Clinical Notes : Neurology

1. Migraine

A migraine is a headache that lasts for 4–72 hours and presents with at least two of the following symptoms:

  • unilateral localisation,

  • moderate to severe pain intensity,

  • aggravation by movement,

  • and a pulsating feeling.

The headache is also usually accompanied by nausea, vomiting, photo- and phonophobia.(1)

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Phase 1: Prodrome:

A migraine headache is generally preceded by a premonitory phase that lasts for hours before the headache begins.(1)

Between 30% and 40% of "migraineurs" (i.e. people who suffer from migraine) experience the prodrome. (5)

This phase is characterised by fatigue, mood changes and gastrointestinal problems, which could persist throughout the entire migraine attack.(1)

Possible prodrome symptoms include:

 

Phase 2: Aura

One in five migraineurs also experience an aura, which consists of visual, sensory or motor disturbances.(1)

The possible forms of aura include:

  • Alice in Wonderland Syndrome: a rare form of Migraine aura in which the distinctive symptom is a type of metamorphosia, a distortion of body image and perspective, which Migraineurs know, while it’s occurring is not real. “Alice in Wonderland” syndrome can occur at any age, but it is more commonly experienced by children.

  • allodynia: hypersensitivity to feel and touch to the point that what would be “normal” is painful

  • aphasia

  • auditory hallucinations: hearing sounds that aren’t actually present

  • confusion

  • decrease in or loss of hearing

  • dizziness

  • hemiplegia: one-sided paralysis (occurs in hemiplegic Migraine only)

  • olfactory hallucinations: smelling odors that aren’t actually present

  • parasthesia: prickling, stinging, burning, numbness, and / or tingling, usually of the extremities or face

  • vertigo: sensation of whirling or spinning, not to be confused with dizziness

  • visual:

    • wavy lines (sometimes described as “looking like heat rising from pavement”)

    • “blank” or tiny blind spots

    • blurry vision

    • partial loss of sight

    • phosphenes: brief flashes of light that streak across the visual field

    • scotoma: an area of decreased or lost vision. Some people describe scotoma as being like having tiny blank spots in their vision. Some compare it to tiny snowflakes.

    • unilateral (one-sided) (occurs in retinal Migraine only)

 

Wavy lines (like heat rising)

Phosphenes

Scotoma

Phase 3: Headache

A Migraine attack can occur without the headache phase.

When that occurs, the descriptive terms “acephalgic” or “silent” are applied.

Symptoms and characteristics of the headache phase may include:

  • headache

    • frequently unilateral (one-sided). The headache can shift from one side to the other, become bilateral (on both sides), or be bilateral entirely

    • often pulsating or throbbing

    • worsened by physical activity

    • duration of four to 72 hours in adults, one to 72 hours in children

    • Because the trigeminal nerve becomes inflamed during a Migraine, and because of its location, pain may occur around eyes, in the sinus area, and the teeth and jaw.

  • confusion

  • dehydration

  • dizziness

  • depression, anxiety, panic

  • diarrhea or constipation

  • fluid retention

  • hot flashes and / or chills

  • nasal congestion and / or runny nose

  • nausea and / or vomiting

  • neck pain

  • osmophobia (heightened sensitivity to odors)

  • phonophobia (heightened sensitivity to sound)

  • photophobia (heightened sensitivity to light)

  • vertigo

Phase 4: Postdrome

The headache is followed by a recovery phase, or postdrome (also referred to as a ‘migraine-hangover’), with fatigue and continued sensory disturbances.(5)

Postdrome symptoms may include:

 

Classification

Migraine is usually classified as having two major subtypes (2):

Migraine with an aura

Migraine without an aura

 

Migraine is considered to be chronic when it occurs for a minimum duration of four hours per day, and lasts for more than 15 days per month, within a three-month period.(3)

Chronic migraine is frequently associated with the so-called medication-overuse-headache.(4)

 
 

Pathophysiology

Migraine headaches have a controversial pathophysiology.

The most widely acceptable pathophysiological process involves the activation and sensitisation of the trigeminovascular system (TVS).(6)

Trigeminovascular system.

Primary afferents of neurons in the trigeminal ganglion extend from the meningeal vasculature to central terminals in the TNC (brown).

Second-order neurons of the TNC, in turn, project to the posterior thalamus.

The SPG (purple) also provides reflex parasympathetic innervation to meningeal vessels.

Abbreviations:

SPG, sphenopalatine ganglion

TNC, trigeminal nucleus caudalis

When the TVS is activated, the signal travels through the trigeminal ganglion to the neurons in the trigeminocervical complex, with calcitonin gene-related peptide (CGRP) as the main neurotransmitter.(7)

CGRP is a potent vasodilator, produced in the central and peripheral neurons, that has been implicated in the transmission of pain signals and is released during severe migraine attacks.(8)

CGRP facilitates synaptic transmission as a neuromodulator of glutamate release and receptor activation.

