Continuing Education Activity

A hemiplegic migraine is a rare form of migraine in which the migraine headache attack is accompanied by unilateral weakness. Typically, migraine aura has visual symptoms, but motor symptoms are rare. Hemiplegic migraine is a rare subtype of migraine with aura, characterized by the presence of motor weakness as aura manifestation. The motor weakness is often accompanied by other forms of aura, like impairment in vision, speech, or sensation. Hemiplegic migraine can run in the family (familial hemiplegic migraine) or occur sporadically in one individual (sporadic hemiplegic migraine). This activity reviews the cause of hemiplegic migraine and highlights the role of the interprofessional team in its diagnosis and management.

Objectives:

• Describe the clinical features of hemiplegic migraine.
• Summarize the treatment of hemiplegic migraine.
• Review the diagnostic criteria for hemiplegic migraine.
• Explain modalities to improve care coordination among interprofessional team members to improve outcomes for patients affected by hemiplegic migraine.

Introduction

Hemiplegic migraine is a rare subtype of migraine with aura, characterized by the presence of motor weakness as an aura manifestation at the time of migraine attack. Typically, migraine aura has visual symptoms as aura, but occasionally impairment in sensation or speech may also be seen. A hemiplegic migraine is a distinct condition in which motor weakness occurs.

Hemiplegic migraine may run in the family (familial hemiplegic migraine) or occur sporadically in an individual (sporadic hemiplegic migraine).[1]

Familial Hemiplegic Migraine (FHM)

FHM is an autosomal-dominant subtype of hemiplegic migraine that runs in the family. The diagnostic criteria for familial hemiplegic migraine require that at least one first or second-degree relative has had attacks fulfilling the diagnostic criteria for hemiplegic migraine. International Classification of Headache Disorders-3 classifies FHM into four subtypes based on their genetic mutation.

• FHM1 is associated with mutations in the CACNA1A gene on chromosome 19p13 that encodes the alpha-1A subunit of the P/Q-type calcium channel.[2][3] FHM1 is the most common type and accounts for around 50% of cases of FHM. FHM1 is commonly associated with cerebellar degeneration.
• Mutations in the ATP1A2 gene cause FHM2, accounting for less than 25% of cases of FHM.
• Mutations in the SCN1A gene cause FHM 3.
• FHM4 is diagnosed if no known genetic mutation linked to FHM is identified.

Sporadic Hemiplegic Migraine (SHM) occurs only in an individual without a family history of hemiplegic migraine. These individuals may or may not have a family history of migraine with aura.[1][4][5][6]

Clinical Manifestations

The characteristic feature of hemiplegic migraine is the presence of unilateral motor weakness as aura manifestation in at least a few of the attacks. Motor weakness is, however, not the only type of aura present during the hemiplegic migraine attack. Other typical aura symptoms like visual field defects, scotoma, hemianopia, tingling, numbness, ataxia, fever, or lethargy may occur. Motor symptoms often start in the hand and gradually spread to the arm and face. The unilateral weakness may switch sides between or during attacks. Patients may rarely have a bilateral motor weakness either simultaneously or in succession.[7]

The symptoms usually occur over 20 to 30 minutes, although, in rare instances, aura symptoms and motor weakness can develop acutely and mimic a stroke. The symptoms can last for a few hours to days and rarely can last up to 4 weeks. The symptoms resolve completely in a majority of the cases. Most patients with hemiplegic migraine have associated headaches. A headache usually occurs during the aura but can occur after the aura symptoms. Severe hemiplegic migraine attacks may be associated with encephalopathy or coma.[8] Symptoms of a severe attack, including hemiplegia and impaired consciousness, can last for many days to months before they resolve completely. The motor symptoms may outlast a headache. Severe attacks rarely cause permanent brain injury, cerebral atrophy, infarction, cognitive decline, and death.

Seizures independent of hemiplegic migraine attacks have been reported in some patients with FHM, with higher rates in patients with FHM2.

Migraine attacks typically start in the first or second decade of life, with the frequency of attacks decreasing with age.

Etiology

Hemiplegic migraine may be precipitated by acute stress, lack of sleep, excessive sleep, emotions, exertion, and head trauma. Some reports have also suggested conventional angiography as a trigger for hemiplegic migraine.[9]

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%.[10] A Danish study indicated the prevalence of sporadic hemiplegic migraine is 0.002%, and familial hemiplegic migraine is 0.003%.

