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MIGRAINE HEADACHE 

Timothy C. Hain, MD, Chicago IL. Page last modified: October 12, 2014

Definitions

More precisely, migraines are recurrent headaches separated by symptom-free intervals and accompanied by nausea and light sensitivity. Migraines are often accompanied by visual symptoms and are relieved by sleep; furthermore there is usually a throbbing quality. More often than not there is a family history of migraine.

Migraine is a "committee" diagnosis - -meaning that a group of people got together somewhere and decided what they were going to call a "migraine". There are several other "committee" diagnoses relevant to vertigo -- including Meniere's disease. For "committee" diagnoses, "ruling out everything else" is usually required by the diagnostic process. Some disorders that we deal with commonly in dizzy persons, such as "cervical vertigo", don't have a committee, and being undefined, are less studied than disorders fortunate enough to have their own committee. On the other hand, if one needs a committee to define something, it means that the "somethings" very existence is subject to negotiation.

Accordingly, Formal criteria for migraine, have been defined by the IHS (international headache society) in a very long document. Because headaches are common and because the IHS criteria include nearly anything you can imagine, migraine is a very "inclusive" disorder. It is to be hoped that eventually a blood test or genetic test will be developed.

If one attempts to distill out the most useful parts of the IHS document, migraine usually involves a combination of headache and sensory sensitivity.

Concerning sensitivity, there are various types of sensory inputs which may trigger migraine headache -- light (photophobia), sound (sonophobia), smells (such as perfume), and motion -- persons with migraine are often prone to become motion-sick.They are more sensitive to medications than most people, and they often have symptoms triggered by weather changes.

Psychological testing shows unsurprisingly that people with an active migraine headache don't think as well as usual (Meyer JS et al, 2000).

Although migraines are usually episodic, they can be chronic too.  Chronic migraine is the most severe of all migraine syndromes, with headaches averaging grater than 15 days/month.  Each year, about 2.5% of those with episodic migraine develop chronic migraine (Manack et al, 2011)

Although migraine headache is usually unilateral, opposite sides of the head are characteristically affected during different attacks. About 20% of Migraine's are preceded by an "aura" (see picture on the right), meaning visual symptoms, dizziness, numbness, or weakness. In fact, about 1% of the time, the aura may dominate the migraine, and there may be minimal or no headache ! Migraine auras usually last 5 to 60 min. Visual auras begin in central field of vision and move to the periphery. Another common visual aura is a scotoma (black spot). There is a genre of art called "migraine art", based on migraine aura. There are also sensory auras -- they often move from hand to arm to face and ipsilateral tongue. Presumably, any part of the brain might have an aura. The possibilities are endless !

Visual aura mimics include AVM, TIA, retinal disease, and some focal seizures.

There are numerous defined variants of migraine in the very long IHS document.

Common alternative diagnoses to migraine headache:

Tension headaches are presently thought by many neurologists to be a milder type of migraine. They are usually described as a dull ache in the back of the head, over the ears, in the forehead or in a tight band round the neck. Like migraines as well as nearly any medical problem, tension headaches are made worse by stress.

Sinus headache is generally overdiagnosed (and operated upon). Roughly 9/10 persons who self-diagnose sinus headache actually have migraine. (Schreiber et al, 2004).

Neck related headaches are extremely common, and are usually recognized by their association with posterior pain and aggravation by neck movement.

Other medical problems such as brain tumors or aneurysms are rare in people with headache, but need to be considered, especially in headaches of recent onset.

WHO GETS MIGRAINE ?

About 11 million Americans have significant problems with migraine headaches and about 10-15% of the population get migraines, at least occasionally (Stewart et al, 1994; Lipton et al, 2002). Women are especially likely to get migraine (3:1 female:male ratio, 4:1 during childbearing years). The age group between 30 and 45 has the peak incidence, roughly 25%.

Women get more migraine than men because of hormonal fluctuations, and the incidence appears to be increasing in women recently (Rozen et al, 1999). Women who have recently transitioned into menopause have more migraine.

Children -- According to Bille (1962), about 4% of children have migraines. Mortimer (1992) found 8% of children aged 3-11 experience headache, with an overall incidence of 3.7 to 4.9% of migraine.

WHAT CAUSES MIGRAINE ?

