An article published Online First and in the April edition of The Lancet Neurology reports that a new hand-held device that delivers a magnetic pulse to the back of the head could be a promising non-invasive, non-drug treatment option for patients with migraine. This device offers efficient pain relief for up to 48 hours after treatment in some patients with migraine with aura. Treatment has to be given at the onset of symptoms. It does not cause any serious side-effects.

There are two major types of migraine:

• migraine without aura
• migraine with aura

In migraine with aura, a variety of focal neurological features occur in association with the headache, usually beginning before the onset of pain. These include visual symptoms such as spots of light, zigzag lines, and regions of visual loss, as well as non-visual symptoms including tingling and numbness, and weakness and difficulties with language.

There are two types of transcranial magnetic stimulation (TMS):

• Single pulse (sTMS): In sTMS, used in the present study, individual magnetic pulses are applied.
• Repetitive TMS (rTMS): In rTMS a series of pulses is used. rTMS has been approved by regulatory bodies for use in diagnostic testing and for the treatment of depression. There is therefore a large body of data supporting the safety of TMS with much higher exposures than used in the present study. The device used in this study is portable and suitable for self-treatment outside medical settings.

There is confirmation that single-pulse transcranial magnetic stimulation (sTMS) might disrupt the electrical events in the brain that underline migraine aura. Earlier small-sized studies indicate that sTMS reduces migraine pain and that it is well tolerated. But, previous trials used large and expensive devices not suitable for use outside a clinic. This made it difficult to verify if the effect of TMS was authentic.

To test the limitations of the earlier findings, Richard B Lipton from the Albert Einstein College of Medicine, New York, USA, and colleagues carried-out a randomized, sham-controlled trial. They assessed the safety and effectiveness of a new, hand-held sTMS device suitable for home use, in the treatment of migraine with aura. The trial involved an identical device designed to deliver an inactive (sham) impulse to ensure patients and investigators were masked to treatment. Both active and sham treatment was associated with a clicking sound and vibration of the device to maintain blinding. Blinding was successful as demonstrated by the fact that 80 percent of patients in both groups thought they received active sTMS. A total of 201 patients were randomly assigned to sham stimulation (99) or sTMS (102). They were instructed to treat up to three attacks over three months while experiencing aura. They were required to record pain and associated symptoms before and at regular intervals after treatment.

Results indicated that sTMS was considerably more efficient than placebo for the treatment of migraine with aura. More patients were pain free at follow-up intervals of 2, 24, and 48 hours. They were free of headache recurrence. In addition, they did not need rescue medication, compared with sham stimulation. Out of the 164 patients who treated at least one attack, 39 percent in the sTMS group were pain free 2 hours after treatment compared with 22 percent in the sham group. This results in a therapeutic gain of 17 percent.

Furthermore, sTMS treatment did not intensify associated symptoms. Also, it was non-inferior to sham stimulation for:

• the improvement of nausea
• photophobia which is an excessive sensitivity to light
• phonophobia which is a heightened sensitivity to sounds

More significantly, sTMS treatment was well tolerated. There were no device-related serious adverse events reported. Also, the prevalence and severity of side-effects was low and comparable between the two groups. In addition, patients hardly ever experienced errors when using the device. They rated it an average 8 out of 10 for user-friendliness.

The authors mention: “Although the exact mechanisms of migraine remain under study, administration of sTMS in people with migraine with aura decreases progression of the attack in some individuals…and could be a promising acute treatment.” They say in closing that further research is required in order to examine the range of sTMS doses. The optimum timing of treatment and cost effectiveness also need to be established.

In an associated note, Hans-Christoph Diener from University Hospital Essen in Germany comments that these findings demonstrate that: “the use of TMS could be a major step forward in the treatment of migraine with aura, particularly in patients in whom presently available drug treatment is ineffective, poorly tolerated, or contraindicated.”

