Embed Size (px)
Citation preview
Migraine PathophysiologyA Clinical Perspective
Learning Objective
After completing this activity, the participant should be better able to:
Differentiate trigeminovascular pathways and brain regions associated with migraine symptoms
Explain central and peripheral processes involved in migraine pathophysiology
2
Overview
The genesis of aura is cortical spreading depolarization (depression) [CSD]
Migraine pain can occur with or without aura
The phases of migraine correspond to different brain area changes seen on functional imaging
Targeted anti‐CGRP and anti‐CGRP receptor monoclonal antibodies offer new levels of efficacy, tolerability, and adherence for migraine prevention
3
4
Dodick and Silberstein, Migraine. (graphic from the WSJ)
An inherited neurological disorder characterized by neurological, sensory, autonomic, vestibular, cognitive, and gastrointestinal symptoms
Why Is Pathophysiology of Migraine Important From a Clinical Perspective?
Understand biology/underlying symptoms
Understand rationale/implications for therapeutic targets/strategies
Disease education/patient counseling
5
Lancet 2012; 380: 2197–223
Migraine Is Inherited
Monogenetic
Polygenetic
6
Migraine Is a Widespread Neurologic Disorder, Associated With Heavy Patient Burden and Social Stigma
Prevalence
Burden
Stigma
Headache disorders account for the 3 most prevalent neurologic disorders worldwide, including: Tension-type headache (1.5 billion) Migraine (958.8 million) Medication overuse headache (58.5 million)
Collectively, these disorders contribute ~17% to the global burden of neurologic diseases
Responsible for substantial proportion of the global nonfatal disease-related burden 5th most burdensome condition worldwide 2nd most disabling neurologic disorder
Patients with headache have been stigmatized by: Healthcare Professionals: View them as drug seekers with a nonserious disease Family and Friends: Fail to appreciate their suffering Educators, Employers, and Insurers: Believe headache should not lead to performance
decrements Policymakers: Consistently underfund research into emerging treatments for migraine
World Health Organization. Global Health Estimates 2015: disease burden by cause, age, sex, by country and by region, 2000-2015. Geneva, 2016. http://www.who.int/healthinfo/global_burden_ disease/estimates/en/index2.html. Accessed August 15, 2018; GBD 2015 Neurological Disorders Collaborator Group. Lancet Neurol. 2017;16(11):877-897.
7
Migraine Genetics
Strong familial aggregation
Relative Risk (1.5‐3.8); Twin heritability 40%‐65% Complex disorder with environmental triggers
Migraine with aura and migraine without aura within same families and same individual
Comorbidity with several disorders (eg, depression, epilepsy) indicates potential shared genetic factors
8
Postdrome
Headache
Cutaneous Allodynia
HeadacheHeadache
The Phases of Migraine
Charles A. Migraine. N Engl J Med. 2017;377(6):553-561; Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition. (beta version). Cephalalgia. 2013;33(9):629-808..
Prodrome
Neck Pain, Fatigue, Mood Change, Light Sensitivity, Sound Sensitivity
Nausea
Aura
Visual Changes, Numbness/Tingling, Language Dysfunction, Cognitive Dysfunction, Brainstem Symptoms
9
Prodrome HeadachePhase
Postdrome
Headache
Time
Aura
30%75%
YawningPolyuriaDiarrheaFatigueDepressionNeck painPhotophobiaNausea
FatigueDepressionNeck painPhotophobiaNauseaAllodynia
Interictal Phase
FatigueDepressionNeck painPhotophobiaNauseaAllodyniaMild Headache DizzinessCognitive
The Phases of Migraine
10
Areas of Brain Activation During Premonitory Phase
Hypothalamus (very early): yawning, thirst, mood, craving
Periaqueductal gray: pain
Locus coeruleus: sensory modulation
Occipital cortex: photophobia
Nucleus tractus solitarius (NTS): nausea
11
Maniyar FH et al. Brain. 2014;137(Pt 1):232-241; Maniyar FH et al. J Headache Pain. 2014;15:84.
