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migraine genetics ppt


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Dr Barun Migraine Genetics

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migraine genetics ppt

  2. 2. • Lifetime prevalence of any type of headache is • > 90% in men • > 95% in women.
  3. 3.  PRIMARY HEADACHE:  Migraine  Tension type headache  Cluster headache  Trigeminal autonomic cephalgia  SECONDARY HEADACHE:  Systemic or brain infection  Head injury  Ischaemic or haemorrhagic stroke  Brain tumours  Lumbar puncture headache
  4. 4.  Scalp and aponeurosis  Middle meningial arteries  Dura mater  Dural sinuses  Falx cerebri  Proximal segments of the large pial arteries
  5. 5.  According to ICHD-3  PART ONE : PRIMARY HEADACHE  1. Migraine  2. Tension type headache  3.Cluster headache and other trigeminal-autonomic cephalgias  4. Other primary headaches
  6. 6. • PART TWO: THE SECONDARY HEADACHES • 5. Headaches attributed to head and / or neck trauma • 6. Headache attributed tocranial or cervical vascular disorder • 7. Headache attributed to non-vascular intra-cranial disorder • 8. Headache attributed to a substance or its withdrawal • 9. Headache attributed to infection
  7. 7. • 10. Headache attributed to disorder of homeostasis • 11. Headache or facial pain attributed to disorder of cranium, neck, eyes, ears, nose, sinuses, teeth, mouth, or other facial or cranial structures • 12. Headache attributed to psychiatric disorder.
  8. 8. ◦ PART THREE: CRANIAL NEURALGIAS, CENTRALAND PRIMARY FACIAL PAIN AND OTHER HEADACHES  Cranial neuralgias and central causes of facial pain  14. other headache, cranial neuralgia, central or primary facial pain
  9. 9.  The term ‘Migraine’ is of French origin derived from a Greek name ‘hemikranios’, meaning unilateral headache.  Migraine is a common disabling primary headache disorder.  Epidemiological studies have documented its high prevalence and high socio-economic and personal impacts.
  10. 10.  In the Global Burden of Disease Survey2010, migraine was ranked as the third most prevalent disorder and seventh-highest specific cause of disability worldwide. • In a survey it was seen that > 90% patients reported of impaired ability of function during migraine attacks, 53% reported severe disability requiring bed- rest. About 31% missed atleast 1 day from work or school due to migraine.
  11. 11.  Initial attacks occur mostly in adolescents.  Usually when the attack begins denovo in older people, migraine is unlikely.  In children, there is a little preponderance in males.  After puberty it is female predominant.  Evidence of positive family history is present in >90% cases.  Migraine tends to recur with varying frequency throughout life, attack gets milder and less frequent in older age groups.
  12. 12. ◦ ICHD-3rd ed (Beta version)  1. Migraine  1.1 Migraine without aura  1.2 Migraine with aura  1.2.1 Migraine with typical aura  Typical aura with headache  Typical aura without headache  1.2.2 Migraine with brainstem aura
  13. 13.  1.2.3 Hemiplegic migraine  Familial hemiplegic migraine (FHM)  Familial hemiplegic migraine type 1 (FHM1)  Familial hemiplegic migraine type 2 (FHM2)  Familial hemiplegic migraine type 3 (FHM3)  Familial hemiplegic migraine, other loci  Sporadic hemiplegic migraine
  14. 14.  1.2.4 Retinal migraine  1.3 Chronic migraine  1.4 Complications of migraine  1.4.1 Status migrainosus  1.4.2 Persistent aura without infarction  1.4.3 Migrainous infarction  1.4.4 Migraine aura-triggered seizure
  15. 15.  1.5 Probable migraine  1.5.1 Probable migraine without aura  1.5.2 Probable migraine with aura  1.6 Episodic syndromes that may be associated with migraine  1.6.1 Recurrent gastrointestinal disturbance  Cyclical vomiting syndrome  Abdominal migraine  1.6.2 Benign paroxysmal vertigo  1.6.3 Benign paroxysmal torticollis
  16. 16.  True pathogenesis of migraine is still not clear.  Previously vascular theory was supposed to be the cause,  True In the vascular theory it was thought that vasoconstriction followed by vasodilatation explained the causes of aura followed by headache.
