Neuroscience Week 3: Headaches Flashcards
Be able to recognize the characteristics of the types (tension, cluster, migraine both classical and complicated) and etiologies of headaches.
Objective 2
How do we treat these types of headaches?
Objective 3
Know how the triptans and ergotamine drugs work, and recognize the major side effects, toxicities & contraindications.
Objective 4
Which drugs are used as preventative and which are used abort migraine Recognize the drug classes and prototypes for prophylactic treatment of migraine
Objective 5
Recognize the proposed pathophysiologies in a migraine (Trigeminovascular, neurogenic inflammation and cortical spreading depression)
Objective 6
Understand what is serotonin syndrome, drug interactions which can produce serotonin syndrome and how we treat it.
I thought there are no pain receptors in the brain, so why do we get headaches?
There are several pain sensitive intracranial structures.
Pain signals may arise from
receptors located in the:
1.)dura mater, 2.) meningeal vessels, 3.)intracranial segments of trigeminal CN V, glossopharyngeal CN IX, and vagus CN X, 4.) intracranial segments of the basilar, vertebral, and carotid arteries; all can transmit pain signals to the second-order neurons in the trigeminal nucleus caudalis (TNC) in the medulla and to the dorsal horn of the upper cervical spine.
Secondary neuron activity of the TNC
The activity of second-order neurons in those two areas can be modified by inputs from the nucleus raphe magnus (serotonerg ic), periaqueduct al gray area, locus ceruleus (noradrenergic), and rostral trigeminal nuclei, and by descending inhibitory transmissions from the cerebral cortex.
These correspondingly modified signals are then relayed to the contralateral dorsomedial and ventroposteromedial nuclei of the thalamus, a common destination for pain transmissions, and then on to the insular cortex, the anterior cingulate cortex, and the somatosensory cortex.
Sensory nerve fibers associated with cranial vasculature
- Trigeminal sensory nerve fibers : calcitonin gene-related peptide (CGRP), substance P, neurokinin A and pituitary adenylate-cyclase activating peptide (PACAP), as well as nitric oxide synthase (NOS).
- Parasympathetic nerve fibers: vasoactive intestinal peptide (VIP), PACAP, neuropeptide Y (NPY) and acetylcholine and NOS.
- Sympathetic nerve fibers: norepinephrine, NPY and adenosine triphosphate (ATP).
Potent vasodilators
4 listed
- NOS,
- CGRP
- PACAP
- NPY
are potent vasodilators.
Endothelial Vasodilators
ATP is an endothelial vasodilator
CGRP AKA
calcitonin gene-related peptide
Most headaches occur in this way
With the onset of some headaches, there is an increased release of the vasodilator calcitonin gene-related peptide (CGRP), a potential vasodilator. There is also increased mast cell degranulation and release of histamine, sensitizing the individual to small changes in intracranial pressure, and causing the characteristic throbbing quality of pain.
treatment for headaches target
Treatments for a headache may target the pain circuitry peripherally, centrally or both. During the natural course of some types of headache, both initial peripheral sensitization and, in most cases, subsequent central pain sensitization occurs. During peripheral sensitization, primary afferent neurons may become irritable and increase their spontaneous firing because of neurogenic inflammation and dilation of meningeal blood vessels.
Central sensitization and cutaneous allodynia
Central sensitization is often marked by the development of cutaneous allodynia (the perception of pain in response to a normally non-painful stimulus), and this may involve the scalp, face, and even the arms. Cutaneous allodynia occurs in 79% of people who get migraine headaches. During central sensitization, the excitatory thresholds of second-order neurons in the TNC and the dorsal horn of the cervical spine is reduced.
Classification of Headaches
Classify the headache type (not the patient) by 4 main characteristics
- ) Quality (pressing throbbing, etc.)
- ) Intensity (mild, moderate severe)
- ) Location (unilateral, bilateral, etc.)
- ) Response to routine physical activities.
- ) Associated features (nausea, vomiting hypersensitivity to light or noise, auras) and ask about use of analgesics
Chronic Tension Headache Description
Occurs equally in women and men
Usually related to musculoskeletal spasm of neck and shoulders
Rebound headaches common from excessive symptomatic medications (ie. OTC preparations, opioid use, barbiturate combination therapies, especially short-acting agents.