Well, its messy - -current theories usually contain one or more of the following ideas:

Because migraine is so broad, there may actually be many causal variants. It seems unlikely that there could be so many "causes" in a single disorder.

The current consensus is that migraines are caused by abnormality in the brain which represents a combination of familial tendency, trigger factors such as stress, sleep disturbance, hormonal fluctuations, and certain foods. While in the past migraine was felt to be related to vasospasm, presently it is thought that the blood flow changes are not primary. Instead, it is felt that migraine is related to abnormal sensitivity to sensory inputs (Goadsby PJ, 2001). Nevertheless, there is reasonable evidence in the other direction -- for example, migraine is associated with a mutation in a gene that controls a potent vasoconstrictor (Tzourio et al, 2001), and there is also evidence for vascular muscle dysfunction in migraine (Napoli et al, 2009; Asghar et al, 2011).

Our most effective medications for migraine (ergots, triptans) manipulate a blood chemical called serotonin. Medications that manipulate another neurotransmitter (dopamine), are also often effective treatments for migraine although they have side effects and abnormal dopamine is unlikely to the core central problem (Mascia et al, 1998)

Another neurotransmitter called CGRP -- calcitonin gene-related peptide also appears to be important to migraine. CGRP causes cranial vasodilation and faciliates pain reception. During a migraine attack, trigeminal activation results in release of CGRP. CGRP is increased in persons with chronic migraine. The neurology field is currently hoping for drugs that antagonize CGRP.

Migraine does not appear to be related to allergy or immune disturbances in most instances (at least we have a few causes not on the list !).

References:

HOW ARE MIGRAINES DIAGNOSED ?

The diagnosis is made through identification of characteristic features of the headache and examination.

Patients with migraine typically have sensory amplification symptoms --

In our practice, we have also observed that many patients with migraine are very sensitive to changes in barometric pressure, and also that they are more sensitive to medication.   Migraine shares central allodynia with fibromyalgia, which interestingly enough, is often treated with a similar repertoire of centrally acting medications (e.g. SNRI's, gabapentin).

We also see patients who have selectively excessive sensory amplifications -- phonophobia, allodynia and motion intolerance being the main variants. All of these have other causes -- photophobia in particular was recently reviewed by Digre and Brennan (2012), who point out that dry eyes is a common cause too.

Interestingly, patients with migraine are "wired differently" and have thicker sensory cortex than patients without migraine (DaSilva et al, 2007). They are more "sensitive" to pain (Lipton et al, 2008). Patients with migraine have visual cortex that is more excitable than normal during migraine attacks (Denuelle et al, 2001).

Tests for migraine

Being a "committee diagnosis", tests are used to exclude other entities rather than make a positive diagnosis. No X-rays or blood tests are required to make the diagnosis, but in persons with severe and recent headaches, neurological findings, or complicated medical histories, the physician may recommend an MRI or CT scan (Silberstein, 2000). Imaging is generally not necessary if the examination is normal and the headache pattern is unchanged. Lumbar punctures are obtained when subarachnoid hemorrhage or meningitis is suspected. Migraine headaches are often misdiagnosed by patients themselves as sinus headaches. A study suggested that 88% of 2991 patients who had diagnosed themselves as having sinus headache, actually had migraine (Schreiber et al, 2004).

White matter lesions in migraine:

MRI scans may reveal white matter lesions in young persons with migraine. These can and often are confused with white matter lesions due to multiple sclerosis or white matter lesions that occur in older people (periventricular white matter lesions). For more information, see this link: white-matter

Unusual tests for Migraine

MR angiography can be used to diagnose vascular malformations. MR venography can be used for saggital sinus thrombosis. MR also may detect low-pressure type headaches, tumors, as well as the Chiari malformation. Fortunately all of these are rare.

Persons with prolonged auras (> 60 min) should get coagulopathy testing--to look for lupus antibody, anticardiolipin antibody, protein's C and S, factor V Leiden. However, this is a low-yield endeavor, and headaches are not significantly associated with lupus (Mitsikostas et al, 2004).

It would seem likely to us that tests of high sensory reactivity, or inability to block out unwanted distractors, would be a reasonable method of screening for Migraine. Perhaps there is room for more research ?

References regarding migraine causes

HOW ARE MIGRAINE'S TREATED?

