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Pathophysiology of Migraine
Pathophysiology of Migraine     Outline   Migraine is an inherited central nervous system     (CNS)    disorder   Migrai...
Pathophysiology of Migraine   Implementing Pathophysiology Into Treatment   Focus had been on acute therapy to manage ind...
Pathophysiology of Migraine   Classic Vascular Theory of Migraine            Aura Phase                   Headache Phase  ...
Pathophysiology of Migraine   Blood Flow During Aura and Headache Phase                                            CBF=cer...
Pathophysiology of Migraine   The Genetic Basis   P/Q type Ca++      channel     –   Presynaptic     –   Voltage gated   ...
Pathophysiology of Migraine   The P/Q Gene Product                                                             FHM=familia...
Pathophysiology of Migraine   Hyperexcitable Cortex   Migraineurs have a lower threshold for occipital cortex    excitati...
Pathophysiology of Migraine   Threshold Levels for Triggered Headaches            1.0            0.9            0.8Probabi...
Pathophysiology of Migraine   Imaging of Cortical Spreading Depression (CSD)                              Hadjikhani N et ...
Pathophysiology of Migraine   Cortical Spreading Depression     Wave of oligemia begins in      occipital cortex and spre...
Pathophysiology of Migraine   Trigeminovascular Migraine Pain Pathways    Preventive medication target                    ...
Pathophysiology of Migraine   Brain Stem Involvement in Migraine   Brain stem   aminergic nuclei can modify trigeminal pa...
Pathophysiology of Migraine   Red Nucleus and Substantia Nigra                 Sagittal View of Imaging Plane             ...
Pathophysiology of Migraine   Iron Homeostasis               R2* Map                                   Substantia Nigra   ...
Pathophysiology of Migraine   Changes in Periaqueductal Gray           16                  PAG              Red nucleus   ...
Pathophysiology of Migraine   Disease Progression: Changes in PAG     Changes, observed over time in the PAG—center of   ...
Pathophysiology of Migraine     Disease Progression: White Matter Lesions   Study setting: Holland   Population:     –  ...
Pathophysiology of Migraine     Disease Progression: White Matter Lesions                              Posterior Circulati...
Pathophysiology of Migraine   Disease Progression: White Matter Lesions   Migraineurs have more MRI-detectable white matt...
Pathophysiology of Migraine   Proposed Mechanisms of Migraine Headache     Abnormal cortical                              ...
Pathophysiology of Migraine   Migraine Mechanisms                              Iadecola C. Nature Medicine. 2002;8:111-112.
Pathophysiology of Migraine   Central Sensitization                                  Migraineurs develop increased       ...
Topiramate: A Neuromodulator With Stabilizing Properties   Mechanisms of Action                        Voltage-Gated Ion C...
Topiramate  Neuroprotective Potential   Attenuates glutamate-, NMDA-, AMPA-, and Kainate-    induced neurotoxicity in vit...
Topiramate  Inhibition of Neuronal Activation   Mechanism   of topiramate action in migraine investigated    using anesth...
Topiramate  Inhibition of Trigeminovascular Traffic                                                                    % I...
Pathophysiology of Migraine   Summary     Understanding pathophysiologic events may help      physicians to manage migrai...
Pathophysiology of Migraine   Summary      Imaging data suggest anatomic changes occur in       chronic migraineurs     ...
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Pathophysiology of migraine

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Pathophysiology of migraine

  1. 1. Pathophysiology of Migraine
  2. 2. Pathophysiology of Migraine Outline  Migraine is an inherited central nervous system (CNS) disorder  Migraineurs have hyperexcitable brains  Migraine can be progressive in some patients  Migraine is progressive during an attack – Central sensitization  Topiramate mechanism of action in migraine prevention – Multiple mechanisms – Reduced CNS excitation in animal model
  3. 3. Pathophysiology of Migraine Implementing Pathophysiology Into Treatment  Focus had been on acute therapy to manage individual migraine episodes  New advances in pathophysiology have transformed the concept of what migraine is – Migraine is a CNS disorder – Genetic predisposition  This has paved the way for improved treatment – Treatment of migraine as a disorder – Emphasis on preventive + acute
  4. 4. Pathophysiology of Migraine Classic Vascular Theory of Migraine Aura Phase Headache Phase Spasm of Cerebral Arteries Vasodilation of Cerebral Arteries Wolf HG. Headache and Other Head Pain. 1963.
  5. 5. Pathophysiology of Migraine Blood Flow During Aura and Headache Phase CBF=cerebral blood flow. Laurizen M. Brain. 1994;118:199-210.
