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Hemiplegic migraine

Hemiplegic migraine
Literature review current through: Jan 2024.
This topic last updated: Jul 07, 2022.

INTRODUCTION — Hemiplegic migraine is a form of migraine that is characterized by an aura consisting of unilateral weakness along with other symptoms such as impairment of vision, speech, or sensation. Hemiplegic migraine may occur either in families or only in one individual (sporadic).

This topic will review the pathophysiology, clinical features, diagnosis, and management of familial and sporadic hemiplegic migraine. Other aspects of migraine are discussed elsewhere.

(See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults".)

(See "Pathophysiology, clinical features, and diagnosis of migraine in children".)

(See "Acute treatment of migraine in adults".)

(See "Preventive treatment of episodic migraine in adults".)

(See "Acute treatment of migraine in children".)

(See "Preventive treatment of migraine in children".)

CLASSIFICATION — The primary feature that separates hemiplegic migraine from other types of migraine with aura is the presence of motor weakness as a manifestation of aura in at least some attacks. Migraine auras most often manifest as visual disturbances but can also involve sensory, verbal, and rarely motor disturbances. Thus, hemiplegic migraine is an uncommon subtype of migraine with aura. (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on 'Migraine aura'.)

Hemiplegic migraine may be familial or sporadic, as discussed in the following section.

PATHOPHYSIOLOGY AND GENETICS — The weakness that characterizes hemiplegic migraine is a manifestation of motor aura. The aura of hemiplegic migraine is most probably caused by cortical spreading depression, a self-propagating wave of neuronal and glial depolarization that spreads across the cerebral cortex. (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on 'Cortical spreading depression'.)

Familial hemiplegic migraine — The first three types of familial hemiplegic migraine (FHM) account for some, but not all, of the patients who have familial hemiplegic migraine. They are channelopathies numbered according to the gene involved:

Familial hemiplegic migraine type 1 (FHM1) is caused by variants in the CACNA1A gene.

Familial hemiplegic migraine type 2 (FHM2) is caused by variants in the ATP1A2 gene.

Familial hemiplegic migraine type 3 (FHM3) is caused by variants in the SCN1A gene.

Because these types of familial hemiplegic migraine are transmitted in an autosomal dominant pattern, the child of a parent with familial hemiplegic migraine has a 50 percent chance of inheriting the variant, though the penetrance is variable.

Each genetic variant increases the susceptibility to cortical spreading depression, which most researchers agree initiates the aura of migraine and may initiate the migraine itself in these individuals. (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on 'Cortical spreading depression'.)

FHM1 – FHM1 is associated with variants in the CACNA1A gene on chromosome 19p13 that encodes the alpha-1A subunit of the P/Q-type calcium channel [1-5]. The estimated penetrance of CACNA1A variants ranges from 67 to 89 percent [3,6,7].

In addition to FHM1, variants in the CACNA1A gene have been implicated in spinocerebellar ataxia type 6, episodic ataxia type 2, and benign paroxysmal torticollis of infancy [1,8,9]. (See "Autosomal dominant spinocerebellar ataxias", section on 'SCA6' and "Overview of the hereditary ataxias", section on 'Episodic ataxias' and "Acquired torticollis in children", section on 'Benign paroxysmal torticollis'.)

FHM2 – FHM2 is associated with variants in the ATP1A2 gene on chromosome 1q23 that encodes a catalytic subunit of a sodium/potassium ATPase [5,10,11]. The estimated penetrance of variants in ATP1A2 ranges from 63 to 87 percent [6,7,12].

In addition to FHM2, variants in ATP1A2 have been associated with migraine with brainstem aura, several types of epilepsy, and rarely with alternating hemiplegia of childhood [13-17]. (See "Migraine with brainstem aura" and "Epilepsy syndromes in children".)

FHM3 – A variant in the SCN1A gene on chromosome 2q24 that encodes the transmembrane alpha subunit of the brain sodium channel has been described in several familial hemiplegic migraine pedigrees [18-22]. The estimated penetrance of variants in SCN1A is 100 percent [6,11,18-21].

In addition to FHM3, variants in the SCN1A gene have been linked to a number of epilepsy syndromes. (See "Clinical features and evaluation of febrile seizures", section on 'Genetic susceptibility'.)

Additional types – The specified types of familial hemiplegic migraine likely account for only a small proportion of cases. The best available evidence comes from a 2007 Danish population-based study that included 44 families with FHM [7]. Variants in the CACNA1A or ATP1A2 genes were found in only 14 percent of families, and no SCN1A variants were detected. In addition to these established familial hemiplegic migraine genes, variants in other genes have been reported in familial forms of hemiplegic migraine.

FHM associated with variants in the PRRT2 gene – Variants in the PRRT2 gene, initially recognized as a cause of several paroxysmal disorders, including episodic (or paroxysmal) kinesigenic dyskinesia 1, benign familial infantile epilepsy, and familial infantile convulsions with paroxysmal choreoathetosis, were identified in 2012 as a possible cause of familial hemiplegic migraine [23-26]. In a 2022 analysis of 697 patients with hemiplegic migraine, pathologic variants were found in 105 patients, including 17 percent who were found to have variations in PRRT2 [27]. None of these patients had pathologic variants in the CACNA1A, ATP1A2, or SCN1A genes. The estimated penetrance of variants in PRRT2 in this cohort was 88 percent. These data suggest variants in PRRT2 may represent a fourth type of FHM.

