The neuropathology of 18 cardiac transplant recipients was reviewed with the clinical findings. Pathological changes were noted in the central nervous system (CNS) in 94% of the patients, the most frequent being cerebral vascular in origin (72%). Eight patients (44%) had multiple cerebral infarcts and morphologically, a large number of these antedated the transplantation. In addition 4 patients had acute focal ischemic changes which occurred after transplantation. Intracranial hemorrhage was noted in 5 patients (28%), including one case of fatal intracerebral hemorrhage following an acute hypertensive episode after the transplantation. While systemic infection was common (10 patients), there were only 5 cases of intracranial infection; including 3 cases of cytomegalovirus infection, one of candidiasis and one of aspergillosis. Post-transplant seizures, occurring in a third of the patients, were related to a variety of causative factors such as sepsis, intracranial hemorrhage, cerebral ischemia, metabolic encephalopathy and cyclosporin neurotoxicity. Of note in this series was the absence of CNS lymphoma or other systemic lymphoproliferative disorder.

Unlike the numerous dispersed bulbospinal pathways that are already well myelinated at term, the more compact corticospinal and corticobulbar tracts are only beginning their myelination cycle in late gestation and do not complete it until two years of age. During this same period, these pathways also develop extensive ramification of terminal axonal segments, growth of collateral axons, and proliferation of synapses. Despite their immaturity in the fullterm human newborn, several proposed functions may be attributed to the descending pathways from the neonatal cerebral cortex: a) a contribution to the differential development of passive muscle tone and resting postures; in general they function as an antagonist to the “subcorticospinal pathways” in mediating proximal flexion and distal extension, except for the rubrospinal tract which is probably synergistic with the corticospinal tract; b) enhancement of tactile reflexes originating in the brainstem and spinal cord, including suck and swallow; c) relay of epileptic activity of cortical origin; d) inhibition of complex stereotyped motor reflexes including many phenomena formerly termed “subtle seizures”; e) a possible influence on muscle maturation, particularly in relaying cerebellar impulses that modify the histochemical differentiation of myofibres. However, the bulbospinal tracts are probably more influential on muscle development. The corticospinal and corticobulbar tracts subserve different needs in the newborn than at older ages, but are functionally important pathways even at birth.

C'est avec une appréhension certaine que j'ai accepté le redoutable honneur d'être le conférencier cette année de la Société Canadienne de Neurologie dont je fais partie depuis trente ans.

C'est avec la même appréhension que j'ai choisi d'évoquer certains aspects de la carrière d'un grand de I'histoire du 20e siècle des sciences neurologiques, Joseph Babinski.

Je souhaite que vous soyiez indulgents à l'endroit de l'apprenti historien que je voudrais être.

A review of published reports on conventional and unconventional viruses, aluminum, neurotoxic metals and trace elements, neurotoxins of biological origin and immune systems, suggest that environmental factors, possibly multiple ones, play a significant role in the etiology of Alzheimer's disease. A complex interaction between genetic predisposition to this illness, natural aging processes, environmental factors over a life-time exposure and pathological alterations of the host immune system is proposed.

It is well known that pure absence epilepsy is a benign form of seizure disorder, while most others, particularly partial and convulsive seizures may have transient or permanent deleterious consequences and are more difficult to bring under therapeutic control by anticonvulsants. The hypothesis is proposed that the preservation of GABA-ergic inhibition in absence attacks and its breakdown in most other seizures may explain these differences. Breakdown of GABA-ergic inhibition allows NMDA receptors to become active. This opens the way for Ca2+ to enter the cell. Such Ca2+ entry is a long-lasting phenomenon. It is likely to be massive during most seizures except during absence attacks, and may therefore damage the neuron transiently or permanently. It may even destroy it. Ca2+ entry is also a crucial factor in the activation of the second messenger cascade which involves cytosolic as well as nuclear (genomic) components. Activation of this cascade converts short-lived electrophysiological processes occurring at the membrane into much longer-lasting intracellular processes. These may include plastic changes at the synaptic and receptor level and may account for kindling and the increasing therapy-resistance of long-standing seizure disorders. Changes resulting from massive Ca2+ entry into the neuron may explain why most seizures, except absence attacks, may have deleterious consequences of various kinds, some short-lived, some of longer duration, and some even permanent.

Daily trends in blood pressure, osmolality and electrolytes were analyzed in a series of 173 operated aneurysm cases who had subarachnoid hemorrhage (SAH) and were admitted within 4 days of the ictus. High blood pressure was associated with a greater risk of mortality and the development of clinically significant vasospasm (VSP). High osmolality shortly after admission was related to mortality but not VSP. Changes in sodium and potassium had no obvious relationship to mortality or VSP.

