Migrena hemiplegică pediatrică: o trecere în revistă

Introduction

The defining feature that distinguishes hemiplegic migraine (HM) from other types of migraine with aura (MA) is the presence of motor aura. The diagnostic criteria for HM have been revised in the most recent edition of the International Classification of Headache Disorders⁽¹⁾. Hemiplegic migraine may occur in a sporadic form (SHM) or as a familial form (FHM), the latter typically following an autosomal dominant inheritance pattern⁽¹⁾. SHM and FHM share similarities in terms of epidemiology, triggering factors, clinical presentation, as well as neuroradiological and neurophysiological findings. However, the two forms differ in aspects such as age of onset, underlying genetic mutations and the broader neurological profile associated with each^(2,3).

Types of hemiplegic migraine and genes involved

Specific genetic subtypes of familial hemiplegic migraine have been identified:

• FHM type 1 (FHM1) is associated with mutations in the CACNA1A gene (which encodes a calcium channel) located on chromosome 19p13.
• FHM type 2 (FHM2) involves mutations in the ATP1A2 gene (which encodes a Na⁺/K⁺-K-ATPase) on chromosome 1q23.
• FHM type 3 (FHM3) is linked to mutations in the SCN1A gene (which encodes a sodium channel) on chromosome 2.

Of note, HM-associated genes exhibit pleiotropy, with distinct mutations potentially giving rise to overlapping clinical or familial phenotypes, including a spectrum of paroxysmal neurological conditions.

Main symptomatology:

• unilateral weakness or paralysis (temporary)
• severe, pulsating headache
• visual disturbances (flashing lights, blurred vision, scotomas)
• aphasia or difficulty speaking
• nausea and vomiting
• confusion or even loss of consciousness in severe cases.

Diagnosis:

• based on ICHD-3 criteria (International Classification of Headache Disorders)
• must exclude other serious conditions, like stroke, epilepsy, ADEM brain tumors.

Triggering factors

Nearly half of all patients report experiencing at least one trigger during their first episode of hemiplegic migraine⁽⁴⁾. Several factors can act as triggers for hemiplegic migraine. Minor head trauma is among the most frequently reported triggers, occurring in both sporadic (SHM) and familial (FHM) forms, across all three FHM subtypes. Overall, a history of minor head injury is noted in up to 45% of HM cases. In contrast, such trauma is rarely reported in patients with migraine with aura (MA). Emotional stress ranks as the second most common potential trigger, reported in up to 43% of cases. Other possible precipitating factors include intense physical activity, previous catheter angiography, fever, heat or sun exposure, and sleep deprivation – many of which are also frequently reported in patients with MA and migraine without aura (MWA)^(5,6).

Natural history and epidemiology of headache and migraine in children

Headache disorders, including migraine, are among the most common neurological complaints in the pediatric population. The prevalence of migraine in children varies widely depending on age, with estimates ranging from approximately 3% in early childhood to 10-15% in adolescence. Migraines often begin between the ages of 5 and 15 and tend to be more common in girls after puberty.

The natural history of pediatric migraine is characterized by fluctuations in frequency and severity over time. Many children experience a decrease in headache frequency and intensity as they transition into adulthood, though some continue to suffer from chronic migraines. Early diagnosis and management are crucial to reduce the impact on quality of life, school attendance and social development. Epidemiological studies indicate that genetic and environmental factors both contribute to migraine susceptibility. Family history is a significant risk factor, with children having a first-degree relative with migraine being more likely to develop the condition themselves. Common triggers in children include stress, sleep disturbances, dietary factors and hormonal changes, particularly during puberty. Understanding the natural course and epidemiology of pediatric migraine helps guide appropriate treatment and preventive strategies, aiming to improve long-term outcomes for affected children^(7,8).

