New Developments in MigraineNew Developments in Migraine-or--or-((Why do humans get so many headaches?)Why do humans get s...
Despite what we were allDespite what we were alltaught, migraine istaught, migraine is notnot aavascular disordervascular ...
I believe that migraine is aI believe that migraine is adisorder of electrical hyperdisorder of electrical hyperexcitabili...
I believe that all humans withI believe that all humans withnormal head anatomy who havenormal head anatomy who havesponta...
Trigeminal Nucleus CaudalisTrigeminal Nucleus Caudalis perceives pain for the face and theperceives pain for the face and ...
The pain system of the head was putThe pain system of the head was putthere to tell us not to bang our heads.there to tell...
PET Scans in Migraine PatientsPET Scans in Migraine Patientsshow that the posterior brain stem is hyper metabolicshow that...
The migraine sufferer has a normalThe migraine sufferer has a normalwiring diagram but inherits a gene thatwiring diagram ...
The Gene Mutations that CauseThe Gene Mutations that CauseMigraineMigraine
Genes that cause migraine affect theGenes that cause migraine affect theelectrical excitability of brain cellselectrical e...
Ca++ channel in a membraneCa++ channel in a membrane Our cellular electricity is more like a car battery, charges floatin...
Voltage gated Ca ++ channels turn cells“on”Voltage gated Ca ++ channels turn cells“on”Ca++ pumpsCa++ pumps turn them “off”...
Migraine is a Channel DisorderMigraine is a Channel Disorder There are now multiple reported Ca++There are now multiple r...
This may be why the brain stem nuclei areThis may be why the brain stem nuclei areinappropriately “on” in migraine patient...
Any migraine sufferer will tell you, (ifAny migraine sufferer will tell you, (ifyou ask), that they go to bed not justyou ...
1960’s Magnetic Field Studies1960’s Magnetic Field StudiesStarting with the visual aura they observedStarting with the vis...
Magnetic Field StudiesMagnetic Field Studieselectrical suppression, starting in the back during visual aura, movingelectri...
Magnetic Field StudiesMagnetic Field Studieselectrical suppression, starting in the back during visual aura, movingelectri...
Spreading Depression of Dr.Spreading Depression of Dr.LeaoLeao Observed in animal brain slices: Stimulating the brain ele...
Newest Brain Discoveries thatNewest Brain Discoveries thatExplain Spreading DepressionExplain Spreading Depression Confoc...
Astrocytes are more influential thanAstrocytes are more influential thanpreviously imaginedpreviously imagined Astrocytes...
Spreading Depression of Leao is anSpreading Depression of Leao is aninter cellular calcium waveinter cellular calcium wave...
Astrocytes link blood signals toAstrocytes link blood signals toneuronal signalsneuronal signals A single astrocyte and i...
Most headaches are “migraine”Most headaches are “migraine” I believe that all the headaches that most of us have areI bel...
What is unique about the head pain systemWhat is unique about the head pain systemthat makes it turn on spontaneously?that...
What about the other migraine symptoms?What about the other migraine symptoms?They’re not in the trigeminal caudal nucleus...
What causes this excitation? RememberWhat causes this excitation? Rememberour friend the astrocyte?our friend the astrocyte?
Astrocytes act more as a syncytiumAstrocytes act more as a syncytiumjoining all of the neurons of the brainjoining all of ...
Migraine as an astrocyte disorderMigraine as an astrocyte disorder The channel abnormalities linked to migraine areThe ch...
Why would humans have so manyWhy would humans have so manygenes to give them headaches?genes to give them headaches? Thos...
Migraine and Sleep are intertwinedMigraine and Sleep are intertwined I believe that the unique aspect of the trigeminal c...
What about chronic neck pain and “tension headaches”What about chronic neck pain and “tension headaches” If mild head inj...
Are daily headaches migraine too?Are daily headaches migraine too? What some authors are calling “transformed migraine”Wh...
Key Points of Brainstem Hyper excitabilityKey Points of Brainstem Hyper excitability• Activation observed in the posterior...
Sleep disorders cause migraineSleep disorders cause migraine• Most patients with daily headache have a primary sleepMost p...
Hormones and MigraineHormones and Migraine
Any migraine theory has to explain:Any migraine theory has to explain: Why do migraines start at puberty?Why do migraines...
HypothalamusGnRHAnterior PituitaryLH/FSHOvariesinhibin, estradiol, progesteroneAdapted from MacGregor EA. Neurologic Clini...
Gonadotropin Releasing HormonesGonadotropin Releasing Hormones The releasing hormones (GnRH) boss the ovaries and theThe ...
Children Have Headaches TooChildren Have Headaches Too There is absolutely no difference between adults withThere is abso...
Episodic Treatment: TriptansEpisodic Treatment: Triptanssumatriptan, naratriptan, eletriptan, etc.sumatriptan, naratriptan...
Where are the Serotonin receptors ?Where are the Serotonin receptors ? Most of the serotoninMost of the serotoninmeasured...
Serotonergic cells in Raphe Nuclei of theSerotonergic cells in Raphe Nuclei of thePeriaquiductal GreyPeriaquiductal Grey ...
