We present a working and flexible classification of inherited ataxic syndromes based on the use of simple tools available to every clinician: a good history (particularly pinpointing the age of onset, the rate of progression and the mode of inheritance) and a neurological examination (identifying the presence of ataxia, deep tendon reflexes in the knee, optic nerve, retinal and/or 8th nerve signs). This classification is easily coded for computer translation on any personal computer. The place occupied by a given disorder may, by contiguity, give a clue to its pathophysiology.

The literature is reviewed on the afferents and efferents of the caudate/putamen, globus pallidus and substantia nigra, and on the neurotransmitters occurring in the various tracts. Emphasis is placed upon the diverse roles played by GABA and glutamate as transmitters in motor pathways and upon the probability that the substantia nigra pars reticulata plays a pivotal role in the output of the basal ganglia. Excessive stimulation of the projection from the pedunculopontine tegmental area to the substantia nigra is shown to cause destruction of dopaminergic neurons in the latter nucleus, suggesting another possible mechanism for cell death in Parkinson’s disease.

In this address I shall discuss head trauma from an angle which may be unusual for neuroscientists. Our preoccupations are diagnostic challenges and management problems, but that which we experience at the bedside is only a narrow segment of a continuum which started with trauma somewhere in a war, on the road, at home, on the football field, in the boxing ring, and in many other distinct locations. When our role is over, there are only three places where head trauma victims can be found; in cemeteries, where every year, 5,000 new graves are made to accommodate fatal head injuries in Canada; in chronic hospitals, which are already overloaded with victims of various insults to the brain, and, of course, within society, which accepts the fully recovered or tolerates the subtle and not so subtle consequences of so-called ‘minor’ head injuries.

The past fifteen years has seen the classification of diverse substances into a group known as calcium antagonists (CAs). They have a common ability to reduce the transmembrane transport of extracellular calcium ions (CAe2+). This flow of calcium into vascular smooth muscle is ultimately associated with the development of tension and vasoconstriction. Some CAs appear to have a predilection for cerebral as opposed to systemic arteries and so may function as specific cerebral arterial vasodilators. It has been proposed that they might be useful in certain types of cerebral ischemia such as that due to arterial occlusion or prolonged vasoconstriction. Animal experiments and initial clinical trials give grounds for cautious optimism that CAs may become as useful in neurology as they have recently become in cardiology.

The year is included in the title of this review because the subject is the diversity of conditions that result in myoglobinuria, and new causes keep appearing as conditions in society change or new drugs are introduced. The syndrome is often linked to seamier aspects of society or medicine : war; sadistic drill sergeants; drug abuse; attempted suicide; self-medication or inadequate supervision of drug therapy. On the other hand, study of myoglobinuric syndromes has informed us about new hereditable biochemical causes and we have learned more about the action of viruses on muscle.

The problem of antiepileptic drug interactions is significant in that many epileptic patients are treated with multiple drug therapy. Moreover, patients may also be receiving additional medication for other concurrent disorders. Most drug interactions are pharmacokinetic, involving changes in absorption, protein binding, metabolism, or excretion. As a result, plasma levels of the antiepileptic drug may decrease leading to exacerbation of seizures. Alternatively, plasma levels may rise resulting in toxic side effects. Similar changes may also occur with drugs given for other disorders. In this paper, possible mechanisms of drug interactions are discussed. This is followed by a description of clinically significant interactions involving phenytoin, carbamazepine, barbiturates, valproic acid, benzodiazepines, and succinimides. Potentially serious drug interactions may be minimized by using as few medications as possible and by regularly monitoring plasma levels of antiepileptic drugs.

In 1969, Roger Guillemin and Andrew Schally independently reported the isolation and identification of the first hypothalamic neuropeptide, thyrotropin releasing factor (TRF). Following this landmark event in neuroendocrinology the ensuing years have witnessed a cascade of isolations of new neuropeptides and a virtual revolution in neurobiology. The discipline of neuroendocrinology has been remarkably impacted by the evidence that all of the “hypophysiotrophic” releasing factors presently identified are distributed widely throughout the brain with neurotransmitter or neuromodulator roles quite different from their actions of regulating the secretion of pituitary hormones. The study of these neuropeptide systems in activity of the central nervous system looms as one of the most exciting and significant eras in brain research. Although it is premature to assign specific roles for the presently known neuropeptides in pathogenesis of neurological diseases, our limited current knowledge already points to a numberof syndromes and clinical disorders which may be related to neuropeptide imbalance. Congential insensitivity to pain undoubtedly involves several peptide systems including Substance P, enkephalin, somatostatin and the endorphins. The opiocortins (β-endorphin, ACTH) of the brain as well as those of the pituitary gland are directly involved in the homeostatic mechanisms brought into action by such trauma as brain and spinal cord injury, septic shock and hemorrhage. The role of peptides in regulation of cerebral circulation will likely be identified with the etiology of stroke and the production of painful hemicranial syndromes. Among the most prevelant disorders of the human nervous system are the dementias and psychoses (Alzheimer’s disease, schizophrenia); subtle changes in brain peptide and receptor activity are being considered as responsible contributors to these diseases.