While not an ion channel gene, PRRT2 encodes a protein that interacts with the synaptosomal-associated protein SNAP25 [28], which may play a role in regulating voltage-gated calcium channels [29,30].

Others genetic variants – Some cases of familial hemiplegic migraine may be caused by variants in genes other than CACNA1A, ATP1A2, SCN1A, and PRRT2. In a study that examined 101 patients with hemiplegic migraine and no known variant in CACNA1A, ATP1A2, and SCN1A, variants in the PRRT2 gene were found in only 4 percent [24].

Variants in the SLC4A4 gene that encode for the sodium bicarbonate cotransporter, a known cause of proximal renal tubular acidosis (RTA) with ocular abnormalities, have been associated with familial forms of migraine in a few patients [31]. The phenotype appears to be variable and includes familial hemiplegic migraine with proximal RTA and typical migraine with or without aura. (See "Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis", section on 'Proximal (type 2) RTA'.)

Sporadic hemiplegic migraine — Patients who are the first member of their family to have hemiplegic migraine are classified as having sporadic hemiplegic migraine. Some cases of sporadic hemiplegic migraine are caused by one of the genetic variants that cause familial hemiplegic migraine, due to either de novo mutations or inheritance from an asymptomatic parent [32,33]. In population- and clinic-based studies, variants in the CACNA1A and the ATP1A2 genes have been identified in up to 20 percent of patients with sporadic hemiplegic migraine [6,33-35]. However, in patients with severe sporadic hemiplegic migraine associated with additional neurologic manifestations, the frequency of these variants may be much higher [32].

One patient with sporadic hemiplegic migraine with seizures and ataxia was found to have a variant form of the SLC1A3 gene that encodes the glutamate transporter EAAT1 causing neuronal hyperexcitability [36].

EPIDEMIOLOGY — Hemiplegic migraine is a rare disorder. In a population study from Denmark, the estimated prevalence of hemiplegic migraine is 0.01 percent [37]. The familial and sporadic versions occur with equal prevalence [38]. The average age of onset is 12 to 17 years (range 1 to 51 years) [3,38].

Like other forms of migraine, females have a higher prevalence of hemiplegic migraine, with female to male ratios ranging from 2.5:1 to 4.3:1 [38-40].

CLINICAL MANIFESTATIONS — Hemiplegic migraine is characterized by migraine attacks that include motor weakness during the aura phase. Attacks may variously include severe headache, scintillating scotoma, visual field defect, numbness, paresthesia, unilateral weakness, aphasia, fever, lethargy, coma, and seizures. The symptoms can last for hours to days, or rarely weeks, but most resolve completely. The clinical symptoms of sporadic hemiplegic migraine are indistinguishable from those of familial hemiplegic migraine [41].

Attack frequency and triggers — The mean frequency of attacks is three per year. However, the attack frequency is quite variable and ranges from a few per lifetime to 250 per year [42]. In many patients, the frequency of attacks falls after age 50 years, and hemiplegic attacks can evolve into more typical migraine attacks without hemiparesis [3,39]. Though most attacks occur without one, reported triggers of hemiplegic migraine attacks include acute stress, bright light, intense emotions, too little or too much sleep, exertion, and mild head trauma [39,42-45]. Attacks have also been triggered by conventional angiography and by regadenoson, an agent commonly used for cardiac stress tests [3,46].

Aura — Motor aura is the hallmark of hemiplegic migraine, but it is never the only type of aura present during a hemiplegic migraine attack [3,38,40]. Two or more auras are always experienced. Each one tends to evolve over 20 to 30 minutes and may take hours to gradually improve, typically beginning with a visual aura and followed successively by sensory, motor, aphasic, and brainstem symptoms, usually in that order [38]. The aura symptoms associated with migraine with brainstem aura (basilar-type migraine) (see "Migraine with brainstem aura") include vertigo, dysarthria, ataxia, bilateral visual, sensory or motor symptoms, hyperacusis, tinnitus, and diminished consciousness [38,40,47].

Motor symptoms most often start in the hand and gradually spread up into the arm and then the face [6]. The unilateral features of hemiplegic migraine may switch sides between or during attacks. However, bilateral motor signs occur in up to one-third of patients with familial hemiplegic migraine [3], affecting both sides either in succession or simultaneously. The degree of motor weakness can vary from mild to severe [6].

In a minority, motor weakness or other aura symptoms can develop acutely (ie, in less than five minutes) and may mimic a stroke [38,40]. The auras of hemiplegic migraine are often prolonged; 41 to 58 percent of patients have auras lasting >60 minutes and 2 to 8 percent have auras lasting ≥24 hours [3,38,40,48]. In unusual cases, reversible hemiplegia can last up to four weeks [6].

Headache — Most patients with hemiplegic migraine have headache with each attack [38,40]. The headache usually occurs during the aura, most often after the development of visual disturbances, but may occur before the aura. The headache can be bilateral or unilateral, and unilateral headache may be contralateral or ipsilateral to the aura symptoms [12,49,50]. The severity of headache ranges from mild to excruciating.

