The first J. C. Richardson lecture was given by Dr. Denis Williams, Editor of “Brain,” and The Senior Physician, The National Hospital, Queen Square, London W.C.I. It was presented in the Medical Sciences Building, University of Toronto on January 28th, 1974 and is printed here in its entirety.

The histocompatibility antigens (HL-A) have been determined in 100 multiple sclerosis (M.S.) patients and 143 randomly selected controls. In the M.S. group there was a statistically significant increase in the frequency of HL-A 7 and W 18 with an insignificant increase in HL-A 3. The variance from normal HL-A patterns in the M.S. population may play some role in establishing the substrate for this disease. Studies in experimental animals have shown that susceptibility to autoimmune disease and to virus infection is linked to the major histocompatibility locus. This has interesting implications for both the “slow virus” and the “autoimmune” theories of the etiology of multiple sclerosis.

Four patients with neurapraxic lesions are described; in spite of the absence of impulse activity in muscle fibers no other signs of denervation could be detected. These observations are interpreted as indirect evidence for the role o f a non-impulsive (axoplasmic flow) system in certain trophic phenomena. The relationship of the present findings to the spectrum of neuropathic lesions is considered.

The suppressive effect of various amino acids against ouabaininduced seizures was investigated in young female rats. The amino acids were injected into the left lateral ventricle 10 minutes prior to the intraventricular administration of 5 μg. of ouabain. Animals receiving 1.9 x 10-1 M solutions of hypotaurine and of β- alanine were almost completely protected from the ouabain seizures. Administration of L-alanine and of glycine was also effective, although running and leaping seizures still occurred to some extent. Betaine reduced only clonic-tonic and whole body flexion and extension seizures. In contrast, L-proline exclusively suppressed clonic-tonic and focal clonic seizures. Rats injected with isethionic acid showed increases in incidence of running and leaping seizures while L-arginine in high concentrations caused aggravation in clonic-tonic seizures. L-cysteine, even in low concentrations, also brought about an increase in the occurrence and incidence of clonic-tonic seizures. The ED50of hypotaurine was 10.11 x 10-2 M for running seizures and 4.63 x 10-2, M for clonictonic seizures; that of β -alanine was 14.01 x 10-2 M for running seizures and 5.50 x 10-2 M for clonic-tonic seizures. However, hypotaurine and β -alanine, the most effective compounds tested in the present studies, provided less protection than taurine previously examined by us under similar conditions (Izumi et al., 1973).

Earlier theories as to the anatomical basis of pain postulated a direct ‘pain pathway’ from specific receptors in the periphery. Anatomical studies linked this with small myelinated and unmyelinated fibers in the peripheral nerves. Subsequently, hypotheses were advanced which postulated that pain depended upon particular spatial and temporal patterns of sensory input into the nervous system rather than upon specific sets of fibers.

More recent physiological studies have demonstrated the existence of peripheral receptors that respond exclusively to noxious stimuli and morphometric studies on peripheral neuropathies in man clearly implicate small myelinated and unmyelinated axons in the conduction of pain. Morphometric studies have also shown that spontaneous pain in neuropathies may be associated with a selective loss of small fibers. These observations therefore support the earlier concept of a specific nociceptive pathway involving small caliber fibers in the peripheral nerves. It is evident that this afferent pathway is capable of modification in the spinal cord both by peripheral inputs and by descending impulses. The notion of a ‘pain pathway’ as such is probably best avoided.

Two suspected cases of viral encephalitis are presented. Viral nucleocapsids were not seen, but cytoplasmic paramyxovirus-like aggregates and nuclear filamentous bodies were frequently encountered. Both structures were seen in the same cell. Contrary to other reports, the cytoplasmic aggregates were mostly observed in hematogenous mononuclear cells, less frequently in neuronal cell elements and rarely in endothelial cells. The non-specific nature of these structures is emphasized.

A study of the course of 17 patients with subacute polyneuritis was undertaken. Ten were given corticosteroids. Assessment of time of turnaround, that is the beginning of clinical improvement, showed that some patients responded promptly to steroids whereas a few did not. A comparison of turnaround times between the treated and untreated cases shows a statistically significant effect of steroids in hastening the onset of recovery. This is not due to bias in selection of those for steroid treatment.

From the present review it seems clear that the physiopathogenesis of the chronic subdural hematoma is far from being completely understood. However, an analysis of the known data can be summarized as follows:

The development of subdural hematomas most likely occurs following minimal trauma in those patients with predisposing factors.

Experimental data substantiates the fact that an accumulation of clotted blood in the subdural or subcutaneous space induces the formation of the fibroplastic neomembrane. The hypothesis that blood must come in contact with cerebrospinal fluid in order for the growth to occur, is still controversial.

It has been virtually disproven that osmosis, referring to the electrolyte gradient as measured by freezing point depression, has any significance as a growth inducing factor.

The protein oncotic gradient theory, having been the most widely accepted explanation as to the progressive enlargement of the subdural hematoma sac, has little experimental data supporting it.

A larger body of clinical evidence exists supporting the concept that plasma and/or erythrocytes continuously penetrate into the subdural cavity, where enhanced fibrinolytic activity is present.

However, this chronic rebleeding cannot fully explain the observed growth, because the composition of the hematoma fluid is somewhat different from serum or plasma, and the protein content is also progressively diluted by fluid arising from an unknown source.

There is some clinical and experimental evidence to suggest that a production - reabsorption balance may be a significant growth variable.

No work has been done to define the role, if any, of local inflammatory mechanisms in the chronic subdural hematoma.

Sound clinical evidence has shown that after the initial formation of the subdural clot, growth follows, then a slow, complete reabsorption usually occurs. Aside from the plausible production - reabsorption balance concept, it is not known why the evolution proceeds in this manner.

