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Migraine and Tension-Type Headache: NOT Two Ends of a Spectrum! Gary W. Jay, MD, DAAPM, FAAPM


Disclosures  Consultant/Independent Contractor: INC Research, LLC  President Elect: The Eastern Pain Association


Learning Objectives  Identify the pathophysiology of migraine and tension-type headache  Describe the various forms of migraine and tension-type headache  Differentiate the various migraine and tension-type headache treatment alternatives  Review various Central aspects which combine to produce chronic headache and pain diatheses


Epidemiology-1  In the USA, > 30 M people have 1 or more migraine headaches/year – 18% of females and 6% of males1

 Migraine accounts for 64% of severe headaches in women and 43% in males  Approx. 75% of all people who experience Migraine are women – 1 in 6 American women has migraine • 1.Lipton, et al, Neurology, 2002.


Epidemiology-2  Incidence of migraine with aura peaks in boys at about 5 YOA, and in girls about 12-13 YOA – Incidence of Migraine without aura peaks in boys at age 10-11, in girls at age 14-171

 Prior to puberty, both prevalence and incidence of migraine are higher in boys than girls – After 12 YOA, prevalence increases in both males and females, peaking at 3040 YOA

 Female to male ratio increases from 2.5:1 at puberty to 3.5:1 at 40 YOA2 • 1. Stewart et al, Am J Epidem, 1991; • 2. Hsu et al, Cephalalgia, 2011.


Epidemiology-3  Decreased attack severity and frequency after menopause  Onset post 50 YOA is rare, but can begin after 60


Migraine Classification-1  Migraine without aura (Common migraine)  Probably Migraine without aura  Migraine with aura (Classic migraine)  Probably migraine with aura  Chronic Migraine  Chronic migraine associated with analgesic overuse


Migraine Classification (Cont.)1  Childhood periodic syndrome that may not be precursors to or associated with migraine  Complications of migraine  Migrainous disorder not fulfilling above criteria  Hemicrania Continua • 1. International Classification of Headache Disorders, 2nd Ed,, Cephalalgia, 2004.


IHS Criteria for Migraine without Aura (2004)  Migraine without aura (about 75-80% of migraine) is formally diagnosed: At least five lifetime attacks that fulfill the following: The Headache must have two of the following four characteristics: – Moderate to severe intensity – Throbbing quality – Unilateral – Aggravated by Activity – IN ADDITION, at least one of the following two: – Nausea and/or vomiting – Photophobia and phonophobia


IHS Criteria for Migraine with Aura (2004)  15-20% of migraine attacks  Different from Migraine without aura by the presence of – Period of local neurological symptoms preceding the headache, including: • Visual, sensory or speech symptoms • Visual symptoms may include scotoma or seeing zig-zag lines: • Sensory auras may be numbness or tingling in the face or fingers • There may also be speech difficulties


New Appendix Criteria for Chronic Migraine (2004)  Headache (tension-type or migraine) on 15 or more days/month for at least 3 months  Headache occurring in a patient who has had at least five IHS migraine attacks  On 8 or more days/months, if the headache have fulfilled – IHS criteria for migraine or are – Treated and relieved by triptan/ergot before the expected development of symptoms fulfilling IHS migraine criteria – No Medication overuse headache (MOH) as defined by IHS 8.2


Chronic Migraine and MOH-1  Contradiction in definition, as some define development of chronic migraine by the intake of analgesic or vasoconstrictor medications  Overuse of symptomatic medication is considered one of the most important risk factors for migraine progression: – Opiates- critical dose of exposure is around 8 days per month, in men>women – Barbiturates- critical dose of exposure is around 5 days per months, in woman>men – Triptans-Migraine progression seen in patients with high frequency of migraine at baseline (10-14d/mo)1


Chronic Migraine and MOH-2  Effect of NSAIDs varied with headache frequency, induced migraine progression in patients with a high baseline frequency of headaches1  It was noted that medications containing barbiturates or opioids are associated with a twofold increased risk for progression to transformed migraine.  In patients with episodic migraine, the annual incidence of transformed migraine was 2.5% • 1. Bigal, Neurology, 2008.


New Appendix Criteria for MOH (IHS, 2004)    

Headache present on 15 or more days/mo Regular overuse for three months of more of acute medication as defined in IHS 8.2 Headache has developed or markedly worsened during medication overuse MOH Duration definition: – Intake on a regular basis for three months or more – On 10 or more days/months, the patient takes: • • • •

Opiates Combination analgesics Triptans Ergots

– On 15 or more days/mo, the patient takes simple analgesics


Chronic Migraine and MOH-3  Treating chronic migraine: Diener suggested counseling followed by Topiramate or OnabotulinumtoxinA, and then admission to a detoxification program if necessary.1 – He felt that counseling would be sufficient in 50% of patients

 Jay notes treatment with the Raskin protocol in an interdisciplinary Headache Center is appropraite2 • 1. Diener, , 53rd Annual Scientific Meeting, AHS, 2011; • 2. Jay, HEADACHE HANDBOOK, CRC Press, 1999.


A “Stop the presses” Moment  Broussard (Am J Obstet Gynecol, 2011) indicates that the use of opioid analgesics, including codeine and hydrocodone, just before or during early pregnancy leads to a greater risk for birth defects. – Their Study included more than 17,000 infants with birth defects whose mothers reported whether they had taken therapeutic opioid analgesics in any dose, duration or frequency during one month prior to pregnancy and the first trimester • 454 (2.6%) reported opioid analgesic treatment • Statistically significant associations were found between opioid use and septal defects, pulmonary valve stenosis, hypoplastic left heart syndrome and tetrology of Fallot


Not in the IHS Information  Children who experience physical and emotional abuse or neglect are more likely to have migraines and headaches as adults

– “Dose response relationship between abuse and headache” – Growing evidence that genes are involved in either increased vulnerability or resilience in response to early stressful experiences • 1. Buse, 4th Annual Headache Cooperative of the Pacific, 2011; • 2. Tietjen GE et al, Headache, 2010.