The best strategy seems to be adjust the intensity of treatment to the severity of ones migraine condition (stratified care). It doesn't work as well to start cautiously, and then escalate if the first treatment doesn't work (Lipton et al, 2000). There are (at least) 6 different ways to manage Migraine. In all instances, it is best to keep a "log" of headaches, such as a diary, in order to determine whether or not a particular treatment is effective. In our neurology practice in Chicago, we use this form. It often works very well to simply print out a calendar on a page, and using a "traffic light" color scheme (green=good, red=bad), indicate days that one has symptoms.

1. Avoid trigger factors:

2. Simple non-drug treatment that should be tried first

3. Pain medications

4. Prophylactic medications: For those who have more than 2 severe headaches/month and in patients with complicated migraine (migraine with stroke-like features), a daily medication may be worth while. These are generally highly effective (about 75% effective), but do require daily regular use. These drugs fall into three major classes: anticonvulsants, antidepressants, and antihypertensives. Examples are: Amitriptyline (Elavil), Corgard, Depakote, Inderal, Nardil, Verapamil (Calan, Isoptin). These drugs seem to work via several pathways: some are beta-blockers (e.g. Inderal, Corguard), some are calcium channel blockers (e.g. verapamil), some work in mysterious ways (e.g. Depakote, Nardil, amitriptyline). More information about these is in the next section.

5. Acute, specific medications (also called "abortive" medication): For those who have severe but infrequent headache. Highly effective, especially Imitrex (sumatriptan). There are numerous others in the same family -- Zomig, Maxalt, and Axert, and Frova to name a few brand names. There are also older (cheaper) drugs, called ergots, that have similar effects but have more side effects -- examples of these types of drugs are: Cafergot, DHE, and Ergotamine. Drugs that are dopamine blockers include Metoclopramide and  prochlorpromazine.

6. Nausea medications: For those with prominent nausea. The "cyclic vomiting" variant of Migraine often calls for vigorous uses of these agents. These drugs are usually highly effective, but cause some major side effects. Examples are: Compazine, Phenergan, Reglan, Thorazine, Tigan. These drugs also have some utility as abortive agents, presumably because of their effects on the dopamine pathways. Droperidol is very effective in Migraine (Ashkenazi et al, 2003). but because of it's "black box warning" related to sudden death from cardiac side effects, we think it is best not used for a recurrent non life-threatening condition like migraine. Haloperidol is also very effective, and can be useful in occasional persons with severe vomiting.

References:


Migraine prevention drugsalgorithm

An extensive discussion of migraine prophylactic drugs can be found herebullet Algorithm for treatment (pdf)

There are three main groups - - seizure medications (e..g Topamax -- topirimate), blood pressure medications (e.g. verapamil or propranolol), and antidepressants (e.g. nortriptyline or venlafaxine). The author of this review usually starts patients with topamax, and proceeds on to try effexor, verapamil, propranolol and then ami or nor triptyline. It is very unusual that headache control is not attained with a single drug. When one "group" doesn't work, he may combine two or 3 groups simultaneously (anticonvulsant, blood-pressure agent, antidepressant).

Migraine abortive drugs

A tabular discussion of migraine abortive drugs can be found here

Triptans and other agents that act on serotonin receptors:

Imitrex (sumatriptan) is an example of a category of drugs called triptans. As a general comment, other than the generic sumatriptan, the triptans are terribly expensive but very effective. At this writing, this category includes sumatriptan, naratriptan, zolmitriptan, rizatriptan, almotriptan, frovatriptan and eletriptan. These drugs are all group-1 agents. These drugs are 5HT-1B and 1D (serotonin) receptor agonists. Some also affect 5HT-1F. Serotonin does a lot of things in the body and there are many receptors, presently ranging from 5HT1-7. Other drugs that affect serotonin are the SSRI and SNRI families of antidepressants and the "setron" family of antinauseants, such as ondansetron, which antagonize the 5HT-3 receptor. The FDA has advised caution when taking both triptans and SSRI/SNRI's together. We have never encountered problems, but nevertheless we suggest avoiding taking large amounts of triptans and SSRI/SNRI's together. This mainly is a difficulty when someone has two conditions - -major depression and migraine - -simultaneously.

Imitrex was first released as an injection given under the skin (subcutaneously) at time of headache. Imitrex is not recommended for patients < 18 years of age although several studies have been performed on adolescents with similar results to adults.

