Although numerous etiological or triggering factors have been suggested in sudden infant death syndrome (SIDS), the underlying mechanism of death is ultimately cardiac and/or respiratory in nature. As there is no evidence of lung or heart abnormalities, attention has focussed on the neural control of respiration and cardiac function. It is important to appreciate the methodological limitations involved in utilizing autopsy material and the criteria for selection of appropriate controls. This report reviews the pathological evidence for developmental delay in SIDS emphasizing delay of neural maturation of both myelination and synapses. Other abnormalities of the nervous system apparently associated with hypoxia-ischemia such as brainstem astrogliosis are also discussed. The occurrence of SIDS at a precise age together with our preliminary studies indicate that neural developmental delay is an important link in the chain of events leading to SIDS.

In 1971, Andermann and Andermann described an autosomal recessive syndrome found within the Charlevoix and the Saguenay populations (Quebec, Canada) characterized by agenesis of the corpus callosum (ACC) associated with motor and sensory neuropathy, mental retardation and dysmorphic features. A study of CT in 64 patients demonstrated a total ACC in 37 cases (57.8%), partial ACC in 6 cases (9.4%) and the presence of the corpus callosum in 21 cases (32.8%). The latter was confirmed by MRI in 3 cases. CT of patients without ACC revealed a high frequency of developmental or degenerative midline anomalies, particularly interhemispheric fissure enlargement and posterior fossa atrophy. The clinical presentation and the natural course of the neuropathy, the intellectual impairment and the behavioural manifestations are identical amongst individuals with or without ACC. Individuals with or without ACC are found within the same family and often within the same sibship. These observations support the hypothesis of a single genetic syndrome in which the constant manifestation is the motor and sensory neuropathy.

Positron emission tomographic (PET) data on local cerebral metabolic rates for glucose (LCMR) are reported for 32 regions of interest (ROI)s in cross-sectional studies on 57 patients with clinically diagnosed Alzheimer's disease (AD) and 20 neurologically normal controls, and in serial studies on 13 of the AD cases, including a familial, young-onset case where the diagnosis has been confirmed at autopsy. Extensive psychological testing was done on all the AD cases. Almost all cortical regions showed a significant decline in LCMR with age in the control subjects. There were the expected cortical metabolic deficits in AD and the serial studies showed a general increase in such deficits over time in 12 of the 13 cases. The regions showing the greatest declines with time in serial studies are the same as those showing the most severe deficiencies in cross-sectional studies. The young-onset case did not show a greater rate of metabolic decline than many of the older cases studied. Results on individual psychological tests tended to correlate with metabolic rates in multiple, rather than single, cortical regions, suggesting intact neuronal networks are required for good performance. The correlations with cortical metabolic activity found were of a sign indicating that the higher the metabolic rates and the better the left:right asymmetry index, the better was the performance.

We report two cases of Alzheimer disease (AD) — one of them familial — in which the patient also had amyotrophic lateral sclerosis (ALS), and one patient with familial AD who had a son with ALS. Three further cases of probable ALS were found in pedigrees of AD reported from the literature. It is proposed that this association is not coincidental, but may suggest an etiological factor in common.

The contribution of the cerebellar cortex to coordination of a multi-joint throwing movement was studied by measuring various movement and EMG parameters while normal control subjects and patients with cerebellar cortical atrophy threw a ball at a target. Although patients did not throw as accurately as controls, several coordination measurements were normal in the patients. These included parameters used by us to assess elbow-wrist coordination and the coordination of hand opening with activation of more proximal arm muscles. Postural support for the movement at the shoulder was also normal in that the shoulder was not pushed backwards by the reaction forces resulting from the rapid forward acceleration of the forearm and hand. In contrast, however, patients were unable to coordinate the muscles so as to produce the same hand direction from trial to trial when throwing at the same target. In addition, EMG onset times were abnormal in the antagonist muscles relative to agonist EMG bursts and kinematic parameters of the movement. In conclusion, our patients with cerebellar cortical atrophy showed abnormalities in visual-motor coordination, in that they were unable to consistently produce the appropriate hand direction in response to a visual target. Agonist-antagonist relationships were also impaired. Other aspects of coordination, such as the relative timing of EMG onsets of agonist muscles, even when these were active at different joints, were normal.

