HEMIPLEGIC MIGRAINE

Juan Moya & Louise Landqvist HMS International clerkship program Pediatric Neurology

Familial Hemiplegic migraine (FMH)

Sporadic Hemiplegic migraine (SHM)

FHM and SHM share the same symptoms, but FHM is genetically/family linked.

NATURE

Description: Migraine with aura including motor weakness and at least one first- or seconddegree relative has migraine aura including motor weakness. Many patients have altering hemiplegic and normal migraines*

(*Ducros et al, 2001)

EPIDEMIOLOGY

Prevalence of migraine is 12% Prevalence of femilial hemiplegic migraine is 1/10,000 FHM and SHM present equally frequent Females affected more often than males

ETHIOLOGY
Not fully mapped out yet, hot spot for reesearch! Triggers of migraines differ inbetween patients but may include:

Hormonal changes Certain odors Flashing lights Sound Dehydration Alcohol consumption Altered sleep- or eating patterns

PATHOPHYSIOLOGY
Not completely understood today Previosly considered to origin from either vascular or neurogenic origin New theories focus on Neurovascular Origin, involving

1. Cortical spreading depression (CSD) 2. Trigeminovascular System (TGVS)

PATHOPHYSIOLOGY

CSD (cortical spreading depression) Characteristics

y y y

Short-lasting, intense wave of neuronal/glial depolarization High fluxes of Ca++, Na+ & K+ Posterior long-lasting inhibition of neuronal activity

Many studies done with experimental designs in mice-models

CSD
Associated with Cerebral Blood Flow (CBF) alterations

Small, brief reduction of CBF followed by increasing flow After that, new reduction of CBF (approx. 1 hour)

(Piper et al., 1991)

CSD AND MIGRAINE AURA

CSD and changes in CBF would constitute the basis for migrain aura via the CSD pattern on visual cortex
Increase of blood oxygen level-dependent (BOLD) through occipital cortex (rate> 3.5 mm/min) * y Posterior decrease in signal y Related to electrophysiological events: depolarization of cortex at a rate of 2-5 mm/min ** y Different Studies have demonstrated abnormal [ ] of Ca++, K+ and glutamate ***
y

The route of CSD spreading correlates with the patients visual aura symptoms, and later with neurological symptoms.
*Hadjikhani et al., 2001 **Leao, 1944 ***De Vries, 2009

POSITIVE VS. NEGATIVE SYMTOMS

Neuronal excitation status upbring

y

positive aura symptoms ( paresthesia,

scintillation), via initial transient hyperexcitation of neurons

negative symptoms ( numbness, scotomas) via

neuronal depression following the hyperexcitation

TRIGEMINOVASCULAR SYSTEM (TGVS)

Neurovascular
y

TGVS innervates cortical vessels, which cause pain when dilated.

Afferent sensory route from cortical meningeal vessels project to Nucleus caudalis (brainstem) high order pain centers migrain headache.
*De Vries, 2009

TRIGEMINOVASCULAR SYSTEM (TGVS)

Release of K+, H+ and Nitric Oxid in the neocortex (extracellular space) y Local effect over blood vessels y Depolarization of trigeminal terminals activacion of brainstem nucleus y Collateral trigeminal axons release proinflammatory peptides in meninges

*Iadecola, 2002.

Trigeminal brainstem nucleus induces meningeal-cortical vessels vasodilatation, via spenopalatine ganglion

Pain perception is regulated by higher-order centers projections, coming from the brainstem
*Iadecola, 2002.