  17. 17.  IN FAVOUR-Radioactive xenon cerebral blood flow studies show significantly reduced regional blood flow through cortex during aura stage of migraine.  AGAINST-  1.functional MRI studies show that a phase of focal hyperemia precedes the phase of oligemia during migraine attack  2. headache may begin while the cortical blood flow remains low.
  18. 18.  Now-a-days neurophysiological and neurofunctional studies support a primary neuronal theory, according to which a neuronal hyperexcitability is the biological basis for susceptibility to migraine.  Migrainous brain is qualitatively and quantitatively different from nom-migrainous brain, that cause thresold of susceptibility governed by some factors, resulting in neuronal hyperexcitability and spontaneous depolarisation.
  19. 19. Abnormal Neuronal activity Instability in release of neuropeptides e.g., Substance P, neurokinin A, calcitonin gene-related polypeptide, serotonin Promote vasodilation and plasma protein extravasations. Initiate inflammatory response, sensitizes surrounding tissues and produce headache Activates trigeminovascular system, which in turn, stimulate pain stimulating neurons in brain stem and upper spinal cord Activates nociceptive trigeminovascular system and causes prolong pain Cerebral cortex, thalamus or hypothalamus in response to stress, emotion.
  20. 20.  The factors include deficit in mitochondrial oxidative- phosphorylation, alteration in neuronal voltage gated calcium channel function, intracellular magnesium defficiency.  The electrical event produced by this neuronal hyperexcitability is known as cortical spreading depression. It is more aptly described as spreading activation followed by depression, which the cause of visual schintillation followed by positive scotoma.  Spreading cortical depression can directly activate trigeminal vascular nociceptive afferents.
  21. 21.  Once activated impulse are transmitted centrally to trigeminal nucleus caudalis, there from relay in thalamic centres and then to parietal cortex.  At the same time neuropeptides like substane P, calcitonon gene related peptide, neurokinin A are released from widely branching trigeminal axon nerve terminals.  This results in neuronal inflammation and explains the cause of pain im migraine.
  22. 22.  Serotonin ( 5- hydroxytryptamine), a neurotransmitter is thought to be an important mediator of migraine.  Unstable serotonergic neurotransmission, has lower threshold for migraine.  There are 7 classes of 5-HT receptors  Out of 7, 2 involve in migraine pain.
  23. 23.  Serotonin causes vasodilation in large artery  Serotonin causes vasoconstriction in small artery and capillary  During migraine the level of serotonin is low in blood.
  24. 24.  Migraines the second most common cause of headache, affecting approximately 15% of women and 6% of men.  It is usually an episodic throbbing headache,associated with certain features like, sensitivity to light, sound or movement, nausea and vomiting often accompanies the headache.  So migraine is benign, recurring syndrome of headache associated with other neurological dysfunctions with varying admixtures.
  25. 25. It has been suggested that migraine episode can be divided into five distinct phases: • Premonitory symptoms • Aura • Headache and associated symptoms • Resolution • Recovery
  26. 26.  It is also known as ‘common migraine’  It is not preceded or accompanied by any neurological symptoms  May be preceded by alteration in mood or enegy level, excessive yawning, thirst, hunger. Headache may occur within hours or in the next day.  Pain is usually unilateral and supraorbital but may be holocephalic.  Pain is throbbing in nature.  May be associated with nausea, vomiting photophobia etc.
  27. 27.  Here aura precedes the headache.  Aura consists of transitory visual, sensory or language disturbances or other focal cerebral or brainstem symptoms.  Aura occurs in 20-25% of the migraineurs and generally does occur in every attack.
  28. 28.  Classically visual symptoms occurs first, followed by sensory symptoms and then by language symptoms.  Most common aura is the visual disturbance known as “schintillating scotoma” or “teichopsia”. This generally starts as an arc of white or coloured light, having definite zigzag pattern, then gradually expands from a point to involve a quadrant or hemifield of vision in both the eyes.
  29. 29.  Negative scotoma. Loss of local awareness of local structure Positive Scotoma. Additional structures One side loss of perception. Zigzag structure
  30. 30.  Positive scotoma is followed by a spreading zone of vision loss ie, negative scotoma.  Usually congruent homonymous field defect.  Visual disturbances causes reading and driving difficult.  There may be change in perception of shape of viewed objects, called ‘metamorphopsia’.