The average age of onset is 12 to 17 years. Female to male prevalence ratios range from 2.5 to 1 to 4.3 to 1.[11]

Pathophysiology

Weakness associated with a hemiplegic migraine is a manifestation of motor aura. Migraine aura is believed to be caused by a self-propagating wave of neuronal and glial depolarization that spreads across the cerebral cortex, known as cortical spreading depression.

A genetic role has been identified, especially for familial hemiplegic migraine (FHM).

• Mutations in the CACNA1A gene, located on chromosome 19p13, cause FHM1. This gene is responsible for encoding the alpha-1A subunit of the P/Q type calcium channel. The penetrance of CACNA1 mutation ranges from 67 to 89%.[8]
• FHM2 is associated with mutations in the ATP1A2 gene on chromosome 1q23. This gene is responsible for encoding a catalytic subunit of sodium/potassium ATPase.[12] The penetrance of ATP1A2 variants ranges from 63 to 87%.[8][13]
• FHM3 is associated with mutations in the SCN1A gene on chromosome 2q24 that encodes a transmembrane alpha subunit of the brain sodium channel. The penetrance of this mutation is estimated to be 100%.
• Some studies have associated mutation in the gene PRRT2 with familial hemiplegic migraine. PRRT2 encodes a protein that interacts with synaptosomal-associated protein (SNAP25), which may play a role in THE regulation of voltage-gated calcium channels.[14] A study carried out in 2022 with 697 hemiplegic migraine patients revealed pathologic variants in 105 patients, and 17% of these had variations in PRRT2.[15]

The known genetic mutations do not account for all familial hemiplegic migraine, and at least 25% of these families do not have mutations in the genes presently identified for familial hemiplegic migraine.

Some studies have suggested that 10 to 20% of sporadic hemiplegic migraine may have mutations in the CACNA1A and the ATP1A2 genes.[4][16] However, the frequency of these variants may be much higher in patients with severe sporadic hemiplegic migraine associated with other neurological symptoms.[17]

History and Physical

Diagnosis of hemiplegic migraine is primarily clinical and can be challenging at times. The characteristic feature for diagnosis is an episodic, reversible, unilateral motor weakness as migraine aura manifestation, along with at least one other kind of aura. It is essential to rule out other common pathologies that could potentially cause a headache and neurological deficits. A good history of symptoms, potential triggers, family history, and other associated symptoms is essential for diagnosis.

The mean frequency of attacks is three per year. However, they may reach up to 250 per year in some cases. The attacks may occur with or with triggers. The triggers include acute stress, exertion, intense emotions, too little or too much sleep, bright light, and mild head trauma.[18]

A 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.[19] Exam between the attacks is typically normal. Most patients with FHM1 and others with FHM2 have cerebellar signs like ataxia, dysarthria, and nystagmus. SHM is rarely associated with cerebellar abnormalities.

Two or more auras are almost always evident, each evolving over 20 to 30 minutes and taking hours to resolve. Auras typically manifest in this order: visual, sensory, motor, aphasic, and brainstem symptoms.[11] Motor symptoms usually first appear in the hand and then move centrally to the arms and face. The unilateral symptoms may alternate on the right and left sides between or during attacks. However, in turn, or simultaneously, bilateral symptoms have also been reported in one-third of the patients. Motor weakness can vary from mild to severe.[8] Reversible hemiplegia can last up to four weeks in rare cases.

The headache can be mild to excruciating in intensity, can be bilateral or unilateral, irrespective of the side of aura symptoms, and may manifest either before or during the development of visual symptoms.[20]

Signs and symptoms specific to severe attacks include delusions, somnolence, cerebral edema, seizures, fever, meningismus, cerebrospinal fluid pleocytosis, confusion, agitation, delusions, somnolence, cerebral edema, and cerebral infarction.[21]

Evaluation

Brain imaging like computed tomography (CT) and magnetic resonance imaging (MRI) head, cerebrospinal fluid (CSF) analysis, and electroencephalogram (EEG) may be required to rule out other pathologies, especially if the attacks are new in onset, have prolonged symptoms, and have no family history.[22]

Brain imaging (CT or MRI head) during attacks is usually normal. In very few cases, cortical edema and cortical or meningeal enhancement may be seen in the hemisphere contralateral to the hemiparesis.[23] Susceptibility-weighted MRI during the acute phase might reveal a transient prominence of the cerebral veins corresponding to the neurologic deficit.[24] As transient hypoperfusion followed by hyperfusion is associated with migraine aura, hypoperfusion without infarction and hyperperfusion and vasodilatation can be observed (depending on the time of the imaging) in magnetic resonance perfusion-weighted imaging and angiography.