New research shows that migraine and depression may share a strong genetic component. The research is published in the January 13, 2010, online issue of Neurology®, the medical journal of the American Academy of Neurology.

“Understanding the genetic factors that contribute to these disabling disorders could one day lead to better strategies to manage the course of these diseases when they occur together,” said Andrew Ahn, MD, PhD, of the University of Florida in Gainesville, who wrote an editorial accompanying the study and is a member of the American Academy of Neurology. “In the meantime, people with migraine or depression should tell their doctors about any family history of either disease to help us better understand the link between the two.”

The study involved 2,652 people who took part in the larger Erasmus Rucphen Family study. All of the participants are descendants of 22 couples who lived in Rucphen in the 1850s to 1900s.

“Genealogical information has shown them all to be part of a large extended family, which makes this type of genetic study possible,” said study author Gisela M. Terwindt, MD, PhD, of Leiden University Medical Center in the Netherlands.

Of the participants, 360 had migraine. Of those, 151 had migraine with aura, which is when headaches are preceded by sensations that affect vision, such as seeing flashing lights, and 209 had migraine with no aura. A total of 977 people had depression, with 25 percent of those with migraine also having depression, compared to 13 percent of those without migraine.

The researchers then estimated the relative contribution of genetic factors for both of the disorders. They found that for both types of migraine, the heritability was estimated at 56 percent, i.e., 56 percent of the trait is explained by genetic effects. For migraine with aura, the estimate was 96 percent. “This finding shows that migraine with aura may be a promising avenue to search for migraine genes,” Terwindt said.

Comparing the heritability scores for depression between those with migraine and those without showed a shared genetic component in the two disorders, particularly with migraine with aura. “This suggests that common genetic pathways may, at least partly, underlie both of these disorders, rather than that one is the consequence of the other,” Terwindt said.

Researchers in the US believe they have discovered why light can make the pain of migraine worse, even in some blind people: they found photoreceptors in a part of the brain called the thalamus appear to process both light and pain, revealing for the first time that it is possible for neural pathways for pain and non-image-forming light sensitivity to converge.

The study was the work of senior author Dr Rami Burstein, an associate professor of anesthesia and neuroscience at Beth Israel Deaconess Medical Center and Harvard Medical School in Boston, Massachusetts, and colleagues, and appeared online in advance on 10 January in Nature Neuroscience.

Burstein told the media that up to 90 per cent of migraine sufferers experience photophobia, where light makes the migrane hurt more.

“We had no clue in the world where in the world light and pain talk to each other in the brain,” he said. “They have completely different pathways in the brain.”

But for light to make pain worse, the pathways have to converge somewhere, thought the researchers.

So first they studied 20 blind migraine sufferers, 6 of whom had no light perception at all, no functioning optic nerve, and experienced no photophobia.

The remaining 14 blind migraine sufferers could sense light and dark and also had photophobia. Burstein and colleagues wrote:

“We found that exacerbation of migraine headache by light is prevalent among blind individuals who maintain non-image-forming photoregulation in the face of massive rod/cone degeneration.”

Burstein said this suggested that the optic nerve is critical to photophobia, ie for the light to exarcebate the headache.

In the next stage of the study, the researchers studied neural pathways in rats.

With “single-unit recording and neural tract tracing” they found “dura-sensitive neurons in the posterior thalamus whose activity was distinctly modulated by light”.

The thalamus is the brain’s sensory switching center: it receives sensory signals from different parts of the body and redirects them to various sensory, motor and cognitive areas of the brain’s cortex.

The researchers wrote that the cell bodies and dendrites (filamentous fingers through which cells link up and pulse electrical signals to each other) of these “dura/light-sensitive neurons were apposed by axons originating from retinal ganglion cells (RGCs), predominantly from intrinsically photosensitive RGCs, the principal conduit of non-image-forming photoregulation”.

Burstein and colleagues proposed that these findings suggest:

“Photoregulation of migraine headache is exerted by a non-image-forming retinal pathway that modulates the activity of dura-sensitive thalamocortical neurons.”

