What Anti-Epileptic Drugs Are FDA-Approved For Monotherapy?

FDA-Approved Anti-Epileptic Drugs  For Monotherapy
FDA-Approved Anti-Epileptic Drugs For Monotherapy

These are the FDA-Approved anti-epileptic drugs for monotherapy, the list is small:


  1. Felbamate for newly diagnosed and refractory focal.


  1. Lamotrigine for refractory focal and conversion to monotherapy.


  1. The next group consists of oxcarbazepine, topiramate, lacosamide, eslicarbazepine. These are all approved as monotherapy for newly diagnosed and refractory focal.


Note that levetiracetam is widely used as initial monotherapy for focal and generalized seizures although it is not FDA-approved for any monotherapy indication. This also holds for gabapentin, pregabalin, and zonisamide, although they are widely used as initial monotherapy.


Other than efficacy for a certain epilepsy syndrome, the type of adverse effects often guides choices. Drugs that may cause weight gain are valproic acid, gabapentin, pregabalin, carbamazepine, ezogabine, and perampanel. By contrast, topiramate, zonisamide, and felbamate may decrease weight. Lamotrigine and felbamate tend to be “alerting.” Pregabalin, lamotrigine, valproic acid, and carbamazepine may reduce anxiety. Zonisamide tends to be sedating. The sodium-channel blockers, such as carbamazepine and lacosamide, may cause imbalance and blurred vision. There are many other factors in choosing, such as enzyme induction and risks to the fetus. Those considered “safer in pregnancy” are levetiracetam, carbamazepine, oxcarbazepine, zonisamide, lamotrigine, and surprisingly phenytoin.


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Why Persons With Epilepsy Don’t Take Their Medication?

In fact, over one-third fails to take their epilepsy medication at least 80% of the time. This is termed nonadherence and leads to high rates of morbidity and mortality.


Surprisingly, a single daily dose compared to 3 times a day improved adherence only from 57% to 65%. Depakote was taken least at 55% and Keppra most at 79%. This is unrelated to drug efficacy, and perhaps side effects were the cause.


Dr Paul Farmer, who established free medical clinics in Haiti and then went on to treat multidrug-resistant tuberculosis in Peru, said that noncompliance is the fault of the doctor, not the patient. If this is true, how can we improve compliance?


For patients, the main reason is forgetting, not depression, not denial. Warning patients about the risk of sudden death from a seizure and other intensive educational efforts seem to be of limited help. Simple memory aids seem better, such as associating doses with daily routines, using weekly pill boxes (very important), electronic pill bottle recording (not universally available), or setting alarms on smartphones. Pharmacies contacting physicians when medications are not refilled would also be helpful, but this would require extra time by the pharmacy and by the physician to contact the patient. According to Dr Edward Faught, who commented on the study, insurers should take this role because of potential cost savings.


Finally, giving patients “permission” to admit they do not take their medications consistently is critical. I would frame the question this way: “All my patients miss doses, how often do you?”


See Neurology, August 2, 2016, page 452-453 and page 466-472.


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Neurologists Should View MS In The Same Way That Rheumatologists View Rheumatoid Arthritis

The goal of treating rheumatoid arthritis has, in recent years, been a complete remission, i.e., cessation of disease activity. Neurologists seem much more cautious and risk-averse in treating multiple sclerosis.


Dr Gavin Giovannoni has been a forceful advocate of a different approach. He outlined this strategy at the 2016 AAN Annual Meeting.


His goal is to treat simultaneously all the pathogenic processes that underpin progressive MS. These strategies include:


  1. Anti-inflammatory therapies, which deal with both adaptive and innate immune responses.


  1. Neuroprotective therapies.


  1. Remyelination strategies.


Controlling the initial autoimmune-driven inflammatory component is key. Thereafter, neuroprotection should be sought for all stages of the disease. Lastly, remyelination medications fully improve recovery from relapses. They are less likely to lead to regaining lost function.


Further, he believes that aggressive treatment early in the disease is best. He views stem cell therapy as most effective and Lemtrada next for patients with poor prognostic factors and who have demonstrated an early aggressive course.


