Concussions and Multiple Sclerosis

For many years researchers have been studying the possible link between head concussions in early life and the onset of Multiple Sclerosis in later years. However the results have been disappointing except for a new study.

Montgomery, Hiyoshi et al. studied the large, prospective, collected data of the National Swedish patient register—with hospital diagnoses and the clinical data of patients diagnosed with MS—to compare the information of more than 2000 individuals diagnosed with MS up to 2012 who were matched with more than 72,000 non-MS ones, controlling for sex, year of birth, age and vital status at the time of diagnosis and county of diagnosis. The events of head concussion and broken bones in the extremities were singled out from birth to 10 years old, and from the ages of 11 to 20.

One single concussion occurring between the ages of 11 and 20 provoked an adjusted odds ration of teens later been diagnosed with MS of 1.22% while two or more concussions were associated with an odds ratio of 2.33. The investigators did not find any relationship between children aged 10 or younger who had head concussions with the later onset of the disease; the same was true for young people that had broken bones but no concussions. Interestingly enough they found that the longer the hospital stay for head concussion was, the more likely the possibility of developing MS also was; the odds ratio for developing MS following a single day of hospitalization was 1.15, compared to 1.55 for two days and 1.75 for three days or more.

Dr. Montgomery, professor of Clinical Epidemiology at Örebro University in Sweden, said “in adolescents with more than one concussion, it’s a doubling of the risk for MS. But the risk of developing MS is very low to begin with. That’s why we want to know more about susceptibility. That’s a study we’re going to do now, to look at genetic susceptibility. Then we might see a more precise estimate of risk for individuals.” A previous study showed that brain injury triggers an autoimmune process in nervous tissue. If a genetically susceptible individual has a brain lesion during adolescence, then the statistical possibility of developing MS later in life might increase.

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Neuromodulation for Migraines

For several years we have been using the TENS machines to stimulate the Peripheral Nervous System in order to get needed relief for chronic neuro-muscular problems. The same physiological principle is being used to stimulate the Central Nervous System. One of the stealthiest developments in the treatment of Migraines has been the technological development of devices that will control the episodes. Various regulatory issues have delayed their introduction in the commercial market but they will soon become an option if insurers start to cover them. Here is a review of the three devices that have been approved by the FDA.

Transcutaneous Supraorbital Neurostimulation. It is the first device that was approved by the FDA and its commercial name is “Cefaly.” It is applied on a set of electrodes on the forehead to stimulate both supraorbital nerves. According to a scientific study the device must be used for 20 minutes per day for at least three months in order to noticed a significant reduction of headache days. It has both a high-intensity and low-intensity settings in the USA; in the EU and Canada it has a preventive, acute and chronic settings. With an approximate cost of U$ 400, it is not yet covered by the Payors.

Single-Pulse Transcranial Magnetic Stimulation. The second approved device is a single-pulse transcranial magnetic stimulator that is commercially available under the name “Spring TMS”; it is applied in the back of the skull and sends pulses forward up to the frontal area. It blocks the slow activation of cortical neurons dubbed as “cortical spreading depression” (CSD) that forms the basis of the auras patients experiment before an attack. A study found it effective at the beginning to wipe out the aura and the expected fit; the FDA has approved the deployment of two pulses right before an attack. In a preventive mode, 4 pulses are applied in both the morning and at night.It is only available to rent for 3 months with a price of U$ 150 per month.

Non-invasive Vagal Nerve Stimulation. The third device is a stimulator of the vagus nerve placed on the neck that is used for cluster headaches and set at two cycles in the treatment and prevention protocols. Two studies have shown that it can end an acute episode of cluster headache but it was not effective in the treatment of chronic cluster attacks. Also not effective in chronic migraines after 2 months, it might be effective at longer time points. It can block the CSD and down-regulate the thalamo-cortical pathways.