Essentially, as they explained to the media, they had discovered a group of photoreceptors (known as melanopsin, a light sensitive pigment) projects onto neurons on the thalamus that also process pain signals.

Burstein said:

“We identified a new pathway in the brain that originates in the eye and goes to the brain areas where neurons are found that are active during migraine attacks.”

“The light can increase the electrical activity in neurons that are active to begin with,” he explained.

One expert said these findings should put to rest any suggestion that patients exaggerate their sensitivity to light; they are not whining or imagining their symptoms.

Dr Richard Lipton, director of the Montefiore Headache Center and professor of neurology and epidemiology at Albert Einstein College of Medicine in New York City, commented that:

“This provides an anatomic and physiological basis for a common experience — that light makes pain worse, not because you’re a whiner, but because there is an anatomic pathway that links the visual system to the pathway that produces head pain.” .

“”That odd bit of clinical symptomatology has a firm basis in brain science,” added Lipton, who was not an author of the study.

However, while the findings help us understand more about migraine and photophobia, they are unlikely to help migraine patients in the near future, said Dr Michael Palm, an assistant professor of neuroscience and experimental therapeutics and internal medicine at Texas A&M Health Science Center College of Medicine, College Station, and director of the Parkinson’s and Headache programs at Texas Brain and Spine Institute in Bryan.

“This gives us a little better insight as to the theory and mechanism behind migraine,” said Palm, who was also not an author of the study.

“We are making progress in understanding this phenomenon,” he added.

Researchers from the American Headache Society’s Women’s Issues Section Research Consortium found that incidence of childhood maltreatment, especially emotional abuse and neglect, are prevalent in migraine patients. The study also found that migraineurs reporting childhood emotional or physical abuse and/or neglect had a significantly higher number of comorbid pain conditions compared with those without a history of maltreatment. Full findings of the study appear in the January issue of Headache: The Journal of Head and Face Pain, published on behalf of the American Headache Society by Wiley-Blackwell.

According to a report by the U.S. Department of Health and Human Services, state and local child protective services (CPS) investigated 3.2 million reports of child abuse or neglect in 2007. CPS classified 794,000 of these children as victims with 59% classified as child neglect; 4% were emotional abuse; 8% as sexual abuse; and 11% were physical abuse cases. Both population- and clinic-based studies, including the current study, have demonstrated an association between childhood maltreatment and an increased risk of migraine chronification years later.

To conduct this study, Gretchen E. Tietjen, M.D, from the University of Toledo Medical Center, and colleagues, recruited a cross-sectional survey of headache clinic patients with physician-diagnosed migraine at 11 outpatient headache centers. Childhood maltreatment was assessed using the Childhood Trauma Questionnaire (CTQ), a 28-item self-reported quantitative measure of childhood abuse (physical, sexual, and emotional) and neglect (physical and emotional). Self-reported physician-diagnosed history of comorbid pain conditions such as irritable bowel syndrome (IBS), chronic fatigue syndrome (CFS), fibromyalgia (FM), interstitial cystitis (IC), and arthritis was recorded on the survey.

A total of 1348 patients diagnosed with migraine completed the surveys. Researchers found migraineurs who reported childhood emotional abuse or physical neglect had a significantly higher incidence of comorbid pain conditions compared with those without a history of maltreatment. In the study population, 61% had at least 1 comorbid pain condition and 58% reported experiencing childhood trauma either by abuse or neglect. The number of different maltreatment types suffered in childhood correlated with the number of comorbid pain in adulthood.

Specifically, physical abuse was associated with a higher incidence of arthritis; emotional abuse was linked to a greater occurrence of IBS, CFS, FM, and arthritis; and physical neglect connected with more reports of IBS, CFS, IC, and arthritis. In women, physical abuse and physical neglect was associated with endometriosis (EM) and uterine fibroids, emotional abuse with EM, and emotional neglect with uterine fibroids.

