Hoffmann (H) reflexes were elicited from the soleus muscle during treadmill walking in 21 spastic paretic patients. The soleus and tibialis anterior muscles were reciprocally activated during walking in most patients, much like that observed in healthy individuals. The pattern of H-reflex modulation varied considerably between patients, from being relatively normal in some patients to a complete absence of modulation in others. The most common pattern observed was a lack of H-reflex modulation through the stance phase and slight depression of the reflex in the swing phase, considerably less modulation than that of normal subjects under comparable walking conditions. The high reflex amplitudes during periods of the step cycle such as early stance seems to be related to the stretch-induced large electromyogram bursts in the soleus in some subjects. The abnormally active reflexes appear to contribute to the clonus encountered during walking in these patients. In three patients who were able to walk for extended periods, the effect of stimulus intensity was examined. Two of these patients showed a greater degree of reflex modulation at lower stimulus intensities, suggesting that the lack of modulation observed at higher stimulus intensities is a result of saturation of the reflex loop. In six other patients, however, no reflex modulation could be demonstrated even at very low stimulus intensities.

Clinical diagnosis of Parkinson's syndrome (PS) is reasonably easy in most cases but the distinction between different variants of PS may be difficult in early cases. The correct diagnosis is not only important for counselling and management of patients but also in conducting pharmacological and epidemiological studies. There is very little critical literature on the pathological verification of the clinical diagnosis in PS. We report our 22 year experience to address that issue. Between 1968 and 1990, 65 PS patients came to autopsy. Complete data are available in 59 (M- 50, F-19) cases. The initial diagnosis made by a qualified neurologist was idiopathic Parkinson's disease (IPD) in 43 cases. Of those 28 (65%) had Lewy body pathology. After a mean duration of 12 years the final diagnosis was IPD in 41 cases which was confirmed in 31 (76%). The IPD could not be clinically distinguished from cases with severe substantia nigra neuronal loss without inclusions or from those with neurofibrillary tangle inclusions and neuronal loss at the anatomical sites typically involved in IPD. All progressive supra-nuclear palsy, olivopontocerebellar atrophy, Jakob-Creutzfeldt's disease and the majority of the multiple system atrophy cases were diagnosed correctly during life. The correct clinical diagnosis in most non-IPD variants of PS was possible within 5 years of onset (range: 2 months to 18 years). We recommend that studies aimed at including only the IPD cases restrict the enrollment to those cases that have had PS motor manifestations for five years or longer duration.

It is a great honor for me to present the Richardson Lecture this year. Although I was not personally acquainted with Dr. Richardson, his contributions to Canadian neurology are legendary, not the least of which is immortalized in the disease he and his colleagues first described in 1964: Steele-Richardson-Olszewski syndrome.

I have entitled my talk “Challenges for Neurology in the 90s: Will We Survive?”, to highlight some of the issues that I believe are important for us to consider as we embark upon our academic enterprise during the last decade of the 20th century. There are a number of opportunities as well as, potentially, major difficulties that we face, and I wish to focus attention on some of them.

The analgesic effects of transcutaneous electrical nerve stimulation (TENS) and vibratory stimulation (VS), used both separately and simultaneously, were compared in 24 patients suffering from chronic pain. We tested the hypothesis that these combined procedures might improve the pain reducing effects obtained with a single type of stimulation, since they make it possible to recruit a larger number of large diameter afferents and/or to increase the discharge frequencies. Four 35-minute treatment sessions (VS, TENS, VS+TENS, Sham stimulation) were run with each patient. The vibrations (100 Hz) and TENS (100 Hz) were applied to the surface of the painful region. The sham stimulation treatment consisted of positioning the TENS electrodes without actually delivering any current. The short form of the McGill pain questionnaire was used to assess the subjects' pain levels. The assessments took place immediately after any treatment (Oh.), and again 4 hours and 24 hours later. The results showed that dual stimulation not only alleviated pain in more cases than either VS or TENS alone, but also had stronger and more long-lasting analgesic effects. On the other hand, all three types of stimulation used produced stronger analgesic effects than those obtained with the sham stimulation.