Treatment: PreventionTreatment: Prevention• Use the triptans early!Use the triptans early!• Treat the sleep first if possi...
Daily Preventatives are allDaily Preventatives are allChannel StabilizersChannel Stabilizers Verapamil SR 180 to 360 (car...
Are there other things like Migraine?Are there other things like Migraine? Episodic vertigo is a channel disorder as well...
Mouse models of MigraineMouse models of Migraine One of the Ca++ channelOne of the Ca++ channelmutations that causesmutat...
Epilepsy and ChannelsEpilepsy and Channels If you can make a mouse epileptic with aIf you can make a mouse epileptic with...
Most epilepsy medications are “channel stabilizers”.Most epilepsy medications are “channel stabilizers”.They act on malfun...
Can Epilepsy be like Migraine?Can Epilepsy be like Migraine? If there is no abnormality of the brain anatomy it is aIf th...
Do animals have migraines?Do animals have migraines?(Bella can’t tell us if she has a headache.)(Bella can’t tell us if sh...
ReferencesReferences1.1. Joutel A, Bousser MG, Biousse V, etJoutel A, Bousser MG, Biousse V, et aal.l. A gene for fA gene ...
ReferencesReferences6.6. Jurkat-Rott, K., Freilinger, T., Dreier, J. P., Herzog, J., Gobel, H., Petzold,Jurkat-Rott, K., F...
Migraine 2010
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  • The hypothesis of migraine pathophysiology is consistent with the clinical observations that sinus-like symptoms often accompany migraine. Migraine is a neurovascular disorder involving activation of the TNC. Pain can be referred anywhere along the trigeminal nerve network including the sinus area. Activation of the TNC can cause reflex activation of the cranial parasympathetic nerves and thereby lead to sinus-like symptoms.
  • But it is now recognized that during menstruation, it is more complex than just a change in estrogen and progesterone. In fact, there are multiple migraine triggers (eg, sleep, light, weather, foods, etc) as well as multiple neurotransmitters that are involved. Multiple things can occur during the menstrual cycle that can trigger a migraine. This makes sense, when one considers the fact that the majority of female migraineurs experience migraines outside of the menstrual cycle as well as within the cycle. For these reasons, simply treating with hormones is often inadequate, especially across attacks and across people.
  • Migraine 2010

    1. 1. New Developments in MigraineNew Developments in Migraine-or--or-((Why do humans get so many headaches?)Why do humans get so many headaches?)Stasha Gominak, M.D.Stasha Gominak, M.D.East Texas Medical Center Neurologic InstituteEast Texas Medical Center Neurologic Institute700 Olympic Plaza, Suite 912700 Olympic Plaza, Suite 912Tyler, TexasTyler, Texas
    2. 2. Despite what we were allDespite what we were alltaught, migraine istaught, migraine is notnot aavascular disordervascular disorder
    3. 3. I believe that migraine is aI believe that migraine is adisorder of electrical hyperdisorder of electrical hyperexcitability of the head painexcitability of the head painsystem coming from asystem coming from abrainstem “migrainebrainstem “migrainegenerator”generator”
    4. 4. I believe that all humans withI believe that all humans withnormal head anatomy who havenormal head anatomy who havespontaneous head pain havespontaneous head pain have“migraine”. It comes in“migraine”. It comes indifferent sizes but all with thedifferent sizes but all with thesame mechanism.same mechanism.
    5. 5. Trigeminal Nucleus CaudalisTrigeminal Nucleus Caudalis perceives pain for the face and theperceives pain for the face and thefront 2/3 of the head.front 2/3 of the head.Dorsal Horn C2-C4Dorsal Horn C2-C4 perceives pain for the back 1/3 of the headperceives pain for the back 1/3 of the headand the neck.and the neck.The Head Pain SystemThe Head Pain System
    6. 6. The pain system of the head was putThe pain system of the head was putthere to tell us not to bang our heads.there to tell us not to bang our heads.
    7. 7. PET Scans in Migraine PatientsPET Scans in Migraine Patientsshow that the posterior brain stem is hyper metabolicshow that the posterior brain stem is hyper metabolicWeiller C, May A, Limmroth V, et al. Nature Med 1995;1:658-660Weiller C, May A, Limmroth V, et al. Nature Med 1995;1:658-660
    8. 8. The migraine sufferer has a normalThe migraine sufferer has a normalwiring diagram but inherits a gene thatwiring diagram but inherits a gene thatallows the pain wires to turn “on”allows the pain wires to turn “on”without a blow to the head.without a blow to the head.
    9. 9. The Gene Mutations that CauseThe Gene Mutations that CauseMigraineMigraine
    10. 10. Genes that cause migraine affect theGenes that cause migraine affect theelectrical excitability of brain cellselectrical excitability of brain cells There are now about 40 genes that are linked toThere are now about 40 genes that are linked tomigrainemigraine All of these genes are mutations in the cellularAll of these genes are mutations in the cellularapparatus that allows us to turn our cells on andapparatus that allows us to turn our cells on andoff: Channel Mutations.off: Channel Mutations. About half the genes are Ca++ channelAbout half the genes are Ca++ channelmutations the other half are Na+ channelmutations the other half are Na+ channelmutations.mutations.