Neurobiological features and clinical diagnosis

Hemiplegic migraine is a rare genetically influenced subtype of migraine characterized by transient motor weakness or paralysis (hemiplegia) during the aura phase. The neurobiological basis of HM centers around abnormal neuronal excitability and cortical spreading depression (CSD), a phenomenon widely accepted as the underlying mechanism of migraine aura.

1. Cortical spreading depression (CSD)

CSD is a wave of depolarization followed by suppression of neural activity that slowly propagates across the cerebral cortex. This wave correlates with the aura symptoms in migraine, including visual disturbances and motor weakness. In hemiplegic migraine, the CSD affects the motor cortex, causing temporary hemiparesis or paralysis. The spread and intensity of CSD appear exaggerated in HM, leading to more profound neurological deficits than in typical migraine with aura.

2. Genetic mutations and ion channel dys­func­tion

Genetic factors play a pivotal role in hemiplegic migraine, particularly in familial cases (FHM). Mutations in three key genes have been identified; each encoding ion channels or transporters critical for maintaining neuronal ion homeostasis: CACNA1A (encodes the a1A subunit of the P/Q-type voltage-gated calcium channel). Mutations lead to altered calcium influx in neurons, resulting in increased excitatory neurotransmitter release and neuronal hyperexcitability.

ATP1A2 (encodes the a2 subunit of the Na⁺/K⁺ ATPase pump): mutations impair ion pump function in astrocytes, disrupting extracellular potassium clearance and glutamate reuptake, facilitating CSD.

SCN1A (encodes the a subunit of the voltage-gated sodium channel Nav1.1): mutations alter sodium channel function, contributing to neuronal hyperexcitability and susceptibility to seizures and migraine.

These mutations disrupt the delicate balance of excitatory and inhibitory signaling in the brain, lowering the threshold for triggering CSD and the consequent aura symptoms.

3. Neurotransmitter imbalance

Hemiplegic migraine is also associated with alterations in neurotransmitter systems, including glutamate, gamma-aminobutyric acid (GABA) and serotonin. Elevated glutamate levels increase excitatory signaling, promoting CSD, while reduced GABAergic inhibition fails to counterbalance this effect. Serotonergic dysfunction may modulate vascular tone and nociception, contributing to migraine pain.

4. Vascular and metabolic changes

During an hemiplegic migraine attack, neuroimaging studies (such as functional MRI and PET scans) reveal transient changes in cerebral blood flow and metabolism corresponding to the CSD wave. Initially, there is a brief hyperemia (increased blood flow), followed by prolonged oligemia (reduced blood flow). These vascular changes likely contribute to aura symptoms and headache generation.

5. Neuroinflammation and glial activation

Emerging evidence suggests that neuroinflammatory processes and glial cell activation may play roles in sustaining HM attacks. Activated astrocytes and microglia release inflammatory mediators that can sensitize neurons and perpetuate migraine pathology⁽⁹⁾.

Clinical diagnosis

Diagnosing hemiplegic migraine in children can be challenging due to the overlap of symptoms with other neurological conditions such as stroke, epilepsy or encephalitis. The clinical hallmark of HM is the presence of transient unilateral motor weakness accompanied by typical migraine features (headache, visual aura, sensory disturbances). Attacks typically begin in childhood or adolescence, and can last from minutes to days. The diagnosis relies primarily on clinical criteria, including a detailed history of episodic hemiparesis with migraine headache, supported by family history in FHM cases. The International Classification of Headache Disorders (ICHD-3) provides specific diagnostic criteria for hemiplegic migraine.

Neurological examination between attacks is typically normal. Neuroimaging and EEG are essential for excluding other causes and for supporting the diagnosis. Genetic testing can confirm familial forms when mutations are identified, but it is not mandatory for diagnosis. Early and accurate diagnosis is critical to guide appropriate management, prevent unnecessary investigations, and provide genetic counseling⁽¹⁾.

