Clinical Diagnosis and Genetics of Hemiplegic Migraine: Comparison
Please note this is a comparison between Version 2 by Wendy Huang and Version 3 by Wendy Huang.

Hemiplegic migraine (HM) is a rare form of migraine with an aura characterized by transient motor weakness or hemiparesis (motor aura). HM is also associated with other non-motor aura manifestations (visual, sensory, aphasic, or basilar-type/brainstem symptoms) and with other symptoms typically accompanying migraine, such as nausea, vomiting, photophobia, or phonophobia. A motor aura represents the peculiarity of HM compared to other forms of migraine with aura (MA), and its diagnostic criteria have been updated in the latest classification of headache disorders. HM can be sporadic (SHM) or familial (FHM), with autosomal dominant inheritance.

  • hemiplegic migraine
  • familial hemiplegic migraine
  • sporadic hemiplegic migraine
  • children

1. Introduction

SHM and FHM are similar with respect to epidemiology, trigger factors, clinical features, and neuroradiological and neurophysiological findings, but the two forms differ in terms of age of onset, genetics, and associated neurological picture [1][2][3].
Although a strong familial history is common among all types of migraine, HM is the only one in which monogenic conditions have been identified, and mutations in CACNA1A, ATP1A2, and SCN1A determine a significant number of familial clusters and sporadic cases. Nevertheless, other genes have been recently associated with HM, and in a relevant number of sporadic cases, it is possible that an underlying genetic cause is yet to be identified [1][4][5].
HM can affect both children and adults, with onset frequently occurring at a pediatric age [3][4][5][6][7][8][9][10]. Early transient neurological symptoms (isolated seizures, transient hemiparesis without a headache, and prolonged clumsiness after minor head trauma) can occur between the ages of 1 and 4 and long before the very first episode of HM is observed [4].
HM presents with similar clinical features both in adults and children; however, some remarkable differences have been reported. The prevalence of non-motor auras among children is lower than it is among adults [3][4]. In addition, the frequency, intensity, and duration of HM attacks often decrease during adulthood [1][6][11]. Moreover, HM prevalence in adults is greater among females than it is among males (6:1) [3], while gender representation is similar in children [4][12].

2. Clinical Diagnosis

HM is a subtype of migraine with aura, and the aura is characterized by motor weakness (or plegic symptoms), typically with a duration of less than 72 h [13]. The diagnostic criteria of the International Classification of Headache Disorders (ICHD-3) [13] are reported in Table 1.
Table 1. ICHD-3 diagnostic criteria of HM [13].
HM Diagnostic Criteria
A. Attacks fulfilling criteria for 1 MA and criterion B below.

B. Aura consisting of both of the following:

1. Fully reversible motor weakness;

2. Fully reversible visual, sensory, and/or speech/language symptoms.
1 MA = migraine with aura.
Thomsen et al. [1][5] proposed some minor revisions to the diagnostic criteria, which are summarized in Table 2.
Table 2. Revisions of diagnostic criteria of HM proposed by Thomsen et al. [1][5].
HM Diagnostic Criteria Minor Revisions
Aura (B2 in Table 1) could consist of at least 2 symptoms instead of 3

A gradual development of aura (in at least 60 min)

Presence of headache is not mandatory

1 BM could be included as a symptom
1 BM = basilar migraine.
Basilar migraine (BM) or “migraine with brainstem aura”, is a type of MA clearly originating from the brainstem, but without motor weakness. BM may have at least two of the following fully reversible brainstem symptoms: dysarthria, vertigo, tinnitus, hypoacusis, diplopia, ataxia not attributable to the sensory deficit, and decreased level of consciousness (GCS < 13), but no motor or retinal symptoms [13]. Moreover, if at least one first- or second-degree relative has had attacks fulfilling the criteria for HM, a diagnosis of FHM can be conducted, otherwise the diagnosis of SHM is established [13].

