Dr. Ron’s Research Review – October 12, 2016

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This week’s research review focuses on high-dose biotin for multiple sclerosis.

A pilot study used high doses of biotin (100-600 mg/day; median = 300 mg/day divided in three doses for 2 to 36 months, mean=9.2 months) in 23 consecutive patients with chronic progressive multiple sclerosis. (Sedel et al., 2015a)

In four patients with prominent visual impairment related to optic nerve injury, visual acuity improved significantly. Visual evoked potentials in two patients exhibited progressive reappearance of P100 waves, with normalization of latencies in one case. Proton magnetic resonance spectroscopy (H-MRS) in one case showed a progressive normalization of the Choline/Creatine ratio. One patient with left homonymous hemianopia kept on improving from 2 to 16 months following treatment׳s onset. Sixteen patients out of 18 (89%) with prominent spinal cord involvement were considered as improved as confirmed by blinded review of videotaped clinical examination in 9 cases. In all cases improvement was delayed from 2 to 8 months following treatment onset.
The gradual worsening of neurological disability in patients with progressive MS is caused by progressive axonal loss or damage. The triggers for axonal loss in MS likely include both inflammatory demyelination of the myelin sheath and primary neurodegeneration caused by a state of virtual hypoxia within the neuron.
Progression in MS is often considered as a consequence of both demyelination and energy failure. An unmyelinated axon may use up to 5000 times more energy than a myelinated axon, and energy production may be compromised because of mitochondrial injury. The resulting mismatch between increased energy demand for nerve conduction and decreased supply by impaired mitochondria could bias demyelinated axons towards a state of ‘virtual hypoxia’ culminating in degeneration.
High-dose biotin promotes axonal remyelination by enhancing myelin production and reduces axonal hypoxia through enhanced energy production. Biotin could target the main metabolic processes related to progressive MS by (1) activating the Krebs cycle in demyelinated axons to increase energy production; (2) activating the Krebs cycle in oligodendrocytes to increase the production of citrate required for lipids synthesis and; (3) activating ACC1 and ACC2, the rate- limiting enzymes in the synthesis of long chain fatty acids required for myelin synthesis. (Sedel et al., 2015b)

Dr. Ron


 

Articles

High doses of biotin in chronic progressive multiple sclerosis: a pilot study.
            (Sedel et al., 2015a) Download
BACKGROUND:  No drug has been found to have any impact on progressive multiple sclerosis (MS). Biotin is a vitamin acting as a coenzyme for carboxylases involved in key steps of energy metabolism and fatty acids synthesis. Among others, biotin activates acetylCoA carboxylase, a potentially rate-limiting enzyme in myelin synthesis. OBJECTIVES:  The aim of this pilot study is to assess the clinical efficacy and safety of high doses of biotin in patients suffering from progressive MS. STUDY DESIGN:  Uncontrolled, non-blinded proof of concept study METHODS:  23 consecutive patients with primary and secondary progressive MS originated from three different French MS reference centers were treated with high doses of biotin (100-300mg/day) from 2 to 36 months (mean=9.2 months). Judgement criteria varied according to clinical presentations and included quantitative and qualitative measures. RESULTS:  In four patients with prominent visual impairment related to optic nerve injury, visual acuity improved significantly. Visual evoked potentials in two patients exhibited progressive reappearance of P100 waves, with normalization of latencies in one case. Proton magnetic resonance spectroscopy (H-MRS) in one case showed a progressive normalization of the Choline/Creatine ratio. One patient with left homonymous hemianopia kept on improving from 2 to 16 months following treatment׳s onset. Sixteen patients out of 18 (89%) with prominent spinal cord involvement were considered as improved as confirmed by blinded review of videotaped clinical examination in 9 cases. In all cases improvement was delayed from 2 to 8 months following treatment׳s onset. CONCLUSIONS:  These preliminary data suggest that high doses of biotin might have an impact on disability and progression in progressive MS. Two double-blind placebo-controlled trials are on going.

Targeting demyelination and virtual hypoxia with high-dose biotin as a treatment for progressive multiple sclerosis.
            (Sedel et al., 2015b) Download
Progressive multiple sclerosis (MS) is a severely disabling neurological condition, and an effective treatment is urgently needed. Recently, high-dose biotin has emerged as a promising therapy for affected individuals. Initial clinical data have shown that daily doses of biotin of up to 300 mg can improve objective measures of MS-related disability. In this article, we review the biology of biotin and explore the properties of this ubiquitous coenzyme that may explain the encouraging responses seen in patients with progressive MS. The gradual worsening of neurological disability in patients with progressive MS is caused by progressive axonal loss or damage. The triggers for axonal loss in MS likely include both inflammatory demyelination of the myelin sheath and primary neurodegeneration caused by a state of virtual hypoxia within the neuron. Accordingly, targeting both these pathological processes could be effective in the treatment of progressive MS. Biotin is an essential co-factor for five carboxylases involved in fatty acid synthesis and energy production. We hypothesize that high-dose biotin is exerting a therapeutic effect in patients with progressive MS through two different and complementary mechanisms: by promoting axonal remyelination by enhancing myelin production and by reducing axonal hypoxia through enhanced energy production.

 

References

Sedel, F, et al. (2015a), ‘High doses of biotin in chronic progressive multiple sclerosis: a pilot study.’, Mult Scler Relat Disord, 4 (2), 159-69. PubMed: 25787192
Sedel, F, et al. (2015b), ‘Targeting demyelination and virtual hypoxia with high-dose biotin as a treatment for progressive multiple sclerosis.’, Neuropharmacology, PubMed: 26327679