Robert W. Baumhefner

Multiple sclerosis de novo CNS IgG synthesis Effect of ACTH and corticosteroids

ACTH gel and corticosteroids were given to 28 clinically definite multiple sclerosis (MS) patients to determine whether de novo central nervous system (CNS) IgG synthesis (rate and cerebrospinal fluid [CSF] IgG oligoclonal bands) could be eradicated. The most effective treatments were ACTH gel and ACTH gel followed by prednisone; all 11 patients had a significant reduction in rate (p < 0.051, which became normal in eight patients (< 3.3 mg per day). In order of effectiveness, the other drugs used were: dexamethasone or prednisone given orally, and hydrocortisone administered intrathecally. For most treatments, reduction of the rate of CNS IgG synthesis occurred within days and persisted for months after cessation of treatment. The MS CNS immune reaction was not eradicated when IgG synthesis rate became normal, because CSF IgG oligoelonal bands persisted. None of the chronic progressive, severely disabled patients demonstrated significant change in neurologic function or persistent adverse effects.

Comparative evaluations of neuroperformance and clinical outcome assessments in chronic progressive multiple sclerosis: I. reliability, validity and sensitivity to disease progression:

There remains controversy regarding the most sensitive and valid outcome assessments to use in multiple sclerosis (MS) clinical trials. A double blind, placebo controlled, parallel group multicenter clinical trial to evaluate the clinical efficacy of cyclosporine A in chronic progressive MS incorporated several major clinical and performance outcome assessment modalities and a large sample size, both of which provide a unique opportunity to explore the relationship among MS disease status and the various outcome measures over time. The measures included a structured neurological examination, the Kurtzke Functional System scales and Expanded Disability Status Score, and the Incapacity Status Scale from the MS Minimal Record of Disability, die Harvard Ambulation Index, and neuroperformance testing. A test-retest reliability index, principal component analyses and a signal-to-noise ratio metric were used to comparatively evaluate the reliability, validity and sensitivity to disease progression of the various outcome assessments. The goal was to provide a rational basis for selection of behavioral outcome assessments in future MS clinical trials by identifying the primary dimensions of MS measured by the candidate outcome assessments and providing an objective basis for selecting tests that are most sensitive to MS disease and its progression over a two year trial period. We conclude that the components of the major clinical and performance measures show excellent reliability and cross validation. Principal component analyses of all outcome assessments yielded six primary underlying factors for describing disease status in chronic progressive MS that included lower extremity/pyramidal dysfunction, cerebellar/brainstem and upper extremity dysfunction, somatosensory dysfunction, visual dysfunction, mental or intellectual dysfunction and bowel/bladder problems. Signal-to-noise ratios indicated that upper and lower extremity composites of neuroperformance test kerns provided the most sensitive indicators of MS disease progression in the placebo group over the 2 year trial period.

Effects of Temperature in Multiple Sclerosis: A Review of the Literature

A review of the literature indicates that up to 80% of multiple sclerosis (MS) patients report worsening of symptoms with elevated body temperature; there are also anecdo tal reports of amelioration or improvement in some signs and symptoms of MS with low ering of core temperature. This paper reviews the possible physiological basis for tem perature effects in multiple sclerosis and discusses clinical trial design issues for objective evaluation of the therapeutic use of cooling in the symptomatic management of MS, cooling. garments, and core temperature measurement.

Isotachophoresis quantitation of subtractions of multiple sclerosis intra‐blood‐brain barrier IgG synthesis modulated by ACTH and/or steroids

We combined the IgG is otachophoresis (ITP) method and a formula to quantitate IgG synthesis rate inside the blood-brain barrier (intra-BBB) in multiple sclerosis (MS) patients. In MS, most IgG synthesized was cathodic, but synthesis occurred in both anodic and cathodic regions. In addition, ACTH and/or steroids were found to reduce cathodic IgG synthesis more than anodic.

Preliminary Evaluation of Lowering Tympanic Temperature for the Symptomatic Treatment of Multiple Sclerosis