Patients with FHM1 can have cerebellar atrophy. MRI head may show cortical hemispheric atrophy and cortical laminar necrosis in severe hemiplegic migraine cases.[25]

Electroencephalography (EEG) is performed when there is a suspicion of alternate diagnoses like seizures.[22]

Cerebrospinal fluid (CSF) may show nonspecific CSF pleocytosis in a few cases.

Genetic testing is not recommended in all cases. It may be useful for patients with early-onset FHM associated with atypical neurologic manifestations and in patients with FHM when attack severity and neurologic manifestations diverge from other affected relatives.[26][27][28]

Diagnostic Criteria

Diagnostic criteria for a hemiplegic migraine as per the International Classification of Headache Disorders-3 are as follows:

At least two attacks fulfilling the criteria fulfilling criteria for migraine with aura

The aura consists of both of the following:

• Fully reversible motor weakness

• Fully reversible visual, sensory, and/or speech/language symptoms  Following are certain criteria specified by the International Classification of Headache Disorders, 3rd edition (ICHD-3), which can help in diagnosing migraine with aura[13]:

  • A. At least two attacks that fulfill criteria B and C

  • B. One or more of the following aura symptoms that are reversible: Visual, retinal, sensory, brainstem, motor, speech, or language

  • C. At least 3 of the six characteristics below:
    • At least one aura symptom that spreads gradually over greater than 5 minutes
    • Two or more symptoms in succession
    • At least one unilateral aura symptom
    • At least one positive aura symptom
    • Each aura symptom lasting 5 to 60 minutes
    • Aura accompanied by or followed by headache within 60 minutes
  • D. No other ICHD-3 diagnosis accounting for the symptoms

Treatment / Management

Symptoms of a hemiplegic migraine can be scary and distressing. Establishing a correct diagnosis and initiating proper treatment is essential to help manage and prevent attacks. Treatment of hemiplegic migraines involves pharmacological treatment with abortive and preventive medications. Severe attacks may need hospitalization and additional measures.

Patients with a hemiplegic migraine may be managed with the same abortive and preventive medications used for a typical migraine with aura except for agents that may exacerbate ischemia. Treatment of acute episodes is mainly with NSAIDs and antiemetics. Intranasal ketamine given at the onset of attack has shown benefit in patients with familial hemiplegic migraine. The use of triptans for a hemiplegic migraine is controversial.

Verapamil has been used as a prophylactic and abortive agent for hemiplegic migraine. Other drugs that have been used for prophylactic treatment include flunarizine, ketamine, lamotrigine, and naloxone. Nonrandomized studies have suggested acetazolamide may be effective as a preventive medication for familial hemiplegic migraine.[29] For prophylactic treatment, initial therapy with verapamil, flunarizine, or acetazolamide is recommended for patients with hemiplegic migraine. Patients who do not respond to these medications should try lamotrigine, particularly in patients who have predominant aura symptoms than a headache.[30] Other preventive medications that can be used (like in other typical migraines with aura) are amitriptyline, topiramate, and valproic acid.

Triptans and ergotamines are usually contraindicated in a hemiplegic migraine because of concern for potential cerebral vasoconstriction. Some specialists also recommend avoiding beta-blockers as preventive therapy for patients with hemiplegic migraines, like migraines with brainstem aura.

