Biotin, used at high dose, has some impact on disease progression and permanent disability in patients with progressive multiple sclerosis. Overall, 21/23 patients ( 91.3% ) exhibited some qualitative or quantitative clinical improvement with high doses of Biotin.
Similar positive results were noted in patients with SPMS ( secondary progressive ) and PPMS ( primary progressive ) suffering from optic neuropathies, homonymous hemianopia or spinal cord involvement.
In all cases, clinical improvement was delayed by 2–8 months ( mean=3 months ) following treatment׳s onset.
Only 2 patients with severe tetraparesis did not show any response to treatment, probably related to its short duration ( 8 and 7 months respectively ).
Indeed, in patient 11 with a severe tetraparesis, treatment׳s benefit only started 8 months after treatment׳s initiation.
The range of dose was determined empirically after having observed some clinical improvement in a single patient with 300 mg/day of Biotin. Several attempts to decrease or increase the dosage were performed. Increasing the dose to 600 mg/day in one patient was not associated with additional benefit whereas decreasing the dose to 100 mg/day in one patient was associated with worsening. In 5 cases, increasing the dosage from 100 to 300 mg/day was followed by an additional improvement.
From these observations, the dose of 300 mg/day was thought to be associated with the best clinical response.
In addition, the treatment appeared to be safe: transient diarrhea, the only minor adverse effect, was noted in 2 patients. Two patients died in the course of the trial but in both cases, death could not be attributed to the treatment.
Although these data rely on an open label study with the possibility of a placebo effect, they are in marked contrast with the natural history of progressive forms of multiple sclerosis where almost no spontaneous or sustained improvement occurs ( Confavreux et al., 2000 ). Furthermore, clinical treatment׳s efficacy was confirmed in few patients by unbiased quantitative measures such as VEP ( visually evoked potential ) and H-MRS ( proton magnetic resonance spectroscopy ) that both showed continuous improvement during the first year of treatment.
The normalization of VEP latencies and of the choline / creatine ratio suggests the possibility of myelin repair that would also account for the delayed efficacy.
In contrast, the treatment is unlikely to be associated with an anti-inflammatory effect. Indeed, biotin did not prevent from inflammatory attacks as observed in 4 patients who displayed relapses while on treatment.
On the other hand, the question whether high doses of Biotin could favor attacks of the disease still remains.
Of note, in the study, the rate of relapses did not significantly change before and after treatment but more data are still needed.
High doses of biotin have never been hypothesized as a potential treatment for multiple sclerosis. The discovery that this might represent a therapeutic option in chronic progressive multiple sclerosis both in its secondary and primary forms relies on a serendipity.
However a posteriori, the observed effects do rely on a strong rational. Progression in multiple sclerosis ( either secondary or primary ) is often considered as a consequence of both demyelination and energy failure ( Luessi et al., 2012, Stys et al., 2012 ).
A large proportion of ATP produced in the nervous system is used by the NA/K ATPase to restore the membrane resting potential. In the normal condition, myelin insulation reduces the energy demand during impulse propagation because only the nodes of Ranvier are excited.
In contrast, in unmyelinated fibers where the entire membrane is involved, much more ATP is needed for ion pumping. As a consequence, it has been estimated that an unmyelinated axon may use up to 5000 times more energy than a myelinated axon ( Quarles et al., 2006 ).
In multiple sclerosis, in addition to the fact that demyelinated fibers increase their energy demand, energy production may be compromised because of mitochondrial injury ( Witte et al., 2013 ).
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 ( Luessi et al., 2012, Stys et al., 2012 ).
Biotin is a water-soluble vitamin that serves as an essential coenzyme for carboxylases catalyzing the transfer of a carboxyl ( COOH ) group to targeted substrates ( Zempleni and Mock, 1999 ).
The five biotin-dependent carboxylases are: pyruvate carboxylase ( PC ), propionly-CoA carboxylase ( PCC ), beta-methylcrotonyl-CoA caboxylase ( MCC ), and acetyl-CoA carboxylase ( ACC ), with the latter enzyme existing in two distinct isoforms one of which is in the cytosol ( ACC1 ) and the other is attached to the outer mitochondrial membrane ( ACC2,Tong, 2013 ).
PC, PCC and MCC are expressed in astrocytes and neurons ( Hassel, 2000, Ballhausen et al., 2009 ) and are involved in the production of oxaloacetate, succinyl- CoA and acetyl CoA CoA that are key intermediates for the tricarboxylic acid ( Krebs ) cycle which plays a central role in neuronal energy production.
Activation of the Krebs cycle by very high doses of Biotin may therefore increase the energy production in axons, thus avoiding the virtual hypoxia phenomenon.
On the other hand, ACC1 ( and ACC2 ) is involved in the synthesis of malonyl CoA from acetyl CoA and citrate. The synthesis of Malonyl CoA represents the rate-limiting and committed step of long-chain fatty acid biosynthesis.
In the nervous system, ACC immunoreactivity is high in oligodendrocytes ( Tansey et al., 1988 ), and its activity is detected in purified myelin ( Chakraborty and Ledeen, 2003 ), suggesting that ACC ( either ACC1 or ACC2 ) might be a key regulator for myelin synthesis.
Furthermore, studies in cell cultures have shown that lactate, the main energetic substrate in the central nervous system, is oxidized in the Krebs cycle to produce ATP in neurons, whereas oligodendrocytes use lactate in part to produce membrane lipids presumably for myelin ( Sanchez-Abarca et al., 2001, Rinholm et al., 2011 ).
Overall, high doses of Biotin, could target the main metabolic processes related to progressive multiple sclerosis 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.
The adequate daily intake of Biotin in adults is 30 mcg and the dose used in this study was 10,000 more. Oral Biotin is completely absorbed, urinary excretion of biotin and its metabolites being similar after intravenous and oral administration ( Wang et al., 2001 ). Biotin is transported across the blood–brain barrier by a saturable system; the apparent Km being about 100 micromol/L, a value several orders of magnitude greater than the concentration of free biotin in plasma even after administration of very high doses ( Zempleni and Mock, 1999, Spector and Mock, 1987 ). Accordingly, it is expected that high doses of biotin administered orally will reach the brain to be incorporated into apocarboxylases in fine ( Spector and Mock, 1988 ).
In conclusion, these data suggest that high doses of Biotin may impact disease׳s progression and improve clinical sequelae in primary and secondary progressive multiple sclerosis. They rely on a case reports series and need to be confirmed. ( Xagena )
Sedel F et al, Mult Scler Relat Disord 2015; 4 : 159–169