The effects of traumatic brain injury (TBI) and aging were compared on tests of simple and complex reaction time (RT). Simple RT was not significantly affected by aging or TBI. TBI patients, however, tended to be slower on Simple RT tasks, and had a larger standard deviation. Individuals over age 60 and patients of any age with TBI demonstrated slower RT with choice RT tests. In addition, both groups (those over 60 and TBI patients) were less able than other groups to inhibit the processing of redundant information. For the TBI patients, this occurred primarily on reassessment. These results suggest that the deficit in both aging and TBI is not only a generalized neuronal slowing but a more specific impairment in attentional control processes, exhibited as a deficit in focused attention.

Patients with tumors of the central nervous system (CNS) remain difficult to treat despite recent advances in surgical, chemotherapeutic and radiotherapeutic techniques. A better understanding of the molecular and cellular biology of neoplasia is providing neuroscientists with a framework on which to devise novel therapies for these patients. It thus becomes imperative that neurologists and neurosurgeons be aware of these advances in basic science that may eventually have a positive impact on patient management. This paper reviews our present knowledge of the process of CNS oncogenesis and the roles that chemicals, viruses, oncogenes, growth inhibitor genes, and growth factors play in the process.

Brain death and the persistent vegetative state (PVS) share the following features: 1.) There is death of neurons in the brain; 2.) Both require an etiology which is capable of causing neuronal death. 3.) The potential for cognition is totally and permanently lost; 4.) Intensive medical support is usually withdrawn. In contrast, the diagnosis of brain death depends on death of the brainstem, while PVS implies permanent and total loss of forebrain function. While brainstem death can be diagnosed clinically, accurate prognosis in PVS requires additional investigation. Thus far, the EEG is the most specific test of neuronal function in the cerebral cortex. Brain death is equivalent to death, while PVS is not; management of the latter is more complex because of medical, social, ethical and legal factors.

Transplantation of autologous adrenal medulla tissue into the striatum has recently been proposed as a treatment for Parkinson's disease. We report the use of positron emission tomography (PET) to evaluate patients who had adrenal implants placed into the right caudate. 6-[18F] fluoro-L-dopa (6-FD) scans were performed to study the integrity and activity of the implant, and the nigrostriatal dopamine system before and six weeks after transplantation surgery. [68Ga] Gallium-ethylenediaminetetraacetate (Ga) scans were also performed to assess the blood brain barrier. The Ga scans performed on two patients showed increased permeability of the blood brain barrier at the surgical site. 6-FD PET scans in five patients did not show a consistent change in striatal uptake following adrenal medullary implantation after six weeks. Further assessment of implant viability with 6-FD PET scans after longer follow up may provide useful information if the blood-brain barrier becomes re-established with the passage of time.

The molecular genetic strategies aimed at isolating and characterizing the defective gene(s) in familial Alzheimer's disease, the inherent limitations of the techniques and recent progress in the field are reviewed. Three independent groups have found an apparent linkage to chromosome 21 but two other groups have not, suggesting that familial Alzheimer's disease may be etiologically heterogeneous.

We describe an ultra-high resolution technique for recording evoked potentials (EPs) that are thousands of times smaller than the total EEG power. We report that two superimposed visual stimulus patterns, one modulated at F1 Hz and the other at F2 Hz , can generate 20 or more EP frequency components, each of which is contained within a bandwidth of no more than 0.004 Hz. We have developed a theoretical method for calculating the amplitudes and phases of these various cross-modulation components for different arrangements of model neurons. The relative amplitude of the various cross-modulation components seems to be a 'signature' of the particular neural model and this offers a way of testing theoretical neural models against EP data. As an illustration we compare the nonlinear EP components evoked by dichoptic stimulation with unpatterned flickering light against several models of binocular interaction. These nonlinear binocular interaction terms may offer a means of investigating binocularity in amblyopic children or infants who have low acuity in one or both eyes.

Because of the naturally low fibrinolytic activity of CSF many erythrocytes entrapped in subarachnoid blood clot undergo hemolysis in situ, releasing vasogenic oxyhemoglobin (OxyHb) in high concentrations around the basal cerebral arteries. In order to promote more rapid clearance of erythrocytes from the basal subarachnoid cisterns we are currently investigating intrathecal thrombolytic therapy with human, recombinant, tissue plasminogen activator (rt-PA) in a primate model of subarachnoid hemorrhage (SAH) and cerebral vasospasm (VSP). In the present study 16 monkeys were divided into 4 groups of 4, and each group received a different dose of sustained-release gel rt-PA at the time of experimental SAH. Cerebral angiography seven days later showed that whereas no VSP occurred in the groups receiving 0.5 or 0.75 mg of rt-PA, mild to moderate VSP occurred in the groups receiving 0.125 or 0.25 mg of rt-PA. Analysis of the combined 2 smaller dosage groups revealed significant (P<0.05) reduction of lumen caliber in the clotside internal carotid (C3 and C4), proximal anterior cerebral (A1) and middle cerebral (MCA) arteries. Gross subarachnoid clot remained in all of the animals in the 0.125 and 0.25 mg dose groups, in 2 of the animals in the 0.5 mg dose group, and none of the animals in the 0.75 mg dose group. It was concluded that 0.75 mg of gel rt-PA is sufficient to completely lyse a 4.25 ml SAH and prevent VSP in our primate model. The literature on fibrinolysis and erythrocyte clearance in cerebrospinal fluid (CSF) is reviewed.

