Menstrual migraines that occur in the days following menstrual bleeding may be related to low ferritin caused by blood loss rather than to estrogen fluctuations according to research led by Anne H. Calhoun, MD, from the University of North Carolina and Carolina Headache Institute–Research, Durham. As she states;
“End menstrual migraine (EMM) is a common complaint in women evaluated for menstrual related migraine, yet these migraines occur many days after the estrogen withdrawal that precipitates menstrual-related migraine,”
“[We] believe that end menstrual migraine is not hormonally mediated, but rather that it is causally related to menstrual blood loss, resulting in a brief relative anemia with consequent migraine,” the researchers add.
Menstrual Blood Loss
The study was prompted by the researchers’ clinical observations that some patients being treated for regularly occurring menstrual migraine experienced the migraines at the end of menstruation.
“We suspected a relationship to menstrual blood loss and have been routinely checking ferritin levels for this complaint for a few years,” they report.
They evaluated data on 119 consecutive patients seen over 6 weeks at the clinic.
Among 85 women with regular menses who were appropriate for evaluation, 30 (35.3%) had EMM. Their mean EMM duration was 2.6 days, with the headache graded as severe on at least one day.
Of the 30 patients, as many as 28 (93.3%) showed levels of ferritin, an intracellular protein that stores iron and releases it in response to tissue demand, to be below the generally accepted lower desirable limit of 50 ng/mL (mean, 21.9 ng/mL). Of those women, as many as half had levels below 18 ng/mL, the established minimum for women.
“While adequate iron levels are certainly important, adequate iron stores are equally important, [and] with inadequate ferritin, these iron stores can quickly be depleted,” the authors note.
The researchers also note that chronic headache is a recognized symptom of low ferritin levels.
The authors call for larger epidemiologic studies to confirm the prevalence of EMM and to better characterize the disorder.
They recommend the following diagnostic criteria for EMM: (1) predictable migraine headache (with or without aura) that (2) occurs immediately after or toward the end of menstrual bleeding.
Richard Katesmark comments ; “ Various mineral & vitamin deficiencies have been identified over the years as potential causes, or contributors, to migraine. Intuitively it would make sense that regular post-mentrual headpain may be related to iron levels. So if you fit the above criteria for EMM it may be worth trying a good quality ferritin supplement for a few months & see if it helps “
For further information please contact the clinic.
Results of a new study presented at the international congress of Headache & migraine has found that people with migraine who exercise can reduce the frequency of their attacks, but doing so requires a really good workout a couple of times a week for the most benefit.
Researchers at the University of Basel, Switzerland, report that both moderate continuous exercise (MCT) and high-intensity interval training (HIT) resulted in a significant reduction in migraine days among migraineurs, with HIT being associated with the highest reduction.
“HIT is a safe training modality for migraineurs showing more pronounced effects on migraine attack reduction, cerebrovascular health indices and maximal oxygen uptake compared to MCT,” the researchers, with lead author, Alice Minghetti, MSc, Department of Sport, Exercise and Health, University of Basel, Switzerland, concluded. “Thus, supervised aerobic exercise should be considered a complementary preventive and treatment strategy for migraineurs.”
To test the efficacy of exercise in reducing migraine frequency, the researchers randomly assigned migraineurs to a 12-week regimen of HIT (n = 8), MCT (n = 8), or a control group with no exercise training (n = 8).
The HIT and MCT groups participated in exercise twice a week for 12 weeks. HIT consisted of 4 consecutive sets of running exercise for 4 minutes at 95% of maximal heart rate followed by 3 minutes at 75% of maximal heart rate, for a total exercise time of 28 minutes per session.
MCT consisted of running for 45 minutes at 70% to 75% of maximal heart rate.
Richard Katesmark comments; “It has been known anecdotally for sometime that regular exercise is often beneficial for migraine sufferers, so some research confirming this is welcome.
Of course there will be exceptions as some types of migraine can be triggered by vigorous exercise.
Also it is very important people should gradually build their fitness levels (taking professional advice where necessary), & not suddenly launch themselves into intensive exercise programmes.”
I have already discussed the possible links between migraine & low Vit D levels ( see winter Migraines below ). A possible Link between low Vit D & chronic headache has now been suggested.
Researchers from the University of Eastern Finland have now published a study investigating the relationship between vitamin D status and the risk for frequent headache.