“Our study found that while childhood maltreatment is associated with depression, the child abuse-adult pain relationship is not fully mediated by depression,” explained Dr. Tietjen. Results from this study, as well as three recent population-based studies, indicate that associations of maltreatment and pain were independent of depression and anxiety, both of which are highly prevalent in this population.

Addex Pharmaceuticals (SWISS: ADXN) announced that it has decided to end prematurely the migraine prevention study 206.

Routine safety monitoring of blinded data in study 206 has revealed an incidence of abnormalities of liver function tests that is higher than expected in this population. The abnormalities are apparent from day 28 of dosing but the incidence and severity appear to increase progressively with increasing duration of participation in the study. Despite the fact that the treatment allocation remains blinded, Addex is of the opinion that the risk to benefit profile of the drug observed in the study is not sufficiently favorable to justify continuation of the trial and is terminating the study in the best interests of patient safety. The full benefit risk profile of ADX10059 in this indication will be evaluated once the study has been unblinded and all efficacy and safety data have been analyzed.

“No liver function abnormalities have been seen in any of the previously reported clinical trials, several of which explored higher doses, including the recently reported study ADX10059-204, a 2-week study of monotherapy in 103 GERD patients. Study 205 a 4-week study of ADX10059 as an add-on therapy to PPIs in GERD patients, is due to un-blind around the end of the year. The data from that study will also help in the determination of the overall safety profile of the drug,” said Charlotte Keywood, chief medical officer.

“This is an unfortunate and unexpected development,” said Vincent Mutel, chief executive officer. “We are working to rapidly understand the relationship of the liver function abnormalities to the treatment and the implications for development of ADX10059 in migraine prevention and other indications.”

Study ADX10059-206 is a double-blind, placebo-controlled, dose range finding, multi-center European Phase IIb trial in 240 patients who suffer from three or more migraine attacks per month. Following a one-month baseline period, patients take study medication for 3 months. The primary endpoint compares migraine frequency and severity in the last month of treatment with the baseline. The data are being un-blinded and will be analyzed and any indications of efficacy will be reported in early January.

Study ADX10059-205 is a double-blind, placebo-controlled, multi-center U.S. and European Phase IIb trial in 280 GERD patients who are partial responders to proton pump inhibitors (PPIs). In Study 205 ADX10059 is being used as an add-on therapy to the patients’ existing PPI treatment. There was a baseline symptom evaluation period followed by four weeks of administration of twice-daily ADX10059 (50mg, 100mg or 150mg). The primary endpoint is patient reported symptom control compared to baseline. Data are expected to be communicated in early January.

Study ADX10059-204 was a double-blind, placebo-controlled, multi-center European Phase IIb trial in 103 GERD patients known to respond well to PPIs. There was a two-week baseline symptom evaluation period followed by two weeks of administration of ADX10059 120 mg twice daily. ADX10059 achieved the co-primary endpoints of patient reported symptom control compared to baseline and the effects of ADX10059 on lower esophageal sphincter (LES) function as well as multiple secondary endpoints. There were no serious adverse events in the study and safety monitoring parameters were within normal limits. Mild or moderate adverse events included dizziness, vertigo and sleep disturbance.

Migraine is a condition distinguished by recurrent episodes of a characteristic headache, which can be accompanied by a variety of other symptoms such as nausea, and sensitivity to light and sound. The average migraine patient suffers 12 attacks a year. The International Headache Society estimates that about 25% of migraine patients have three or more attacks per month and could benefit from migraine prevention treatment. A migraine attack, which typically lasts about 24 hours but can range from 4-72 hours, has three distinct phases: the prodrome phase, when an array of individual warning signs — like blurred vision or tingling of the skin — may begin to appear; the headache phase; and the postdrome phase, when many patients report fatigue or other “hangover-like” symptoms. As migraine attacks are prolonged, many patients and especially those with frequent attacks, lose a significant amount of work and family time to suffering caused by the disease. Indeed, migraine is currently estimated to cost employers $13 billion annually in lost productivity in the United States. Prevalence of migraine is estimated at 12% in the United States, where about 30 million people suffer from migraine.