Premonitory Phase
HeadachePhase
Postdrome
Time
Aura
30%
Aura
12
Migraine Aura
Secondary to neuronal dysfunction Symptoms resemble those due to direct brain stimulation
May be due to spreading depression or its human homolog
13
Aura, CSD, and Spreading Hyperemia/Oligemia
14
Propagation:2 – 3 mm/min
Lashley: Spreading Aura
Silberstein SD et al. Headache in Clinical Practice. 2nd ed. Boca Raton, FL: Taylor & Francis Group, LLC; 2002. Republished with permission of ISIS MEDICAL MEDIA LIMITED, from Headache in Clinical Practice, Silberstein SD, Lipton RB, Goadsby PJ. 2nd ed. 2002; permission conveyed through Copyright Clearance Center, Inc.
Olesen: Spreading
Hyperemia/OligemiaLeão: CSD
CSD=cortical spreading depression.
Cortical Spreading Depolarization (Depression)
Hadjikhani N et al. Proc Natl Acad Sci U S A. 2001;98(8):4687-4692.
Cat Cortex
Courtesy of Parsons.
15
Cortical Spreading Depolarization (Depression) and Secondary Blood Flow Changes
Dodick DW, A phase-by-phase review of migraine pathophysiology, Headache, John Wiley and Sons. © 2018 American Headache Society. Reprinted with permission.
16
Dura
Trigeminal Ganglion
Trigeminal Cervical Complex (TCC)
Ophthalmic Division of Trigeminal Nerve
The Anatomy of Migraine Headache
17
What Causes Headaches?
1.Traction, tension, or displacement of pain‐sensitive structures
2.Distention or dilation of intracranial vasculature
3. Inflammation of pain‐sensitive structures
4.Obstruction of CSF pathways with consequent increased intraventricular pressure
5.Activation of peripheral nociceptors or pain centers in the brain
6.Activation of anatomical regions whose afferents converge onto trigeminal nucleus (neck, heart, sinuses, TMJ, pericranial muscle, lung apex)
18
The Anatomy of Migraine Headache
19
Au=auditory; CGRP=calcitonin gene-related peptide; ECT=ectorhinal; Ins=insula; M1/M2=motor cortices; PACAP-38=pituitary adenylate cyclase-activating polypeptide; PAG=periaqueductal gray; PB=parabrachial nucleus; PtA=parietal association; RS=retrosplenial; SSN=superior salivatory nucleus; S1/S2=somatosensory cortices; TCC=trigeminal cervical complex; TG=trigeminal ganglion; VC=visual cortices; V1=ophthalmic branch of trigeminal nerve; V2=maxillary branch of trigeminal nerve; V3=mandibular branch of trigeminal nerve.
Dodick DW, A phase-by-phase review of migraine pathophysiology, Headache, John Wiley and Sons. © 2018 American Headache Society. Reprinted with permission.
Premonitory Phase
HeadachePhase
Postdrome
Headache
Time
Aura
30%
How Does CSD Trigger Headache?
20
Cortical Spreading Depression Activates Dural Trigeminal Pain Fibers
21
Tolner EA, Houben T, Terwindt GM, de Vries B, Ferrari MD, van den Maagdenberg AM. From migraine genes to mechanisms, Pain, 156 suppl 1, S64-S67, https://insights.ovid.com/pubmed?pmid=25789438. Reprinted with permission. Adapted from Zhang X et al. J Neurosci. 2010;30(26):8807–8814.
Delay between CSD and trigeminal activation correlates with delay between aura and headache
Premonitory Phase
HeadachePhase
Postdrome
Headache
Time
Aura
How Does Headache Occur in the Absence of Cortical Spreading Depression?
22
Parasympathetic Hypothesis
23
Meningeal blood vessels densely innervated by parasympathetic fibers
Preganglionic parasympathetic neurons in superior salivatory nucleus increase activity following activation of meningeal nociceptors
Ongoing activity in meningeal nociceptors depends on enhanced activity in the SPG
Parasympathetic tone enhanced during migraine– Lacrimation, teary eyes,
nasal congestion
Sphinopalatine ganglion block relieves migraine pain
Dodick DW, A phase-by-phase review of migraine pathophysiology, Headache, John Wiley and Sons. © 2018 American Headache Society. Reprinted with permission.