    11. 11. Ca++ channel in a membraneCa++ channel in a membrane Our cellular electricity is more like a car battery, charges floatingOur cellular electricity is more like a car battery, charges floatingin water our brain uses Ca++, K+, Cl-, Na+.in water our brain uses Ca++, K+, Cl-, Na+. The channels move these ions in and out of our cells to turnThe channels move these ions in and out of our cells to turnthem “on” or “off”.them “on” or “off”. Most channels move a specific ion.Most channels move a specific ion. There are now multiple Ca++ channels, K+ channels, etc., eachThere are now multiple Ca++ channels, K+ channels, etc., eachhas a specific role, or several specific roles, in our body.has a specific role, or several specific roles, in our body.
    12. 12. Voltage gated Ca ++ channels turn cells“on”Voltage gated Ca ++ channels turn cells“on”Ca++ pumpsCa++ pumps turn them “off”turn them “off” As the voltage of the cell risesAs the voltage of the cell risesthe “voltage gated” Ca++the “voltage gated” Ca++channels all open.channels all open. Ca++ floods the cell, the cellCa++ floods the cell, the cellis now very positive inside; it isis now very positive inside; it is“on”.“on”. It sends it’s message off downIt sends it’s message off downthe axon.the axon. It’s job is finished, now it isIt’s job is finished, now it istime to turn “off”. To turn offtime to turn “off”. To turn offit has to pump out the positiveit has to pump out the positivecharges.charges.Voltage gatedCa++ channelLots of +’s cell isLots of +’s cell isONON ++++++++++++++++++++++++++++++
    13. 13. Migraine is a Channel DisorderMigraine is a Channel Disorder There are now multiple reported Ca++There are now multiple reported Ca++channel and Na+ channel mutations thatchannel and Na+ channel mutations thatare linked to migraine.are linked to migraine. Also mutations of the Ca++ pumps andAlso mutations of the Ca++ pumps andmost recently Na-K ATPase.most recently Na-K ATPase.Refs 1-6Refs 1-6
    14. 14. This may be why the brain stem nuclei areThis may be why the brain stem nuclei areinappropriately “on” in migraine patientsinappropriately “on” in migraine patients
    15. 15. Any migraine sufferer will tell you, (ifAny migraine sufferer will tell you, (ifyou ask), that they go to bed not justyou ask), that they go to bed not justbecause their head hurts but becausebecause their head hurts but becausethey also “can’t think right”they also “can’t think right”Migraine is not just a disorder of head pain.Migraine is not just a disorder of head pain.Any theory about migraine has to explainAny theory about migraine has to explainthis global change in brain functioningthis global change in brain functioning..
    16. 16. 1960’s Magnetic Field Studies1960’s Magnetic Field StudiesStarting with the visual aura they observedStarting with the visual aura they observed electrical suppression, startingelectrical suppression, startingin the back during visual aura, moving slowly forward taking 15 minutes toin the back during visual aura, moving slowly forward taking 15 minutes togo from back to frontgo from back to front
    17. 17. Magnetic Field StudiesMagnetic Field Studieselectrical suppression, starting in the back during visual aura, movingelectrical suppression, starting in the back during visual aura, movingslowly forward, 15 minutes to go from back to frontslowly forward, 15 minutes to go from back to front
    18. 18. Magnetic Field StudiesMagnetic Field Studieselectrical suppression, starting in the back during visual aura, movingelectrical suppression, starting in the back during visual aura, movingslowly forward, 15 minutes to go from back to frontslowly forward, 15 minutes to go from back to front
    19. 19. Spreading Depression of Dr.Spreading Depression of Dr.LeaoLeao Observed in animal brain slices: Stimulating the brain electricallyObserved in animal brain slices: Stimulating the brain electricallycauses a slowly spreading electrical wave.causes a slowly spreading electrical wave. Travels 3mm/min, contiguously, taking about 15 minutes toTravels 3mm/min, contiguously, taking about 15 minutes tocross the braincross the brain What conveys this slowly moving wave? Is it directly related toWhat conveys this slowly moving wave? Is it directly related tomigraine in humans? Why is it so slow?migraine in humans? Why is it so slow?
    20. 20. Newest Brain Discoveries thatNewest Brain Discoveries thatExplain Spreading DepressionExplain Spreading Depression Confocal microscopesConfocal microscopesshow us brain cells in 3show us brain cells in 3dimensions.dimensions.NeuronAstrocyte
    21. 21. Astrocytes are more influential thanAstrocytes are more influential thanpreviously imaginedpreviously imagined Astrocytes are electricallyAstrocytes are electricallyactive cells that can talk toactive cells that can talk toone another and other brainone another and other braincells.cells. Their dendrites wrap aroundTheir dendrites wrap around20-30 neurons with multiple20-30 neurons with multipleendings on the surface of theendings on the surface of theneurons giving excitatory orneurons giving excitatory orinhibitory input to theinhibitory input to theneurons.neurons. Each astrocyte is assignedEach astrocyte is assignedseveral neurons and a bloodseveral neurons and a bloodvessel.vessel.