GERD (gastroesophageal reflux disease) is a chronic condition caused by stomach contents flowing back into the esophagus on a regular basis. The underlying cause of this is an abnormally functioning lower esophageal sphincter (LES) muscle that allows stomach contents to pass back into the esophagus too easily. GERD leads to painful symptoms like heartburn and can also damage the lining of the esophagus. It is a common disorder with prevalence at about 15% in the United States and between 10% and 25% in EU. Marketed GERD products work by reducing the acidity of the stomach contents but do nothing to reduce reflux events, so that in many patients symptoms of GERD persist.

ADX10059 is a metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulator (NAM). Glutamate overstimulation is thought to contribute via different mechanisms to pathology in both migraine and GERD. ADX10059 has been shown in clinical studies to reduce symptoms of acute migraine and, separately, to reduce reflux and GERD symptoms.

Addex Pharmaceuticals discovers and develops allosteric modulators for human health. Allosteric modulators are a different kind of orally available small molecule therapeutic agent, which we believe will offer a competitive advantage over classical drugs. Our lead allosteric modulator product, ADX10059, an mGluR5 negative allosteric modulator (NAM), has achieved clinical proof of concept and is in Phase IIb testing for the treatment of GERD and, separately, migraine prevention. ADX48621, our next-stage mGluR5 NAM, has completed Phase I testing and will enter Phase II for Parkinson’s disease levodopa-induced dyskinesia (PD-LID) in 2010.

Many alcoholic beverages contain byproducts of the materials used in the fermenting process. These byproducts are called “congeners,” complex organic molecules with toxic effects including acetone, acetaldehyde, fusel oil, tannins, and furfural. Bourbon has 37 times the amount of congeners that vodka has. A new study has found that while drinking a lot of bourbon can cause a worse hangover than drinking a lot of vodka, impairment in people’s next-day task performance is about the same for both beverages.

Results will be published in the March 2010 issue of Alcoholism: Clinical & Experimental Research and are currently available at Early View.

“While the toxic chemicals called congeners could be poisonous in large amounts, they occur in very small amounts in alcoholic beverages,” explained Damaris J. Rohsenow, professor of community health at the Center for Alcohol and Addiction Studies at Brown University. “There are far more of them in the darker distilled beverages and wines than in the lighter colored ones. While the alcohol alone is enough to make many people feel sick the next day, these toxic natural substances can add to the ill effects as our body reacts to them.”

Rohsenow added that few studies have looked at the effects of high- versus low-congener beverages on next-day hangover or performance, and some of those early studies were not careful to wait until breath alcohol levels (BALs) were close to zero before measuring performance, so results may have included some of alcohol’s direct effects.

“We wanted to investigate next-day effects of bourbon versus vodka while ensuring that BALs were zero or almost zero when we studied performance, and we used a variety of performance measures classified by their relevance to safety,” said Rohsenow. “We wanted to use a new hangover questionnaire that included only the symptoms that had been found to be valid in laboratory studies of hangover. We wanted to find out if bourbon’s effects the next day were due to different effects on sleep, so people’s sleep patterns were recorded while they slept. Finally, we wanted to know if performance impairments the morning after drinking were associated with how hung-over the person felt.”

Researchers recruited and paid 95 (58 women, 37 men) healthy, heavy drinkers to participate in one acclimatization night, followed by two drinking nights. The participants drank bourbon or vodka to an average of 0.11 g% BAL on one night, with a matched placebo on the other night, randomized for type and order. Polysomnography recordings were made overnight; self-report and neurocognitive measures were assessed the next morning.