Compound Dose Tmax T 1/2
Rizatriptan (Maxalt) 10 1 2-2.5
Eletriptan (Relpax) 40 1-1.25 4-7
Sumatriptan (Imitrex) 100 2.5 2-2.5
Zolmitriptan (zomig) 2.5 2.5 3
Almotriptan (Axert) 12.5 2.5 3.6
Naratriptan (Amerge) 2.5 2-3 5-6
Frovatriptan (Frova) 2.5 2-4 25
(modified from Matthew and Loder, 2005)

Presently triptans are also available as a pill (50-100 mg is best for sumatriptan), as a nasal spray and as a sublingual preparation (Maxalt and Zomig). The sublingual forms are generally preferred because of fast and effective action. Eletriptan, a recent addition, has a nasal form that is well suited to rapid treatment (Ashkenazi and Silberman, 2003), and both rizatriptan and eletriptan have a very rapid onset of action when taken orally.

A recent addition is frovatriptan (Frova) , which has a very long half-life (about 26 hours). Longer half-life drugs have less recurrences. The triptans are very effective for migraine (about 60-85% relief from active drug vs. 20-40% in placebo) but also very expensive (roughly $75/injection or squirt).

There are now some agents which cost a much less -- Sumatriptan, being generic, is not unusually expensive. Generic versions of the injectable sumatriptan are also reasonably priced. We can probably anticipate similar drops in the prices of relpax and maxalt, once they emerge from patent protection. The triptans usually relieve migraine associated nausea as well as headache. These drugs are also reported somewhat effective for tension headache (Lipton et al, 2000).

Because of the high cost, some pharmacy programs limit quantities to about 8 uses/month. For the injection form, chest pain occurs in 3-5% of patients, usually from esophageal spasm. Myocardial infarctions, however, have rarely been reported after triptan use. For the nasal spray, a bitter taste in the mouth is the most common side effect (Ryan et al, 1997). Sumatriptan can be used up to twice/day.  Very surprisingly, sumatriptan is not generally effective in children (Hamalainen, 1997), although some reports suggest that the nasal spray may work. 

Triptans shouldn't be used by persons with heart trouble or blocked arteries (Maasen, Vandenbrink et al, 1998). Triptans should not be used within 24 hours of using an "ergot" type medication (see below) or Sansert (no longer available).  Use in hemiplegic or basilar migraine (i.e. migraines with stroke like symptoms) is generally contraindicated. In the author's practice, these drugs are also avoided in persons with MRI evidence of small infarcts, which is common in persons with severe migraine. Coadministration with MAO inhibitors is contraindicated (see preventive treatments). See table under "addictive medications" for guides for use. While triptans are generally effective in cluster headache, extreme caution is advised, because of the temptation to overuse this drug, and also the tendency for cluster to occur in persons with higher risks of heart attack.

Similar medications to sumatriptan (Imitrex) are zolmitriptan (Zomig), rizatriptan (Maxalt), and eletriptan (Relpax). Amerge (naratriptan) is a slower onset, more prolonged version. While triptans are not recomended for use in a preventive, "prophylactic" mode, nevertheless Amerge is sometimes used for several days in a row to prevent menstrual migraine. Frova is a very long half-life triptan. Axert (almotriptan) is also somewhat longer lasting. Relpax is one of the stronger ones (Sandrini, Farkkila et al. 2002; Farkkila, Olesen et al. 2003). Some pharmacy programs limit use of Zomig to 6 tablets/month of the 2.5 mg form, or 3 tablets of the 5 mg form, and Amerge to 9 tablets. It is generally felt that it is unreasonable to use triptans more often than every other day. Triptans can lead to rebound (withdrawal) headaches (Limmroth et al, 1998). Inappropriate use of medication including dependence is certainly possible and, because of it's high price, may impact health care spending significantly (Gaist et al, 1998)

An older similar medication, DHE (dihydroergotamine), also group 1, is less used because of greater incidence of side effects. DHE and other ergots are broader in their action than the triptans and this is probably the reason for their increased side effects vs. the triptans. Nevertheless, DHE is now been recent released as a nasal spray preparation (Migranal). DHE are contraindicated in patients with renal or hepatic insufficiency, coronary, cerebral or peripheral vascular disease, and uncontrolled hypertension. These agents are also contraindicated in women who are or may be become pregnant. Caution should be used with ergots in lactating women, in patients also receiving peripheral vasoconstrictors, 5-HT1 agonists, propranolol, nicotine and macrolide antibiotics (PCS, 1999).