Migraine Phases  Premonitory symptoms (prodrome)  Aura  Headache  Resolution  Postdrome – Not every attack has or every patient has all phases


Prodrome  Up to 80% of migraineurs  Begins 24 hours prior to headache1  Symptoms include fatigue, yawning, change in appetite, increased energy, frequent urination, difficulty with memory, cold hands, irritability, loss of concentration, hyper/hypo-sexuality (Typically ANS)  If recognized, treatment can begin soon after the onset of headache2 • 1. Cady, Headache, 2004; • 2. Luciani et al, Cephalagia, 2000.


Headache -1  Lasts 4-72 hours in adults  Pain can begin mild, diffuse, and become mod to severe  Associated symptoms- nausea, vomiting, sonophobia and photophobia  BEGIN TREATMENT EARLY • 1. Schoenen, Biomed Pharmacother, 1996; • 2. Lipton et al, Neurology, 2002.


Headache -2  When the migraine becomes severe, some patients may develop allodyniacephalgic (hair hurts) and/or extracephalgic – The allodynia comes soon after the onset of headache

 The chest, extremities and back muscles may become tender  This suggest central sensitization- a physiological state in which central neurons transmit noxious sensory signal independent of sensory signals from the periphery1 • 1. Aurora et al, Headache, 2007.


Headache -3  Guy et al (Cephalalgia, 2010) found that modalities of cephalic and extracephalic cutaneous allodynia (CA) were different, with extracephalic CA being mostly thermal, while cephalic CA was mostly mechanical, suggesting different mechanisms for the two  Whether a patient shows signs of CA is a predictor of whether or not that patient can become migraine pain free with triptan treatment – Need for NSAIDs preceding triptans if CA exists1

• 1.Burstein, Clinical Neurology News, 2008.


Postdrome  Post headache, many patients experience “hang-over” type symptoms: cognitive difficulties, dizziness, fatigue and concern that the headache may recur  The postdrome may last 24-48 hours

• 1. Burstein et al. Brain, 2000.


Aura’s indicating need for full neurological workup1  Motor symptoms\hemiplegic aura  Brain symptoms: severe dysarthria, vertigo, syncope, bilateral sensory definition  Prolonged aura: Greater than 60 mins  Atypical aura

– Alice in Wonderland: hallucinatory, changes in perception of space and time – Migralepsy: seizure associated with migraine • 1. Cady, in Jay, 2009.


Migraine and Epilepsy-1  Patients with one disorder are at least twice as likely to have the other1  In the Epilepsy Family Study, 44% reported physician diagnosed migraine, higher than the general population  In another study, 14% of adult patients with seizures with identified diagnosis of migraine, along with migraine induced seizures in 1.7%2

– Some of these patients had better treatment results with a combination of antimigraine meds and ACMs • 1. Silberstein and Lipton, Elsevier, 2002; • 2. Velioglu et al, Cephalalgia, 1999.


Migraine and Epilepsy-2  A genetically determined dysfunction of ion channels (calcium, sodium/potassium) seems to point to a common underlying mechanism for both paroxysmal disorders1 – Mutations in the three known genes for familial hemiplegic migraine can cause epilepsy

 Alterations of cortical hyperexcitability as a possible pathological mechanism underlying the onset of migraine and epileptic attacks has been noted2 • 1. Haan et alo, Cephalalgia, 2007; • 2. Piccinelli et al, Headache, 2006.


Pathophysiology-1  Neurovascular Theory

– Migraine is primarily a neurogenic process with secondary vascular changes (via CSD)1 – Interictal migraineur has a state of neuronal hyperexcitability in the cerebral (primarily occipital) cortex- demonstrated via fMRI2 • Patients with Epilepsy have similar interictal neuronal irritability • Explains increased susceptibility of the migrainous brain to headaches3 • 1. Cutrer, Headache, 2008; • 2. : Waeber, et al, Neurology, 2003; • 3. Welch, Neurology, 2003.


Migraine Brain  The brain of the migraineur is genetically more excitable and more vigilant than the brain of an person without migraine1,2  The brain of a migraineur doesn’t extinguish sensory stimuli as rapidly or as completely as the brain of those without migraine3,4  fMRI of 12 patients with migraine vs. 12 healthy controls showed pts with migraine, but not controls, had highly significant hypoactivity in the nucleus cuneiformis5 – Part of a descending processing pathway for pain signals • • • • •

1. Schoenen, Neurol Sci, 2006; 2. Coppola et al, Cephalalgia, 2007; 3. Aurora et al, Headache, 2007; 4. Schoenen, Biomed Pharmacother, 1996; 5. Borsook, 50th Annual Scientific Meeting of the AHS, 2008.


Pathophysiology-2  1944 Leao- theory of cortical spreading depression (CSD) (J Neurophys) – Well defined wave of neuronal excitation in the cortical gray matter spreading from site of origin at ave. 4mm/min (2-6mm/sec) – Ensuing cellular depolarization causes the primary cortical phenomenon (Aura Phase) • Basis is release of potassium or glutamate from neural tissue, which depolarizes adjacent tissue, which releases more neurotransmitters, propagating the CSD


Pathophysiology-3  PET scans show moderately reduced blood flow during a migrainous aura, but the spreading oligemia does not correspond to specific vascular territories1

– The flow is reduced secondary to reduction in metabolism – CSD presumably induces clinical manifestation of migraine aura, the spreading oligemia can be clinically silent (migraine without aura: CSD may not be involved in Migraine without aura1,2) • 1. Yokota et al, J Cereb Blood Flow and Metab, 2002; • 2. Hauge et al, Lancet Neurology, 2009.


Pathophysiology- 4  Activation of the trigeminovascular system from CSD stimulates nociceptive neurons on dural blood vessels to release plasma proteins and algetic substances including CGRP, SP, VIP, and NKA

– This yields a sterile inflammatory state accompanied by continued vasodilation, increasing pain – Initial cortical hyperperfusion in CSD is partly mediated by release of trigeminal and parasympathetic neurotransmitters from perivascular nerve fibers, while delayed meningeal blood flow increase is mediated by a trigeminal-parasympathetic brainstem connection – Altered descending modulation in the brainstem may contribute to the headache phase of migraine, leading to a loss of inhibition or enhanced facilitation, resulting in trigeminovascular neuron hyperexcitability1 • 1. Moulton et al, PLoS One, 2008.