  31. 31.  Though uncommon, there may be retinal dysfunction too, which leads to unilateral flashes of light, scattered areas of vision loss, altitudinal defects or transient unilateral vision loss. When headache follows such uniocular vision loss, it is called ‘retinal migraine’.
  32. 32.  Sensory aura is second most common following visual aura, and is again characterised by positive symptoms (paraesthesia) followed by negative symptoms (numbness)  Paraesthesia of migraine has prediliction for face and hands, probably because of large representation of these structures in the sensory cortex or thalamus.  The rate of spread of a sensory aura is important to distinguish it from a sensory seizure and the sensory disturbance of a TIA
  33. 33.  Language aura, which can be expressive or receptive type. Alexia and agraphia can also occur. There may be mild confusion and difficulty in concentrating.  There is an other variant called hemiplegic migraine, in which there is weakness of limbs or facial muscles on one side of body
  34. 34.  When a visual, sensory, motor, or psychic disturbance characteristic of migraine aura is not followed by a headache, the episode is termed migraine aura without headache, a migraine equivalent, or acephalgic migraine.  Most commonly encountered in patients who have a past history of migraine with aura, the episodes can begin de novo, usually after 40 years of age,
  35. 35.  First encountered in childhood or adolescence.  Prevalence is almost equal in men and women.  Headache is usually severe and occipital.  Aura starts with typical migrainous disturbance of vision, lasting for 10-45 mins, and is bilateral.
  36. 36.  Tingling sensation of face, lip, hands occur often, ataxia of gait, ataxia of speech, vertigo, tinnitus, dysarthria also occurs.  Brainstem reticular function involvement may cause impairment of consciousness in childhood.  Headache usually subsides after sleeping.  Gradually with increased maturation of nervous system, it becomes less common, and generally replaced by migraine without aura.
  37. 37.  Very uncommon  Onset in childhood  Recurrent attacks are stereotypical  Begins with unilateral orbital or retro-orbital pain, accompanied by vomiting, that lasts for 1-4 days.
  38. 38.  During the painful stage or after the pain has subsided, ipsilateral ptosis occurs, and within a few hours it progresses to complete paralysis of III rd cranial nerve.  Rarely IV th and VI th cranial nerves may also be involved. N Neural deficit may remain hors to several months.
  39. 39.  Familial hemiplegic migraine is a form of migraine headache that runs in families.  Along with the other features of migraine with aura, in familial hemiplegic migraine some other features may be seen like, fever, seizures, prolonged weakness, coma.
  40. 40.  Although most people with familial hemiplegic migraine recover completely between episodes, neurological symptoms such as memory loss and problems with attention can last for weeks or months  About 20 percent of people with this condition develop mild but permanent difficulty coordinating movements (ataxia), which may worsen with time.  There may be involuntary eye movements .
  41. 41.  The worldwide prevalence of familial hemiplegic migraine is unknown. Studies suggest that in Denmark about 1 in 10,000 people have hemiplegic migraine.
  42. 42.  Familial hemiplegic migraine type 1  Familial hemiplegic migraine type 2  Familial hemiplegic migraine type 3
  43. 43.  Mutations in the CACNA1A, ATP1A2, SCN1A, and PRRT2 genes have been found to cause familial hemiplegic migraine.  The first three genes provide instructions for making proteins that are involved in the transport of charged atoms (ions) across cell membranes.  The movement of these ions is critical for normal signaling between nerve cells (neurons) in the brain and other parts of the nervous system.
  44. 44.  The function of the protein produced from the PRRT2 gene is unknown, although studies suggest it interacts with a protein that helps control signaling between neurons.  Researchers believe that mutations in theCACNA1A, ATP1A2, and SCN1A genes can upset the balance of ions in neurons, which disrupts the normal release and uptake of certain neurotransmitters in the brain.
  45. 45.  Although the mechanism is unknown, researchers speculate that mutations in the PRRT2 gene, which reduce the amount of PRRT2 protein, also disrupt normal control of neurotransmitter release.  The resulting changes in signaling between neurons lead people with familial hemiplegic migraine to develop these severe headaches.
  46. 46.  This condition is inherited in an autosomal dominant pattern  In most cases, affected individuals have one affected parent.  However, some people who inherit an altered gene never develop features of familial hemiplegic migraine. (This situation is known as reduced penetrance.)  A related condition, sporadic hemiplegic migraine, has identical signs and symptoms but occurs in individuals with no history of the disorder in their family.