“First, while alcohol in the beverage did increase how hung-over people reported feeling the next morning compared to drinking a placebo, bourbon made people feel even worse than vodka did,” said Rohsenow. “Second, alcohol in the beverage did make people do worse when they needed to pay attention for a continuous period of time while making rapid accurate choices, but they did no worse after bourbon than after vodka on these tasks. Therefore, while people felt worse, they didn’t perform worse after bourbon than after vodka. However, people were not aware that they were performing worse since they thought their driving ability was not impaired in the morning even though they could not react as well.” She added that other studies have found that professional pilots do worse on aspects of flying that require continuous attention across tasks the morning after drinking to intoxication.

“A third finding was that while alcohol in the beverages made people sleep less well because they woke up more during the night, this was no worse after bourbon than it was after vodka,” Rohsenow said. “This means that bourbon’s greater effects on hangover are not due to it having greater effects on sleep. Fourth, people who reported more hangover symptoms also did worse in their ability to pay attention for a continuous period of time while making rapid accurate choices.”

Regarding this last finding, that people with more hangover symptoms – feelings of headache, nausea, general lousiness, thirst and fatigue – also performed worse when required to pay continuous attention and make choices, Rohsenow said that feeling worse was perhaps distracting them, or that it just hurt more to use the extra energy needed to pay close attention. “A second possibility is that as alcohol was metabolized into other substances in the body before leaving, these substances had a direct effect on the nervous system in addition to increasing hangover so that these were two separate but related after-effects of drinking to intoxication,” she said.

The bottom line, said Rohsenow, is that becoming intoxicated to a .11 g% BAL makes it less safe for a person to engage in behaviors required for safety-sensitive performance the next morning. “Many safety-sensitive occupations require that workers be able to pay close attention to a number of tasks over a period of time, and to respond quickly with the right choices, and drinking to excess was found to impair this performance just after alcohol had left people’s bodies.”

A study in the Dec. 15 issue of the Journal of Clinical Sleep Medicine indicates that significant associations exist between parent-reported insomnia symptoms and medical complaints of gastrointestinal regurgitation and headaches in young school-aged children.

Results of multivariate regression analysis show that parent-reported insomnia was 3.3 times more likely in children with gastrointestinal regurgitation and 2.3 times more likely in children with headaches. Nineteen percent of children met the criteria for insomnia, which was defined as often having trouble falling asleep and/or waking up often in the night. Gastrointestinal regurgitation was reported in 7.5 percent of children with insomnia and two percent of children who did not have sleep disturbances. Headaches were reported in 24.4 percent of children with insomnia and 13.2 percent of children without disturbed sleep.

Lead author Ravi Singareddy, MD, assistant professor in the department of psychiatry at Penn State College of Medicine in Hershey, Pa., said that children who have insomnia symptoms should be screened by their physician for underlying medical conditions.

“The first and most important step in children with medical complaints and sleep disturbances would be an evaluation for underlying medical disorders and providing treatment,” said Singareddy. “If the associated sleep disturbances do not improve despite improvement in medical complaints the disturbances should be further assessed and treated.”

Data from 700 children between the ages of five and 12 years (mean 8.8 years) were collected from the Penn State Children’s Cohort for this cross-sectional study. All children underwent a medical and psychiatric history, physical examination, overnight polysomnography and neuropsychological testing. Comprehensive sleep and development questionnaires were completed by a parent. To assess gastrointestinal regurgitation the parent was asked, “Does food or liquid come back up into your child’s mouth or does your child complain of tasting food or liquid back up in his mouth?”

Children with sleep disturbances had significantly more parent-reported complaints of gastrointestinal symptoms (heartburn, pain/colic and regurgitation), headaches and bedwetting. After controlling for demographic variables; apnea-hypopnea index; learning, psychiatric and behavioral disorders; and socioeconomic and minority status, only gastrointestinal regurgitation and headaches remained significantly associated with insomnia symptoms.

