Hemiplegic Migraine

Hemiplegic migraine is a rare form of migraine with aura. Hemiplegia in hemiplegic migraine is an aura symptom i.e. patients experience unilateral weakness in addition to the migraine headache attack

Introduction

  • Hemiplegic migraine is a rare form of migraine with aura.
  • Aura refers to additional neurological symptoms that occur with, or sometimes before, the development of the migraine headache.
  • Hemiplegia in hemiplegic migraine is an aura symptom i.e. patients experience unilateral weakness in addition to the migraine headache attack.
  • Typical hemiplegic migraine attacks start in the first or second decade of life.
  • They can include gradually progressing visual, sensory, motor, aphasic, and often basilar-type symptoms accompanied by headaches.
  • Can mimic stroke and seizures.
 
The hallmark of hemiplegic migraine is unilateral weakness that accompanies a migraine headache attack.

Classification

  • There are 2 classes (types) of hemiplegic migraine
      1. Familial hemiplegic migraine (FHM)
      1. Sporadic hemiplegic migraine (SHM)

Familial hemiplegic migraine (FHM)

  • FHM is an autosomal-dominant subtype of hemiplegic migraine that runs in the family.
  • At least two or more people in the same family experience hemiplegic migraine.
  • Three different genes have been implicated in FHM — CACNA1A, ATP1A2 and SCN1A.
  • These genes encode for various subunits of different ion channel proteins in the brain.
  • Mutations in any of these genes can cause this disorder.
  • Consequently, familial hemiplegic migraine can be described as a channelopathy.
  • These known genetic mutations do not account for all familial hemiplegic migraine.
  • At least 25% of these families have mutations in the genes that are not yet identified.
  • International Classification of Headache Disorders-3 (ICHD-3) further classifies FHM into 4 subtypes based on the genetic mutation associated with them.
    • FHM1 is associated with mutations in the CACNA1A gene. FHM1 is the most common type and accounts for around 50% of cases of FHM. FHM1 is commonly associated with cerebellar degeneration.
    • FHM2: Mutations in the ATP1A2 gene cause FHM2, and it accounts for less than 25% of cases of FHM.
    • FHM3: Mutations in the SCN1A gene cause FHM 3. The penetrance of this mutation is estimated to be 100%.
    • FHM4 is diagnosed if no known genetic mutation linked to FHM is identified.

Sporadic hemiplegic migraine (SHM)

  • SHM is diagnosed when someone experiences all the symptoms of hemiplegic migraine but has no first- or second-degree relative affected by migraine aura including motor weakness.
  • SHM is thought to be caused by a de-novo mutation.
  • The three main genes that cause FHM seem to have minor roles in pure sporadic hemiplegic migraine.
  • Some studies have suggested that 10% to 20% of sporadic hemiplegic migraine may have mutations in the CACNA1A and the ATP1A2 genes.

Epidemiology

  • A migraine is a common disorder occurring in 15% to 20% of the population.
  • Hemiplegic migraine is a rare condition, with a reported prevalence of 0.01%.
  • Both familial and sporadic hemiplegic migraines often begin in childhood.
  • The average age of onset is 12 to 17 years.
  • Women are 3 times more likely to be affected.
  • On average, 50% of children who have a parent with hemiplegic migraine will develop this disorder.

Pathophysiology

  • Migraine aura is indicative of a reversible cerebral cortical dysfunction that is most probably caused by cortical spreading depression.
  • Cortical spreading depression is characterized by a brief neuronal excitation, which initiates a self-propagating depolarization wave that moves across the cortex at a rate of 3–5 mm/min and is followed by a prolonged inhibition of neuronal activity.
  • A genetic role has been identified, especially for familial hemiplegic migraine (FHM).
    • CACNA1A gene implicated in FHM1 is responsible for encoding the alpha-1A subunit of the P/Q type calcium channel.
    • FHM2 is associated with mutations in the ATP1A2 gene that is responsible for encoding a catalytic subunit of sodium/potassium ATPase.
    • FHM3 is associated with mutations in the SCN1A gene that encodes a transmembrane alpha subunit of the brain sodium channel.
    • Some studies have associated mutation in the gene PRRT2 with familial hemiplegic migraine.

