Hemiplegic migraine (HM) is a rare subtype of migraine characterized by episodes of severe migraine and aura symptoms involving motor weakness or numbness, usually affecting one side of the body (hemiparesis), as well as visual, sensory, or speech disturbances (1). Severe attacks can be accompanied by seizures, coma, encephalopathy, fever, cerebellar involvement, cerebral edema, or cerebral infarction (2) and are often misdiagnosed as having postictal confusion, Todd’s paresis, and diagnosed as having epilepsy or viral encephalitis.

We report two cases of atypical hemiplegic migraine that started as an acute encephalopathy. The atypical clinical presentation of these two patients led to a challenging diagnosis. Therefore, we are reporting it to deepen the understanding of this disease. The goal is to reduce misdiagnosis, give patients appropriate and effective treatment, and improve the quality of their survival.

Blood samples (2 ml) were collected from patients and their parents. DNA was isolated from peripheral blood using a DNA Isolation Kit (Blood DNA Kit V2, CW2553). Concentrations were determined on a Qubit fluorometer (Invitrogen, Q33216) using a Qubit dsDNA HS Assay Kit (Invitrogen, Q32851). Agarose gel (1%) electrophoresis was performed for quality control. DNA libraries were prepared with a KAPA Library Preparation Kit (Kapa Biosystems, KR0453) following the manufacturer's instructions. Hybridization of pooled libraries to the capture probes (IDT xGen Exome Research Panel v1.0) and removal of non-hybridized library molecules were carried out according to the SeqCap Hybrid Mix System. Sample dilution, flow cell loading, and sequencing were performed according to the Illumina specifications. DNA libraries were sequenced on the Illumina NovaSeq platform as paired-end 200-bp reads.

Sequence variants were annotated using population and literature databases, including 1000 Genomes (http://www.1000genomes.org/), dbSNP (https://www.ncbi.nlm.nih.gov/snp/), GnomAD (http://gnomad.broadinstitute.org/), ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/), HGMD (http://www.hgmd.cf.ac.uk/ac/index.php), and Online Mendelian Inheritance in Man (OMIM) (http://omim.org/). The variant interpretation was performed according to the American College of Medical Genetics (ACMG) guidelines.

The overall estimated prevalence of HM is 0.01% (5). The prevalence of sporadic HM (SHM) is at least 0.002% and the prevalence of familial HM (FHM) is at least 0.003% based on the Danish population (6–8). The onset is usually in the first or second decade (9). The frequency, intensity, and duration of HM attacks often decrease with age (5, 8). Emotional and intense physical stress, viral infections, and head trauma are the more commonly reported trigger factors for HM attacks (10). The two patients in this paper were both male and the age of onset was all before 5 years of age. For patient #1, the trigger was mild head trauma. The trigger for Patient #2 is unclear, and the child had runny nose before this episode, so we hypothesized that it might be related to a viral infection.

HM can be divided into FHM and SHM (11). If one first- or second-degree relative has similar symptoms, the disorder can be classified as FHM. Otherwise, it is classified as SHM (11). FHM can be classified as FHM1 (OMIM #141500), FHM2 (OMIM #602481), or FHM3 (OMIM #609634) according to mutations in CACNA1A, ATP1A2, or SCN1A, respectively (1, 5, 11). SHM can be caused by a de novo mutation in a gene that causes the familial form or by the inheritance of a gene mutation from an asymptomatic parent with FHM (12). A review study by Bonemazzi et al. found that pediatric SHM patients have longer and more severe attacks compared to FHM patients, especially during the initial years after disease onset, while FHM cases tend to have the disease for longer periods (8).

A comprehensive search was performed using PubMed, Web of Science, and Scopus. We selected only papers that reported complete clinical information about the patients with CACNA1A or ATP1A2 gene mutation. We screened 97 articles finally. Together with our two cases, a total of 160 patients (73 CACNA1A and 87 ATP1A2) were identified and all features are summarized in Table 1.