According to the authors, the cross-sectional nature of the study did not allow for the assessment of a cause-and-effect relationship, which could be bidirectional in nature. The insomnia symptoms may have resulted in medical complaints since it is known that the respiratory, cardiovascular and gastrointestinal systems undergo significant physiological changes during sleep. Activation of the stress response system in association with hyperarousal also could have been responsible for both the sleep disturbances and the comorbid medical complaints in these children.

The authors suggest that future studies should explore the possible underlying pathophysiological causes of such comorbidity between insomnia symptoms and medical complaints in children. These studies should explore whether treatment of sleep complaints improves the associated medical complaints and vice versa.

The AASM published “Practice parameters for behavioral treatment of bedtime problems and night wakings in infants and young children” in the journal SLEEP in 2006. About 94 percent of the studies that were reviewed reported that behavioral interventions as a whole produced clinically significant improvements in bedtime resistance and night waking.

In 2003 an AASM task force of sleep experts examined the use of medications to treat insomnia in children. A consensus meeting summary was published in 2005 in the Journal of Clinical Sleep Medicine. The task force emphasized that behavioral treatment approaches to bedtime struggles and night waking in children have a well-documented empirical basis and are the mainstay of treatment, and that pharmacologic approaches should be largely considered adjuncts in the treatment of pediatric insomnia.

An international team of scientists has discovered that the human body has an entirely unique and separate sensory system that is largely imperceptible in most people and is based on blood vessels and sweat glands and not on nerves. They found that people lacking known nerve receptors can still touch and feel, and the discovery of how this is possible may help us understand unexplained pain such as fibromyalgia.

An article on the discovery appears in the the the December 15 issue of the journal PAIN, and describes the work of researchers at Albany Medical College, New York, USA, the University of Liverpool and Cambridge University in the UK, and other research centres.

Senior author Dr Frank Rice, a Neuroscience Professor at Albany Medical College (AMC) told the media that the discovery was:

“Almost like hearing the subtle sound of a single instrument in the midst of a symphony.”

“It is only when we shift focus away from the nerve endings associated with normal skin sensation that we can appreciate the sensation hidden in the background,” added Rice, who is a leading authority on the nerve supply to the skin.

Rice and colleagues got the opportunity to discover this hidden sensory system when lead author Dr David Bowsher, Honorary Senior Research Fellow at the University of Liverpool’s Pain Research Institute, diagnosed two unrelated adult patients with a previously unknown abnormality consisting of “congenital absence of pain with hyperhidrosis (CAPH)”.

The condition meant that both patients were born with very little ability to feel pain. The condition is rare, and people who have it also have excessively dry skin, often have severe mental handicaps and are prone to harming themselves by accident.

Bowsher explained that:

“Although they had a few accidents over their lifetimes, what made these two patients unique was that they led normal lives. Excessive sweating brought them to the clinic, where we discovered their severe lack of pain sensation.”

He said he and his colleagues became more curious when they did tests with sensitive instruments and found that all the skin sensation on both the patients was severely impaired, including their ability to sense temperature and mechanical contact.

The authors wrote that “sural nerve biopsy showed that all types of myelinated and unmyelinated fibers were severely reduced”.

“But, for all intents and purposes, they had adequate sensation for daily living and could tell what is warm and cold, what is touching them, and what is rough and smooth,” said Bowsher.

Bowsher sent skin biopsies to Rice’s lab in the US, where they specialize in examining the nerve endings of skin at the multimolecular level to help analyze chronic pain linked to conditions like nerve injuries, diabetes and shingles. Rice’s lab developed the method in collaboration with the Karolinska Institute in Stockholm, Sweden.

Rice explained that under normal conditions:

“The skin contains many different types of nerve endings that distinguish between different temperatures, different types of mechanical contact such as vibrations from a cell phone and movement of hairs, and, importantly, painful stimuli.”

But to their surprise, the samples that Bowsher sent them:

“Lacked all the nerve endings that we normally associated with skin sensation.”

Rice and colleagues were puzzled: “how were these individuals feeling anything?”