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Fatigue in Multiple Sclerosis

Fatigue is the worst debilitating symptom of patients with MS (multiple sclerosis) as it severely limits their participation in the public sphere and the workforce, besides alienating their interpersonal relationships. It has a subjective component, i.e. how patients feel, and an objective one, i.e. the diminished performance in physical and intellectual tasks. Kluger et al. created a unified taxonomy to guide its treatment in the medical settings.

Perceived fatigue is what the patient actually feels at any given time; it can be defined as a lack of purpose in daily activities that hampers performance.

Fatigability (also called performance fatigability) is what can be objectively measured by an examiner; it is defined by the measure of change in the performance of a physical or a cognitive task over a certain period of time.

Perceived fatigue is measured by the “Neurological Fatigue Index” (NFI-MS), which was approved by the FDA. It is made of 23 standard questions that cover three domains of fatigue; physical, cognitive and sleep quality. It also has a summary scale that covers the physical and cognitive domains. Fatigability can be measured with a 6-Minute Walk Test (6MWT), a grip strength test and the response speed to different cognitive tests. The third measurement of fatigability is carried out with the “Continuous Performance Test” (CPT) that checks the timely attention in front of a computer screen.

Mayis Aldughmi et al. studied the perceived fatigability and fatigability in 52 patients with mild forms of MS with a mean age of 46 years. The percent change score of the 6MWT was not statistically associated with the physical domain, the cognitive domain or the summary scale. The grip strength test change scores were not statistically associated with physical domain, the cognitive domain or the summary scale. But the performance fatigability was statistically associated with the three parameters of the NFI-MS. The data illustrates that performance fatigability during an attention-based test is associated with increased physical and cognitive perceived fatigue and the overall perceived fatigue. However those assessments of performance fatigability during a physical task did not yield some significant results. This study showed that the presence of depression was associated with fatigue.

In this study MS patients had fatigue after 3 performance fatigability tests: walking, handgrip and attention. Only attention had a statistically significant association with perceived fatigue, unlike the other 2 performance measures.

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Is gene editing dangerous?

When President Clinton and Prime Minister Tony Blair jointly announced in June 2000 the completion of the first draft of the human genome, i.e. the DNA library that determines how our bodily cells are made and/or replaced in particular ways, the media heralded it as the first major step to develop new ways to cure and prevent diseases; its 3 billion U$ cost was largely paid with public funding. During the first decade of the new century, private companies used that information to design new tests for genetic diseases like Down’s syndrome.

The latest test for Down’s syndrome measures small amounts of fetal DNA in the mother’s bloodstream, which has replaced the need for amniocentesis. Couples anxious to find out the possibility of that condition can now avoid the dangers of invasive procedures, with the real risk of a miscarriage; the increased discovery of the trait will certainly increase the rate of abortions. Genetic testing has become a novel area of consumption for wealthy classes as companies have designed easy to use direct-to-consumer testing kits. The interpretation of the results can be difficult to interpret without professional advice; moreover the use of different criteria and databases by companies might yield contradictory, perplexing results for the same medical condition.

The humongous amount of genetic information of the populations is being collected and stored by public and private entities with various missions. The “Genetic Information Non-discrimination act” of 2008 made it illegal for American insurance companies that provide health care services to base their acceptance protocols on this information but surprisingly enough the same does not apply to life insurance and long-term care—a big loophole.

However there is an even bigger potential threat to Humankind and life in our planet that has been created in the last few years: the CRISPR technique. Jennifer Doudna and Samuel H. Sternberg, researchers at the University of California at Berkeley, recently published a book about the use of gene editing in modern medicine and the serious ethical questions that it arises. The advent of gene editing came with the discovery in the 1980s of parts of microbial genomes that were consistently replicated in the DNA sequences. They were called “clustered regularly interspersed short palindrome repeats” or CRISPR and scientists found out that they can activate certain proteins called CRISPR-associated or CAS that can attack and annul certain DNA. The microbe can detect an invasion of extraneous DNA and get rid of it.

These scientific discoveries paved the way for the design of CRISPR that can alter and control the DNA of living beings, including humans. However there are still some technical limitations to the complexity of the DNA that can be introduced in cells to change their genetic material. Eventually the technique will be refined with the grave potential of a biological weapon. At present scientists from UCLA and the Broad Institute are fighting in court about the ownership of the patents needed to commercialize this product.

