Hemispheric Migraine headache is defined as a severe and rare condition of of migraine with aura. Headache pain of a migraine may precede with temporary chemical imbalances, as the levels of the serotonin, dopamine or norepinephrine in the brain have become too low or too high, affecting transmit messages. Hemispheric Migraine headache occurs 5 to 90 minutes before the onset of the headache, but sometime through the duration of the headache.
II. Symptoms (2)
1. Impaired vision
2. Loss of motor control
3. Speech, language and hearing difficulty
4. Paralysis or numbness on one side of the body
5. Flashing lights
6. Diminished vision
7. Impairment of consciousness and fever (1)
8. Motor weakness, coma, fever and seizures
9. Intellectual deficiency
10. Etc.
III. Causes
Causes of Hemispheric Migraine Headaches is the result of Gene mutations due to
gene mutation in heredity that lead to the development of Hemispheric Migraine Headaches, including the CACNA1A, ATP1A2 and SCN1A genes (6) and other causes of Sporadic hemiplegic migraine,such as diseases.
IV. Types of Hemispheric Migraine Headaches
A. Familial
of which with the above but includes involvement of the family history of the diseases as the result of gene nutation, familial hemispheric migraine headache is classified into 3 different types, CACNA1A (FHM1) gene, the ATP1A2 (FHM2) and the SCN1A (FHM3), depending to the specific gene mutation.
Type I: Familial hemiplegic migraine type 1 CACNA1A (FHM1)
Familial hemiplegic migraine type 1 is defined as a condition of mutation of gene CACNA1A of that affects the Voltage-dependent calcium channels mediate the entry of calcium ions into excitable cells, and their functions in regulating muscle contraction, hormone or neurotransmitter release, etc. CACNA1A mutations can give significant symptoms other than (hemiplegic) migraine as reason for presentation.
Familial hemiplegic migraine type 1 is accounted approximately half of hemiplegic migraine of all cases. There are evidences that the risk is up to 90% of a loss of motor control presented with patient of Familial hemiplegic migraine type 1 as the result of the death of cells in the cerebellum.
Type II: Familial hemiplegic migraine type 2 ATP1A2 (FHM2)
Familial hemiplegic migraine type 2 (FHM2) is defined as a condition of an autosomal dominant form of migraine with aura as a result of mutations of the α2-subunit of the Na,K-ATPase, an isoform almost exclusively expressed in astrocytes in the adult brain. There are report that FHM2 and FHM1 mutations share the cortical spreading depression as a key migraine trigger(7)
Type III: Familial hemiplegic migraine type 3 SCN1A (FHM3)
The SCN1A gene is located on chromosome (2q24) and codes for a sodium channel protein type 1 and considered a high resistant molecule when compared to FHM1 and FHM2because of it is associated with
recurrent seizures. According to "Familial hemiplegic Migraine Type 3, FHM3 - SCN1A" (8), SCN1A mutations follow an autosomal dominant pattern of inheritance with incomplete penetrance. New mutations are possible. Others show that if one parent is affected, their children will have a 1 in 2 chance of inheriting the condition.
B. Sporadic
of which with above symptoms and same types of gene mutation but no family history of the diseases, according to "Sporadic hemiplegic migraine and epilepsy associated with CACNA1A gene mutation" (9), there is evidence that sporadic case of FHM1 linked to S218L CACNA1A gene mutation with the triad of prolonged hemiplegic migraine, cerebellar symptoms, and epileptic seizures. Sporadic cases are more difficult to diagnose and often require several investigations to rule out more ominous possibilities(10)
IV. Diseases associated with Hemispheric Migraine Headaches
1. Sturge-Weber syndrome
Sturge-Weber syndrome is defined as a condition of is a rare neurological and skin disorder presented at birth with a port-wine stain birthmark on the face, glaucoma, seizures, mental retardation, etc., researchers suggested that prolonged HM attacks are associated with complex changes of both cerebral perfusion and glucose metabolism. A pathophysiological model explaining both the association between SWS/HM and the observed imaging changes is presented(3)
2. Cytotoxic edema
Cytotoxic edema is defined as a condition of swelling of all the cellular elements of the brain , as a result of the failure of ATP-dependent ion (sodium and c
alcium) transport.According to the University of Colorado School of Medicine, there are associated of the presumed HM and late cytotoxic edema.(4)
3. Recessive twinkle mutations
In the reports of 20-year follow-up of 23 patients has shown that refractory status epilepticus, migraine-like headaches and severe psychiatric symptoms are also pathognomonic for the disease, All adolescent patients have experienced phases of severe migraine, and seven patients had antipsychotic medication. Epilepsia partialis continua occurred in 15 patients leading to generalized epileptic statuses in 13 of them. Eight of these patients have died (11)
4. Parry-Romberg syndrome (PRS)
Parry-Romberg syndrome (PRS) is a sporadic disease is defined as a condition of slow and progressive atrophy affecting one side of the face, the skin, the subcutaneous tissue, the muscles, the cartilages, and the underlying bony structures with neurological symptoms usually include focal epilepsy, migraine, and unilateral brain lesions on the same side as the atrophy(12)
5. Etc.
V. Complications
1. Stroke
In the investigation of the increased risk of stroke in the studied mice with familial hemiplegic migraines, Dr. Eikermann-Haerter K and the team said that (FHM1) mutations in Ca(V)2.1 voltage-gated Ca(2+) channels render the brain more vulnerable to ischemic stroke. Compared with wild-type mice, 2 FHM1 mutant mouse strains developed earlier onset of anoxic depolarization and more frequent peri-infarct depolarizations associated with rapid expansion of infarct core(5)
2. Neurovascular changes
Cerebral blood flow changes during attacks of hemiplegic migraine with prolonged aura (HMPA) longer than 24 h in patients with familial hemiplegic migraine (FHM) with a novel gene mutation, frequently are associated with hyperperfusion and middle cerebral artery vasodilation(6)
3. Etc.
Diagnosis
Depending to the differentiate of symptoms of which are similar but difference than others with a complete medical history and physical exam.