Other neurologic findings — Examination during an attack may reveal the presence of a Babinski sign or unilateral hyperreflexia [39]. Motor and sensory findings more often involve the upper rather than lower limbs [38,39]. In between attacks, most patients have a normal neurologic examination [38], but a majority of patients with familial hemiplegic migraine type 1 (FHM1) [3,51] and a minority with familial hemiplegic migraine type 2 (FHM2) [12,52,53] have cerebellar findings, including gaze-evoked nystagmus, dysarthria, or gait or limb ataxia.

Severe attacks — In addition to attacks with visual, sensory, motor, aphasic, and brainstem auras, some patients with hemiplegic migraine have more severe attacks accompanied by encephalopathy or coma [6]. Severe attacks affect a variable proportion of patients in different reports, ranging from 1 percent in a population-based study of patients with familial hemiplegic migraine from Denmark [38] to 33 percent in a study of patients with genetic variants in CACNA1A (ie, FHM1) [3]. The encephalopathy can manifest as confusion, agitation, delusions, somnolence, or deep coma [12,54-56]. Seizures, fever, meningismus, cerebrospinal fluid pleocytosis, cerebral edema, or cerebral infarction can also occur with severe attacks [6]. The aura symptoms of severe attacks, including hemiplegia and impaired consciousness, can be prolonged and last days to months before completely resolving [3,52,57-59]. In rare instances, severe attacks can lead to permanent brain injury, cerebral infarction, cerebral atrophy, global or regional hypometabolism, cognitive decline, or death [60-67].

Genotype-phenotype correlations — The subtypes of familial hemiplegic migraine cannot be reliably distinguished on the basis of clinical features alone. In addition, sporadic hemiplegic migraine cannot be reliably distinguished from the familial type except for the lack of family history. The phenotype of hemiplegic migraine may change within an individual, and often family members suffer different symptoms though they share identical genetic variants [49]. However, there are differences in the range of phenotypic expression of the three specified familial subtypes:

FHM1 is caused by variants in the CACNA1A gene (see 'Familial hemiplegic migraine' above). Approximately half of the families with FHM1 have cerebellar involvement, including gaze-evoked nystagmus, ataxia, and vermian atrophy [1-5]. In addition, some families have severe attacks with coma, prolonged hemiplegia, or both, with full recovery. Transient cerebral edema and cerebral atrophy are uncommon clinical features. Neuronal impairment in the superior cerebellar vermis has been suggested by metabolic alterations found on magnetic resonance spectroscopy [68]. Co-occurrence of familial hemiplegic migraine with childhood epilepsy and cerebellar ataxia in a single family with a variant form of CACNA1A has also been reported [69]. A severe phenotype is associated with the S218L variant of CACNA1A, in which mild head trauma may lead to attacks with prolonged hemiplegia, coma, cerebral edema, or even death [59,60,70]. The R583Q genetic variant is associated with a heterogeneous phenotype in a single large family, with manifestations including various combinations of migraine with aura, transient focal neurologic deficits without headache, cerebellar ataxia, and coma triggered by minor head trauma [71].

FHM2 is caused by variants in the ATP1A2 gene (see 'Familial hemiplegic migraine' above). The clinical features of FHM2 are less well-defined than for FHM1, but different ATP1A2 variants have been linked to different phenotypes, including frequent and long-lasting hemiplegia, recurrent coma, or seizures with intellectual disability [5,10,12,16,72,73]. Cerebellar involvement has also been described in some patients with FHM2 [12,52,74].

Familial hemiplegic migraine type 3 (FHM3) is caused by variants in the SCN1A gene (see 'Familial hemiplegic migraine' above). Only a few families with this genotype have been reported, and the phenotype includes epilepsy [18-20]. In two unrelated families with FHM3, a novel phenotype called elicited repetitive daily blindness has been described, consisting of repetitive stereotyped spells of blindness, usually bilateral, lasting up to 30 seconds followed by instantaneous recovery [21,75]. The visual loss can occur spontaneously or can be triggered by eye rubbing, sudden changes of light, or sudden standing.

Associated neurologic conditions — Patients with hemiplegic migraine may have other associated headache disorders or neurologic conditions.

Migraine with aura has been associated with familial and sporadic hemiplegic migraine in Danish population studies; no similar association was found with migraine without aura [76,77].

Trigeminal autonomic cephalgias may be found in patients with hemiplegic migraine. One report from a tertiary headache referral center observed the co-occurrence in 10 patients of hemiplegic migraine and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) or short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) [78]. Both SUNCT and SUNA are rare types of headache that are classified as trigeminal autonomic cephalgias, a group of primary headache disorders characterized by unilateral trigeminal distribution pain that occurs in association with ipsilateral cranial autonomic features. (See "Short-lasting unilateral neuralgiform headache attacks: Clinical features and diagnosis" and "Pathophysiology of the trigeminal autonomic cephalalgias".)

Chronic cerebellar ataxia may occur in some patients with familial hemiplegic migraine [48,79].

