Author Of 2 Presentations
LB1211 - Histaminergic basis of fatigue in Multiple Sclerosis (ID 2069)
The histaminergic tuberomammillary system through its varied connections control the circadian rhythm and regulate wakefulness and sleep, satiety and hunger, memory and learning, as well as energy and tiredness. Blocking brain histamine receptors lead to tiredness and sleep. In this study we examined if raising brain histamine levels can improve fatigue in severely fatigued patients with multiple sclerosis.
To validate the concept that raising brain histamine will alleviate fatigue in severely fatigued patients with multiple sclerosis
A strategy was developed to raise brain histamine by loading patients with l-histidine, the precursor for histamine. Conversion systemically from l-histidine to histamine was blocked using histidine decarboxylase inhibitor, lodosyn, which has no access to the brain across the blood brain barrier.All subjects received a fixed dose lodosyn, 50 mg po bid. Three groups of l-histidine loading wereundertaken. Group-1 received 250 mg po bid, Group-2 500 mg po bid and group 3, 1 gm po bid. Pharmacokinetic (PK) and pharmacodynamic (PD) studies were conducted to measure blood and CSF l-histidine and histamine levels before and during treatment. Response to treatment was gauged using the visualanalogue fatigue scale (VAFS), Fatigue severity scale (FSS) and the modified fatigue impact scales (MFIS). To be considered a responder, patients had to improve in all three scales and show at least a 20% improvement from their mean screening/baseline MFIS scores.
A dose-based response to improvement of fatigue was observed anywhere from 30% to 88% in MFIS scores with the least responders in Group 1 and most in Group 3. Improvement was noted in all three domains of the MFIS; the physical, cognitive and psychosocial. Improvement in the cognitive domain was associated with subjects reporting improved attention, concentration and improvement of the“brain fog”. Responders reported an overall sense of well being while others reported no change.
This proof -of-concept study has identified a population of MS patients with fatigue that respond to treatment using elevation of brain histamine. This novel approach opens up a new avenue to identify drugs that raise brain histamine as a mechanism of treatment of fatigue in MS and possibly other disorders with fatigue where histamine may play a pivotal role in the pathogenesis of this common and severely disabling symptom. Additionally this treatment could also provide an approach to help cognitive impairment in multiple sclerosis since raising brain histamine can facilitate also the enhanced release of a number of neurotransmitters including acetylcholine, implicated in the pathogenesis of cognitive impairment in various disorders including multiple sclerosis.
P0882 - Motor Impairment in Multiple Sclerosis: Analysis from the North American Registry for Care and Research in Multiple Sclerosis (ID 1759)
North American Registry for Care and Research in Multiple Sclerosis (NARCRMS) is a longitudinal registry studying the course of MS in the disease-modifying era.
To examine motor performance metrics of upper and lower extremity function in NARCRMS participants at enrollment, using the Expanded Disability Status Scale (EDSS) and 25-foot walk times.
Recruitment began in 2016 and by June 24, 2020, 737 patients were enrolled at 25 MS sites across the US and Canada. People with any sub type of MS within 15 years of disease onset and an EDSS of up to 6.5 are eligible for enrollment. Various clinical metrics are collected including motor performance for upper and lower extremities. Our initial observations about EDSS, 25-foot timed walk and the 9-hole peg test are reported below
EDSS and 25-foot walk times were available in 632 patients and upper extremity function in 609 patients. A mean walking speed of 4.96 seconds was recorded in patients with an EDSS of 0 (n=105). 5.11 was the mean speed until an EDSS of 3.0 (n=39) where a mean speed of 5.41 seconds was recorded. Walking truly became affected at an EDSS of 3.5 (n=27) where a mean speed of 6.48 seconds was recorded. Thereafter mean speed progressively declined at every EDSS increase. For an EDSS of 4.0 (n=28), mean speed was 7.78 seconds; for an EDSS of 4.5 (n=6), mean speed was 9.16 seconds and continued to increase until an EDSS of 6.5 (n=11) where mean speed was 19.1 seconds. For the 9-hole peg test, patients with an EDSS of 0 (n=101) had a mean speed of 20.3 seconds in the dominant and 21 seconds in the non-dominant hand. Hand function remained unimpaired until an EDSS of 2.0 and significant slowing occurred in patients with EDSS ranging from 2.5 to 6.5. For an EDSS of 2.5 (n=44), mean speed was 25.3 seconds in the dominant and 24.4 seconds in the non-dominant hand. For an EDSS of 4.0 (n=26), mean speed was 26.3 seconds in the dominant and 26.0 seconds in the non-dominant hand. For an EDSS of 6.5 (n=11), hand function had declined to a mean speed of 40.1 seconds for the dominant and 56.4 seconds for the non-dominant hand.
A linear correlation of the 25-foot walk speed to EDSS increases was remarkable, reiterating the commonly held belief that the EDSS is a “walking scale”. Decline in hand function at an EDSS of 2.5 was unexpected since hands are often perceived to be unaffected early in MS and seldom observed as impaired by patients. Progressive decline of hand function at every EDSS increase would suggest that the 9-HP test is a good marker of declining hand function and should be included in clinical monitoring of patients.