Many patients have “mixed headaches”
Chronic tension headache Treatment
Physical therapy – Stretching- Relaxation techniques- Posture correction
Muscle relaxants
Tricyclic antidepressants
Non-steroidal anti-inflammatory medications
REBOUND OR MEDICATION OVER-USE HEADACHES Description
Rebound headaches (medication-overuse headaches) are caused by regular, long-term use of medications, often those used to treat headaches, such as migraine. Pain relievers offer relief for occasional headaches. But if you take them more than a couple of days a week, they may trigger rebound headaches. Any medication taken for pain relief can cause rebound headaches. Rebound headaches usually stop when you stop taking the pain medication. Signs and symptoms of rebound headaches may differ according to the type of original headache being treated and the medication used
Rebound headaches Common features
Occur every day or nearly every day, often waking you in the early morning
Improve with pain relief medication but then return as your medication wears off
Other signs and symptoms may include:
- Nausea
- Listlessness
- Restlessness and difficulty concentrating
- Memory problems
- Irritability
Rebound Headaches (a Complication)
Rebound headaches are usually a complication of Migraine or another headache disorder, a complication that can present huge obstacles to headache treatment.
Cluster headache Description
Cluster headache is a primary headache syndrome that is characterized by excruciatingly severe, strictly unilateral attacks of orbital, supraorbital or temporal pain, which last 15–180 min and are accompanied by ipsilateral autonomic manifestations (e.g. lacrimation and rhinorrhea). Hypothalamic dysregulation plays a key role in this type of primary headache
Cluster headache Clinical Presentation
- Occurrence males > females
- Usually no family history Headaches can occur up to 3 times a day over a several month period, orbital supraorbital or temporal
- Pain – abrupt onset, unilateral and usually remains on the same side of the head from attack to attack.
- Attacks can last for 15-180 min The attacks typically occur with circadian rhythmicity, being experienced at fixed hours of the day or night Ipsilateral eye injected, nostril blocked
- Partial Horner syndrome can occur (miosis, ptosis and anhidrosis) hemifacial sweating CGRP and VIP are released
Cluster headache Treatment
- Oxygen works in many cases but why is not known.
- Short course of corticosteroids
- lidocaine intranasal ipsilateral to the headache
- “Triptans”
- Ergotamine-DHE
*
Cluster headache Prophylactic Treatment
- Verapamil –calcium channel blocker
- Lithium
- mood stabilizer Valproate, Topiramate etc
- antiseizure drugs
- Ergotamines
- BoTox
Classical Migraine Headache
- With visual aura, such as scintillating scotoma (diminished vision within a field) or fortification spectra (zig zag lines at outer edge of visual field) – thought to represent neuronal spreading depression within the occipital lobe
- The remainder of clinical presentation is the same as with common migraine
Complicated Migraine Headache
Involves significant neurological deficits (cranial nerve palsy, paresthesia, hemiopia, hemiparesia, dysphasia, seizure, etc)
Neurological symptoms tend to persist into the headache phase
Recovery may take hours to days or weeks
Rarely may represent a stroke if neurological symptoms are due to vasoconstriction or spasm then treatment should NOT include ergotamines or “Triptans”
Rare Forms of Migraine
3 listed
- Familial Hemiplegic Migraine
- Basilar migraine (BM)
- Retinal migraine
Migraine Headaches Common Clinical Presentation
- No aura
- With nausea, vomiting, photophobia
- Sleep alleviates symptoms
- Positive familial history frequent
- Unilateral, throbbing quality of pain
Familial Hemiplegic Migraine
A hemiplegic migraine is a very rare but well-described form of migraine. Tends to run in families with 60-80% have an affected family member. A recurrent headache associated with temporary unilateral hemiparesis or hemiplegia, at times accompanied by ipsilateral numbness or tingling, with or without a speech disturbance. Attacks typically the last one to three days- severe, incapacitating, unilateral, pulsating headache. The focal neurologic deficit may precede or accompany the headache, which is usually less dramatic than a motor deficit. Other migraine symptoms may variably be present. Patients may also experience disturbance of consciousness, and rarely coma. The neurologic deficit is transient and usually clears in minutes to hours, or resolves with the beginning of the headache phase. Hemiplegic migraines are associated with four different mutations in the gene encoding the P/Q voltage-gated calcium channel. The point mutation produces a missense mutation that codes for a substitution at a residue that is highly conserved among the Ca2+ channel 1-subunits
Basilar migraine (BM)
also known as Bickerstaff syndrome, consists of headache accompanied by dizziness, ataxia, tinnitus, decreased hearing, nausea and vomiting, dysarthria, diplopia, loss of balance, bilateral paresthesias or paresis, altered consciousness, syncope, and sometimes loss of consciousness. BM is observed most frequently in adolescent girls and young women. Localized vertebrobasilar vasoconstriction leading to transient posterior circulation ischemia may contribute to the symptomatology of the disorder. A novel mutation in the ATP1A2 gene, similar to FHM, has been reported in members of one family with BM. Differential diagnosis includes various causes of syncopal, inner ear disease, intoxication, and posterior fossa pathologies.