Doudna et al. are adamantly opposed to the use of CRISPR to alter the genetic components of human beings, akin to the eugenics of Nazi Germany. But there is a fine line between radical alteration and enhancement of body features as the controversial use of Botulinum toxin has shown us lately. These authors also believe that the greatest controversy at the present time is the use of CRISPR to design “gene drives”—the artificial bits of DNA used to control pest like mosquitoes that transmit communicable diseases. Even though there is a Public Health need to eradicate the Anopheles mosquito that transmit malaria in African nations, killing thousands every year, there is not a proper understanding of the ecological consequences of this action. Eventually the mosquito might also mutate to develop its drives-resistance.

There is not a global consensus as to how these gene-drives should be used amongst the nations and private institutions, which has created a legal void. We must discuss these controversies in our communities as their effects will eventually reach all of us in the next few decades, whether we like it or not. The future is knocking at our door.

What do you think? Please tell us.

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Prevention of Migraines

Research studies had shown that during an attack of acute migraine and cluster headaches there is an elevation of humanized calcitonin gene-related peptide (CGRP) monoclonal antibodies in the jugular vein blood of patients. At the 59th Annual Scientific Meeting of the American Headache Society, encouraging data on four of these monoclonal antibodies—eptinezumab, renumab, fremazumab and galcanezumab—were presented to the audience.

Eptinezumab, injected as a single dose, decreased the monthly migraine days (MMD) as well as the number of severe migraines in the participants. Most of the patients in this multiple site study were women younger than 40 years old with an average MMD of approximately16 days. The initial 12 weeks-report (the study is scheduled to run for 48 weeks) showed that there were more patients with reduction of MMD when they took the 300 and 100 mgrs dosage—33 and 31% respectively—than the participants on placebo. Approximately half of the patients given Eptinezumab had a reduction of their MMD compared to 41% of placebo, which was statistically significant. The drug was well tolerated and there were no serious adverse instances.

Erenumab, which unlike the other three drugs that attack the CGRP ligand, is an anti-CGRP receptor monoclonal antibody. Almost 700 patients from all over the planet who had more than 15 MMD were enrolled in the 12 weeks-randomized controlled trial, lest they had failed with three other preventions; a subcutaneous injection of 70 or 140 mgr was given monthly. In both dosage groups there was an average reduction o 6.6 in MMD from a baseline of 18 days, compared to a 4.2 reduction in MMD in the placebo group. A greater number in both groups—40 and 41% respectively—had at least a 50% reduction in MMD, compared to the placebo group, which had 23%. Both groups had the same safety profile and there were no serious instances.

Galcanezumab was studied in EVOLVE-2, a six months phase III trial that recruited patients with at least 4 to 14 MMD with or without an aura. More than 900 patients were randomized in a 1:1: 2 proportion to receive a subcutaneous injection of galcanezumab of 120 mg/month, an injection of 240mg/month or a placebo. Patients in the 120 mg group had a reduction of 4.29 MMD and those in the 240 mg had 4.18 MMD, compared to 2.28 MMD for the placebo group. There was a 50% reduction in MMD for 59.3% in the 120 mgr group and 56.35 in the 240 mgr group compared to placebo. There was not a significant difference in safety and there were no instances.

Fremanezumab was studied for both quarterly and monthly regimes in patients that had had a previous 28 days run-in period. Moe than a thousand participants were randomized 1:1:1 to three monthly doses of placebo or 675 mgr for the first month followed by a placebo for 2 months or an initial dose of 675 mgr of the drug followed by two monthly doses of 225 mgr of it. Participants in the monthly regime had a reduction of 4.6 MMD and those in the quarterly regime had one of 4.3 MMD, compared to 2.5 for the placebo. The drug was well tolerated and on site injection pain was the only event.