TGVS: BRAINSTEM INVOLVEMENT

Aminergic nuclei are modifying factors in trigeminal pain processing During migraine attacks, PET has demonstrated brainstem activation It is unclear if brainstem plays a role either as generator or regulator in this process Brainstem activation can persist after treatment
*Walker et al, 1995

AFFECTED GENES
Autosomal CACNA1A

dominant inheritance pattern

(FHM1) ATP1A2 (FHM2) SCN1A ( FHM3)

All

FHM-genes codify ion channels

GENETIC CORRELATION TO PATOPHYSIOLOGY

Ion channels are directly related to neuron excitability
y

FHM1 gene 1 subunit of Voltage-gated Ca++ channels (missense mutations) FHM2 gene deletions) FHM3 gene channels Na+/K+ pump (aminoacid changes &

1 subunit of Voltage-gated Na+

(GeneReviews, 2009)

CLINICAL MANIFESTATIONS OF HM

Episodes of prolonged aura (up to several days or weeks) Hemiplegia Fever Meningismus
(=symptoms of meningitis without the actual illness and accompanying inflammation)

Impaired consciousness ranging from confusion to profound coma Headache, which may begin before the hemiplegia or be absent Ataxia The onset of the hemiplegia may be sudden and simulate a stroke. Nausea and/or vomiting Phonophobia and/or photophobia

DIAGNOSTIC CRITERIA FOR FHM

Diagnostic criteria: At least 2 attacks fulfilling criteria B and C

A. Aura consisting of fully reversible motor weakness and at least one of the following: y fully reversible visual symptoms including positive features (e.g., flickering lights, spots or lines) and/or negative features (i.e., loss of vision y fully reversible sensory symptoms including positive features (i.e., pins and needles) and/or negative features (i.e., numbness) y fully reversible dysphasic speech disturbance B. At least two of the following:
at least one aura symptom develops gradually over 5 minutes and/or different aura symptoms occur in succession over 5 minutes y each aura symptom lasts 5 minutes and <24 hours y headache fulfilling criteria BD for Migraine without aura begins during the aura or follows onset of aura within 60 minutes
y

C. At least one first- or second-degree relative has had attacks meeting the

criteria above
D. Not attributed to any other disorder
International Headache Society, 2004

SYMPTOMS ASSOCIATED WITH FHM MUTATIONS SPECIFICALLY

FHM1 Cerebellar ataxia Epilepsy Trauma-triggered attacks

(Symptom above can occur during attacks, or in between) Associated with FHM2 Associated with FHM3

DIFFERENTIAL DIAGNOSIS
Stroke TIA Epilepsy Vascular diseases Meningitis Sepsis Aquired brain injury Poisoning Metabolic crisis

y

Mitochondrial disorders

INVESTIGATIONS

Review of y Medical history (including family medical history) y Symptoms Full neurological work up Rule out more severe conditions Genetic sequence analysis A lumbar puncture is also necessary to rule out pseudomigraine with temporary neurological symptoms and lymphocytic pleocytosis. This condition is more prevalent in males and often associated with transient hemiparesis and aphasia. Functional imaging CSD, change of blood flow, define secondary effects of migraine*
*Schwedt and Dodik 2009

Gardner K. Familial Hemiplegic Migraine. Neurology Department, U. of Pittsburgh. 2007. http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=fhm

COMPLICATIONS
FHM is often associated with other episodic brain disorders * Comorbidity seen with: Epilepsy Depression Patent foramen ovale Brain edema Stroke Anxiety disorders Mental retardation Coma (possibly fatal)

Incidence of comorbidity depends on age, smoker, and use of oral contraceptives. # High-frequency migraineurs have 16-fold increase in white matter and cerebellar leasions.

*Goadsby et al. 2002, # Bousser and Welch, 2005, Kruit et al., 2004

LONG-TERM COMPLICATIONS

Permanent cerebellar signs (nystagmus, ataxia, dysarthria)

Intellectual defiency Less frequently various types of seizures

ABORTIVE TREATMENT

Migraine-specific abortives, the triptans and ergotamines, are currently contraindicated in the treatment of Hemiplegic Migraine because of their vasoconstrictive properties and concerns about stroke.

Possible drugs include: NSAID's antiemetics Non-narcotic analgesics

PREVENTITIVE TREATMENT

Given the severity of the symptoms and the contraindication of abortive medications, preventive regimens are considered especially important in the treatment of Hemiplegic Migraine. Since FHM1 codes for a calcium channel, calcium channel blockers are sometimes especially effective preventive medications for FHM.

Thank you for your attention!