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.

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.

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.

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.

This study presents the clinical characteristics of 8 victims of multiple sclerosis from the hamlet of Henribourg, Saskatchewan with a population of less than 75 people. A diligent victim of the disease had observed that six female classmates from the early 1940's had later developed multiple sclerosis. Two male military personnel who had also resided briefly in close proximity, during the same common exposure time, also later developed multiple sclerosis. The mean onset time of developing the disease after leaving the area was 20 years. This cluster-focus suggests a common exposure to an environmental factor or a common infective agent in the etiology of multiple sclerosis.

The mechanism for the preferential distribution of emboli to cerebral arterial bordcrzone regions, known to cause some watershed infarcts was studied. We hypothesized that emboli of a specific size range are selectively directed to the arterial borderzones due to the tendency of emboli to bypass the small arterial branches which emerge proximal to major borderzones. To test this hypothesis we perfused the brains of cadavers with suspensions of 90-210 µm glass microspheres and chemically extracted the particles from various arterial territories and a watershed zone. Particles in the 150-210 µm size range were found to be preferentially distributed to the watershed zone whereas particles less than 150 µm in size were randomly dispersed in leptomeningeal arteries of all vascular regions. To assess the role of branch size on the concentration of emboli at bifurcations, we perfused artificial analogs of evenly and unevenly branching bifurcations with suspensions of 90-150 µm and 150-210 µm particles. Branching cylinders with symmetrical branches contained the same concentration of particles, independent of particle size. In contrast, when one branch was one-quarter the size of the other, the concentration of 150-210 µm particles in the asymmetric branch was approximately 65% of the main trunk. Particles 90-150 µm in size were evenly distributed despite variation in branch size. These results indicate that emboli, of a limited range of size, may be selectively propagated to the distal ramifications of subarachnoid arteries located in the watershed zone rather than diverging into small calibre branches which arise along the way.

Seventeen patients with petrous meningiomas managed at St. Michael's Hospital, during the years 1973-1987, were retrospectively reviewed. There were 15 females and 2 males; their ages ranged from 42 to 68 years (mean age: 53 years). The clinical presentation most commonly included headache and eighth cranial nerve dysfunction; the average duration of symptoms was 6 years (3 month - 27 years). Computed tomography was performed in 15 cases. The mean tumour size was 2.5 centimeters (0.5 - 4 cm). The most common site of tumour origin was at or medial to the poms acousticus. Meningioma was suspected preoperatively in 10 of the 15 patients who had preoperative CT scans. Complete excision was obtained in 12 cases. There were no operative deaths after initial resections. Postoperative morbidity included worsening of pre-existing hearing loss in six patients, transient facial nerve palsies in six, permanent facial nerve palsies in four and new facial or corneal hypesthesia in three. Two patients developed cerebrospinal fluid fistulae. Tumour recurrence occurred into two patients in whom a complete resection was anticipated. Also, in two patients with incompletely resected tumours second operations were required. Fourteen patients are alive, 13 of whom care for themselves independently. The average follow-up was 5 years (6 months - 9 years). It seems appropriate to recommend initial radical surgical excision of these benign tumours, where possible, in order to prevent tumour recurrence.

Central type benzodiazepine receptors were studied in 9 patients with Friedreich's ataxia and 12 healthy subjects using positron emission tomography (PET) and [11C]Ro 15-1788, a specific antagonist of the central type benzodiazepine receptors, as radioligand. A standard PET procedure was used in 5 patients and 8 controls to obtain brain kinetics of the total binding of the radioligand. The remaining subjects were intravenously injected with a saturating dose of unlabeled Ro 15-1788, 30 minutes after the tracer injection, to determine the nondisplaceable binding of [11C]Ro 15-1788. A semi-quantitative method was used to quantify the [11C]Ro 15-1788 data. None of the quantification indices in the cerebellar hemispheres, or in the other brain areas investigated, was significantly modified in patients with Friedreich's ataxia. These findings suggest that brain benzodiazepine receptors are unaffected in Friedreich's ataxia.

Eight patients with myotonic dystrophy underwent comprehensive neuropsychological testing and overnight polysomnography to assess whether the waking cognitive impairment might be attributable to sleep structure abnormalities or to sleep-related respiratory problems. Patients showed substantial neuropsychological deficits, fragmented nocturnal sleep and, in half the patients, sleep apnea and/or hypopnea both mainly of central type. There was no statistically significant correlation between the degree of daytime cognitive deficit and the degree of sleep fragmentation or of respiratory problems at night. It was concluded that the neuropsychological deficit in mytonic dystrophy cannot be attributed to a secondary effect of nocturnal sleep apnea or sleep disruption but probably represents a direct effect of CNS lesions.