Molecular mechanisms of CSD  CSD up regulates genes: those encoding cyclo-oxygenase 2 (COX-2), tumor necrosis factor alpha and interleukin-1beta, gelanin and metalloproteinases  Activation of metalloproteinase causes leakage of the BBB, allowing potassium, nitric oxide, adenosine and other products released by CSD to reach and sensitize the dural perivascular trigeminal afferent endings1  Increased activity of matrix metaloproteinase-2 (MMP-2) is found in migraineurs2 • 1. Richter et al, Schmertz, 2008; • 2. martins-Oliveira et al, Clin Chim Acta, 2009.


A migraine Generator?-1  Thought to be the trigeminal Nucleus Caudalis  In animal models of migraine, a number of receptor systems mediating c-fos expression are within the trigeminal nucleus caudalis  Intracranial, unmyelinated c- and A delta- fibers of the of the trigeminal nerve transmit pain stimuli from the meninges to the trigeminal nucleus caudalis (Sp5C)  Peripheral nerve endings surround meningeal vessels (the trigeminovascular system) and contain neuroactive neuropeptides (CGRP, SP, NKA)  Activation of the trigeminovascular system promotes a meningeal sterile inflammatory response via the release of neuropeptides by peripheral endings.


A migraine Generator?-2  Orthodromic conduction along trigeminovascular fibers transmits information centrally with induction of immediate early c-fos genes within post-synaptic Sp5C neurons as a marker of stimulation of the TG  At least 10 receptors modulate c-fos expression in the Sp5C: 5-HT(1B), 5HT(1D), 5-HT(1F), 5-HT(2B), NK-1, GABA(A), NMDA, AMPA, class III metabotropic glutamate receptors and opioid mu receptors  C-fos expression is a marker of cephalgic nociception • 1. Mitsikostas, et al. Brain Res Brain Res Rev, 2001.


A migraine Generator?-3  CGRP, in animals and humans, shows the trigeminal ganglion and the trigeminal nucleus caudalis are likely to be sites of action of CGRP in migraine1-3  Immunohistochemical studies have detected 5-HT(1D) receptors in trigeminal sensory neurons, including peripheral projections to the dura and within the trigeminal nucleus caudalis and solitary tract while 5-HT(IB) receptors are present on smooth muscle cells in meningeal vessels.  These findings indicate that Triptans (selective 5-HT(1)) agonists decrease headache by abolishing neuropeptide release in the periphery and blocking neurotransmission by acting on second-order neurons in the trigeminocervical complex • • •

Lassen et al, Cephalalgia, 2002; 2. Sexton et al, Neuroscience, 1986; 3. Ma et al, Neuroscience, 2003.


Migraine Risk Factors1  Interleukins  Increased levels of C-reactive protein  Tumor necrosis factor (TNF-alpha) and adhesion molecules (markers of systemic inflammation)  Oxidative stress and thrombosis  Increased body weight, high blood pressure, hypercholesterolemia  Impaired insulin sensitivity  High homocysteine levels, stroke and coronary heart disease • 1. Hamid, Atherosclerosis, 2009.


Migraine Variants  Acephalgic Migraine  Hemiplegic Migraine  Basilar Migraine (Bickerstaff’s)  Childhood Periodic Syndromes  Retinal Migraine (Opthalmic, ocular)  Opthalmoplegic Migraine  Complicated Migraine  Migralepsy  Acute Confusional Migraine  Vertiginous Migraine


Migraine with Prolonged Aura  Discussed  Aura >60 min needs full neurological workup


Acephalgic Migraine-1  An aura without headache  More common in older patients with a history of migraine with aura  Suspected in patients with history of recurrent attacks of unilateral transient monocular blindness in patients with otherwise absent risk factors for other causes of carotid disease and a personal/family history of migraine


Acephalgic Migraine-2  Symptoms may include:

– Scintillating scotomata, – Formed stereotyped visual hallucinations in a single visual field or bilaterally – Micropsia – Tunnel vision – Paroxysmal vertigo – Hemisensory dysesthesias – Auditory hallucinations

 Must be differentiated from transient ischemic attack, occipital lobe seizures or temporal lobe seizures1 • 1. Tomsak et al, Headache, 1987.


Hemiplegic Migraine-1  A history of recurrent transient hemiplegia or hemiparesis that occurs during a migraine attack  Patients may experience disturbance of consciousness and rarely coma1-3  Neurologic deficit is transient, clearing in minutes to hours, or resolves with the beginning of the headache4-6  Two main forms: Familial and Sporadic • • • • • •

1. Feely Et al, Acta Neurol Scand, 19+82; 2. Kors, et al, Neurology, 2004; 3. Spranger et al. Eur Neurol, 1999; 4. Benatar et al, Neurology, 2005; 5. Crawford, et al, Headache, 1997; 6. Koenderink et al. Bichim Biophys Acta, 2005.