  47. 47.  Criteria adapted from the Headache Classification Subcommittee of the International Headache Society  Familial hemiplegic migraine (HM) is a category of migraine with aura (MA).  Diagnostic criteria for HM are as follows:  Headaches fulfill criteria for MA  Aura includes some degree of hemiparesis and may be prolonged but fully reversible.  HM is categorized as familial if at least one first degree relative (i.e., parent, sib, and/or offspring) or second degree relative has identical attacks.  HM is sporadic if no first- or second degree relative meets criteria for hemiplegic migraine.
  48. 48.  Targeted variant analysis  Deletion or duplication analysis  Sequence analysis of the entire coding region  Mutation scanning of entire coding region
  49. 49.  Chronic migraine, was previously referred to as transformed migraine.  Characterized by headaches (tension-type and/or migraine) on 15 or more days per month, with at least 8 days per month fulfilling International Headache Society diagnostic criteria for migraine for at least 3 months in the absence of ongoing medication overuse (Olesen et al., 2006).
  50. 50.  Patients with chronic migraine usually have a history of episodic migraine that began in their second or third decade.  Though in majority evolution from episodic to chronicity is gradual, in
  51. 51.  The prevalence of a family history of migraine was recognized in the 17th century.  Most striking evidence of a genetic basis for migraine has come from investigations of familial hemiplegic migraine.
  52. 52.  In 1993, FHM was mapped to chromosome 19p13 in linkage studies.  About 50% of tested families have mutations in CACNA1A, a gene located on chromosome 19p13 that codes for the α1-subunit of a brain-specific voltage-gated P/Q-type calcium channel (Ophoff et al., 1996).  Recent reports (Terwindt et al., 2001) not only implicate CACNA1A in FHM, but it may be overrepresented in patients with migraine without hemiplegia.
  53. 53.  Gardner et al. (1997) reported another locus for FHM on chromosome 1q31 in a 39-member four- generation pedigree showing a clear FHM phenotype.  This region on chromosome 1 contains a neuronal calcium channel α1E-subunit gene.
  54. 54.  Subsequent studies in other families have found two additional mutations linked to FHM. One that mapped to chromosome 1q21-q23 (De Fusco et al., 2003) is located in a gene coding for a subunit of a sodium/potassium pump (ATP1A2).  Another mutation identified on chromosome 2q24 is located in a gene that encodes a sodium channel subunit (Dichgans et al., 2005).
  55. 55.  A recent study based on a genome-wide screen of 50 multigeneration yielded significant evidence of linkage between the migraine with aura phenotype and marker D4S1647 located on chromosome 4q24 (Wessman et al., 2002).
  56. 56.  DURATION OF HEADACHE :  Migraine : 3 hours to 3 days  Tension type headache : 30 mins to 3 wks to 3 years  Cluster headache : 30 mins to 3 hours  Paroxysomalnhemicranias : 3-30 min  SUNCT : 3 seconds  Status migrainous : > 3 days  Chronic headache : > 3 months
  57. 57.  Acute or subacute and progressive headache  New onset headache in adult life (>40 years)  Change in headache pattern : intensity, frequency, new features or decreased response to treatment  Headache associated with,  Nause, vomiting not explained by migraine or illness  Nocturnal occurance or morning awakening  Worsening by change in posture or valsalva  Confusion, seizure or weakness
  58. 58.  Repeated attacks of headache lasting for 4-72 hours in patients with a normal physical examination, no other reasonable cause for the headache, and :  Atleast 2 of the following features: ◦ Unilateral pain ◦ Throbbing pain ◦ Aggravation by movement ◦ Moderate or severe intensity Plus at least 1 of the following features: • nausea /vomiting • Photophobia and phonophobia
  59. 59.  Neuroimaging used in some cases to exclude secondary causes of headache or ischemic complications.  Migraine is an independent risk factor for ischemic stroke
  60. 60.  • change in headache pattern  • side-locked headaches (unilateral headaches that never change sides)  • new onset of chronic daily headache.  • prolonged aura  • Higher possibility of ischemic complication (women with migraine with aura ,younger than 45 years and use of estrogen containing oral contraceptives).
