparative gliosis and foamy macrophages was seen in the white matter, which was considered secondary to cortical devastation. The morphometric study on Purkinje cell loss showed interesting distribution of the lesions. The severely affected portions were the central lobe and culmen in the vermis, and the ala lobuli centralis and quadrangular lobe in the hemisphere, respectively. The lingula was strikingly spared. The finding was compared with that of other cerebellar disease in reviewing the literature.
A pancerebellar syndrome of subacute progression associated with cerebellar atrophy is highly suggestive of a paraneoplastic cerebellar degeneration (PCD). We describe a 27-year-old woman with systemic lupus erythematosus (SLE) that presented with a subacute pancerebellar syndrome. Serum and CSF anti-Yo, anti-Hu and anti-Ri antibodies were not found neither in blood, nor in CSF. Brain MRI showed a cerebellar atrophy. The cerebellar ataxia improved markedly following corticosteroids administration. This case probably demonstrates that an antineuronal antibody negative subacute cerebellar disease may not only be a manifestation of paraneoplastic disease, but that it can also be associated with SLE.
Spasticity in man is presented as a disinhibition of spinal cord mechanisms, the responses to stretch depending on the interaction of the reflex effects of group Ia with those of group II afferent fibres. The reflex responses to muscle stretch and shortening in Parkinson's disease do not depend on an abnormality of spinal reflex mechanisms. The superimposition of physiological tremor or alternating tremor in rigidity produces the classical cog-wheel sensation. The phase lead of the action tonic stretch reflex was found to be reduced in patients with athetosis and cerebellar disease, thus diminishing damping of unwanted movements. The more complex transmission characteristics of the action tonic stretch reflex of normal man are absent in patients with spasticity and cerebellar lesions, presumably due to interference with long-loop pathways. In normal subjects gain of the reflex loop increases with voluntary contraction but in spasticity gain remains high irrespective of contraction level.
The impulsive test is brief and comfortable to the patient. The SVM is the best discriminator of the variables examined. By using percent differences between CW and CCW responses in the same subject at the same stimulus magnitude, we can define a range for the normal population and indicate patients outside that normal range. The impulsive test gives directional information in patients with unilateral lesions. In patients with severe bilateral loss of vestibular function, measurable responses are still obtainable; while in patients with primary cerebellar disease, responses are increased. The test may also be useful in giving anatomic information about posterior fossa lesions.
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We present a of 22 years old patient who has a severe cerebellar disease that started during the first years of life, borderline mental level, epilepsy and Klinefelter syndrome. Brain magnetic resonance (MR) imaging revealed swollen white matter with a loss of signal on T1-weighted slices and an increase in signal intensity on T2-weighted images in both cerebral hemispheres and in both cerebellar dentate nuclei. MRI alterations did not change during the studies performed from 4 to 21 years. Blood and urine were analyzed and showed great elevation of L-2-hydroxyglutaric acid (L-2-HGA) and more discrete elevation of its metabolites and lysine. The parents of the patient are first cousins.
OBJECTIVE: The aim of the study was to examine intracortical excitability in cerebellar patients. METHODS: Short-latency intracortical inhibition (SICI), long-latency intracortical inhibition (LICI) and intracortical facilitation (ICF) to paired transcranial magnetic stimulation (TMS) were investigated in 8 patients with 'pure' cerebellar syndromes and in 14 age-matched normal controls. The conditioning stimulus for short-latency intracortical inhibition and intracortical facilitation was set at 70% of the resting motor threshold (RMT) and preceded the test stimulus (110-120% of the resting motor threshold) by interstimulus intervals (ISIs) of 1-30 ms. For the long-latency intracortical inhibition determinations, the conditioning stimulus was set at 120% of the resting motor threshold and preceded the test stimulus (also 120% of the resting motor threshold) by interstimulus intervals of 30-500 ms. RESULTS: No statistically significant differences were found between patients and controls as regards either short-latency intracortical inhibition or intracortical facilitation. A significant prevalence of long-latency intracortical inhibition was present in cerebellar patients at interstimulus intervals of 200-500 ms (conditioned MEP amplitude=29-41% of test MEP) as compared to controls (71-96% of test MEP). The amplitude of conditioned MEPs was persistently less than 45% of the test MEP in six patients, who were studied at interstimulus intervals up to 1000 ms. CONCLUSIONS: Long-latency intracortical inhibition was prevalent and abnormally longer-lasting in patients. Tonic hyperactivation of a subpopulation of GABAergic interneurons in the motor cortex of patients may be the mechanism responsible for this abnormality. Our findings seem to be specific to cerebellar diseases and are the opposite of those found in movement disorders such as dystonia and Parkinson's disease. These data suggest that the cerebellum and the basal ganglia may have opposite influences in tuning the excitability of the motor cortex.
Findings of a study of 39 sheep with progressive ataxia from 14 farms in the Yass district of New South Wales are described. Microscopic lesions in 25 sheep, 3.5 to 6 years of age, diagnosed as having clinical cerebellar disease, consisted of an apparent primary loss of cerebellar Purkinje neurons, and glial cell accumulation. It is suggested that this previously unreported disorder may be an hereditary cerebellar abiotrophy of Merino sheep. A further 14 sheep, 1 to 4 years of age, had distinguishable clinical signs referable to a spinal cord lesion with widespread segmental axonal ballooning, or "spheroids", in the white matter of the brain and spinal cord. It is suggested that these sheep have a unique form of neuroaxonal dystrophy, described here as segmental axonopathy, and that this is likely to be the same condition described previously as Murrurindi disease (Hartley and Loomis 1981).