Obesity has been recognized for many years to be a risk factor for cardiovascular disease and stroke. More recent studies have concluded that obesity in the teens increases the risk of developing multiple sclerosis.
Migraine now joins this list. Obesity is an important risk factor in converting from episodic migraine, meaning less than 15 headache days a month, to chronic migraine, meaning 15 or more headache days a month. Patients with chronic migraine have much more disability, utilize medical resources more, have a poorer quality of life, are more difficult to treat, and have higher rates of depression.
Why this should be so probably relates to the fact that fat cells are proinflammatory, secreting adipokines and other deleterious cytokines. Other risk factors in converting episodic to chronic migraine include inadequate treatment of individual attacks of migraine, lower socioeconomic status, smoking, and snoring. Likely, the increased risk with snoring relates to obesity.
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This was big news several months ago. A phase I drug Clinical Trials in France resulted in a death in 1 healthy volunteer and neurological deficits in 3 others. The details were published in the New England Journal of Medicine, November 3, 2016. The drug was considered to be an analgesic, anti-inflammatory, and possibly effective for neuropathic pain. It targeted the endocannabinoid system. The manufacturer was Bial, a pharmaceutical company based in Portugal.
The medication seemed safe in animal testing, and this led to a phase I trial, which is designed to test safety and not efficacy in humans. Bial went ahead with the study even though other drug companies had tested molecules that were similar and seemed ineffective.
This trial started in January 2016, with 8 volunteers. Two received placebo and six a 50 mg dose of the medication. All 6 of the treated patients were hospitalized with adverse effects, starting on the fifth day of drug administration. Nevertheless, the researchers continued to treat the other patients.
The toxicity was neurological. MRI showed hyperintense lesions, mainly in the brainstem and hippocampal areas.
Lessons are obvious. Researchers should know when to stop. The dosing should have been staggered rather than all patients being treated at the same time.
Volunteers in phase I trials have no possibility of benefit from the trial, unlike patients in phase II and phase III trials. They do so largely because they are being compensated. Several years ago The New Yorker published an article explaining that there is a group of young men for whom clinical trials are their livelihood. Phase I trials are essential in development of medications. They are ethical as long as there is true informed consent and appropriate safeguards are in place.
According to a study in the October 20, 2016, issue of the New England Journal of Medicine, surprisingly so, specifically 1 out of every 6 patients admitted for first-time syncope. It was found in 24% of patients who presented with syncope when no other cause was found and even 13% among those who had another potential cause.
Keep in mind that in the study of 560 patients most were older than 75 years. They were screened with a D-dimer blood test, and the diagnosis was confirmed with a CT angiogram of the chest or V/Q scanning.
Patients were identified at 11 hospitals in Italy over a 4-year period. Lead author is Paolo Prandoni. Comments by several experts varied from great skepticism to a feeling of being validated for similarly held beliefs. If the results can be validated, they will likely change clinical practice for elderly patients with syncope. Benefits of anticoagulation would outweigh risks of CT angiography.
An important analysis termed “Trends in Dietary Supplement Use Among US Adults From 1999-2012” by lead author Kantor was published in JAMA, October 11, 2016. An editorial was written by Dr P.A. Cohen.
The main finding is that about 50% of adults in the United States used supplements within the last 30 days, and this proportion was unchanged from 1999-2000 compared to 2011-2012. This is despite the fact that multiple studies have yielded mainly disappointing results about potential health benefits, and there is more and more evidence of harm.
The Dietary Supplement Health and Education Act of 1994 is an important reason for continued widespread use. This act states that supplements are presumed to be safe until the FDA detects evidence of harm, which usually occurs only after extensive use and exposure to many consumers. For example, supplements containing Ephedra were linked to serious adverse effects, including myocardial infarctions, seizures, strokes, sudden deaths. Beta-carotene supplements were found to actually increase the risk of lung cancer among smokers. The National Institutes of Health has invested 250 to 300 million dollars per year in dietary supplement research. They found that echinacea does not treat the common cold, St. John’s wort does not treat major depression, vitamin E does not prevent prostate cancer, glucosamine and chondroitin do not treat arthritis, and that ginkgo biloba does not improve cognition.
