FHM. There are few neurological phenomena that are as perplexing as CACNA1A-related hemiplegic migraines. Neither migraines, seizures, nor strokes, CACNA1A-related hemiplegic migraines are poorly characterized neurological events that often defy explanation. In a recent publication, we characterized how hemiplegic migraines in children with CACNA1A-related disorders present across time. Here is what we found.

Figure 1. Longitudinal trajectories and severities of hemiplegic migraines and seizures in individuals with pediatric CACNA1A-related disorders. All events are plotted left to right, with graphs starting at age 0. (Note: Multiple events within a year were collapsed into 1 event.) Intensity is ranked from 1 (mildest—smallest dot and lightest color) to 5 (most severe—largest dot and darkest color). Above the x-axis: hemiplegic migraine (HM) events (shades of blue). Below the x-axis: seizures (shades of yellow to red). Each individual demonstrated a unique pattern. A noteworthy finding was that no HM events occurred before the age of 1 [modified author manuscript from Schaare et al., 2025 under a Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND)]

Hemiplegic migraine. More than 20 years ago, I learned about the three causes of hemiplegia in children as a third-year resident during my child neurology rotation: strokes, post-ictal paralysis (Todd’s paralysis), and hemiplegic migraines. When our lecturers spoke about this triad of hemiplegias in children, the focus was on post-ictal paralysis, which is a phenomenon medical students were entirely unaware of. Hemiplegic migraines, it seemed, are something we took for granted, given that they already had the word “hemiplegia” in them. Now, more than two decades later, let me revisit what we know about these unusual conditions that initially appear somewhat self-explanatory by name.

CACNA1A-related HM. In brief, hemiplegic migraines (HM) are a rare and severe type of migraine that resemble stroke symptoms. These episodes are characterized by temporary weakness or paralysis on one side of the body, known as hemiplegia. In some individuals, this is accompanied by intense headaches, nausea, and sensitivity to light and sound, but in many individuals with CACNA1A-related HM, there is no evidence of headache. In contrast, these events may result in significant brain swelling that necessitates hospital admission and sometimes monitoring in an ICU setting. Treatment often occurs with acetazolamide, verapamil, or anti-seizure medications such as valproic acid or benzodiazepines.

Longitudinal trajectories. CACNA1A-related HM range from brief, self-limiting symptoms to life-threatening events associated with brain swelling. What had bothered me about CACNA1A-related HM for a long time was the fact that there was no information about the development and severity of these events over time. Also, it was unclear whether the severity of HM events can be predicted. Do mild events in individuals with CACAN1A-related disorders stay mild, or are patients at risk for more severe events in the future? In addition, some CACNA1A-related HM events occur in the setting of seizures and status epilepticus. However, it was unclear how common the association with seizures was and whether this connection was causally related. We tried to address these questions in our recent publication by Schaare and collaborators.

HM over time. In brief, we assessed 163 patient years in 15 individuals with CACNA1A-related HM. All individuals had missense variants, including several variants for which prior functional data clearly pointed towards a prominent gain-of-function effect. We have not seen CACNA1A-related HM in individuals with loss-of-function variants, an important fact to relay to families with respect the necessity of action plans for CACNA1A-related HM. In our study by Schaare et al., we observed that the longitudinal course of CACNA1A-related HM lacks recognizable patterns or timing. Mild HM events can be followed by severe events, and HM may occur after long periods of freedom from these episodes. In addition, we find little correlation with seizure patterns, even though seizures and HM may overlap in some individuals.

What you need to know. In our study by Schaare and collaborators, we describe the longitudinal disease course in individuals with pediatric CACNA1A-related HM. We find that both the severity and timing of HM events defy the patterns that we have observed. Plus, if individuals have HM and seizures, the correlation between both neurological features is cryptic. In summary, we have provided a first longitudinal phenotypic map for CACNA1A-related disorders that will allow us to expand the granularity of phenotypic information on this rare disease, eventually leading to clinical trial readiness.

Ingo Helbig

Ingo Helbig is a child neurologist and epilepsy genetics researcher working at the Children’s Hospital of Philadelphia (CHOP), USA.