Reprinted from Allergy Research Group Focus, August 2016
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Multiple sclerosis (MS) strikes over 2.3 million people worldwide, with about 200 new cases diagnosed each week in the US, and yet the disease is in many ways still a 'black box' of mystery.1,2 Why is the course so variable? What brew of genes and environment triggers the devastating symptoms? Is multiple sclerosis in essence a disease of inflammation, ongoing infection, or autoimmunity? Is it an amalgam of all three? Are there other etiologies?
An intriguing new framework is now emerging from European clinics and universities that offers a new answer: the lesions of multiple sclerosis may initially be triggered by a deficit of energy metabolism in neurons and their mitochondria (the energy powerhouses that populate every cell). In fact, mitochondria may play a key role throughout the different stages of the disease.3
This is a new mechanism that has not been described before. Until now it was thought that white blood cells called lymphocytes attacked the body's own tissue, directly leading to the inflammation, demyelination (stripping of the protective lipid sheath around a nerve cell), and neuronal (nerve cell) degeneration of MS.4 But though white blood cells and autoimmunity are key players later in the disease, it turns out that early demyelination can occur in the absence of lymphocytes.5 In its very acute, earliest phase, the lesions of MS may be triggered by hypoxia – insufficient oxygen – in neurons.6,7
This new understanding zooms in on tissue energy metabolism, and fits beautifully with other recent, landmark research showing that high-dose biotin (a water soluble B vitamin known as vitamin B7) can stabilize and even reverse symptoms of progressive MS, possibly by restoring energy metabolism and myelin in atrophied neurons.8,9 As neuroimmunologist and physician Hans Lassmann, MD, of the Center for Brain Research at Austria's Medical University of Vienna, puts it: "Therapies which raise tissue energy levels over prolonged time periods may not only have a symptomatic effect, but may be neuroprotective."9
About 85% of MS sufferers are diagnosed with relapsing-remitting disease (RRMS), marked by attacks called relapses or exacerbations, and followed by partial or complete periods of recovery (remissions).10
About 50% of relapsing-remitting MS worsens over time, until it transitions into secondary progressive MS (SPMS). Primary progressive MS (PPMS), in contrast, strikes about 10% of MS patients – marked by progressive and increasing disability from disease onset, along with occasional plateaus, temporary minor improvements, or acute relapses still consistent with the definition.11 The saddest and most frustrating aspect of PPMS is that there is no disease modifying treatment that has proved effective for the progressive forms of MS.
What initiating role does cellular energy play in early and ongoing disease?12 And what new therapies might emerge that maintain mitochondrial integrity and tissue metabolism?
Therapies which raise tissue energy levels over prolonged time periods may be neuroprotective in multiple sclerosis.
– Hans Lassmann, MD
A Curious Similarity Between Stroke and MS Lesions
In the early 2000s, researchers began to probe striking concordances between early white matter lesions in stroke and similar lesions in multiple sclerosis. In a series of fascinating 2003 papers, Hans Lassmann noted that both stroke and MS share hypoxia-like metabolic tissue injury – a result of too little oxygen available to vulnerable neurons. When not enough oxygen is available, cells cannot function properly.13-15 It turns out that MS, as well as white-matter stroke and virus-induced encephalitis, are all marked by the presence of hypoxia-inducible factor 1-alpha (HIF-1α), a highly sensitive indicator of tissue injury due to hypoxia. HIF-1α most likely builds up as a response to changes within cells that, even if injured, have managed to survive the hypoxic conditions.12
For stroke, the damage and pathology are clearly vascular in origin. But for multiple sclerosis, Lassmann and others suggest that metabolic disturbances alone might initiate the injury. The damage could be triggered by excessive excitotoxins (such as the amino acid glutamate, which functions as a neurotransmitter in the brain). Excitotoxins might damage and interfere with functioning of the mitochondria. Mitochondria are the energy powerhouses of every cell, and when they suffer from collapse or dysfunction, the entire cell is compromised. Glutamate and other excitatory neurotransmitters are indeed increased in multiple sclerosis and can injure the brain's highly sensitive neuronal network.16-18 "Such a mechanism may in part be responsible for tissue damage in a demyelinating brain," write Lassmann and colleagues. Metabolic injury due to hypoxia might lead to demyelination of the axon – the long threadlike part of a nerve cell, along which impulses are conducted.4
In highly active lesions, free radical damage is present in the form of reactive oxygen species (ROS) and reactive nitric oxide intermediates (RNI), which may also directly impair mitochondrial function, metabolism, and cellular energy. The resulting tissue damage leads to a metabolic hypoxia that looks like the hypoxia in stroke.3 Oxygen tension in the central nervous system is normally relatively low anyway. Within the white matter of the brain, however, it is especially low – and MS lesions often show up there.10 Cells called oligodendrocytes are particularly vulnerable to hypoxia, because they have the demanding task of creating the myelin sheath around axons (a single oligodendrocyte can support the myelin of 50 axons) and supporting axon function with molecules necessary for energy metabolism.19 In addition, mitochondrial dysfunction occurs in chronically demyelinated axons, leading to hypoxialike tissue injury.20 Mitochondria are central to axonal degeneration in all stages of MS, and play a significant role in energy metabolism and cell homeostasis.3
Tissue hypoxia may play a key role in two of the most important aspects of MS: neurological deficits and demyelination.
Oxygen to the Rescue?