They assessed 2601 men, aged 42-60 years in 1984-1989, from a population-based cohort derived from the Kuopio Ischemic Heart Disease Risk Factor Study.
They made cross-sectional associations of self-reported frequent headache, defined as weekly or daily headaches and blood vitamin D levels.
In those with frequent headache, the average serum vitamin D concentration was 38.3 nmol/L; while in those without frequent headache, the average vitamin D concentration was 43.9 nmol/L.
Those in the lowest serum vitamin D quartile had 113% higher odds for frequent headache compared with those in the highest quartile.
The authors concluded that low serum vitamin D concentrations are associated with a markedly higher risk for frequent headaches in men.
Richard Katesmark suggests reading below post on winter migraines for further advice & info on importance of Vit D.
Added Sept 2017 -Post script; Yet another bit of research ( this time from India ) has found that Patients suffering from chronic tension type headaches are more likely to have low blood levels of Vit D than non-headache controls.
Whenever there is a heatwave, such as the one where having a moment, there is always an increase in the number of referrals to my clinic. I would like to comment on some of the reasons for this.
• Sunlight & reflected glare; One of the commonest reasons for increased headache/migraine frequency in summer. Wearing a brimmed hat/baseball cap to shield the eyes from direct sun and a pair of effective sunglasses (making sure their dark enough and of decent quality) are obvious precautions, not to mention keeping to the shade when possible.
Less obvious but also important is reflected light on computer screens, desks
and other surfaces. Use of blinds/curtains can clearly help as can repositioning office
& home furniture.
N.B; there is a brand of sunglasses called `Migralens` (http://www.migralens.com/) which are designed specifically for migraine sufferers which specifically cut out the type of light thought to trigger migraines.
• Dehydration; This is a common cause of headaches in summer. Most people underestimate the extra fluids they need to drink during hot weather especially if taking even gentle exercise.
Exact amounts are difficult to give as it varies with age, activity levels and the environment, but here are some guidelines;
In `normal` weather; Men should drink at least 3 litres/5 pints (about 13 cups) per day. Women- at least 2.2 litres/4 pints (about 9 cups)per day.
In `hot` weather these amounts should be increased by a minimum 1.5 to 2 litres, ie an extra 2-3 pints every day that it is hot. This needs to be even more if exercising, where you may be losing as much as 2 litres per hour as perspiration!!
Note that thirst can be a relatively late sign of dehydration, so drink before you become thirsty! And remember the extra fluid should not be taken in the form of drinks which contain caffeine (coffee, tea & certain soft drinks -always check the label)
Whilst on the subject of drinking it is worth noting that in the hot weather people’s consumption of alcohol also often increases. Needless to say if, like many people, alcohol is one of your triggers this would cause an increase in headaches/migraine.
• Mineral losses; Linked to fluid loss/ dehydration is loss of minerals (electrolytes) leading to changes in concentration ratios between certain important body chemicals. In some people this might increase the tendency to headaches/migraines. Therefore it may be worth taking extra mineral supplements such as dioralyte during particularly hot weather.
• Heat and humidity; Clearly difficult to influence, but the judicious use of fans/dehumidifiers/portable air conditioning units can help.
• Sleep disturbance; In my opinion this can be a very important factor in `heatwave headaches`. We all know it is hard to sleep when it is hot at night and the sleep we do get is often disturbed and therefore of poor quality. Again there’s little one can do about this apart from using fans etc as mentioned above. However if you notice you are waking earlier it may also be due to the increased morning light in which case the fitting of `blackout` curtains /blinds is advisable.
• Missing meals/ change of diet; Most people eat less when it is hot, perhaps even skipping meals, this can lead to low blood sugar levels which ( as discussed in another blog below ) is often a factor in causing headaches/migraine. So try to eat regularly despite the heat.
• Hay fever ; Generally this tends to be worse in the spring and summer and occasionally it will trigger/aggravate headaches if originating in the sinuses( see earlier blog below for info on sinus headaches)
So if you are one of those people whose headaches seem worsen as soon as the Bar-B-Q weather arrives, one or more of the above could be the cause. Try making a few changes as mentioned and see if it helps.
As winter draws in it would seem an opportune moment to discuss vitamin D and migraines.