The authors present clinical experience with 28 cases of ruptured anterior cerebral artery (ACA) aneurysms managed personally during a 36 month period, and 10 unruptured ACA aneurysms. The cases included five giant aneurysms and four distal ACA aneurysms. Management strategy was uniform and included early operative intervention (except in the setting of deteriorating neurologic deficit, not attributable to hydrocephalus or hematoma), and vasospasm prophylaxis including calcium channel blockers and hypervolemic hemodilution and arterial hypertension. Modern diagnostic adjuncts including transcranial doppler were used as they became available. Good outcome (outcome grade 1 or 2) was observed at 6 months in 71% (20/28) of ruptured cases and in 90% (9/10) of unruptured cases; fair outcome (outcome grade 3) was observed in 14% (4/28) of ruptured cases and in 10% of unruptured cases; bad outcome (outcome grade 4 or 5) was observed in 14% (4/28) of ruptured cases. There were no instances of rebleeding after admission to the hospital. There was a single mortality in a patient moribund on admission. Delayed ischemic deterioration (DID) was documented in 46% (13 of 28) of the ruptured cases, and was a major source of morbidity in 7 of the 9 instances of fair or poor outcome in the series. Management outcome, including the occurrence of subtle neuropsychological difficulties commonly described in cases with ACA aneurysms, is discussed with relation to the incidence of DID, the clinical course of DID, and the possible impact of various therapeutic strategies.

In cynomolgus monkeys rendered parkinsonian by systemic injection of MPTP, severe cell losses were noted in the ventrolateral portion of the substantia nigra pars compacta (SNc), compared to a relative sparing of neurons in the ventral tegmental area (VTA) and dorsomedial portion of SNc. Most spared neurons in the SNc-VTA complex were found to contain the calcium binding protein calbindin (CaBP). At striatal levels the dopaminergic (DA) innervation, as visualized by tyrosine hydroxylase immunoreactivity, was markedly reduced in the ‘sensorimotor’ territory, variably affected in the ‘associative’ territory, and relatively well preserved in the ‘limbic’ territory. The immunoreactivity for enkephalin was enhanced and that for substance P was decreased in the sensorimotor territory, whereas the inverse was observed in the limbic territory. The distribution of the two peptides was highly heterogeneous in the associative territory. These findings suggest that the influence of the DA input on peptide expression varies from one striatal territory to the other, and that CaBP may protect midbrain DA neurons from MPTP toxicity.

Wilder Penfield's development of surgical methods for treating focal cerebral seizures, beginning with his early work in Montreal in 1928, is reviewed. The reliance on seizure pattern and focal brain pathology was enormously enhanced by the advent of EEG and direct electrical recording from the cortex during surgery. The recognition in the early 1950's of mesial temporal structures in the pathogenesis of temporal lobe epilepsy with automatism lead to more rational and successful surgical treatment. Positron emission tomography and especially magnetic resonance imaging have recently added to the essential diagnostic information of focal epilepsy provided by EEG.

A potent in vitro inhibitor of lipid peroxidation, U78517F, has been employed to assess its influence on C6 astrocytoma growth in monolayer culture and tumor growth and protein extravasation in the rat C6 astrocytoma spheroid implantation model. Results demonstrate that 1 μM concentration of U78517F inhibits cell division, but is not tumoricidal to C6 astrocytoma cells in monolayer culture. Concentrations of 5 μM and above significantly decreased astrocytoma cell viability. Following spheroid implantation, rats were treated with one of these U785I7F regimes: 12 mg/kg/day for 13 days post-implantation, 4 mg/kg/day for 13 days post-implantation or 12 mg/kg/day commencing seven days post-implantation until 13 days post-implantation. Tumor wet and dry weights were lower in all treatment groups, but these decreases were not statistically significant. Protein extravasation as measured by Evans blue extravasation was not significantly reduced by any treatment regime used. It is concluded that U78517F inhibits C6 astrocytoma growth in monolayer culture at and above 5 μM concentrations, but the treatment regimes utilized did not significantly decrease tumor growth or permeability in the C6 astrocytoma spheroid implantation model.

To determine whether a history of exposure to rural environmental factors leads to an increased likelihood of developing idiopathic Parkinson's disease, we conducted a case-control study of 130 cases and 260 randomly selected community controls (matched with the cases by sex and age ± 2.5 years at a ratio of 2 controls: 1 case) in the city of Calgary. The data were collected by personal interviews and were analyzed using conditional logistic regression for matched sets. The ages of the cases ranged from 36.5 to 90.7 years (mean = 68.5 ± 11.3 years). The mean age at diagnosis was 61.1 ± 12.4 years. The mean duration of disease was 7.8 ± 0.6 years. Eleven (9.1%) cases were diagnosed before age 40. In this sample from the Province of Alberta, Canada, no significant increase in risk for Parkinson's disease was associated with a history of rural living, farm living, or well water drinking in early childhood or at any time during the first 45 years of life.