1. Attacks last from 4 to 72 hours
2. Patients are usually symptom-free between attacks
3. Headache is at least two of the following
a. Unilateral (on one side)
b. Pulsating
c. Moderate to severe
d. Aggravated by routine activities
4. Accompanying symptoms may include
a. Photophobia (more sensitive to light)
b. Phonophobia (more sensitive to noise)
c. Nausea and Vomiting
5. Etc.
Types of diagnosis
The aim of the diagnosis is to rule other causes of the diseases
1. CT scan
CT scan can dive your doctor a three-dimensional view of your blood vessels of the brain to look for masses and other abnormalities that cause migraine headache
2. Magnetic resonance imaging (MRI)
By using radio waves and magnetic fields to take pictures, MRI scan provides very high quality of a cross-sectional slice and lengthwise slices of the brain and thus providing the better and detail image of location of tumor and the surrounding structures. It is one of most likely early test ordered by a doctor to diagnose tumors, strokes, aneurysms, neurological diseases and other brain abnormalities and the blood vessels around the brain.
3. Spinal tap (lumbar puncture)
A spinal tap is a procedure performed when a doctor needs to look at the cerebrospinal fluid (also known as spinal fluid), by inserting a thin needle between two vertebrae in your lower back to extract a sample. If your doctor suspects the onset of migraine headache is caused by inflammation of the membranes and cerebrospinal fluid surrounding your brain and spinal cord
4. Etc.
E. Prevention E.A. Do's and Do not's list, if you are experience migraine headache because of foods, food additives, chemical compounds, alcohol, smoking, stress, life style, etc.
1. Food elimination diet
Certain foods which trigger the over production of IgG antibodies if
eliminated from the diet can result in the decreased number of migraine
like headaches over 4weeks, some studies suggested that using the ELISA
test with subsequent diet elimination advice significantly reduce the
number of migraine like headaches at 4 weeks.(E.A.1)
2. Diet restriction Diet restriction based on IgG antibodies is an effective strategy in reducing the frequency of migraine attacks. In the study conducted by Istanbul Faculty of Medicine, Department of Neurology, Istanbul, Turkey in a 6-week baseline, IgG antibodies against 266 food antigens were detected by ELISA(E.A.2)
3. Foods and chemical compounds trigger migraine headache
a. Certain foods can trigger the migraine headache attack through an allergic reaction. Citrus fruits, tea, coffee, pork, chocolate, milk, nuts, vegetables and cola drinks have been cited as possible allergens associated with migraine. If you are experience the attack after taking some of those, the best way is to avoid them. Researchers also suggested that substances are tyramine, phenylalanine, phenolic flavonoids, alcohol, food additives (sodium nitrate, monosodium glutamate, aspartame) and caffeine may be the cause of modifications in vascular tone and bring migraine on(E.A,3)
a. Certain foods can trigger the migraine headache attack through an allergic reaction. Citrus fruits, tea, coffee, pork, chocolate, milk, nuts, vegetables and cola drinks have been cited as possible allergens associated with migraine. If you are experience the attack after taking some of those, the best way is to avoid them. Researchers also suggested that substances are tyramine, phenylalanine, phenolic flavonoids, alcohol, food additives (sodium nitrate, monosodium glutamate, aspartame) and caffeine may be the cause of modifications in vascular tone and bring migraine on(E.A,3)
4. Alcohol
As we all known that a small dose of alcohol increase the protective effect on cardiovascular disease, but excessive drinking can increase the frequency of migraine headache as alcoholic drinks are a migraine trigger in about one third of patients with migraine in retrospective studies on trigger factors(E.A4)
As we all known that a small dose of alcohol increase the protective effect on cardiovascular disease, but excessive drinking can increase the frequency of migraine headache as alcoholic drinks are a migraine trigger in about one third of patients with migraine in retrospective studies on trigger factors(E.A4)
5. Smoking
There is evidence that migraine was associated with several lifestyle and socioeconomic factors, In the investigation conducted by University of Copenhagen with a questionnaire containing validated questions to diagnose migraine and questions on lifestyle and socioeconomic factors was sent to 46,418 twin individuals residing in Denmark. 31,865 twin individuals aged 20-71 and most associations such as low education and employment status were probably due to the negative effects of having migraine while others such as smoking were risk factors for migraine.(E.A.5)
6. Others may trigger headache migraine attacks to certain people, such as
a. Too much work (Stress)
b. Too little sleep (Sleep related)
c. Passive smoking (Smoking)
d. Perfume (Chemical compound)
e. Etc.(E.A.6)
7. Moderate exerciseThere is evidence that migraine was associated with several lifestyle and socioeconomic factors, In the investigation conducted by University of Copenhagen with a questionnaire containing validated questions to diagnose migraine and questions on lifestyle and socioeconomic factors was sent to 46,418 twin individuals residing in Denmark. 31,865 twin individuals aged 20-71 and most associations such as low education and employment status were probably due to the negative effects of having migraine while others such as smoking were risk factors for migraine.(E.A.5)
6. Others may trigger headache migraine attacks to certain people, such as
a. Too much work (Stress)
b. Too little sleep (Sleep related)
c. Passive smoking (Smoking)
d. Perfume (Chemical compound)
e. Etc.(E.A.6)
In a study of Forty women with general migraine attending the Neurology Department of the Faculty of Medicine Faculty of Dokuz Eylül University, regular long-term aerobic exercise is found in reduced migraine pain severity, frequency and duration possibly due to increased nitric oxide production.(A.E.7)
8. Management of migraine
Hygiene and behaviour measures capable of ensuring the best possible well-being (regular meals and balanced diet, restriction of alcohol and smoking, regular sleeping pattern, moderate physical exercise and relaxation) have found to reduce the frequent migraine attack(E.A.8)
9. Avoid medication overuse headache (MOH)
There are report that overuse of migraine medication can result of
increased frequency to daily or near-daily as a rebound effect comes
into play(E.A.9)