Some of you maybe aware that it has been estimated that between 10 & 20% of people in the UK may have lower than ideal Vitamin D levels in their bodies (indeed some studies suggest it may be as high as 60-70% during the winter months).
In addition to this some research has shown a possible link between low Vitamin D & chronic migraine. Furthermore individuals with low vitamin D have been shown to be more likely to suffer chronic pain in general and to be less responsive to many common pain relievers.
Vitamin D is vitally important too many of the bodies metabolic pathways (the most well known being ensuring bone health). Some is obtained Directly from the diet (egg yolks, cheese, oily fish, mushrooms), but most is synthesised from x which can be converted into Vitamin D In the skin when is it exposed to UVB rays in bright daylight.( it does not have to be direct sunshine)
It is thought that the combination of poor diet (low in vitamins), wearing high factor suncream, and covering up during the summer, combined with short daylight hours in the winter, is resulting in chronically low vitamin D levels in a large percentage the population ( especially those who live in the northern hemisphere).
Therefore if your migraines/Chronic headaches seem to be worse during the winter months it may be worth considering whether you are vitamin D deficient.
What are the signs?
General symptoms associated with low vitamin D status Include:
Lack of energy and fatigue
Headaches and migraines
Poor immune system/Vulnerability to infections(colds/flu etc)
Generalised muscle aches and pains
( n.b. Clearly the above are all non-specific symptoms and can have many other causes.)
It is possible to have your Vitamin D status checked via blood tests, however you could simply try taking vitamin D supplements for a few of months & see if you feel any better.
Needless to say it also makes sense to ensure your basic diet is healthy. In addition during the darker months try and get out to ensure as much daylight as possible (or if this is not possible purchase a decent lightbox -use of which helps replace UVB rays).
For vitamin D, the recommended intake is 600-800 IU daily for adults ( 400- 600iu for children), not exceeding 4000 IU daily. Assuming no problems ( see below) it should be taken for at least 3 months
Always buy a good make of supplement ( I recommend Solgar) . I prefer Vit D3 ( cholecalciferol ) which is the natural form of Vit D.
Vitamin D Warnings.
Vitamin D could cause an allergic skin reaction..
This vitamin may also affect your blood sugar levels. If you have diabetes, your Dr may need to monitor you while you’re taking vitamin D.
Also, tell your doctor if you currently have, or have ever had, or take medications for any of the following:
High or low blood pressure
Kidney problems and kidney stones
An immune disorder
Heart disease or other heart problem
Check with your doctor if you have any misgivings about taking this or any other supplement.
Possible Signs of overdose
Confusion or disorientation
Weight loss or poor appetite
Nausea, vomiting, or constipation
As its the new year I thought I’d give you a brief summary of what has happened in headache research in 2016 in the medical world.
A large research program reanalyzed the results of 20,000 patients included over a number of different randomized trials, to compare triptans with placebo and other treatments. The rate of being pain-free after triptan intake was only somewhere between 18% and 50%. Although this seems rather unimpressive, the triptans were still superior in comparison with other migraine medications.
Clearly better medications need to be developed (especially for patients who have contraindications for triptans or for whom side-effects are unacceptable)
The most promising new drugs in the pipeline for migraine and cluster headache has been in the use of antibodies against calcitonin gene-related peptides. When the results of phase 2 trials in episodic migraine and chronic migraine were published the responder rate, defined as a reduction of migraine frequency of at least 50%, was achieved by one half of the patients.
Importantly the tolerability so far appears to be excellent. and there have basically been almost no side effects. All of these drugs are now in phase 3 randomized trials for episodic and chronic migraine, & also for episodic and chronic cluster headache. Hopefully next year, further information will be published to confirm how effective and well tolerated these new drugs are.
Another interesting study investigated the optimal duration of botulinum toxin for the treatment for chronic migraine. Investigators treated patients for 1 year and then stopped the treatment. It turned out that about one half of the patients did so well that they no longer needed botulinum toxin, whereas the other half deteriorated again and treatment had to be continued.
(nb there has also been some data showing that botulinum toxin might also be effective in patients with trigeminal neuralgia. If confirmed by further trials this has the potential to help sufferers who cannot use or tolerate the usual medication)
There was a new published paper on closure of patent foramen ovale (PFO) in patients who have migraine and migraine with aura, suggesting it had little, if any, benefits.