Epilepsy has also been reported in patients with hemiplegic migraine. In one Danish study, 7 percent of patients with FHM1 were reported to have epilepsy [38]. Benign familial infantile epileptic syndromes have been reported in patients who subsequently developed hemiplegic migraine, including some families with FHM2 [15,80].

DIAGNOSIS — The diagnosis of hemiplegic migraine remains clinical, and genetic testing is not necessary for all patients.

Diagnostic approach — Evaluation of patients with headache and neurologic symptoms where the diagnosis of hemiplegic migraine is considered includes the application of established diagnostic criteria and clinical investigations to exclude entities in the differential diagnosis. A diagnosis of hemiplegic migraine is made if the following are satisfied:

The patient's symptoms fulfill the diagnostic criteria. The key features are the occurrence of episodic, reversible motor weakness as a manifestation of migraine aura in conjunction with at least one other kind of aura (visual, sensory, aphasic, or brainstem). Since motor aura is a necessary feature for the diagnosis, the clinician must establish as clearly as possible whether the patient actually experienced motor weakness as an aura symptom. Although seemingly straightforward, this determination is often challenging because patients may confuse or misinterpret ataxia or numbness as weakness. (See 'Diagnostic criteria' below.)

Testing to exclude other considered causes within the differential diagnosis is necessary for patients in whom the diagnosis of hemiplegic migraine is not established, who have prolonged or atypical symptoms, or if the cause of acute symptoms is uncertain. Specific investigations are individualized by patient and guided by symptom characteristics. (See 'Differential diagnosis' below and "Differential diagnosis of transient ischemic attack and acute stroke".)

A thorough family history is essential to distinguish familial from sporadic hemiplegic migraine. In some cases, the diagnosis will change from sporadic to familial hemiplegic migraine over time if a family member develops hemiplegic migraine [81].

Diagnostic criteria — The International Classification of Headache Disorders, 3rd edition (ICHD-3) diagnostic criteria for hemiplegic migraine require that all of the following be satisfied [82]:

At least two attacks fulfilling criteria for migraine with aura (table 1)

Aura consisting of both of the following:

Fully reversible motor weakness

Fully reversible visual, sensory, and/or speech or language symptoms

Not better accounted for by another ICHD-3 diagnosis

The ICHD-3 diagnostic criteria for familial hemiplegic migraine additionally require that at least one first- or second-degree relative has had attacks fulfilling the criteria for hemiplegic migraine [82]. Criteria for sporadic hemiplegic migraine specify that no first- or second-degree relative has had attacks fulfilling criteria for hemiplegic migraine.

While the ICHD-3 criteria require fully reversible aura symptoms, in patients with hemiplegic migraine, motor symptoms may be prolonged (eg, up to 72 hours) and rarely may lead to permanent neurologic deficits. (See 'Severe attacks' above.)

Tests to exclude other etiologies — We recommend diagnostic testing in patients with acute headache and neurologic symptoms to exclude other causes of weakness such as stroke or seizure if:

Symptoms are prolonged or atypical, or

The cause of acute symptoms is uncertain, or

The patient does not already carry a diagnosis of hemiplegic migraine

Specific investigations are individualized by patient and guided by symptom characteristics. (See 'Differential diagnosis' below and "Differential diagnosis of transient ischemic attack and acute stroke".)

Neuroimaging — Brain imaging (eg, brain magnetic resonance imaging [MRI] or computed tomography [CT]) in patients with headache and neurologic signs can help identify alternative causes such as intracranial hemorrhage, ischemic stroke, tumors, or abscesses. CT is more readily available than MRI and may be preferred for detecting subarachnoid hemorrhage or structural abnormalities, but MRI is preferred as it is more sensitive for stroke, lesions in the posterior fossa, inflammatory lesions, and neoplasms [83]. The use of neuroimaging is also supported by a practice parameter from the American Academy of Neurology [84].

Neurovascular studies (eg, magnetic resonance [MR] angiography or CT angiography) can identify vascular occlusions such as carotid dissection or cerebral venous sinus thrombosis. Conventional contrast cerebral angiography should be avoided if possible, as it is a known trigger of hemiplegic migraine attacks. (See 'Attack frequency and triggers' above.)

During attacks of hemiplegic migraine, brain imaging is usually normal, whether by CT or MRI. In a minority, however, CT or MRI may reveal abnormal findings associated with hemiplegic migraine such as cortical edema and cortical or meningeal enhancement contralateral to the hemiparesis [36,85-87]. In two small studies, susceptibility-weighted MRI during the symptomatic phase of hemiplegic migraine revealed transient prominence of the cerebral veins in brain regions that corresponded with the neurologic deficits [88,89]. In severe cases of hemiplegic migraine, brain MRI may reveal cortical hemispheric atrophy and cortical laminar necrosis [61,90]. Chronic cerebellar atrophy is frequently observed in patients with familial hemiplegic migraine type 1 (FHM1) [51,58].