10. Etc.
E.B Nutritional Supplements for Migraine Headache
1. Magnesium
Some studies indicated that deficiency of magnesium is associated with patient with migraine headache as may promote cortical spreading depression, affecting serotonin receptor function, and influence synthesis and release of a variety of neurotransmitters and suggested that empiric treatment with at least oral magnesium is warranted in all migraine sufferers.(E.B.1)
2. Calcium
Calcium deficiency can lead to Hypocalcemia, a serum level of calcium that is below normal, it is manifested by increased neuromuscular irritability, leading to neuromuscular hyperexcitability, anxiety, dysautonomia, oculofrontal headache and migraine(E.B.2)
3. DLPA (DL-phenylalanine)
DL-phenylalanine, an essential amino acid of which is important for our body converts phenylalanine to tyrosine, another amino acid then to epinephrine and norepinephrine, which are important brain chemicals called neurotransmitters. Some researchers suggest that DL-phenylalanine (DLPA) appears to potentiate pain relief and also ease depression in patients receiving opiates for chronic non-malignant pain(E.C.9)
4. Vitamin B2
Riboflavin therapy supplemented may be appropriate alternatives in patients with migraine disorder as it significant decreases in headache frequency, intensity, duration and medication intake (E.C.7)
5. Melatonin
Serotonin, a type of neurotransmitter, passes messages between nerve cells, low serotonin levels in the brain may increase the risk of the process of constriction of the blood vessels as it alters levels of dopamine and stress hormones, and may be part of a complex cellular membrane trafficking dysfunction involving not only the serotonin transporter but also other transporters and ion channels of which trigger a migraine (B.A.7)
6. Coenzyme Q 10 (CoQ10)
In some studies found that deficiency of CoQ10 are common in pediatric and adolescent migraine, but determination of deficiency and consequent supplementation may result in clinical improvement and involving more scientifically rigorous methodology to confirm this observation.(E.B.3)
7. Omega 3 fatty acids
Diet with long-chain n-3 polyunsaturated fatty acids might reduce
frequency and severity of migraines in adolescents in astudy conducted
by Divisions of Adolescent Medicine. Dr. Harel Z, and the team also sadi
that results of this preliminary study suggest that both fish oil and
olive oil may be beneficial in the treatment of recurrent migraines in
adolescents. Further studies are warranted to compare each of these
treatments with other interventions.(E.B.4)10. Etc.
E.B Nutritional Supplements for Migraine Headache
1. Magnesium
Some studies indicated that deficiency of magnesium is associated with patient with migraine headache as may promote cortical spreading depression, affecting serotonin receptor function, and influence synthesis and release of a variety of neurotransmitters and suggested that empiric treatment with at least oral magnesium is warranted in all migraine sufferers.(E.B.1)
2. Calcium
Calcium deficiency can lead to Hypocalcemia, a serum level of calcium that is below normal, it is manifested by increased neuromuscular irritability, leading to neuromuscular hyperexcitability, anxiety, dysautonomia, oculofrontal headache and migraine(E.B.2)
3. DLPA (DL-phenylalanine)
DL-phenylalanine, an essential amino acid of which is important for our body converts phenylalanine to tyrosine, another amino acid then to epinephrine and norepinephrine, which are important brain chemicals called neurotransmitters. Some researchers suggest that DL-phenylalanine (DLPA) appears to potentiate pain relief and also ease depression in patients receiving opiates for chronic non-malignant pain(E.C.9)
4. Vitamin B2
Riboflavin therapy supplemented may be appropriate alternatives in patients with migraine disorder as it significant decreases in headache frequency, intensity, duration and medication intake (E.C.7)
5. Melatonin
Serotonin, a type of neurotransmitter, passes messages between nerve cells, low serotonin levels in the brain may increase the risk of the process of constriction of the blood vessels as it alters levels of dopamine and stress hormones, and may be part of a complex cellular membrane trafficking dysfunction involving not only the serotonin transporter but also other transporters and ion channels of which trigger a migraine (B.A.7)
6. Coenzyme Q 10 (CoQ10)
In some studies found that deficiency of CoQ10 are common in pediatric and adolescent migraine, but determination of deficiency and consequent supplementation may result in clinical improvement and involving more scientifically rigorous methodology to confirm this observation.(E.B.3)
7. Omega 3 fatty acids
E.C. Diet for Migraine headache
Certain diet may trigger the attack of migraine headache as a result of allergic reaction in certain people, but it may be helpful to people who are experience migraine headache with no allergic effects
1. Water
Water, an essential for the body’s proper functioning, and dehydration may trigger the migraine attack. Un a study of Fifty migraineurs were asked if insufficient fluid intake could provoke their migraine attacks conducted by The City of London Migraine Clinic, twenty replied "yes," 7 were doubtfully positive, and 23 said "no." In addition 14 of 45 migraineurs at a meeting of the British Migraine association (UK) also recognized fluid deprivation as one of their migraine triggers.(E.C.1) Adding fluid deprivation to migraine patient may reduce the numbers of migraine attacks.
2. Fish oil and Olive oil
Omega-3 PUFA, from fish oil-eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been studied to consist anti-inflammatory properties of which are useful in the management of inflammatory and autoimmune diseases, including rheumatoid arthritis, Crohn's disease, ulcerative colitis, psoriasis, lupus erythematosus, multiple sclerosis and migraine headaches.(E.C.2)
3. Broccoli
Broccoli is a very good source of magnesium and a good source of calcium. Magnesium, plays an essential in many intracellular processes and in migraine pathogenesis, low levels of magnesium may promote cortical spreading depression, hyperaggregation of platelets, affect serotonin receptor function, and influence synthesis and release of a variety of neurotransmitters of which can trigger migraine headache(B.A.8)
4. Sardines
Sardines contain measurable amount of Omega 3 fatty acid, calcium and CoQ10 of which can be helpful in reducing the frequency of migraine headache (E.B.3)(E.B.2)
5. Spinach
Spinach is an excellent source of both calcium, magnesium, vitamin B2 (riboflavin)
Riboflavin therapy supplemented may be appropriate alternatives in patients with migraine disorder as it significant decreases in headache frequency, intensity, duration and medication intake (E.C.7)
6. Mustard Greens
The World's Healthiest Foods recommends mustard greens as an excellent source of calcium and a very good source of magnesium of which are important in preventing and treating migraine headache (See E.B.1 and 2)
7. Fish
Beside rich in Omega 3 fatty acids, all fish contain more or less DL-phenylalanine, an essential amino acid of which is important for our body converts phenylalanine to tyrosine, another amino acid then to epinephrine and norepinephrine, which are important brain chemicals called neurotransmitters. Some researchers suggest that DL-phenylalanine (DLPA) appears to potentiate pain relief and also ease depression in patients receiving opiates for chronic non-malignant pain(E.C.9)
8. Etc.
For The World Most Healthy Foods, please visit http://healthy-foods-index.blogspot.ca/2011/03/healthy-foods-list.html
Certain diet may trigger the attack of migraine headache as a result of allergic reaction in certain people, but it may be helpful to people who are experience migraine headache with no allergic effects
1. Water
Water, an essential for the body’s proper functioning, and dehydration may trigger the migraine attack. Un a study of Fifty migraineurs were asked if insufficient fluid intake could provoke their migraine attacks conducted by The City of London Migraine Clinic, twenty replied "yes," 7 were doubtfully positive, and 23 said "no." In addition 14 of 45 migraineurs at a meeting of the British Migraine association (UK) also recognized fluid deprivation as one of their migraine triggers.(E.C.1) Adding fluid deprivation to migraine patient may reduce the numbers of migraine attacks.
