The FDA Should Approve Marijuana to Treat Spasticity in Multiple Sclerosis

Readers of a review article by Giacoppo and others in Multiple Sclerosis and Related Disorders, 2017, pages 22-31, will probably agree with this statement. Sativex is a branded oromucosal spray containing tetrahydrocannabinol and cannabidiol in a 1:1 ratio. It has been available for years in Canada and has been approved in several European countries since 2013. Combining the two compounds reduces unwanted cognitive effects.

This review was a literature search extending back ten years. Spasticity affects 80% of MS patients, responds poorly to currently available medications and worsens disability and quality of life. 83% of MS-Sativex treated patients had reduction of spasticity. 65% were considered responders in the first month. There was no evidence that other MS symptoms worsened. 60% continued treatment long term. Those who stopped cited lack of efficacy or side effects. 83% thought they benefited.

10%, and usually only for in the first month, had side effects, such as dizziness, fatigue, and dry mouth. Less than 1% had psychiatric side effects, including paranoia, hallucinations, panic, suicidal ideation and cognitive decline. These generally cleared with lowering the dose or stopping treatment. There was no evidence of tolerance, abuse, diversion or addiction.

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Noninvasive Vagal Nerve Stimulation for Cluster headaches

A new device provides noninvasive electrical stimulation of the vagus nerve in the neck to treat episodic cluster headaches. It is call gammaCore and was recently approved by the FDA and will probably be available by prescription in the United States in fall 2017. It is about the size of a cell phone, handheld, applied to the neck at the start of an attack.

Cluster headaches have been called “suicide headaches” because the pain is very intense. They can occur multiple times a day during a cluster. Injectable sumatriptan is almost always very effective within several minutes but may lead to severe adverse effects in people with coronary artery disease or multiple risk factors for that. Also, it is expensive and insurers will not pay for several doses a day. Inhaled oxygen is also effective for most patients. This obviously is less convenient as an oxygen tank is needed and is not covered by Medicare or Medicaid for treatment of cluster headaches. Thus, the gammaCore device is welcome.

There have been 2 “pivotal” trials. Thirty-four percent of patients who use the stimulator experience pain relief in 15 minutes compared 10% who used a sham device. It was effective only for episodic cluster but not for chronic cluster. Patients with episodic cluster, go into remissions whereas those with chronic do not. It is not clear why there was a difference in response as the pathophysiology is the same in both episodic and chronic. Some headache specialists were disappointed that the response rate was only 1/3, “therapeutic gain” is almost 25%. This is considered significant in pain studies

Look for more neuromodulating devices in the future. For cluster, the focus will be on stimulating the sphenopalatine ganglion.

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New Insights into Sudden Death in Epilepsy

A practice guideline, prepared by the American Academy of Neurology, was published recently in Neurology.

SUDEP stands for sudden unexpected death in epilepsy. This has been recognized for many years but the specific risk has not been consistently established. People with epilepsy can die during a seizure, presumably from post- ictal respiratory depression.

SUDEP, according to the guideline, affects 1 in 4,500 children and 1 in 1,000 adults with epilepsy per year. Lifetime risk is obviously higher. Keep in mind that 4,499 of 4,500 children will not be affected and this applies to 999 out of 1,000 adults. This should be the approach in counseling patients and families as after being informed of an adverse event, people commonly overestimate that risk and this may increase anxiety greatly.

Some groups have higher risks. The most important risk factor is the frequency of generalized tonic-clonic seizures. Those with 3 or more per year have a 15-fold higher risk. Nocturnal seizures may increase risk because they are unwitnessed. Use of a remote listening device may help.

Reducing risk of generalized tonic-clonic seizures will obviously reduce risk of sudden death. Factors that further increase risk include never having been treated with an antiepileptic drug, number of drugs used overall, intellectual disability, male sex, and anti-anxiety drug use.

The following factors do not seem to increase risk: overall frequency when this includes all seizure types, medically refractory partial seizures, monotherapy vs polytherapy, frequent changes on antiepileptic drugs, structural lesion on MRI, duration of epilepsy, and age of epilepsy onset.

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Update On Migraine And Stroke

There is good evidence that patients with migraine with aura but not without aura have about a twofold increased risk of stroke. Why this is so, however, is not known. According to a new study, the cause may be cardiac embolism. Patients from the ARIC study of over 15,000 participants, aged 45 to 64 years who had migraine and stroke, were identified. The mean age of the patients was 59 years. Those with migraine with visual aura had increased risk of cardioembolic ischemic stroke of almost fourfold. Those with migraine without aura did not.