Neuroprotective therapies include sodium channel blockers, such as phenytoin, lamotrigine, riluzole, and oxcarbazepine; ion channel-1 blockers, such as amiloride; SSRIs, such as fluoxetine; phosphodiesterase inhibitors, such as ibudilast; microglial inhibitors, such as laquinimod and minocycline; and drugs that improve mitochondrial function, such as biotin and idebenone.


Regarding remyelination, there are 6 compounds in clinical trials. A monoclonal antibody to LINGO-1 is furthest along. Next is a retinoid X receptor agonist, then a muscarinic antagonist (benztropine). Also in trials is an antihistamine H3 antagonist, developed by GSK and termed clemastine; an anti-SEMA4D (VX15); and lastly biotin.


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Sleep Disorders In Parkinson’s

These sleep disorders in parkinson’s are mainly excessive daytime sleepiness, insomnia, rapid eye movement behavior disorder of sleep, and restless legs syndrome. Sleep can also be affected by nocturia, difficulty turning over in bed, hallucinations, dyskinesias, pain, dystonia.


How can we treat these symptoms? The best evidence is for using modafinil for excessive daytime sleepiness. Caffeine may be effective but with less robust evidence. The antidepressant doxepin may help insomnia. Rivastigmine may be effective for RDB of sleep, along with clonazepam, generally used first-line. Other studies show that stopping sedative medications and reducing dopamine agonists during the daytime help. Amoxetine, a “stimulating” antidepressant, could also help daytime sleepiness and would simultaneously be helpful for depression. Quetiapine and memantine do not help daytime sleepiness.


For insomnia, studies support use of doxepin, melatonin, eszopiclone. Nortriptyline but not paroxetine may also improve sleep quality, especially in patients with depression. Dopamine agonists have been long used to treat RLS and are FDA-approved to do so.


The most surprising new finding is that rivastigmine may help RBD, when it is refractory to clonazepam and melatonin. Less surprising is that modafinil helps daytime sleepiness.


See Parkinsonism & Related Disorders, 2016, page 25-34. Lead author is T.M. Rodrigues, MD.


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Got Another Guideline (GAG)

Medicare Access and CHIP Reauthorization Act (MACRA)
Medical Payment Alternatives

Why is it that just when we get used to evidence-based care, we now have to do value-based care? I find evidence-based care for common neurological disorders, such as epilepsy and dementia, valuable. Guidelines provide a framework and act as a reminder to maintain good quality.


But now, there is money on the table. The Medicare Access and CHIP Reauthorization Act (MACRA) was passed by Congress last year. When it comes into play, probably in 2017, physicians must choose between a Merit-Based Incentive Payment System or an Alternative Payment Model. The APM is broadly similar to the old concept of IPAs and capitation. None of us looks back at those years fondly, and this new payment model may prove to be a disaster for neurologists and their patients. Specialists will most likely participate in MIPS and not APM. There is a fixed pool of money in MIPS, so there will be winners and losers.


The American Academy of Neurology admirably has developed a “Payment Alternatives Team” and is partnering with its members to establish appropriate care for headaches and epilepsy, which I assume will be loosely based upon evidence-based guidelines.


We should applaud the AAN. For neurologists in private practice, this is truly a brave new world.


See Neurology Today, June 25, 2016, page 30.


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What Is The Hawthorne Effect?

The mere act of being recruited into a clinical trial has clinical and biological effects. These are independent from placebo and nocebo effects. These biases are the Hawthorne effect.

Fullerton Neurology and Headache Center.
Fullerton Neurology and Headache Center.

Workers in a factory near Chicago, the Hawthorne Works, were observed in higher or lower amounts of light to determine which increased productivity. The conclusion was that productivity was improved only because the workers were being observed. Similarly, subjects in clinical trials often show improvement because of better attention, better observation, better care, better compliance, and better adherence. Advocates of surgical safety checklists, developed to reduce morbidity and mortality, were surprised when they learned that the mere fact that surgeons were under observation, and not any specific details of the checklist, improved performance. In clinical trials, some subjects improve between recruitment and the beginning of treatment, before any therapy has been given.


Social interaction among participants in a trial leads to more biases. Both placebo and nocebo responses can be seen. Mass psychogenic illnesses are an example of nocebo responses. They correlate with empathy scores and pain catastrophizing. These social and psychological factors may be crucial for nocebo hyperalgesia.
See Lancet Neurology, 2016, volume 15, page 736.