2. Fish oil and Olive oil
Omega-3 PUFA, from fish oil-eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been studied to consist anti-inflammatory properties of which are useful in the management of inflammatory and autoimmune diseases, including rheumatoid arthritis, Crohn's disease, ulcerative colitis, psoriasis, lupus erythematosus, multiple sclerosis and migraine headaches.(E.C.2)
3. Broccoli
Broccoli is a very good source of magnesium and a good source of calcium. Magnesium, plays an essential in many intracellular processes and in migraine pathogenesis, low levels of magnesium may promote cortical spreading depression, hyperaggregation of platelets, affect serotonin receptor function, and influence synthesis and release of a variety of neurotransmitters of which can trigger migraine headache(B.A.8)
4. Sardines
Sardines contain measurable amount of Omega 3 fatty acid, calcium and CoQ10 of which can be helpful in reducing the frequency of migraine headache (E.B.3)(E.B.2)
5. Spinach
Spinach is an excellent source of both calcium, magnesium, vitamin B2 (riboflavin)
Riboflavin therapy supplemented may be appropriate alternatives in patients with migraine disorder as it significant decreases in headache frequency, intensity, duration and medication intake (E.C.7)
6. Mustard Greens
The World's Healthiest Foods recommends mustard greens as an excellent source of calcium and a very good source of magnesium of which are important in preventing and treating migraine headache (See E.B.1 and 2)
7. Fish
Beside rich in Omega 3 fatty acids, all fish contain more or less DL-phenylalanine, an essential amino acid of which is important for our body converts phenylalanine to tyrosine, another amino acid then to epinephrine and norepinephrine, which are important brain chemicals called neurotransmitters. Some researchers suggest that DL-phenylalanine (DLPA) appears to potentiate pain relief and also ease depression in patients receiving opiates for chronic non-malignant pain(E.C.9)
8. Etc.
For The World Most Healthy Foods, please visit http://healthy-foods-index.blogspot.ca/2011/03/healthy-foods-list.html
F. Treatments in conventional medicine
F. A. Types of therapy (Non medication treatment)
1. Biofeedback and Cognitive-behavioral therapy
Some studies find that following sequence: blood-volume-pulse biofeedback followed by cognitive behavioral therapy (Group I) or were given the treatment in reverse order (Group II). The application of biofeedback helps the patient to recognize the influence of thoughts and emotions on bodily reactions and therefore prepares the way for successful cognitive treatment.(F.A.1)
2. Relaxation training/thermal biofeedback (RTB)
Relaxation therapy is a technique helped to enhance the relaxation response with an aim to relieve stress, control anxiety, improve sleep, and have a better quality of life in general. In the study conducted by University of Pittsburgh Medical Center, found that 41.3% of patient reported a significant headache reduction in relaxation training/thermal biofeedback (RTB).
(F.A.2).
3. Etc.
F. B. Medication
F.B.A. Medication to relieve acute migraine pain
Depending to the severity of the disease, acute attacks may be best prescribed by a prescription version of an NSAID, of which have a potent vasoconstricting action (constricting blood vessels) and patients are instructed to take them during or at the onset of a migraine. including
1. Triptan
a. Triptan are a family of tryptamine-based drugs used in the treatment of migraine headache and cluster headache. In the comparison of subcutaneous sumatriptan and oral administration formulation, subcutaneous formulation has a faster time of onset and high rate of efficacy when compared with the oral formulation, but the oral formulation appears to be better tolerated.(F.B.A.1)
b. Side effects of Triptan are not limit to
b.1. Nausea
b.2. Dry mouth
b.3. Tingling
b.4. Burning,
b.5. Dizziness
b.6. Drowsiness
b.7. Warm or cold sensations
b.8. Feelings of heaviness, pressure, or tightness
b. Other severe symptoms include coronary spasm, heart disease, shortness of breath, changes in vision, etc.
2. Ergotamine
Ergotamine has been used to treat migraine for a century and is still considered to be the most effective therapeutic agent for acute attacks andt good responses of the medication are associated with plasma concentrations of 0.2 ng/ml or above within one hour of administration.
In the same study, researchers also emphasized the principal adverse effects of ergotamine include nausea, vomiting, weakness, muscle pains, paraesthesiae and coldness of the extremities and suggested dosage must therefore be limited to no more than 10mg per week to minimise toxicity.(F.B.A.2)
3. The oral calcitonine gene-related peptide antagonist telcagepant
In a recent study conducted by University of Liège, in comparison of the oral calcitonine gene-related peptide antagonist telcagepant(CGRP) and triptans, found that its efficacy is almost comparable but its tolerance is superior. The same is true for the 5HT-1F agonist lasmiditan, another agent devoid of vascular effects. Researchers also said that the drugs with a better efficacy or side-effect profile than triptans may soon become available for acute treatment. The future may also look brighter for some of the very disabled chronic migraineurs thanks to novel drug and neuromodulation therapies.(F.B.A.3)
4. Etc.
F.B.B. Medication to prevent migraine pain
Medication used to prevent migraine pain are normal prescribed for patient who are experience frequent migraine attacks, severe side effects from acute treatment drugs or ineffectiveness of acute treatment drugs and together with behavioral therapy and lifestyle adjustments.
1. Beta-blocker (usually propranolol [Inderal] or timolol [Blocadren])
a. Beta-blocker are also known as beta-adrenergic blocking agents, use to block norepinephrine and epinephrine from binding to beta receptors on nerves to prevent migraine headache. Some researchers suggested that the addition of combined β blocker plus behavioural migraine management, but not the addition of β blocker alone or behavioural migraine management alone, improved outcomes of optimised acute treatment.(F.B.B.1)
b. Side effects are not limit to
b.1. Beta-blocker may interact with other medicines, such as thioridazine, chlorpromazine, etc.
b.2. Most common side effects include dastrointestional discomfort such as stomach cramps, nausea and vomiting.
b.3. The medication may also increase nervous symptoms, including headache, depression, confusion, dizziness, etc.
b.4. Etc.
