Most descriptions treat the cerebellum as a uniform structure, and the possibility of important regional heterogeneities in either chemistry or physiology is rarely considered. However, it is now clear that such an assumption is inappropriate. Instead, there is substantial evidence that the cerebellum is composed of hundreds of distinct modules, each with a precise pattern of inputs and outputs, and expressing a range of molecular signatures. By screening a monoclonal antibody library against cerebellar polypeptides we have identified antigens – zebrins – that reveal some of the cerebellum’s covert heterogeneity. This article reviews some of these findings, relates them to the patterns of afferent connectivity, and considers some possible mechanisms through which the modular organization may arise.

Parkinsonian features, notably resting tremor may be seen in some essential tremor patients but the significance of those is unknown. The reported risk of parkinsonism in essential tremor patients varies from being unchanged to 35 times higher than expected. We studied 9 patients with essential tremor who had autopsies. In 6 of the 9 (66%) resting tremor was noted and in 3 (33%) cases fully developed parkinsonism was noted. The parkinsonism was consequent to neuroleptic usage in 2 and to basal ganglia status lacunaris and cribrosus in one case but no consistent abnormalities were noted in 3 essential tremor only and 3 essential tremor plus resting tremor cases. We conclude that resting tremor is an age-related natural evolution in some essential tremor patients. We recommend that the additional diagnosis of parkinsonism in the essential tremor be made only when resting tremor, bradykinesia and rigidity are all evident. The risk of ideopathic Parkinson's disease in essential tremor cases is similar to the general population.

As survival rates for childhood acute lymphoblastic leukemia have increased, concerns over improved quality-of-life have also increased. Although 3-10% of children may experience acute transient neurotoxicity during induction chemotherapy, they are felt to be at low risk for late sequelae. We report three previously healthy boys with newly-diagnosed acute lymphoblastic leukemia who presented with obtundation and severe seizures during late induction with a standard four drug chemotherapy regimen. While all three are disease-free survivors, they unexpectedly have persistent and medically intractable partial complex seizures, broad-based neuropsychological impairment and striking neuroimaging abnormalities. These findings suggest that children with leukemia who develop an acute encephalopathy during induction chemotherapy are at risk for long-term neurological and neuropsychological sequelae, despite the cessation of further potentially neurotoxic therapy.

Parkinson’s disease prevalence rates were examined for the Province of Alberta by age, sex and census division. Using the claims administrative data from the Alberta Health Care Insurance Plan, a cohort of all registered individuals (2.4 million) was extracted and followed for the five year period, April 1, 1984 to March 31, 1989. No new members were added to the cohort and an attrition rate averaging 6% per year was observed. The overall crude prevalence rates of 248.9 and 239.8 per 100,000 population were noted for males and females respectively. Both sexes were found to have a statistically significant variation across Alberta’s 19 census divisions. For males, examination of standardized morbidity ratios found a low risk of Parkinson’s disease associated with five census divisions, of which two contained Alberta’s two largest cities. An excess risk was associated with four primarily rural census divisions. Females, on the other hand, had a low risk associated with one rural census division and excess risk in four census divisions. The uneven distribution within Alberta offers support for an environmental theory of etiology which may be associated with rural living.

Quantitative immunogold cytochemistry at the electron microscopic level was used to assess the endogenous contents of glutamate, aspartate, homocysteic acid, and glutamine (a precursor of glutamate) in the cerebellar climbing fiber terminals. Of the three excitatory amino acids, only glutamate appeared to be enriched in these terminals. The climbing fiber terminals also displayed immunoreactivity for glutamine. The level of aspartate immunoreactivity was far higher in the nerve cell bodies in the inferior olive than in their terminals in the cerebellar cortex. Homocysteic acid immunolabelling was concentrated in glial cells including the Golgi epithelial cells in the Purkinje cell layer. Our immunocytochemical data indicate that glutamate is a more likely climbing fiber transmitter than aspartate and homocysteic acid.

