Eight anticonvulsant drugs – including clonazepam, diazepam and phenobarbital – were tested for their effects on GABA-stimulated chloride uptake in rat cerebral cortical microsacs (unfiltered synaptoneurosomes). “Mid” and “high” therapeutic concentrations were screened, and, if significant enhancement was found, full concentration-response tests were done. In the initial screens, enhancement of GABA-stimulated uptake was found only with phenobarbital, clonazepam and diazepam. In subsequent concentration-response tests, the effects of phenobarbital were found to occur throughout the range of normal, anticonvulsant concentrations, whereas the effects of clonazepam and diazepam were observed only above the concentrations normally used for the chronic control of seizures or anxiety. These data suggest that phenobarbital's anticonvulsant effects are mediated via the GABAA receptor complex, but that the low-dose effects of the benzodiazepines may be mediated via some other mechanism.

99mTc-HM-PAO single photon emission computed tomography (SPECT) was used to image 30 patients referred for the assessment of dementia. SPECT images revealed various patterns of regional cerebral perfusion (rCBF) in the subgroups of patients with the clinical diagnoses of Alzheimer's disease (AD, n = 14), Pick's disease (n = 1), and multi-infarct dementia (n = 7). In three patients, SPECT clarified the clinical differential diagnostic possibilities. Using a relative rCBF quantification technique, the relationship between specific cognitive impairments and rCBF in the AD patients was determined. There was a significant correlation between language impairment and left hemisphere hypoperfusion, whereas, apraxia correlated with hypoperfusion in the left parietal region. Thus, HMPAO SPECT is useful as an aid in the differential diagnosis of dementia and the technique of relative rCBF quantification with SPECT may contribute to the understanding of the clinico-anatomical relations of cognitive deficits in dementia.

The relationships between cerebral blood flow (CBF), cerebral metabolism (cerebral metabolic rate of oxygen, CMRO2) and cerebral oxygen extraction (arteriovenous difference of oxygen, AVDO2) are discussed, using the formula CMRO2 = CBF × AVDO2. Metabolic autoregulation, pressure autoregulation and viscosity autoregulation can all be explained by the strong tendency of the brain to keep AVDO2 constant. Monitoring of CBF, CMRO2 or AVDO2 very early after injury is impractical, but the available data indicate that cerebral ischemia plays a considerable role at this stage. It can best be avoided by not "treating" arterial hypertension and not using too much hyperventilation, while generous use of mannitol is probably beneficial. Once in the ICU, treatment can most practically be guided by monitoring of jugular bulb venous oxygen saturation. If saturation drops below 50%, the reason for this must be found (high intracranial pressure, blood pressure not high enough, too vigorous hyperventilation, arterial hypoxia, anemia) and must be treated accordingly.

Diabetic polyneuropathy is a major complication of diabetes mellitus that frequently leads to foot ulceration. Because of economic impact of foot ulceration and subsequent amputation, major initiatives are under way in the United States and the United Kingdom to reduce their incidence by up to 50%. Although diabetic ulcers may have an ischemic and neuropathic component, the majority are neuropathic. Results from studies have shown a strong association between the neuropathy and the subsequent development of foot ulcers. However, other predisposing factors such as high foot pressures, inappropriate footwear, and other extrinsic pressure usually must be present, together with neuropathy, to cause foot ulcers. Therefore, the challenge to the physician is to identify the patient at risk and intervene so as to educate and prevent the occurrence of foot ulcers.

No new antiepileptic drugs (AEDs) were licensed in the United States from 1978 to 1992. In late 1992, felbamate and gabapentin were recommended for approval, and in early 1993, lamotrigine. In July 1993, felbamate was licensed, and gabapentin and lamotrigine may soon follow. Lamotrigine, vigabatrin and clobazam are in use outside the US. Tiagabine, oxcarbazepine, fosphenytoin, topiramate, vigabatrin and zonisamide are in Phase II clinical testing in the US. All of the new AEDs are effective against partial and tonic-clonic seizures. Few controlled clinical trials have been done in patients with absence and myoclonic seizures. Mechanisms of action of the new drugs have not been clearly defined. The new AEDs will provide an opportunity to improve the care of epileptic patients. Even with optimal management with currently available drugs, some 30% of patients remain refractory to medical management.