There was also an interesting but small study in cluster headache to treat acute attacks with a civamide nasal spray, which seemed to be effective. A phase 3 trial is now ongoing.
Further trials have had positive results for transcutaneous stimulation of the vagus nerve in cluster headache.This method is safe and well tolerated, and is now being investigated in frequent episodic migraine, chronic migraine, and cluster headache, compared with sham stimulation.
The potential use of statins for the prevention of migraine was first proposed in a case report a decade ago. A 58-year-old man was prescribed a statin for high cholesterol . He had a history of recurrent typical aura with migraine (approximately two episodes per month) since he was 20 years old. After he began statin therapy, his migraine attacks disappeared.
An open-label study followed with propranolol ( a beta bloker often used for prevention of migraine) daily in women with more than six migraine attacks per month and a statin in women with high cholesterol and more than six migraine attacks per month. Both drugs had a high efficacy (possibly owing to factors such as high expectation for cure); the response rate for propranolol was 88% with a 50% decrease in attacks and 83% for the statin.
A cross-sectional population study of nearly 6000 people found that statin use was associated with a lower prevalence of severe headache or migraine . When the variable of vitamin D status was analyzed, statin use among participants who had optimal blood vitamin D level ( >57 nmol/L )had a much lower risk for severe headache or migraine , while no association was found with people with lower vitamin D levels.
A double-blind, controlled study randomly assigned 57 adults with episodic migraine to either a daily statin plus vitamin D3 1000 IU twice daily or identical placebo for 24 weeks. In the statin/vitamin D group, eight patients (25%) experienced 50% reduction in the number of migraine days at 12 weeks and nine patients (29%) at 24 weeks; only one patient (3%) in the placebo group experienced a reduction in migraine days.
Statins have other biochemical effects in addition to lowering cholesterol, effects that may play a role in reducing migraine attacks. Statins might reduce migraine attack frequency by improving endothelial function, arterial stiffness, and vascular tone. Other actions, such as reducing inflammatory responses and decreasing platelet aggregation and thrombosis, also could contribute to the beneficial effect on migraine.
Firstly, from my perspective the constant use of any drugs to prevent headache/migraine should only be considered when all other conservative treatments have failed.
Also it is important to remember that Statin drugs are currently not recommended or mentioned in guidelines for migraine/headache prevention.
That having been said however, for patients who do not respond to the more common migraine prevention treatments, a statin might be worth a try based on limited evidence and a good safety profile ( although there is an ongoing debate as to whether statins cause side effects such as muscle aches & pains).
Some evidence also suggests that statins might be more effective with adequate vitamin D levels, so determining adequacy of vitamin D would be a sensible first step. Whether one statin is more effective than another for migraine is unknown. More research is required in larger numbers of patients to establish the place of statins in migraine prevention.
Many people have heard of ‘Tension-type’ headaches (TTH), and lots of headpain sufferers will have been given this diagnosis. The name would suggest the headaches are either due to physical ‘tension’(for example in the muscles of the neck), or psychological ‘tension’ (stress/anxiety). However research in the past has shown little correlation between TTH & muscle tenderness/tightness &/or anxiety/depression.
Frequently the diagnosis/label is used as a ‘catch all’, based on whether;
1) the headpain has certain characteristics’
2) that other types of headpain have been excluded.
Thus TTH is a relatively non-specific diagnosis & the actual cause may be hard to ascertain.
I was therefore interested in the following article published in Medscape;
A new study shows that patients with tension-type headache (TTH) have relatively weak neck extension muscles ( these are the muscles that bend your neck backwards & also contribute to keeping the head upright).
Researchers found that these patients are 26% weaker than controls with respect to neck extension muscles, that they have a 12% smaller extension/flexion ratio, and that they have a borderline significant difference in the ability to generate muscle force over the shoulder joint.
“We found that patients with tension-type headache exhibited decreased muscle strength in the neck extensor muscles, which caused this reduced ratio between extension and flexion,” said lead study author Bjarne Madsen, a physiotherapist and PhD student in the Department of Sports Science and Clinical Biomechanics, University of Southern Denmark and Danish Headache Center Glostrup Hospital.
With this reduced ratio, the muscles in the front of the neck pull the head forward, which causes continuous muscular activity in the neck, explained Madsen. “This can lead to pain and, over time, it can cause tension-type headache.”
