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.

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.

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.

A few human diseases may be viewed from a phylogenetic perspective. Some metabolic or degenerative diseases selectively affect recently evolved or exclusively mammalian structures of the brain and spare the older structures. Examples include Krabbe’s leukodystrophy, olivopontocerebellar atrophy, Friedreich’s ataxia, Pick’s disease, and Leber’s optic atrophy. Some pathologic conditions in man are similar to normal anatomy in other species, although the mechanisms may differ. Congenital muscle fiber-type disproportion in rodents, Dandy-Walker cyst in birds, and agenesis of the corpus callosum in marsupials are representative of this category. Loss of basal dendritic spines from pyramidal cells in Pick’s disease is reminiscent of certain large neurons normally found in the cortex of reptiles. Changes in metabolism in the evolution of mammals in general and of man in particular may explain some aspects of’phylogenetic diseases’. Some potential examples are the shift from predominantly phospholipids to galactolipids in myelin composition as mammals evolved, and the greater toxicity of cyanide and other poisons of oxidative metabolism in mammals than in other vertebrates because of less reliance on anaerobic metabolism as an alternative energy source.

Although many types of sports and recreational activities have been identified as common causes of acute spinal cord injury, hockey has been a rare cause of acute cord injury in Canada or elsewhere. For example, from 1948 to 1973 there were no patients with cord injuries due to hockey in a series of 55 patients with acute cord injuries due to sports or other recreational activities admitted to two Toronto hospitals. In contrast, between 1974 and 1981, the Acute Spinal Cord Injury Unit, Sunnybrook Medical Centre treated six patients with cervical spinal injury due to hockey, five of whom were seen during a 13 month period from September, 1980 to October, 1981. Five of the six sustained a severe acute cervical spinal cord injury, and one a cervical root injury. The cord injury was complete in two cases, while three had complete motor loss but incomplete sensory loss below the level of the lesion. All were males aged 15 to 26 years. Of the players with cord injury, four struck the boards with the neck flexed, and one struck another player with the neck flexed. The one player without cord injury struck the boards with his neck extended. The commonest bony injury was a burst fracture of C5 or C6. One of the patients with a complete cord injury died three months later of a pulmonary embolus, and the other patients with cord injury showed some recovery of root function, but little or no cord recovery. The reasons for the increase in spinal injuries in hockey are unknown.

Acute vasospasm of the transclivally exposed basilar artery of anesthetised cats was produced by the subarachnoid injection of platelet-rich plasma (PRP) treated with enough adenosine diphosphate (ADP) to induce platelet aggregation and secretion. Vasorelaxation was produced by the topical application of the calcium antagonist verapamil. Changes in the internal diameter of the basilar artery were determined by measuring the blood column diameter from photomicrographs taken sequentially, at 5 minute intervals, through the operating microscope. Changes in blood vessel diameter are expressed as a plus or minus percentage of the pretreatment diameter. Arterial blood pressure and blood gas values were kept in the physiological range for the cat.

The subarachnoid injection of PRP-ADP produced severe constriction of the basilar artery (mean constriction at 5 minutes after injection: -40.7% ± 2.8 SEM). Platelet-free plasma, ADP alone and Elliott’s A solution had no spasmogenic effect when injected into the subarachnoid space. The topical application of the calcium channel blocker verapamil (0.1 mg per kg) 30 minutes after the injection of PRP-ADP, with the basilar artery still in spasm (mean constriction: -23% ± 3.5 SEM), produced prompt and dramatic vasodilation (mean dilation at 5 minutes after application: + 52.7% ±18.1 SEM). This spasmolytic effect persisted in a decremental fashion for the 60 minute period of observation, by which time the previously constricted vessel had returned to its normal size. These observations indicate that the platelet fraction of whole blood may be involved in the genesis of acute vasospasm following subarachnoid hemmorhage and that this phenomenon can be readily reversed by calcium antagonism.

We report a 59 year old woman who presented with double vision, nuchal pain and mild dementia. On neurological examination she demonstrated third, sixth and seventh nerve palsies and ataxia. Following intravenous ACTH and oral prednisone therapy she showed a remarkable recovery which left her with only a left facial weakness. She remained well for two years. She then developed bulbar palsy and profound dementia. Pathological examination revealed progressive supranuclear palsy (PSP). This patient demonstrated a greater variability in the course of PSP than has previously been recognized.

Forty patients with MS initially tested in our laboratory were recalled for repeat PSVEP testing approximately two years later. Twelve normal controls were tested in a similar manner approximately two years apart. The PSVEP positive peak latency changed little in the 24 control eyes (mean 1.4 msec, range 0-6) over the study interval. Most MS patient eyes also showed little change in PSVEP latency over the two year study interval. Fifty-eight eyes changed 8 msec or less. Eighteen eyes showed a PSVEP latency increase of 10 msec or more. Six of these eighteen eyes were symptomatic (attack of clinical optic neuritis), twelve asymptomatic during the study interval. Symptomatic eyes tended to have greater latency increases during the study interval than asymptomatic eyes.