Hemiplegic Migraine-2  Familial Hemiplegic Migraine – FHM is a genetically heterogeneous autosomal dominant disorder and channelopathy; most effected families have mutations on the CACNA1A gene (a defect linked to abnormal voltage-dependent P/Q type calcium channel alpha-1A) on 19p131-4 • In FHM type 2, mutation seen on ATP1A2 (R548H) on 1q23, encoding the alpha2-subunit of sodium/potassium pumps5,6 and FHM type 3 has a mutation in sodium channel gene SCN1A7

– Mutations on the CACNA1A and ATP1A2 regions can be detected – PET studies showed glucose hypometabolism in the contralateral perisylvian region early during a HM8 • • • • • • • •

1. Kraus et al, J Biol Chem, 2000; 2. Beauvais et al. Eur Neurol, 2004; 3. Melliti et al, J Physiol, 2003; 4. ophoff et al, Neurologia, 1997; 5. Jurkat-Rott et al, Neurology, 2004; 6. Marconi et al, Ann Meurol, 2003; 7 Vanmolkot et al, Hum Mutat, 2007; 8. Guedj et al, Headache, 2010


Hemiplegic Migraine-3  Sporadic Hemiplegic Migraine (SHM)- motor weakness in the absence of family history of similar attacks- linked to CACNA1A and ATP1A2 genes1

– Diagnosis is confirmed with repeated stereotyped reversible episodes esp. in the presence of a positive family history of similar attacks – Absence of first-and or second-degree relatives with similar disorder raises suspicion of SHM2 – Differential DX- focal seizures with postictal paralysis, mitochondrial cytopathies, intracranial hemorrhage, mass, infection or cerebral infarction3 • 1. Black, Curr Pain Headache Rep, 2004; • 2. Thomsen et al, Cephalalgia, 2004; • 3. Dora et al, Headache, 2001.


Hemiplegic Migraine-4  Alternating Hemiplegic Migraine- occurs in childhood (alternating hemiplegia of childhood- AHC)

– Is chronic progressive disorder, associated with high prevalence of neurological deficit1 – Differentiated from FHM by infantile onset and characteristic associated symptoms2 – Onset prior to 18 months3; characterized by vomiting, HA, alternating hemiplegia, LOC, paroxysmal ocular palsies, choreoathetosis, autonomic dysfunction and mental retardation4 – SPECT scans have progressive decrease of cerebral perfusion in AHM

• • • •

1. Haan et al, Cephalalgia, 2000; 2. Swoboda et al, Ann Neurol, 2004; 3. Lance, Cephalalgia, 2000; 4. Alsup et al, J Neurosci Nurs, 1991.


Hemiplegic Migraine-5  Treatment: – Acute- antiemetics, NSAIDs, non-narcotic pain meds – Don’t want to use vasoconstrictors (Triptans, ergots) – Prophylaxis: beta blockers, topiramate, CA channel blockers and other ACMS


Basilar Migraine-1  Bickerstaff’s syndrome or migraine  Present with symptoms of vertebrobasilar insufficiency which may precede a HA – Most common- dizziness and vertigo, but also HA with ataxia, tinnitus, decreased hearing, N&V, diplopia, loss of balance, bilateral paresthesias or paresis, altered consciousness, syncope1 – Mostly found in adolescent girls and young women2 • 1. Kuhn et al, Eur J Emerg Med, 1997; • 2. Lapkin et al, Am J Dis Child, 1978.


Basilar Migraine-2  Localized vertebrobasilar vasoconstriction leading to transient posterior circulation ischemia1  Novel mutation of the ATP1A2 gene has been found in one family  Diff Dx- various causes of syncope, inner ear disease, intoxication and posterior fossa pathology2 • 1. La Spina, Headache, 1997; • 2. Evans, Headache, 2002.


Childhood Periodic Syndromes-1  Multiple cyclic attacks of pain or vomiting with or without migraine headaches- common in children and adolescents, common precursors to migraine when older  Cyclic Vomiting Syndrome – – – –

Recurrent attacks of violent or prolonged vomiting without headache, may last hours1,2 Suspect with family history of migraine Attacks may be precipitated by infection, menstruation, physical or emotional stress During attacks, other symptoms of migraine may be seen, including nausea, lethargy, yawning, drowsing, subtle clumsiness, attention deficit or developmental delay3

• • •

1. Crevits, et al, Clin Neurol Neurosurg, 2005; 2. Cupini et al, Headache, 2003; 3. Jay, CRC Press, 1999.


Childhood Periodic Syndromes-2  Secondary to abnormal activity in area postrema  Gastroparesis, occurring during migraine, may also be an etiological factor for cyclic vomiting and abdominal migraine1,2  Preclude mitochondrial disorders (lactate levels)  Early use of IV fluids and analgesic medications – Some respond to triptans or ergotamine – Antiemetics usually not effective – Prophylactic meds : cyproheptadine and TCAs best for children3 • 1. Li Bu, Semin Pediatr Neurol, 2001; • 2. Olson et al, J Pediatr, 2002; • 3. Jay, CRC Press, 1999.


Childhood Periodic Syndromes-3  Abdominal Migraine – Typically occurs in children, seen in adults1 – Paroxysmal midabdominal pain lasing from 1 to 72 hours, associated with N&V, flushing or pallor – May be associated with other migraine prodromes- fatigue and drowsiness – Aura and HA absent or minimal – These children may show subtle clumsiness, attention deficit or developmental delay2

• 1. d’Onofrio et al, Eur J Neurol, 2006; • 2. Jay, CRC Press, 1999.


Childhood Periodic Syndromes-4  May develop migraine late in life, family history of migraine is common  Usually relieved by sleep  Antiemetic's may help abort an acute attack  Prevention- low doses of TCA and/or flunarizine (calcium channel blocker)1-3 • 1. Catto-Smith et al, Semin Pediatr Surg, 2003; • 2. Kothare, Eur J Paediatr Neurol, 2005; • 3. Jay, CRC Press, 1999.


Retinal Migraine-1  Also called opthalmic or ocular migraine, is not an uncommon cause of transient monocular blindness in young adults1  Recurrent attacks of unilateral visual disturbance or blindness lasing minutes to an hour, associated with minimal to no HA – Must rule out amaurosis fugax (ischemia of retinal arteries)2,3 • 1. Blau, et al, Lancet, 1993; • 2. Grosbergg et al, Curr Pain Headache Rep, 2005; • 3. Jay, CRC Press, 1999.


Retinal Migraine-2  Described as gradual visual disturbance in a mosaic pattern of scotomata that gradually enlarges, yielding total unilateral visual loss  Postural changes, exercise and oral contraceptives may precipitate attacks  May result from transient vasospasm of the choroidal or retinal arteries  Personal or family history of migraine confirms the DX  R/O carotid artery disease  Avoid vasoconstrictors, use prophlactics, ie, calcium channel blockers1-3 • 1. Appleton et al, Am J Dis Child, 1988; • 2. Killer et al, Retina, 2003; • 3. Jay, CRC Press, 1999.