2. Anticonvulsants (usually divalproex [Depakote] or topiramate [Topamax])
a. Anticonvulsants or anti seizure are medication used to treat epileptic seizures, bipolar disorder as mood stabilizers and neuropathic pain. In the study conducted by Department of Neurology, Canisius Wilhelmina Ziekenhuis, anticonvulsants, considered as a class, reduce migraine frequency by about 1.3 attacks per 28 days compared with placebo, and more than double the number of patients for whom migraine frequency is reduced by > or = 50% relative to placebo.(F.B.B.2)
b. Side Effects are not limit to
1. The medication may also increase central nervous symptoms such as dizziness, drowsiness, unsteadiness, feeling dull difficulty concentrating, focusing, mood swing, etc.
2. The medicine may cause gastrointestinal discomfort such as nausea, and vomiting.
3. Other side effects include liver or kidney damage and decrease the amount of platelets in your blood
4. Etc.
3. Tricyclic antidepressants (usually amitriptyline [Elavil])
a. Tricyclic antidepressants are also known as cyclic antidepressants, a chemical compound used to treat depression by affecting chemical messengers, neurotransmitters, in the brain. In the study conducted by Ohio University, Athens, found that amitriptyline is more effective than placebo for migraine and tension headache. Amitriptyline also seems to be more effective than serotonin reuptake inhibitors, although few direct comparisons are available.(F.B.B.3)
b. Side Effects are not limit to
b.1. The medication may cause central nervous symptoms, such as blurred vision, confusion, drowsiness, etc.
b.2. Loss of sexual desire
b.3. Lowered blood pressure
b.4. Tremors and sweating
b.5. Etc.
The doses and duration is depending to the nature of the migraine, but in general, patient started the medication at a low dose, and then gradually increased.
F.B.C. Medication for children
According to the recommendation of The American Academy of Neurologys practice guidelines
1. children Under 12 years old
a. Ibuprofen (Advil)
a.1. Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) used as as an analgesic for relief of symptoms pain as aresult of inflammation of certain diseases. In adult, researchers found that ibuprofen 200 and 400 mg are effective in reducing headache intensity and rendering patients pain-free at 2 hours. Photophobia and phonophobia improved with 400 mg dosing (F.B.C.1). Children should reduce the amount of medication according to the guideline.
a.2. Side Effects are not limit to
a.2.1. Common side effects include nausea, dyspepsia, gastrointestinal ulceration/bleeding, headache, dizziness, rash, etc.
a.2.2. Less common side effects include esophageal ulceration, heart failure, renal impairment, confusion, etc.
a.2.3. Etc.
b. Acetaminophen
b.1. Acetaminophen is a pain reliever to treat moderate to moderately-severe pain. Some researchers suggested that Tramadol/acetaminophen reduces the severity of pain, photophobia, and phonophobia associated with migraine headache, but does not reduce migraine-associated nausea. Tramadol/APAP might be an appropriate option for the management of moderate-to-severe migraine headache(F.B.C.2)
b.2. Side effects are not limit to
b.2.1. Common side effects include nausea, vomiting, sweating, diarrhea, irritability, etc.
b.2.2. Less common side effects include liver or kidney failure, heart problems, seizures, etc.
b.2.3. Etc.
2. Children 12 and older
a. Sumaptriptan (Imitrex) is a triptan sulfa drug used for the treatment of migraine headaches. some researchers found that nasal sumatriptan may be effective in aborting migraine in young children (aged 5 to 12 years). It also suggests that there may be subgroups for which it works well. This information suggests that double-blind, placebo-controlled studies are necessary to determine the overall effectiveness of nasal sumatriptan in this age group(F.B.C.3)
b. Side effects are not limit to
b.1. Most common side effects include flushing, sensations, weakness, drowsiness, or dizziness, etc.
1. PeppermintF. A. Types of therapy (Non medication treatment)
1. Biofeedback and Cognitive-behavioral therapy
Some studies find that following sequence: blood-volume-pulse biofeedback followed by cognitive behavioral therapy (Group I) or were given the treatment in reverse order (Group II). The application of biofeedback helps the patient to recognize the influence of thoughts and emotions on bodily reactions and therefore prepares the way for successful cognitive treatment.(F.A.1)
2. Relaxation training/thermal biofeedback (RTB)
Relaxation therapy is a technique helped to enhance the relaxation response with an aim to relieve stress, control anxiety, improve sleep, and have a better quality of life in general. In the study conducted by University of Pittsburgh Medical Center, found that 41.3% of patient reported a significant headache reduction in relaxation training/thermal biofeedback (RTB).
(F.A.2).
3. Etc.
F. B. Medication
F.B.A. Medication to relieve acute migraine pain
Depending to the severity of the disease, acute attacks may be best prescribed by a prescription version of an NSAID, of which have a potent vasoconstricting action (constricting blood vessels) and patients are instructed to take them during or at the onset of a migraine. including
1. Triptan
a. Triptan are a family of tryptamine-based drugs used in the treatment of migraine headache and cluster headache. In the comparison of subcutaneous sumatriptan and oral administration formulation, subcutaneous formulation has a faster time of onset and high rate of efficacy when compared with the oral formulation, but the oral formulation appears to be better tolerated.(F.B.A.1)
b. Side effects of Triptan are not limit to
b.1. Nausea
b.2. Dry mouth
b.3. Tingling
b.4. Burning,
b.5. Dizziness
b.6. Drowsiness
b.7. Warm or cold sensations
b.8. Feelings of heaviness, pressure, or tightness
b. Other severe symptoms include coronary spasm, heart disease, shortness of breath, changes in vision, etc.
2. Ergotamine
Ergotamine has been used to treat migraine for a century and is still considered to be the most effective therapeutic agent for acute attacks andt good responses of the medication are associated with plasma concentrations of 0.2 ng/ml or above within one hour of administration.
