J. G. McLeod

Treatment of multiple sclerosis with the monoclonal anti-CD4 antibody cM-T412: Results of a randomized, double-blind, placebo-controlled MR-monitored phase II trial

We report the results of a randomized, double-blind, placebo-controlled exploratory trial of the chimeric monoclonal anti-CD4 antibody cM-T412 in 71 patients suffering from active relapsing-remitting and secondary progressive multiple sclerosis. Infusion of the antibody produced frequent but usually minor side effects and resulted in a long-lasting reduction of circulating CD4-positive T cells. There was no significant effect on the primary measure of efficacy, the number of active lesions on monthly gadolinium-enhanced MRI over 9 months. Further statistical evaluation provided evidence that the degree of depletion of CD4-positive cells was important with regard to treatment efficacy; using CD4 counts as a covariate there was a statistically significant effect on the number of active lesions over 18 months (p= 0.04). There was a statistically significant reduction of 41% in the number of clinical relapses (a secondary efficacy parameter) after 9 months(p = 0.02), which was still present after 18 months, but this finding may be partly due to physician unblinding. Other secondary efficacy parameters (Expanded Disability Status Scale progression, number of courses of methylprednisolone) were not influenced by anti-CD4 treatment. We conclude that intravenous treatment with the monoclonal antibody cM-T412 in the dosage we used results in a substantial and sustained reduction of the number of circulating CD4-positive cells, but is not able to reduce MS activity as measured by monthly gadolinium-enhanced MRI, and is therefore unlikely to have a beneficial effect on the clinical disease course. We found preliminary evidence suggesting that more aggressive depletion of CD4-positive cells might lead to a more substantial reduction in MRI activity.

Prevalence of chronic inflammatory demyelinating polyneuropathy in New South Wales, Australia

A prevalence study of chronic inflammatory demyelinating polyneuropathy (CIDP) was performed in New South Wales (NSW), Australia, with a prevalence day of August 6, 1996, which coincided with a national census. The population of NSW was 5,995,544, and the crude prevalence of CIDP was 1.9 per 100,000 population. It was higher in male patients than in female patients, and the age‐specific prevalence reached a maximum of 6.7 per 100,000 population in the 70‐ to 79‐year‐old age group. The prevalence in the city of Newcastle, with a population of 448,663, was 2.0 per 100,000 population and is representative of the whole of NSW. The estimated crude annual incidence was 0.15 per 100,000 population. The mean age of onset was 47.6 years (median, 53.5 years), 51% of patients had a relapsing‐remitting course, the mean duration on prevalence day was 7.1 years (median, 5 years), and 87% of patients were able to walk without walking aids or other assistance.

Chronic polyneuropathy of undetermined cause.

The case histories of 519 patients with peripheral neuropathy on whom sural nerve biopsy had been performed were reviewed. In 67 patients (50 males, 17 females) (13%) who had symptoms of a symmetrical polyneuropathy for more than one year, the cause remained undiagnosed in spite of intensive investigation. Patients with inflammatory neuropathy were not included, but represented 17% of the whole series. The mean age of onset of symptoms was 50.6 years, and the median time from onset of symptoms to initial investigation was 2 years. Males were affected more commonly than females in a ratio of 3:1. The clinical features in 43 patients were those of a mixed motor and sensory neuropathy, in 17 patients a predominantly sensory neuropathy and in 7 patients a predominantly motor neuropathy. The mean CSF protein was 0.73 g/l and in only six patients was it greater than 1 g/l. Nerve conduction studies most commonly demonstrated mild slowing of motor conduction and impairment of sensory conduction. The usual pathological changes on sural nerve biopsy were those of chronic axonal degeneration. Forty seven patients (70%) were re-examined at intervals of time which ranged from 4 months to 12 years after their initial presentation and nerve biopsy (median, 3 years). As a group, they were only mildly disabled, the condition had a very slowly progressive course and there had been little change in their disability. A possible aetiological factor was found in 17 of the 47 patients (36%) and included malignancy, alcoholism, and benign paraproteinaemia. It is concluded that with intensive investigation the cause of chronic polyneuropathy of duration greater than one year remains undetermined in only about 13% of patients and that continued follow-up is worthwhile since a diagnosis may be established on re-examination.

Alcoholic neuropathy: An electrophysiological and histological study

Abstract Nerve conduction studies and sural nerve biopsies were performed on 11 patients with alcoholic neuropathy. There was significant slowing of motor and sensory conduction. There was a reduction in density of myelinated fibres of all diameters in the nerves. Single fibres were teased from the sural nerves; the predominant pathological changes were of axonal or Wallerian degeneration and regeneration. In the cases of patients who presented with an acute onset of neuropathy caused by a heavy bout of drinking and a poor diet, active axonal degeneration was a prominent feature in the nerves. By contrast, in those patients with a chronic neuropathy who gave a long history of heavy alcoholic intake and a good diet, regenerating fibres were seen in the nerves and there was little evidence of active axonal degeneration.