Other ergots --

Ergot medications often undergo shortages -- these very old drugs are so often unavailable on a world scale. For example, at ergotomaine was mysteriously unavailable when Imitrex was first introduced.

Ergotamine tartrate (Wigraine) SL or suppository. This is obviously an "ergot" type medication too. Take at time of headache, repeat in 30 minutes if not effective. Wait 3 days before using again. Should NOT be used by persons with heart trouble or poor circulation. Coldness and tingling in the legs suggest a need to stop treatment. Otherwise, contraindications are similar to DHE (see above). Ergotamine is rarely used, being replaced by Imitrex.

Cafergot. This is another ergot preparation, a group 2. It is used at time of headache. Same dose and precautions as Ergotamine tartrate. Suppositories are more effective than the oral dose (maximum 2/day).

As basic research suggests that these medications inhibit firing in trigeminal pain pathways via 5HT1B and D receptors  (Goadsby and Hoskin, 1998), in theory at least, this group might also relieve other types of head pain such as sinus headache, tension headache, and toothache. Generally, it is not used for these purposes, and a good response to a "triptan" is considered a reasonable indication that the patient has a migraine.

Other abortive agents:

Midrin (isometh/APAP/Dichlor) was taken off the market as of 2011, for reasons that we have been unable to trace down. We speculate that there were reports of toxicity, that were not released, or a "buy out" by a competitor. It has reemerged thereafter, but with a change in formula.   Midrin was a group-2 drug, also considered an "ergot" type medication, although the pharmacology (see below) suggests that it is basically a combination of a vasoconstrictor, a sedative and analgesic. The instructions were: Take at time of headache, repeat in 30 minutes, up to maximum of 5. Wait 3 days before using again. The ingredients in Midrin also include dichlorophenazone (a combination of chloral hydrate and phenazone) and acetaminophen.  Chloral hydrate, of course, is a sedative.   Phenazone and acetaminophen are both mild analgesics.  The rationale for combining them is obscure. Isometheptene is a sympathomimetic, that causes vasoconstriction.   Similar to caffeine.

Naproxen (Alleve 220 mg) and Ibuprofen (Motrin 200 or 400 mg). These medications are "non-steroidals". There are many others -- there is no reason to suspect that they vary in any significant way other than side effects. Non-steroidals or "NSAID" medications are both useful for pain at the time of headache, and may also help on a daily basis. Main problems with them are stomach irritation and diarrhea. Don't take large amounts as these drugs can damage the kidney and liver too. Take with food. Aspirin may work as well. Cost for one of the older type NSAID's is about 0.20 $/day.

There are also other very strong nonsteroidals -- examples being Cambia (a powered variant), Sprix (a nasal spray), and injectable nonsteroidals.

Droperidol has been reported as an effective acute treatment for migraine (Silberstein et al, 2003). Because droperidol has been associated with occasional life-threatening side effects, however, we do not recommend it for this purpose.

Steroids, according to Silberstein (2000), are not effective acute therapies for migraine. Nevertheless, they are often used in a short course to "break" a severe bout of migraine or cluster headache. This suggests they may be effective subacute treatment.

Treatment References:

ADDICTION TO HEADACHE MEDICATIONS

One is physically addicted when one takes a medication daily, and suffers withdrawal symptoms unrelated to the primary purpose of the drug, when one attempts to stop. Certain common patterns of drug use are generally considered addictive. For example, daily use of narcotics or use of sedative medications during the day usually indicates a physical addiction.

Narcotic drugs are often abused. In a study of migraine treatment in which daily narcotics were prescribed, there was evidence for dose violations (taking more than prescribed), multisourcing, lost prescriptions in about 50% of persons on narcotics (Saper et al, 2004). Diversion of drugs is also a significant concern.

While few people want to be addicted to drugs, from time to time, these agents are needed to keep patients comfortable and productive. In this situation, there should be regular physician supervision and consideration of other approaches than the addictive medication.

If one wishes to stop an addictive medication, one must usually "wean" off. In general, this means cutting down the dose by a significant amount (say by 1/2), every week, until it is entirely stopped. Going "cold turkey" with addictive medications is usually a bad idea.