In the same study, researchers also emphasized the principal adverse effects of ergotamine include nausea, vomiting, weakness, muscle pains, paraesthesiae and coldness of the extremities and suggested dosage must therefore be limited to no more than 10mg per week to minimise toxicity.(F.B.A.2)
3. The oral calcitonine gene-related peptide antagonist telcagepant
In a recent study conducted by University of Liège, in comparison of the oral calcitonine gene-related peptide antagonist telcagepant(CGRP) and triptans, found that its efficacy is almost comparable but its tolerance is superior. The same is true for the 5HT-1F agonist lasmiditan, another agent devoid of vascular effects. Researchers also said that the drugs with a better efficacy or side-effect profile than triptans may soon become available for acute treatment. The future may also look brighter for some of the very disabled chronic migraineurs thanks to novel drug and neuromodulation therapies.(F.B.A.3)
4. Etc.
F.B.B. Medication to prevent migraine pain
Medication used to prevent migraine pain are normal prescribed for patient who are experience frequent migraine attacks, severe side effects from acute treatment drugs or ineffectiveness of acute treatment drugs and together with behavioral therapy and lifestyle adjustments.
1. Beta-blocker (usually propranolol [Inderal] or timolol [Blocadren])
a. Beta-blocker are also known as beta-adrenergic blocking agents, use to block norepinephrine and epinephrine from binding to beta receptors on nerves to prevent migraine headache. Some researchers suggested that the addition of combined β blocker plus behavioural migraine management, but not the addition of β blocker alone or behavioural migraine management alone, improved outcomes of optimised acute treatment.(F.B.B.1)
b. Side effects are not limit to
b.1. Beta-blocker may interact with other medicines, such as thioridazine, chlorpromazine, etc.
b.2. Most common side effects include dastrointestional discomfort such as stomach cramps, nausea and vomiting.
b.3. The medication may also increase nervous symptoms, including headache, depression, confusion, dizziness, etc.
b.4. Etc.
2. Anticonvulsants (usually divalproex [Depakote] or topiramate [Topamax])
a. Anticonvulsants or anti seizure are medication used to treat epileptic seizures, bipolar disorder as mood stabilizers and neuropathic pain. In the study conducted by Department of Neurology, Canisius Wilhelmina Ziekenhuis, anticonvulsants, considered as a class, reduce migraine frequency by about 1.3 attacks per 28 days compared with placebo, and more than double the number of patients for whom migraine frequency is reduced by > or = 50% relative to placebo.(F.B.B.2)
b. Side Effects are not limit to
1. The medication may also increase central nervous symptoms such as dizziness, drowsiness, unsteadiness, feeling dull difficulty concentrating, focusing, mood swing, etc.
2. The medicine may cause gastrointestinal discomfort such as nausea, and vomiting.
3. Other side effects include liver or kidney damage and decrease the amount of platelets in your blood
4. Etc.
3. Tricyclic antidepressants (usually amitriptyline [Elavil])
a. Tricyclic antidepressants are also known as cyclic antidepressants, a chemical compound used to treat depression by affecting chemical messengers, neurotransmitters, in the brain. In the study conducted by Ohio University, Athens, found that amitriptyline is more effective than placebo for migraine and tension headache. Amitriptyline also seems to be more effective than serotonin reuptake inhibitors, although few direct comparisons are available.(F.B.B.3)
b. Side Effects are not limit to
b.1. The medication may cause central nervous symptoms, such as blurred vision, confusion, drowsiness, etc.
b.2. Loss of sexual desire
b.3. Lowered blood pressure
b.4. Tremors and sweating
b.5. Etc.
The doses and duration is depending to the nature of the migraine, but in general, patient started the medication at a low dose, and then gradually increased.
F.B.C. Medication for children
According to the recommendation of The American Academy of Neurologys practice guidelines
1. children Under 12 years old
a. Ibuprofen (Advil)
a.1. Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) used as as an analgesic for relief of symptoms pain as aresult of inflammation of certain diseases. In adult, researchers found that ibuprofen 200 and 400 mg are effective in reducing headache intensity and rendering patients pain-free at 2 hours. Photophobia and phonophobia improved with 400 mg dosing (F.B.C.1). Children should reduce the amount of medication according to the guideline.
a.2. Side Effects are not limit to
a.2.1. Common side effects include nausea, dyspepsia, gastrointestinal ulceration/bleeding, headache, dizziness, rash, etc.
a.2.2. Less common side effects include esophageal ulceration, heart failure, renal impairment, confusion, etc.
a.2.3. Etc.
b. Acetaminophen
b.1. Acetaminophen is a pain reliever to treat moderate to moderately-severe pain. Some researchers suggested that Tramadol/acetaminophen reduces the severity of pain, photophobia, and phonophobia associated with migraine headache, but does not reduce migraine-associated nausea. Tramadol/APAP might be an appropriate option for the management of moderate-to-severe migraine headache(F.B.C.2)
b.2. Side effects are not limit to
b.2.1. Common side effects include nausea, vomiting, sweating, diarrhea, irritability, etc.
b.2.2. Less common side effects include liver or kidney failure, heart problems, seizures, etc.
b.2.3. Etc.
2. Children 12 and older
a. Sumaptriptan (Imitrex) is a triptan sulfa drug used for the treatment of migraine headaches. some researchers found that nasal sumatriptan may be effective in aborting migraine in young children (aged 5 to 12 years). It also suggests that there may be subgroups for which it works well. This information suggests that double-blind, placebo-controlled studies are necessary to determine the overall effectiveness of nasal sumatriptan in this age group(F.B.C.3)
b. Side effects are not limit to
b.1. Most common side effects include flushing, sensations, weakness, drowsiness, or dizziness, etc.