    22. 22. Spreading Depression of Leao is anSpreading Depression of Leao is aninter cellular calcium waveinter cellular calcium wave Astrocytes have gap junctions thatAstrocytes have gap junctions thatopen between adjoining cellsopen between adjoining cellsallowing them to directly shareallowing them to directly sharetheir ionic environments.their ionic environments. Spreading depression is aSpreading depression is aspreading inter cellular calciumspreading inter cellular calciumwave traveling through thewave traveling through theastrocyte population throughastrocyte population throughthese gap junctionsthese gap junctions The wave travels slowly,The wave travels slowly,3mm/min, and contiguously,3mm/min, and contiguously,because it isbecause it is transmitted by thetransmitted by theastrocytes, not the neuronsastrocytes, not the neurons
    23. 23. Astrocytes link blood signals toAstrocytes link blood signals toneuronal signalsneuronal signals A single astrocyte and it’sA single astrocyte and it’sneurons are called “neurons are called “astrocyteastrocyteneurovascular unitneurovascular unit”” A chemical blood signal isA chemical blood signal isreceived by the astrocyte,received by the astrocyte,then sent to the neuronsthen sent to the neuronsamplifying the messageamplifying the message Thus spreading depressionThus spreading depressionhas a similar arterialhas a similar arterialvasoconstrictive wave thatvasoconstrictive wave thataccompanies it.accompanies it. But I believe the change inBut I believe the change inmental status is the neuronalmental status is the neuronaleffect not the vascular effect.effect not the vascular effect.
    24. 24. Most headaches are “migraine”Most headaches are “migraine” I believe that all the headaches that most of us have areI believe that all the headaches that most of us have are“migraine” meaning a“migraine” meaning a genetically inherited tendency to turngenetically inherited tendency to turnon the head pain system without a blow to the head.on the head pain system without a blow to the head. ThisThis excludesexcludes people who have headache because of brainpeople who have headache because of braininfection, a blow to the head, a brain tumor, or a stroke. All ofinfection, a blow to the head, a brain tumor, or a stroke. All ofthose people have head pain because of irritated nerve endings.those people have head pain because of irritated nerve endings. Always have a scan. The headache of a brain tumor is noAlways have a scan. The headache of a brain tumor is nodifferent than daily headache from migrainedifferent than daily headache from migraine.. Why do humans think headaches are “normal”? It is the onlyWhy do humans think headaches are “normal”? It is the onlypain syndrome we think is “normal”.pain syndrome we think is “normal”.
    25. 25. What is unique about the head pain systemWhat is unique about the head pain systemthat makes it turn on spontaneously?that makes it turn on spontaneously?The other, analogous pain areas of the rest of the spinal cord don’tThe other, analogous pain areas of the rest of the spinal cord don’tjust switch on when ever they feel like it.just switch on when ever they feel like it.
    26. 26. What about the other migraine symptoms?What about the other migraine symptoms?They’re not in the trigeminal caudal nucleusThey’re not in the trigeminal caudal nucleus Nausea from theNausea from theChemotrigger ZoneChemotrigger Zone Facial congestion fromFacial congestion fromthe Salivatory Nucleusthe Salivatory Nucleuswhich innervates thewhich innervates themucosa of the sinusmucosa of the sinuscavitiescavities .. Several brainstem nucleiSeveral brainstem nucleiare being excitedare being excitedtogether.together.
    27. 27. What causes this excitation? RememberWhat causes this excitation? Rememberour friend the astrocyte?our friend the astrocyte?
    28. 28. Astrocytes act more as a syncytiumAstrocytes act more as a syncytiumjoining all of the neurons of the brainjoining all of the neurons of the brain
    29. 29. Migraine as an astrocyte disorderMigraine as an astrocyte disorder The channel abnormalities linked to migraine areThe channel abnormalities linked to migraine areprobably manifested in theprobably manifested in the astrocytesastrocytes,, not innot inthe neurons, thus the syndrome is not a singlethe neurons, thus the syndrome is not a singlebrainstem nucleus, but abrainstem nucleus, but a regionregion of the brain thatof the brain thatis hyper excitable.is hyper excitable. Snuggled right up against the migraineSnuggled right up against the migrainebrainstem generator is thebrainstem generator is the sleep switchsleep switch, which, whichisis designed to go on and off spontaneously.designed to go on and off spontaneously.
    30. 30. Why would humans have so manyWhy would humans have so manygenes to give them headaches?genes to give them headaches? Those 40 genes for migraine are probably notThose 40 genes for migraine are probably notthere to cause headaches, they’re there to makethere to cause headaches, they’re there to makethe sleep switch work better.the sleep switch work better. Sleep is the most important thing we do everySleep is the most important thing we do everyday. If you sleep better you survive longer andday. If you sleep better you survive longer andhave more children.have more children.
