CACNA1a encodes for the alpha-1A-subunit of the P/Q type calcium channel [4, 5]. These channels are expressed at central synapses and are particularly abundant in cerebellar granule and Purkinje cells [6,7,8]. They are also expressed at pre-synaptic terminals and modulate the synaptic release of neurotransmitters [9, 10].
Pathogenic variants in CACNA1a includes missense and nonsense point mutations, short and large deletions and tri-nucleotide repeat expansions. Single nucleotide pathogenic variants cause both gain-of-function and loss-of-function variants that have some correlation with phenotype. Clinically, pathogenic variants in CACNA1a span a spectrum of phenotypes that include familial hemiplegic migraine Type 1 (FHM1) and Episodic Ataxia Type 2 (EA2) with FHM1 being caused typically by gain-of-function variants and EA2 being caused by loss-of-function variants, although there can be overlap [11]. CACNA1a variants have also been associated with developmental delay, autism spectrum disorders, epilepsy and paroxysmal movement disorders (benign paroxysmal torticollis of infancy, paroxysmal tonic upgaze) [12,13,14,15,16,17,18].
Regarding the specific variant identified in this patient, the c.5126 T > C (p.I1709T) variant has been reported in patients with familial hemiplegic migraines with status epilepticus [19, 20]. Furthermore, there have also been prior reports of acute unilateral cerebral edema that can occur in patients with CACNA1a associated FHM1 in addition to other forms of familial hemiplegic migraines [21,22,23]. The pathologic mechanisms that lead to unilateral cerebral edema in familial hemiplegic migraine is unclear. However, one explanation is that the cortical spreading depression observed in FHM is associated with cerebral edema due to changes in ion gradients and decreased extracellular space due to cellular swelling with resultant hyperemia (increased perfusion) and diffusion restriction changes on MRI [24,25,26,27].
Most patients tolerate ECT well with the most common side effects including nausea, headaches, and brief periods of retrograde/anterograde amnesia [1, 28, 29]. Conventional bilateral ECT has been associated with a variety of transient neurological signs and symptoms, such as abnormal reflexes, aphasias, various agnosias, and Gerstmann syndrome. Transient hemiparesis or Todd paralysis was first reported with unilateral ECT in 1953, with other cortical dysfunction associated with the hemisphere stimulated, such as agnosia, sensation or visual changes, or language dysfunction. ECT in children and adolescents constitutes less than 1% of ECT in the United States [3, 30]. However, the most common side effects in this cohort—headache, memory problems, muscle soreness, and nausea/vomiting—are similar to the side effect profile in older patients [28, 29]. Another cohort analysis of ECT in adolescents reported prolonged seizures (defined as seizures longer than 3 min) in 4% (2 of 49 ECT treatments) of patients. There have been no published reports of prolonged focal neurologic deficits in adolescents treated with ECT.
In adult studies, unilateral ECT has previously shown hemisphere dependent deficits that typically resolve within 30 min (hemiplegia typically resolved by 15 min), but prolonged non-dominant hemisphere related deficits have been reported hours to days after treatment, but were largely visuo-spatial related deficits [31]. While deficits associated with unilateral ECT typically resolve within 30 min, some deficits have been reported hours to days after treatment. In one case report, a 58-year-old with depression received right-sided ECT and subsequently developed right facial droop, right upper and lower extremity weakness, and aphasia. Her motor symptoms resolved by 72 h, and her aphasia completely resolved by day five. An MRI obtained in this patient at day three following ECT was reportedly normal. The patient had previously received ECT without issue [32].
Regarding the imaging findings in this patient, although MRI has been used to evaluate structural changes related to long-term use of ECT and largely shows regional volumetric changes or differences in fractional anisotropy in different white matter tracts, there are few reports of MRI findings concerning for ischemia but none similar to the findings in this patient [33, 34]. There are rare reports of acute ischemic strokes following ECT, but our imaging pattern was not that of an arterial ischemic stroke [33, 34]. Overall, the MRI findings in the patient presented in this report are not consistent with reported imaging changes associated with ECT.
In conclusion, we present a case of a patient that developed prolonged right-sided hemiplegia following right sided ECT and subsequently found to have CACNA1a pathogenic variant. While ECT is generally a well-tolerated treatment based on published data, there is limited data on its use in children and in patients with specific genetic conditions. In the patient presented here, given their CACNA1a pathogenic variant, the episode of ECT potentially triggered a hemiplegic migraine and cortical spreading depression (CSD), which would be consistent with their MRI changes, cerebral edema and prolonged hemiplegia [35, 36]. It is not clear why ECT on the right hemisphere caused left sided symptoms, but during unilateral ECT, spread of seizures to contralateral side has been observed [31]. In this case, even though the ECT was on the right side, it seemed to trigger a seizure that also affected the left hemisphere based on the initial clinical semiology of this patient. In FHM associated cerebral edema, the imaging findings are typically unilateral which is not completely understood, but animal models have shown increased susceptibility to spreading depressions as a mechanism for cerebral edema. Of note, mild head trauma has been associated with some of these episodes which suggests that mild stressors may be triggers for hemiplegic migraine episodes [37]. Other potential diagnoses include a prolonged Todd’s paralysis related to their episode of status epilepticus, but their prolonged recovery and imaging findings are more consistent with an FHM episode given their underlying genetic disorder. Hemiplegia-hemiconvulsive-epilepsy is another entity with similar presentation, but variants in FHM related genes that include CACNA1a have been identified in some of these patients and typically these patients present during early childhood following febrile illness and go on to develop intractable epilepsy, which was not the case in the patient presented in this report [38].
This case highlights an unusual presentation of a patient with a pathogenic CACNA1a variant. In addition, the adverse events experienced by this patient suggest that care should be taken in patients undergoing ECT with CACNA1a related disorders. This case report also reinforces the role of genetic testing in patients with neurodevelopmental disorders as the results can help identify potential risk factors for side effects from specific treatments.