Vastus lateralis muscle biopsies of four unrelated male neonates showing myotubular (i.e. centronuclear) myopathy (MM) were compared with muscle from four human fetuses in the myotubular stage of development, a 31 week preterm infant and four term neonates. The perimysium, blood vessels, spindles, myelinated intramuscular nerves, and motor end-plates in MM are as well developed as in term neonatal muscle. The cytoarchitecture of myofibres in MM is more mature than that of fetal myotubes in the spacing of central nuclei, Z-band registry, development of the sarcotubular system, and in the condensation of nuclear chromatin and nucleoli. Triads in MM may retain an immature oblique or longitudinal orientation. Myofibrillar ATPase shows normal differentiation of fibre types, consistent with nonnal innervation. Spinal motor neurons are nonnal in number and in RNA fluorescence. Immunoreactivity for vimentin and desmin in myofibres of MM is uniformly strong, as in fetal myotubes and unlike mature neonatal muscle. Maternal muscle biopsies of two cases also showed scattered small centronuclear myofibres reactive for vimentin and desmin. The arrest in morphogenesis of fibre architecture in MM is not a general arrest in muscle development. Persistence of fetal cytoskeletal proteins that preserve the immature central positions of nuclei and mitochondria may be important in pathogenesis. Vimentin/desmin studies of the infant and maternal muscle biopsies are useful in establishing the diagnosis.

The effect of hypervolemic-hemodilution, with and without hypertension, on blood-brain barrier permeability was investigated in rats, after 180 minutes of middle cerebral artery occlusion (MCAo), and 60 minutes of reperfusion. One of the following conditions was maintained during MCAo: 1) Control — hematocrit and blood pressure were not manipulated; 2) Hypervolemic-Hemodilution/Normotension — the hematocrit was decreased to 30%; 3) Hypervolemic-Hemodilution/Hypertension — the hematocrit was decreased to 30% and mean arterial pressure increased by 30 mmHg with phenylphrine. In all groups, Evans Blue was administered, and its concentration determined by spectrophotometric assay. Evans Blue (μg{g-1 of brain tissue [mean ± SD]) was greater in the Hypervolemic- Hemodilution/Hypertension group (71 ± 20) versus the Control (13 ± 9) and Hypervolemic-Hemodilution/ Normotension (17 ± 10) groups (p < 0.05). No other differences were present. These results support the hypothesis that during MCAo, hypervolemic-hemodilution/hypertensive therapy effects an increase in blood-brain barrier permeability in the early period of reperfusion.

Weakness of distal muscles of one upper limb which progresses over 1 year and then appears to arrest (“monomelic amyotrophy”) has been reported mainly in Japan and India. We report 5 cases of a similar syndrome occurring in Canada. In our cases the wasting affected the forearm muscles of one upper limb (sparing brachioradialis and extensor carpi radialis). There was minimal wasting and electromyographic changes in the opposite upper limb. The CT myelogram showed unilateral wasting of the cervical cord.

Manual tracking performance was studied in five patients with cerebellar incoordination due to unilateral cerebellar hemisphere lesions. The subjects were required to track a target on an oscilloscope screen by moving a cursor controlled by flexion-extension movements of the wrist. In comparison to normal subjects, the cerebellar patients, using their clinically affected arm, demonstrated irregular tracking patterns with inappropriate accelerations and decelerations, numerous high velocity peaks of movement, and an increased time lag between the cursor and the target.

The addition of a viscous load provided by feeding back wrist velocity to a torque motor coupled to the apparatus resulted in significant improvement in tracking performance and suppression of the high velocity peaks. Increasing elastic stiffness by feeding back wrist position or inertial load by adding weights to the hand did not improve performance on this task. It is proposed that a hypotonic cerebellar limb behaves like an underdamped mechanical system. The addition of viscous loads helps restore more normal damping during voluntary movements of the arm.