ADDICTIVE DRUGS:

Narcotics include Tylenol #3, anything with codeine or hydrocodone, Darvocet, Darvon, Demerol, Vicodin, Percodan, Roxanal, Stadol, and many others. Drug dependence is characterized by repetitive use of a substance that results in problems in three or more areas of life such as : 1). Development of tolerance 2). Development of withdrawal 3). use of substance in larger amounts or for longer periods than intended 4). unsuccessful efforts to cut down on use of substance 5). spending a great deal of time in activities necessary to obtain substance 6). giving up social, occupational or recreational activities because of drug use 7) continuing to use substance despite physical or psychological problems associated with use.

Sedatives or drugs containing sedatives (Fiorinal, Fioricet, Valium, Ativan, Xanax, Klonapin, Equinil). Addiction consists of either daily excessive use (e.g. 5 Fiorinals/day), or significant withdrawal symptoms unrelated to the primary indication for the drug -- for example, unable to sleep after stopping Ativan, Valium or Xanax. Barbituate overuse can be treated with phenobarbital which allows a slow taper. Barbituates are sometimes associated with chronic daily headache (see section below on rebound) in women.

While not generally used for headache, amphetamines such as Dexadrine and Ritalin, and of course alcohol are also addictive.

Ergot drugs and Triptan drugs(DHE, ergotamine, any drug with "ergot" in the name, and anything with "triptan" in the name). The main problem here is "rebound" headaches (see below). Recommendations for MAXIMUM use of medications follow.

Medication Maximum Recommended Use
Caffeine 2 treatments/week
Codeine 2 treatment days/week
Oxycodone (i.e. Percocet) 2 treatment days/week
Butlbital (i.e. Fiorinal) 2 treatment days/week
Proproxyphene (i.e. Darvon) 2 treatment days/week
Butorphanol (i.e. Stadol) 2 treatment days/week
Ergotamine tartrate 8 treatment days/month. Maintain 4 day gap between treatment days
Sumatriptan 6 treatment days/month or 2 treatment days/week

Adapted from table 6 in: Solomon G, Cady R, Klapper J, Ryan R. National Headache Foundation: Standards of care for treating headache in primary care practice. Cleveland Clin. J. Med 64/7, 1997, 373-383

References:


DRUGS THAT OFTEN CAUSE HEADACHE AS A SIDE EFFECT

We do not recommend that you stop prescription medications without the permission of your doctor. However, certain medications can trigger headaches. Note that some medications in the same category that cause headache, may relieve headache. There are far too many medications that cause Migraine to list here, however the most common ones are listed.


REBOUND HEADACHE

Migraine headaches often evolve or transform into daily headaches, and this pattern has been termed the "analgesic rebound headache". Common features are thought to be:

Some authors suggest that in addition there is tolerance to analgesic medication, and efficacy of usually effective medication is compromised by ongoing consumption of immediate relief medications. Treatment involves withdrawal of analgesic medication. This sometimes must be done during a hospital setting

A recent review by Bigal and Lipton (2008) suggested that risk of progresson of acute migraine to chronic migraine, and associated rebound headache can be predicted from a combination of frequency of intake and the type of medication. They indicate that there is both an effect of medication inducing chronic headaches as well as pain inducing chronic medication use -- in other words, this is a "chicken and egg" problem.

Bigal and Lipton suggest that drugs generally recocognized as addictive -- opiates and barbituates -- should be carefully monitored and limited as much as practical. From their data, it would also seem prudent to limit and attempt to decrease the frequency the use of drugs not usually considered addictive -- namely triptans and anti-inflamatory medications.

In our clinical practice, we will sometimes attempt a strategy of small amounts of several headache drug categories. This strategy is predicated on the hypothesis that habituation and addiction is less likely in persons who are not consistently on drugs of the same mechanism. If, all of these drugs work through the same mechanism to convert intermittent headache into chronic, this strategy would not work. More study is needed.

Other very reasonable approaches to the problem involve use of migraine prevention drugs rather than analgesics, and use of approaches such as "ice to the back of the neck", to avoid use of daily analgesics.

References:
Copyright October 12, 2014 , Timothy C. Hain, M.D. All rights reserved. Last saved on October 12, 2014