CGRP (red circles) released from presynaptic terminals (light blue) leads to additional release of glutamate (brown circles) and CGRP.

At postsynaptic terminals (dark blue), CGRP increases neuronal excitability by cAMP-dependent phosphorylation of AMPARs and NMDARs, leading to increased conductance and synaptic facilitation.

In addition, neuronal CGRP may act in a paracrine fashion on nearby glia (yellow) and dural mast cells (not shown) to indirectly influence the neurons. Abbreviations:

AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor

cAMP, cyclic adenosine monophosphate; CGRP, calcitonin gene-related peptide

CLR, calcitonin-like receptor

NMDAR, N-methyl-d-aspartate receptor

RAMP1, receptor activity-modifying protein

CGRP-induced hypersensitivity to sensory stimuli.  Under normal conditions, CGRP levels are relatively low, neurotransmission is normal, and sensory input is properly filtered.

Triggers of migraine lead to an increase in CGRP levels, causing enhanced synaptic transmission and thereby pain and altered sensory perception. Abbreviation:

CGRP, calcitonin gene-related peptide.

Diagnosis

The diagnosis is made, based on the clinical presentation or symptoms of the patient, and by excluding other causes of frequent headaches.(9)

In many cases the pain experienced during migraine attacks, occurs unilaterally.(10)

The pain is described as severe and is accompanied by nausea and/or vomiting, hypersensitivity to light, sound and odour.7

Chronic migraine diagnosis relies on the International Classification of Headache Disorders (ICHD-3) beta criteria, because there are no biological markers for chronic migraine.(3)

 
 
 

Migraine prevention

Migraine attacks can range in intensity from moderate to severe, and may be preceded by other symptoms.(8)

The migraines can change from being episodic to being chronic.

Although episodic migraine can remain unchanged for years, there is also the likelihood that it could remit or develop into a situation whereby it may be classified as chronic, with an increasing severity and frequency of headaches per month.(8)

When the headaches do become chronic, optimal preventative migraine therapy may differ for each individual migraineur.(8)

These drugs will, on average, reduce migraine frequency by 50% in about 40–45% of patients, however compliance and adherence are poor because of their many adverse effects.

 

β-blockers

  • atenolol

  • metoprolol

  • nadolol

  • propranolol

  • timolol

Use of these drugs should be carefully monitored in patients who exhibit undesirable adverse effects and switched to a different class, such as the anti-epileptic agents (e.g. valproic acid).(2)

 

Anti-epileptic agents

  • carbamazepine

  • valproate

  • gabapentin

  • topiramate

  • lamotrigine

In this class, topiramate is one of the most effective therapy options to consider in patients with chronic migraine.(2)

 

Serotonin-receptor antagonists

  • methysergide is a 5-HT2 receptor antagonist and 5-HT1B/D receptor agonist

  • pizotifen, a 5-HT2 receptor antagonist

Currently, pizotifen  is mainly considered for use in patients that are refractory to other prophylactic drugs, due to the high cardiac adverse effect profile. The use of pizotifen should not be longer than six months.(15)

 

Other agents

  • Calcium channel blockers

    • Flunarizine is a calcium channel blocker that also has antihistaminergic properties

      • It is used for migraine prophylaxis and in some instances, as a first line drug in children with hemiplegic migraines.(16)

    • verapamil

  • Angiotensin II-receptor antagonists

    • candesartan

  • Antidepressants

    • amitriptyline

    • venlafaxine

  • Botulinum toxin A

    • Onabotulinum toxin A is classified as a neurotoxin, which is primarily a product of the anaerobic bacterium, Clostridium botulinum

    • The toxin appears to exert its mechanism of action by inhibiting the release of nociceptive mediators involved in the pathogenesis of migraine.(4)

    • These include substance P, CGRP and glutamate; it inhibits these nociceptive mediators from the peripheral nerve terminals of primary afferents.(4)

    • In the two randomised clinical trials that the drug underwent, it was evident from the data collected that onabotulinum toxin A is a safe, well-tolerated, and an effective prophylactic treatment in patients suffering from chronic migraine.(3)

 
 

Managing acute attacks

Acute migraine attacks should be treated early, when the pain is still mild and current guidelines for the treatment of acute mild to moderate migraine attacks recommend (9):

  • non-steroidal anti-inflammatory drugs (NSAIDs)

  • aspirin

  • paracetamol.