Etiology and Common Precipitating Factors

  • It can be triggered by:
    • Acute stress
    • Bright light
    • Physical exertion
    • Emotions
    • Lack of sleep
    • Excessive sleep
    • Certain foods
    • Certain odors
    • Head trauma

Diagnostic Criteria

🧠
Diagnostic criteria for hemiplegic migraine per International Classification of Headache Disorders (ICHD-3)
Criteria A:
  • At least two attacks fulfilling criteria B and C
Criteria B:
  • Aura consisting of both of the following:
    • Fully reversible motor weakness
    • Fully reversible visual, sensory and/or speech/language symptoms.
Criteria C:
  • At least three of the following six characteristics:
    • At least one aura symptom spreads gradually over ≥5 minutes
    • Two or more aura symptoms occur in succession
    • Each individual aura symptom lasts 5-60 minutes
    • At least one aura symptom is unilateral
    • At least one aura symptom is positive
    • The aura is accompanied, or followed within 60 minutes, by headache
Criteria D:
  • Not better accounted for by another ICHD-3 diagnosis
Source: ICHD-3 The International Classification of Headache Disorders 3rd edition. https://ichd-3.org/1-migraine/1-2-migraine-with-aura/1-2-3-hemiplegic-migraine/

Clinical features

These include aura symptoms, headache and other paroxysmal symptoms

Aura symptoms

  • Motor weakness is accompanied with at least one other aura symptom, sensory aura being the most common
  • Although visual auras frequently have positive features (e.g., flickering spots or zigzag lines), negative features (e.g., scotomas) may or may not occur
  • These visual symptoms start from central vision and gradually progress towards peripheral vision just to disappear in 20 minutes or more
  • Sensory auras in hemiplegic migraine have both positive (e.g., pins and needles, feeling of pain or cold) and negative (e.g., numbness, alien-limb syndrome, substantial deep sensory loss) features
  • Motor weakness is also first seen in these areas of the body that are affected by sensory deficits
  • Sensorimotor symptoms frequently begin in a finger and gradually progress to involve the hand, arm, whole limb, face, tongue and leg on the same side
  • They can be bilateral, unilateral, switching from one side to another after every successive attack or occurring exclusively on one side
  • Speech deficits usually involve impairment in expressive components rather than the comprehensive
  • Basilar-type aura can manifest as dysarthria, vertigo, tinnitus, hypacusia, diplopia, bilateral visual symptoms, ataxia, altered sensorium, simultaneous bilateral paresthesia

Headache

  • 95% of patients experience headache that may occur during or before the aural symptoms
  • It can be bilateral, ipsilateral or contralateral to the motor weakness
  • It is usually similar to that of a typical migraine headache without aura (i.e. a severe pulsating headache with nausea, vomiting, phonophobia, and photophobia).
  • It can span over 3 days in 2% of patients and can sometimes be severely crippling

Other paroxysmal symptoms

  • Severe attacks can occur with altered consciousness lasting for several days to several months manifesting as
    • Confusion
    • Somnolence
    • Seizures
    • Encephalopathy
    • Coma
  • Patients with hemiplegic migraine are also more likely to have migraine with aura and migraine without aura
  • Epilepsy often precedes the first attack of hemiplegic migraine and hence occurs during childhood
  • Elicited repetitive daily blindness (temporary blindness that moves from peripheral to central vision, lasts up to 10s and often triggered by abrupt change in light, direct exposure to light, standing, and eye rubbing)

Differential Diagnosis

Differential Diagnosis
Differentiating Feature
Investigation
Comments
Stroke
Sudden onset in stroke vs progressive and migrating motor/sensory involvement in HM Timing of the headache: after motor symptoms in HM and before them in hemorrhagic strokes Prevalence of negative symptoms in stroke
Hyperacute MRI will diffusion restriction in stroke whereas acute changes not seen in HM but FLAIR changes can be seen in both
Regardless should not change management from stroke point of view as prevalence of HM is far less than stroke in general population.
Seizure
Sudden onset lasting 1-2 minutes; HM auras are progressive and can be >20 minutes
EEG and MRI
Seizures can coexist and even occur as etiology of HM. Routine assessment and treatment for seizure is required regardless.
CNS infection
Fever, altered sensorium and neck rigidity point towards CNS infection rather than HM
CBC, ESR, CSF analysis and MRI
CSF findings and neuroimaging are very much in line with an infective process
Brain tumor
Sensorimotor symptoms progressively worsen with time and headache is typically frontal or occipital that is aggravated by bending or Valsalva maneuver
CT, MRI and proton MR spectroscopy
Headache, motor weakness and other aural symptoms in hemiplegic migraine resolve completely once the migraine attack is over
Alternating Hemiplegia of Childhood
Dystonia, epilepsy, cognitive impairment, hemiplegia, quadriplegia, choreoathetosis and nystagmus
CT or MRI, EEG and ATP1A3 gene sequencing
Symptoms usually begin before 18 months of age in alternating hemiplegia of childhood and resolve when the patient is asleep whereas in HM the onset is usually later in childhood around the age of 10 years
Stroke-like migraine attacks after radiation therapy (SMART)
History of radiation therapy even two or three decades back
MRI with contrast (thick cortical gyral enhancement on neuroimaging)
 

