Familial hemiplegic migraine type 2 with cerebral vasospasm and acute encephalopathy caused by an ATP1A2 gene variant: a case report

Introduction

Hemiplegic migraine (HM) is a rare monogenic subtype of migraine with aura, typically manifesting in the first or second decade of life. Based on familial inheritance patterns, HM is classified as familial HM (FHM) or sporadic HM. FHM—an autosomal dominant disorder—is further subdivided into FHM1 (CACNA1A mutations), FHM2 (ATP1A2 mutations), and FHM3 (SCN1A mutations), with additional causative genes remaining unidentified (1).

Clinically, HM presents with headache, visual field defects, sensory disturbances, aphasia, unilateral motor weakness, encephalopathy, seizures, and ataxia. Symptom severity ranges widely from transient hemiplegic episodes to recurrent coma, permanent cerebellar ataxia, seizure disorders, or intellectual disability (2). Given the condition’s rarity, diagnosis remains challenging and requires exclusion of alternative causes of motor weakness. Notably, cerebral vasospasm documented during acute HM attacks is exceptionally uncommon. We herein present a pediatric FHM2 case featuring cerebral vasospasm and acute encephalopathy secondary to an ATP1A2 gene variant, aiming to enhance clinical recognition of this entity. We present this article in accordance with the CARE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-484/rc).

Case presentation

An 11-year-old female patient presented with fever, headache, altered consciousness, and right-sided weakness for 48 hours. Her temperature reached a maximum of 39 ℃ with 2–3 febrile spikes daily. No infectious symptoms (cough/vomiting/diarrhea) were noted. The headache was consistently localized to the left temporal region, though its qualitative features (e.g., throbbing, pressure-like) could not be precisely characterized due to the patient’s encephalopathic state. Neurological deficits included impaired consciousness and right-sided motor weakness (inability to lift limbs against gravity), with preserved left-limb function. The patient is the first child born at full term via spontaneous vaginal delivery and has achieved all cognitive and motor developmental milestones within normal limits. For 8.5 years, the patient has experienced recurrent episodes of headache accompanied by unilateral limb weakness and occasional blurred vision, each lasting 30–60 minutes. These attacks occurred at a frequency of up to 7–8 episodes per month without identifiable triggers, and were typically relieved by rest or oral ibuprofen. Irregular prophylactic flunarizine was used for symptom management. The patient’s mother has experienced recurrent headaches accompanied by unilateral limb weakness since childhood (onset at age 10 years), typically triggered by fatigue or emotional stress. These episodes last between 30 minutes and several hours, and resolve with rest or oral medication.

Neurological examination on admission

The patient presented with impaired consciousness (Glasgow Coma Scale score 8: E2V2M4) and bilateral pupils measuring 2 mm that were equal and reactive to light. Cranial nerve assessment was limited by reduced alertness. Motor examination revealed right-sided hemiparesis [Medical Research Council (MRC) grade 2 strength] with normal tone, while left limb strength and tone remained intact. Deep tendon reflexes (biceps/triceps/patellar/achilles) were normal and symmetric bilaterally. Pathological signs included right-sided upper motor neuron involvement, evidenced by positive Babinski and Chaddock signs, with negative responses on the left and absent bilateral ankle clonus. Sensory, cerebellar, and meningeal assessments were non-contributory due to obtundation, though nuchal rigidity was absent (Figure 1).

Figure 1 Clinical course figure. CSF, cerebrospinal fluid; dsDNA, double-stranded DNA; ENA, extractable nuclear antigens; FLAIR, fluid-attenuated inversion recovery; ICA, internal carotid artery; ICP, intracranial pressure; MCA, middle cerebral artery; MRA, magnetic resonance angiography; MRC, Medical Research Council; MRI, magnetic resonance imaging; NGS, next-generation sequencing; q.12h, every 12 hours; q.d., once a day; q.n., once every night; VEEG, video electroencephalography.

Laboratory and diagnostic tests

All results were normal for routine blood, urine, and stool tests, biochemical blood tests, coagulation function, erythrocyte sedimentation rate, blood lactate, blood ammonia, thyroid function, thyroid antibodies, extractable nuclear antigens (ENA) spectrum, and double-stranded DNA (dsDNA). Cerebrospinal fluid (CSF) routine examination, biochemistry, and pathogen next-generation sequencing were also normal. Autoimmune encephalitis antibodies and central nervous system demyelinating antibodies tested negative in both CSF and serum. Echocardiography and abdominal ultrasound showed no abnormalities. Cranial computed tomography (CT) revealed no abnormalities. On day 2 of illness, cranial magnetic resonance imaging (MRI) (Figure 2) demonstrated mild cortical signal hyperintensity with mild diffusion restriction involving the left frontal, temporal, parietal, and occipital lobes. Concurrent magnetic resonance angiography (MRA) (Figure 3) showed reduced caliber and irregular contour of the left internal carotid artery siphon segment, left middle cerebral artery (MCA) main trunk, and several of its branches compared to the contralateral side. A repeat MRA performed on day 5 revealed improved caliber and contour of these previously noted vascular segments. Video electroencephalogram (EEG) captured nearly continuous, moderate amplitude generalized slow-wave activity (1.5–3 Hz) during both wakefulness and sleep, observed diffusely over bilateral hemispheres with left-sided predominance. Subsequent whole-exome sequencing identified an inherited ATP1A2 variant (c.2464G>A, p.Glu822Lys) of maternal origin. This variant was classified as “uncertain significance (PM2_Supporting+PP3_Moderate+PP1)” per the American College of Medical Genetics and Genomics (ACMG) guidelines.