Most disorders of motor activity including disturbances of muscle tone and of locomotor activity observed in patients with neurological disorders have been reproduced experimentally in animals. Most motor disorders of the extrapyramidal type including those associated with Parkinson’s disease and choreiform and athetoid involuntary movements, have been reproduced exclusively in primates. This is most likely related to the highly complex organization of the extrapyramidal and related nervous mechanisms subserving the corresponding peculiar type of motor control in the primate brain. Other types of motor disturbances including cervical and trunkal dystonias, ataxia, hypotonicity, spasticity and intention tremor, however, have been successfully induced in various mammalian species. The latter types of motor disorders are related to disturbances of central nervous mechanisms which show similar patterns in the brains of different animal species. Histopathological and neurochemical changes associated with extrapyramidal disorders have been discovered and more precisely determined as a consequence of the development of new technical approaches. Therefore numerous morphological, physiological and neurochemical data concerning the extrapyramidal system are now available but a better knowledge of their precise and subtle interrelationship is greatly needed in order to develop more efficient therapeutic procedures.

Recombinant DNA techniques have provided the means to generate large numbers of new genetic linkage markers. This technology has been used to identify a DNA marker that coinherits with the Huntington’s Disease (HD) gene in family studies. The HD locus has thereby been mapped to human chromosome 4. The discovery of a genetic marker for the inheritance of HD has implications both for patient care and future research. The same approach holds considerable promise for the investigation of other genetic diseases, including Dystonia Musculorum Deformans.

We have been able to trace 40 cases of classical Friedreich's disease from 14 previously unrelated French Canadian kindreds to one common ancestral couple arriving in New France in 1634: Jean Guyon and Mathurine Robin.

One member of this couple presumably introduced one gene for Friedreich's disease into the French Canadian population. This gene has now been traced over 12 generations to both parents of the present cases. We plan to use this knowledge to study the spectrum of clinical manifestations of this gene and to carry out gene chromosomal localization studies, using the techniques of linkage and of molecular biology. Such studies in rare autosomal recessive disorders have previously been judged to be almost impossible.

In this essay I present a new “global approach hypothesis” to explain the pathophysiology of Parkinson’s disease: “Susceptibility to Parkinsonism is genetically determined and is reflected in all cells. I propose that idiopathic Parkinson’s disease is the combined result of a generalized cell aging process accelerated, in susceptible individuals, by a variety of often repetitive trigger factors. These factors have in common the fact that they cause a transient increase in turnover within catecholamine producing neurons, centrally as well as peripherally. This results in accumulation within these neurons of free radicals. When the level of the toxic substances, in quantity or in time of exposure, exceeds the scavenging capacity of the cell, damage to organelles and to membranes results, leading to the formation of Lewy bodies through an autoimmune reaction to damaged filaments and to cell death, particularly in the pigmented neurons of the brainstem. The progressive cell depletion leads to a compensatory increase in catecholamine turnover in the remaining pigmented cells, and an ever-accelerating degenerative process. The resulting neurotransmitter imbalance in the basal ganglia explains the symptoms of Parkinson’s disease”. In the light of this hypothesis, our research objectives should be (1) to delineate the limits of true Parkinson’s disease from all phenocopies; (2) to identify individuals susceptible to parkinsonism and the most common trigger factors; (3) to reduce the metabolic effects of unavoidable trigger factors and (4) to protect susceptible individuals by increasing the functional availability of free radical trapping agents.

To investigate the neural generators of the subcortical somatosensory evoked potential (SEP) waves we studied the far-field SEPs in 20 normal adults. We stimulated the median nerve at the wrist and used a 40k gain, 25 msec sweep and a 150-3000 Hz bandpass. We recorded SEPs simultaneously over C3′ and C4′ using a non-cephalic clavicle reference. The following series of six positive waves were found reliably in all subjects: P9, PI 1, P13, P14, P16 and P17.

The P16 and P17 probably arise from the thalamus and/or thalamocortical projections. Recent evidence suggests that the thalamus is not a closed field and thus one should be able to find corresponding waveforms in far-field recordings. We believe that this is a function of the bandpass used and with the above paradigm these components can be reliably recorded.

We found significant ipsilateral and contralateral amplitude asymmetries beginning with the negative deflection after P14 and including P16 and P17. The amplitude was greater over the contralateral hemisphere. This suggested that both P13 and P14 are generated prior to decussation of the afferent fibres in the medial lemniscus. Bilateral recording allowed detection of this asymmetry which has not been previously reported as a means of determining the electrophysiological correlates of lateralization.

