This paper is directed primarily to clinicians who diagnose and treat patients with neurological disorders. It is an attempt to illustrate that even with modern imaging technology and other advances in laboratory testing, a thorough understanding of neurophysiology and its anatomical substrate still plays an important role in the diagnosis and management of patients with neurological diseases. One area in neurophysiology in which there has been great progress in the last few decades is the ocular motor system. Particular interest has been focused on the ways that the brain can adapt to lesions, and more specifically, how the ocular motor system keeps itself calibrated in the face of normal development and aging as well as in response to disease and trauma. Since disorders of eye movements are such common and often dramatic manifestations of neurological disease it seems appropriate to bring some of the newer concepts in ocular motor physiology to the “bedside”.

Diabetic polyneuropathy is a complex disease of progressive nerve fiber loss. Initial screening and diagnosis in clinical practice usually depend on assessment of subjective complaints. A need exists for objective, simple, and reproducible assessment tools that can be readily used in clinical practice. The importance of early diagnosis is highlighted by the recent North American Diabetes Control and Complications Trial where intensive insulin therapy reduced the risk of developing diabetic neuropathy by 61%. At the University of Michigan, we have developed an outpatient neuropathy program. Patients are given a questionnaire and a brief screening examination, designated the Neuropathy Screening Instrument. Diabetic neuropathy is confirmed and staged in patients with a positive Neuropathy Screening Instrument, by a quantitative neurologic examination and nerve conduction studies, designated the Diabetic Neuropathy Score. The Michigan program has been compared with well-established instruments and has been found to be sensitive and reproducible for screening and diagnosis. We believe the program provides a valuable tool for the clinician in the practice setting and should allow diagnosis and intervention earlier in the course of diabetic neuropathy.

In choosing an antiepileptic drug, not only efficacy but also potential adverse effects have to be considered. Adverse effects that have to be taken into account include acute and chronic systemic toxicity, cognitive side effects, and teratogenesis. Acute toxicity may be dose-related, allergic or an idiosyncratic reaction. Chronic toxicity may involve the nervous system or other organs. In determining the role of new antiepileptic drugs such as lamotrigine, vigabatrin, felbamate, and gabapentin a proper evaluation of both efficacy and adverse effects is required.

The neonatal cat model of kaolin-induced hydrocephalus is associated with progressive and severe ventriculomegaly. In this experiment we studied the evolution of the histopathological changes in hydrocephalic (n = 23) cats from 5–168 days after the induction of hydrocephalus along with age-matched controls (n = 10). In the periventricular white matter, extracellular edema and axonal damage were present within days of the onset of hydrocephalus. This was followed by reactive gliosis, white matter atrophy, and in some animals gross cavitation of the white matter. Even in the chronic, apparently compensated state there was ongoing glial cell death. Six cats were shunted an average of 23.6 ± 6.5 days after the induction of hydrocephalus because they were no longer able to feed independently. In spite of clinical improvement the white matter changes persisted. Overt cortical changes were minimal except where areas of white matter destruction encroached upon the deep layers. The white matter changes are very similar to those seen in periventricular leukomalacia and suggest that ischemia plays a role in neonatal brain injury caused by hydrocephalus.

At least four distinct cerebral diseases — Wernicke-Korsakoff, Marchiafava-Bignami, pellagrous encephalopathy, and acquired hepatocerebral degeneration — have a close association with chronic alcoholism. Each is characterized by a distinctive pathologic change and a reasonably wellestablished pathogenesis; in each the role of alcohol in the causation is secondary. The question posed in this review is whether there is, in addition to the established types of dementia associated with alcoholism, a persistent dementia attributable to the direct toxic effects of alcohol on the brain — i.e., a primary alcoholic dementia. The clinical, psychologic, radiologic, and pathologic evidence bearing on this question is critically reviewed. None of the evidence permits the clear delineation of such an entity. The most serious flaw in the argument for a primary alcoholic dementia is that it lacks a distinctive, well-defined pathology, and it must remain ambiguous until such time as its morphologic basis is established.

Electrophysiological studies are a reproducible and noninvasive method of assessing peripheral nerve function. The sensitivity of these methods has been validated in population-based and clinical studies, and the variability of test results is typically lower than with other noninvasive tests of nerve function. It has been recommended that standardized procedures including temperature control and equipment calibration be utilized with electrophysiological testing. The failure to detect significant changes in nerve conduction studies from clinical studies may be due to poor standardization of technique and inadequate sample size to detect differences. Baseline results from a multicenter, randomized trial indicate that different electrophysiological measures are highly correlated and reproducible. This and future studies that incorporate standardized techniques and an adequate sample size should be able to detect significant differences between treatments and identify effective therapeutic interventions for diabetic neuropathy.