Methylprednisone at 100 mg daily for five days resolved symptoms of a child with hemiplegic migraine and severe symptoms.[31]

Triggers for a hemiplegic migraine headache should be identified and avoided if possible.[8][32][33]

Differential Diagnosis

Hemiplegic migraine episodes can mimic several other neurologic conditions that can cause a headache and neurological deficits. Some of the differentials include:

• TIA (symptoms reversible in both TIA and hemiplegic migraine, but TIA symptoms are more sudden and less likely to have other aura symptoms like nausea, vomiting, and photophobia, among others.)
• Infections like meningitis, encephalitis, and brain abscess can cause a headache and motor symptoms; other symptoms like rash, fever, CSF analysis, and neuroimaging can help to distinguish
• Brain tumors typically cause more progressive neurologic symptoms and have neuroimaging findings.
• Seizures with postictal paralysis can be distinguished by paroxysmal symptoms like limb jerking at the onset and postictal confusion.
• Inherited disorders like mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), hereditary hemorrhagic telangiectasia, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), can cause a headache, and neurologic deficits can be distinguished by clinical features, neuroimaging, and genetics.[34]
• Metabolic disturbances like homocystinuria and ornithine transcarbamylase deficiency can rarely present with a headache and stroke-like symptoms.[35]
• The syndrome of stroke-like migraine attacks after radiation therapy (SMART) is differentiated by a history of cerebral radiation and characteristic imaging findings.
• Alternating hemiplegia of childhood caused by variants in the ATP1A3 gene.[36] Features that help to distinguish it from migraine include cognitive impairment, dystonia, nystagmus, epilepsy, and ataxia.[37]
• Another possible differential that could occasionally present with headache and stroke-like events with paroxysmal hemiparesis is Sturge-Weber syndrome.[38]

Treatment Planning

Table 1. First-line medications for hemiplegic migraine

Table 2. Alternate treatment

Prognosis

In most patients with hemiplegic migraine, aura symptoms resolve completely, although they may be prolonged. In rare cases, hemiplegic migraine leads to permanent neurological deficits, cerebral infarctions, cognitive decline, or death. Poor outcomes are often associated with an early onset of 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, and it is important to remember that patients with hemiplegic migraine can have strokes. Further, acute ischemic strokes can also occur in these individuals due to vascular risk factors. Hence acute stroke interventions and vascular risk factor reduction must be considered in such individuals.[42][43][44]

Complications

Status Migrainosus

This is a debilitating migraine attack that tends to last for more than 72 hours. Some patients with status migrainous require hospitalization due to intense pain.

Migrainous Infarction or Stroke

Patients with migraine with aura have a higher risk of stroke. Migrainous infarction is a migraine attack in patients with aura, wherein the aura symptoms last for more than an hour, and infarction is seen on the neuroimaging.[45]

Persistent Aura without Infarction

This can be seen in patients whose aura lasts more than a week after the migraine headache has ended. Patients can have symptoms similar to migrainous infarction, but neuroimaging does not show any infarction.

Migraine-aura Triggered Seizure

This is a seizure that is triggered by a migraine attack with aura. The seizure typically occurs within an hour after a migraine attack.

Mental Health Issues

Some patients with migraine headaches are at an increased risk of having a major depressive disorder, bipolar disorder, or posttraumatic stress disorder.

Some rare complications are as follows:

• Permanent neurologic deficits[46]
• Cognitive decline
• Death

Consultations

Timely diagnosis and management of migraine headaches are essential, as they can sometimes be confused with stroke and other types of headaches. Patients usually present to emergency doctors, internists, or family physicians. Neuro physicians are also consulted.

Deterrence and Patient Education

Timely diagnosis and management of migraine headaches are essential, as they can sometimes be debilitating and affect the quality of life. Patients should be educated about the different phases of migraine headaches and the benefits of abortive and prevention therapy. Patients should be educated about lifestyle changes, which can help in reducing the frequency and severity of migraine attacks. Patients should also be instructed to go to a doctor in case of worsening symptoms or the occurrence of new neurological symptoms, which might warrant neuroimaging.

Enhancing Healthcare Team Outcomes

A hemiplegic migraine is a very rare migraine headache accompanied by unilateral weakness. It can be very upsetting to the patient and their family. Typically an interprofessional approach involving the family clinician (MD, DO, NP, or PA), a pharmacist, and a clinical headache specialist working with a nurse experienced in headache education to educate the patient and family will result in the best outcome. All team members must document their observations, interactions, and interventions in the patient's medical record and, when necessary, be able to communicate with other team members about the case. [Level 5]