Basilar migraine (BM) AKA
Bickerstaff Syndrome
Retinal migraine
recurrent attacks of unilateral visual disturbance or blindness lasting mins to 1 hour, associated with minimal or no headache.
Migraine Pathophysiology
Trigemnial Reflex Pathology Migraine dysfunction of the trigeminal-autonomic reflex via brain stem pathways that normally modulate sensory input. Migraine is thought to be a dysfunction of the sensory input modulation within the diencephalon (Thal. & hypothal) and the brain stem. (Locus ceruleus & Periaquiductal gray)
The extra and intracranial vessels are innervated with small unmyelinated fibers from the trigeminal nerve. The trigeminal nociceptive input from the meningeal vessels passes through the trigeminal ganglion and synapses on second-order neurons in the trigeminocervical complex these neurons project through the quintothalamic tract and then decussating in the brain stem they form synapses with neurons in the thalamus. There is a reflex connection between neurons in the pons in the superior salivatory nucleus which results in a cranial parasympathetic outflow through the pterygopalatine ganalion,
Activation of the Trigeminovascular system is thought to be responsible for the pain. Vasoconstriction due to 5HT while over active vasodilation is linked to CGRP. . Ophthalmic division of the Trigeminal nerve innervates the meningies and the large intracranial vessels, densely innervated with nociceptive fibers.-Activation of these fibers releases CGRP and substance P leads to migraine
The initial vasoconstriction is followed by a rebound vasodilation in intracranial arteries. CGRP acts on smooth-muscle cells to cause potent dilation CGRP-containing sensory nerve fibers act to counter vasoconstrictor influences. CGRP is thought to be a major player in migraine pain.
Rebound vasodilation leads to plasma protein extravasation in dura mater, leading to “neurogenic” inflammation (resident macrophages and mast cells.
- Cortical Spreading depression- is another phenomenon seen in migraine. CSD is a slow propagating wave of sustained strong neuronal depolarization. Transient intense spike activity followed by neuronal suppression that can last for minutes. It is associated with increase regional cerebral blood flow and depressed cortical activity. This is followed by a sustained hyperpolarization.
CSD Activates trigeminal afferents and causes inflammation of pain sensitive meninges that generates aura. Blocking CSD prevents the aura but does not stop the pain. About 20-30% of episodic migraine have auras
Cortical Spreading depression
is another phenomenon seen in migraine. CSD is a slow propagating wave of sustained strong neuronal depolarization. Transient intense spike activity followed by neuronal suppression that can last for minutes. It is associated with increase regional cerebral blood flow and depressed cortical activity. This is followed by a sustained hyperpolarization.