  61. 61.  CT SCAN is of extremely low yield in patients who undergo imaging for chronic headachewithout neurologic abnormality.  CTPerfusion may be very useful to analyze acute attacks perfusion regional changes.  MRI  It is more sensitive than CT in the detection of an intracranial abnormality
  62. 62. CT study of apatient within amigraine attack with prolonged aura. NECT is normal. CTPerfusion showed areas of hypoperfusion in left frontal and temporalregions.
  63. 63.  • White matter hyperintensities are more  prevalent in– migraineurs compared to the generalpopulation (12–47% of all patients).  – More than 60% of migraineurs with aura  – Patients with frequent attacks
  64. 64.  When the attack is finished, theneurologic deficit usually resolves fully  • Unilateral symptoms may switch sides between attacks.  • MRI finding  – cortical hemispheric thickening (hyper in T2)  – No vascular territory  – No contrast enhancement or diffusion restriction.  – Midline shift and sulcal effacement
  65. 65.  PET scan showed brainstem activation during the migraine attack.  Maximum activation was around the dorsal midbrain, which contains the dorsal raphe nucleus and periaqueductal grey matter, and the dorsolateral pons, which contains the locus coeruleus.
  67. 67.  Should be started as early as possible during the aura phase, should not wait for headache to begin.  Once the attack is fully developed, the oral preparations are less effective.  Aspirin, acetaminophen, naproxen, ibuprofen,or oral analgesic in combination with caffeine may be effective.  Caffeine helps by inducing vasoconstriction, and reduces the firing of serotonergic brainstem neurons.  But caffeine containing analgesic use foe more then 2 days in a week, increases headache.
  68. 68.  New class of antimigraine drugs, having selective agonistic activity on 5 HT1B and 5 HT1D receptors.  Activity on 5 HT1B causes vasoconstriction, on 5 HT1D inhibits sensory neuropeptide release from perivascular trigeminal afferents.  Activation of 5-HT1B/5-HT1D receptors can attenuate the excitability of cells in the TNC, which receives input from the trigeminal nerve.  5-HT1B/5-HT1D agonists may act at central as well as peripheral components of the trigeminal vascular system.
  69. 69.  1. local reaction at the injection site, usually of mild or moderate severity, and a transient tingling or flushed sensation that may localize or generalize.  2. unpleasant sense of heaviness or pressure in the neck or chest  3. has been shown to produce a minor reduction incoronary artery diameter
  70. 70.  Patients with any history suggestive of coronary insufficiency.  Untreated hypertension or peripheral vascular disease and  Those using ergot preparations.  Women during pregnancy  Hemiplegic migraine or basilar-type migraine.
  71. 71.  Though now is supplemented by newer agents, ergots still have role in symptomatic patients.  Mechanism of action: agonistic activity on 5 HT receptors  Have both vasodilator and vasoconstriction effects depending on dose and resting tone of target vessels.  Mode of administration : oral, parenteral, rectal. Oral route is less effective.  The ergot preparation can be repeated in 60 minutes if needed.  If more than 6 mg of ergotamine is required per week, use an alternative preparation.
  72. 72.  Coronary artery disease  Pregnancy  Peripheral vascular disease  In patients having aura for prolonged time or any neurologic deficit.
  73. 73.  Gepants (olcegepant, telcagepant)  A novel CGRP antagonist is currently undergoing evaluation in human trials. If found to be efficacious and safe, the CGRP antagonist, which has little vasoconstrictive effect on vascular smooth muscle, benefit patients in whom triptan and ergotamine use is precluded because of comorbid coronary artery disease.
  74. 74.  A preventive program is appropriate when attacks occur weekly or several times a month, or when they occur less often but are very prolonged and debilitating.  The most effective prophylactic agents available typically reduce headache frequency by at least 50% in approximately 50% of patients.
  75. 75.  β-Adrenergic antagonists are widely used for prophylaxis of migraine headaches.  Propranolol in doses of 80 to 240 mg/day, if tolerated, should be given a trial of 2 to 3 months. Compliance increases with the use of a long-acting form of propranolol given once daily.  Side effects: not severe- Lethargy or depression may occur.  Hypotension, bradycardia, impotence, insomnia, and nightmares can occur.  Contraindication: patients having asthma severe depression  should be used with caution in patients using insulin or oral hypoglycemic agents, because it may mask the adrenergic symptoms of hypoglycemia.
