When Hemiplegic Migraine Defies Expectations: Diagnostic Complexity in a Rare Genetic Disorder

Abstract

Introduction

Familial hemiplegic migraine (FHM) is a rare and complex inherited subtype of migraine with aura, characterised by migraine with a reversible motor aura, and may present with a wide spectrum of neurological symptoms, making diagnosis particularly challenging.

Case Presentation

We report a case of FHM presenting with prolonged hemiparesis, severe headache, altered consciousness, and fever. This constellation of symptoms initially suggested acute stroke, encephalitis, or status epilepticus. A precise clinical history and targeted genetic testing (CACNA1A, ATP1A2, SCN1A, and PRRT2) proved essential for establishing the diagnosis.

Conclusion

This case highlights the wide phenotypic variability of FHM and the risk of misdiagnosis in emergency settings. Early recognition through careful clinical assessment and appropriate genetic testing enabled appropriate management and avoided unnecessary interventions.

Introduction

Familial hemiplegic migraine (FHM) is a rare but severe subtype of migraine with aura, transmitted in an autosomal dominant pattern, with an estimated prevalence of approximately 0.01% in the general population [1]. It is characterised by transient unilateral motor weakness accompanied by headaches and other neurological symptoms such as paraesthesia, visual disturbances, or aphasia. FHM is genetically heterogeneous, mainly linked to (likely) pathogenic variants in the CACNA1A, ATP1A2, SCN1A, and PRRT2 genes [2, 3]. Among these, variants in the CACNA1A gene are the most common and result in altered calcium channel activity, leading to variable clinical presentations [2]. From a pathophysiological point of view, type 1 FHM linked to variants in the CACNA1A gene are mostly gain-of-function mutations that increase the release of neurotransmitters, including glutamate, promoting neuronal hyperexcitability, and decreasing the activation threshold of the invasive cortical depolarisation responsible for the aura in migraine [4].

Given its rarity and phenotypic variability, FHM can pose significant diagnostic challenges. Acute episodes often mimic ischaemic stroke, reversible cerebral vasoconstriction syndrome (RCVS), or encephalitis, requiring thorough diagnostic evaluation. Brain imaging, electrophysiological examinations, and targeted genetic testing are essential tools for differentiating FHM from structural, vascular, metabolic, or autoimmune pathologies.

We present the case of a 19-year-old woman who experienced a first severe episode of FHM after a history of moderate sensory and motor auras. Genetic testing identified biallelic variants (i.e., affecting both alleles) in the CACNA1A gene (GRCh38, NM_001127222.2): c.(5123T>C);(5335C>T) suggesting potentially synergistic effects contributing to its atypical progression. This case highlights the importance of a comprehensive evaluation and underscores the usefulness of genetic testing in better understanding the complex phenotypes of migraine. The reporting of this case conforms to the CARE guidelines, and the completed CARE checklist is provided as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000553486).

Case Presentation

Our clinical case concerns a 19-year-old woman who was admitted to the emergency department in March 2024 with complaints of headaches and left-sided weakness. Prior to admission, the patient experienced severe pulsating right-sided headaches occurring during the day, associated with episodes of nausea, vomiting, photophobia, and phonophobia, fulfilling the diagnostic criteria of migraine of the International Classification of Headache Disorders, 3rd edition [5]. Subsequently, the patient developed left hemiparesis, which rapidly progressed to left hemiplegia upon admission within less than 24 h. The patient also had a fever of 38.5°C and newly diagnosed hypertension. Neurological examination revealed drowsiness with spatial and temporal disorientation, left hemiplegia, left hypoesthesia, moderate dysarthria, left lower facial paralysis, and left lateral homonymous hemianopia. Laboratory tests revealed hyperneutrophilia associated with a slight increase in C-reactive protein and a significant elevation in creatine phosphokinase and lactate dehydrogenase enzymes. A brain CT scan with angiographic sequences revealed an irregularity in the right middle cerebral artery in its M1 segment, complicated by stenosis (Fig. 1), while perfusion imaging confirmed extensive hypoperfusion in the right carotid territory.

Fig. 1.

CT angiography sequences showing asymmetry in the size of the Sylvian arteries with irregular appearance and stenosis of the M1 segment of the right middle cerebral artery. Collateral vascularisation is less pronounced on the right side.