Figure 2 Dynamic changes on MRI. A cranial MRI performed (A-D) demonstrated mild cortical FLAIR signal hyperintensity with mild diffusion restriction involving the left frontal, temporal, parietal, and occipital lobes (red arrows indicated FLAIR hyperintensity in the occipital lobe with restricted diffusion in the temporal lobe). By a one-month follow-up, cranial MRI (E-H) showed complete resolution of prior signal abnormalities, with no significant residual parenchymal lesions. FLAIR, fluid-attenuated inversion recovery; MRI, magnetic resonance imaging.

Figure 3 Dynamic changes on MRA. The MRA (A) on day 2 of the patient’s illness showed reduced caliber and irregular contour of the left internal carotid artery siphon segment, the left MCA main trunk, and several of its branches compared to the contralateral side (red arrows indicated left internal carotid artery and MCA). By day 5, follow-up MRA (B) revealed improved caliber and contour of these previously noted vascular segments. By a one-month follow-up, MRA (C) demonstrated that the left internal carotid artery siphon segment and the main trunk of the left MCA remained slightly thinner than normal, an improvement compared to the day 5 examination. MCA, middle cerebral artery; MRA, magnetic resonance angiography.

Treatment

The patient received multimodal therapy including intravenous mannitol for intracranial pressure reduction, intravenous methylprednisolone (2 mg/kg/day), intravenous levocarnitine (1 g once a day), and intravenous vitamin C (1 g once a day), supplemented by oral flunarizine (5 mg once every night) and topiramate (50 mg every 12 hours). After 72 hours of treatment, her consciousness level significantly improved, right limb muscle strength recovered to MRC grade 4, and headaches resolved.

Follow-up

One month after discharge, the patient continued to take her medications regularly. During follow-up, she had no episodes of headache, hemiplegia, or impaired consciousness. A follow-up cranial MRI (Figure 2) showed no significant abnormalities, and MRA (Figure 3) revealed that the left internal carotid artery siphon segment and the main trunk of the left MCA were slightly thinner, with improvement compared to the previous examination.

All procedures performed in this study were in accordance with the ethical standards of the Beijing Children’s Hospital Ethics Committee. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the parents of the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

This pediatric case involves a 2-year history of recurrent HM attacks, with a high frequency of 7–8 episodes per month. Typical episodes manifest as unilateral limb weakness accompanied by headache, resolving completely within 30 minutes to several hours. The current acute episode occurred without identifiable triggers and was characterized by fever, prolonged headache (>72 hours), multiday encephalopathy, and persistent hemiplegia. Acute-phase neuroimaging revealed left cerebral cortical swelling on MRI, while MRA demonstrated dynamic cerebral vasospasm that spontaneously resolved on follow-up. EEG showed diffuse slow-wave activity (predominantly theta/delta rhythms) localized to the left hemisphere. Genetic analysis identified a heterozygous variant in the ATP1A2 gene (c.2464G>A, p.Glu822Lys), inherited maternally from the mother with a history of recurrent headaches. This variant is predicted to be deleterious by multiple software tools [rare exome variant ensemble learner (REVEL) score 0.93, sorting intolerant from tolerant (SIFT) rating “damaging” (score 0.001), Polyphen2 rating “probably_damaging” (score 0.989), and MutationTaster rating “disease_causing” (score 1)], is absent in multiple normal population databases (including 1000g2015aug_all, ESP6500, ExAC_EAS, etc.), and is located in a highly conserved amino acid region across multiple species (Figure S1). Protein structure modeling suggests that the three-dimensional structure of the protein is altered after the mutation (Figure S2). Although this evidence does not elevate the ACMG classification, it indicates that the variant is likely deleterious. Functional studies would provide definitive evidence, which is also a limitation of the current study. The case was ultimately diagnosed as FHM2.