Opthalmoplegic Migraine-1  Rare, predominantly in children, characterized by a migraine-like attack followed within days by periorbital pain and diplopia secondary to cranial neuropathies- HA may or may not be present.  The Oculomotor nerve most commonly involved, with ptosis and pupillary involvement followed by abducens nerve and rarely the trochlear nerve involvement – Other symptoms include alteration of consciousness, acute confusion, recurrent vomiting or seizures, – The attack lasts from days to months, spontaneously resolves – Has been seen in adults1-4

• • • •

1. Ferrante, Cephalalgia, 2006; 2. Weiss et al, Pediatr Neurol, 2004; 3. Lee, et al, Headache, 2002; 4. Jay, CRC Press, 1999.


Opthalmoplegic Migraine-2  Now classified as a neuralgia by the International Classification of Headache Disorders (IHCD)-II  Possibly secondary to recurrent demyelinating cranial neuropathies  DDx includes problems involving the parasellar, orbital and posterior fossa leading to HA and opthalmoplegia1-3  Prednisone used with mixed results, ? Benefit of prophylactic medications • 1. Doran et al, J Neurol, 2004; • 2. Levin et al, Curr Pain Headache Rep, 2004; • 3. Jay, CRC Press, 1999.


Complicated Migraine-1  Complications may include: – Chronic migraine – Status migrainosis – Persistent aura without infarction – Migrainous infarction – Migraine-triggered seizure

 These complications are rare (<1%) of migraineurs1 • 1. Tourbah et al, Headache, 1988.


Complicated Migraine-2  Persistent Aura – An aura lasting > 60min, even hours or days • With not radiographic evidence of CVA, you have a migraine with persistent aura


Complicated Migraine-3  Migrainous Infarctions

– Migraine with aura is associated with the presence of silent infarctions or white matter changes on MRI1 – When a CVA occurs during a typical migraine with aura attack, term “migrainous infarction” is used – Don’t know if Migraine and stroke have the same underlying etiologies or similar ischemic factors, or migraine is associated with other conditions that can cause CVA.2,3 – Don’t use vasoconstrictors- use NSAIDs, nonnarcotic pain meds- prophylactic meds are important • (ACMs, beta-blockers, calcium channel blockers)

• 1, Gladstone et al, Neurologist, 2005; • 2. Agostoni et al, Neurol Sci, 2006; • 3. Jay, CRC Press, 1999.


Migraine and Stroke-1  Inflammatory biomarkers link migraine to stroke in young women

– Inflammatory cytokines IL-6, TNF-alpha and transforming growth factor beta 1 are all elevated in young women with migraine and these levels correlate with headache frequency, BMI and high sensitivity Creactive protein – These markers of endothelial activation- inflammatory and coagulation biomarkers- were elevated in premenopausal migraineurs interictally, compared to a control group, suggesting a role in endothelial dysfunction in migraine-related stroke – “Migraine is a risk factor for stroke in young women”1 – Migraine is associated with an inflammatory state that occurs between headaches but it also appears to be related to headache frequency

1. Tietjen et al, Stroke, 2009.


Migraine and Stroke-2  Migraine with aura is a risk factor both for cardiovascular mortality and for all cause mortality1

– Among the migraine with aura group, hazard ratios for cardiovascular mortality and allcause mortality were 1.27 NS 1.21 respectively compared to the non-headache group. • The migraine with aura group’s hazard ratios for coronary heart disease and stroke were 1.28 and 1.40 respectively compared to a non-headache group • Possible mechanism for the link between migraine and CV disease include a genetic component, ischemic events caused directly by migraine and “the hypothesis that migraine might be a systemic disorder that is affecting vasculature” • 1. Gudmundsson et al, BMJ, 2010


Migraine and Stroke-3  Blood vessel microemboli appear to be a potential source not only of ischemia and stroke, but also of migraine with aura1  On this continuum, one may develop a stroke on the severe end, and on the other end, migraine with aura – TIAs may reside in between

 Cortical Spreading Depression may be triggered by microemboli that become stuck in blood vessels just long enough to depolarize the surrounding tissue  Moskowitz et al (Lancet Neurol, 2010) propose that a subpopulation of migraine with aura patients exhibits a transient, regional, hypoperfusion syndrome, which appears to cause local hypoxia, the disruption of ionic gradients and local depolarization that then propagates (CSD)


Complicated Migraine-4  Migralepsy

– Migraine and epilepsy are comorbid conditions, but nature of relationship is unclear- ? Hyper-irritable CNS1 – Migralepsy- migraine triggered seizures, when a seizure occurs during or within an hour of a migraine with aura attack – ? Supratentorial focal cerebral edema seen on MRI: EEGs typically normal, interictally, but migraineurs may have diffuse slowing2 – ACMs best treatment • 1. Milligan et al, Epilepsia, 2005; • 2. Mateo et al, Headache, 2004.


Complicated Migraine-5  Acute Confusional Migraine

– Rare, almost exclusively in young children – Disorientation, episodes of confusion, vomiting, with or without headache1,2 – Relieved by sleep – Transient global amnesia may be related2,3 – DDx- seizures, various causes of confusion (toxic, metabolic, mitochondrial, infectious encephalopathies) – Prophylactic therapies best • 1. Nezu et al, Brain Dev, 1997; • 2. Sheth et al, Pediatr neurol, 1995; • 3. Jay, CRC Press, 1999.


Complicated Migraine-6  Vertiginous Migraine

– Recurrent episodes of vertigo related to migraine1,2 – In 1/3 of headaches, lasts 5-60min

• +/- N&V, photophobia, HA in the setting of a personal or family history of migraine makes DX

– DDx- vertebrobasilar insufficiency and paroxysmal vestibular syndrome3 – Min/rare response of migraine prophy treatment, use drugs (TCAs) with anticholinergic aspects4

• • • •

1. Catto-Smith et al, Semin Pediatr Surg, 2003; 2. Thakar et al, J Laryngol Otol, 2001; 3. Kitamura et al, Auris Nasus Larynx, 1990; 4. Jay, CRC Press, 1999.