In addition, several studies have demonstrated abnormalities on advanced perfusion-based or nuclear imaging studies. Hyperperfusion may be found on MR perfusion-weighted imaging or single photon emission computed tomography (SPECT) and vasodilation may be identified on noninvasive or conventional angiography. Other reports have found hypoperfusion without infarction, in some cases accompanied by vasoconstriction. These differences may be related in part to the timing of the imaging studies, as migraine aura is initially associated with transient hypoperfusion followed by hyperperfusion [57,61,91-101]. In one patient with sporadic hemiplegic migraine and a genetic variant in the CACNA1A gene who was followed for 15 years, imaging with fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) showed that glucose metabolism was reduced in the bilateral supratentorial cortices and in the left cerebellum [65]. In another report of a patient with familial hemiplegic migraine type 2 (FHM2; caused by a variant in ATP1A2), imaging with 18F-FDG PET during an attack of hemiplegia showed glucose hypometabolism in the contralateral perisylvian cortex that was only partially reversed 78 days later [66].

Ancillary testing — Routine use of additional investigations such as electroencephalography (EEG) should be reserved for patients with symptoms (eg, loss of consciousness, history of seizures) specifically suggestive of an alternative diagnosis such as seizure [83,102]. Likewise, laboratory testing may be infrequently useful to evaluate specific conditions such as metabolic encephalopathy (eg, hypoglycemia or uremia). Lumbar puncture for cerebrospinal fluid may be useful in evaluating for specific conditions such as subarachnoid hemorrhage or the syndrome of transient headache and neurologic deficits with cerebrospinal fluid lymphocytosis (HaNDL) [83]. The benefit of lumbar puncture needs to be evaluated against the risk of developing post-dural puncture headache. (See 'Differential diagnosis' below and "Post dural puncture headache".)

Genetic testing — Genetic testing may be useful to help establish the diagnosis of hemiplegic migraine as the cause of severe symptoms in patients without a family history (ie, sporadic cases); in addition, genetic testing may be helpful for cases of familial hemiplegic migraine when the attack severity or symptoms diverge from those of affected relatives [6,32]. However, the yield of genetic testing is low in patients with adult-onset hemiplegic migraine, particularly when there are no associated permanent neurologic features. (See 'Pathophysiology and genetics' above.)

Differential diagnosis — The differential diagnosis of hemiplegic migraine primarily includes cerebrovascular disease (eg, transient ischemic attack [TIA] and ischemic or hemorrhagic stroke), seizure with postictal paralysis, other forms of migraine, and tumor. Other entities that may mimic hemiplegic migraine include the syndrome of stroke-like migraine attacks after radiation therapy, HaNDL, alternating hemiplegia of childhood, central nervous system infections, certain hereditary and metabolic disorders, and Sturge-Weber syndrome.

TIA and ischemic stroke – The symptoms of TIA and hemiplegic migraine are fully reversible, and neuroimaging is often unrevealing in both conditions. However, both a TIA and an ischemic stroke typically have a sudden onset of symptoms rather than a gradual progressive spread of one aura symptom after another. Ischemic events are also less likely to have positive symptoms such as visual scintillations or paresthesia and are less likely to have migrainous symptoms such as nausea, vomiting, photophobia, and phonophobia (see "Differential diagnosis of transient ischemic attack and acute stroke"). An exception might be brain ischemia caused by cervical artery dissection, which can have both a progressive spread of symptoms and some migrainous features [103-105]. (See "Cerebral and cervical artery dissection: Clinical features and diagnosis".)

Brain tumors – Brain tumors typically cause progressive rather than transient neurologic symptoms and are clearly differentiated from hemiplegic migraine by neuroimaging findings of one or more mass lesions.

Seizures – Epilepsy with hemiparesis attributed to postictal (Todd) paralysis is usually distinguished from hemiplegic migraine by paroxysmal symptoms at seizure onset, such as limb jerking, head turning, and loss of consciousness, and by the presence of postictal confusion.

SMART syndrome – The syndrome of stroke-like migraine attacks after radiation therapy (SMART) may include discrete spells of unilateral headache, hemiparesis, hemisensory, and visual and speech impairments that may or may not resolve. SMART should be differentiated from hemiplegic migraine by the history of previous cerebral irradiation and characteristic imaging findings of thick cortical gyral enhancement [106-108]. Patients with SMART syndrome are unlikely to have a family history of hemiplegic migraine and are more likely to have associated seizures. (See "Delayed complications of cranial irradiation", section on 'Migraine-like headache (SMART) syndrome'.)

HaNDL syndrome – The syndrome of transient HaNDL, like hemiplegic migraine, may present with episodic headache, hemiparesis, and aphasia and may have ictal regional blood flow abnormalities or be triggered by angiography. Unlike hemiplegic migraine, HaNDL is not familial and is monophasic with resolution in three months. Spinal fluid lymphocytosis is required for the diagnosis of HaNDL, but it has occasionally been found in patients with familial hemiplegic migraine [3,39,109-111]. (See "Syndrome of transient headache and neurologic deficits with cerebrospinal fluid lymphocytosis (HaNDL)".)

Alternating hemiplegia of childhood – Alternating hemiplegia of childhood (AHC) is a rare condition caused (in the majority of patients) by variants in the ATP1A3 gene [112]. In two reports, familial occurrence of AHC was linked to variants in the ATP1A2 gene, allelic with FHM2 [13,113] (see 'Familial hemiplegic migraine' above). AHC is characterized by periodic episodes of hemiplegia or quadriplegia beginning in infancy [112]. Associated features include dystonia, paroxysmal eye movements (eg, nystagmus), epilepsy [114], cognitive impairment, and ataxia, which help to distinguish it from hemiplegic migraine. (See "Types of migraine and related syndromes in children", section on 'Alternating hemiplegia of childhood'.)