Cerebral blood flow (CBF) and central conduction time (CCT) were recorded from 58 subarachnoid hemorrhage patients and from 49 age-matched controls. CBF was calculated following Xenon inhalation and CCT was determined from somatosensory evoked potentials (SSEP's) following median nerve stimulation. Each patient had a CT scan on the day of admission which was graded from I-IV. CBF, CCT and neurological grade (Hunt and Hess classification) were concomitantly recorded 1, 4, 7 and 14 days after subarachnoid hemorrhage. Mean CBF was highest in patients with neurological grades I and II (48.6 ± 12.3 and 48.1 ± 10.3 ml/lOOgm/min respectively) and lowest in patients with neurological grade IV (37.3 ± 9.6 ml/lOOgm/min). Patients in neurological grade I or II had mean CBF and CCT measurements that were significantly different from those obtained from patients in neurological grade IV (P < 0.05). Neurological grade and CT scan grade correlated with CBF (P < 0.0001) better than CCT (P = 0.015). Unexpectedly low CBF's from patients in neurological grades II and III (< 37 and < 31 ml/lOOgm/min respectively) failed to significantly prolong CCT suggesting CCT is unable to detect marginal ischemia. A significant correlation between CBF and CCT occurred only when CBF was < 30 ml/lOOgm/min (R = 0.75, P = 0.05). It appears that prolonged CCT is associated with a drop in CBF only when CBF drops below a certain threshold.

Brain tumor growth results from the relative proportion of cells contained in three populations: a) cycling/proliferative; b) quiescent (Go)/static, and c) terminally differentiated/dying. The cycling compartment can be detected by the mouse monoclonal Ki-67 antibody, an available, rapid, safe, sensitive, and specific method for immunostaining of proliferative cells. We report the Ki-67 labeling index (LI) in 48 brain tumors. Malignant brain tumors have elevated Lis, ranging from 6.0% to 56.9%: anaplastic astrocytoma, 8.0 ± 7.3; glioblastoma multiforme, 10.1 ±4.2; germinoma, 11.7; medulloblastoma, 13.1 ± 6.6; metastases, 40.3 ± 13.1. By contrast, slow-growing tumors showed lower values (P < .001), approaching 1%: acoustic schwannoma, 0.4 ± 0.6; pituitary adenoma, 1.3 ± 1.9; meningioma, 1.2 ± 1.2; low-grade astrocytoma, < 1; pilocytic astrocytoma, 5.6. Human brain tumors can therefore be ranked according to the percentage of cycling cells with the acoustic schwannoma among the least proliferative and the metastatic carcinoma among the most proliferative. Within a given histotype, the Ki-67 LI may have prognostic and therapeutic implications for the individual patient. Already important for neuro-oncology research, the Ki-67 labeling index should be added to the armamentarium of the clinical neuropathologist to complement the standard histopathologic diagnosis with a cytokinetic analysis of cellular proliferation.

Dendritic spheroid bodies (SBs) and Lewy bodies (LBs) were identified in comparable numbers in the substantia nigra pars compacta (SBC) of nine parkinsonian cases and one case of striatonigral degeneration but were not found irt cases of Huntington's disease or neurologically normal controls. The immunohistochemical profile of the SBs in dystrophic dendrites of nigrostriatal dopaminergic neurons was remarkably similar to that of the LBs found within dendrites or free of the SNC neuropil. Both types of inclusions stained positively with antibodies to tyrosine hydroxylase, ubiquitin and microtubule-associated protein-2 (MAP2), and negatively for Tau-2, although they had different ultrastructural appearances. A few intracellular LBs were stained by antibodies to neurofilament proteins (NFs) 68, 160, and 200 kD, but dendritic SBs and extracellular LBs were not so stained. These data indicate that dendritic SBs and extracellular LBs may have a common molecular pathogenetic origin in Parkinson's disease. On the other hand, the SBs seen in the pars reticulata (SNR) and in the distal nigrostriatal axons even in control cases were generally stained by antibodies to NFs and ubiquitin but not to MAP2. This latter staining pattern in similar to that shown by SBs in the anterior horn in ALS and in the cerebellum of neurologically normal brains and is believed typical of axonal as opposed to dendritic SBs.

A group of 57-head injured patients showing computerized tomographic (CT) findings compatible with “diffuse brain injury” or of the so called “diffuse axonal injury” is analyzed. Thirty-four patients showed intraparenchymal hemorrhage in the CT scan study, 8 intraventricular hemorrhage and 15 patients had both intraparenchymal and intraventricular hemorrhage. Forty percent (23/57) of those with these findings had associated intracranial focal lesions. The deep nuclei are the most common location of intraparenchymal hemorrhage. Signs of brain stem hemorrhage were seen in 9 patients. Forty-nine percent of patients in this series had a good outcome. Old age (>60), abnormal motor response, abnormal eye signs, associated with focal lesions, and evidence of brain stem hemorrhage are reliable prognostic parameters for a grave outcome.