Evidence for the astrocytic lineage in medulloblastomas rests largely on the detection of the glial fibrillary acidic protein (GFAP) from which intermediate filaments (IF) specific for astrocytes are assembled. Astrocyte progenitor cells from the mouse neopallium however express another IF protein, vimentin, before they acquire GFAP in vivo and in vitro. The purpose of the current study was to determine if cells obtained from a focally GFAP-positive posterior fossa medulloblastoma previously shown to acquire GFAP in response to dibutyryl cyclic AMP (dBcAMP), also express vimentin before expressing GFAP. More than 80% of cells in the tumor section contained vimentin while fewer than 1% of cells contained GFAP; occasional clusters of malignant GFAP-positive cells and clusters of cells negative for both vimentin and GFAP were also identified in the tumor. One hundred per cent of cultured cells in the first 10 passages from the tumor contained vimentin and no cells expressed GFAP. When cells were cultured in the presence of dBcAMP, Western immunoblotting showed an increase in vimentin which reached maximal values within 24 h followed by an increase in GFAP which reached maximal values at 72 h. The increase in vimentin followed by that of GFAP in cultured medulloblastoma cells has not previously been reported and suggests that most astrocyte progenitors which are derived from medulloblastoma and cultured in vitro may be at a developmental stage which corresponds to the proastroblast stage in the developing mouse brain. Most medulloblastoma cells in tumor sections in which vimentin is present but GFAP is absent may be in maturation arrest in vivo at the proastroblast stage of normal astrocyte development while vimentin and GFAP-negative islands of cells may represent astrocyte progenitor cells at an earlier stage of differentiation (e.g. glioblasts).

The clinical histories and pathological findings of 27 autopsied cases of orthotopic liver transplantation (OLT) were reviewed. Fatal OLT was complicated in 93% of cases by neurological dysfunction, usually manifested by encephalopathy, with or without seizures. The etiology of the encephalopathy was largely multifactorial (44%) or undetermined (20%). Subarachnoid hemorrhage, central pontine myelinolysis, meningitis, brain infarction, polyclonal B cell lymphoma and spinal cord necrosis were common neuropathological findings. These diagnoses were often masked by other systemic illnesses. The role of cytomegalovirus (CMV) in neurologic dysfunction was explored with in situ hybridization and immunohistochemical techniques. OLT cases showed a significantly higher (89%) frequency of CMV genomic material in brain tissue compared to age-matched non immunocompromised (NIC) patients (23%). All OLT cases with encephalopathy of undetermined cause demonstrated unusually prominent hybridization to the CMV probe. CMV may be an important cause of encephalopathy in such patients.

Normal pituitaries, pituitaries showing CHC and selected adenomas were assessed for their possible content of intermediate filaments (IF), using immunohistochemical techniques. Normal pituitaries were stained for each of the five known IF (Cytokeratins (CK), glial fibrillary acidic protein (GFAP), desmin, vimentin, and neurofilaments (NF)). Desmin could not be demonstrated, and NF staining was limited to processes in the posterior gland. In serial sections, CK was demonstrated in some corticotrophs, somatotrophs, and lactotrophs. Vimentin was limited to processes in the posterior gland. Folliculo-stellate cells (FSC), demonstrated by staining for SlOO protein, exhibited a small subpopulation staining for CK, and another subpopulation staining for GFAP. GFAP was also demonstrated in glial processes in the posterior gland. Cells showing Crooke's hyaline change stained intensely for CK. Null cell adenomas did not stain for CK. Corticotroph adenomas, somatotroph adenomas, with or without fibrous bodies, and lactotroph adenomas contain CK-immunoreactive cells. We conclude that CK is the major IF present in the anterior pituitary gland, within some normal corticotrophs, somatotrophs and lactotrophs, and also in adenomas derived from these cells.

The National Cancer Institute of Canada Clinical Trials Group conducted a phase II trial of trimetrexate given in a daily × 5 intravenous bolus schedule every 3 weeks in patients with measurable recurrent anaplastic glioma and limited prior treatment. There were no responses in 14 evaluable patients. We conclude that trimetrexate, given as described, is not an active agent in this disease.

We examined the role of the environment in the development of Parkinson's disease (PD). A group of 42 parkinsonians have been compared with a group of 84 matched controls. The epidemiological study (1987-1989) covered the territory of the Community Health Department of Valleyfield, in southern Quebec (Canada). Odds ratio adjusted for age and sex were calculated for seven environmental factors. A decreased risk for PD was associated with residence in rural areas (OR: 0.31; p ≤ 0.05) and residence near industry or mining (OR: 0.15; p ≤ 0.05). An increased risk for PD seems to be associated with occupational exposure to the three metals Mn, Fe and Al (OR: 2.28; p = 0.07) especially when the duration of exposure is longer than 30 years (OR: 13.64; p ≤ 0.05). Other environmental factors not found to be associated with PD were: pesticides manipulation, farm work, industrial work and well water consumption.