150 aphasiacs and 59 controls were examined with a scorable, comprehensive battery, designed to be used by the clinician and the research worker. The subtests of Fluency, Information, Comprehension, Repetition and Naming were added and compared to a hypothetical normal of 100 obtaining the “aphasia Quotient.” This is a measurement of the severity of language impairment. On the basis of their performance on the subtests, the patients were classified according to taxonomic principles into Global, Motor (Broca’s), Isolation, Sensory (Wernicke’s), Transcortical Motor, Transcortical Sensory, Conduction and Anomic groups (in order of severity). This classification is considered a clinically valid baseline for research, diagnosis and prognosis.

A neural net model with random interconnections is shown capable of exhibiting the features of Parkinson’s disease, including cogwheel rigidity, resting tremor, and dysdiadochokinesis. These properties are simulated uniquely for extrapyramidal disease, with spasticity and hypereflexia predicted for other upper motoneuron lesions.

After a review of the literature concerning hereditary cases of cerebral palsy, a family is reported in which ataxic diplegia appears to be inherited as a sex-linked and probably recessive condition occurring in 3 males in successive generations. This ataxic diplegia, occurring after an unremarkable perinatal course, is associated with mild to moderate mental retardation, congenital nystagmus and significantly small stature and prevents the acquisition of free walking. Associated extrapyramidal features may gradually become more marked, while the nystagmus may subside. The condition is similar to that described in three previous reports in the literature. No evidence of linkage with other sex-linked disorders has been found, Xga typing showed that recombination between the Xg locus and the locus for hereditary ataxic diplegia has occurred once out of three possible opportunities. In the absence of neuropathological findings or specific biochemical tests, the differential diagnosis from Pelizaeus-Merzbacher disease cannot be made with certainty. The differentiation from other progressive sex-linked neurological disorders is discussed.

Keratin and cholesterol particles released by a craniopharyngioma were shown to be the agents involved in the production of a foreign-body granulomatous arachnoiditis and ependymitis. Some of the particles were seen embedded in the reactive subepen-dymal glial tissue along the aqueduct of Sylvius. It was thought they were a major factor leading to the aqueduc-tal stenosis. However, we have also considered that the change in cerebro-spinal fluid hydrodynamics following the ventriculopleural shunt contributed to the occlusion of the aqueduct.

The term “benign congenital myopathy” describes a group of muscle disorders characterized by proximal or diffuse muscle weakness, a relatively non-progressive course, normal serum muscle enzyme assays and the presence of a distinctive morphological feature. We report here a 55 year old woman, with fingerprint body myopathy who exhibits all of the above features. She has been affected from birth, able to walk since the age of 12, and has not deteriorated in the past thirty years. Muscle biopsy reveals fatty infiltration, numerous small fibers undergoing structural change, good differentiation into type I and II fibers, and excessive intracellular lipid and lipochrome. Only on electron microscopic study is the distinctive feature of numerous subsarcolemmal round to ovoid fingerprint bodies observed. Many fibers also contain large collections of tubular aggregates, filamentous bodies, and autophagic vacuoles.

The fingerprint bodies are similar to the ones described by A. Engel in a 5 year old girl. Thus, a rare opportunity is provided to study an individual who has had this disease for over fifty years.

The syndrome “visceral larva migrans” produced by migration of nematode larvae (commonly Toxocara species) in the extraintestinal tissues in unusual hosts, including man (particularly children of dirt eating age), with the production of reactive granulomatous lesions, was first described in 1952. About 200 cases have been reported since. Well documented cases are rare due to the difficulty in histological verification. Three cases have been reported in Canada but these were not verified. We believe the present report is the first verified case of visceral larva migrans in Canada and the fifth case of human cerebral involvement by Toxocara in the English literature. It is hoped that this report will emphasize the need for further research into the role of host versus parasite and will underline the potential danger, albeit remote, of household pets to children. Indeed, prevention is the only line of attack, as there is no effective drug against the migrating larvae of Toxocara.

The classical vascular mechanism of migraine attacks demonstrated by Wolff — intracranial vasoconstriction during the prodromal stage and passive vasodilatation of extracranial arteries during the painful phase — has been confirmed by modern methods. Arterial distension is, however, not sufficient to explain the origin of the pain: to give rise to an acute migraineous pain, it must be associated with a lowered pain threshold of the receptors situated in the wall of the affected vessels. A number of humoral factors — plasmakinin, serotonin, histamine — intervene in the chain of events that culminates in migraine headache.

At the start of the attack, the blood platelets release serotonin, the mast cells in the affected area release histamine and proteolytic enzymes that split plasmakininogens to form plas-makinins. Free serotonin and histamine increase capillary permeability and favor transudation of plasmakinin into the vessel walls andperivascular tissues. The combined effect of serotonin and plasmakinin on the vessel wall receptors reduces their pain threshold. On the other hand, the bulk of the released serotonin is excreted as 5-HIAA, and plasma serotonin falls. Since serotonin has a constricting effect on the extracranial arteries and a dilating one on the capillaries, the fall in its plasma level induces hypotonia of these arteries and capillary constriction, which results in a passive distension of the arterial walls. The two factors necessary for the production of pain are thus present: a low pain threshold and vascular distension. In addition to these three main humoral mediators, the part played by tyramine in migraine of alimentary origin, the precipitating effect of estrogen decrease in mentrual migraine and the hypothetical role of prostaglan-dins and prolactin are discussed.

A feasibility study for the development of a human visual prosthesis has led several workers to observe the effects of electrical stimulation of the human visual cortex. Experience with such stimulations of three normal-sighted patients is reported. The results confirm some of the findings of other workers, but do not show that multiple phosphenes were experienced by our patients, using strictly limited parameters of stimulation.