  76. 76.  Propranolol  Timolol  Nadolol  Atenolol  Metoprolol
  77. 77.  Amitriptyline and other tricyclic antidepressants can be helpful in migraine prophylaxis.  Mechanism of action: Blockade of noradrenaline uptake at catecholamine terminals and inhibition of serotonin reuptake may be related, but the action of antidepressants in migraine is unclear at present.  The benefit seems to be independent of their antidepressant action.
  78. 78.  Drugs used:  Amitriptyline  Imipramine  Desipramine  Nortriptyline  Dosage : Amitriptyline 10 to 150 mg at night
  79. 79.  Morning drowsiness, dryness of mouth, weight gain, tachycardia, and constipation are common.  The anticholinergic side effects may decrease with time. If tolerated, give the tricyclic agents a trial of at least 3 months after reaching a therapeutic dose.  The optimal dose for migraine prophylaxis is determined by titration to the effective or maximum tolerated dose within the therapeutic range (usually 40-150 mg)
  80. 80.  Drugs used: verapamil, Flunarizine, sometimes Nimodipine  Prevent vasoconstriction  Prevent platelet aggregation and alterations in release and reuptake of serotonin.  Verapamil in doses of 80 to 160 mg 3 times a day reduces the incidence of migraine with aura, but it is not as useful in migraine without aura.
  81. 81.  Flunarizine is weak calcium channel blocker that also inhibits Na channels. Frequency of attacks are reduced, but effect on intensity and duration is less documented.  It is claimed to be cerebro-selective calcium channel blocker, may benefit by reducing intracellular calcium overload due to brain hypoxia and other causes.  Side effect: sedation, constipation, dryness of mouth, hypotension, flushing, weight gain, rarely extra- pyramidal symptoms.
  82. 82.  Their mechanisms of action in migraine prophylaxis are unknown.  Valproic acid, given in the form of divalproex sodium, is generally effective at a range of 500 to 1750 mg/day taken in divided doses.
  83. 83.  Side effect:  Sedation, dizziness, increased appetite, increased bleeding time, increased fragility of hair, and an asymptomatic increase in liver function test values.  Contraindication:  women who are at risk for becoming pregnant, because it is associated with an increased risk for neural tube defects.
  84. 84.  Gabapentin is effective in the reduction of migraine incidence (Mathew et al., 2001)  It appears relatively well tolerated, although dizziness and sedation may limit its use in some patients.  The usual therapeutic dose range for gabapentin is 900 to 2400 mg/day.
  85. 85.  Topiramate is a recent addition to the antimigraine.  Topiramate has effects not only on γ-aminobutyric acid (GABA) but also on non-NMDA glutamate and carbonic anhydrase activity.  Side effects :It may have prominent sedating and cognitive side effects. paresthesia and weight loss, mildly increased risk for kidney stones.  Slow gradual titration of the drug (15-25 mg/wk initially) to the therapeutic range of 75 to 200 mg/day the most successful strategy.
  86. 86.  Cyproheptadine is a peripheral serotonin antagonist. It has weak anti-bradykinin activity and prevents platelet aggregation.  In adults, it has a minor role in prevention of migraine, but it is more effective in children.  Side effect:-it causes drowsiness  significant weight gain.
  87. 87.  Riboflavin administered orally in a dose of 400 mg/day has been shown to be effective in migraine prophylaxis in a prospective randomized controlled study
  88. 88.  Till date BTX-A is available with good amount of thrapeutic trial, BTX-B and BTX-F are also expanding the horizon  Causes chemo-denervation, muscle paralysis, interferes with the release of acetylcholine from the presynaptic terminal  Muscle paralysis from BTX-B was not as complete or long-lasting as that from BTX-A  Patients resistant to BTX-A often initially respond to BTX-B
  89. 89. Onabotulinumtoxin A injection exert its effect by reducing the release of proinflammatory and vasodilating neuropeptides from nociceptive terminals. Botulinum toxin blocks the release of glutamate from nociceptive terminals and therefore may reduce or inhibit the development of peripheral and central trigeminal sensitization. Doses of approximately 150 units are injected in muscles of the forehead, as well as the temporalis, splenius capitis, and trapezius. The effect, when it occurs, usually appears within 7 to 10 days and persists for up to 3 months. Side effects are minimal when avoiding lateral forehead injection.