Other inherited conditions – The symptomatology of other systemic disorders can include recurrent migraine-like headaches and neurologic deficits. They are distinguished from hemiplegic migraine on the basis of their clinical features, neuroimaging abnormalities, and genetics. These conditions include:

The syndrome of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) [115]. (See "Mitochondrial myopathies: Clinical features and diagnosis", section on 'MELAS'.)

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) [116]. (See "Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)".)

Hereditary hemorrhagic telangiectasia [117]. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)".)

Sturge-Weber syndrome is a rare congenital vascular disorder characterized by facial capillary malformation (port wine birthmark) and associated capillary-venous malformations affecting the brain and eye. While it is not ordinarily confused with hemiplegic migraine, there are case reports of patients with Sturge-Weber syndrome who develop attacks of headache and stroke-like events with paroxysmal hemiparesis [118-120]. (See "Sturge-Weber syndrome".)

Infections – Central nervous system infection (meningitis, encephalitis, abscess) can cause headache and hemiparesis, but clinical signs (eg, rash, fever, nuchal rigidity), cerebrospinal fluid analysis (eg, pleocytosis), and neuroimaging findings (eg, meningeal enhancement or parenchymal lesion) usually point to the correct diagnosis. (See "Clinical features and diagnosis of acute bacterial meningitis in adults" and "Viral encephalitis in adults" and "Pathogenesis, clinical manifestations, and diagnosis of brain abscess".)

Metabolic disturbances – Some metabolic disturbances, including ornithine transcarbamylase deficiency [121] and homocystinuria [122], can occasionally present with headache and stroke-like attacks but are rarely confused with hemiplegic migraine.

MANAGEMENT — The management of hemiplegic migraine typically involves pharmacologic treatment with agents typically used to abort or prevent migraine that do not potentiate the risk of cerebral vasoconstriction. Because of associated neurologic impairments, patients with severe attacks may require hospitalization and additional measures. (See 'Severe attacks' above.)

Abortive and preventive medications — There are no randomized controlled trials of therapy specifically for hemiplegic migraine. However, there is limited evidence from case reports and small series of multiple medications treating hemiplegic migraine.

First-line options — Our approach to initial therapy for patients with hemiplegic migraine is as follows:

For patients with frequent or prolonged aura, we use oral sustained-release verapamil.

Studies involving a small number of patients support the use of verapamil in hemiplegic migraine [44,50,63]. Sustained-release verapamil is started at 120 mg once daily and increased to 120 mg twice daily (total 240 mg daily). The dose can be further titrated up to 120 mg three times a day (total 360 mg daily) for most patients if needed. However, we avoid exceeding a maximum verapamil dose of 120 mg daily for small or older adult patients. In one report of four patients with sporadic hemiplegic migraine, treatment with verapamil (120 mg one to three times a day) was associated with complete resolution of attacks within the first month in two patients and a >50 percent reduction in attack frequency and severity in a third patient [50]. By contrast, other investigators have reported little or no improvement in hemiplegic migraine despite treatment with verapamil [6].

For patients in whom the headache pain predominates, we use flunarizine (where available), topiramate, or amitriptyline.

Hemiplegic migraine may respond to flunarizine [11,123,124]. The usual starting dose of flunarizine is 2.5 to 5 mg given once daily (in the evening), and the dose can be further titrated up to 10 mg per day as needed. In one study that included 13 children with hemiplegic migraine, flunarizine (2.5 to 10 mg daily) treatment was associated with a ≥50 percent reduction in attack frequency in 11 (85 percent) [124]. However, flunarizine is unavailable in the United States.

Since hemiplegic migraine is a subset of migraine with aura, preventive medications commonly used to treat typical migraine with aura such as topiramate or amitriptyline may be beneficial [125,126]. Topiramate is started at 25 mg per day, and the daily dose is increased, as tolerated, by 25 to 50 mg every week to a maximum of 100 mg twice daily. Amitriptyline is started at 10 mg at bedtime and may be increased weekly up to 50 mg at bedtime. (See "Preventive treatment of episodic migraine in adults".)

For patients with familial hemiplegic migraine, we use acetazolamide.

Treatment with acetazolamide (250 mg twice a day) is associated with improvement in some patients with familial hemiplegic migraine [4,127,128]. The utility of acetazolamide for hemiplegic migraine is further supported by nonrandomized studies showing its effectiveness in channelopathies that are genetically colocalized with familial hemiplegic migraine type 1 (FHM1) (see 'Familial hemiplegic migraine' above). These include hypokalemic periodic paralysis (see "Hypokalemic periodic paralysis", section on 'Preventive treatment') and episodic ataxia type 2 (see "Overview of the hereditary ataxias", section on 'Episodic ataxias').

The decision to continue the medications as preventive therapy after an attack is based upon frequency and severity of attacks, patient preferences regarding use of a daily medication for intermittent symptoms, and whether the agent selected may also effectively treat a separate medical condition. If used as an abortive agent only, these medications are typically discontinued upon resolution of symptoms.