The majority of HM cases exhibit either reversible MRI abnormalities or normal neuroimaging findings, while persistent structural lesions are rarely documented. HM frequently manifests as a stroke mimic during or immediately after an attack (3). The most characteristic neuroimaging feature is widespread cortical edema localized to the symptomatic cerebral hemisphere, with focal mild gadolinium enhancement occasionally observed on contrast-enhanced MRI (4). In FHM patients with progressive cerebellar ataxia and/or dysarthria, cerebellar atrophy may be present (5). Isolated case reports describe reversible cerebral vasoconstriction during acute HM episodes, typically resolving within 24–48 hours (6). The scarcity of reported vascular abnormalities stems from two key factors: the inherent rarity of HM, and the temporal dissociation between vasomotor events (predominantly occurring during the aura phase) and clinical presentation (typically at headache onset). Current acute evaluation protocols prioritize CT and conventional MRI to exclude stroke, with MRA not routinely performed. Standard MRA sequences lack sufficient spatial resolution to detect subtle arterial changes, necessitating supplemental high-resolution vessel wall imaging or arterial spin labeling perfusion mapping to capture nuanced hemodynamic alterations. The observed vasoconstriction may arise through dual pathophysiological pathways: Neurogenic dysregulation mediated by cortical spreading depression-induced perivascular neurotransmitter surges (glutamate/K⁺), triggering abnormal smooth muscle contraction via N-methyl-D-aspartate (NMDA) receptor overactivation. Vasomotor imbalance stemming from trigeminovascular system-derived calcitonin gene-related peptide (CGRP) overproduction, which disrupts endothelial nitric oxide synthase function and promotes sustained vascular tone through CGRP receptor hyperactivation and protein kinase A-dependent calcium channel sensitization (7).

According to the “International Classification of Headache Disorders”, 3rd edition, the diagnosis of FHM primarily relies on clinical manifestations and a positive family history (8). In acute-phase presentations, particularly severe episodes with acute encephalopathy, rapid differential diagnosis is critical to distinguish FHM from mimics including acute cerebral stroke, moyamoya disease/syndrome, central nervous system infections, alternating hemiplegia of childhood and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes. This urgency arises from overlapping neurological features during acute attacks, such as cortical edema, seizures, and altered consciousness.

Currently, there is no unified treatment protocol for FHM complicated by acute encephalopathy, with most evidence derived from individual case reports (2). During the acute phase, when cerebral vasospasm occurs, sympathomimetic drugs such as triptans and ergotamine are contraindicated in FHM patients. In the early stages of acute encephalopathic manifestations in HM patients, preventive interventions targeting glutamate excitotoxicity—such as the NMDA receptor antagonist memantine—combined with mitochondrial protective agents including butylphthalide, idebenone, and coenzyme Q10, may reduce the severity of encephalopathy in the short term and promote neuronal recovery. Additionally, steroid hormones combined with hypertonic saline have demonstrated efficacy in HM patients with cerebral edema.

Conclusions

This report describes a unique case of internal carotid artery vasospasm occurring in HM, which, to our knowledge, has not been previously reported in the literature. Investigating alterations in the cerebrovascular system contributes significantly to understanding the clinical manifestations and underlying mechanisms of HM.

Acknowledgments

We thank the patient included in this study and her parents.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-484/rc

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-484/prf

Funding: This work was supported by the National Natural Science Foundation of China (No. 82001791).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-484/coif). M.L. reports that this work was supported by the National Natural Science Foundation of China (No. 82001791). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the Beijing Children’s Hospital Ethics Committee. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the parents of the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Di Stefano V, Rispoli MG, Pellegrino N, et al. Diagnostic and therapeutic aspects of hemiplegic migraine. J Neurol Neurosurg Psychiatry 2020;91:764-71. [Crossref] [PubMed]
2. Russell MB, Ducros A. Sporadic and familial hemiplegic migraine: pathophysiological mechanisms, clinical characteristics, diagnosis, and management. Lancet Neurol 2011;10:457-70. [Crossref] [PubMed]
3. Terrin A, Toldo G, Ermani M, et al. When migraine mimics stroke: A systematic review. Cephalalgia 2018;38:2068-78. [Crossref] [PubMed]
4. Nandyala A, Shah T, Ailani J. Hemiplegic Migraine. Curr Neurol Neurosci Rep 2023;23:381-7. [Crossref] [PubMed]
5. Pelzer N, Hoogeveen ES, Ferrari MD, et al. Brain atrophy following hemiplegic migraine attacks. Cephalalgia 2018;38:1199-202. [Crossref] [PubMed]
6. Safier R, Cleves-Bayon C, Vaisleib I, et al. Magnetic resonance angiography evidence of vasospasm in children with suspected acute hemiplegic migraine. J Child Neurol 2014;29:789-92. [Crossref] [PubMed]
7. Paungarttner J, Quartana M, Patti L, et al. Migraine - a borderland disease to epilepsy: near it but not of it. J Headache Pain 2024;25:11. [Crossref] [PubMed]
8. The International Classification of Headache Disorders. 3rd edition (beta version). Cephalalgia 2013;33:629-808.