A Miserable Human Malady
PKGhatak,MD
One of these days, someone will invent a misery detector to record the misery index of human diseases and I bet sixty four thousand dollars that Migraine will top that list. Misery from chemotherapy, though bad, does not come close; after all, it lasts only a few weeks. But migraine attacks happen once or twice a week, every week for the entire span of patients' lives. Also, migraine attacks come at the most inconvenient time - final examination, job interview, wedding, childrens' birthday parties, vacation, etc. and an attack lasts as long as 3 days and patients experience absolute misery, and the entire family also suffers from its consequences. And in those weeks the patients are free of migraine, their mental peace is replaced by anxiety in anticipation of a migraine attack
Archaeological digs from very ancient burial sites uncovered human skulls with holes; they speculated that surgery was performed to relieve intracranial pressure or release bad spirits, as they believed was the cause of migraine. Egyptians recorded illnesses that were no doubt Migraine attacks. Greek physicians, in ancient times, noted two distinct types of migraines- one that was preceded by an aura and the other without an aura.
Migraine attacks proceed in four stages – prodrome, aura, headache and postdrome. It is now recognized that people who suffer from migraine are born with a certain inherited vulnerability to have an exaggerated brain response to common sensory stimuli.
Inherited vulnerability:
It has a complex genetic basis. The familial hemiplegic migraine with aura is an autosomal dominant inheritance. Mutation of genes controlling voltage gated calcium channels on chromosome 19 is implicated in this disorder, in type II familial hemiplegic migraine sodium/potassium pump controlling gene on chromosome I and mutation of dopamine D2 receptor gene increase susceptibility. Calcium channels mediated the release of serotonin in the mid-brain and the imbalance of calcium/ magnesium is implicated in the genesis of aura. Migraine with intermittent ataxia, the calcium channel related gene mutation, is noted.
Prodrome and Aura: These two are distinct. Prodrome symptoms are vague but very familiar to an individual sufferer and generally precede an attack by a day, whereas, an aura is a focal neurological symptom, usually visual, auditory, other sensations and motor functions, usually proceeds up to one hour before the headache begins. Postdrome: feels like a hangover and my last 24hrs. Aura is present in about 20 to 25 % of migraine patients. It is a nerve cell derived depression of the subcortex, that starts at the back in the visual cortex then slowly marches forward to the frontal lobe. It is a result of abnormal ion movement across the cells. Like prodrome aura is hereditary, it is an exaggerated response to ordinary stimuli.
Headache: may last 3 days, it is intense, usually localized to one side of the head, throbbing in nature or sense of drilling inside the head, associated with nausea, vomiting, watery nasal discharge and increased tearing and other symptoms related to the activation of parasympathetic nerves.
For centuries physicians believed the pain of migraine was due to intense vasodilatation. Throbbing headaches, a high prevalence of heart disease, hypertension and stroke in migraine patients point to the vascular origin. This was supported by the fact that a good response was achieved by the use of vasoconstrictor ergotamine.
A headache in migraine is currently believed to be due to a neurovascular event, even though the precise cause is unknown. The meningeal blood vessels of the frontal and middle fossa of the brain and venous sinuses in between Dural folds are densely innervated by unmyelinated C fibers and thinly myelinated delta fibers of the trigeminal nerve. Similar structures in the posterior fossa are supplied by the upper cervical nerves. Nerve cells synthesize Calcitonin Gene Related Protein (CGRP). CGRP granules migrate down to the nerve terminals and are stored as vesicles at terminals. After an appropriate stimulus, the nerve terminals release CGRP. CGRP binds with CGRP Receptors (CGRPR) and physiological actions begin with marked vascular dilatation. The extravasation of plasma and release of Substance P(SP) initiate headaches. It is a sterile inflammation and often lasts for 3 days.
In humans, Calcitonin Gene Related Protein (CGRP) was discovered in a patient with medullary thyroid cancer arising from parafollicular cells otherwise known as C-cells of the thyroid gland. A gene known as the CALC gene is responsible for the production of a large molecule of pre-pro-polypeptide. This molecule is cleaved into Calcitonin, CGRP, Pre-adrenomedullin, and Islet amyloid precursor protein. Besides nerve cells of the CNS and peripheral nervous system, other cells also produce CGRP; these are endothelial cells, immune cells and cells of intestinal vasculature.