 

When NSAIDs fail to control the early mild to moderate pain, treatment should be escalated to triptans:

  • sumatriptan

  • zolmitriptan

  • naratriptan

  • rizatriptan

  • eletriptan

  • almotriptan

  • frovatriptan

Sumatriptan was specifically formulated for the treatment of acute migraine attacks. It has a high specificity for the 5-HT1B and 5-HT1D serotonin receptors.2 This mechanism of action produces cerebral vasoconstriction, secondary to their inhibition of calcitonin gene-related peptide (CGRP) and inflammatory peptide release.(2)

The concomitant use of other agents that increase serotonin levels, such as the SSRIs and the serotonin-noradrenaline reuptake inhibitors (SNRIs), should be avoided due to the danger of developing serotonin syndrome.(11)

The triptans should also be avoided in patients with a history of ischemic heart disease, cerebrovascular disease and uncontrolled hypertension.(12)

 

The opioids should probably only be reserved as rescue treatment, or for very infrequent use in moderate to severe cases.

The therapy needs to the supervised very closely. (11)

 

Antiemetic agents may be used as adjuncts to the acute therapeutic regimen. (12)

 

Corticosteroids are also useful as rescue treatment in patients with status migrainosus,

i.e. a severe, debilitating migraine headache that lasts as least 72 hours, but for less than one week. (12)

Ergot alkaloids, such as ergotamine, are 5-HT-receptor agonists and bind to α-adrenoceptors and dopamine receptors.(4)

Their use has been reduced since the arrival and introduction of the triptans.(4)

Their use has also been declining due to their unwanted side-effects, inconvenience and a high likelihood for causing medication-overuse headaches.(2)

 

Many of the drugs used for the treatment of acute migraine attacks are also used for treating chronic migraine.(9)

 

Drugs currently under clinical development include (13)

  • highly-selective 5-HT1F-receptor agonist

    • lasmiditan, with a seemingly good cardiovascular safety profile

  • CGRP antagonists

    • olcegepant

    • telcagepant has been discontinued due to safety concerns (14).

 

Migraine in pregnancy and lactation

  • Hormonal changes

    • migraine respites are common during pregnancy
       

  • Safe Pain Medication

    • paracetamol in moderation

    • aspirin and NSAIDs in first and second trimester only

    • for nausea, metoclopramide or domperidone are unlikely to cause harm throughout pregnancy and lactation

    • triptans (19)

      • sumatriptan no higher risk of birth defects

      • inadvertent use of triptans, very unlikely to cause adverse effects

      • due to insufficient evidence, triptans are not recommended as a routine

  • Safe Nausea Medication

    • metoclopramide or domperidone, unlikely to cause harm

  • Migraine and breastfeeding

    • Safe painkillers : ibuprofen, diclofenac, paracetamol

    • Safe nausea meds : domperidone

    • Triptans

    • manufacturers of almotriptan, eletriptan, frovatriptan and rizatriptan, recommend avoiding breast-feeding for 24 hours after treatment

    • manufacturers of sumatriptan recommend avoiding breast-feeding for 12 hours after treatment

    • manufacturers of naratriptan and zolmitriptan recommend caution when considering administration to women who are breast-feeding.

    • The American Academy of Pediatrics (AAP) Committee on Drugs advises that use of sumatriptan is compatible with breast-feeding

    • Ergotamine and dihydroergotamine : contraindicated during pregnancy and lactation.

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1. Russo AF.

Calcitonin Gene-Related Peptide (CGRP): A New Target for Migraine.

Annu Rev Pharmacol Toxicol. 2015;55(1):533-52.

View/access

2 Schellack N, Schellack G.

An Overview of Migraine Management and Treatment.

S Afr Pharm J. 2013;80(9):26-31.

View/access

3. Carod-Artal FJ.

Tackling Chronic Migraine: Current Perspectives.

J Pain Res. 2014; 185.

View/access

4. Roceanu A, Antochi F, Bajenaru O.

New molecules in migraine treatment.

Farmacia. 2015;63(4):475-81.

 

5. Migraine.com

Migraine Phases. 2017 .​

View/access

6. Espinosa-Sanchez JM, Lopez-Escamez JA.

New Insights into Pathophysiology of Vestibular Migraine.

Frontiers in Neurology. 2015;6:n pag.

View/access

7. Ferrari MD, et al.

Migraine Pathophysiology: Lessons from Mouse Models and Human Genetics.

The Lancet Neurology. 2015;14.(1): 65-80.

View/access

8. Diener HC, et al.

New Therapeutic Approaches for The Prevention and Treatment of Migraine.

The Lancet Neurology. 2015;14(10): 1010-22.

View/access

9. Schwedt TJ.

Chronic Migraine.