Aura presentations

Motor aura

Motor aura is a defining criterion for hemiplegic migraine; nevertheless, individuals with hemiplegic migraine may also experience episodes consistent with migraine with aura or migraine without aura^(10-12). Studies show that 9.5-30% of HM patients report MWA, 9-39% report MA, and approximately 15% experience both⁽¹³⁾. Furthermore, around 5% of individuals diagnosed with HM also report symptoms consistent with tension-type headache (TTH).

The presence of muscular weakness or plegia defines the motor aura in hemiplegic migraine. These motor deficits most commonly involve the hands, arms, legs, feet, tongue, face, or one side of the body. The onset of motor weakness is consistently gradual, taking at least 5 minutes to develop, and it is typically unilateral in distribution, often resulting in a hemiparetic presentation.

Sensory aura

Sensory aura in hemiplegic migraine is most charac­terized by hypoesthesia, numbness or paresthesia, which typically spreads gradually and may present as hemisensory irradiation. These sensory disturbances are reported in up to 97% of HM attacks^(14,15). Like motor aura, sensory aura frequently presents unilaterally. However, it may shift sides or, in some cases, develops bilaterally. The most affected regions include the hands, arms, face, tongue, legs and trunk, with the sensory symptoms often occurring on the same side as the hemiparesis.

Visual aura

Visual aura occurs in approximately 74% to 97% of hemiplegic migraine attacks^(12-15). It typically presents with a gradual onset, being most often unilateral. The most common visual disturbances include scintillating scotomas, phosphenes, flickering lights or lines, blurred vision, hemianopsia and zigzag patterns, frequently affecting central vision.

Aphasic aura

Aphasic aura is a common feature of hemiplegic migraine, occurring in approximately 60% to 81% of cases^{(2-6,8-10,12,14)}. In up to 95% of these, it is characterized by impaired language production, including aphasia, dysphasia, difficulty articulating speech and word-finding difficulties. In some instances, impaired language comprehension may also be present.

Basilar-type or brainstem aura

It is observed in approximately 60% to 73% of hemiplegic migraine episodes^(6,14). The clinical spectrum typically encompasses dysarthria, postural instability, appendicular ataxia manifesting as clumsiness or object dropping, lingual numbness or stiffness, vertigo and diplopia. Less prevalent manifestations include hypoacusis, nonspecific dizziness, transient impairment of consciousness, tinnitus, atonic “drop” attacks, pharyngeal hypoesthesia, dysphagia, aural pressure and otalgia^(12,14).

Comparative analyses reveal no substantial differences in basilar-type symptomatology between sporadic (SHM) and familial hemiplegic migraine (FHM) subtypes⁽⁴⁾. While traditionally attributed to transient dysfunction of brainstem structures, accumulating evidence suggests that these symptoms more frequently arise from concurrent bilateral cortical involvement, rather than isolated brainstem pathology.

Phenotypic distinctions between non-motor auras in hemiplegic migraine and typical aura

While the sequence and nature of non-motor aura symptoms demonstrate considerable overlap between hemiplegic migraine and migraine with aura (MA), basilar-type aura remains exclusive to HM^(2,3). Notably, hemiplegic migraine is characterized by the simultaneous occurrence of two or more non-motor aura symptoms, a phenomenon rarely observed in MA, where multiple aura symptoms tend to emerge sequentially^(2-4).

Although both conditions exhibit similar temporal progression and total aura duration, several studies report a longer overall aura duration in HM compared to migraine with aura. Within hemiplegic migraine, indivi­dual aura components tend to have comparable durations, yet visual and sensory auras are significantly prolonged relative to those in MA. The duration of aphasic aura is also reported to be equal to or longer in hemiplegic migraine, depending on the study cohort^(3,14).

The topographic distribution of sensory aura in hemiplegic migraine is generally more widespread than in migraine with aura, frequently involving the face, upper and lower extremities⁽¹⁴⁾. Visual aura in both HM and MA typically manifests unilaterally with flickering lights; however, in hemiplegic migraine, it tends to originate peripherally as a scotoma, often sparing the central visual field, whereas in migraine with aura, it frequently begins centrally and presents as zig-zag patterns.