Postdromal Phase
24
Linde M. Acta Neurol Scand. 2006;114(2):71-83; Cady RK. Headache. 2007;47(suppl 1):S44-S51.
ProdromePhase
HeadachePhase
Postdrome
Headache
Time
Aura Interictal Phase
FatigueDepressionPhotophobiaNauseaAllodynia
Postdrome: Unlike Prodrome Phase, Is Associated With a Global Reduction in Cerebral Blood Flow
25
Adapted from Denuelle M et al. Cephalalgia. 2008;28(8):856–862; Pyari Bose et al. J Neurol Neurosurg Psychiatry. 2017;88(suppl 1):A1–A83.
Subjects – migraine without aura with GTN‐triggered migraine attacksSubjects with spontaneous migraine
relieved with sumatriptan
GTN=glyceryltrinitrate (nitric oxide donor).
Interictal Phase
26
Linde M. Acta Neurol Scand. 2006;114(2):71-83; Borsook D et al. Neuron. 2012;73(2):219-234.
ProdromePhase
HeadachePhase
Postdrome
Time
Aura Interictal Phase
PhotophobiaNauseaAllodyniaMild Headache Cognitive
Enhanced Cognitive and Emotional Processing of Pain in Migraine: High Expectation, Hypervigilance, and Anxiety for Pain
27
Schwedt TJ et al. Cephalalgia. 2014;34(12):947-958; Hadjikhani N, Ward N, Boshyan J, et al, Cephalalgia, 33, 15, pp. 1264-1268, copyright © 2013 by SAGE Publications. Reprinted by Permission of SAGE Publications, Ltd.
BOLD=blood oxygen level-dependent; DLPCF=dorsolateral prefrontal cortex.
Migraine with aura Migraine without aura
Carpal tunnel syndromeTrigeminal neuralgia
Synthesis
Migraine aura probably due to CSD
Aura triggered in excitable cortex
CSD can trigger headache: activates vascular and dural nociceptors; may also activate trigeminal nucleus caudalis through direct descending central pathways
28
Therapeutic Targets
29
Migraine Pathophysiology Conclusions
Has a significant genetic component
Associated with interictal and ictal dysfunction of brain circuits involved in modulation of sensory information processing
Trigeminal activation is responsible for headache pain
CGRP is an important trigeminal neuropeptide involved in sensory transmission and is a target for acute and preventive treatment
30
Migraine Treatment Targets
Adapted from Edvinsson L et al. Nat Rev Neurol. 2018;14(6):338-350.
31
0
50
100
150
CGRP Substance P CGRP Substance P CGRP Substance P CGRP Triptan
baseline
activation
Cat Human Cat Human
(pmol/l)
Trigeminal Ganglion Superior Sagittal MigraineSinus
*
*
*
*
*
*
*
Goadsby PJ et al. Ann Neurol. 1988;23(2):193-196; Zagami AS et al. Neuropeptides. 1990;16(2):69-75; Goadsby PJ et al. Ann Neurol. 1990;28(2):183-187.
CGRP Release in Relevant Animal Models and Humans During Attacks; Levels Restored After Effective Pain Relief
32
Calcitonin Gene-related Peptide
Neuropeptide belonging to calcitonin family
In humans, 2 forms• α‐CGRP (37‐amino acid peptide)
–formed from the alternative splicing of the calcitonin/CGRP gene located on chromosome 11
• β‐CGRP –main isoform of enteric NS (differs in 3 amino acids)
33
CGRP Receptor
34
Neuronal excitabilityNeurotransmitter release
Vasodilation
Adapted from Edvinsson L et al. Nat Rev Neurol. 2018;14(6):338-350.
Calcitonin Receptor Family
35
Walker CS, Hay DL. CGRP in the trigeminovascular system: a role for CGRP, adrenomedullin and amylin receptors? British Journal of Pharmacology, John Wiley and Sons. © 2013 The Authors, British Journal of Pharmacology © 2013 The British Pharmacological Society. Reprinted with permission.