For all the Migraine patients and their family members that have to live with its excruciating physical, emotional and economic burdens—as my family had to endure with the crippling attacks that my dear father Mario had—the possibility of relief, specially if it means less monthly attacks, is good news.

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CDC report on Opioids

Researchers at the Center for Disease Control (CDC) published an online article in JAMA where they analyzed the trends of opioids’ consumption in the USA during the past decade. Their analysis is based on data from the QuintilesIMS Transactional Data warehouse, which stores the approximate quantity of opioids’ prescriptions by surveying 50,000 US pharmacies; they examined data form 2006 to 2015 at the county, regional and national levels.

“Annual opioid rates increased from 72 to 81.2 per 100 persons from 200 to 2010, were continuous from 2010, were continuous from 2010 to 2012, and then decreased by 13% to 70.6 per 100 persons from 2102 to 2105.” The US consumption of opioids peaked in 2010 with 782 MME (morphine milligram equivalents) per capita and then slid down to 640 MME per capita in 2015.

“The average duration of opioid prescriptions increased, in part because of the continued increase in longer opioid prescriptions (greater or equal to 30 days) through 2012, followed by a stabilization of the rate, and a substantial decrease in shorter prescriptions (less than 30 days) after 2012.” The average prescribed supply increased from 13, 3 days in 2006 to 17.1 days in 2015.

The CDC report found many variations in the geographic distribution of the opiod prescription, which was significantly higher in rural counties with a large population of unemployed whites who also had diabetes and arthritis. At long last the CDC bureaucrats recognized that the dismal economic conditions of certain areas is a critical factor of the raging opioid epidemic; however they also found differing prescription patterns amongst physicians.

They claim that there are approximately 2 million addicted people in the USA, which provoked 33,091 deaths in 2105, half of them involving the use of prescribed drugs; the economic cost was estimated at 78.5 billion dollars.

Even though prescription of opioids is coming down, the number of deaths from drug overdosing keeps rising in the USA, in spite of all the concerted efforts of federal and state authorities to address this Public Health threat.

Perhaps it’s time to consider better care alternatives like Cannabis and its derivatives.

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New focus in Alzheimer’s research

The sustained search for a treatment for Alzheimer’s disease has created many experimental therapies that target the accumulation of a protein called Amyloid Beta in the patient’s brains. On one hand the clinical results with the available treatments have been mixed because the Abeta levels do not correlate well with the severity of symptoms and on the other hand some studies suggest that the loading of this protein begins two or three decades before the patients’ show symptoms, which makes an early prevention impractical.The deterioration of the patients’ clinical picture seems to correlate well with the loss of excitatory neurological synapses that allow connectivity of cells.

Dr. Margolis et al., researchers at the Gladstone Institute of Neurological Disease at the University of California at San Francisco, found in 2010, that a protein called EphB2, which regulates the NMDA function essential for the proper synaptic connectivity, was decreased in the brains of AD patients. The decay of the Ephexin 5 had the collateral of slowing the function of the excitatory synapses, which could explain Autism’s cognitive dysfunction. Recently that fortuitous finding has been used in some new studies.

When the researchers added Amyloid Beta to the brains of healthy mice, there is an increased production of Ephexin 5. The analysis of brain tissues from the autopsy of patients with AD showed increased levels of EphB2. The researchers hypothesized that if they could get rid of EphB2, the process of degeneration of excitatory synapses could be halted or at least slowed.After using genetic engineering techniques to destroy the gene controlling the production of EphN2, they discovered that the animals with severe damage did not lose their excitatory synapses, which spared their memories.

Even though Amyloidosis cannot be ultimately stopped, the preservation of synaptic function might prevent the onset of memory loss in AD patients. If the scientists can determine how the abnormal protein damages the neurons, they can provide therapeutic alternatives to make them “amyloid-resistant.” These preventive measures can be instituted in later stages of the disease, unlike the ones pertaining amyloid that must be started in the 40s or 50s. As there are no drugs that can be safely given for forty years to AD patients, researchers are now focusing on an earlier stage of the disease and the medical therapies that can help patients avoid the ravages of it.

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