Objective : Two pilot studies were designed to assess the effects of acute cooling in the laboratory (experiment one) and daily home cooling (experiment two) on objective indices of MS impairment and disability. Methods: Experiment one was a single group, repeated measures design in which nine MS outpatients with a history of heat lability were tested for immediate effects of lowering tympanic temperature in the laboratory. Subjects were tested under three experimental conditions separated by about one week: cooling with each of two cooling garments (the Life Support Systems, Inc., Mark VII MicroClimate System™ and the Steele Vest™ Body Cooling System) and no cooling. Experiment two was a prospective, unblinded, parallel group study in which twelve chronic progressive MS outpatients with a history of heat lability entered a six-week cooling protocol. Subjects used a cooling suit at home to lower body temperature two times per day. Five additional MS patients were in a non-cooling control group. In both experiments subjects were evaluated by clinical, neuroperformance, and quality of life indices, and were tested with a reduced battery of indices immediately before and after cooling on their weekly visit to the laboratory. Results: In experiment one, significant temperature decreases (mean 0.6°C) were achieved with both cooling garments, but no statistically significant change in performance post-cooling was found on any test measure. In experiment two, eight out of twelve subjects reported reduced fatigue and improved ability to ambulate immediately after and up to two to three hours after cooling. There was a significant immediate post-cooling (non-cumulative) improvement on tandem gait and standing balance. Additionally, seven subjects reported long-term improvements in quality of life over the cooling weeks. No statistically significant cumulative effect of cooling was found on objective indices of motor and cognitive function. Conclusions: The results provided weak subjective support for both acute and cumulative effects of cooling. A placebo effect cannot be ruled out. The study raised important questions regarding development of an appropriate sham cooling procedure, measurement of core temperature changes, and other design issues in evaluating cooling in MS patients.

Size of multiple sclerosis (MS) plaque volume in cerebrum correlates directly with intra-BBB IgG synthesis rate in vivo

Sjogrens syndrome (SS) is a common autoimmune disorder estimated to affect at least 2% of the population. CNS complications occur in approximately 25% of SS patients. A subset of CNS-SS patients have clinical, electrophysiologic, neuroradiologic, and immunologic features indistinguishable from those observed in MS. We have evaluated over 30 CNS-SS patients who met criteria for definite MS and in whom MS was considered the most likely diagnosis prior to diagnosis of SS. Characteristically, the CNS disease is multifocal, involving both the brain and spinal cord, and recurrent. Electrophysiologic studies show one or more multimodality evoked response abnormalities in 80%. CSF analyses show an elevated IgG index in one half, one or more oligoclonal bands in 90%, and a mild reactive lymphoid pleocytosis in half of patients. Magnetic resonance imaging studies show multiple areas of increased signal intensity predominantly within the white matter in subcortical a n d periventricular regions in 14/16 patients (lesions indistinguishable from those observed in MS patients). Brain tissue from CNS-SS patients shows vasculopathy with microinfarcts, but no plaques. Serum and CSF SC5b-9, is present in CNS-SS as well as in MS indicating activation of the terminal complement pathway. Differential immunogenetic associations particularly within the HLA-D region may distinguish these two disorders. These studies suggest that SSCNS is an autoimmune neurologic disorder which may mimick MS. Thus, although these two neurologic disorders share clinical, neuroradiologic, and immunologic features, they appear to be histopathologically and immunogenetically distinct.

JC virus in urine of chronic-progressive multiple sclerosis patients and control individuals

The o~ectrve of the research IS rhe study of clm~cs and unmunolo~ m pattents wth muittple sclerosis in acute paiod (30 pat.) and during rermssmn (17 pat.). axed 20-35. Tw~cal cfimcal wmutoms m acute Mod: wtlcal. se&ive; pyramidal a& vcstibular&&lhun disclubanccs. T~#cal mmmnological changes in ttus peiod: immunode#iiiency of T systw. deuease of Ig A, muease of 1~ M and level of cuculzv ~XIUIK complexa. actwatron of phagocytes. high level of antiDNA antibody. adwalmn of components of ;Uicr~-kynine system and pr ocesss of peroude oxygenation of llpnis. renusaon neurologul sympmms decreased. disturbances of movements and muscular coordination xrgressed. sensitivity restored. The positive mummological dynamics took place though T~mmunodeficrmcy was presaved. Thus the prcwnce of parallelisms m cluucs and mmmnology in various stages of the bsease was drscovered.

Performance outcome assessments in MS clinical trials are more sensitive to disease progression and treatment effects than clinical assessments

Results. The average length of stay for 37 patients with clmically definite MS was four weeks. The average variance per admission wee seven 49% were procedural and 51% related to goal achievement. Goal achievement averaged 75% per admission. Tone problems t24%l, fatiQue (23%) and cognitive factors (19%) were significant in non achievement. Fii per cent of goals set related to gait/mobility and transfers. The correlation between goal achievement and changes in disabilin, as measured by the Barthel and the Functional Independence Measure was not significant. Resulting changes to the running of the Unit Include: adoption of a key worker system, improved carer liaison, improved Induction of staff and reduced duration of stay.