3. Genetics and Relation with Other Migraine Types

Specific genetic subforms of FHM have been identified: FHM type 1 (FHM1) is associated with mutations of the CACNA1A gene (coding for a calcium channel) on chromosome 19 p13; FHM type 2 (FHM2) with mutations of the ATP1A2 gene (coding for a K/Na-ATPase) on chromosome 1q23; and FHM type 3 (FHM3) with mutations of the SCN1A gene (coding for a sodium channel) on chromosome 2 [13]. The ICHD-3 has recognized each genetic subform (FHM1, 2, 3) as a distinct entity [13]. The diagnostic criteria are listed in Table 3.
Table 3. ICHD-3 diagnostic criteria of FHM1, FHM2, and FHM3 [13].
A. Attacks fulfilling criteria for FHM A. Attacks fulfilling criteria for FHM A. Attacks fulfilling criteria for FHM
B. A mutation on the CACNA1A gene has been demonstrated. B. A mutation on the ATP1A2 gene has been demonstrated. B. A mutation on the SCN1A gene has been demonstrated.
ICHD-3 has also introduced the definition of “FHM, other loci”, in order to include all patients who fulfilled the clinical diagnostic criteria for FHM, but with no mutation detected on the CACNA1A, ATP1A2, or SCN1A genes using genetic testing [13]. Sporadic cases of HM can be determined using de novo mutations in FHM-related genes in patients without familial history of HM. The prevalence of CACNA1A, ATP1A2, and SCN1A mutations varies greatly among studies (7–63%) [3][4], mainly depending on the characteristics of the studied population. Pediatric cohorts and cohorts including only patients with early and severe disease onset showed a higher prevalence of gene mutations [4][12][14], while it was significantly lower in wider populations mostly including adult cases; for example, Hiekkala et al. found that 7% of the Finnish FHM families and none of the SHM patients had mutations in CACNA1A or ATP1A2 genes [3]. For this reason, some authors recommend genetic screening in patients with HM onset below 6 years of age and in those with accompanying neurologic symptoms, due to a higher risk of carrying mutations in CACNA1A or ATP1A2 genes in these cases [7][15]. Moreover, early paroxysmal motor or non-motor manifestations in childhood can precede the first HM attack, especially in mutated patients. These paroxysmal manifestations should be further investigated, especially in cases with a family history of HM [4]. Mutated patients could manifest a more severe phenotype: more extensive ictal motor weakness, attacks more often associated with confusion, brain edema, brainstem manifestations, abnormal neurological examination with mental retardation, and progressive ataxia [16]. A more frequent occurrence of HM triggered by mild head trauma is also reported in genetically positive patients [16]. Other rarer genes have been associated with HM clinical spectrum, such as PRRT2 [17][18], SLC4A4 [19], and SLC1A3 [20]. Ten pediatric patients with Glut1 deficiency syndrome due to SLC1A2 mutations showed HM-like attacks; only three were tested for typical HM genes and one showed a coexisting mutation in the CACNA1A gene. Further studies are needed to better understand if SLC1A2 mutations alone could cause HM-like acute manifestation or if other secondary mutations are needed to determine the HM phenotype [21]. Interestingly, genes associated with HM are pleiotropic and different mutations can result in mixed clinical or familial phenotypes, including different paroxysmal neurological disorders [20]. The phenotypic spectrum of the main HM genes has been summarized in Table 4.
Table 4. Phenotypic spectrum of the main HM genes.
Gene Phenotypic Spectrum
CACNA1A 1 HM, transient focal neurologic deficit without headache, coma after minor brain injury, progressive cerebella ataxia [9][22]
ATP1A2 HM, epilepsy, intellectual disability, prolonged HM attacks, confusion, and coma, 2 BM [11][23]
SCN1A HM, epilepsy [24]
PRRT2 benign familial childhood epilepsy, episodic kinesigenic dyskinesia, familial childhood seizures with paroxysmal choreoathetosis [17]
SLC4A4 HM, renal tubular acidosis, glaucoma [19]
SLC1A3 HM [20]
SLC1A2 epilepsy—Glut1 deficiency syndrome, HM-like attacks [21]
1 HM = hemiplegic migraine. 2 BM = basilar migraine.
Despite all the remarkable findings about the genetic background of HM in recent years, the genetic cause still remains unknown in a significant proportion of HM cases and in the pediatric population. Polygenic interaction and/or multifactorial conditions could account for a considerable part of non-monogenic HM cases, as in other more common types of migraine [20]. However, there may be other unknown loci associated with HM [13]. The correlation between HM and more common types of migraine (MA, migraine without aura—MWA, BA), from a pathophysiological and genetic perspective is still debated [1][2]. However, patients with FHM have 7 times increased risk of MA than the general population [2]. In addition, 70% of SHM and 94% of FHM patients have one or more first-degree relatives with attacks of common MA, MWA, or both [4][6][10][11][15]. SHM patients have a significantly higher risk of MA but not of MWA [9][25]. Compared with the general population, first-degree relatives of probands exclusively having SHM exhibited a 2 times higher risk of MA [2]. Interestingly, mutations in HM-related genes were also found in common types of MA, MWA, and BM [6]. Ducros et al. reported that 11% (13/117) of subjects with mutations in the CACNA1A gene had no attacks of HM, in particular: 15% (2/13) of cases had no symptoms, 38.5% (5/13) were affected by MA, 8% (1/13) by MWA, 8% (1/13) by recurrent headaches with loss of consciousness, and 23% (3/13) had single transient episodes of unknown clinical significance (dysarthria, unilateral paresthesia, and confusion with fever) [1][7]. These findings could support the hypothesis that even the monogenic forms of SHM and FHM could represent a small part of a broader phenotypic spectrum in continuity with more common types of migraine [6].


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