    31. 31. Migraine and Sleep are intertwinedMigraine and Sleep are intertwined I believe that the unique aspect of the trigeminal caudalI believe that the unique aspect of the trigeminal caudalnucleus is not the nucleus itself but instead its proximitynucleus is not the nucleus itself but instead its proximityto the periaquiductal grey.to the periaquiductal grey. Most daily headache sufferers have a sleep disorderMost daily headache sufferers have a sleep disorderunderlying.underlying. But if you don’t have a migraine gene your sleepBut if you don’t have a migraine gene your sleepdisorder won’t produce headache.disorder won’t produce headache. Patients with a migraine gene often have a headachePatients with a migraine gene often have a headachethat lasts longer after mild head injury as well. Theythat lasts longer after mild head injury as well. Theycan’t turn “off” their migraine generator.can’t turn “off” their migraine generator.
    32. 32. What about chronic neck pain and “tension headaches”What about chronic neck pain and “tension headaches” If mild head injury can become chronic daily headache because the painIf mild head injury can become chronic daily headache because the paincenter cannot turn off, thencenter cannot turn off, then Mild irritation of cervical roots might also lead to daily headache.Mild irritation of cervical roots might also lead to daily headache. To make the neck pain resolveTo make the neck pain resolve we have to decrease the excitability of the brain stemwe have to decrease the excitability of the brain stemcentercenter that receives the input instead of focusing on the neck.that receives the input instead of focusing on the neck. The neck looks normal because it is normal.The neck looks normal because it is normal.
    33. 33. Are daily headaches migraine too?Are daily headaches migraine too? What some authors are calling “transformed migraine”What some authors are calling “transformed migraine”is just daily migraine, some days milder, some daysis just daily migraine, some days milder, some daysmore severe.more severe. Daily headache or daily “migraine” is probably one ofDaily headache or daily “migraine” is probably one ofthe biggest causes of daily, non radiating neck pain.the biggest causes of daily, non radiating neck pain. Sinus headaches without green or yellow snot are justSinus headaches without green or yellow snot are justmigraine in the face.migraine in the face. In order to assume this theIn order to assume this the anatomy must be normal,anatomy must be normal,so always scan first.so always scan first.
    34. 34. Key Points of Brainstem Hyper excitabilityKey Points of Brainstem Hyper excitability• Activation observed in the posterior brain stem on PETActivation observed in the posterior brain stem on PETscans is probably that whole region of the brainstem.scans is probably that whole region of the brainstem.• Activation of the posterior brain stem can result in painActivation of the posterior brain stem can result in painanywhere along the trigeminal-cervical network;anywhere along the trigeminal-cervical network;including the head, the neck, and the face.including the head, the neck, and the face.• Activation of the TNC can cause cross-over activationActivation of the TNC can cause cross-over activationof the Salivatory Nucleus leading to sinus congestionof the Salivatory Nucleus leading to sinus congestionsymptoms, nausea through the chemotrigger zone,symptoms, nausea through the chemotrigger zone,hypersensitivity to light sound and smell throughhypersensitivity to light sound and smell throughconnections to the thalamus.connections to the thalamus.
    35. 35. Sleep disorders cause migraineSleep disorders cause migraine• Most patients with daily headache have a primary sleepMost patients with daily headache have a primary sleepdisorder, either sleep apnea, restless leg syndrome ordisorder, either sleep apnea, restless leg syndrome orperiodic limb movements of sleep.periodic limb movements of sleep.• Many just don’t get into the right phases of sleep.Many just don’t get into the right phases of sleep.• Most of these patients have vitamin D deficiency withMost of these patients have vitamin D deficiency withor without accompanying B12 deficiency.or without accompanying B12 deficiency.• Measure D 25OH, B12, iron and replace all that are lowMeasure D 25OH, B12, iron and replace all that are lowfirst. D 60-80 ng/ml. B12 > 500.first. D 60-80 ng/ml. B12 > 500.• The good sleep cures the headache, not the D or B12,The good sleep cures the headache, not the D or B12,so if sleep is still terrible help with that also.so if sleep is still terrible help with that also.
    36. 36. Hormones and MigraineHormones and Migraine
    37. 37. Any migraine theory has to explain:Any migraine theory has to explain: Why do migraines start at puberty?Why do migraines start at puberty? Why do they start in boys and girls around theWhy do they start in boys and girls around thesame age but get much better in boys?same age but get much better in boys? Why are they worse around the menses?Why are they worse around the menses? Why are they much worse perimenopausally?Why are they much worse perimenopausally? Why do they go away after menopause?Why do they go away after menopause?