  6. 6. Pathophysiology of Migraine The Genetic Basis  P/Q type Ca++ channel – Presynaptic – Voltage gated – Occipital cortex – Trigeminal nucleus caudalis – Linkage to chromosome 19  Na-K ATP Pump – Linkage to Chromosome 1 Figure courtesy of AHS Ambassadors Program. Ophoff RA et al. Cell. 1996;87:543-552. De Fusco M et al. Nat Genet. 2003;33:192-196.
  7. 7. Pathophysiology of Migraine The P/Q Gene Product FHM=familial hemiplegic migraine. Figure courtesy of AHS Ambassadors Program. Ophoff RA et al. Cell. 1996;87:543-552.
  8. 8. Pathophysiology of Migraine Hyperexcitable Cortex  Migraineurs have a lower threshold for occipital cortex excitation than controls  Genetic component: – P/Q calcium channel, Na+/K+ ATPase – Mitochondrial defects  Probably due to: – Hyperactivity of excitatory neurotransmission Na+, Ca++ channels, glutamate – Lower activity of inhibitory neurotransmission GABA GABA=gamma aminobutyric acid. Aurora SK et al. Neurology. 1998;50:1111-1114.
  9. 9. Pathophysiology of Migraine Threshold Levels for Triggered Headaches 1.0 0.9 0.8Probability 0.7 P=.053, Cox Regression of 0.6Phosphene 0.5 0.4 0.3 0.2 0.1 0.0 0 10 20 30 40 50 60 70 80 90 100 Stimulus Intensity No Triggered HA Triggered HA HA=headache. Aurora SK et al. Headache. 1999;39:469-476.
  10. 10. Pathophysiology of Migraine Imaging of Cortical Spreading Depression (CSD) Hadjikhani N et al. Proc Natl Acad Sci USA. 2001;98:4687-4692.
  11. 11. Pathophysiology of Migraine Cortical Spreading Depression  Wave of oligemia begins in occipital cortex and spreads forward at rate of 2-3 mm/min – Begins with aura and persists for hours after headache – CBF changes not in distribution of any cerebral artery – Consistent with primary neuronal event producing secondary vascular changes James MF et al. J Physiol. 1999;519:415-425.
  12. 12. Pathophysiology of Migraine Trigeminovascular Migraine Pain Pathways Preventive medication target Neuropeptide Release Vasodilatation Central Sensitization Pain Signal Transmission Acute medication target Hargreaves RJ, Shepheard SL. Can J Neurol Sci. 1999;26(suppl 3):S12-S19.
  13. 13. Pathophysiology of Migraine Brain Stem Involvement in Migraine  Brain stem aminergic nuclei can modify trigeminal pain processing  PET demonstrates brain stem activation in spontaneous migraine attacks  Brain stem activation persists after successful headache treatment  Brain stem: generator or modulator? PET=positron emission tomography. Weiller C et al. Nat Med. 1995;1:658-660.
  14. 14. Pathophysiology of Migraine Red Nucleus and Substantia Nigra Sagittal View of Imaging Plane Inferior Colliculus Mammillary Body Oblique Imaging Plane Welch KMA et al. Headache. 2001;41:629-637.
  15. 15. Pathophysiology of Migraine Iron Homeostasis R2* Map Substantia Nigra Red Nuclei Periaqueductal Grey Matter Welch KMA et al. Headache. 2001;41:629-637.
  16. 16. Pathophysiology of Migraine Changes in Periaqueductal Gray 16 PAG Red nucleus 14 * 12 * 10 R2’ 8 (1/ms) * * 6 4 2 0 Control Episodic migraine Chronic daily headache Group-wise Comparison: ANOVA (One-way Analysis of Variance). *Significant difference, P<.05. PAG=periaqueductal gray. Welch KMA et al. Headache. 2001;41:629-637.
  17. 17. Pathophysiology of Migraine Disease Progression: Changes in PAG  Changes, observed over time in the PAG—center of the brain’s powerful descending analgesic neuronal network –Iron deposition –Secondary to free-radical cell damage during migraine attacks  Degree of PAG structural alteration depends on duration of headache history, not the age of the patient Repeated migraine attacks, repetitive damage, decreased threshold for further migraine attacks Welch KMA et al. Headache. 2001;41:629-637.
  18. 18. Pathophysiology of Migraine Disease Progression: White Matter Lesions  Study setting: Holland  Population: – Migraineurs with or without aura – Group-matched controls  Methods: – 3-mm magnetic resonance imaging sections – One neuroradiologist, blinded to the migraine diagnosis and clinical data, rated infarcts and white matter lesions Kruit et al. JAMA. 2004; 291:427-434
  19. 19. Pathophysiology of Migraine Disease Progression: White Matter Lesions Posterior Circulation Infarct 6 9 8 5 7 4 6 Prevalence P=.02 P=.03 5 (%) 3 4 2 3 2 1 1 0 0 Migraineurs Controls Migraine with aura Migraine without aura Kruit et al. JAMA. 2004; 291:427-434.