BMJ. 24 Mar2014:348(5):g1416-g1416. doi: 10.1136/bmj.g1416

View/access

10. Weatherall MW.

The Diagnosis and Treatment of Chronic Migraine.

Therapeutic Advances in Chronic Disease. 2015;6(3):115-23.

View/access

11. Tepper SJ, Spears RC.

Acute treatment of migraine.

Neurol Clin. 2009;27:417-27.

View/access

12. Minor DS, Wofford MR.

Headache disorders. In: Pharmacotherapy: a pathophysiological approach. DiPiro JT, et al., eds. 7th ed. New York: McGraw-Hill Medical; 2008.

 

13. Magis D, Schoenen J.

Treatment of migraine: update on new therapies.

Curr Opin Neurol. 2011;24:203-10.

View/access

14. Durham PL, Vause CV.

CGRP receptor antagonists in the treatment of migraine.

CNS Drugs. 2010;24(7): 539-48.

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15. Schürks M, Diener H, Goadsby P.

Update on the prophylaxis of migraine.

Curr Treat Options Neurol. 2008;10(1):20-29.

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16. Mohamed BP, Goadsby PJ, Prabhakar P.

Safety and efficacy of flunarizine in childhood migraine: 11 years’ experience, with emphasis on its effect in hemiplegic migraine.

Dev Med Child Neurol. 2012;54(3):274-7.

View/access

17. Headaches in over 12s : Diagnosis and Management

NICE Guideline CG150

November 2015

View/access

18. Pharmacological Management of Migraine

SIGN Guideline 155

February 2018

View/access

19. Guidelines for All Healthcare Professionals in the Diagnosis and management of Migraine, Tension-Type Headache, Cluster Headache, Medication-Overuse Headache

BASH - British Association for the Study of Headache

2010

View/access

20. Migraine

Clinical Skills Guideline (CSK) NICE

March 2019

View/access

21. Migraine : Diagnosis and Management from a GP Perspective

Quality and Safety in Practice Committee, Irish College of General Practice, ICGP

January 2019

View/access

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The following are available in Ireland :

atenolol (Amolin, Atecor, Ateni, Atenomel,Tenormin)

metoprolol (Betacor, Metacor)

propranolol (Beta-prograne, Inderal)

carbamazepine (Tegretol)

valproate (Epilim, Epilim Chrono)

gabapentin (Gabin, Neurontin, Neurostil)

topiramate (Topamax)

lamotrigine (Lamictal, Lamoro, Larig)

pizotifen (Sanomigran)

flunarizine (Sibelium)

verapamil (Isoptin, Isoptin SR, Veramil, Verap, Verisop)

candesartan (Atacand, Blopress, Candist, Catasart)

venlafaxine (Efexor XL, Ireven, Vedixal, Vedixal XL, Venex XL, Venlafaxine Teva, Venlofex, Vensir XL)

 

sumatriptan ( Imigran, Sumatran)

Imigran FTab : for adults between 18 and 65 yrs

50-100 mg dose at onset of attack.

Patients who do not respond should not take a second dose for same attack.

If symptoms recur in patients who respond, repeat dose after minimum 2 hrs.

Max. dose 300 mg. in 24 hrs

contra MAOIs, lithium, SSRIs, ergotamine, St.John's Wort

caution, CVA or coronary risk, hypertension, hepatic or renal disease, pregnacy/lactation

 

almotriptan (Almogran)

 

eletriptan (Relpax)

Relpax : for adults between 18 and 65 yrs

40 mg dose at onset of attack.

Patients who do not respond should not take a second dose for same attack.

If symptoms recur in patients who respond, repeat 40 mg.dose after minimum 2 hrs.

max. dose 80 mg. in 24 hrs

If symptoms recur after 24 hrs, repeat 40 or 80 mg.dose max. dose 80 mg. in 24 hrs
contra MAOIs, lithium, SSRIs, ergotamine, St.John's Wort

caution, CVA or coronary risk, hypertension, hepatic or renal disease, pregnacy/lactation

 

frovatriptan (Frovex)

naratriptan ( Naraverg)

 

zolmitriptan (Zomig)

Zomig Rapimelt : for adults between 18 and 65 yrs

2,5 mg dose at onset of attack.

Patients who do not respond should not take a second dose for same attack.

If symptoms recur in patients who respond, repeat dose after minimum 2 hrs, increasing to 2,5 

Max. dose 300 mg. in 24 hrs

contra MAOIs, lithium, SSRIs, ergotamine, St.John's Wort

caution, CVA or coronary risk, hypertension, hepatic or renal disease, pregnacy/lactation

The following are N/A in Ireland :

nadolol

timolol (N/A except in combination with other drugs)

methysergide

amitriptyline

rizatriptan

onabotulinum toxin A

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