We report three patients with striatonigral degeneration highlighting the correlation between magnetic resonance imaging (MRI) and the pathological changes. The “slit-like void signal” observed in the putamen is typical of striatonigral degeneration and can be used to assist diagnosis during life. Our histochemical studies support the concept that increased iron deposition in the putamen is responsible for this MRI picture.

We describe eleven mid-western Canadian aboriginal infants with a unique, progressive muscle disorder. All except one had muscle biopsy and/or autopsy. The infants were normal newborns who rapidly developed rigidity of all skeletal muscles, with early, respiratory insufficiency. Death occurred before 18 months of age. Electromyography showed increased insertion activity and profuse fibrillation potentials; motor unit potentials and interference pattern are normal until late in the course. Pathologic features include progressive, granular to powdery Z-band transformation, myofibrillar loss, and muscle regeneration. SDS-gel electrophoresis of one muscle sample revealed increased 54kDa and reduced 80kDa protein fractions. This disease differs from other conditions with Z-band alterations because of continuous muscle activity and relentless clinical progression. The clinical features, elevated serum creatine kinase, electromyographic and muscle biopsy findings suggest a dystrophic process. The recognition of this condition as an autosomal recessive disorder allows appropriate genetic counselling.

Although fatigue is recognized as a symptom of MS, there have been insufficient methods for evaluating this symptom. We administered the Fatigue Impact Scale to 85 MS patients and 20 hypertensive patients. Neurologic impairment, mental health, and general health status were also assessed. MS patients reported significantly higher fatigue impact than hypertensive patients. Most MS patients reported fatigue as either their worst (14%), or one of their worst (55%) symptoms. Disease classification and neurologic impairment had little bearing on Fatigue Impact Scale scores in the MS sample. The best predictive models for mental health and general health status in the MS sample both included the Fatigue Impact Scale as a significant factor. This study demonstrates that: 1) fatigue is a very prevalent and severe problem in MS, 2) fatigue impact cannot be predicted by clinical measures of neurologic impairment, 3) fatigue has a significant effect on the mental health and general health status of MS patients.

In our centre, 111 patients have been treated with linear accelerator stereotactic radiosurgery. Angiographic, CT and MRI images are generated and the target coordinates calculated in 3 dimensions. For CT scanning, cross sections of perpendicular and oblique fiducial markers are seen. For follow-up CT scans done without the frame, a virtual frame is generated by means of a computer program that places fiducial markers on each CT scan cut, as if the patient had been wearing the OBT frame and the scan produced with the gantry parallel to the base of the frame. The position of the oblique marker may be calculated by knowing the thickness and position of each CT cut. Various natural fiducial markers (bony landmarks) are identified by coordinates in the scan with the patient wearing the real frame and in the scan with the virtual frame applied. A transformation matrix is utilized to establish the equivalence between the original CT scan with the real frame applied and subsequent scans without the real frame but with the virtual frame applied. In effect, the virtual frame is re-applied in exactly the same position as the real frame. Lesion measurements may then be duplicated and growth or regression accurately established. The uncertainty in this system of re-application resides in possible patient movement, CT scan slice thickness and inter-observer error in the identification of natural fiducial markers.

Complications were examined in a single surgeon’s series of 207 consecutive adult patients undergoing first craniotomy for intra-axial brain tumour. The study group consisted of 114 gliomas, 74 metastatic tumours and 19 miscellaneous lesions. There were 25 infratentorial tumours and 182 supratentorial tumours (39 deep and 143 superficial). The total number of patients sustaining complications was 52 for an overall complication rate of 25.1%; the rate was higher for infratentorial tumours (44.0%) than supratentorial tumours (22.8%) regardless of histology (p = 0.012). There were 5 deaths for a mortality rate of 2.4%. Forty-seven patients incurred operative morbidity (22.7%); 7 out of the 47 had multiple complications. Sixteen patients sustained transient worsening due to edema (7.7%) and 6 patients sustained permanent neurological deficit (2.9%). Medical complications were suffered by 17 patients (8.2%). Major complications which significantly altered the quality and/or quantity of survival were suffered by 9 patients overall (4.3%).