A brain MRI scan performed immediately afterwards showed a diffuse cortical signal abnormality in the right hemisphere with T2 hyperintensity associated with a hyperintense signal on diffusion weighted imaging and normal apparent diffusion coefficient, indicating the presence of vasogenic oedema without acute cerebral ischaemia. Vermis atrophy was also observed. Analysis of the cerebrospinal fluid revealed no abnormalities. The following day, an electroencephalogram was performed, revealing lateralised periodic discharges in the right fronto-parietal region (Fig. 2). The patient was temporarily transferred to another institution for diagnostic arteriography. Diffuse vasospasm of the right Sylvian circulation was identified, with distal flow slowing. Following identification of the vasospasm, treatment with nimodipine (60 mg, 6 times a day) was initiated for a period of 14 days. The patient’s clinical condition improved within a few days. Follow-up transcranial Doppler also showed favourable progression of the vasospasm in the right Sylvian artery. Two days later, a follow-up MRI revealed complete resolution of the diffusion abnormalities and T2 hypersignals in the right hemisphere, as well as significant regression of the stenosis of the right middle cerebral artery. A few weeks later, the patient was readmitted with a similar, albeit less severe, clinical presentation. During this second hospitalisation, the patient reported similar episodes in her mother and the occurrence of migraines with moderate sensory and motor auras during the patient’s adolescence. Genetic testing (capture-based targeted next-generation sequencing of 243 genes associated with epilepsy [Kapa HyperCap V3, Roche; Illumina sequencing]) was then performed and revealed the presence of 2 heterozygous pathogenic variants in CACNA1A gene (GRCh38, NM_001127222.2): c.5123T>C, p.(Ile1708Thr) and c.5335C>T,p.(Arg1779Ter), confirming the diagnosis of type 1 FHM. In order to phase the variants despite the lack of parental DNA, we performed long-read sequencing (adaptative sampling on GridION sequencer (ONT), SQK-LSK114 library preparation kit, FLO-MIN114 flow cell). Analysis of reads spanning both positions of interest revealed that the 2 variants (NM_001127222.2:c.[5123T>C];[5335C>T]) (Fig. 3) are present in trans. This finding was corroborated by the phasing algorithm Clair3 (version 1.0.4), confirming that the variants are present on alleles of distinct parental origin. The patient was placed on prophylactic β-blockers (propranolol) in gradually increasing doses up to 40 mg per day initially and high-dose vitamin B2 (riboflavin, 400 mg per day). The treatment was well tolerated by the patient. The outcome has been favourable, with no recurrence of severe episodes to date (October 2025).

Fig. 2.

Electroencephalogram showing lateralized periodic discharges (LPDs) in the right fronto-parietal region.

Fig. 3.

Long-read sequencing showing trans configuration of the two CACNA1A variants.

Type 1 FHM is characterised by significant phenotypic variability, largely explained by genotypic heterogeneity. To date, more than 500 CACNA1A (likely) pathogenic variants have been described [6]. The clinical course, in terms of frequency, severity, and presentation of episodes, varies not only from 1 patient to another but also within a group of patients carrying the same mutation (i.e., variable expressivity) [7]. Some patients have pure FHM, while others may develop associated conditions such as mental retardation, epilepsy, or permanent cerebellar signs (nystagmus, ataxia), depending on the type of variant involved [7]. The incidence of epilepsy in patients with FHM is around 7%, but it is more frequently associated with ATP1A2 variants (type 2 FHM) [1, 8, 9]. More than a third of patients’ experience, in addition to their usual symptoms, severe episodes characterised by impaired consciousness, prolonged aura, pyrexia, and meningeal signs [7]. The diagnosis of the first episode of hemiplegic migraine (HM) is a major clinical challenge, particularly when the presentation is severe, requiring a comprehensive evaluation to rule out other aetiologies such as stroke, encephalitis, RCVS, or cerebral venous thrombosis.