Complicated Migraine-7  Odds and Ends: – Benign Coital headache • Sudden onset (70%) just before, during or immediately post orgasm • Subacute, crescendo headache (25%) (starts prior to orgasm) • Postdural HA- least common, more likely to have N/V

– R/O organic causes- berry aneurism, etc. • Indomethacin, DHE, triptan two hours prior • Robert, About.com, 2003, accessed July 25.


Complicated Migraine-8  Exertional Headache1

– Adolescence through 50 YOA, occurs with lengthy exercise sessions, begins at the height of exercise and fades when exercise ends • Can last up to 2 days • Can have N/V, Photophobia and sonophobia

– Second to increased venous pressure in the CNS – Must R/O serous diagnosis – These patients typically have migraine or a family history of migraine • 1. Miles et al, Migraine.com, 2010, accessed July 25, 2001


Migraine Treatment-1  Acute – Triptans (5-HT1b/d/f) (Standard of care) – Ergots – DHE-45 – NSAIDs – (NSAID + Triptan) – NEW: Glial modulators (AV411, COL-144) • CGRP antagonists haven’t moved forward


Menstrual Migraine  Possibly more difficult to treat  Migraine prevalence increases in females during adolescence, in part doe to changing levels of estrogen and progesterone at puberty  In one study, menstrual-related headaches reported in 42.1% of subjects, and pure menstrual headaches observed in 3.4%  Treatment: Naproxen and frovatriptan (mini-prophylaxis)


Migraine Treatment-2  Prophylactic Medications – Topiramate – OnabotulinumtoxinA – Also used (terrible side effects): • TCAs • Calcium Channel blockers • Beta-blockers


Migraine Treatment-3  Behavioral Therapy – Cognitive Behavioral Therapy

 Biofeedback therapy  Acupuncture  Yoga – Not all inclusive CAM treatments


EBM Evidence â&#x20AC;&#x201C;based guideline update: Pharmacologic treatment for episodic migraine prevention in adults: Report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society Silberstein SD, Holland S, Freitag F, et al Neurology 2012; 78;1337

Note: 284 articles found, 29 classified as Class I or Class II Studies with completion rates below 80% were downgraded- several studies in the original guideline have been downgraded


April 2012 EBM Guidelines from APS and AAN1  Level A- medications with established efficacy (≥ 2 Class 1 Trials) – Antiepileptic Drugs

• Divalproex sodium • Sodium valproate • Topiramate

– Β-Blockers

• Metaprolol • Propranolol • Timolol

– Triptans (MRM) • Frovatriptan


April 2012 EBM Guidelines from APS and AAN2  Level B- Medications are probably effective (1 Class 1 or 2 Class II studies) – Antidepressants/SSRIs/SNRIs/TCA • Amitriptyline • Venlafaxine

– Β-Blockers • Atenolol • Nadolol

– Triptans (MRM) • Naratriptan • Zolmitriptan


April 2012 EBM Guidelines from APS and AAN3  Class-C: Medications are possibly effective (1 Class II study) – ACE inhibitors • Lisinopril

– Angiotensin Receptor Blockers • Candesartan

– Α- Agonists

• Clonidine • Guanfacine

– AEDs

• Carbamazepine


April 2012 EBM Guidelines from APS and AAN3a – β-Blockers • Nebivolol • Pindolol

– Antihistamines • Cyproheptadine


April 2012 EBM Guidelines from APS and AAN4  Level U: Inadequate or conflicting data to support or refute medication use – Carbonic Anhydrase Inhibitor • Acetazolamide

– Antithrombotics

• Acenocoumarol • Coumadin • Picotamide

– Antidepressants/SSRIs/SNRIs • Flovoxamine • Fluoxetine


April 2012 EBM Guidelines from APS and AAN4a – AEDs

• Gabapentin

– TCAs

• Protriptyline

– β- Blockers

• Bisoprolol

– Ca++ Blockers • Nicardipine • Nifedipine • Nimodipine • Verapamil


April 2012 EBM Guidelines from APS and AAN4B – Direct Vascular Smooth Muscle Relaxants • Cyclandelate


April 2012 EBM Guidelines from APS and AAN5  Other- Medications that are established ass possibly or probably ineffective – Established as not effective • AED

– Lamotrigine

– Probably not effective – Clomipramine

– Possibly not effective – – – – –

Acebutolol Clonazepam Nabumetone Oxcarbazepine Telmisartan


Tension-Type Headache


Tension-Type Headache (TTHA)  Most common primary HA disorder – Life time prevalence 98% in women and 89% in men

 Generally less debilitating than migraine acutely, can still induce significant disability  We’ve all pretty much had one!


Infrequent Episodic Tension-Type Headache  Description:  Infrequent episodes of headache lasting minutes to days. The pain is typically bilateral, pressing or tightening in quality and of mild to moderate intensity, and it does not worsen with routine physical activity. There is no nausea but photophobia or phonophobia may be present.  Diagnostic criteria:  At least 10 episodes occurring on <1 day per month on average (<12 days per year) and fulfilling criteria B-D  Headache lasting from 30 minutes to 7 days  Headache has at least two of the following characteristics: – bilateral location – pressing/tightening (non-pulsating) quality – mild or moderate intensity – not aggravated by routine physical activity such as walking or climbing stairs  Both of the following: – no nausea or vomiting (anorexia may occur) – no more than one of photophobia or phonophobia  Not attributed to another disorder International Classification of Headache Disorders, 2nd Ed,, Cephalalgia, 2004.


