What causes hemiplegic migraines in pediatric patients?

Causes of Hemiplegic Migraines in Pediatric Patients

Hemiplegic migraines in pediatric patients are primarily caused by genetic mutations affecting ion channels, with the three main causative genes being CACNA1A, ATP1A2, and SCN1A. 1

Genetic Causes

Primary Genetic Mutations

• CACNA1A gene: Encodes a calcium channel subunit
• ATP1A2 gene: Encodes a sodium-potassium pump
• SCN1A gene: Encodes a sodium channel 1, 2

These mutations affect ion transporters, disrupting normal neuronal function and leading to the characteristic symptoms of hemiplegic migraine 2. The prevalence of hemiplegic migraine is approximately 1 in 10,000 people 2.

Classification Based on Genetics

1. Familial Hemiplegic Migraine (FHM):

   • Defined by having at least one first- or second-degree relative with motor weakness during aura 2
   • Autosomal dominant inheritance pattern 2
   • Three subtypes based on the affected gene:
     • FHM1: CACNA1A mutations
     • FHM2: ATP1A2 mutations
     • FHM3: SCN1A mutations 3

2. Sporadic Hemiplegic Migraine (SHM):

   • No family history of hemiplegic migraine 2
   • May be caused by de novo mutations in the same genes as FHM 4
   • Some cases may have ATP1A2 mutations without family history 5

Contributing Factors and Comorbidities

Associated Conditions

• Cerebral arteriopathy: Some children with familial hemiplegic migraine mutations may develop persistent neurological deficits, suggesting increased stroke risk 6
• Prothrombin gene mutations: May coexist with ATP1A2 mutations and increase stroke risk 5
• Comorbid epilepsy: SCN1A mutations are also associated with various epilepsy syndromes 1
• Cerebellar ataxia: Permanent cerebellar signs (nystagmus, ataxia, dysarthria) may be present, particularly with CACNA1A mutations 2

Pathophysiological Mechanisms

Neuronal Dysfunction

• The genetic mutations affect ion channels and transporters, leading to neuronal hyperexcitability 7
• This triggers cortical spreading depression - a wave of neuronal depolarization followed by inhibition that spreads across the cerebral cortex 6

Vascular Changes

• During attacks, regional cerebral blood flow is reduced, corresponding with the reversible aura symptoms 4
• MR angiography has shown dilatation of cerebral arteries during attacks that resolves afterward 5

Clinical Presentation and Diagnosis

Characteristic Features

• Motor weakness (hemiparesis) during aura, always associated with other aura symptoms 2
• Common accompanying symptoms include:
  • Sensory disturbances
  • Visual aura
  • Speech disorders
  • Basilar-type symptoms (in up to 70% of patients) 2

Severe Manifestations

• Prolonged hemiplegia
• Confusion
• Coma
• Fever
• Seizures 2

Diagnostic Approach

The American Academy of Neurology recommends genetic testing for CACNA1A, ATP1A2, and SCN1A mutations in pediatric patients with hemiplegic migraine, especially if there are additional symptoms like chronic ataxia or epilepsy 1.

Neuroimaging

• MRI is the preferred imaging modality to exclude other causes of focal neurological deficits 6
• Conventional cerebral angiography is contraindicated as it may provoke an attack 7

Management Considerations

Acute Treatment

• Acetaminophen (15 mg/kg) and NSAIDs like ibuprofen (7.5-10 mg/kg) are first-line options 1, 7
• Triptans should be used with extreme caution in hemiplegic migraine due to theoretical concerns about vasoconstriction 1, 4

Preventive Treatment

• First-line preventives include:
  • Amitriptyline combined with cognitive behavioral therapy
  • Topiramate
  • Propranolol (for patients without asthma) 1
• Second-line options include:
  • Flunarizine
  • Sodium valproate
  • Lamotrigine
  • Verapamil
  • Acetazolamide 7

Important Cautions

• Nimodipine is contraindicated in hemiplegic migraine 4
• For female patients of childbearing age, discuss teratogenic effects of topiramate and valproate 1

Hemiplegic migraine in children significantly impacts quality of life and school performance, making early identification of the genetic causes and appropriate management crucial for reducing disability and improving outcomes.