Evaluation

  • Diagnosis of a hemiplegic migraine is mostly clinical.
  • The characteristic feature for diagnosis is episodic, reversible, unilateral motor weakness as migraine aura manifestation, along with at least one other kind of aura.
  • Neurologic exam during an attack may show unilateral hyperreflexia and positive Babinski sign.
  • Motor and sensory symptoms are typically more prominent in the upper extremities than lower.
  • Exam between the attacks is typically normal.
  • Most patients with FHM1 and few patients with FHM2 have cerebellar signs like ataxia, dysarthria, and nystagmus.
  • CT and MRI head, CSF analysis, and EEG to rule out other pathologies, especially if the attacks are new in onset, have prolonged symptoms, and have no family history.
  • Neuroimaging is usually normal except in very few cases where cortical edema and cortical or meningeal enhancement may be seen in the hemisphere contralateral to the hemiparesis. ADC map is usually normal with changes that can be seen in T1, T2, DWI and FLAIR.
  • MRI head may show cortical hemispheric atrophy and cortical laminar necrosis in severe hemiplegic migraine cases.
  • Patients with FHM1 can have cerebellar atrophy.
  • Genetic testing is not recommended in all cases
 

Figure 1: MRI Findings in Hemiplegic Migraine

Figure 1: From Left to Right: MRI done on days 2, 4, 7, 11, 15, 154. MRI obtained on day 2 did not reveal any acute intracranial abnormality. However, scattered, non-enhancing punctate T2-FLAIR hyperintensities in subcortical white matter were present bilaterally in the frontal lobes. Day 4: Diffuse DWI and T2-FLAIR hyperintensities throughout the left cerebral hemisphere cortices, most pronounced over the lateral convexity. Possible associated T2 shine through rather than restricted diffusion. Associated sulcal effacement from gyral swelling. Day 7:Diffuse DWI and T2-FLAIR hyperintensities throughout the left cerebral hemisphere cortices similar to the MRI findings obtained on day 4. Subtle hypointensity on ADC in left cerebral hemisphere cortices and posterior temporal lobe. Day 11: Diffuse DWI and T2-FLAIR hyperintensities throughout the left cerebral hemisphere cortices similar to previous MRI findings. Mild hypointensity on ADC in the left cerebral hemisphere cortices and temporal lobe is more prominent compared to previous MRIs. Day 15: Diffuse DWI and T2-FLAIR hyperintensities throughout the left cerebral hemisphere cortices similar to previous MRIs. Mild hypointensity on ADC in left cerebral hemisphere cortices is even more prominent compared to previous MRIs. Day 154:Previously demonstrated left cerebral hemisphere cortical swelling and restricted diffusion has resolved. No new parenchymal signal abnormality or abnormal enhancement. Scattered non-enhancing punctate T2-FLAIR hyperintensities were present in subcortical white matter of bilateral frontal lobes similar to the first MRI
Figure 1: From Left to Right: MRI done on days 2, 4, 7, 11, 15, 154. MRI obtained on day 2 did not reveal any acute intracranial abnormality. However, scattered, non-enhancing punctate T2-FLAIR hyperintensities in subcortical white matter were present bilaterally in the frontal lobes. Day 4: Diffuse DWI and T2-FLAIR hyperintensities throughout the left cerebral hemisphere cortices, most pronounced over the lateral convexity. Possible associated T2 shine through rather than restricted diffusion. Associated sulcal effacement from gyral swelling. Day 7:Diffuse DWI and T2-FLAIR hyperintensities throughout the left cerebral hemisphere cortices similar to the MRI findings obtained on day 4. Subtle hypointensity on ADC in left cerebral hemisphere cortices and posterior temporal lobe. Day 11: Diffuse DWI and T2-FLAIR hyperintensities throughout the left cerebral hemisphere cortices similar to previous MRI findings. Mild hypointensity on ADC in the left cerebral hemisphere cortices and temporal lobe is more prominent compared to previous MRIs. Day 15: Diffuse DWI and T2-FLAIR hyperintensities throughout the left cerebral hemisphere cortices similar to previous MRIs. Mild hypointensity on ADC in left cerebral hemisphere cortices is even more prominent compared to previous MRIs. Day 154:Previously demonstrated left cerebral hemisphere cortical swelling and restricted diffusion has resolved. No new parenchymal signal abnormality or abnormal enhancement. Scattered non-enhancing punctate T2-FLAIR hyperintensities were present in subcortical white matter of bilateral frontal lobes similar to the first MRI
Source: Fear, D., Patel, M. & Zand, R. Serial magnetic resonance imaging findings during severe attacks of familial hemiplegic migraine type 2: a case report. BMC Neurol 21, 173 (2021). https://doi.org/10.1186/s12883-021-02201-z