    38. 38. HypothalamusGnRHAnterior PituitaryLH/FSHOvariesinhibin, estradiol, progesteroneAdapted from MacGregor EA. Neurologic Clinics 1997;15(1):125-141.Menstruation and Releasing HormonesMenstruation and Releasing Hormones
    39. 39. Gonadotropin Releasing HormonesGonadotropin Releasing Hormones The releasing hormones (GnRH) boss the ovaries and theThe releasing hormones (GnRH) boss the ovaries and thetesticles. GnRH starts to spike in boys and girls at puberty.testicles. GnRH starts to spike in boys and girls at puberty. GnRH is also aGnRH is also a neurotransmitteneurotransmitter. There are GnRH receptorsr. There are GnRH receptorsin the brainstem. GnRH levels affect sleep snd brainstemin the brainstem. GnRH levels affect sleep snd brainstemexcitability.excitability. After age 18 the boys have a constant daily testosterone level,After age 18 the boys have a constant daily testosterone level,(their GnRH levels stay steady), but their sisters have monthly(their GnRH levels stay steady), but their sisters have monthlyGnRH spikes at ovulation and menstruation.GnRH spikes at ovulation and menstruation. At menopause ovaries are out of eggs, estrogen goes down andAt menopause ovaries are out of eggs, estrogen goes down andso GnRH levels go up. Low doses of estrogen replacement mayso GnRH levels go up. Low doses of estrogen replacement maynot be enough to inhibit GnRH completely. Women innot be enough to inhibit GnRH completely. Women inmenopause can’t stay asleep when their vitamin D is low andmenopause can’t stay asleep when their vitamin D is low andGnRH is high.GnRH is high. Fix the D/B12 system first to get the sleep as good as possibleFix the D/B12 system first to get the sleep as good as possibleand the headaches might go away. Estrogen/progesteroneand the headaches might go away. Estrogen/progesteronereplacement also makes sleep better.replacement also makes sleep better.
    40. 40. Children Have Headaches TooChildren Have Headaches Too There is absolutely no difference between adults withThere is absolutely no difference between adults withheadache and children with headache.headache and children with headache. All of the children I see with headache have poor sleepAll of the children I see with headache have poor sleepand vitamin D deficiency.and vitamin D deficiency. Some have leg pain from kicking in sleep (which isSome have leg pain from kicking in sleep (which isbasically what the kids with rickets complained of).basically what the kids with rickets complained of). Children who get significant headaches before pubertyChildren who get significant headaches before pubertyall have sleep disorders and D deficiency. Fix that first.all have sleep disorders and D deficiency. Fix that first.Always have a CT scan.Always have a CT scan.
    41. 41. Episodic Treatment: TriptansEpisodic Treatment: Triptanssumatriptan, naratriptan, eletriptan, etc.sumatriptan, naratriptan, eletriptan, etc. They work on Serotonin 1B and 1D receptors that areThey work on Serotonin 1B and 1D receptors that arefeedback inhibitors of Serotonin releasefeedback inhibitors of Serotonin release.. They are not pain relievers or anti-inflammatories.They are not pain relievers or anti-inflammatories. We told our patients to “save them for your migraines”,We told our patients to “save them for your migraines”,but our patients were smarter.but our patients were smarter. ““if I can get my medicine soon enough it works”if I can get my medicine soon enough it works” It turned out that the triptans worked better when usedIt turned out that the triptans worked better when usedearlier, on the little headaches, teaching us that all theearlier, on the little headaches, teaching us that all theheadaches are migraine in mechanism.headaches are migraine in mechanism. I believe they act on the Serotonergic Raphe NucleiI believe they act on the Serotonergic Raphe Nuclei
    42. 42. Where are the Serotonin receptors ?Where are the Serotonin receptors ? Most of the serotoninMost of the serotoninmeasured throughout themeasured throughout thebrain originates from thebrain originates from theRaphe nuclei in theRaphe nuclei in thebrainstem.brainstem. So the triptans are probablySo the triptans are probablynot acting primarily on bloodnot acting primarily on bloodvessels in the brain they arevessels in the brain they areworking at the “migraineworking at the “migrainebrainstem generator”. Tobrainstem generator”. Toturn it “off”.turn it “off”.
    43. 43. Serotonergic cells in Raphe Nuclei of theSerotonergic cells in Raphe Nuclei of thePeriaquiductal GreyPeriaquiductal Grey Brain serotonin levels are directlyBrain serotonin levels are directlyrelated to the level of vigilance orrelated to the level of vigilance oralertness.alertness. The brainstem chemoreceptorThe brainstem chemoreceptortrigger zone is in the same area,trigger zone is in the same area,controlling nausea, (the newer anticontrolling nausea, (the newer antinausea agents act on serotonergicnausea agents act on serotonergicreceptors in the brainstem).receptors in the brainstem). Animal studies show that theAnimal studies show that theSerotonergic Raphe Nuclei directlySerotonergic Raphe Nuclei directlycontrol the level of excitability ofcontrol the level of excitability ofthe TNC.the TNC.Ref 9Ref 9Trigeminal NucleusCaudalis
    44. 44. Treatment: PreventionTreatment: Prevention• Use the triptans early!Use the triptans early!• Treat the sleep first if possible, before a dailyTreat the sleep first if possible, before a dailypreventative.preventative.• Very severe headaches not responding to triptans mayVery severe headaches not responding to triptans mayneed a daily preventative.need a daily preventative.• Once the daily headache patient gets on the rightOnce the daily headache patient gets on the rightpreventative medication, (correcting their genetic hyperpreventative medication, (correcting their genetic hyperexcitability), their headaches become episodic and areexcitability), their headaches become episodic and areno different than any other migraine.no different than any other migraine.• After the preventative medication decreases the severityAfter the preventative medication decreases the severityand incidence of the headaches, try the triptans again.and incidence of the headaches, try the triptans again.