Elements consistent with a cell mediated immune response were identified immunohistochemically in amyotrophic lateral sclerosis (ALS) spinal cord and Alzheimer disease (AD) hippocampus. T helper/inducer and cytotoxic/suppressor lymphocytes were detected in affected tissues in both diseases. In addition, abundant reactive microglia were found expressing the major histocompatibility glycoproteins HLA-A,B,C and HLA-DR, as well as receptors for the Fc chain (Fcyγl), for complement 3 and 4, and for vitronectin. In AD, the complement proteins Clq, C4d, C3d and C5b-9 were found on dystrophic neurites, neuropile threads and some neurofibrillary tangles. In ALS, the only complement proteins identified were C4d and C3d. The integrin ligands vitronectin and ICAM-1 were also identified in affected tissues in both diseases.

Thiamine status was evaluated using the erythrocyte transketolase activation assay in 20 alcoholic patients admitted on a voluntary basis to a Detoxification Unit. Electromyographic evaluation revealed significant reductions of motor and sensory conduction velocities in the alcoholic group. 38% of alcoholic patients had at least one abnormal peripheral nerve conduction parameter. Findings were consistent with an axonal type of neuropathy. 30% of alcoholic patients showed significant erythrocyte transketolase activation deficits indicative of severe thiamine deficiency. In the case of peroneal nerve, reduced conduction velocities were negatively correlated with abnormal transketolase parameters. These findings are consistent with a contributory (but not exclusive) role of thiamine deficiency in the pathogenesis of alcoholic peripheral neuropathy. Deficiencies of other vitamins as well as direct neurotoxic effects of alcohol could also be involved in this phenomenon.

Preoperative EEG investigations of patients with temporal lobe seizures include extracranial interictal and ictal recordings during wakefulness and sleep, including long-term EEG and video-monitoring. Interictal epileptiform discharges when evaluated conservatively and in conjunction with other EEG and non-EEG localizing information, provide valuable guidance for the identification of the area to be resected, as do ictal recordings. When extracranial EEG features in conjunction with non-EEG data provide conflicting localizing information, intracranial recordings with stereotaxically implanted depth and epidural electrodes are used. Intracranial recordings must be designed to avoid biasing the exploration strategy in favor of one's preferred localizing hypothesis. Patients with evidence for bitemporal epileptogenic dysfunction in extracranial EEG recordings are suitable candidates for intracranial recordings. The majority of the patients explored in this manner show that all or more than 80% of their seizures arise from one temporal lobe. Excision of that lobe yields satisfactory results in a fair proportion of these patients. The number of satisfactory outcomes is, however, still somewhat less than in patients with unilateral temporal foci in extracranial EEG recordings.

The first section of this article deals with specific anatomic and pathophysiologic factors which contribute to a poor EEG localization of the interictal epileptic abnormality and to the unreliable seizure onset localization commonly reported in patients with frontal lobe epilepsy. The localizing effectiveness of long term EEG monitoring was reviewed in four different groups of frontal lobe epileptic patients who underwent preoperative EEG investigation with extracranial and intracranial electrodes. The results of this study reveal a continuum distribution of interictal epileptic disturbances, ranging from focal abnormalities to lobar or multi-lobar epileptogenesis. A frontal lobe localization of the seizure generator based on ictal recordings obtained with extracranial electrodes is rather poor and much more reliable results can be obtained by depth-electroencephalography.

Expression of the immediate early gene c-fos is increased in mammalian neurons by a number of stimuli and the usefulness of this gene as a marker of neuronal activation has been demonstrated in several systems. Directlyacting dopamine agonists of the D1-type (SKF 38393, CY 208-243) and indirectly-acting dopamine gonists (amphetamine, cocaine) all produce a rapid and transient increase in Fos protein levels in varying patterns in striatum and cerebral cortex. irectly-acting dopamine agonists only produce c-fos activation in denervated (supersensitive) striatum whereas cocaine and amphetamine activate c-fos in striatum in naive animals. Remarkably, D2 selective antagonists such as haloperidol, albeit in high doses, also activate c-fos expression. Activation of c-fos and other immediate early genes may play a part in the development of such long-term dopamine-related effects as dyskinetic movements and addiction.