CGRP is present in two distinct forms of isomers namely Alpha and Beta. CGPR Alpha is mostly seen in the nervous system and CGRP Beta in the GI tract. Initially, two separate CGRP receptors were identified, one for Alpha CGRP and the other for Beta. Now it is known that one CGRP receptor binds both Alpha and Beta isomers.
These two isomers are present in both the nervous system and in the GI tract but Alpha CGRP is dominant in the CNS and peripheral nervous system. Whereas Beta CGRP is mostly present in the GI system.
Blocking Antibody:
Antibodies are designed to bind with CGRP Receptors (CGRPR) thereby blocking CGRP to attach with its receptors, as a result, the vasodilatation and release of chemicals are prevented and headache is averted. Like CGRP receptors, antibodies are also chemically polypeptides. Antibodies are denatured by gastric acid and digestive enzymes of the gut when administered orally. The antibodies are given as an injection which limits their use at the moment when the drug is needed most. A search for small molecule antibodies against the CGRP molecule itself resulted in the production of several drugs
Preventive therapy for migraine:
Erenumab: This is a humanized anti CGRP Receptor antagonist. It is administered by subcutaneous injections. This antibody binds CGRP Receptors and blocks them from combing with CGRP. As a rest dilatation of vessels and release of chemicals are prevented so also prevents the start of inflammation and pain.
Frenanezumab. It is an antibody to Alpha and Beta CGRP. It does not cross blood brain barrier and is not degraded by the liver or eliminated by the kidney. It is given by injection. It binds with CGRP and the blood level of CGRP falls. And thereby prevents migraine from happening.
Galcanezumab: It is an antibody to CGRP Alpha and Beta. Its mechanism of action is similar to Frenanezumab.
All these three drugs are effective in reducing attacks of migraine at least by 50%. They have a good safety profile.
To avert an attack of migraine the following devices are in various stages of development and approval-
Transcranial Magnetic Stimulator (TMS). It is a patient operated, handheld battery power device, that delivers a quick, sharp, single magnetic pulse to the back of the head over the occipital cortex. It is used in cases of migraine with aura. It reduces migraine attacks.
Vegas nerve stimulator. It is a handheld battery power electric stimulator. When activated it delivers two 90-second electric pulses to the side of the neck over the vagus nerve. It lessens migraine attacks. It probably works by releasing the neurotransmitter glutamine.
Supraorbital transcutaneous stimulator. Mini electrical pulses are delivered to the forehead from a battery powered instrument by the patient at the very onset of an attack with good effect in averting a full blown migraine.
Implantable occipital nerve stimulator. An electrode is implanted along the occipital nerve at the back of the head and connected to a programmable battery pack is placed in a surgically created pocket in the chest wall. Like a heart pacemaker, this device delivers electrical pulses, as programmed, to abate a migraine attack.
Sphenopalatine ganglion stimulator. A small device is implanted in the gum just above the 2nd molar tooth. Electrical stimuli are delivered by the patient by pushing a button of a battery powered remote controller.
Other medications are still in use but not as effective as CGRP receptor antibodies and antibodies to CGRP.
Triptan: Triptan has been in use for a long time and for a while it was the only drug that had a somewhat predictable effect on migraine. Triptan binds serotonin 5HT1B and 1D receptors at the neurovascular junction. It is effective in limiting the duration of migraine but is not preventive. It is a potent vasoconstrictor and not safe in patients with coronary artery disease and hypertension.
Recently a new generation of triptan 5HT1F agonists has been investigated. It has a selective preference for receptors in blood vessels supplied by the trigeminal nerve.
Nasal Oxytocin: It is a vasoconstrictor and reduces sterile inflammation in an attack of migraine.
Botox injection. Initially, the use of Botulinum toxin used in controlling headaches of migraine was thought to be a novel idea and initial results were encouraging. But recent experiences are not so glorifying; overuse and side effects are significant. It is still in use but in more selected cases.
Recent advances in brain imaging techniques and studies on experimental animals improved our understanding of the cause and progression of migraine. These advances are directly linked to the development of new drugs and devices. The CGRP receptor antibody drug has proved to be the game changer, now orally administrable CGRP antibody going to extend the success further, and one day migraine headaches can be effectively treated and even migraine attacks will be prevented.
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