    45. 45. Daily Preventatives are allDaily Preventatives are allChannel StabilizersChannel Stabilizers Verapamil SR 180 to 360 (careful in renal failure)Verapamil SR 180 to 360 (careful in renal failure) Atenolol 100 mg qd (Ca++ channel active in migraine)Atenolol 100 mg qd (Ca++ channel active in migraine) Topiramate75-100mg hsTopiramate75-100mg hs Zonisamide 100mg -200mg BID, 300-400 qhsZonisamide 100mg -200mg BID, 300-400 qhs Divalproex sodium 500- 1000 qd (ER) or BIDDivalproex sodium 500- 1000 qd (ER) or BID GabapentinGabapentin CyproheptidineCyproheptidine Other, newer seizure medications, Levetiracetam,Other, newer seizure medications, Levetiracetam,Lamotragine, Oxcarbazepine, Tiagabine, PregabalinLamotragine, Oxcarbazepine, Tiagabine, Pregabalin
    46. 46. Are there other things like Migraine?Are there other things like Migraine? Episodic vertigo is a channel disorder as well. Ca++ orEpisodic vertigo is a channel disorder as well. Ca++ orNa+. (Na+. (Assumes normal anatomy so always have aAssumes normal anatomy so always have ascanscan.).) Ringing in the ears is a “turning on” of the centralRinging in the ears is a “turning on” of the centralbrainstem hearing system and frequently acts likebrainstem hearing system and frequently acts likemigraine: i.e., comes on spontaneously for hours tomigraine: i.e., comes on spontaneously for hours todays, can be daily, gets worse when the sleep is bad.days, can be daily, gets worse when the sleep is bad. When it’s both sides,When it’s both sides, no hearing loss,no hearing loss, with or withoutwith or without“dizzy”, treat it the same way you would migraine;“dizzy”, treat it the same way you would migraine;check the vitamin levels, get the sleep better.check the vitamin levels, get the sleep better.
    47. 47. Mouse models of MigraineMouse models of Migraine One of the Ca++ channelOne of the Ca++ channelmutations that causesmutations that causesmigraine is found in mice.migraine is found in mice. Unfortunately the miceUnfortunately the mice cancannot tell us if they have anot tell us if they have aheadacheheadache They do have staggeringThey do have staggeringepisodes and occasionally,episodes and occasionally,epilepsy.epilepsy. There are alsoThere are also inheritedinheritedepilepsy syndromes andepilepsy syndromes andvertigo syndromesvertigo syndromes that arethat arecaused by Ca++ channelcaused by Ca++ channelmutations.mutations.Boy do Ihave aHeadache!
    48. 48. Epilepsy and ChannelsEpilepsy and Channels If you can make a mouse epileptic with aIf you can make a mouse epileptic with achannel mutation it should not be surprising thatchannel mutation it should not be surprising that Most of the inherited epilepsies are now knownMost of the inherited epilepsies are now knownto be channel disorders as well, usually Na+ orto be channel disorders as well, usually Na+ orCl- channels.Cl- channels. So this iswhat theymeant by“knockoutmouse”
    49. 49. Most epilepsy medications are “channel stabilizers”.Most epilepsy medications are “channel stabilizers”.They act on malfunctioning channels to make them actThey act on malfunctioning channels to make them actmore normally. Which is probably why some of them aremore normally. Which is probably why some of them arealso migraine preventatives and treat vertigo.also migraine preventatives and treat vertigo. LyricaLyrica NeurontinNeurontin DepakoteDepakote TopamaxTopamax TrileptalTrileptal TegretolTegretol KeppraKeppra GabatrilGabatril DiamoxDiamox ZonegranZonegran LamictalLamictal DilantinDilantin
    50. 50. Can Epilepsy be like Migraine?Can Epilepsy be like Migraine? If there is no abnormality of the brain anatomy it is aIf there is no abnormality of the brain anatomy it is aspontaneous “turning on” of neurons in the brain.spontaneous “turning on” of neurons in the brain. It gets worse when the sleep is worse.It gets worse when the sleep is worse. We use the same medicines.We use the same medicines. Can be genetically linked to vertigo attacks andCan be genetically linked to vertigo attacks andmigraine.migraine. Any of the hyperexcitability disorders that we useAny of the hyperexcitability disorders that we useseizure medicines for can be thought of asseizure medicines for can be thought of asinappropriate “turning on” of a part of the nervousinappropriate “turning on” of a part of the nervoussystem.system.
    51. 51. Do animals have migraines?Do animals have migraines?(Bella can’t tell us if she has a headache.)(Bella can’t tell us if she has a headache.)I always get a headachewhen I have to ride inthe car.
