This paper reviews our recent studies on the mechanism of cerebral vasospasm following subarachnoid hemorrhage (SAH) in monkeys. Middle cerebral artery (MCA) vasospasm was maximal at 7 days, resolving by 14 days, and absent at 28 days after SAH. Arterial fibrosis was not detected during vasospasm, although there was intimal hyperplasia with fibrosis 28 days after SAH. On scanning electron microscopy, smooth muscle cells from vasospastic arteries had corrugated cell membranes and appeared similar to cells contracted pharmacologically, suggesting that vasospastic smooth muscle is contracted. Morphometric analysis of arteries obtained 7 days after SAH showed no significant increases in arterial wall area of vasospastic arteries compared with normal MCAs. The results suggest vasospasm in monkeys is not due to hypertrophy, hyperplasia, or fibrosis in the arterial wall. Vasospasm may be mainly vascular smooth muscle contraction, which damages the arterial wall, leading to secondary structural changes in the arterial wall which occur after angiographic vasospasm.

Parkinson syndrome (PS) is a common disorder in the North American population. The annual incidence rate is 20.5/100,000 population and the mean survival after onset is approximately 12.3 years. The estimated prevalence rate is about 300/100,000 population. The incidence and prevalence rates rise with advancing age. Both the widespread use of levodopa and the improved health care in general have increased the longevity in PS. The survival in PS from the time of the first clinic visit is still significantly shorter when compared with the regional age and sex matched population. The cause of IPD may be related to some environmental factor(s) – most likely a toxin. Genetic factors are not the cause but in some families, may predispose to IPD.

Transient forebrain ischemia was induced in rats whose brain temperature was 31, 33, 35, 38, or 40°C. The development of regional injury was followed using magnetic resonance (MR) imaging, with the ultimate extent of neuronal injury quantified histopathologically. Animals in the hypothermic groups showed minimal changes in MR images over 4 days; normothermic animals snowed intensity enhancement attributed to progressive edema developing in the striatum and, later, in the hippocampus. Ischemia at 40°C resulted in widespread edema formation by I day post-ischemia; animals in this group did not survive beyond 30 hours. Histopathological analysis at 4 days (1 day for the hyperthermic group) post-ischemia showed that neuronal damage in the normothermic group was confined to the hippocampus and striatum. Minimal damage was found in the hypothermic groups; damage in the hyperthermic group was severe throughout the forebrain. There were no differences in the pre-ischemia 31P MR spectra for the different groups. During ischemia, the increase in intensity of the Pi peak and the fall in tissue pH increased with temperature in the order hypothermic < normothermic < hyperthermic group of animals. Post-ischemia energy recovery was similar in all groups, while pH recovered more rapidly in hypothermic animals.

Patients with predominantly unilateral parkinsonian signs may provide a unique opportunity to evaluate the cerebral representation of cognitive functions characteristically affected in idiopathic Parkinson’s disease. Twenty hemiparkinsonian patients (ten left and ten right) and 10 healthy controls, matched for age and education, were studied with neuropsychological tests and positron emission tomography. Both right and left hemiparkinsonians evidenced impairments in visuospatial and verbal episodic memory function, but had no deficits in executive abilities, compared to controls. None of the neuropsychological test scores distinguished right from left hemiparkinsonians. Glucose metabolic profiles were identical for the three groups in all cortical areas assessed; in the subcortex however, lenticular hypermetabolism contralateral to the predominant side of motor involvement was evident in the left hemiparkinsonian group. Correlational analysis revealed that higher glucose metabolic rates in the basal ganglia of these hemiparkinsonians were associated with lower visuospatial test scores. In frontal and parietal cortex, decreasing glucose metabolism was positively associated with neurobehavioral function; in temporal cortex, measures of attention and memory decreased with increasing glucose metabolic rates.

Rational treatment of diabetic polyneuropathy depends upon establishing its cause, which is at present unknown. A number of animal models of diabetes have been examined and although abnormalities are detectable in the peripheral nervous system they do not duplicate the degenerative neuropathy encountered in the human. The relevance of these abnormalities is therefore uncertain, although they may reflect the earlier changes in man. For human neuropathy, it is likely that vascular lesions or an abnormal susceptibility to mechanical injury are responsible for focal neuropathies. The evidence that ischaemia and hypoxia are responsible for the diffuse sensory neuropathy and autonomic polyneuropathy is still equivocal and it is often difficult to establish whether the vascular changes are primary or secondary. Metabolic explanations, such as sorbitol accumulation in nerve, have not so far been adequately validated by responses to treatment. The manifestations of diabetic neuropathy are complex and a single explanation should not be sought.