  20. 20. Pathophysiology of Migraine Disease Progression: White Matter Lesions  Migraineurs have more MRI-detectable white matter lesions than controls  Lesions increase with attack frequency, possibly indicating progression – Increased risk of posterior circulation infarcts highest in migraineurs with aura with an attack frequency ≥1/month – Increased risk of deep white mater lesions highest in female migraineurs (with or without aura) with an attack frequency ≥1/month  Even one headache per month could predispose migraineurs to subclinical brain lesions Kruit et al. JAMA. 2004;291:427-434.
  21. 21. Pathophysiology of Migraine Proposed Mechanisms of Migraine Headache Abnormal cortical Abnormal brain activity stem function Hyperexcitable brain Excitation of brain (↑Ca++, ↑Glu, ↓Mg++) stem, PAG, etc. Cortical Spreading Depression Activation/Sensitization of TGVS Headache Pain Vasodilation Central Sensitization Neurogenic Inflammation TGVS=trigeminal vascular sensitization. Adapted from Pietrobon D, Striessnig J. Nat Rev Neurosci. 2003;4:386-398.
  22. 22. Pathophysiology of Migraine Migraine Mechanisms Iadecola C. Nature Medicine. 2002;8:111-112.
  23. 23. Pathophysiology of Migraine Central Sensitization  Migraineurs develop increased sensitivity to stimuli due to increased nerve excitability  79% of migraine patients suffered from cutaneous allodynia during attacks due to central sensitization Burstein R et al. Ann Neurol. 2000;47:614-624; Burstein R et al. Headache. 2002;42:390-391.
  24. 24. Topiramate: A Neuromodulator With Stabilizing Properties Mechanisms of Action Voltage-Gated Ion Channels = Topiramate Ca2+ channel Na+ channel K+ channel Ligand-Gated Ion Channels GABAA AMPA/kainate receptor receptor Cl- Cl- Cl- Shank RP et al. Epilepsia. 2000;41(suppl 1):S3-9.
  25. 25. Topiramate Neuroprotective Potential  Attenuates glutamate-, NMDA-, AMPA-, and Kainate- induced neurotoxicity in vitro  Promotes neurite outgrowth in neuronal cells in culture  Enhances nerve regeneration and recovery of function after injury in vivo (facial nerve compression model)  Demonstrated Disease Modification In Models of: – Focal and global hypoxia – Periventricular leukomalacia – Traumatic brain injury – Status epilepticus – Peripheral nerve regeneration Smith-Swintosky VL et al. Neuroreport. 2001;12:1031-034.
  26. 26. Topiramate Inhibition of Neuronal Activation  Mechanism of topiramate action in migraine investigated using anesthetized cat model – Superior sagittal sinus (SSS) electrically stimulated to mimic nociceptive activation – Recordings taken in the Trigeminal Nucleus Caudalis (TNC)  Topiramate reduced SSS-evoked firing of neurons in the TNC in a dose-dependent fashion (IC50 ≈ 5 mg/kg) Storer RJ, Goadsby PJ. Poster presented at: American Academy of Neurology 2003; June 5-8, 2003; Honolulu, Hawaii.
  27. 27. Topiramate Inhibition of Trigeminovascular Traffic % Inhibition  SSS stimulated 60 – Record from TNC 53 50 48 40 35  Topiramate reduced SSS- evoked TNC firing within 30 30 minutes % 20 10  Mechanism of action in migraine 0 3 mg/kg 5 mg/kg 50 mg/kg Storer RJ, Goadsby PJ. Poster presented at: American Academy of Neurology 2003; June 5-8, 2003; Honolulu, Hawaii.
  28. 28. Pathophysiology of Migraine Summary  Understanding pathophysiologic events may help physicians to manage migraine better  Current research indicates that migraine is a familial disorder of the brain characterized by neuronal hyperexcitability and often central sensitization  Migraine may be due to an imbalance in excitatory and inhibitory neurotransmission and ion channel abnormalities
  29. 29. Pathophysiology of Migraine Summary  Imaging data suggest anatomic changes occur in chronic migraineurs  Central sensitization may result in cutaneous allodynia, a marker for severe headache  Modern acute and preventive migraine treatments, such as triptans and neuromodulators, interact with pre- and postjunctional targets; their mechanism of action may help explain pathophysiologic pathways – Topiramate reduces neuronal activation in trigeminal nucleus caudalis

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