Motor evoked potentials (MEPs) were recorded from selected non-wasted, non-denervated hand muscles in 40 patients with Amyotrophic Lateral Sclerosis (ALS) with both upper and lower motor neuron signs. In most the compound muscle action potential (CMAP) of the target muscle was normal. Compared to the control group, cortical threshold in ALS varied considerably and there was a significant (r2 = 0.702) inverse, exponential, correlation between cortical threshold and MEP/CMAP ratio. There was a linear correlation between threshold and disease duration (r2 = 0.66) so that early in the disease threshold was normal and later the motor cortex could not be stimulated. It is suggested that early in ALS normal threshold reflects glutamate-induced hyper-excitability of the corticomotoneuron. The findings lend support to the hypothesis that ALS is primarily a disease of the corticomotoneuron.

The results obtained with neuronal grafting in an animal model of heredo-degenerative ataxia (the pcd mutant mouse) have been extremely useful to unmask new aspects of neural plasticity. The grafted embryonic Purkinje cells invade the deficient molecular layer of the host by migrating radially through adult Bergmann fibers. There, they start building their dendritic trees and, by promoting the axonal sprouting of specific adult neuronal population in a timed sequence, they receive appropriate synaptic contacts, starting ten days after grafting. Twenty-one days after grafting, the grafted Purkinje cells have acquired their adult dendritic pattern and synaptic investment. Both the detailed timetable and the nature of the cellular interactions between embryonic and adult neural cells are remarkably similar to those occurring during normal development. These results raise the possibility that embryonic Purkinje cells can induce in adult neural cells a new type of plasticity, that of recreating a permissive microenvironment for the synaptic integration of the grafted neurons, leading to the anatomical restoration of the cortical circuit of the mutant cerebellum.

Clinical differentiation between forms of progressive dementia can prove difficult, particularly when relatively rare forms of dementia are involved. Factors such as family history of dementia, age at onset, presenting features such as personality change, cognitive deficits, psychiatric symptoms, and clinical course (progressive deterioration; retention of skills over time) may prove useful for directing investigations to identify underlying pathology and genetic implications. This is illustrated by two patient reports. Each patient had the onset of memory/behavioral problems at approximately age 40 years, was initially given a psychiatric, non-dementing diagnosis, and had a positive family history for early onset behavioral and memory problems. After longitudinal assessment, the diagnosis of Alzheimer disease was confirmed at autopsy in one patient and a diagnosis of familial, adult-onset metachromatic leukodystrophy in the other.

We investigated the serum fatty acid profiles of cholesterol esters, phospholipids and triglycerides in 24 patients with Friedreich's disease and 16 patients with other forms of spinocerebellar degeneration. In 8 patients with Friedreich's disease we also analyzed the fatty acid profile of the lipoprotein fractions. We found no major differences in fatty acid profiles between ataxic patients and sex and age-matched controls; in particular there was no decrease of linoleic acid in Friedreich's disease. The level of linoleic acid in serum cholesterol esters decreased with increasing disability of patients.

A retrospective study of patients with cerebrospinal fluid shunt infections was undertaken from 1975 to 1989 in a university hospital. The data were analyzed with emphasis on the choice of treatment and outcome. There were 44 infectious episodes in 38 patients for an overall rate of 2.6%, including 30 ventriculoperitoneal, 11 ventriculoatrial and 3 lumboperitoneal shunts. The most frequently isolated pathogens were staphylococci in 61% of the cases followed by gram-negative bacilli in 25%. Different modalities of treatment were used: support (2), intravenous antibiotics alone (6), intravenous antibiotics and shunt revision (3), intravenous antibiotics and shunt removal with or without prior externalization of the distal end (33: 13 + 20). The cure rate was 94% (31/33) with this last modality of treatment. Only 3 patients received intraventricular antibiotics. All deaths occurred in patients treated with support only (2) or with antibiotics alone (1). Four of the six recurrent episodes occurred in patients treated with antibiotics alone (2) or with a shunt revision (2). We conclude that carefully chosen intravenous antibiotics combined with shunt removal preceded or not by externalization of the distal end as an alternative therapy to repeated ventricular taps or insertion of an external ventricular drainage device is an appropriate therapy.

The decisive conclusions to be drawn from the available epidemiological data, mostly geography and prevalence, of MS are: (1) a north-south (as well as west-east in the United States) gradient exists independent of genetic/racial factors; (2) major differences in prevalence occur in the absence of latitude differences; (3) individuals from the same ethnic derivation have either similar prevalence rates or very different prevalence rates in widely separated geographical areas and (4) specific resistant isolates are shown to exist regardless of latitude. Existing information leads to the almost inescapable conclusion that the epidemiology of MS cannot be explained by any single known environmental or genetic factor(s) in isolation. A combination of a heterogeneous distribution of both genetic and environmental factors appears to be required to explain the available data on MS.