    52. 52. ReferencesReferences1.1. Joutel A, Bousser MG, Biousse V, etJoutel A, Bousser MG, Biousse V, et aal.l. A gene for fA gene for faamilimiliaal hemiplegic migrl hemiplegic migraaineinemaps to chromosome 19. Nat Genet 1993;5:40-45.maps to chromosome 19. Nat Genet 1993;5:40-45.[[2.2. Joutel A, Ducros A, VJoutel A, Ducros A, Vaahedi K, ethedi K, et aal. Genetic heterogeneity of fl. Genetic heterogeneity of faamilimiliaal hemiplegicl hemiplegicmigrmigraaine. Am J Hum Genet 1994;55:1166-1172.ine. Am J Hum Genet 1994;55:1166-1172.3.3. Ophoff RA, Terwindt GM, Vergouwe MN, etOphoff RA, Terwindt GM, Vergouwe MN, et aal. Fl. Faamilimiliaal hemiplegic migrl hemiplegic migraaineine aandndepisodicepisodic aattaaxixiaa type-2type-2 aare cre caaused by mutused by mutaations in the Ctions in the Caa2+ ch2+ chaannel genennel geneCCAACNL1CNL1AA4. Cell 1996;87:543-552.4. Cell 1996;87:543-552.4.4. Terwindt GM, Ophoff RTerwindt GM, Ophoff RAA, H, Haaaan J, etn J, et aal. Vl. Vaaririaable clinicble clinicaal expression of mutl expression of mutaationstionsin the P/Q-type cin the P/Q-type caalcium chlcium chaannel gene in fnnel gene in faamilimiliaal hemiplegic migrl hemiplegic migraaine. Neurologyine. Neurology1998;50:1105-1110.1998;50:1105-1110.5.5. Ophoff ROphoff RAA, v, vaan Eijk R, Sn Eijk R, Saandkuijl Lndkuijl LAA, et, et aal.l. Genetic heterogeneity of fGenetic heterogeneity of faamilimiliaallhemiplegic migrhemiplegic migraaine. Genomics 1994;22:21-26.ine. Genomics 1994;22:21-26.6.6. DucrosDucros AA, Joutel, Joutel AA, V, Vaahedi K, ethedi K, et aal. Ml. Maapping ofpping of aa second locus for fsecond locus for faamilimiliaallhemiplegic migrhemiplegic migraaine to 1q21-q23ine to 1q21-q23 aand evidence of further heterogeneity.nd evidence of further heterogeneity. AAnnnnNeurol 1997;42:885-890.Neurol 1997;42:885-890.7.7. HHaans M, Luvisetto S, Willins M, Luvisetto S, Williaams ME, etms ME, et aal. Functionl. Functionaal consequences of mutl consequences of mutaations intions inthe humthe humaann aalphlphaa11AA ccaalcium chlcium chaannel subunit linked to fnnel subunit linked to faamilimiliaal hemiplegicl hemiplegicmigrmigraaine. J Neurosci 1999;19:1610-1619ine. J Neurosci 1999;19:1610-1619
    53. 53. ReferencesReferences6.6. Jurkat-Rott, K., Freilinger, T., Dreier, J. P., Herzog, J., Gobel, H., Petzold,Jurkat-Rott, K., Freilinger, T., Dreier, J. P., Herzog, J., Gobel, H., Petzold,G. C., Montagna, P., Gasser, T., Lehmann-Horn, F., Dichgans, M. (2004).G. C., Montagna, P., Gasser, T., Lehmann-Horn, F., Dichgans, M. (2004).Variability of familial hemiplegic migraine with novel A1A2 Na+/K+-Variability of familial hemiplegic migraine with novel A1A2 Na+/K+-ATPase variants.ATPase variants. NeurologyNeurology 62: 1857-186162: 1857-18617.7. Elliott MA, Peroutka SJ, Welch S, May EF. Familial hemiplegic migrElliott MA, Peroutka SJ, Welch S, May EF. Familial hemiplegic migraaine,ine,nystagmus, and cerebellar atrophy. Ann Neurol 1996;39:100-106.nystagmus, and cerebellar atrophy. Ann Neurol 1996;39:100-106.8.8. van den Maagdenberg AM, Pietrobon D, Pizzorusso T, Kaja S,van den Maagdenberg AM, Pietrobon D, Pizzorusso T, Kaja S, BroosBroos LA,LA,CesettiCesetti T, van deT, van de VenVen RC,RC, TotteneTottene A, vanA, van derder KaaKaa J,J, PlompPlompJJ, Frants RR, Ferrari MDJJ, Frants RR, Ferrari MD.. A Cacna1a knockin migraine mouse modelA Cacna1a knockin migraine mouse modelwith increased susceptibility to cortical spreading depression.with increased susceptibility to cortical spreading depression.Neuron. 2004 Mar 4;41(5):701-10.Neuron. 2004 Mar 4;41(5):701-10.9.9. Knight YE, Bartsch T, Kaube H, Goadsby PJ. P/Q Type Calcium-channelKnight YE, Bartsch T, Kaube H, Goadsby PJ. P/Q Type Calcium-channelblockade in the periaqueductal gray facilitates trigeminal nociception: Ablockade in the periaqueductal gray facilitates trigeminal nociception: Afunctional genetic link for migraine? Jour Neurosci 2002 ;22: RC213 1-6.functional genetic link for migraine? Jour Neurosci 2002 ;22: RC213 1-6.

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