CSD Activates trigeminal afferents and causes inflammation of pain sensitive meninges that generates aura. Blocking CSD prevents the aura but does not stop the pain. About 20-30% of episodic migraine have auras
Abortive treatment of Migraine
5-HT 1d/b, receptor agonists -“Triptans” Triptans are inhibitory autoreceptor agonists at the 5hT1B/D receptor. Triptans cause vasoconstriction thereby blocking further CGRP and Sub P release from the trigeminal nerve terminal release (inhibits neurogenic inflammation) in the vessel wall during the activation of the trigeminovascular system. Sumatriptan and ergotamine block the development of neurogneic plasma extravasation in dura by blocking neuropeptide release. The triptans can be used for cluster headache as well.
Sumatriptan (Imitrex)
Rizatriptan (Maxalt)
Zolmitriptan (Zomig)
Naratriptan (Amerge)
Frovatriptan (Frova)
Eletriptan (Relpax)
Almotriptan (Axert)
Ergot alkaloids Dihydroergotamine Ergotamine
Opioid analgesics
Barbiturates
NSAIDS- naproxen, ibuprofen
Antiemetics/ antipsychotic-chlorperazine (compazine), chlorpromazine (thorazine) This later group of pharmacotherapies just relieve the nausea component.
5-HT1B/1D auto-receptors in migraines
This figure shows the sites which have 5-HT1B/1D auto-receptors which are activated by the “triptans” leading vasoconstriction and a decrease in CGRP release. Remember auto-receptors hyperpolarize the presynaptic terminal leading to decreased neurotransmitter release. CGRP is found throughout the trigeminovascular system and in central brain regions regarded as important in migraine pathogenesis. CGRP serum concentrations can be reversed with triptan administration—an effect that coincides with migraine symptom relief
Antagonists to the Calcitonin gene-related peptide
- Antagonists to the calcitonin gene related peptide receptors are being developed for migraine.
- There are several anti-CGRP drugs which are in late stage clinical trials which may be available in 2018 Most are monocolonal antibodies like erenumab and fremanezumab and glacanezumab.
- Telcagepant (a CGRP receptor antagonist, Merck, this drug was halted in phase 3 trials due to liver toxicity).
Sumatriptan-Pharmacokinetics & side effects
97% bioavail. subQ , 14% from oral. ½ life is 2 hours metabolized by MAOA isozyme.
- Side effects mostly associated with injection … Lightheadedness muscle aches nausea or vomiting
- Rare side effects: Severe chest pain Shortness of breath Convulsions Swelling of the eyelids
- Can cause atrial and ventricular arrhythmias, myocardial infarction and transient myocardial ischemia
- Contraindicated-coronary vasospasms, so avoid with patients with ischemic heart disease or coronary artery spasm, vasospasms,
- or in combination with on other 5HT elevating drug
Ergotamine
- Nonselective, partial 5HT agonist at some blood vessels, nonselective 5HT antagonist at smooth muscle. Causes smooth muscle contraction. variant ergonovine that has selecitvity for uterine smooth muscle
- DiHydroE is a vasoconstrictor. Used in cluster and abortive for migraine • Inhibits neuropeptide release and blocks neurogeneic inflam.
- Some antagonist effects at DA & alpha adrenergic receptors.
- Nausea by direct action on CTZ. Leg weakness and muscle pain, numbness in fingers and toes. Constricts arteries and veins.
- Can cause coronary vasospasm. coronary artery vasoconstriction, angina, and with frequent use: myocardial infarction, coronary artery disease and stroke
- Contraindication: pregnancy (fetal damage), peripheral vascular and coronary heart diseases. Raynaud’s syndrome Severe or uncontrolled hypertension Hyperthyroidism Sepsis Porphyria Hepatic or renal disease
- Can cause serotonin syndrome when used in combination with other serotonin elevating drugs.
Prophylactic Treatments of Migraines
WHAT IS SEROTONIN SYNDROME?
A clinical triad of abnormalities brought on by an elevation of serotonin levels due to drug interactions:
- Cognitive effects: hypervigilance, mental confusion, hallucinations, agitation, headache, coma.
- Autonomic effects: shivering, sweating, fever, hypertension, tachycardia, nausea, diarrhea.
- Somatic Neuromuscular effects: myoclonus/clonus (muscle twitching), hyperreflexia, incoordination tremor.