If hypoxia plays a role in MS, can oxygen therapy help? Researchers at the Institute of Neurology in London have shown just that: extra oxygen can halt or prevent lesions in hypoxic tissue.6 In an ingenious experiment, the scientists tested the effect of breathing 100% oxygen (known as normobaric oxygen) on MS-like lesions in animals. Normobaric oxygen has already been used in stroke and traumatic brain injury with beneficial results.21 MS-like spinal lesions with demyelination were induced and animals were exposed to 2 days of either room air, or air saturated with 80% oxygen. Magnetic resonance imaging (MRI) showed not only that oxygen decreased the size of demyelinating lesions, but that myelin was preserved around axons in the animals treated with oxygen.6 "Understanding how the experimental lesion is formed," the researchers write, "has revealed a novel therapeutic strategy to prevent the demyelination from occurring … tissue hypoxia [may] play a key role in two of the most important aspects of MS, namely the production of neurological deficits, and at least some of the demyelination." The scientists go on to speculate that the initiating trigger for MS may be less important than its ability in susceptible individuals to create an environment in the brain tissue marked by hypoxia, nitric oxide, and superoxide. "It is striking that the demyelination can be greatly reduced, or even prevented, by simply raising inspired oxygen at normobaric pressure for the first 2 days when the lesion is vulnerable to hypoxia." They caution, however, against speculative use of oxygen as an acute therapy in MS until the safety is proven; they are currently investigating it in their laboratory.6
High-Dose Biotin: Another Novel Approach to Restoring Tissue Metabolism
"No drug to date has been found to have any impact on progressive multiple sclerosis," says neurologist and neuroscientist Frédéric Sedel, MD, PhD, of Salpêtrière Hospital in Paris, France.22 But what about a vitamin? Sedel's surprising research demonstrates that high doses of the water soluble B vitamin biotin (also known as vitamin B7) may be able to stabilize or even reverse progressive MS, preventing its relentless decline.23
Biotin is highly bioavailable, and both absorption and excretion are rapid. At doses up to 20 milligrams in humans, excretion of biotin and its metabolites are similar for intravenous dosing and oral supplementation, indicating 100% bioavailability of oral biotin.24 The vitamin is mainly eliminated through the urine.25 Biotin has many functions in the body – such as regulating blood sugar and helping the body metabolize fats and proteins – but where MS patients are concerned, it may offer two other benefits.26
One, it increases levels of adenosine triphosphate (ATP) via the mitochondria, which supplies every cell with energy. Two, it promotes myelin repair by helping the body synthesize fatty acids.8 It does this by acting as a coenzyme, or helper, for a molecule called acetyl-CoA carboxylase. Thus, maintains Sedel, it could potentially alleviate MS symptoms in two ways: first, by increasing ATP levels and reversing the functional or so-called virtual hypoxia found in MS. Second, it may promote direct myelin repair.
In the initial pilot study conducted by Sedel and colleagues, 23 patients aged 23 to 76 years, with primary and secondary progressive MS, were treated with high doses of biotin (100–300 mg/day) from 2 to 36 months, for an average of 9.2 months. All patients had disease that was progressing for a minimum of the previous 12 months. Patients were evaluated by various methods – 4 patients who had visual loss from chronic optic neuropathy were given vision tests; in 18 patients who had spinal cord involvement, walking distance and muscle strength were tested. Clinical exams were videotaped, and typical MS symptoms such as fatigue, swallowing difficulties, and urinary dysfunction were measured. Videotapes of 9 patients, both before and after treatment, were viewed and rated "blindly" (not labeled as to whether the video was taken before or after treatment) by an independent, specialist center.27
When we compare these results to other trials in progressive MS that involved more than 6000 patients overall, this is clearly the best effect ever observed. – Ayman Tourbah, MD
Biotin Leads to Quantitative and Qualitative Improvement
Results of treatment were impressive. The 4 patients with optic neuropathy had improvement in visual acuity after 3 months of treatment. Sixteen of the 18 patients with spinal cord involvement displayed improvement after 2 to 8 months on the biotin. Seven patients who had paraparesis (partial paralysis of the lower limbs) improved. The supplement was well tolerated with virtually no adverse effects, except diarrhea in two patients. Overall, 21 of 23 patients experienced qualitative and quantitative improvement. The dose of 300 mg/day was associated with the best overall clinical response. "The results were in marked contrast with the natural history of progressive forms of MS where almost no spontaneous or sustained improvement occurs," writes Sedel.25
At the April, 2015 American Academy of Neurology (AAN) conference in Washington, DC, results of a randomized Phase III trial with both placebo and control groups were presented.28 After 12 months of treatment, patients on biotin had overall, global improvement that was significant. Walking scores were improved compared with the placebo, and a statistically significant number of patients showed confirmed improvement at 9 and 12 months compared with the best scores obtained at two visits before treatment. Not one patient in the placebo group improved to that level. The relapse rate was 3.9% in the biotin group and 7.8% in the placebo group (not statistically significant). At the April 2016 AAN conference in Vancouver, 24 months of results were presented. High-dose biotin significantly reversed disease progression compared with placebo for the first 12 months of the study, and the benefit was sustained over the second 12 months.29 Lead study author and neurologist Ayman Tourbah said at the presentation: "This is the first time that a 'drug' has reversed the progression of the disease in a statistically significant proportion of patients. In addition, if we look at the mean Expanded Disability Scale (EDSS) change, the data compare very favourably with all previous trials that looked at the same endpoint. Almost no progression was observed in patients treated with … [high dose biotin] for 24 months and this has never been observed before. When we compare these results to other trials in progressive MS that involved more than 6,000 patients overall, this is clearly the best effect size ever observed. Results … point to the fact that targeting neuron and oligodendrocyte metabolism represents a promising and novel disease modifying therapy approach in progressive MS."30
There is something profound that these findings on biotin and MS are trying to tell us. – Donald Mock, MD, PhD
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