The purpose of this experiment was to quantify and analyse multijoint coordination of patients with Parkinson’s disease (N=5) and control subjects (N=5) during forward and backward stepping motions executed at different cadences. Coordinates of reflective markers placed on the shoulder, hip, knee, ankle and metatarsal joints were recorded in the sagittal plane using a video motion analysis system. Kinematic and kinetic analyses provided angular displacements and velocities as well as joint moments of force and powers. Results suggest the presence of two types of discoordination: one type is velocity-dependent, hence related to bradykinesia, whereas the other type appears to reflect qualitatively different coordination patterns.

In rodents damage from repetitive transient cerebral ischemia is more severe than that seen with a single ischemic insult of similar duration. Mild hypothermia has been shown to be very effective in protecting the brain during single ischemic insults. We tested the protective effects of hypothermia in repetitive ischemic insults. We used the gerbil model of repetitive ischemia (three minutes ischemia repeated at one hourly intervals three times) and histological evaluation was done using the silver staining technique. Our study reveals that a decrease in body and scalp temperature by 1-2 degrees Celsius can significantly reduce neuronal damage in the cerebral cortex, CA1 region of the hippocampus and substantia nigra reticulata during repetitive ischemia. As the hypothermia was induced after the initial insult, we believe this offers an opportunity for intervention in the clinical settings.

The study investigated features of life-style and dietary habits early and late in life of patients with idiopathic Parkinson’s disease (IPD). Seventy-one patients and 103 controls were interviewed personally with a structured questionnaire. Living in villages during primary school time was significantly more frequent among patients, and in the urban environment patients had lived less frequently in larger-sized towns. Mushroom harvesting during childhood was more frequent among patients. No difference between patients and controls was found in childhood water supply, habits of fishing in the countryside or at the seaside, and eating such fish. Actual food preference in patients was greater for almonds and plums, while no difference was found in the actual intake of mushrooms, peanuts, oil-dressed salad, fish and animal offals. The study did not indicate a higher consumption of foods known to harbour heavy metals and pesticides in IPD patients either long before or during the disease. Reduced consumption of foodstuffs rich in vitamin E, as reported previously for premorbid patients, is no longer observed in patients with overt disease.

Cerebral vasospasm may result from lipid peroxidation induced by oxyhemoglobin in the subarachnoid space after subarachnoid hemorrhage. To test this theory, vasospasm was induced in monkeys by intrathecal injections of oxyhemoglobin or supernatant fluid from autologous blood incubated in vitro. Concentration of malondialdehyde (MDA), a product of lipid peroxidation, was elevated in cerebrospinal fluid (CSF) in association with vasospasm caused by oxyhemoglobin and supernatant fluid. Intrathecal injections of methemoglobin or bilirubin did not cause vasospasm or increased CSF MDA. Activity of glutathione peroxidase in CSF increased significantly after injection of oxyhemoglobin and methemoglobin. There were no significant changes in CSF superoxide dismutase activity although there was a trend towards higher activities in animals treated with oxyhemoglobin, methemoglobin, bilirubin, and supernatant fluid. These results show oxyhemoglobin-induced vasospasm is associated with MDA and lipid peroxidation in the subarachnoid space. Furthermore, detection of peroxidation products after injection of oxyhemoglobin in the absence of erythrocyte membranes indicates that oxyhemoglobin may directly damage cerebral arteries and brain by inducing lipid peroxidation in these structures. Depletion of free-radical scavenging enzymes in CSF did not seem necessary for development of vasospasm. In fact, there was a tendency for vasospasm to elevate enzyme activities, as if production of scavengers was induced by excess free radicals in the subarachnoid space.

Levodopa is the most potent symptomatic treatment for Parkinson’s disease but adverse reactions are common and the initial response is not maintained. Further there is recent evidence that suggests that free radicals generated from the oxidative metabolism of dopamine may contribute to the pathogenesis of Parkinson’s disease. This raises the possibility that levodopa therapy by way of its conversion to dopamine may promote free radical formation and accelerate the rate of neuronal damage. Levodopa sparing strategies designed to minimize the cumulative levodopa dosage employed over the course of the disease seem a rational way to treat Parkinson patients in face of current information. Such a strategy would include the use of dopamine agonists as primary symptomatic therapy, the introduction of levodopa as an adjunct when dopamine agonists can no longer sufficiently provide satisfactory clinical control and the use of the lowest dose of levodopa that will provide satisfactory clinical control. In this way symptomatic control is not compromised on theoretical grounds, but the cumulative levodopa dose is minimized in an effort to reduce the likelihood of free radical formation with their potential adverse consequences on disease progression.