Metal deficiency or toxicity states have been recognized as a cause of several neurological disorders and are suspected in others. We analyzed four brain regions (frontal cortex, caudate nucleus, substantia nigra, and cerebellum) in 36 human brains for concentrations of 24 metals (Ag, Al, As, B, Be, Ca, Cd, Co, Cr, Cu, Fe, K, Pb, Mg, Mn, Mo, Na, Ni, P, Se, Ti, V, W, Zn). Regional metal concentrations, measured using atomic absorption and atomic emission spectroscopy, were compared between 9 Parkinson's disease (PD) brains, 15 brains from patients with other chronic neurological diseases, and 12 control brains. No significant metal concentration differences were noted between brains from PD and other chronic neurologic disease. However, parkinsonian brains (PD and parkinsonism secondary to neurofibrillary tangle disease) showed lower concentrations of magnesium in the caudate nucleus and copper in the substantia nigra than control brains. These findings may represent an etiologically important clue to parkinsonism.

We assessed parkinsonian rigidity objectively at the wrist to determine the optimal angular velocity and displacement for detecting abnormality. The wrist was moved passively with a torque motor and the average work done for one complete cycle was computed. This objective rigidity score (ORS) was compared with a clinical rigidity score (CRS). ORS was more pronounced at faster movement velocities in parkinsonian patients, whereas in normal subjects there was only a modest increase in the score. Angular velocities of 140 to 190 degrees/second and displacements of ±25 to ±30 degrees were most sensitive for detecting parkinsonian rigidity and had good correlation with the CRS.

Fourteen patients with intractable epilepsy underwent surgical resection of their epileptogenic focus. Hippocampal and temporal cortical samples were obtained, and subjected to high performance liquid chromatography with electrochemical detection. Levels of 5-hydroxyindoleacetic acid (5-HIAA) in actively spiking temporal cortex were 0.454 ± 0.012 ng/mg (mean ± SEM), contrasting with less actively spiking cortex values of 0.248 ± 0.042 ng/mg and normal literature values, obtained from post-mortem material, of 0.140 ± 0.050 ng/mg. Similarly, homovanillic acid (NVA) levels were significantly increased in epileptic tissue compared to normal literature values. Actively spiking cortex values were 0.172 ± 0.001 pg/mg, less active cortex values were 0.058 ±0.012 pg/mg, and literature values were 0.011 ± 0.002 pg/mg. Although a direct statistical comparison between the data reported here and literature values may not be valid, the findings show a continuum from normal through increasingly active electrode sites, likely reflecting a true biologic phenomena. Similarly, statistically significant increases in 5-HIAA and HVA levels were found in hippocampal tissue, which also showed significantly lower dihydroxyphenylacetic acid levels. We conclude that raised levels of serotonin and dopamine metabolites in actively spiking cortex likely reflect an increase in their turnover, and are an epileptic epiphenomenon. Exaggeration of turnover may represent the “metabolic noise” of epilepsy, rather than a concerted strategy of local or distal neurons to contain an epileptogenic focus.

Genetic linkage analysis requires the identification and documentation of large families with many affected members present, preferably in more than one generation. The IMAGE Project has been establishing a population- based Alzheimer disease (AD) registry in the Saguenay - Lac-Saint-Jean region of the Province of Quebec. The population of this region has a well-documented ancestry, with reliable genealogical records (since 1842) computerized by SORER We have recently begun to investigate the pedigrees of selected probands (definite, probable and possible) from the IMAGE registry in order to identify informative pedigrees for genetic linkage analysis. Interviews were carried out with close relatives of the probands (at least one informant per sibship) to identify secondary AD cases. The questionnaires used pertain to the accuracy of genealogical records, to family medical history and to a retrospective diagnosis of AD for people with cognitive deficits. By these means, we have documented a large extended pedigree in which a total of 15 individuals with cognitive deficits were ascertained over three generations. Of these cases, 7 are still living and there is autopsy confirmation in another one. Computer simulations using the program SIMLINK revealed that this is a potentially informative family for linkage analysis. Horizontal extension of the pedigree to second cousins of the proband is now being carried out. This will render the family IMAGE/1 even more informative in genetic linkage analysis studies.