This lower ratio “indicates that a higher relative loading of the neck extensor muscles could be present in everyday activities,” write the authors. “This possibly contributes to additional tension in the extensor muscles as well as disturbed stabilization in the neck and coordination of head movements.”
A reduced extension/flexion ratio may contribute to TTH onset and eventually to the development of chronic TTH, said the authors
As mentioned at the beginning of this post TTH is poorly understood & is often used as a bit of an ‘umbrella’ type label, covering a variety of headpain types which may be subtly different & have different causes (including among others muscle tension, psychological factors etc.). In my opinion with some cases it may even be a mild ‘version’ of migraine-type headpain.
So once again a detailed history & examination is important to establish the best approach regarding management + treatment of TTH, and yes, this may include exercises to strengthen the neck muscles !
I thought I would reproduce the following research findings (published in Medscape Medical News.) as it is relevant to both my osteopathic practice when examining patients with limb pain, which is frequently (but as the following article shows, not always), caused by trapped nerves in the neck & also to my work as a specialist in Migraine.
From a joint British-Chilean study;
Although limb pain is not included as a manifestation of migraine in international headache classifications, children and adults may experience recurrent limb pain as part of the migraine spectrum, a new study suggests. The four-generation study reveals a familial form of limb pain and migraine.
Researchers performed a prospective clinical and pedigree analysis involving a 27-member family followed for 8 years. They defined migraine limb pain as intermittent arm or leg pain during a migraine episode, cluster headache, or cluster migraine with no other explanation but that may also occur in the absence of headache. The pedigree analysis showed an autosomal dominant inheritance pattern manifesting mainly as limb pain in children and as migraine in adults.
“It’s common in adults. It’s as common as hemiplegic migraine, and in children, one third of children will have some periodic syndrome like limb pain associated with their migraines,” Heather Angus-Leppan, MD, MSc, consultant neurologist at the Royal Free Hospital and senior lecturer at University College London, United Kingdom, and immediate past president of clinical neurosciences at the Royal Society of Medicine, told Medscape Medical News.
Eight of the 27 members of this family had benign recurrent limb and/or body pain. Pain began as early as age 8 years and as late as age 30, and it recurred over 5 to 52 years. Sites of pain were the arm, hand, shoulder, chest, and neck. Limb pain was unilateral but could vary sides from episode to episode. Headache (7 of 8 members with some form of aura) occurred before, during, or after limb pain, and limb pain in adults could occur without headache.
The spectrum of manifestations of the condition may change over the lifetime. Children frequently have limb pain without headache. “The limb pain in children acts like migraine in that the person is often pale with it, they often withdraw from activity, and then they get completely better,” Dr Angus-Leppan said. For many children, episodes become less frequent as they age, but migraine headache or other manifestations may develop.
Elderly people may have less severe headache and more visual aura. Therefore, she says, taking a good history is important to be able to categorize symptoms as part of a migraine syndrome, which can lead to effective treatment.
Limb Pain With Migraine Amenable to Treatment
Dr Angus-Leppan emphasized that recognition of limb pain in migraine is important for preventing unnecessary investigations and getting people on appropriate treatments.
In adults, a migrainous cause of limb pain may be mistaken for nerve entrapment, radiculopathy, thoracic outlet syndrome, chronic fatigue syndrome, functional symptoms, or arthritis. In children, possible red herrings are growing pains, bone or joint pathology, and school avoidance.
Once recognized, “this syndrome responds very well to acute treatment and to migraine prophylaxis,” Dr Angus-Leppan said. “It works as well as in other migraine manifestations.”
In terms of diagnosis, if the limb pain occurs in a clear-cut attack of migraine, it should be fairly obvious to make the connection. “But my impression is that sometimes patients don’t mention limb pain or other somatic pain manifestations,” he said.
Other pains on a migraine spectrum may include pseudoangina with headache, and patients may end up in the intensive care unit for suspected coronary thrombosis,
Young children also may have abdominal pain and often are suspected of having appendicitis, “and many children will have had their appendices removed, and in fact, they’ve been having a migrainous equivalent,” probably accounting for a considerable proportion of normal appendices being removed, he cautioned.
Migraine may present with other unusual symptoms, such as Reynaud’s phenomenon and syncope (fainting), and these cases respond “rather spectacularly to calcium antagonists.” So a good medical history may reveal such cases and lead to very effective therapy, as well as avoid unnecessary testing, referrals, misdiagnosis, delayed diagnosis, and suffering.