Other effects: metabolic acidosis, rhabdomyolysis, renal failure, and disseminated intravascular coagulation (DIC)
Drugs causing serotonin syndrome
SSRIs, second generation antidepressants, MAOIs, linezolid, tramadol, meperidine, fentanyl, ondansetron, MDMA, LSD, St. John’s wort, ginseng (this is not a complete listing)
Treatment for serotonin syndrome
Sedation (benzodiazepines), intubation and ventilation; consider 5-HT2 block with cyproheptadine (serotonin receptor antagonist) or chlorpromazine (greater antagonistic effect on 5HT than D2)
Does sumatriptan lead to serotonin syndrome?
Triptans do not produce it on their own (as a monotherapy). SSRIs can produce Serotonin syndrome on their own. The data suggest that the combination of Triptans and serotonin reuptake inhibitors does not lead to serotonin syndrome. But some examiners may still think triptans and SSRIs are contraindicated and ask a question based on this assumption.
Secondary Headache type examples
Systemic infection (e.g. meningitis)
Medication overuse
Head injury
Vascular disorders
Subarachnoid hemorrhage
Brain tumor
Pain-sensitive intracranial structures
- Great venous sinuses
- Dural arteries
- Arteries forming the circle of Willis
- Pain-sensitive fibers of intracranial segments of CN: V, IX, X
- Dura Matter (at skull base)
Pathways of Headache pain
Triggers of migraine
- caffeine
- wine
- chocolate
- change of routine
- lack of sleep
- menstruation
Case 1
- What type of headache is this?
- Is it a primary or secondary headache?
- What is the cause of this headache?
- How would you treat this headache?
Medication-overuse headache
is a secondary headache because it is caused by something else
How to Treat a Medication-overuse headache
Question : Which of the following medications are implicated in causing medication overuse headache?
A. Analgesics
B. Caffeine
C. Antiepileptics
D. Triptans
E. Ergotamine
F. Opiates/narcotics/barbiturates
G. All of the above
All of the Above
Case 2
- What type of headache is this?
- What are the key findings leading to the diagnosis?
- What is your abortive medication plan?
- How do these drugs work?
- What side effects or contraindications are there to consider?
- Common Migraine Headache
- key patient findings; nausea, triggers such as chocolate or wine, no aura, +FHx, photophobia and phonophobia, usually throbbing and unilateral and is a female
- abortive medication are triptans such as sumatriptan
What are the Triptan drugs and how do they work?
act on the serotonin 5ht1b,1e,1d receptors as agonists
these receptors sit mostly presynaptically
What are the key patient findings that lead you to the diagnosis of common migraine?
Mrs. Zhang needs acute (abortive) medications. What is your proposed treatment?
overview of migraine physiology
Sumatriptan as
CGRP inhibitor
disregulation of the trigeminal nerve in the brain stem can?
be like allodynic where a touch of the hand can become quite painful
What happens during a migraine
Nerve involved in migraines
Trigeminal nerve is disregulated
Sumatriptan is generally contraindicated in?
- Postpartum Yes
- uncontrolled HTN Yes
- Coronary vasospasm Yes
- Ischemic cardiac disease Yes
What preventative medications are there for migraines?
Botox in migraines
SNAP-25 complex involved in CGRP release or any neurotransmitter so they are injected in the sinus where needed
neural mechanism of aura
Case 3
- What type of headache is this?
- What are the key findings leading to the diagnosis?
- What is your abortive medication plan?
- How do these drugs work?
- What side effects or contraindications are there to consider?
Key features of cluster headache
Conjunctival injection
Lacrimation
Nasal congestion
Rhinorrhoea
Forehead and facial sweating
Miosis
Ptosis
Eyelid edema
Treatment of Cluster headache
Methylprednisolone, (Correct)
Oxygen (Correct)
Sumatriptan, (Correct)
4% lidocaine solution intranasal (Correct)
Partial Horner Syndrome can occur with what head ache type
Cluster headaches
Partial Horner Syndrome Clinical Features
Partial Horner syndrome can occur (miosis, ptosis and anhidrosis) hemifacial sweating
During your examination of Mr. Bibs, he develops a severe headache consistent with his cluster headaches. Which of the following is the best therapy to offer him as an acute treatment of his current headache?