Significant latency increases occurred with equal frequency in previously normal eyes (normal PSVEP on first test) and abnormal eyes (abnormal PSVEP on first test or previous clinical optic neuritis). Significant latency increases occurred with greater frequency in patients with a mixed or progressive course than in patients with a remitting-relapsing course, and in patients with greater disability ratings (Kurtzke 3-7) than in patients with lower disability ratings (Kurtzke 0-2). Bilateral latency increases occurred during the study interval more frequently than expected by chance. Patient age and disease duration did not significantly influence the number of PSVEP latency increases seen during the study interval.

Four eyes decreased in latency by 10 msec or more during the study interval. All these eyes had had an episode of acute optic neuritis which began in the 5 weeks immediately preceding the 1st PSVEP test.

In our MS patients, 13% of eyes per year developed latency increases of 10 msec or more. These may represent new demyelinating lesions. If so, one-third of these lesions were clincally symptomatic.

Auditory brainstem responses (ABRs), visual and somatosensory evoked responses (VEPs and SEPs) and nerve conduction studies were conducted in 5 patients with abetaiipoproteinemia. The ABRs were normal in all cases. The VEPs were of normal amplitude but of increased latencies in two patients. The four eldest patients had delayed cortical SEPs but normal peripheral sensory nerve conduction studies. The peripheral motor conduction velocities were normal in all cases. The peripheral sensory studies showed normal velocity when a response was seen; however, the amplitude of the response was often reduced or it was absent. The electrophysiological studies reported here support a model of axonal loss of large myelinated fibres with secondary demyelination in abetaiipoproteinemia.

Cerebral aneurysms are extremely rare in all animals except man. We report the occurrence of a carotid-ophthalmic aneurysm in a cynomolgous monkey two months following accidental occlusion of the ipsilateral cervical internal carotid artery. This was documented angiographically. The aneurysm was deliberately ruptured by the insertion and withdrawal of fine needles. This produced a large subarachnoid hemorrhage visualized on CT scan. There was a progressive severe fall in cerebral blood flow and moderate vasospasm. The neurological status deteriorated on the tenth day and the animal was sacrificed on day 13. On electron microscopy, the aneurysm showed a fibrous wall, and the endothelium showed balloon-like endothelial cells with gaps. Corrugations occurred in the inner aspect of the anterior circulation arteries.

A 76 year old patient with a long history of headaches was found to have Paget’s disease and communicating hydrocephalus. There were (otherwise) no neurological or musculo-skeletal manifestations of Paget’s disease, but moderate impairment of intellectual function was present. Treatment with disphosphonates did not bring any significant improvement, but three days following a ventriculo-atrial shunting procedure, the patient became headache-free for the first time in several years.

In the literature, patients with hydrocephalus have been shown to respond quite unevenly to atrio-ventricular shunting, but in most instances the descriptions concerned advanced cases with well-established symptoms of dementia, ataxia and incontinence. Our case is reported to stress the importance of early diagnosis and management of hydrocephalus in Paget’s disease for the prevention of widespread neurological dysfunction.

An Amerindian girl with Friedreich’s ataxia presented at the age of 14 years with intermittent bifrontal headaches and abdominal aching, often associated with nausea and recurrent vomiting and an evanescent pink, blotchy rash on the upper trunk. In these attacks she also had hypertension up to 210/160 mm Hg. Renal function studies, including intravenous pyelogram and angiography, were normal. Plasma renin activity (2.5 ng/ml/hr) was also normal. Total body CT scan was negative for phaeochromocytoma, and repeated estimations of 24-hour excretion of urinary VMA were normal or borderline high. Levels of total catecholamines in 24-hour urine were normal twice, but two random specimens during the paroxysmal episodes contained abnormally high levels of norepinephrine and dopamine. Plasma catecholamine concentrations were increased but not as high as with phaeochromocytoma. Blood pressure monitoring demonstrated marked fluctuations with position and temperature. A clonidine suppression test showed a substantial fall of plasma catecholamine levels, consistent with dysautonomia and not with phaeochromocytoma. It is concluded that the patient has dysautonomia of central origin, probably as a manifestation of Friedreich’s ataxia. These findings are discussed in relation to the recent demonstration of increased levels of plasma catecholamines in that disease.

Haemophilus influenzae type b (HIb) is the most common cause of bacterial meningitis in children with a mortality rate ranging from 1.6% to 14%. Most patients have a 2-3 day history of symptoms prior to admission. A few have fulminating disease with rapid neurological deterioration. Review of 191 cases of HIb meningitis revealed a mortality rate of 2.1% but all who died had fulminating meningitis (FM). Four of six patients with FM died. FM patients had symptoms for less than 24 hours before rapid neurological deterioration with increased ICP, seizures, coma and/or respiratory arrest. Review of 10 FM cases revealed that on admission, 5 had hypotension, 3 had thrombocytopenia, and 8 had coma. Typical CSF changes were seen in only 7. All fatal cases died within 24 hours. Brain swelling and tonsillar herniation were found at autopsy. SDS-PAGE outer membrane protein subtyping did not show one “killer strain”. Animal and autopsy data suggest that diminished CSF outflow and cerebral edema contribute to increased ICP. To improve survival of FM patients, initial treatment must (1) decrease ICP below levels impairing cerebral perfusion, (2) maintain adequate ventilation and blood pressure, and include (3) LP when stable, (4) antibiotics, and (5) close monitoring. Utilizing these principles, two FM patients survived without major sequelae.