Alternative options — For adult patients who have persistent aura symptoms that predominate over headache and who do not improve with first-line medications, we suggest lamotrigine. Other alternative agents that have been examined include intranasal ketamine, intravenous naloxone, and onabotulinumtoxinA.

Lamotrigine is started at 25 mg daily with slow titration in 25 mg steps weekly or biweekly up to 100 mg per day if needed. Lamotrigine was found to be beneficial in a case series of 47 patients who had migraine with aura, including the two patients who had hemiplegic migraine [129]. In a prospective open-label study of 59 patients who had migraine with aura, including eight with motor aura, lamotrigine (25 to 300 mg daily) was associated with a reduction in migraine aura intensity and migraine attack frequency compared with baseline [130]. However, an earlier randomized controlled trial with 77 patients who had migraine with and without typical aura did not demonstrate any benefit of lamotrigine for migraine prophylaxis [131].

Of concern, a rash may develop in up to 10 percent of patients during the initial one to two months of lamotrigine therapy, which necessitates discontinuation of the drug. Although the risk of developing Stevens-Johnson syndrome is low (approximately 1 in 1000 adults), it is difficult to initially distinguish between a benign or life-threatening rash. The risk of Stevens-Johnson syndrome is increased dramatically in children, leading to the recommendation that the drug not be used in patients under the age of 16 years. (See "Lamotrigine: Drug information".)

Intranasal ketamine given at attack onset was associated with a reproducible decrease in the intensity and duration of aura in 5 of 11 patients with familial hemiplegic migraine [132]. In one patient with possible sporadic hemiplegic migraine and another with what was termed "complicated migraine" without hemiplegia, intravenous naloxone (0.4 mg) was associated with resolution of the aura-like symptoms, but not the headache pain, within two minutes [133]. (See "Preventive treatment of episodic migraine in adults" and "Preventive treatment of migraine in children".)

In another case series of 11 patients (4 with familial hemiplegic migraine and 7 with sporadic hemiplegic migraine), a regimen of onabotulinumtoxinA injections every 12 weeks produced a reduction in frequency and severity of pain and aura associated with hemiplegic migraine episodes [134].

The use of triptans for hemiplegic migraine is controversial. (See 'Medications generally avoided' below.)

Acute management of severe attacks — Patients with severe attacks of hemiplegic migraine (see 'Severe attacks' above) may require hospital care due to fever, depressed consciousness, or seizures. In addition to usual supportive management of symptoms, therapeutic options for these migraine attacks are the same as for hemiplegic migraine attacks with less severe symptoms [6]. However, patients with recalcitrant severe symptoms may also benefit from treatment with parenteral medications such as corticosteroids.

Evidence to support the use of corticosteroids is based on individual case reports in the pediatric population. In one case, administration of methylprednisolone at 100 mg daily for five days was effective for a child with hemiplegic migraine and severe symptoms [135]. In another, the early treatment of severe attacks with pulse corticosteroids plus hypertonic saline seemed beneficial [136]. This report described a child with sporadic hemiplegic migraine and CACNA1A-related encephalopathy who had recurrent attacks of headache, seizures, hemiplegia, coma, and brain edema on MRI. Treatment with intravenous dexamethasone (0.5 mg/kg daily divided into three doses per day for three days, followed by gradual oral tapering) and hypertonic saline (3% saline solution given at 1.5 mL/kg per hour, adjusted to maintain sodium levels between 145 and 155 mEq/L, given for two days) was associated with a reduction in seizures and attack duration. It is unclear whether such treatment would be effective for other patients with severe attacks of hemiplegic migraine.

Medications generally avoided — We generally avoid triptans and ergotamine derivatives, particularly for patients with severe attacks, because of theoretical concerns and anecdotal evidence that these medications may prolong symptoms or lead to ischemia. In a retrospective case-control study in the Netherlands that included 188 patients hospitalized with ischemic events and 689 age and sex-matched controls, ergotamine overuse was a risk factor for ischemic complications (odds ratio 2.55, 95% CI 1.22-5.36) [137]. Cases of cardiac arrest, cerebral infarcts, and spinal cord infarcts have also been reported in the setting of triptan use [138-142]. In addition, some patients presenting with symptoms consistent with hemiplegic migraine may subsequently be found to have an acute ischemic stroke. Vasoconstrictive medications such as triptans and ergotamines may worsen cerebral ischemia and are felt to be contraindicated in patients with acute stroke. (See "Migraine-associated stroke: risk factors, diagnosis, and prevention", section on 'Medications to avoid'.)

However, the theoretical concern about worsening cerebral vasoconstriction in patients with hemiplegic migraine is based primarily upon the relatively outdated vascular theory of migraine, and some have argued that the contraindication for triptans should be reconsidered [6,143]. Patients with hemiplegic migraine were excluded from the larger randomized controlled trials that evaluated triptans for migraine because of historical concerns regarding vasoconstriction. Limited available evidence suggests that triptans do not increase the risk of ischemic events when used for individuals with hemiplegic migraine. In a retrospective series of 76 patients with hemiplegic migraine, for example, triptans appeared to be beneficial and safe for the treatment of the headache phase [144]. There were no ischemic strokes or permanent neurologic complications reported, although one patient had a prolonged attack of hemiplegic migraine that persisted for several months following triptan treatment. In another retrospective series of 13 patients with migraine with brainstem aura (basilar-type migraine), hemiplegic migraine, and prolonged aura exposed to triptans, there was no increased risk of adverse events [143]. (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on 'Pathophysiology'.)