Infrequent episodic tension-type headache associated with pericranial tenderness  Diagnostic criteria:  Episodes fulfilling criteria A-E for 2.1 Infrequent episodic tension-type headache  Increased pericranial tenderness on manual palpation


Infrequent episodic tension-type headache not associated with pericranial tenderness  Diagnostic criteria:  Episodes fulfilling criteria A-E for 2.1 Infrequent episodic tensiontype headache  No increased pericranial tenderness  Comments:  Increased pericranial tenderness recorded by manual palpation is the most significant abnormal finding in patients with tension-type headache. The tenderness increases with the intensity and frequency of headache and is further increased during actual headache.


Frequent episodic tension-type headache  Description:  Frequent episodes of headache lasting minutes to days. The pain is typically bilateral, pressing or tightening in quality and of mild to moderate intensity, and it does not worsen with routine physical activity. There is no nausea but photophobia or phonophobia may be present.  Diagnostic criteria:  At least 10 episodes occurring on ≥1 but <15 days per month for at least 3 months (≥12 and <180 days per year) and fulfilling criteria B-D  Headache lasting from 30 minutes to 7 days  Headache has at least two of the following characteristics: – – – –

bilateral location pressing/tightening (non-pulsating) quality mild or moderate intensity not aggravated by routine physical activity such as walking or climbing stairs

 Both of the following:

– no nausea or vomiting (anorexia may occur) – no more than one of photophobia or phonophobia

 Not attributed to another disorder


Chronic tension-type headache  Description:  A disorder evolving from episodic tension-type headache, with daily or very frequent episodes of headache lasting minutes to days. The pain is typically bilateral, pressing or tightening in quality and of mild to moderate intensity, and it does not worsen with routine physical activity. There may be mild nausea, photophobia or phonophobia.  Diagnostic criteria:  Headache occurring on ≥15 days per month on average for >3 months (≥180 days per year)1 and fulfilling criteria B-D  Headache lasts hours or may be continuous  Headache has at least two of the following characteristics: – – – –

bilateral location pressing/tightening (non-pulsating) quality mild or moderate intensity not aggravated by routine physical activity such as walking or climbing stairs

– –

no more than one of photophobia, phonophobia or mild nausea neither moderate or severe nausea nor vomiting

 Both of the following:

 Not attributed to another disorder2;3  Notes:  2.3 Chronic tension-type headache evolves over time from episodic tension-type headache; when these criteria A-E are fulfilled by headache that, unambiguously, is daily and unremitting within 3 days of its first onset, code as 4.8 New daily-persistent headache. When the manner of onset is not remembered or is otherwise uncertain, code as 2.3 Chronic tension-type headache.


Chronic tension-type headache associated with pericranial tenderness  Diagnostic criteria:  Headache fulfilling criteria A-E for 2.3 Chronic tension-type headache  Increased pericranial tenderness on manual palpation


Chronic tension-type headache not associated with pericranial tenderness  Diagnostic criteria:  Headache fulfilling criteria A-E for 2.3 Chronic tension-type headache  No increased pericranial tenderness


The Importance of Muscle ď&#x201A;§ Note pericranial muscle tenderness plays a significant diagnostic role ď&#x201A;§ Pericranial muscle tenderness may have multiple etiologies, but arises most commonly secondary to the myofascial pain syndrome


Myofascial Pain Syndrome- MPS-1 ď&#x201A;§ The contribution of muscle to the etiology of tension-type headache was given more credibility by the discovery of Trigger Points (TRPs), small zones of hypersensitivity in muscles of the head, neck and back of headache patients


MPS-2 ď&#x201A;§ When a TRP is palpated, pain may be referred, or spread, to adjacent or even distant sites on the head. Palpation may also elicit tinnitus, vertigo and lacrimation


MPS-3 ď&#x201A;§ Clinically, the MPS characteristically involves a localized or regional pain complaint associated with tender trigger points located in taut bands of skeletal muscle


MPS-4  Trigger points may be: – ACTIVE, with reproducible pain on palpation – LATENT, without clinically associated complaints of pain • May produce muscle dysfunction without pain • TRPs may shift between active and latent


MPS-5  Muscles with TRPs have: – Increased stiffness – Fatigability – Weakness – Restricted range of motion


MPS-6  These muscles may be shortened with increased pain on stretching  Patients may protect the muscle by adopting poor posture and sustained contraction  These muscle restrictions may perpetuate existing TRPs and aid in the development of other TRPs in the same muscle as well as in its antagonists and other agonist muscles


Trigger Point- Pathophysiology-1 ď&#x201A;§ Clusters of multitudes of microscopic, abnormal loci scattered throughout a hypersensitive nodule, or TRP ď&#x201A;§ The primary abnormality is a neuromuscular dysfunction found at the extrafusal skeletal muscle fibers


Trigger Point Pathophysiology-2  Myofascial pain with associated Myofascial trigger points (MTRPs) is a

Neuromuscular Disease


Trigger Point Pathophysiology-3 ď&#x201A;§ The primary dysfunction is an abnormal, excessive production and release of acetylcholine (ACh) from the motor nerve terminal under resting conditions


Trigger Point Pathophysiology-4 ď&#x201A;§ An abnormally high number of miniature endplate potentials induces both endplate noise (SEA- spontaneous electrical activity) AND sustained depolarization of the post junctional membrane of the associated muscle fiber


Trigger Point Pathophysiology-5 ď&#x201A;§ Sustained depolarization can induce continuous uptake and release of calcium ions from the associated sarcoplasmic reticulum, leading to sustained contractions (or shortening of the muscle sarcomeres)


Trigger Point Pathophysiology-6  These factors increase the sites’ energy demands  Constricted local blood vessels, compressed by sustained muscle fiber shortening (contracture) becomes unable to keep up with the effected regions’ oxygen and nutrient demands


Trigger Point Pathophysiology-7 ď&#x201A;§ An Energy Crisis occurs, as increased energy demands occur in a region with an impaired energy supply


Trigger Point Pathophysiology-8  This leads to the release of sensitizing, algetic substances that effect: – Autonomic – nociceptive – non-nociceptive sensory nerves

in the region


Trigger Point Pathophysiology-9 ď&#x201A;§ Local nociceptive sensitization leads to spinal cord dorsal horn sensitization with continuous nociceptive impulses being sent rostrally