We found that about half of them presented with a typical hemiplegic migraine attack, i.e., fully reversible visual, sensory, or speech symptoms or motor weakness. Motor symptoms are most frequently localized in hands, arms, feet, legs, tongue, face, and body (8). The progression of weakness is always gradual, requiring at least 5 min, and the irradiation of the symptom is usually unilateral configuring a hemiparesis in most cases (8). Duration is about 30 min to 24 h (mean duration 5 h) for motor aura (8). Of the two patients we reported, patient #1 presented with hemiparesis symptoms that lasted more than 24 h, which is inconsistent with the description of motor aura symptoms in previous reports. Both patients reported in this paper did not describe any other aura symptoms, such as sensory aura, visual aura, or aphasic aura, which may be related to the patient's young age and lack of expressive skills.

However, some patients started with other atypical symptoms, such as encephalopathy. Of the reported patients with hemiplegic migraine with CACNA1A mutations, 42.4% presented with encephalopathy. Among patients with ATP1A2 mutations, 39.1% presented with encephalopathy. The specific manifestations of encephalopathy were impaired level of consciousness, fever, or seizures, all lasting for >24 h. Patients with mild encephalopathy have only an impaired level of consciousness, while patients with severe manifestations of encephalopathy may have fever and seizures. In this paper, we found that all patients presenting with fever showed signs of encephalopathy. Fever may be central (79). In our group, both probands had a sudden onset of fever without a clear history of infection, and neither antibiotic nor antipyretic was effective for them. The clinical manifestations began to improve after the body temperature returned to normal in both probands. Both our patients manifested focal seizures followed by generalized seizures, of which patient #1 started with status epilepticus in each case. The whole-exome sequencing of patient #1 showed a de novo missense mutation of the CACNA1A gene, c.674C>A (p. Pro825His). By reviewing the literature, only one report of the Pro225His mutation was identified (80). The patient was an 8-year-old female who was born prematurely, and presented with developmental delay, speech and spatial sense impairment, poor concentration, and epilepsy (80). The patient had at least four HM episodes presenting as headaches and seizures (80). The difference is that our patient #1 was born at full term and had normal cognitive and motor development. He had no previous seizures. Similarly, our patient presented this time with status epilepticus and hemiplegia. However, we are currently unable to clarify the clinical phenotype of these mutations due to the paucity of reports. The whole-exome sequencing of patient #2 showed a maternally inherited missense mutation of the ATP1A2 gene, c.2143G>A (p. Gly715Arg). By reviewing the literature, three patients have been reported thus far with the same mutations as patient #2. Together with our case, Table 2 summarizes the clinical features of these four patients. All four patients had their onset in childhood and their age of onset ranged from 1 to 6 years, with our patient #2 having the youngest age of onset. However, because all four patients started with acute encephalopathy, this led to different degrees of diagnostic delay. Patients may present with fever, somnolence, hemiparesis, seizures, or aphasia during the acute phase of encephalopathy. All three patients showed cerebral edema in the acute phase, except for our patient #2 for whom no brain MRI data were in the acute phase. Patients’ encephalopathy symptoms may resolve within a few weeks, with recovery in up to 10 weeks. Combined with the clinical presentation of these four patients, we hypothesized that this mutation may be associated with early and severe HM manifestations.

The mechanism of HM accompanied by acute encephalopathy is still unknown. Toldo et al. reported an 8-year-old female who had a prolonged attack of sporadic HM; the first MRI was negative while the neuroradiological follow-up documented a progressive increase of the cortical swelling with mild hyperintensity on DWI, suggesting intracellular edema (81). Technetium-99m-ethyl cysteinate dimmer (99mTc-ECD) single photon emission computed tomography (SPET) (day 27), performed when the hemiplegia was almost completely resolved but aphasia persisted, showed a marked unilateral cerebral hypoperfusion. This finding suggested a primary neuronal dysfunction with reduced uptake of the radiopharmaceutical by “stunned neuronal cells” (81). The neuroimaging findings have been related to the possible underlying pathogenic mechanisms, ion channel dysfunction caused prolonged neuronal depolarization followed by the shift of water from the extra- to the intra-cell compartment and then cellular swelling and neuronal loss (81).