Acute and chronic toxicity complicates all antiepileptic medications (AED) and is idiosyncratic. Acute toxicity can be categorized into 1) acute brain dysfunction or 2) acute organ dysfunction when AED’s are started. Despite promising in vitro lymphocyte testing, anticipation of acute reactions cannot be offered. Furthermore, screening for AED toxicity by routine blood and urine tests in asymptomatic patients is of doubtful value and should be abandoned. Patients should be informed of possible reactions and immediately report early symptoms. Treatment for acute reactions is largely unstudied. It is unclear how to reintroduce AED’s following acute reactions. Often patients are sensitive to drugs with a similar chemical structure. The “desensitization” protocol of Purvis may be of merit. Three major chronic toxicities of AED’s have been noted – soft tissue and gum hypertrophy, progressive ataxia, and peripheral neuropathy. New AED’s require careful post-marketing surveillance since long term toxicity data are not yet available.

With the development of modern imaging techniques, disturbances of neuronal migration appear to be a major cause of epilepsy, mental retardation and chronic neurological disability in childhood. Sixty-nine cases are presented, including 46 of diffuse migration abnormalities and 23 of localized dysplasia. Patients with diffuse migration disorders presented with mental retardation, gross motor impairment and severe seizure disorders whereas in those with focal anomalies, epilepsy was the chief complaint. Magnetic resonance imaging, although usually diagnostic of migration disorders often does not allow definition of the pathologic type. Some EEG patterns, such as high amplitude fast rhythms or the theta-delta pattern are highly suggestive. Most cases of abnormal migration are sporadic and probably acquired. Some are due to chromosomal anomalies, especially of chromosome 17p where a gene for lissencephaly has been mapped. Familial cases occur with both recessive and possibly dominant inheritance. Epilepsy due to migration abnormalities is often intractable. Resection of dysplastic cortex may be effective for localized disease and callosotomy has been proposed for diffuse anomalies.

Diabetic neuropathy is a major complication of diabetes mellitus affecting to an equal extent type 1 and type 2 patients. Various mechanisms including metabolic and vascular abnormalities have been proposed to explain the progressive pathological changes that occur in peripheral nerve. Regardless of the precise mechanisms, structural abnormalities lead to functional changes which eventually result in the clinical manifestations of diabetic neuropathy. Possible interventions that may influence the progressive disease process include intensive insulin therapy and aldose reductase inhibitors. This article reviews the proposed pathogenetic mechanisms underlying diabetic neuropathy, their effects on nerve histomorphometric changes and ultrastructure typical of diabetic neuropathy, and potential therapeutic interventions and their impact on disease progression.

The PC 10, a monoclonal antibody against proliferating cell nuclear antigen (PCNA), is known to show immunoreactivity in routinely processed paraffin embedded tissue. This antibody was applied to 72 astrocytic tumours from surgical biopsy material obtained in a ten year period. The PCNA labelling index (LI) obtained by image analysis was compared with patient’s survival, age at diagnosis, and Karnofsky score as well as the histological grade of tumour. The survival analysis shows that patients with tumour PCNA LI of more than 6% have significantly poorer prognosis than those with 6% and below. In addition, there is also good correlation between PCNA LI with age, Karnofsky and tumour grade. This study suggests that although the PCNA expression of astrocytoma could be a useful predictor of patient’s outcome, it is not an independent prognostic factor but has derived its statistical association with survival secondarily through its relationship with tumour grade, age and Karnofsky score.

All of the established antiepileptic drugs (AEDs) can produce cognitive side effects, which are increased with polypharmacy and with increasing dosage and anticonvulsant blood levels. However, cognitive side effects are usually modest for AED monotherapy with anticonvulsant blood levels within the standard therapeutic ranges. Further, these effects are offset in part by reduced seizure activity. Controversy exists regarding possible differential cognitive effects of AEDs. A large portion of the literature examining the comparative cognitive effects of AEDs is limited by inadequate study designs. When these design flaws are considered, there is no convincing evidence of clinically significant differences in cognitive side effects of AEDs except possibly for bromide, phenobarbital and benzodiazepines. The role of cognitive side effects should be kept in proper perspective when choosing AED therapy. The cognitive side effects of anticonvulsant drugs may be overt but many times are rather subtle. It is important though to be able to recognize these effects and to put them into perspective as to how they affect our patients.

We studied the influence of sulindac, a nonsteroidal anti-inflammatory agent on experimental streptozotocin-induced diabetic neuropathy. Untreated diabetic rats were compared with nondiabetic rats, diabetic rats treated with low dose insulin and diabetic rats given sulindac (6.0 mg/kg by gavage 5 of 7 days weekly). Neuropathy was assessed by following serial in vivo motor and sensory caudal conduction, resistance to ischemic conduction failure, and in vitro conduction in sural myelinated and unmyelinated sensory fibers. The impact of low dose insulin and sulindac treatment on the microenvironment of the L4 dorsal root ganglion and sciatic endoneurium was asssessed by measuring local perfusion and oxygen tension after 16 weeks of diabetes. Sulindac normalized conduction velocity in caudal sensory fibers, sural myelinated fibers and sural unmyelinated fibers, and reduced the number of diabetic cataracts. Sulindac also normalized a deficit in dorsal root ganglion blood flow and a reduction in sciatic endoneurial oxygen tension in diabetic rats. Low dose insulin improved neuropathy as well but the pattern of benefits was less robust than that of sulindac. Sulindac may be a candidate for a clinical trial in human diabetic polyneuropathy.