They suggest the answer lies in the presence of sensory nerve endings in small blood vessels and sweat glands in the skin, which they had been aware of for some time.

“For many years, my colleagues and I have detected different types of nerve endings on tiny blood vessels and sweat glands, which we assumed were simply regulating blood flow and sweating,” said Rice, but they didn’t think they contributed anything to “conscious sensation”.

But in the samples from England, they found that while the other sensory endings were missing, there were still normal types of nerve endings in the blood vessels and sweat glands.

“Apparently, these unique individuals are able to ‘feel things’ through these remaining nerve endings,” said Rice.

“What we learned from these unusual individuals is that there’s another level of sensory feedback that can give us conscious tactile information,” he added.

Rice suggested that perhaps problems in this hidden sensory system’s nerve endings may help explain “mysterious pain conditions such as migraine headaches and fibromyalgia, the sources of which are still unknown, making them very difficult to treat”.

Pooling results from 21 studies, involving 622,381 men and women, researchers at Johns Hopkins have affirmed that migraine headaches are associated with more than twofold higher chances of the most common kind of stroke: those occurring when blood supply to the brain is suddenly cut off by the buildup of plaque or a blood clot.

The risk for those with migraines is 2.3 times those without, according to calculations from the Johns Hopkins team, to be presented Nov. 16 at the American Heart Association’s (AHA) annual Scientific Sessions in Orlando. For those who experience aura, the sighting of flashing lights, zigzag lines and blurred side vision along with migraines, the risk of so-called ischemic stroke is 2.5 times higher, and in women, 2.9 times as high.

Study participants, mostly in North America and Europe, were between the ages 18 and 70, and none had suffered a stroke prior to enrollment.

Senior study investigator and cardiologist Saman Nazarian, M.D., says the team’s latest analysis, believed to be the largest study of its kind on the topic, reinforces the relationship between migraine and stroke while correcting some discrepancies in previous analyses. For examples, a smaller combination study in 2005 by researchers in Montreal showed a bare doubling of risk, yet mixed together different mathematical measures of risk, while the Hopkins study kept them separate, pooling together only like measures. As well, another half dozen recent and smaller studies from Harvard University yielded mixed results, some showing a link between migraines and ischemic stroke, while one did not show a tie-in.

Nazarian says that while nearly 1,800 articles have been written about the relationship between migraine and ischemic stroke, the Hopkins review was more selective, combining only studies with similar designs and similar groups of people, and more comprehensive, including analysis of unpublished data.

“Identifying people at highest risk is crucial to preventing disabling strokes,” says Nazarian, an assistant professor at the Johns Hopkins University School of Medicine and its Heart and Vascular Institute. “Based on this data, physicians should consider addressing stroke risk factors in patients with a history or signs of light flashes and blurry vision associated with severe headaches.”

Prevention and treatment options for migraine, he says, range from smoking cessation and taking anti-blood pressure or blood-thinning medications, such as aspirin. In women with migraines, stopping use of oral contraceptives or hormone replacement therapy may be recommended.

Such widespread use of hormone-controlling drugs is what Nazarian says may explain why women with migraines have such high risk of ischemic stroke. Contraceptives and other estrogen therapies are both known to contribute to long-term risk factors for cardiovascular diseases and stroke, such as high blood pressure and increased reactivity by clot-forming blood platelets.

Nazarian says the researchers’ next steps are to evaluate if preventive therapies, especially aspirin, offset the risk of ischemic stroke in people with migraines.

Funding support for the study, performed entirely at Hopkins, was provided by the National Institutes of Health Clinical Research Scholars Program.

Other researchers involved in this study were Susan Kahn, M.D., M.Sc.; Miranda Jones, M.P.H.; Monisha Jayakumar, M.P.H.; and Deepan Dalal, M.P.H. The lead study investigator was June Spector, M.D., M.P.H., a former postdoctoral research fellow at Hopkins, now in Seattle.