Sixteen stroke patients suffering from ataxic hemiparesis syndrome were studied with regional cerebral blood flow measured by 133-Xenon inhalation technique (12 patients) and by SPECT (HMPAO) (9 patients). The causative lesions (hematoma in 7 and infarct in 9), unilateral in 15 patients and bilateral in 1, were located in the posterior two-thirds of the corona radiata, thalamocapsular and subthalamus regions, or cerebral peduncle. Ataxia of the cerebellar type was unilateral in 15 patients and bilateral in 1 with similar, deep, bilateral causative lesions. Four patients presented some characteristics of proprioceptive ataxia (mixed ataxia). Associated cognitive disturbances were present in 9 patients and absent in 7. Eleven of the 12 subjects studied by 133-Xenon inhalation technique showed limited centro-parietal hypoperfusion, mainly in the inferior parietal lobule, ipsilateral to the causative lesion and bilaterally in the patient with bilateral lesions and ataxia. Ipsilateral hypoperfusion was confirmed in 7/9 patients studied by SPECT, which also demonstrated contralateral cerebellar hypoperfusion in 4 patients. These findings suggest that ataxic hemiparesis syndrome results from functional depression (diaschisis) consequent to the interruption at many levels of an “inferior parietal associative cortex - cerebellar anterior lobe” circuit.

Electroencephalography (EEG) and evoked potential studies are established monitoring tools in the neurological intensive care unit (ICU). These neurophysiologic techniques provide information on physiological state and response to therapy, and may aid diagnosis and prognosis. Serial studies or continuous monitoring may enable changes to be detected prior to irreversible deterioration in the patient's condition. Current computer technology allows simultaneous display and correlation of electrophysiologic parameters, cardiovascular state and intracranial pressure (ICP). Continuous EEG monitoring in the ICU has been shown to have a decisive or contributing impact on medical decision making in more than three-quarters of patients. In addition, continuous EEG monitoring has revealed previously unsuspected non-convulsive seizures in one-third of patients. SEPs and BAEPs can provide useful prognostic information in coma - however, these tests are etiologically nonspecific and must be carefully integrated into the clinical situation. Motor evoked potentials offer a potentially useful tool for evaluating motor system abnormalities in the ICU.

A number of autoimmune diseases and immune-related conditions were investigated in a series of 100 Alzheimer patients and their families. The group was divided into those who had familial dementia of the Alzheimer type and non-familial dementia of the Alzheimer type. HLA DR3 was associated with the familial dementia of the Alzheimer type patients. Adult exposure to tuberculosis appeared to be a risk factor for familial dementia of the Alzheimer type patients. Autoimmune diseases clustered among the non-familial dementia of the Alzheimer type patients, and also among their relatives. Asthma and infertility were also significantly increased among non-familial dementia of the Alzheimer type relatives. The analysis showed that (1) autoimmunity may be important in the sporadic form of Alzheimer disease; (2) it may be possible to confer a decreased risk for Alzheimer disease among relatives when many autoimmune diseases occur in the family; (3) it may be important to assess environmental risk factors for Alzheimer disease separately in patients with familial and sporadic disease; and (4) the efficacy of drug therapies may be dependent on whether the patients have a familial or sporadic form of Alzheimer disease.

This paper describes the development and testing of a computer algorithm to automate the process of peak identification and somatosensory evoked potential (SSEP) grading. We tested the accuracy of computerized peak detection and evaluated grading schemes using a test set of 60 SSEPs ranked from worst to best by the programmer (RJM) and a blinded grader (PO). The computer algorithm recognized 95% of peaks identified by visual inspection. Twelve percent of peaks identified by the computer were noise. Summed peak to peak amplitude gave the most accurate ranking of SSEPs. Rank correlation between computer and blinded and unblinded expert grading was r = .82 for PO, r = .92 for RJM, p < .0001 for both. Computer and manually summed amplitudes were highly correlated (Pearson r = .98, p < .0001). Correlation between the 2 expert graders was .86, p < .0001. Computer graded SSEPs were significantly related to clinical outcome at 3 months, p < .0001. Automatic grading of SSEPs using summed peak to peak amplitude is highly correlated with expert grading. The measure is objective, continuous, and well suited to statistical analysis.