Five patients had cervical spondylotic myelopathy (CSM) with severe prorioceptive sensory loss in the upper and lower limbs. Despite an advanced age, each recovered considerable function following cervical laminectomy, in follow-up periods of 10 to 40 months. The role of newer methods of investigation including CT scanning, somatosensory evoked responses and nuclear magnetic resonance is discussed. The cause of the proprioceptive sensory loss in these patients cannot be definitively determined, but various ischemic and compressive lesions are discussed as possible pathogenetic mechanisms.

There are a number of different types of involuntary saccadic eye movements which differ from normal saccades in that they take the fovea away from its target. This article presents a classification and description of these abnormal eye movements and indicates how they may be used to increase the precision of neurologic diagnosis.

Evidence from a variety of sources indicates that the mesolimbic-mesocortical dopamine projections may play an important role in some types of reward or reinforcement processes in animals. There is circumstantial evidence that this is also true in humans. Since a reduced ability to experience pleasure or reward (i.e. anhedonia) is a cardinal feature of clinical depression, and since the mesolimbic and mesocortical dopamine projections have been shown to degenerate in Parkinson’s disease, it is suggested that damage to these reward-related systems may contribute directly to the high incidence of depression that has been reported in this disease.

We have examined 138 cases of a disorder previously described in people of Portuguese origin and which has received many names. By computer analysis of 46 different items of a standardized neurological examination carried out in each patient, we have been able to delineate the main components of the clinical presentation, to conclude that the marked variability in clinical expressions does not negate the homogeneity of the disorder, and to describe the natural history of this entity which should be called, for historical reasons, “Machado-Joseph Disease”.

This hereditary disease has an autosomal dominant pattern of inheritance, presenting as a progressive ataxia with external ophthalmoplegia, and should be classified within the group of “Ataxic multisystem degenerations”. When the disease starts before the age of 20, it may present with marked spasticity, of a non progressive nature but often so severe that it can be accompanied by “Gegenhalten” countermovements and dystonic postures but little frank dystonia. There are few true extrapyramidal symptoms except akinesia. When the disease starts after the age of 50, the clinical spectrum is mostly that of an amyotrophic polyneuropathy with fasciculations accompanying the ataxia. For all the other cases the clinical picture is a c.ontinuum between these two extremes, the main determinant of the clinical phenotype being the age of onset and a secondary factor, the place of origin of the given kindred. The ataxic and amyotrophic components are clearly progressive with time in contrast to the spasticity component. Although the majority of known cases are of Portuguese origin, this is not obligatory. The next research endeavour should be a search for the chromosomal site of the gene, using molecular biology technology such as those for recombinant DNA.

Subdural hematomas (SDH) from ruptured aneurysm (RA) are much less common than intracerebral (ICH) hematomas or subarachnoid (SAH) or intraventricular hemorrhage (IVH). With computerized tomography, preoperative diagnosis is now made more often. The authors have collected 18 such cases from a review of 897 cases of RA admitted to eleven medical centers in 1980 and 1981. Nine (50%) of these patients died prior to discharge from hospital. Four (22%) had surgery and died postoperatively and 9 (50%) were operated upon and survived. Thirteen (72%) of the patients showed anisocoria, decreased consciousness and unilateral weakness prior to surgery. Eight (89%) of the fatalities had shown preoperative herniation as opposed to only 5 (56%) of the survivors. The overall incidence of delayed ischemia due to vasospasm was 11% (2 cases). Those who died had greater midline shift and larger SDH on the admission CT scan. Sixteen (89%) of these patients were female. Thirteen (72%) had ruptured aneurysms on the internal carotid artery. All of these hematomas were unilateral and uniformly hyperdense, and the convexity hematomas were crescentic in shape. Seventeen (94%) had evidence of blood in locations other than the subdural space. If the patient is potentially salvageable and has a midline shift, the SDH should probably be evacuated immediately and the aneurysm clipped at the same operation since the development of a tentorial herniation has such an adverse effect on outcome.

Fifty-nine patients were treated in a prospective, randomized comparison of pentobarbital and mannitol for the control of intracranial hypertension resulting from head injury. Patients with elevated intracranial pressure (ICP) after evacuation of intracranial hematomas were randomized to one of two treatment groups; mannitol initially or pentobarbital initially, followed by the second drug as required by further elevation of ICP. Similarly, patients with raised ICP but without hematomas requiring evacuation were randomly assigned to two treatment groups in an identical paradigm.

Those with ICP elevation and no hematoma treated with pentobarbital as initial therapy had a 77% mortality compared to a 41% mortality for those with mannitol as initial treatment. Patients with evacuated hematomas had mortalities of 40% and 43% (no significant difference) for pentobarbital and mannitol respectively. In both no-hematoma and hematoma streams pentobarbital was less effective than mannitol for control of raised ICP.

Multivariate statistical analysis indicates that pentobarbital coma is not better than mannitol for the treatment of intracranial hypertension and may be harmful in no-hematoma patients with intracranial hypertension after head injury.