A. Promethazine
B. Methylprednisolone
C. Oxygen
D. Sumatriptan
E. 4% lidocaine solution intranasal
c, d, e
Simplest acute treatment of cluster headaches
Oxygen
After have managed Mr. Bibbs acute pain you discuss with him the plan for managing his cluster headaches and reducing the frequency of their occurrence. What are options for Mr. Bibbs?
Pathophysiology of Cluster Headache
CGRP Blockers
Ergotamine
Ergotamine Nonselective, partial 5HT agonist at some blood vessels, nonselective 5HT antagonist at smooth muscle. Causes smooth muscle contraction. DiHydroE is a vasoconstrictor. Can cause coronary vasospasm. coronary artery vasoconstriction, angina, and with frequent use: myocardial infarction, coronary artery disease and stroke Contraindication: pregnancy (fetal damage), peripheral vascular and coronary heart diseases. Raynaud’s syndrome Severe or uncontrolled hypertension Hyperthyroidism Sepsis Porphyria Hepatic or renal disease
Verapamil-
Calcium Channel antagonist for angina and arrhythmias, Bradycardia, second and third degree atrioventricular block, heart failure, can cause fatal supraventricular tachycardia in ptx with Wolff-Parkinson-White Syndrome.
Anticonvulsants
many of the anticonvulsants can produce a rare serious skin reaction called Stevens Johnson syndrome (erythema multiforme, and toxic epidermal necrolysis
Your patient comes in to tell you that using his abortive medicine for his cluster headache he felt numbness and tingling in his extremities and blanching and cyanosis in his fingers. Which medicine produces this?
A. Lidocaine
B. Sumatriptan
C. Dihydroergotamine
D. Lithium
E. Naproxen
C.
Serotonin Syndrome
Libby Zion Law
Pain location of:
Sinus
Cluster
Tension
Migraine Headaches
A patient presents to your headache clinic complaining of recurring headaches which happen 2-3 times a day and last for about an hour. This has been going on for several weeks and this occurs in the spring and fall. He describes ptosis and miosis on the affected side along with nasal congestion. You give him a prescription but later he returns with a serious skin condition that you identify as Steven Johnson Syndrome. The drug is prescribed was most likely
A. Sumatriptan
B. NSAID-Caffeine
C. Verapamil
D. Lidocaine
E. Topiramate
E.
A 24 year old woman comes into your clinic complaining of extremely painful headaches which she describes as severe throbbing in quality and occurring about 4 times per month lasting for 8 hours at a time. She tells you that the headaches require her to lie down in a darkened room with no noise and she is sometimes nauseated by the pain. What patient history information would most contraindicate an abortive migraine treatment?
A. history of type-2 diabetes
B. history of atrial fibulation and coronary vasospasms
C. genetic history of channelopathy
D. history of hypothyroidism
E. Substance use disorder
B.
In deciding upon a pharmacotherapy for this patient you select an agent to abort these headaches once they begin. The drug you select will most likely produce what therapeutic action in the brain ?
A. Increase the release of substance P
B. Increase the levels of encephalin
C. Decrease the release of calcitonin gene related peptide
D. Increase the release of serotonin
E. Decrease the activity of nitric oxide synthase
C.
A meningitis related headache would be associated most often with which ROS finding?
a. stiff neck
b. visual aura
c. hemiparesis
d. Horner’s
Stiff neck
Horner’s syndrome would be associated most often with which type of headache
a. migraine
b. tension
c. cluster
d. complicated migraine
Cluster
A 16 year old female patient being treated for depression with a serotonin selective reuptake inhibitor (SSRI) comes into to your headache clinic seeking prophylactic treatment for classic migraines. Which class of drugs would be contraindicated in this patient?
A. Propranolol
B. Verapamil
C. NSAID
D. MAOI
E. caffeine
MAOI
At your headache clinic your patient has a history of hypertension, and a strong family history of MI and A. fib. The migraine treatment which would be contraindicated in this patient is:
A. Propranolol
B. Caffeine
C. Sumatriptan
D. Oxycodone
E. Naproxen sodium
Sumatriptan