CGRP Adrenomedullin Calcitonin Amylin
CGRP1 AM1 AM2 CT AMY1 AMY3 AMY2
CLR CLR CLR CT CT CT CT
RAMP1 RAMP2 RAMP3 None RAMP1 RAMP2 RAMP3
Two CGRP Receptors
Functional cross‐talk between CGRP‐family peptides and their receptors• CGRP activates AMY1 receptor with potency equal to that of amylin
• Both adrenomedullin and amylin activated the CGRP receptor, but with significantly less potency
All antagonists inhibit CGRP’s function at CGRP receptor, but inhibition of cross‐talk different• Anti‐CGRP receptor mAb only inhibited function at CGRP receptor, leaving function at other calcitonin‐family receptors intact
• Anti‐CGRP mAb inhibited CGRP’s function at all calcitonin‐family receptors
mAb=monoclonal antibody.
36
CGRP Receptor Antagonists in Migraine
Potent vasodilator
Widely expressed in CNS and PNS
Trigeminal system activated and CGRP released during migraine and cluster headaches
CGRP receptor antagonists:• Block CGRP at multiple sites in CNS and inhibit pain transmission• Not direct vasoconstrictors
37
4 Injectable MABs to CGRP or Its Receptor:3 Now FDA Approved and Available
Tepper SJ. Headache. 2018;58 (Suppl 3):238–275. Tepper SJ. Headache. 2018;58 (Suppl 3):276–290. Edvinsson L. Headache. 2018;58(suppl 1):33-47; Alder Biopharmaceuticals Press Release. Bothwell, WA: 2018; U.S. Food & Drug Administration. FDA approves novel preventive treatment for migraine. May 17, 2018. https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm608120.htm. Accessed October 28, 2018; Teva Pharmaceutical Industries Press Release. Jerusalem: 2017; Eli Lilly and Company Press Release
38
Erenumab‐aooeAIMOVIG
(fully human)
Fremanezumab‐vfrmAJOVY
(fully humanized)
Galcanezumab‐gnlmEMGALITY(humanized)
Eptinezumab(humanized)
Studied for EM, CM EM, CM, eCH EM, CM, eCH EM, CM
Route and Dosing
Monthly subcu70, 140 mg
Monthly or quarterly subcu;225 mg monthly, or 675 mg
quarterly
Monthly subcu; 240 mg loading dose, then 120 mg SC
monthly thereafterQ3 month IV
Target CGRP receptor CGRP peptide or ligand CGRP peptide or ligand CGRP peptide or ligand
T1/2 (days) 28 31 27 30‐31
Regulatory status
FDA approved for migraine prevention
FDA approvedfor migraine prevention
FDA approved for migraine and eCH
prevention
Submitted to FDA Feb 2019
n=neurologic; umab=fully human; zumab=humanized; Human= 100%; humanized= 90‐95%
EM= Episodic Migraine; CM= Chronic Migraine; eCH= Episodic Cluster Headache
Saper J et al. Paper presented at: American Academy of Neurology 2018 Annual Meeting; April 21-27, 2018; Los Angeles, CA. Abstract S20; Goadsby PJ, et al. Headache. 2017;57(suppl 3):128; Stauffer VL et al. JAMA Neurol. 2018;75(9):1080-1088; Skljarevski V et al. Cephalalgia. 2018;38(8);1442-1454; Dodick DW et al. JAMA. 2018;319(19):1999-2008.
37
27
3936
28
50
43
6259
48
56
50
6157
44
0
10
20
30
40
50
60
70
Eptinezumab 100/300 mg,iv
Erenumab 70/140mg, sc
Galcanezumab 120/240mg, sc
Galcanezumab 120/240mg, sc
Fremanezumab 225/675mg, sc
≥50% Responders, %
Placebo Dose 1 Dose 2
Phase 3 Studies of CGRP mAbs in EM50% Responder Rates
39
Smith J, et al. Headache. 2017:57(suppl 3):130; Tepper S et al. Lancet Neurol. 2017;16(6):425-434; Detke HC, et al. Cephalalgia.2017;37:338; Silberstein SD et al. N Engl J Med. 2017;377(22):2113-2122.