CQA 206-291, a new ergot derivative with a “biphasic” dopaminergic profile, was studied in 6 patients with longstanding Parkinson's disease suffering from pronounced fluctuations in hourly mobility. On alternate days, up to seven single doses, escalating from 0.2 to 20 mg, were given as replacement for the usual first morning dose of levodopa. At the most effective dosage, four of the six patients obtained as good a peak response to CQA (8-20 mg) as to L-dopa. Side effects were common and similar to other ergot derivatives, suggesting that the initial weak dopamine antagonist properties of the parent compound, documented in animals, may be of little clinical significance. However, comparative studies will be needed to confirm this suspicion. The addition of domperidone successfully reduced the incidence and severity of side effects. CQA 206-291 has potent anti-parkinsonian properties; further longer-term treatment trials are indicated.

Immunohistochemical stains for cytokeratins, vimentin, epithelial membrane antigen, carcinoembryonic antigen and S-100 were performed on nine ecchordoses and 10 chordomas. 100% of the ecchordoses were positive for cytokeratin, vimentin and epithelial membrane antigen. 78% were S-100 positive. 100% of the chordomas stained positively for cytokeratin, vimentin and S-100 and 90% were positive for epithelial membrane antigen. No ecchordosis or chordoma was carcinoembryonic-antigen positive. These findings are interesting for two reasons. First, the similar staining properties of chordoma and ecchordosis physaliphora support the embryologic hypothesis of their common origin from the fetal notochord. Second, they indicate that when an ecchordosis causes symptoms prompting surgical resection, differentiation of the lesion from chordoma with routine immunohistochemistry would not be helpful.

Two patients with congenital anomaly of the craniovertebral junction causing disabling hemifacial spasm (HFS) are presented. In one patient, complete cessation of the HFS occurred for a period of two years following simple bony decompression of the craniovertebral junction raising unanswered questions as to the exact pathogenesis of HFS. Eventually both patients required microvascular decompression at the root entry zone of the facial nerve.

Guamanian amyotrophic lateral sclerosis with parkinsonism-dementia (ALS/PD) has been the subject of intensive study since its discovery in 1947 because of its extraordinarily high incidence in a small ethnic group (Chamorros) whose dietary lack and customs have suggested possible causes. As yet, these and other suspected causes have eluded proof. Because of marked similarities between Guamanian ALS/PD and late onset post-encephalitic (encephalitis lethargica) parkinsonism and ALS it is suggested that they have a common cause. The parkinsonism and ALS in the two disorders are clinically very similar and neuropathological studies have shown a very similar distribution of neurofibrillary tangles in neurons. Some clinical differences, such as ocular features in the post-encephalitic cases and dementia in Guamanian ALS/PD, can be explained by differences in the severity of infection and the interval between the encephalitis and onset of sequelae. Although unproven, influenza A (HswilNl strain) has long been suspected as the cause of encephalitis lethargica because of simultaneous pandemics of the two diseases in the 1920s. Because influenza A can persistently infect cells and has a marked propensity to mutate it is an optimal candidate among other RNA viruses for delayed nervous system infection as a possible cause of ALS/PD.

Canadians are suing their doctors for malpractice, at three times the rate they were 15 years ago, and during that period awards to injured patients have quadrupled in size. Since the middle 1970's when the first medical malpractice “crisis” occurred in the United States, Canadian clinical neuroscientists have felt increasingly threatened by the prospect of a lawsuit for negligence. Since medicine is intrinsically a risk taking business, adverse outcomes are inevitable. Nevertheless, accusations of negligence and carelessness set out in a Statement of Claim causes considerable stress for the defendant physician, who frequently reacts with self-doubt, depression and aggressive behaviour. A “tort” is defined as a wrongful act, and the 4 elements comprising the tort of medical malpractice are: a breech of standard care, the breech was the proximate cause of the injury, the injury produced measurable damage, and it was foreseeable that the injury would have been less injurious to the patient if the caregiver had conducted a different course. In order to put these issues into current perspective, this symposium was convened as part of the XXIV Canadian Congress of Neurological Sciences, held in Ottawa June 17, 1989.