In our observation, imaging revealed vasospasm of the right middle cerebral artery, associated with cortical oedema with cortical ribbon widening and hypoperfusion extending beyond the involved vascular territory, diffusely affecting the right hemisphere. Invasive cortical depression causes changes in cerebral blood flow, marked by a phase of hypoperfusion followed by hyperaemia [10]. In our patient’s case, diffuse hypoperfusion was confirmed by functional perfusion imaging. Cadiot et al. [11] showed that the identification of diffuse hypoperfusion, not consistent with a defined arterial territory, associated with vasospasm, is a useful criterion for the diagnosis of migraine with aura. Similarly, Safier et al. [12] argue that transient vasospasms of the middle cerebral artery during HM attacks disappear, on follow-up imaging. Due to the transient nature of the aura, the abnormalities observed on imaging resolve during follow-up examinations [10–12]. RCVS remains a primary differential diagnosis; its clinical profile, manifested by thunderclap headaches, as well as the typical angiographic appearance (bilateral “sausage string pattern”), allow this alternative to be considered.

Although in some cases conventional angiography can aggravate an HM attack [1], in our case, no clinical worsening was observed after the examination. It is also possible to find mainly vermis atrophy in some cases of FHM on MRI, particularly in patients carrying the CACNA1A variant and presenting permanent cerebellar signs on clinical examination [1, 7]. Genetic analysis provides a definitive diagnosis, enabling appropriate management to be adopted, with the prognosis generally favourable [7].

There is no clear consensus among experts regarding the prevention or treatment of HM attacks [13]. To date, no available treatment has been shown to be effective against aura [7]. The treatment of HM attacks is similar to that of classic migraine attacks with aura, consisting of the administration of analgesics and antiemetics. However, the presence of vasospasm highlights the importance of avoiding the use of triptans due to their vasoconstrictive properties, as some authors have observed a worsening of the aura when these drugs are administered [1, 10, 12]. Prophylactic treatment is considered in patients with a high frequency of attacks or severe episodes. Due to the pathophysiological similarities between migraine with aura and epilepsy, certain anti-epileptic treatments, such as topiramate or sodium valproate, may be used in the prevention of attacks. The efficacy of new anti-CGRP biotherapies remains limited at present, based mainly on case reports, which justifies cautious and judicious use of this approach in patients who are severely disabled by their condition. Further studies are therefore needed to validate the therapeutic option of anti-CGRP in patients with HM [13].

Conclusion

This case demonstrates the complexities of diagnosing and managing FHM, particularly in its severe forms. The evidence of vasospasm associated with diffuse hypoperfusion during severe attacks is an additional argument for the diagnosis and underpins the haemodynamic changes associated with invasive cortical depression in migraine with aura. The identification of biallelic variants in CACNA1A gene enabled a definitive diagnosis to be made, other aetiologies to be ruled out, and prophylactic strategies to be guided. Despite the challenges, the prognosis in such cases remains favourable with appropriate management. We would like to emphasise that the main aim of this article was to encourage clinicians to consider FHM as a potential diagnosis in patients presenting with first or recurrent headaches and hemiparesis when no alternative diagnosis has been established.

Statement of Ethics

The authors certify that this work is original and has not been published in whole or in part in any other journal, book, or scientific medium. Nor is it currently under review in any other journal and will not be until the present editorial process is complete. The authors participated in the writing of the manuscript, approved the final version, and agreed to its submission. Each author vouches for the scientific integrity and content of the manuscript and agrees to take responsibility in the event of ethical or scientific misconduct. This study was performed in accordance with the Declaration of Helsinki. This study protocol was reviewed and approved by the Ethics Committee of CHU Tivoli on December 11, 2025. Written informed consent was obtained from the patient for publication of this case report and any accompanying images.

Conflict of Interest Statement

The authors have no conflicts of interest.

Funding Sources

The authors received no financial support for the publication of this article.

Author Contributions

Goossens Amandine: investigation, data curation, and writing – original draft. Pignato Vincenzo: supervision, validation, and writing – review and editing. Delabie Ann-Laurence: validation and writing – review. Demaret Tanguy and Karadurmus Deniz, PhD: investigation (genetic analyses), validation, and writing – review. Each author has read and approved the final version of the manuscript.

Funding Statement

The authors received no financial support for the publication of this article.

Data Availability Statement

The data that support the findings of this study are not publicly available due to patient confidentiality but are available from the corresponding author upon reasonable request.