Peppermint contains high amounts of menthol which have long been used in herbal medicine to treat various pain conditions including headache. In a randomised, triple-blind, placebo-controlled, crossed-over study conducted in the neurology Clinic of Nemazee Hospital, affiliated with Shiraz University of Medical Sciences, Shiraz, southern Iran, from March 2007 to March 2008. Menthol solution can be an efficacious, safe and tolerable therapeutic option for the abortive treatment of migraine(G.1)
2. Feverfew
Feverfew and it's ingredient parthenolide have shown the inhibition of the brain chemicals that dilate blood vessels and cause a migraine. Some researchers suggested that a CO(2)-extract of feverfew decreased the migraine frequency from 4.76 by 1.9 attacks per month in the MIG-99 group and by 1.3 attacks in the placebo group (P = 0.0456). Logistic regression of responder rates showed an odds ratio of 3.4 in favour of MIG-99 (P = 0.0049). Adverse events possibly related to study medication were 9/107 (8.4%) with MIG-99 and 11/108 (10.2%) with placebo (P = 0.654). MIG-99 is effective and shows a favourable benefit-risk ratio.(G.2) while others insisted that there are insufficient evidence from randomised, double-blind trials to suggest an effect of feverfew over and above placebo for preventing migraine.(G.3)
3. Butterbur
Butterbur is a creeping underground plant, genus Petasites of 15 -20 species, belonging to the family Asteraceae, native to Northern Hemisphere. In a comparison in a three-arm, parallel-group, randomized trial comparing Petasites extract 75 mg bid, Petasites extract 50 mg bid, or placebo bid in 245 patients with migraine conducted by Albert Einstein College of Medicine, Petasites extract 75 mg bid is more effective than placebo and is well tolerated as a preventive therapy for migraine.(G.4)
4. Ginkgo biloba
Ginkgo biloba is oldest living tree species, genus Ginkgo, belonging to the family Gink-
goaceae, native to China. Some researchers suggested that Gingkolide B, a herbal constituent extract from Ginkgo biloba tree leaves, seems to be effective as preventive treatment in reducing migraine attack frequency and in attenuating the use of symptomatic medication in our small series of children with primary headache in a small sample of 30 young patients(G.5). Other found that Ginkgolide B is effective in reducing MA frequency and duration. The effect is clearly evident in the first bimester of treatment and is further enhanced during the second(G.6)
5. Cannabis
Cannabis is a herbal plant with three putative varieties Cannabis sativa, Cannabis indica and Cannabis ruderalis, native to Central Asia, and South Asia. clinical cannabis indicated that Migraine has numerous relationships to endocannabinoid function. Anandamide (AEA) potentiates 5-HT1A and inhibits 5-HT2A receptors supporting therapeutic efficacy in acute and preventive migraine treatment. Cannabinoids also demonstrate dopamine-blocking and anti-inflammatory effects. AEA is tonically active in the periaqueductal gray matter, a migraine generator and suggested that Migraine, fibromyalgia, IBS and related conditions display common clinical, biochemical and pathophysiological patterns share an underlying clinical endocannabinoid deficiency that may be suitably treated with cannabinoid medicines(G.7)
6. Lavender
Herbalist suggested that rubbing a little lavender oil on your temples, or dropping some in the bath water can be extremely soothing. For the migraine associated with depression or poor digestion, it may be result of the relaxation and coronary circulative effects of the oil(G.8)
7. Others
Many herbs such a Fenugreek, Black willow, Marjoram, St. John's wort, fennel or caraway seed tea hane been used to relieve pain or symptoms of migraines, but they are not mention here because lack of studies.
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H. In traditional Chinese medicine (TCM)
X. Traditional Chinese Medicine
H.A. According to Flaws & Sionneau, 2001,p.346; Yin & Liu, 2000, p.370; Blackwell, 1991 Migraine Headache is as a condition of tou feng (Wind in the head) or pian tou tong(pain in one half of the head), and is mainly due to emotional factors causes of Liver Yang hyperactivity and sometimes may be influenced by exterior Wind-Cold factors, common cold and allergy(H.A.). In the report the author indicated that differetiation of the MH depending to the patient’s pathology and the pathodynamics underlying any particular clinical case is likely to be complex. As pain is the single most important clinical feature, Blood stasis should beaddressed in all cases. Thus, one of the formulas described under thesubheading of Blood Stasis will be included in all acute stage treatments. In addition, Interior Wind is also a common feature and this often occurs due to Liver Fire or stagnant Heat in the Liver. In some cases there is also Phlegm,which binds with Wind to exacerbate the symptoms.(Part 2MIGRAINE HEADACHE IN TCM)
H.B. Migraine headache caused by Liver Yang rising with Interior Wind
1. Symptoms
a Visual disturbance
b. Dizziness
c. Irritability
d. Red tongue
e. Wiry pulse
f. Etc.
2. Formula Liver Yang rising with Interior Wind - Tian Ma Gou Teng Yin
a. Gastrodia and Uncaria formula has been used in TCM for hundred of years to treat the symptoms of headache and migraine as a result of ascendant Liver Yang with internal movement of Wind, caused by Liver and Kidney Yin deficiency and exuberant Liver Yang. This formula is best used during the early stages of a Migraine and combines well with Corydalis H for a strong, double strike against Migraine pain.
b. The ingredients including
b.1. Tian Ma (Rhizoma gastrodiae elatae)
b.2. Gou Teng (Ramulus cum uncis uncariae)
b.3. Shi Jue Ming (Concha haliotidis)
b.4. Zhi Zi (Fructus gardeniae jasminoidis)
b.5. Huang Qin (Radix scutellariae baicalensis)
b.6. Yi Mu Cao (Herba leonuri heterophylli)
b.7. Chuan Niu Xi (Radix cyathulae officinalis)
b.8. Du Zhong (Cortex eucommiae ulmoidis)
b.9. Sang Ji Sheng (Ramulus sangjusheng)
b.10. Ye Jiao Teng (Caulis polygoni multiflori)
b.11. Fu-shen (Sclerotium poriae cocos pararadicis)
H.C. Liver Fire
1. Symptoms
a. Red face and eyes
b. bitter taste in the mouth
c. thirst
d. dark and scanty urine
e. constipation with dry stools
f. red tongue with a yellow coat
g. rapid pulse
b. Formula Long Dan Xie Gan Tang
The formula Long Dan Xie Gan Tang has been used in TCM to treat pain in the hypochondriac region, headache, dizziness, red sore eyes, trouble with hearing, ear swelling or infection, traveling the Liver and Gallbladder meridians to relieve liver heat and fire
b.1. Long dan cao (Radix gentianae longdancao)
b.2. Huang qin (Radix scutellariae)
b.3. Shan zhi zi (Fructus gardeniae jasminoidis)
b.4. Ze xie (Caulis mutong)
b.5. Mu tong (Semen plantaginis)
b.6. Che qian zi (Rhizoma alismatis orientalis)
b.7. Chai hu (Radix bupleuri)
b.9. Sheng di huang (Radix rehmanniae glutinosae)
b.10. Gan cao (radix glycyrrhizae uralensis)
b.11. Dang qui (Radix angelicae sinensis)
Author note the formula may damage the Kidney due to the presence of Herb Mu Tong
H.D. Liver qi stagnation
1. Symptoms
a. Chest distention
b. Hypochondriac pain
c. Nausea, vomiting
d. Poor appetite
e. Diarrhea
f. Depression
g. Mood swing
f. Normal tongue
g. Wiry pulse
h. Etc.