Some headache specialists also avoid beta blockers and intravenous dihydropyridine calcium channel blockers as preventive therapy for patients who have hemiplegic migraine, migraine with brainstem aura (basilar-type migraine), or migraine with prolonged aura [145]. The concern is that beta blockers may potentially prolong symptoms, limit compensatory cerebral vasodilatory capacitance, or lead to cerebral ischemia [146,147]. Intravenous dihydropyridine calcium channel blockers may potentially lead to cerebral hypoperfusion. In one reported case, intravenous nimodipine possibly provoked a seizure during a prolonged attack of hemiplegic migraine in a patient with familial hemiplegic migraine type 2 (FHM2) [148]. (See 'Differential diagnosis' above and "Initial assessment and management of acute stroke", section on 'Blood pressure management'.)

PROGNOSIS — In nearly all patients with hemiplegic migraine, the aura symptoms eventually resolve completely, though they may be prolonged. However, in rare cases, hemiplegic migraine leads to permanent neurologic deficits, cerebral infarction, cognitive decline, or death [60-64,90,149]. Most such patients have phenotypes characterized by early onset of hemiplegic migraine with severe attacks, recurrent coma, or seizures [6]. (See 'Severe attacks' above.)

In many patients, the frequency of attacks falls after age 50 years, and hemiplegic attacks can evolve into more typical migraine attacks without hemiparesis [3,39].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Migraine and other primary headache disorders".)

SUMMARY AND RECOMMENDATIONS

Classification and pathophysiology – Hemiplegic migraine may be familial or sporadic. The three established types of familial hemiplegic migraine (FHM1, FHM2, and FHM3) are autosomal dominant channelopathies that increase the susceptibility to cortical spreading depression and onset of the migraine. Patients who are the first member of their family to have hemiplegic migraine are classified as having sporadic hemiplegic migraine. (See 'Pathophysiology and genetics' above.)

Clinical features – Hemiplegic migraine is characterized by complex migraine auras that include motor weakness and at least one other feature such as paresthesia, aphasia, or brainstem impairment. Unilateral or bilateral headache commonly accompanies the aura. Severe cases may also include fever, lethargy, coma, and seizures. The symptoms can last for hours to days, or rarely weeks, but most resolve completely. (See 'Clinical manifestations' above.)

Clinical diagnosis – The diagnosis of hemiplegic migraine is made when symptoms fulfill the diagnostic criteria, including at least two episodes of migraine with reversible complex aura consisting of motor weakness and one or more additional features (visual, sensory, aphasic, or brainstem) and are not better accounted for by another diagnosis. (See 'Diagnostic criteria' above.)

Diagnostic testing – Diagnostic testing is indicated for patients without an established diagnosis of hemiplegic migraine and for those with prolonged or atypical symptoms. (See 'Tests to exclude other etiologies' above.)

Brain imaging with CT or MRI can help identify alternative causes such as intracranial hemorrhage, ischemic stroke, tumors, or abscesses. (See 'Neuroimaging' above.)

Genetic testing may help to establish the diagnosis in patients who do not have a family history of hemiplegic migraine and in patients whose symptoms are divergent from those of affected relatives with familial hemiplegic migraine. (See 'Genetic testing' above.)

Differential diagnosis – The differential diagnosis of hemiplegic migraine primarily includes cerebrovascular disease (eg, transient ischemic attack and ischemic or hemorrhagic stroke), seizure with postictal paralysis, other forms of migraine, tumor, infections, and certain hereditary and metabolic disorders. (See 'Differential diagnosis' above.)

Treatment

First line agents – Our initial therapy for hemiplegic migraine depends upon the clinical presentation and family history. (See 'First-line options' above.)

-For patients with frequent or prolonged aura, we suggest oral sustained-release verapamil (Grade 2C).

-For patients for whom the headache pain predominates, we suggest flunarizine (where available), topiramate, or amitriptyline (Grade 2C).

-For patients with familial hemiplegic migraine, we suggest acetazolamide (Grade 2C).

Alternative choices – We use lamotrigine or botulinum toxin as alternative options for patients whose symptoms do not improve with first-line therapies. (See 'Alternative options' above.)

Medications generally avoided – We generally avoid triptans and ergotamine derivatives to treat patients with symptoms of hemiplegic migraine because of theoretical concerns and anecdotal evidence that these medications may prolong symptoms or lead to ischemia. (See 'Medications generally avoided' above.)

Prognosis – In nearly all patients with hemiplegic migraine, the aura symptoms eventually resolve completely, though they may be prolonged. In rare cases, hemiplegic migraine leads to permanent neurologic deficits. (See 'Prognosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges David F Black, MD, who contributed to an earlier version of this topic review.

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Topic 14112 Version 30.0

References

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