Epileptic Encephalopathy due to CACNA1A Variant: A Case Report and Diagnostic Challenges from Resource-Limited Settings

In 2018, nearly 50 million people were estimated to suffer from active epilepsy worldwide [1] approximately 85% of people with epilepsy live in low and middle-income countries where the prevalence of the disease is rising faster than in high-income countries, due to increased risk factors such as perinatal complications, infections and also increasing in number of diagnostic tools and neurologists [2, 3]. Sub-Saharan Africa is one of the areas where there is a greater prevalence of epileptic disorders compared to other regions of the world. In Tanzania, approximately more than 2 people out of 100 have epileptic disorder this means a prevalence of more than 2.4% is reported in the literature [4], as compared to a study done in 2020 in sub-Saharan Africa with a small sample size showed the prevalence being around 1.6% in sub-Saharan Africa in general [5].

Due to the scarcity of diagnostic equipment in sub-Saharan Africa, particularly in Tanzania where hospitals offer little diagnostic tests for the disease and few neurologists are present, most of these cases are unreported. The majority of the reported cases are results of previous risk factors which are well known such as hypoxic brain injury during birth, trauma, and infectious diseases affecting the nervous system [6]. Other causes that are seen to be rare such as genetic factors are poorly reported in these settings, although reported literature has shown the high chances of these epileptic disorders to be genetically linked and affecting the whole course of treatment [7].

Epileptic encephalopathies refer to a group of epileptic disorders, whereby epileptic activity itself impairs cognitive and behavioral function more than what is expected from the underlying pathology alone [8]. With poor prognosis, few cases can be controlled and even cured by prompt diagnosis and successful treatment [9]. Literature shows structural, genetic, and metabolic causes of epileptic encephalopathies, whereby in most cases, syndromes have been seen to overlap; hence, identification of specific electroclinical syndrome is critical as it guides treatment and informs prognosis [9].

Epileptic encephalopathies are broad-spectrum disorders affecting infancy and early childhood classified by clinical features and EEG findings. The spectrum has included pathologies such as early infantile epileptic encephalopathy, infantile spasms, Lennox-Gastaut syndrome, severe myoclonic epilepsy of infancy (Dravet syndrome), and Landau-Kleffner syndrome [10]. Most of these cases have no known etiology, and literature suggests a possible link between certain gene mutations and early structural lesions as cortical development malformations lead to either pathology [11].

The CACNA1A gene is located at chromosome 19p13 which encodes the P/Q calcium channel which plays a vital role in coupling calcium influx to vesicular exocytosis, mediating depolarization in neurons. A minor alteration of the voltage-gated or receptor expression can lead to significant neurologic abnormalities [12]. CACNA1A variants have been seen to be observed in several epileptic patients; although up to date, the pathophysiology leading to epilepsy is idiopathic [12]. These cases are extremely challenging to treat for neurologists as there is no consensus treatment for epilepsy due to mutation in this gene, and in most cases, a combination of anticonvulsants is used without success.