41
23
1518
55
40
28
38
57
41
28
41
0
10
20
30
40
50
60
Eptinezumab Erenumab Galcanezumab Fremanezumab
≥50% Responders, %
Placebo Dose 1 Dose 2
Dose 1: 100 mgDose 2: 300 mg
Dose 1: 120 mgDose 2: 240 mg
Dose 1: 70 mgDose 2: 140 mg
Dose 1: 675 mg‐PBO‐PBODose 2: 675 mg‐225 mg‐225 mg
Studies of CGRP mAbs in CM50% Responder Rates
40
Stauffer VL et al. JAMA Neurol. 2018;75(9):1080-1088; Skljarevski V et al. Cephalalgia. 2018;38(8):1442-1454; Bigal ME et al. Lancet Neurol. 2015;14(11):1081-1090; Smith J et al. Headache. 2017;57(suppl 1):130.
39 39
34 34 3431 33
19 19 18 18
11 11
21
0
10
20
30
40
50
60
70
240 mg 120 mg 240 mg 120 mg 225 mg 675 mg 300 mg
Patient, %
Active Placebo
P < .05P < .0008P < .0001P < .001 P < .001 P ≤ .001 P ≤ .001 P < .0112 P < .0001
GalcanezumabEVOLVE 1
FremanezumabHALO‐EM
GalcanezumabEVOLVE 2
EptinezumabPROMISE 1
Studies of CGRP mAbs in EM75% Responder Rates
41
Edvinsson L. Headache. 2018;58(suppl 1):33-47.
Small Molecules mAbs
Target Specificity Low High
Clearance Liver, kidney RES
Size, kD < 1 kD ~150 kD
Route of Administration Oral, nasal Parenteral
Cross the BBB Yes/no No
T1/2 Minutes to hours 1‐4 weeks
Immunogenicity No Yes
Binding Site Multiple CGRP receptor or peptide
Small Molecules vs mAbs
42
Preventive Trials (EM)Dropout Rates Due to AEs
43
mAbs• No serious treatment related AEs in phase 2 or phase 3 trials
• Generally, tolerability comparable to placebo
Diener HC, et al; MIGR-003 Study Group. J Neurol. 2004;251(8):943-950; Freitag FG et al. Neurology. 2002;58(11):1652-1659; Brandes JL et al; MIGR-002 Study Group. JAMA. 2004;291(8):965-973; Couch JR; Amitriptyline Versus Placebo Study Group. Headache 2011;51(1):33-51; Stauffer VL et al. JAMA Neurol. 2018;75(9):1080-1088; Goadsby PJ et al. N Engl J Med. 2017;377(22):2123-2132; Silberstein S et al. Paper presented at: American Academy of Neurology 2018 Annual Meeting; April 21-27, 2018; Los Angeles, CA. Abstract P4.091; Dodick DW et al. JAMA. 2018;319(19):1999-2008.
Propranolol Valproate Topiramate 100 mg
Amitriptyline
Dropout for AE,active
20% 8% 32% 12%
Galcanezumab120 mg, 240 mg
Erenumab 70 mg, 140 mg
Eptinezumab100 mg, 300 mg
Fremanezumab225 mg/mo, 675 mg
Dropout for AE, active 4.2%, 2.3% 2.2% in each group 2% in each group 1.7% in each group
CGRP mAbs and Current Oral Preventive Medications
44
*Side effects listed pertain to only certain medications; not all oral preventive drugs cause all side effects listed.
mAbs for EM and CM Currently AvailableOral Medications
EM
Specificity + ‐
Formulation sc/IV Solution Oral/Tablet
Dose titration No Yes
Frequency of intake Monthly/Quarterly Daily
Onset of action Fast (hours‐days) Slow (weeks‐months)
Effect in "refractory" patients + ‐
Side effects* Effect on weightMood changeDrowsiness / fatigueCognitive impairmentDizzinessTeratogenicity
‐‐‐‐‐?
++++++
Adherence/long‐term patient outcomes
+ ‐
Reuter U. Headache. 2018;58(suppl 1):48-59.
Conclusions
The genesis of aura is cortical spreading depolarization (depression) [CSD]
Migraine pain can occur with or without aura
The phases of migraine correspond to different brain area changes seen on functional imaging
Targeted anti‐CGRP and anti‐CGRP receptor monoclonal antibodies offer new levels of efficacy, tolerability, and adherence for migraine prevention
45