The major complications of therapy in PD are motor, autonomic and psychiatric. Motor complications may be associated with altered striatal bioavailability of levodopa, and may in part respond to changes in timing of drug administration, redistribution of dietary protein and the use of controlled-release preparations. Since long-term complications seem to be associated with higher cumulative doses of levodopa, the early use of adjunctive agents such as deprenyl and/or dopamine agonists is encouraged. Autonomic effects include impaired bladder and bowel function, impotence and postural hypotension. If conservative measures are ineffective, pharmacotherapy with domperidone, fludrocortisone, indomethacin or adrenergic agents may be required. Depression in PD is associated with decreased levels of noradrenaline and 5-HT and responds to tricyclic antidepressants. Drug-induced psychosis reflects stimulation of mesolimbic-cortical dopamine receptors. Alternatives include reduction of medication, the use of atypical neuroleptics (which may act at novel subtypes of the dopamine receptor) and electroconvulsive therapy.

General protease and collagenase IV activity are involved in the remodelling of the vascular basement membrane that occurs during tumor-induced angiogenesis. This study has assessed the level of these enzymes in tumor, peritumoral or contralateral cerebral cortex tissue during the growth of C6 astrocytoma in the rat spheroid implantation model. General proteolytic activity was increased in tumor tissue beginning on day 8 following spheroid implantation, then increased to a maximum value on day 11 and decreased to control values on day 18. A similar pattern was seen for collagenase IV activity but maximal activity occurred on day 13. The peritumor and tumor patterns of activity were similar. General protease activity was increased in the hemisphere contralateral to the tumor suggesting that the growth of C6 astrocytoma in rat brain was influencing biochemical events distant from the tumor. C6 astrocytoma cells orchestrate a cascade of proteolytic events which may play a crucial role in angiogenesis associated with tumor growth in the model system studied.

Trained telephone interviewers contacted 1,573 adults across Canada about the nature and frequency of headaches suffered by them or by others in their households. Using a table of pain symptoms and other characteristics abstracted from the International Headache Society (IHS) classification, the headaches were assigned to migraine headache, tension-type headache or other diagnostic groups. Of the households sampled, 59% had at least one headache sufferer in residence. The proportion of headache sufferers with migraine was 14%; with tension-type, 36%; and with both, 14%. Migraine headache caused more disability than tension-type headache, with nearly 20% of migraine sufferers taking time off work and disability lasting for a mean of 1 day. It is concluded that the current prevalences of migraine and tension-type headache in Canada fall around the mean of previous studies, that the IHS criteria can form a basis for diagnostic classification and that the functional impact of migraine has been seriously underestimated in the past.

In diabetic animals, reduced endoneurial perfusion and oxygen content have been linked to neuropathic abnormalities and might be amenable to pharmacological manipulation. In streptozotocin-induced diabetic rats, we studied the influence of guanethidine adrenergic sympathectomy, indomethacin treatment and a combined strategy on: serial in vivo motor and sensory conduction, resistance to ischemic conduction failure, in vitro myelinated and unmyelinated conduction, endoneurial perfusion and endoneurial oxygen tension. Unlike previous work diabetic animals had normal endoneurial perfusion but lower endoneurial oxygen tensions after six months of hyperglycemia. Guanethidine worsened sensory conduction despite lower microvascular resistance and an improvement in endoneurial oxygen tension. In contrast, indomethacin improved motor and sensory conduction but not oxygen tension. These studies do not support a linkage between conduction deficits and early endoneurial microangiopathy in experimental diabetes. Indomethacin, or related agents may offer a new therapeutic approach toward diabetic neuropathy through a mechanism independent of the endoneurial microvasculature.

Five siblings with autosomal dominant oculopharyngeal muscular dystrophy (OPMD) underwent P-31 Nuclear Magnetic Resonance Spectroscopy studies of forearm flexor muscles. Mean values of PCr/(PCr + Pi) in the patients were reduced (p = 0.01) and pH elevated (p = 0.02) in resting muscle when compared to controls. During exercise PCr/(PCr + Pi) fell quickly to values less than controls (p < 0.0001) despite submaximal exercise output and developed exercise-induced acidosis which exceeded that of controls (p = 0.05). Acidosis recovered slowly despite relatively normal recovery of PCr/(PCr + Pi) following exercise. Within the patient group, however, one member had normal resting, exercise and recovery values. The studies suggest that OPMD is a more widespread disorder of striated muscle than clinically appreciated. The pattern of findings observed in OPMD differs from those identified in denervation, disuse and mitochondrial myopathy.

Neuropathological findings from 39 acquired immune deficiency syndrome (AIDS) autopsies of primarily neurologically symptomatic patients and 7 brain biopsies from AIDS patients performed at St. Paul’s Hospital, Vancouver, British Columbia are reported. Autopsy findings included human immunodeficiency virus-1 (HlV)-type multinucleated giant cell (MNGC)-associated encephalitis seen in 17 patients, toxoplasmosis in 7 patients, and cytomegalovirus encephalitis and/or microglial nodule-associated nuclear inclusions in brain parenchyma in 9 patients. Central nervous system lymphoma was identified in 11 autopsy patients and in 4 of 7 brain biopsies. Infectious processes including HIV encephalitis were seen in 10 of 11 autopsied patients with lymphoproliferative lesions in the brain parenchyma, while 40% of patients without lymphoma had HIV-type MNGC or opportunistic infections. CNS lymphoma was not significantly increased in incidence in patients with a clinical history of zidovudine treatment, but increased duration of survival after the diagnosis of AIDS was associated with increased incidence of lymphoma in both untreated and zidovudine-treated patients. Patients displaying HIV MNGC within microglial nodules had a shorter mean duration of survival after diagnosis of AIDS than those patients with HIV encephalitis with dispersed MNGC, white matter vacuolation, and gliosis.