Lastly, aphasic aura in hemiplegic migraine more commonly reflects impaired language production, in contrast to migraine with aura, where deficits in language comprehension are more frequently observed.

Other aura characteristics: onset, sequence and duration

The total duration of aura symptoms in hemiplegic migraine is highly variable, ranging from 10 minutes to seven days; however, in most cases, the overall aura duration typically falls between 60 and 120 minutes⁽¹⁵⁾. Individual aura components – visual, sensory, motor, aphasic or basilar – tend to last between 5 and 30 minutes each. The most frequently reported chronological sequence of aura symptoms is visual, followed by sensory, motor, aphasic, and then basilar manifestations.

Quantitative analysis reveals that motor aura generally persists for 30 minutes to 24 hours, with a mean duration of approximately 5 hours. Sensory aura ranges from 1 to 12 hours (mean: approximately 4 hours), visual aura from 5 minutes to 12 hours (mean: approximately 2 hours), and aphasic aura from 1 to 12 hours^(1,6).

Genotypic correlations have also been explored. Pelzer et al. demonstrated that individuals with genetically confirmed HM mutations exhibited longer aura durations compared to mutation-negative patients. Eriksen et al. further observed that, while visual, sensory and aphasic auras rarely exceeded 24 hours, motor aura extended beyond 24 hours in 2% of patients with familial hemiplegic migraine (FHM) and 8% of those with sporadic hemiplegic migraine (SHM)⁽¹⁵⁾.

Notably, there are no significant differences in the progression or duration of aura between familial and sporadic subtypes of hemiplegic migraine.

Systemic and neuropsychiatric features of HM

In addition to aura and motor disturbances, hemiplegic migraine episodes are frequently accompanied by a constellation of systemic and neurological symptoms, many of which overlap with those observed in migraine with aura. The most reported associated features include nausea (84-94%), vomiting (58-80%), photophobia (70-99%) and phonophobia (70-92%)⁽¹⁶⁾.

Additional manifestations specific to hemiplegic migraine or reported with higher prevalence include fever (8-58%) and altered mental status, such as confusion or disorientation, occurring in approximately 36-81% of cases. Other less frequently observed symptoms include osmophobia, nasal congestion, lacrimation, eyelid erythema or edema, motion sickness, Raynaud phenomenon, transient loss of consciousness and epileptic seizures⁽¹⁶⁾.

In pediatric populations, behavioral symptoms such as irritability, agitation and drowsiness are commonly reported during HM attacks. Rare but notable symptoms described in the literature include coma, visual hallucinations, meningismus, cerebrospinal fluid pleocytosis, alien limb phenomenon, apraxia, hyperacusis and torticollis. Of particular interest, Pelzer et al. reported a higher incidence of pleocytosis among patients with confirmed genetic mutations associated with hemiplegic migraine⁽¹⁶⁾.

Co-occurring symptoms

The most reported symptoms, comparable to those seen in migraine with aura, include nausea (84-94% of attacks), vomiting (58-80%), photophobia (70-99%) and phonophobia (70-92%)^{(2,3,10,12,14,16)}. Fever (8-58%), disorientation and confusion (36-81%) have also been documented during hemiplegic migraine episodes⁽¹⁷⁾. Additional symptoms such as sensitivity to odors, nasal congestion, lacrimation, eyelid swelling or erythema, motion sickness, Raynaud’s phenomenon, loss of consciousness and seizures have been sporadically observed during HM attacks. In pediatric cases, irritability, agitation and drowsiness are frequently noted. Rare manifestations include coma, visual hallucinations, meningism, pleocytosis, alien limb phenomenon, apraxia, hyperacusis and torticollis⁽¹⁸⁾. Notably, Pelzer et al. reported a higher frequency of pleocytosis in patients with confirmed genetic mutations.