HLA class II DRBI, DQB1 and DQA1 gene probes were used to study DNA from unrelated French Canadian multiple sclerosis (MS) patients and controls by restriction fragment length polymorphism (RFLP) analysis. An MS-associated and linked series of allele-specific RFLPs or allogenotypes was identified among this relatively homogeneous ethnic group; the allogenotypes include DRwl5, DQw6 and a DQA1 allogenotype termed DQαlb. An additional allogenotype which cross-hybridizes with DQA1 and is termed DQA2 upper (DQA2U), was shown not only to be part of the MS-associated extended haplotype, but also to be independently associated with MS in DRwl5-negative patients. Conversely a second DQA2 allogenotype, termed DQA2 lower (DQA2L) and a DQB1 allogenotype (DQw7) linked to DQA2L showed negative correlations with MS. It seems likely that the relationship of the HLA class II gene region to MS is complex and that MS susceptibility may reflect interaction between disease susceptibility and resistance genes.

Once diagnosed to have MS, relatives of persons who have been previously diagnosed frequently ask whether their disease course will follow that of their relative(s) with MS. The present study compared the following clinical manifestations of MS among 43 index cases and 47 of their relatives, all of whom were diagnosed to have MS and regularly attended the MS Clinic in Vancouver, British Columbia: (i) age of onset of MS, (ii) clinical course, (iii) lesion site(s) and (iv) initial symptom(s) of MS. The results from the present study are preliminary because of the small size of the study group. However, these data suggest that apart from possibly age of onset between sibling pairs, the clinical manifestations of MS are not correlated among relatives who are assessed according to the same methodology. This is significant for counselling newly diagnosed relatives of longstanding MS patients.

Intracortical microstimulation (ICMS) was used to map the primary motor cortex of four adult female baboons, anesthetized with a mixture of halothane and nitrous oxide and supplemented with sodium pentobarbital. The sequence of observed muscle contractions in response to ICMS provided evidence of an orderly mototopic representation of the tongue, face, hand, forearm and upper body. A zone of cortex unresponsive to microstimulation was consistently observed at the border between the face and hand representation of the mototopic map. This zone was observed in all four animals and was consistent over time. Repeated confirmations of the unresponsive nature of these regions were obtained both early and late in the same experiment. No motor-unit responses or muscle contractions were detected by electromyographic (EMG) recording during stimulation of the unresponsive zones. The absence of both visually observed and EMG-recorded contractions and the fact that muscle contractions could be elicited from adjacent regions of cortex with ICMS as low as 1-5 μA provide compelling evidence that the finding reflects a true physiological condition rather than an experimental artifact.

Deficits in visuospatial cognition are frequently cited as an important component of the cognitive changes accompanying Parkinson's disease. To characterize possible differences between Parkinson's (PD) and Alzheimer's (AD) dementia, patients from both groups, matched for overall dementia severity, age and education, were contrasted neuropsychologically. Visuospatial tasks dissociated from memory, were significantly compromised in both patient groups. Differential impairment was evident on visuospatial abstraction and reasoning (Object Assembly), which was most deficient in PD. Visuospatial cognition associated with memory, classified both patient groups as impaired compared to controls, but AD patients demonstrated substantially lower performance levels than those with PD. Parkinsonian dementia thus appears to have some distinct features compared to Alzheimer's disease, which may indicate differences in underlying pathogenic mechanisms.

A patient with tardive dyskinesia dominated by pelvic thrusting movements is described. A retrospective review of the clinical features documented in patients with metoclopramide- and antipsychotic-induced tardive dyskinesias seen over a six year period demonstrated that the occurrence of pronounced pelvic thrusting and respiratory dyskinesias were significantly more common in the metoclopramide treated group. The occurrence of bucco-linguomasticatory movements, limb stereotypies or chorea, and mild truncal or abdominal rocking were not significantly different between the two groups. None of the tardive dystonia patients had metoclopramide as the causative agent. These findings will require confirmation in larger, better matched patient populations. Whether the differences relate to different pharmacologic profiles of drug action, patient populations exposed, or other factors, remains to be elucidated.