Microfilaments and microtubules play a part in the extension of neuronal processes but their roles in the formation of glial processes have not yet been determined. The objectives of this study were to determine the organization of microfilaments in differentiating glial progenitors (RB2 cells) and to study the effects of microfilament or microtubule disruption on process extension. Intense F-actin staining (crown of microfilaments) was observed at the leading edge of a small extending conical tip in differentiating RB2 cells, but was absent in process-bearing TE671 rhabdomyosarcoma cells. No significant difference was noted in the mean number of TE671 cells with processes treated with a microfilament disrupter from that of similarly treated controls. In contrast, a significant difference was noted in the mean number of RB2 cells with processes after microfilament disruption treatment from that of similarly treated controls. Microtubule disruption arrested extension and caused process retraction in both cell types. The results of this study demonstrate that microtubules play an equally important part in the extension and stabilization of the RB2 and TE671 processes. Moreover, the crown of microfilaments concentrated in the glial RB2 process (and not in the TE671 process) may be critical to its extension during differentiation.

Twenty-five patients with spinal epidural abscess were treated at the University of Western Ontario hospitals between July 1980 and July 1990. There were eighteen males (72%) and seven females (28%), with a median age of 60 years. Concurrent illness resulting in immunocompromise was present in 60%. Eleven presented with complete myelopathy, thirteen had limb weakness, and one had no neurological deficit. In twenty cases the abscess consisted of frankly purulent material, while in five the epidural collection consisted of chronic granulation tissue. Staphylococcus aureus was isolated in 64% of the abscesses. Twenty-seven surgical procedures were performed on 21 patients. Ten cases occurred in the cervical spine (40%), seven in the thoracic spine (28%), three in both the cervical and thoracic spine (12%) and five in the lumbosacral spine (20%). Fourteen patients (56%) retained or recovered ambulation and there were five deaths (20%). The progression from back and radicular pain to weakness and eventual paralysis continues to be characteristic of spinal epidural infection. Morbidity and mortality remain unacceptably high because of delay in diagnosis and treatment. Magnetic resonance imaging is the radiological investigation of choice for the diagnosis of spinal epidural abscess. Prompt intervention, before the development of severe neurological deficits, can improve outcome. Immediate surgical drainage combined with antibiotics remains the treatment of choice.

This study was designed to compare flunarizine, a cerebro-specific calcium channel antagonist, and propranolol in the prophylaxis of migraine with or without aura. Following a 1 month single-blind placebo baseline period, 94 patients were equitably randomised under double-blind conditions to take flunarizine 10 mg daily or propranolol 80 mg twice daily for 4 months. Both treatments led to a significant reduction in the frequency of migraines and use of rescue analgesics with a significantly greater decrease in number of attacks for flunarizine after 1 and 4 months. Neither treatment affected the severity nor duration of migraines. Overall, 67% of flunarizine patients and 51 % of propranolol patients responded positively. Propranolol significantly reduced blood pressure and heart rate; flunarizine had no effect on cardiovascular function. Weight gain was noted with both treatments. Flunarizine is at least as effective as propranolol in the prophylactic treatment of migraine and may have a better safety profile.

Features common to amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD) and Alzheimer’s disease (AD) are reviewed. Shared epidemiological aspects include an increasing frequency which is proportional for each disease. We draw attention to geographic non-uniform distribution which, for ALS and PD, correlates positively with latitude. Clinical and pathological overlap occurs in the same patients, and in members of the same family. A high early morning plasma cysteine/sulphate ratio possibly related to the development of proteinacious inclusions, as well as ubiquinated neuronal inclusions, characterize ALS, PD and AD. HLA-DR (the human group II major histocompatibility class) staining is marked in ALS, PD and AD and may represent autoimmunity-incited by-products of neuronal degeneration. Based upon demonstrated glutaminergic connections between the neocortex and anterior horn cells, the entorhinal cortex and the basal ganglia we hypothesize that ALS, AD and PD are phylogenetic disturbances of the neocortical cell. The postsynaptic neuron may degenerate secondarily to anterograde effects of deranged glutamate metabolism. Future therapeutic strategies should be directed to agents that decrease transmission induced by excitatory amino-acids.