Trigger Point Pathophysiology-10 ď&#x201A;§ Over time, continued release of neuroactive, algetic substances can in turn contribute to continued excessive release of ACh from the nerve terminal ď&#x201A;§ Thus develops a self-sustained cycle of continuous energy crisis, release of algetic substances and release of ACh


Trigger Point Pathophysiology-11 ď&#x201A;§ Spinal cord sensitization, over time, also becomes self sustaining secondary to continuous peripheral nociceptive information received from the MTRPs


MPS-7 ď&#x201A;§ Myofascial structures refer pain in reproducible patterns specific for a particular myofascial trigger point


MPS-8  Some commonly referred muscle pain patterns associated with TRPs of the head and neck:  Masseter Muscle--> Pain deep in the ear  Temporalis Muscle--> Normal teeth of the upper jaw and causes unilateral temporal headache  Lateral Pterygoid--> TMJ region


MPS-9 ď&#x201A;§ TRPs in the upper Trapezius, Sternocleidomastoid, Splenii and Suboccipital muscles characteristically refer pain to the head


MPS-10 ď&#x201A;§ Upper Trapezius muscle--> ipsilaterally over the back of the head, including onto the temporal region ď&#x201A;§ SCM (Sternal Division)--> Pain surrounding the eye, at the vertex and occiput; also associated with autonomic dysfunction including lacrimation and ipsilateral scleral injection


MPS-10a  SCM (Clavicular Division) --> “Muscle contraction Headache”, and postural dizziness


MPS-11  The MPS of the head and neck may be associated with other clinical problems in relationship to referred pain from TRPs; these signs and symptoms may mimic: – Migraine Headache – TMJ Dysfunction – Sinusitis – Cervical Neuralgias


MPS-11a ď&#x201A;§ Otological problems- Tinnitus, Vertigo, dizziness, ear pain


Treatment of Acute and Chronic Tension-Type Headache  Abortive Medication (Keep MOH Firmly in mind- DO NOT USE OPIOIDS!)  First Line:

– Aspirin (500-1000 mgs PRN) – Acetaminophen (1000mg PRN- never more than 3000 mgs/24 hrs)

 Second Line

– Diclofenac (12.5-25 mg PRN) – Naproxen sodium (350mg PRN) – Ibuprofen (400mg PRN)

 As patients state: Relaxation and a glass of wine!


Treatment of Acute and Chronic Tension-Type Headache  EBM based Prophylactic Therapy  First line – Amitriptyline (10-100 mgs QHS) – Tizanidine (24 mg QD)

 Second Line – Mirtazepine (15-30 mg/day)


Non-Drug Treatment of Acute and Chronic Tension-Type Headache  Physical therapy to break down myofascial trigger points – To establish a home exercise program for the patient

 May need selective trigger point injections done with lidocaine or benzocaine, to be followed by physical therapy within 3 hours  Biofeedback enhanced neuromuscular re-education and muscle relaxation (EMG)


Chronic Pain and Depression  There exists bidirectional facilitatory and inhibitory processes responsible for: – Allodynia – Hyperalgesia – Pathologic involvement of the sympathetic NS – Persistence of pain after the reduction or cessation of activity in nociceptive afferents


Limbically Activated Pain Disorder (LAPD) ď&#x201A;§ The clinical manifestation of corticolimbic sensitization induced by non-epileptogenic kindling mechanisms in the supraspinal structures that subserve both nociceptive processing and affective regulation


LAPD-2 ď&#x201A;§ Neuroplasticity (with processes which transduce interoceptive and exteroceptive stimuli into cellular memory) has been studied using models of kindling â&#x20AC;&#x201C; A generic term referring to a set of stimulus-induced neuroplastic mechanisms that modify neuronal membrane functions, intracellular messenger systems, synaptic activity and microscopic neuroanatomy of the CNS.


LAPD-3  Neuroplasticity has been studied with: – Models of kindling – Partial kindling – Long-term potentiation (LPT) – Long-term depression (LTD) – Behavioral sensitization – Time-Dependent sensitization (TDS)


LAPD-4  Kindling is one model for nociception-induced neuroplastic changes that develop in the limbic system and other supraspinal structures (corticolimbic sensitization) and can produce a clinical picture of: – Persistent pain – Affective dysregulation – Behavioral disturbance


LAPD-5 ď&#x201A;§ Neurobiologic evidence and clinical observations suggest that nociceptive/chronic pain disorders and emotional/affective disorders have important similarities in clinical phenomenology, pharmacologic treatments and neuroanatomic loci, as well as in their molecular substrates


LAPD-Info ď&#x201A;§ Low levels of mu-opioid receptor binding in the limbic system is associated with stronger than normal responses to emotional stimulation â&#x20AC;˘ Liberzon; Proc Natl Acad Sci USA 2002:99:7084


LAPD-6  Kindling mechanisms have been considered in the pathophysiology of : – Migraine – Trigeminal neuralgia – Other Painful conditions – Recurrent depression – Bipolar illness – PTSD – Drug Addiction


LAPD-7  Distinguishing Features: – Alterations in pain perception that are chronic, often atypical – Resistant to analgesic treatments – Associated with disturbances of mood, sleep, energy, libido, memory/concentration, behavior – Stress intolerance


LAPD-8 ď&#x201A;§ Physical elements of nociception are brought anatomically via spinothalamic projections through both the medial and lateral aspects of the thalamus, and from there, the nociceptive information from the medial aspects of the thalamus co-mingle with elements of the limbic and paralimbic systems


LAPD-9  This invokes or stimulates “neural circuitry” or “neural nets” formed from past experiences which can then “flavor” the new pain problem, with the addition of CORTICOLIMBIC SENSITIZATION, involving the sensory, affective and behavioral aspects of their pain


One Problem- Many Aspects ď&#x201A;§ All chronic pain and headache also needs to be looked at by biological/psychological/ sociological aspects- the LAPD can help to put this into perspective (biolog/psychol- esp. learned)


Migraine and Tension-Type Headache: Not Two Ends of a Spectrum!