Extended HM episodes

The attacks lasting at least 72 hours have been reported in up to 20% of patients^(2,3,5,16). Extended motor aura – defined as reversible hemiplegia persisting for up to four weeks – has been observed in both sporadic (SHM) and familial hemiplegic migraine (FHM), with some studies indicating a higher prevalence in FHM1 and FHM2 cases. Moreover, episodes characterized by sustained aphasia lasting more than 6 hours have been described in pediatric patients with hemiplegic migraine⁽¹⁹⁾.

Neurologically linked conditions

The neurological examination between HM attacks is typically unremarkable^(7,9,10). However, some studies have reported neurological signs in up to 60% of patients^(5,9), with the most frequently observed features including cerebellar ataxia, nystagmus, postural tremor and clumsiness^(2,6,8). In approximately 50% of FHM1 families, chronic progressive cerebellar ataxia has been noted independent of migraine episodes⁽¹⁾, a finding rarely seen in SHM cases.

Beyond migraine symptoms, patients with hemiplegic migraine appear to experience a higher prevalence of psychological disorders, allergies, asthma, Raynaud’s phenomenon, diabetes mellitus, stroke and epilepsy compared to those with MA or MWA. A limited number of studies have also described developmental concerns, such as cognitive and motor delays, praxis difficulties, reduced sustained attention and obesity.

Regarding epilepsy, seizures may precede the onset of hemiplegic migraine attacks by several years⁽¹³⁾. Seizures may occur either during HM episodes – more commonly – or independently. Barros et al. highlighted the co-occurrence of hemiplegic migraine and epilepsy in patients with FHM3 and demonstrated, through functional studies, that SCN1A gene mutations can cause neuronal hyperexcitability via a gain-of-function mechanism, potentially explaining this neurological comorbidity. However, the precise reason why the same pathophysiological pathway may lead to seizures in some instances and to migraine in others remains unclear⁽²⁰⁾.

Neurodiagnostic findings

Recent studies highlight abnormal patterns in both brain imaging and electrophysiological data.

Neuroimaging and vascular assessment

Brain imaging techniques, including magnetic resonance imaging (MRI) and computed tomography (CT), are valuable tools in the differential diagnosis of headache associated with neurological deficits. These modalities aid in identifying conditions such as intracranial hemorrhage, ischemic stroke, brain tumors, or abscesses. Additionally, neurovascular studies – such as MR angiography and CT angiography – can detect vascular abnormalities, including carotid artery dissection or cerebral venous sinus thrombosis⁽²¹⁾. In the majority of cases, brain MRI performed outside of hemiplegic migraine attacks appears normal. When abnormalities are present, the most commonly reported finding consists of white matter hyperintensities on T2-weighted sequences, detected in up to 23% of patients. Cerebellar atrophy has also been observed both in patients with clinical signs of ataxia^(2,12) and in asymptomatic individuals; in the latter group, CACNA1A gene mutations were consistently identified⁽²²⁾.

During HM attacks, unilateral or focal cytotoxic cortical edema has been documented in both familial (FHM) and sporadic (SHM) forms. In one SHM series, brain edema was more frequently observed on MRI in patients carrying pathogenic mutations than in those without⁽²³⁾. Similarly, another study reported cortical edema in 14 out of 43 patients with CACNA1A mutations, compared to just one out of 18 patients without mutations. In most cases (75%), the vasospasm resolved spontaneously, while vasogenic edema was noted in 12.5% of cases, involving the corresponding cortical regions⁽²⁴⁾.

Electrophysiological evaluations
in pediatric hemiplegic migraine

Electrophysiological studies in children with hemiplegic migraine have yielded heterogeneous results, reflecting the complex pathophysiology of this condition. Although interictal electroencephalography (EEG) is frequently normal, abnormalities have been described both during and outside of attacks.