Figure 2: MRI performed 10 days after onset of the second prolonged attack

Figure 2: MRI performed 10 days after onset of the second prolonged attack. Right temporal-occipital hyperintensity on T1-weighted images (A) with gliosis on T2-FLAIR images (B) suggests the chronic stage of cortical necrosis caused by first prolonged attack. Left temporal–occipital cortex hyperintensity on T2-FLAIR images (B) with gyriform enhancement (C), restricted diffusion (D), and normal apparent diffusion coefficient (ADC) (E) suggests the subacute stage of cortical necrosis caused by second prolonged attack. MRA demonstrated vasodilation of the branches of the left middle cerebral artery (MCA) and posterior cerebral artery (PCA) (F).
Figure 2: MRI performed 10 days after onset of the second prolonged attack. Right temporal-occipital hyperintensity on T1-weighted images (A) with gliosis on T2-FLAIR images (B) suggests the chronic stage of cortical necrosis caused by first prolonged attack. Left temporal–occipital cortex hyperintensity on T2-FLAIR images (B) with gyriform enhancement (C), restricted diffusion (D), and normal apparent diffusion coefficient (ADC) (E) suggests the subacute stage of cortical necrosis caused by second prolonged attack. MRA demonstrated vasodilation of the branches of the left middle cerebral artery (MCA) and posterior cerebral artery (PCA) (F).
Source: Hu, Yacen & Wang, Zhiqin & Zhou, Lin & Sun, Qiying. (2021). Prolonged Hemiplegic Migraine Led to Persistent Hyperperfusion and Cortical Necrosis: Case Report and Literature Review. Frontiers in Neurology. 12. 748034. 10.3389/fneur.2021.748034.

Treatment and Management

  • Triggers should be identified and avoided if possible.
  • There are not enough RCTs in hemiplegic migraine patients.
  • So, the treatment of HM is based on empirical data, personal experience of the treating neurologist, and involves a trial-and-error strategy.
  • Treatment involves pharmacological treatment with abortive and preventive medications.
  • Severe attacks may need hospitalization and additional measures.

Abortive Therapy

Refer to Chapter
Of Note; Specifically for Hemiplegic Migraines Triptans should be used carefully given Vasoconstrictive properties
Ergotamine should not be used as can cause or worsen ischemia

Prophylactic Treatment

Refer to Chapter

Complications

  • Permanent neurologic features are more common in FHM
  • These include
    • Cerebellar signs
    • Mental retardation

Prognosis

  • The weakness may last from one hour to several days, but usually goes within 24 hours.
  • In rare cases, hemiplegic migraine leads to permanent neurological deficits, cerebral infarctions, cognitive decline or death.
  • Poor outcomes are often associated with early onset of a hemiplegic migraine with severe attacks, recurrent coma, or seizures.
  • The frequency of attacks decreases after age 50 as the hemiplegic attacks evolve into more typical migraine attacks without motor symptoms. 
  • Migraine with aura increases the risk of stroke in individuals.

Further Reading

  • Russell, M. B., & Ducros, A. (2011). Sporadic and familial hemiplegic migraine: pathophysiological mechanisms, clinical characteristics, diagnosis, and management. The Lancet Neurology10(5), 457-470.
  • Kumar, A., & Arora, R. (2018). Hemiplegic migraine.

Bibliography

  1. Di Stefano, V., Rispoli, M. G., Pellegrino, N., Graziosi, A., Rotondo, E., Napoli, C., ... & Parisi, P. (2020). Diagnostic and therapeutic aspects of hemiplegic migraine. Journal of Neurology, Neurosurgery & Psychiatry91(7), 764-771.
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  1. Hansen, J. M., Hauge, A. W., Ashina, M., & Olesen, J. (2011). Trigger factors for familial hemiplegic migraine. Cephalalgia31(12), 1274-1281.
  1. Pelzer, N., Stam, A. H., Haan, J., Ferrari, M. D., & Terwindt, G. M. (2013). Familial and sporadic hemiplegic migraine: diagnosis and treatment. Current treatment options in neurology15(1), 13-27.
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  1. Hemiplegic migraine. (2017, January 12). American Migraine Foundation. https://americanmigrainefoundation.org/resource-library/hemiplegic-migraine/
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  1. What Is a Hemiplegic Migraine? Healthline. https://www.healthline.com/health/migraine/hemiplegic-migraine
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