2. Formula as a result of Liver Qi deficiency: Xiao Yao San (Bupleurum and Dang-gui Formula)
The formula has been used in TCM to treat anxiety, irritability, stress, and depression due to the challenge of a daily life or premenstrual tension, as a result of liver Qi deficiency
a. Chai Hu (radix burpleuri)
b. Dang Gui (radix angelicae sinensis)
c. Bai Shao (radix paeoniae lactiflorae)
d. Bai Zhu (rhizome atractylodis macrocephalae)
f. Fu Ling (sclerotium poriae cocos)
g. Zhi Gan Cao (honey fried radix glycyrrhizae uralensis)
H.E. Excess syndrome-pattern with Liver Blood stasis:
1. Symptoms
a. Palpable masses in the abdomen
b. Irregular a/or painful menstruation possible with dark clots,
c. purple nails,
d. purple lips
e. Tongue Purple, possibly w/purple spots
f. Wiry pulse
b. Formula for Excess syndrome-pattern with Liver Blood stasis: Chai Hu Shu Gan Tang
The formula has been used in TCM to treat sighing and flank pain due to emotional stress or premenstrual tension, headache as a result liver Blood stasis.
a. Chai hu (Radix Bupleuri Chinensis)
b. Chen pi (Pericarpium Citri Reticulatae)
c. Bai shao (Radix Paeoniae Lactiflorae)
d. Zhi ke (Fructus Aurantii)
f. Chuan xiong (Rhizoma Ligustici Chuanxiong)
g. Xiang fu (Rhizoma Cyperi Rotundi)
h. Gan cao (Radix Glycyrrhizae Uralensis)
H.F. Headache Migraine caused by Wind Phlegm
1. Symptoms
a. Excessive sputum
b. Nausea,
c. Fullness of the chest and/or epigastrium
d. Greasy tongue coat
e. Etc.
2. Wind Phlegm With Heat (if tongue is red tongue with a yellow coat): Wen Dan Tang (Bamboo & Hoelen Formula)
The formula has been used in TCM to treat disharmony between the gallbladder and stomach causes of Qi is blocked in flow transformed phlegm and form of rebellion Qi in the stomach that lead to fear, restlessness, dreaminess and anxiety
a. Zhi Ban Xia (Rhizoma Pinelliae Ternatae)
b. Zhu Ru (Caulis Bambusae In Taeniis)
c. Chen Pi (Pericarpium Citri Reticulatae)
d. Fu Ling (Poriae Cocos)
f. Lian Qiao (Fructus Forsythiae Suspensae)
g. Jin Yin Hua (Flos Lonicerae Japonicae)
h. Yu Jin (Radix Curcumae)
i. Zhi Shi (Fructus Aurantii Immaturus)
3. Formula Wind Phlegm With Cold (if tongue is pale with a white coat): Er Chen Wan (Citrus & Pinellia Combination), ingredients include
The Formula has been used in TCM to treat nausea and abdominal fullness, dizziness and vertigo, etc., as a result of Withe Phlegm with cold causes of phlegm accumulation, spleen-damp, rebellion qi and unharmonization of the center.
a. Chen Pi (Pericarpium Citri Reticulatae)
b. Ban Xia (Rhizoma Pinelliae)
c. Fu Ling (Poriae Cocos)
d. Gan Cao Glycyrrhiza (Radix Glycyrrhizae Uralensis)
f. Sheng Jiang Zingiberis (Rhizoma Zingiberis)
H.F. Blood Stasis
1. Symptoms
a. Fixed pain,
b. Palpitation
c. Pulse appears tense and fast
d. Tongue is purple -
f. bluish-purple
2. Formula for migraine headache caused by blood stasis
Tao Hong Si Wu Wan (Persica, Carthamus & Dang-gui Combination)
The formula has been used in TCM to treat heavy bleeding of dark, purplish, sticky menstrual blood sharp and fixed abdominal pain before or during the menses, dizziness, dull headache, etc. as a result of blood stasis
a. Shu di huang (Rehmannia glutinosa root-prep)
b. Dang gui (Angelica sinensis root)
c. Bai shao (Paeonia lactiflora root)
d. Tao ren (Prunus persica seed)
e. Hong hua (Carthamus tinctorius flower)
f. Chuan xiong (Ligusticum wallichii rhizome)
H.G. Invasion by Exterior Wind Cold
1. Symptoms
a. Generalized body aches
b. Aversion to cold
c. Chills
d. Mild fever
e. Nasal congestion
f. Thin white coat
g. Floating, possibly a little tight
2. Formula for mihraine headache caused by Invasion by Exterior Wind Cold: Chuan Xiong Cha Tiao Wan (Ligusticum & Tea Formula)
The formula has been used in TCM to treat headache, migraine, or headache on the top, aversion to cold and fever, dizziness, nasal obstruction as a result of Exterior Wind Cold
a. Bo he (Herba Menthae Haplocalycis)
b. Chuan xiong (Rhizoma Ligustici Chuanxiong)
c. Jing jie (Herba Schizonepetae Tenuifoliae)
d. Qiang huo (Rhizoma Seu Radix Notopterygii)
e. Bai zhi (Radix Angelicae Dahuricae)
f. Gan cao (Radix Glycyrrhizae Uralensis)
g. Fang feng (Radix Saposhnikoviae Divaricatae)
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Sources
(1) http://www.ncbi.nlm.nih.gov/pubmed/21172953
(2) http://www.ncbi.nlm.nih.gov/pubmed/18405771
(3) http://www.ncbi.nlm.nih.gov/pubmed/22404149
(4) http://www.ncbi.nlm.nih.gov/pubmed/19733861
(5) http://www.ncbi.nlm.nih.gov/pubmed/22144569
(6) http://www.ncbi.nlm.nih.gov/pubmed/22013243
(7) http://www.ncbi.nlm.nih.gov/pubmed/21731499
(8) http://www.mgz-muenchen.de/moleculargenetic-diagnostics-list-detail/familial-hemiplegic-migraine-type-3-fhm3---iscn1ai.html
(9) http://www.ncbi.nlm.nih.gov/pubmed/20071244
(10) http://www.ncbi.nlm.nih.gov/pubmed/15115642
(11) http://www.ncbi.nlm.nih.gov/pubmed/19304794
(12) http://www.ncbi.nlm.nih.gov/pubmed/19555404