During HM episodes, EEG may show focal or diffuse slowing, most commonly over the hemisphere contralateral to the motor weakness. These changes are usually transient and non-epileptiform, often correlating with clinical severity and the extent of neurological impairment. Some studies have also reported hemispheric suppression or asymmetric background activity during prolonged attacks.

Outside of attacks, EEG is typically normal; however, in some pediatric cases, persistent slowing or paroxysmal activity has been described. These findings may reflect underlying cortical dysfunction, although their specificity remains low.

Evoked potentials (such as visual and somatosensory evoked potentials) have been occasionally used to assess functional cortical integrity. In certain HM cases – particularly those with CACNA1A mutations – delayed latencies and abnormal waveforms have been observed, suggesting transient disruption of sensory processing pathways.

Overall, while electrophysiological evaluations can support clinical diagnosis and help monitor brain function during HM episodes, they are not diagnostic on their own. Their main utility lies in excluding alternative diagnoses (e.g., epilepsy, structural lesions) and in providing supportive evidence of functional cortical disturbances in selected cases^(20,24).

Neurochemical and neuropharmacological considerations in HM treatment

We will not detail the treatment strategies within this section, as these are comprehensively outlined in current clinical guidelines and protocols, which are regularly updated and revised. However, it is important to highlight that there is currently no standardized, specific pharmacological treatment approved for hemiplegic migraine.

Acute therapy – though limited – may include triptans and dexamethasone, yet caution is advised regarding the selection, dosing and administration of triptans due to potential safety concerns in HM patients.

Preventive treatment is more commonly considered, with flunarizine and topiramate being the most frequently used agents. Flunarizine has been shown to reduce both the frequency and severity of migraine attacks. Other options, such as valproate and lamotrigine, are considered particularly in patients with familial hemiplegic migraine type 2 (FHM2), especially those carrying mutations in the ATP1A2 gene. Monotherapy with valproate has been associated with a reduction in HM attack frequency, while lamotrigine appears to alleviate aura-related symptoms^(18,25).

Additionally, preventive use of acetazolamide should be considered on a case-by-case basis, depending on the hemiplegic migraine subtype and the presence or absence of aura, as well as its specific characteristics.

Conclusions

Hemiplegic migraine is a rare, likely underdiagnosed and underestimated neurological disorder that can manifest in children, including at a very early age. Typically, the first HM episode occurs after a period in which only subtle and transient neurological signs may be present, often posing a diagnostic challenge for pediatric neurologists. Pediatric hemiplegic migraine displays distinct clinical features and gender distribution compared to adult-onset hemiplegic migraine. These differences should be considered by the International Classification of Headache Disorders (ICHD) to ensure age-appropriate diagnostic criteria. A prompt and thorough differential diagnosis is essential to exclude other acute, potentially life-threatening neurological conditions.

In cases of sporadic hemiplegic migraine (SHM), the clinical presentation in children is notably heterogeneous. Although SHM tends to involve longer and more severe attacks than familial hemiplegic migraine (FHM), it is generally associated with a lower frequency of episodes, particularly in the early years following onset. This discrepancy in frequency becomes less significant in adulthood. Moreover, pediatric patients experience fewer non-motor aura symptoms compared to adults.

Despite the severity of HM attacks, the overall prognosis is favorable in most pediatric cases. However, the potential for associated neurological complications and comorbidities underscores the importance of ongoing clinical monitoring.

Further research in pediatric populations is needed to characterize more precisely the clinical phenotype and natural history of hemiplegic migraine. Such studies will contribute to a better understanding of genotype–phenotype correlations and advance the current knowledge regarding the pathophysiology, diagnosis and prognosis of hemiplegic migraine.

Autor corespondent: Bogdan-Marius Istrate E-mail: istratem.bogdan@yahoo.com

CONFLICT OF INTEREST: none declared.

FINANCIAL SUPPORT: none declared.

This work is permanently accessible online free of charge and published under the CC-BY.