The study was funded by the National Fund for Scientific and Technological Development of the Government of Chile.
Mr Katesmark comments; “ When a patient presents with symptoms it is important to consider ALL the possible causes, in my experience migraine is often NOT considered by many health professionals if the presentation is not typical (i.e. severe headache with visual disturbance). Luckily my work as a migraine specialist has helped me diagnose & successfully treat these rare cases in my general osteopathic clinic. “
Reported in Medscape. October 2015 (http://www.medscape.com/viewarticle/853421?src=wnl_edit_tpal&uac=233195CX)
Children and adolescents with migraine are more than three times as likely as those without headaches to have a mood disorder, such as depression, and almost three times more likely to have other neurologic conditions, such as epilepsy, a new American study shows.
The overlap between headache and mood disorders was particularly “striking” and highlights the need for neurologists to screen for such disorders, according to lead study author, Tara Lateef, MD, assistant professor, George Washington School of Medicine, who is also affiliated with Children’s National Health System, Washington, DC, and Pediatric Specialists of Virginia, Fairfax.
“Doctors should be doing a strong, thorough evaluation to assess for mood disorders,” said Dr Lateef. “These are young kids and if we are seeing that this migraine population is also at risk for having mental health problems, maybe we should be diagnosing this early. I don’t think anybody needs to be reminded of how severe the consequences are if we don’t treat mental illness in a timely fashion.”
Dr Lateef presented her research at the 44th Child Neurology Society (CNS) Annual Meeting.
The study sample included 9014 young people aged 8 to 21 years.
The study found that children with any headache, and specifically those with migraine, reported higher rates of other neurologic conditions. Epilepsy was “a big one,” said Dr Lateef, adding that the connection between headache and epilepsy could be causal — for example, seizure medications leading to headaches — or the two conditions could share a common cause.
Tic disorders were also relatively common among pediatric patients with headaches.
These overlaps are “not entirely surprising” given the “rich neuronal circuitry” in the developing brain, commented Dr Lateef.
Kids with headache had more developmental disorders, too. This includes the neurodevelopmental attention-deficit/hyperactivity disorder.
“When migraine kids do poorly in school, people are often quick to dismiss it, saying it’s probably because of the headaches,” said Dr Lateef. “But research shows that we should be screening these kids for attention-deficit/hyperactivity disorder because it could be an independent comorbidity*.” (*ie conditions that frequently present simultaneously in a patient & that may or may not linked in some way)
Children with migraine were also more than three times as likely to have a mood disorder and twice as likely to have anxiety compared with young nonmigraineurs.
This overlap was “unique to migraine,”. That raises the question of whether it’s an inflammatory pathophysiology for both.”
Another possibility is that both disorders are caused by certain neurotransmitters being elevated or diminished, she said. “But we still don’t know what makes a brain depressed.”
The overlap was “striking” to researchers because they were able to show it in such young children, who are a “pure population” in that they don’t have features that “cloud the issues,” said Dr Lateef.
She stressed that it’s not just psychiatrists who encounter patients with mood disorders and that neurologists and primary care doctors should also look for these conditions.
Richard Katesmark comments “ Firstly it is important to realise that just because a child or adolescent has migraine DOES NOT mean they are necessarily going to develop epilepsy or any of the other conditions mentioned above.
However the above research findings are no surprise to me. Anyone who has read some of my previous posts, or consulted me regarding their migraines and headaches, will know that I consider migraine a type of neurological ‘storm’ reflecting disregulated nerve function within the brain. It is not surprising that this disregulated neurological activity may result in sub optimal function in other areas of the brain controlling, for example, mood.
In the past it has been generally accepted that these coexisting conditions may be cause & effect, so migraine might cause people to be depressed/anxious, or that being depressed means you are more likely to experience headaches. Of course this is possible and in some cases maybe true. However increasing evidence is suggesting possible underlying common brain mechanisms that may result in multiple symptoms of neurological distress ; headpain, epilepsy, vertigo, mood disorders, chronic pain syndromes, etc etc.
The question remains whether these mechanisms are genetic, inflammatory, vascular, or as I’ve mentioned above, neurological. Most likely it is a combination of these factors, not to mention some currently undiscovered factors!”