Cardioembolism was diagnosed if records showed evidence of heart valve disease, a recent intracardiac thrombus, bacterial endocarditis, cardiac arterial procedure, and especially paroxysmal atrial fibrillation or flutter. Patent foramen ovale was not considered a cardioembolic source. The role of PFO in causing ischemic stroke in patients older than 55 is controversial. It is seen on autopsy in 25% of the general population, though perhaps 50% of patients with “cryptogenic stroke” may have PFO seen on transesophageal echocardiogram.

The authors propose several mechanisms. Migraine with visual aura may promote vasospasm, activate platelet aggregation, and increase concentration of pro-coagulant factors. Secondly, calcitonin gene-related peptide (CGRP), consistently elevated during a migraine attack, also can cause coronary vasodilatation. Perhaps that effect could trigger coronary blood flow or velocity changes and thus increase risk of atrial fibrillation.

Keep in mind that these results may not apply to people younger than 45. The important take-home message is that migraineurs who have visual aura and who have ischemic stroke of unknown cause may have significant probability of paroxysmal atrial fibrillation as the cause. Thus, it seems prudent that they undergo long-term cardiac monitoring, as findings would lead to anticoagulation, which would serve to lower risk of recurrent stroke.

See Neurology, December 13, 2016, pages 2504-2505 and 2527-2532.

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New Insights Into Migraine And Risk Of Stroke

Patients who have migraine with aura, but not those who have migraine without aura, have been found in several studies to have higher risk of cardiovascular disorders, including stroke. That risk may be 2 times that of a control group though low in an absolute sense because patients are relatively young without cardiovascular risk factors.

Now, a new study concluded that this increased risk applies to migraine with and without aura. It involved over 17,000 patients who had unspecified migraine. There was found to be increased risk of myocardial infarction, stroke, angina, or coronary revascularization procedures, and cardiovascular mortality ranging from 37% to 73% higher than the control group, which was women without migraine. Conclusion was that women with migraine of any type should be carefully evaluated for cardiovascular risk factors and treated as needed.

A second recent study came to a different conclusion. This consisted of 172 cases of female twins with and without migraine with aura, 34 twin pairs in which neither had migraine, and 139 controls without migraine. The frequency of silent brain infarcts, seen in several previous studies in perhaps 30% of women with migraine, was the primary outcome. The conclusion was that there was no association between these silent brain infarcts or white matter hyperintensities with migraine with aura.

See British Medical Journal, 2016, 353, with lead author T. Kurth; and Brain, 2016, 139, pages 2015-2030 with lead author D. Gaist.

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Nicotine Patches For Parkinson’s

Eight open-label studies and four placebo-controlled studies addressed this question. Seven of the eight open-label showed improvement in motor symptoms, but the placebo-controlled studies were all negative.

A new study was presented at the 4th World Parkinson Congress by Gabriel Villafane. It involved high doses (90 mg per day) of transdermal nicotine and measured the UPDRS for “off” motor scores. Blinded video rating was done.

At 39 weeks, there was no statistically significant difference in motor scores as well as a quality of life measure. There seemed to be a reduction in levodopa doses, reduction in dyskinesias, and improvement in activities of daily living. As expected, adverse effects were more common in the nicotine group.

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A New Blood Test May Become A Biomarker For Multiple Sclerosis Progression

This measures neurofilament-light chain levels. They are a maker to neuroaxonal damage, as the neurofilaments function as a lattice for axons. In the past, lumbar puncture was needed. Now, a blood test has been developed. This studied patients undergoing treatment with fingolimod. Another study involved patients treated with natalizumab. With treatment, levels of the neurofilament-light chains fell, and this correlated with a milder disease course.

These tests need to be validated further, but it is very exciting if a blood test could help guide treatment decisions.

This information was presented at ECTRIMS 2016. Lead author is Piehl.

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A New Non-Invasive Treatment For Essential Tremor

Essential tremor is common, thought to affect 1 in 10 people over the age of 70, and may be severe, causing significant functional disability. It is difficult to treat. Available medications reduce tremor only partly and do not work in a significant number of patients. Further, they may have adverse effects. They include mainly beta-blockers, primidone, and topiramate or zonisamide, used off-label. Deep brain stimulation is very effective but is obviously invasive, with attendant risks.