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Update On Supplements For Migraine

Migraine and Headache supplements
New 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 on supplements for migraine 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.

See Headache Currents (In Headache), May 2016.

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How Many More Studies Do We Need To Stop Prescribing Opioids?

Stop Prescribing Opioids
How Many More Studies Do We Need To Stop Prescribing Opioids?

Almost 23,000 patients prescribed both long-acting opioids versus anticonvulsants and tricyclics, used for pain, were followed, and total mortality, over and above overdose deaths, was assessed. The alternatives to opioids were mainly gabapentin, pregabalin, carbamazepine, and tricyclics, mainly Elavil. Doses of greater than 150 mg of Elavil were excluded. These patients were treated for noncancer pain, mainly low back pain.

The opioid treated group had 1-1/2 to 2 times excess mortality compared to the other groups. This mortality was seen mainly in the first 6 months. Two-thirds of the excess deaths were unrelated to unintentional overdose. One-half were cardiovascular. Patients being treated for palliative or end-of-life care were excluded.

The authors believe that the main cause may be the fact that opioids cause or worsen obstructive and central sleep apnea, and these patients have increased incidence of nocturnal arrhythmias, myocardial infarction, or sudden death. They further stated that for some individual patients, the therapeutic benefits of opioids may outweigh the increase in mortality risk.

In the same journal, a second study beginning on page 2459 by J.C. Ballantyne, MD, looked at the efficacy and tolerability of long-term treatment with opioids for chronic low back pain. Thirteen trials with almost 3500 patients were identified. At least half withdrew for adverse effects or lack of efficacy. There was “moderate quality evidence” that opioids reduce pain in the short-term but no evidence to support long-term use for low back pain.

See JAMA, 2016, page 2415.

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Biotin For Progressive MS?

Biotin For Progressive MS?
Biotin For Progressive MS?

According to a new phase III study, presented at the 2016 AAN Annual Meeting, biotin at a dose of 300 mg daily seemed to reduce the rate of disease progression in both primary and secondary progressive MS. About 13% of the patients also showed an improvement in EDSS or timed 25-foot walk at month 9, which was maintained at month 12, compared to no patient in the placebo arm.

A widely used preparation called Women’s Hair, Skin, & Nails contains biotin, selenium, and zinc. Biotin is available over-the-counter, but highest dose is 10 mg. Thus, an MS patient would need to swallow 30 pills a day at a cost of about $30 a month. Several of my patients have located compounding pharmacies who will prepare a 300 mg pill at a cost of $70 to $100 per month.

Other recent studies regarding supplements for MS have shown benefit using lipoic acid 1200 mg a day, proprionic acid 1 gram a day, and a probiotic preparation termed VSL#3, double strength sachets, 3600 billion CFU/day.

Older studies strongly support the use of vitamin D. Melatonin 10 mg 1 to 2 hours before bedtime has not been rigorously tested in MS patients but may have anti-inflammatory effects. Studies about omega-3 fish oils are conflicting, as are studies with statins.

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Are MS Patients More Likely To Have Cardiovascular Disease?

Four major conditions – diabetes, hypertension, hyperlipidemia, and ischemic disease – have potential adverse effects on mortality and quality of life. A study of 44,000 Canadians with MS and 221,000 controls was done to determine the incidence of these disorders.

Incidence of diabetes rose more steeply with age in the MS population. Hyperlipidemia, hypertension, and ischemic heart disease were similar combining all age groups, but incidence of heart disease was higher in the younger MS population. As expected, all disorders increased with age.

MS is more common in women than men, whereas the comorbidities by contrast are higher in men.

A possible explanation for the finding of detecting more diabetes and hyperlipidemia in the MS population may be more frequent health contacts for those with MS, leading to earlier diagnosis. Other explanations include physical inactivity after MS onset, and the fact that patients with MS are more likely to smoke, at least in Canada, and be overweight.

Further, these vascular comorbidities are associated with more rapid disability in MS.

Those of us who treat MS patients should take a more active role in screening for these disorders and not assume that our patients’ primary care physicians do so consistently.

See Neurology: Clinical Practice, 2016, volume 6, page 120-128. Lead author was Ruth Ann Marrie, MD.

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