The outcome is favorable in most patients; however, neurological conditions and comorbidities can be associated (8). Some studies reported neurological signs in up to 60% of patients, with the most frequent neurological alterations including cerebellar ataxia, nystagmus, postural tremor, and clumsiness (8). The majority of FHM1 patients, often more than half of the families (2), and a small number of FHM2 patients had cerebellar signs, and cerebellar atrophy was seen on brain MRI (82). Cerebellar atrophy may become apparent with age (83). In our group, both patients experienced multiple hemiplegic migraine attacks, but neither of them showed cerebellar signs, cerebellar atrophy, motor development lag, or regression, but it cannot be excluded that this is related to the young age of both patients and long-term follow-up is needed. In addition, Wada et al. considered that the mutation of CACNA1A itself, rather than the frequency of coma attacks, may play a central role in the pathogenesis of progressive cerebellar atrophy (14). Cerebellar signs are rare in patients with FHM2. Three patients reported by Spadaro et al. showed cerebellar symptoms such as nystagmus, gait ataxia, dysmetria, and dysarthria, one of the patients also showed cerebellar atrophy (69). It was thought that the presentation may be related to the patient's alcohol or sedative intake (84). However, in other families, no other reasons for the cerebellar signs such as alcohol, drugs, CACNA1A or SCA mutations, or vascular brain disorders could be found, suggesting that these signs are part of the FHM2 phenotype in this family (69).

We found that about half of the HM patients with the CACAN1A gene mutation had mental retardation, which may be related to the calcium channel impairment caused by the CACNA1A gene mutation. For our patient #1 with CACNA1A gene mutation, he experienced three hemiplegic migraine attacks, and no mental retardation or regression manifestation has been found yet, which may be related to the patient's young age or insufficient follow-up time. Observation of this patient should continue to be strengthened in the future. Overall, more research is needed to explore the underlying mechanisms of acute encephalopathy in HM.

At present, the impact of the ATP1A2 mutation on cognitive profile in HM patients has not been evaluated in detail (40). In this paper, we found that most of the effects of the ATP1A2 gene on intelligence were transient and could gradually return to pre-initiation levels after the remission of HM symptoms. However, Wang et al. reported a patient with cognitive dysfunction in a specific area (40). He had trouble in mathematics and depicting three-dimensional things. It is suggested that a patient with HM with ATP1A2 could develop permanent cognitive dysfunction (40). As for our patient #2, a careful review of his history revealed that the patient and his sister were normal in all aspects except for poor numeracy. The patient's mother had cognitive impairment, but she refused to undergo intelligence testing. The cognitive function test is an issue we need to focus on when following up with patient #2 in the future.

Patients with HM need only symptomatic treatment in the acute phase to bring about symptom relief. Some reports indicated that a prompt recovery had been described in three patients with CACNA1A mutations through the combined use of steroids and hypertonic solutions in the course of encephalopathy and cerebral edema (54, 83, 85). For FHM2, NMDA receptor antagonist memantine could prevent glutamatergic excitotoxicity, and idebenone, dl-NBP, as well as traditional anti-migraine drugs could protect the mitochondria function (73). We report two patients who started with acute encephalopathy and were treated symptomatically in the acute phase. Both patients were given low-dose methylprednisolone combined with mannitol. No drugs such as memantine and idebenone were applied to patient #2 because the diagnosis had not been established before. The WES results can help us select more effective medication in the future.

Prophylactic management is applied to patients with frequent, long-lasting, or severe attacks (12). A single-center cohort study of pediatric migraine lasting 11 years suggested that flunarizine should be used as first-line medication in children with hemiplegic migraine (86). In the two patients we reported, considering the patients’ age, weight, and tolerance to the drug, the dose of flunarizine was 0.2 mg/kg per day, with a maximum amount of 5 mg/d. The two patients we reported were treated with flunarizine for 8and 2 months, respectively, and both were well tolerated without adverse effects. During the current follow-up, patient #1 had occasional headaches that could be resolved with rest. He has not suffered any head trauma and has not undergone severe attacks such as convulsions or encephalopathy. He is still under continued follow-up. Patient #2 did not experience any further headaches or convulsions, probably due to the short follow-up period, and is still under continued follow-up.

Acute encephalopathy is the main manifestation of severe attacks of HM in children, which adds to the difficulty of diagnosis. Physicians should consider HM in the differential diagnosis of patients presenting with somnolence, coma, or convulsion without structural, epileptic, infectious, or inflammatory explanation. Early recognition and treatment of the disease can help improve the prognosis. Whole-exome sequencing can suggest diagnosis and the type. Future multicenter and large sample size studies are still needed to explore the treatment strategy for this disease.