Use of some supplements can be justified, including treatment of vitamin and mineral deficiencies, used for early age-related macular degeneration, vitamin D for multiple sclerosis, and perhaps probiotics for various disorders.
Why do consumers continue this widespread use given this knowledge? Perhaps they are not aware of these negative results. Perhaps they do not have faith in the scientific process and in fact believe there is a conspiracy by the “established” healthcare system. Most researchers believe that perceived benefits are largely placebo effects.
Detecting Alzheimer’s disease by a relatively inexpensive blood test could greatly reduce the cost of population screening and recruitment for clinical trials. This is especially relevant given the hope that monoclonal antibodies directed at amyloid prove to modify the disease course.
A recent study published in Neurology, September 13, 2016, lead author Burnham, describes a simple blood-based signature that reflects neocortical beta-amyloid burden. It is a profile of 4 individual blood makers, specifically amyloid beta 1-42, CXCL-13, IgM-1, IL-17, PPY, and VCAM-1. Individually, they did not have significant predictive power but did in combination.
Specifically, the 12% of healthy controls that had high estimated beta-amyloid burden progressed in comparison to the 5% who had a low burden. Forty percent of subjects with mild cognitive impairment with a high burden progressed in comparison to 5% of those with MCI who did not. These ratios are similar to those utilizing Pittsburgh compound B-PET scan. They outperformed the cerebrospinal fluid amyloid-tau profile, which obviously requires an invasive lumbar puncture, as well as outperformed in measures of hippocampal volume on brain MRI. Keep in mind that there was marked overlap of confidence intervals in analyzing all of these markers.
If findings are confirmed in a large group of patients, this profile would likely come into widespread use. It appears that there are commercially available kits to measure each component.
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Race and ethnicity are not the same. People of the same race share distinctive physical traits and ancestry. Ethnicity, on the other hand, is a shared experience, specifically cultural. DNA varies by less than 0.1% in any two people chosen at random. Further, at least 85% of the 350,000 known genes are present in all people.
African Americans in fact have higher incidence of MS than whites / Caucasians. Hispanic Americans seem to have lower incidence. People who migrate from a high risk to a low risk area in first two decades of life carry the high risk. This is more likely secondary to environmental factors, specifically vitamin D, and viral infections rather than genetic factors. Another important risk factor is obesity, especially in adolescent girls.
African Americans are older at onset and have a more severe course with resultant greater disability.
A Hispanic person can be of any race. In Hispanic Americans, age of onset appears to be younger than white but neuromyelitis optica much higher, with a prevalence of 19%, comparable to those in Asians. In whites, this disorder is seen in only 2% to 3%. Why should this be so? Likely, there is Asian ancestry in Hispanics from Central and South America.
Treatment of MS is greatly affected by race and ethnicity. African Americans are probably less responsive to interferons than whites. On the other hand, Tysabri may be effective in this group, as in Hispanic patients. B-cell therapies may be especially beneficial to African Americans because they have higher IgG index in their cerebrospinal fluid than whites. This, however, has never been tested adequately.
Access to healthcare is less in African Americans and Hispanics, especially low-income groups. About a third of patients in MS who are covered by Medicaid / Medi-Cal had never seen an MS specialist and were not receiving treatment-modifying drugs. Factors include mistrust of the healthcare delivery system (recall the Tuskegee syphilis study), less access to health insurance, greater belief in natural remedies, or as language and cultural barriers.
Tailoring treatment to a diverse group is a poorly met challenge at this time.
See Science of MS Management, summer 2016.
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These are the FDA-Approved anti-epileptic drugs for monotherapy, the list is small:
Felbamate for newly diagnosed and refractory focal.
Lamotrigine for refractory focal and conversion to monotherapy.
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.
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.
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:
Anti-inflammatory therapies, which deal with both adaptive and innate immune responses.
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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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.