Acute idiopathic polyneuritis

Fifty patients with acute idiopathic polyneuritis have been studied clinically and electromyographically, and sural nerve biopsy was performed on 8 patients. Motor and sensory conduction studies were within the normal range in 7 patients (14%), and there was pronounced slowing of motor conduction in 25 patients (50%). There was no apparent correlation between the degree of conduction, and the clinical disability of the patient or the duration of the acute illness. Eighteen patients were re-examined at intervals up to 5 1/2 years after the onset of their illness. Eight patients (44%) were clinically normal at follow-up examination and 4 patients (22%) had a significant disability. There was no relationship between the clinical disability at follow-up examination and the results of initial or final nerve conduction studies. Electromyographic evidence of denervation, however, may indicate that complete clinical recovery will not occur. Segmental demyelination was the primary pathological change found in sural nerve biopsies and there was a significant reduction in the density of myelinated fibres in 2 nerves. It is suggested that a subacute onset of the illness,electromyographic evidence of denervation or gross slowing of conduction, and significant reduction of numbers of myelinated fibres or onion-bulb formation on sural nerve biopsy are factors which may indicate a prolonged course of the illness or incomplete recovery.

An electrophysiological and pathological study of peripheral nerves in Friedreich's ataxia

Abstract Nerve conduction studies were performed on the median, ulnar, and lateral popliteal nerves of 8 patients with Friedreichs ataxia. There was significant slowing of motor conduction, and impairment of sensory conduction. Sural nerve biopsies were performed on 5 of the patients. Histological examination demonstrated a reduction in the numbers of myelinated fibres, particularly those of large diameter. Teased single fibres showed no evidence of active degeneration, but a few fibres were seen to have regenerated after segmental demyelination. A striking feature of the myelinated fibres of two of the nerves was a significant reduction in internodal lengths. Quantitative electron-microscopic studies of the unmyelinated fibres demonstrated that they were present in normal numbers and that their axons were of normal diameter.

The peripheral neuropathy of vitamin B12 deficiency

Nerve conduction studies and sural nerve biopsy were performed on three patients with vitamin B12 deficiency and symptoms of peripheral neuropathy. The pathological findings were those of axonal degeneration; there was no evidence of demyelination. The patients were reviewed at intervals of 5-15 years commencement of treatment; progression of the neuropathy had been arrested by treatment, but in all cases residual neurological abnormalities persisted. In one patient with autonomic neuropathy, the postural hypotension resolved rapidly and fully with treatment.

Cyclosporin A in resistant chronic inflammatory demyelinating polyradiculoneuropathy

The role of cyclosporin A (CsA) in the treatment of resistant chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) was retrospectively reviewed in 19 patients who had failed to respond adequately to corticosteroids, plasmapheresis, intravenous immunoglobulin, and in some cases other immunosuppressive agents. Patients were subdivided into progressive or relapsing types according to the course of disease and response to therapy graded at follow‐up by clinical and electrophysiological criteria. In the progressive group, the mean disability status declined from 3.8 ± 0.7 to 1.8 ± 1.1 grades on a 5‐grade scale following CsA therapy (P < 0.001). In the relapsing group, the mean annual incidence of relapse declined from 1.0 ± 0.5 to 0.2 ± 0.4 after commencement of CsA (P < 0.05). Dose‐dependent, reversible nephrotoxicity was the most serious complication of therapy, and necessitated cessation of CsA in 2 patients. In conclusion, CsA is an efficacious and, with appropriate monitoring, safe therapy for patients with CIDP.

Multiple sclerosis in Australia and New Zealand: are the determinants genetic or environmental?

The prevalence of multiple sclerosis (MS) has been recently reported from nine regions of Australia and New Zealand. There is a marked variation of prevalence with latitude. MS is seven times more common in southern New Zealand than in tropical Queensland. On current evidence, it is suggested that in both countries this variation is predominantly due to environmental rather than genetic factors.

Progressive increase in incidence and prevalence of multiple sclerosis in Newcastle, Australia: a 35-year study

The prevalence of multiple sclerosis (MS) in Newcastle, Australia increased significantly between 1961 and 1981 and the incidence of the disease also increased between the decades 1950-1959 and 1971-1981. The present study sought to determine whether there has been a further increase in the frequency of MS in the subsequent 15 years, and to examine the potential factors underlying this change. The incidence, prevalence and clinical profile of multiple sclerosis were therefore re-examined in Newcastle, Australia in 1996 using comparable diagnostic criteria and methods to those employed in studies in the same region in 1961 and 1981. There has been a significant progressive increase in prevalence from 19.6 to 59.1 per 100,000 population and a significant increase in incidence from 1.2 to 2.4 per 100,000 population from 1961 to 1996. The most pronounced increase in prevalence was in females and in the age-group over 60 years, and there was also an increased incidence in females aged 20-29 years. There was little change in the age of disease onset, but duration of disease in females had increased substantially. The significant increase in prevalence is attributed to increased incidence, particularly in females; and to increased survival. Although such trends in prevalence have been observed in the Northern Hemisphere, this is the first such study in the Southern Hemisphere to show a longitudinal increase in prevalence and incidence over a period of this duration.