The activity of single cells in the cerebellar and motor cortex of awake monkeys was recorded during separate studies of whole-arm reaching movements and during the application of force-pulse perturbations to handheld objects. Two general observations about the contribution of the cerebellum to the control of movement emerge from the data. The first, derived from the study of whole arm reaching, suggests that although both the motor cortex and cerebellum generate a signal related to movement direction, the cerebellar signal is less precise and varies from trial to trial even when the movement kinematics remain unchanged. The second observation, derived from the study of predictable perturbations of a hand-held object, indicates that cerebellar cortical neurons better reflect preparatory motor strategies formed from the anticipation of cutaneous and proprioceptive stimuli acquired by previous experience. In spite of strong relations to grip force and receptive fields stimulated by preparatory grip forces increase, the neurons of the percentral motor cortex showed very little anticipatory activity compared with either the premotor areas or the cerebellum.

Over a period of 12 years, 80 patients underwent ventricular shunting for normal pressure hydrocephalus. Three developed sixth cranial nerve palsy in the first two weeks after surgery. This uncommon complication is usually transitory following the same pattern of abducens palsy after lumbar puncture or spinal anesthesia. Traction on the nerve with local ischemia has been involved as the responsible mechanism in both instances.

The effect of hemodilution, with α-α cross-linked hemoglobin (DCLHb), on brain injury and edema was assessed after temporary middle cerebral artery occlusion in rats. Injury was analyzed with 2,3,5-triphenyltetrazolium chloride (TTC) stain and edema by microgravimety. Part A: DCLHb was given to maintain one of the following hematocrits (Hct) and normotension: 1) 45/Hct, 2) 30/Hct, 3) 16/Hct, or 4) 9/Hct. Brain injury (% of ischemic hemisphere, mean ± SD) was less in the 30/Hct group (31 ±4) versus the 45/Hct group (42 ± 5); and in the 16/Hct (20 ± 3) and 9/Hct (19 ± 4) groups versus the 45/Hct and 30/Hct groups. Edema was less in the hemodiluted groups versus the 45/Hct group. Part B: DCLHb was given to maintain one of the following hematocrits and hyper (HTN) − or normotension (Norm): 1) 45/Norm, 2) 30/Norm, 3) 30/HTN, 4) 16/Norm, or 5) 16/HTN. In hematocrit matched groups hypertension decreased brain injury (30/HTN − 24 ± 2 < 30/Norm − 34 ± 4; and 16/HTN − 17 ± 3 < 16/Norm − 24 ± 4). Edema was not effected by hypertension. These results suggest that hemodilution with DCLHb decreases focal ischemic injury, and is most effective when given in a manner that induces hypertension.

Glutamate excitotoxicity is implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). We report the results of a double blind, placebo controlled, trial using 100 mg of oral daily lamotrigine (3,5-diamino-6-(2,3 dichlorophenyl)-l,2,4-triazine) which inhibits glutamate release. 67 patients were entered and at trial termination of 1.5 years 15 had withdrawn (9 active and 6 placebo) and 12 had died (6 active and 6 placebo). Mean age at entry was 57.5 years for the active and 58.6 years for the placebo groups. Patients were seen at 3 monthly intervals and scored according to neurological deficit based upon age of onset, bulbar and respiratory involvement, ambulation and functional disability. The mean change in clinical scores for the active versus placebo groups over the trial period was 7.1 ± 3.3 and 9.0 ± 3.3 respectively (0.05 < p < 0.10). Changes in cortical threshold and MEP/CMAP ratios to magnetic stimulation also did not differ significantly between the two groups. We conclude that lamotrigine in the doses administered does not alter the course of ALS.

In order to determine the usefulness of Computerized Tomography (CT) scanning in making a diagnosis of dementia of the Alzheimer type, a group of patients diagnosed by NINCDS - ADRDA criteria (n = 22) were compared to a group of normal subjects (n = 49) using certain defined linear CT scan measurements. These measurements included specific measurements of the temporal lobes (temporal horns). Subjects were classified correctly 91.5% of the time with a high degree of probability. A diagnostic equation is presented which will allow testing of these methods in a prospective fashion.