Now, a new device has just received FDA approval. It is termed ExAblate Neuro system. Using ultrasound waves, it could ablate the target brain tissue. The study was randomized, double blind, with 76 patients who received the ExAblate treatment or a sham procedure. Placebo patients were later allowed to “cross over.”

Treated patients had an almost 50% improvement in tremor severity and function.

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Disappointing Results Of A Study Using Non-Invasive Vagal Nerve Stimulation In Chronic Migraine

Botox is the only approved prophylactic chronic migraine medication, although anticonvulsants, tricyclic antidepressants, and beta-blockers are often used off-label in chronic migraine, whereas several are on-label for episodic migraine. More effective treatment for chronic migraine is a great unmet need.

Vagal nerve stimulation is approved for epilepsy and depression. Anecdotal reports of epilepsy patients treated with an implanted VNS device who noted reduction in migraine severity led to small studies. Further, the effects of VNS on epilepsy and depression seem to improve with time on treatment.

Much easier than an implanted device would be a patient-controlled, handheld, non-invasive device, which is now in clinical trials. In this recent study, patients self-administered two 2-minute stimulations 5 to 10 minutes apart to the right side of the neck, 3 times a day. There were no safety issues, but the reduction in headache days a month during the 2-month randomized phase compared to placebo controls was not significant. At 6 months, there seemed to be a significant reduction. The patients who completed the 6-month open-label phase may have been “self-selected,” limiting the validity of this finding. Further, maintaining blinding was a challenge, and there was a high discontinuation rate.

Findings in migraine contrast with those in chronic cluster headache, where prophylactic non-invasive vagal nerve stimulation seems to be helpful and cost-effective.

Despite these somewhat disappointing results, a new study, which contains a 9-month open-label period, is in the planning stages.

See Neurology, August 2, 2016, page 529-538. Lead author is Silberstein.

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Update On Supplements For Migraine

Many patients with migraine use “complementary and alternative medicine” and often do not discuss this with their physicians. There have been guidelines from various professional societies, and recommendations often conflict.

The greatest number of studies has been done with riboflavin, coenzyme Q10, magnesium, butterbur, feverfew, and omega-3 polyunsaturated fatty acids.

Nutraceuticals are lightly regulated by the FDA. It considers them as different from conventional foods and drugs. By contrast, in Canada, there are strict regulations. In 2015, the attorney’s office of New York State brought suit against 4 major US retailers for selling fraudulent and potentially dangerous herbal supplements and demanded that they be removed from store shelves. At a popular retail chain, 3 out of the 6 products tested negative for the herbs listed on their labels.


This is vitamin B2. Patients who take this have a yellow color in their urine. Dose is 400 mg daily. It is usually well tolerated, with minor side effects of diarrhea and increased urination. There is a compound consisting of riboflavin 400 mg daily with magnesium 300 mg and feverfew 100 mg daily. It did not show consistent benefit in one study. There is low quality evidence for use of riboflavin though there are minimal side effects.

Coenzyme Q10

This is widely used, and some patients think it can reduce the risk of heart disease or dementia, though these conclusions are unproven. The migraine dose is 100 mg 3 times a day, obviously less convenient than a single daily dose. There was significant benefit compared to placebo, with effect appearing after the first month and being maximal after 3 months. Side effects were minimal, with only 1 patient having a skin allergy. Some studies show that CoQ10 deficiency may be common in children and adolescents with migraine, and obtaining a serum CoQ10 level before supplementation may be a helpful guide.


The usual dose is magnesium citrate, which contains 600 mg of elemental magnesium daily. Diarrhea was seen in about 20% and gastric irritation in 5%. Similar to CoQ10, some studies show low magnesium levels in migraineurs, and checking levels prior to supplementation may be helpful.


This is derived from a shrub called Petasites hybridus. It was initially available as a particular brand, Petadolex, manufactured in Germany with a method that was said to remove toxins termed pyrrolizidine alkaloids, which have hepatotoxicity. This preparation has been widely used for years and has shown effect in placebo studies. In the last several years, cases have been recognized of significant liver damage from both the Petadolex formulation and other products. Marketing authorization for Petadolex was withdrawn in Germany in 2008. To me, the risks do not outweigh the modest benefit seen in trials.


This is derived from a daisy-like plant. A review of 5 trials covering 343 patients found mixed results and did not convincingly establish that it is effective for preventing migraine. No safety problems were found, and side effects were minimal.

The best evidence is for use of riboflavin 400 mg daily, coenzyme Q10 100 mg three times daily, and magnesium 600 mg daily.

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