A 7-year-old male patient of African descent presented to the emergency department with a complaint of convulsions for 1 day accompanied by on-and-off episodes of vomiting and passing of loose stools. This is a patient who was diagnosed with seizure disorder during infancy and was kept on daily doses of anticonvulsants. The mother reports throughout the illness the patient has been having multiple attacks of tonic-clonic seizures despite being on treatment. At the emergency department, there was no urine or fecal incontinence which was noticed, although seizures were observed which were focal seizures affecting the right upper and lower limbs of the patient. On antenatal and natal history, the patient was delivered by normal spontaneous vaginal delivery and cried immediately after birth scoring 7 and 8 in the first and fifth minutes, respectively. Other antenatal history was unremarkable. On developmental assessment of the patient, it was observed a significant neuropsychological developmental delay at the age of 7 years old, such as the child was not being able to speak and complete meaningful sentences. After administration of 5 mg of diazepam, no active convulsions were noticed. His vital signs were as follows: SpO₂ of 92%, heart rate of 120/min, respiratory rate of 20/min, and body temperature of 38.2 degrees Celsius. Kernig and Brudzinski signs were negative. Pupils were equally reactive to light. There was no sign of increased intracranial pressure. Laboratory testing showed leukocytosis and white blood cell counts of 14,000/mL including 11,000/mL neutrophils. C-reactive protein level was slightly elevated. All other investigations including chest X-ray were all normal. On arrival, the patient was on sodium valproate 500 mg twice a day combination for seizure control and has been on other medications that have been interchanged since seizures were not controlled. A 24-h EEG study when the patient is awake and asleep, Figure 1 shows awake EEG focal delta and sharp waves seen from left frontal and central regions and persisted in sleep. Figure 2 shows normal vertex sharp activity, spindles, and K-complexes. Figure 3a, b shows spike-wave discharges from right parietal-temporal regions with maximum amplitudes at P4-T4 during sleep. After the EEG result, the blood samples were taken for genetic evaluation and showed a known pathogenic variant (c.4043G>A) in the CACNA1A gene in the patient. The CARE Checklist has been completed by the authors for this case report, attached as the online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000540799).

Epileptic encephalopathy is usually noticed during early infancy immediately after birth between 2 months and 12 years of age [13]. The most common presenting symptom is convulsions in 80% of children and in some cases neuropsychological deterioration [13], the patient usually presents with nocturnal seizures either simple or complex, generalized tonic-clonic or myoclonic seizures [13]. This is also seen in our patient with neuropsychological deterioration and a history of seizures where he was diagnosed during early infancy, although there was no diagnostic test which was made previously.

The diagnosis of epileptic encephalopathies is based on age of onset, seizure type, and characteristics of EEG patterns. As explained before, this is a broad spectrum of disorders, and in some cases, they may have overlapping features. Age of first seizure attack, developmental regression, and EEG patterns all aid in the diagnosis of these disorders [9]. Although most of these encephalopathies begin during early infancy, some of them begin during the neonatal period like early infantile epileptic encephalopathy, and some may start from the age of 1 year and above like Lennox-Gastaut syndrome [9]. Currently, with the advancement of technology, there has been a significant association between these seizure disorders with gene mutations [12]. A good example is the CACNA1A variant which has been very notorious in treatment as compared to the other forms of encephalopathies [12]. Most of these cases are refractory to most anticonvulsants and treatment is challenging for neurologists.

The pathophysiology of epileptic encephalopathies is proposed to involve cortical and subcortical regions of the brain. The models propose four elements of electrical disturbances which are (1) a region of abnormal irritable epileptogenic cortex that may be focal as in cases of focal cortical dysplasia or diffuse in case of genetic lesions such as in the CACNA1A variant, (2) altered function in subcortical regions such as cholinergic, serotonergic, and catecholaminergic that receive cortical outflow and in turn regulate cortical input and tone, (3) diffuse cortical hyperactivity resulting from altered function in the subcortical region, (4) encephalopathy is the effect of either 1 or 3 above or a combination of both [14]. This is also seen in our patient’s EEG; there are signs of cortical structural damage.

Treatment of epileptic encephalopathy is challenging for clinicians, as the disease process may involve more than one complicating factor. Most clinicians treat visible seizures, forgetting that the spectrum may consist of disorders that have absent seizures and vice versa [9]. Studies have shown some epileptic encephalopathies such as the CACNA1A variant to be extremely resistant to seizure medications and to date, very few studies have been published to have shown control of seizures in this disease [12]. In most cases, studies have shown control of seizures with a combination of more than one drug, including steroids and immunomodulators, due to the fact that conventional antiepileptic drugs are seen not to be effective in seizure control [14]. In our case the patient has been on antiepileptic medications for more than 4 years which have failed to control seizures to the patient, a combination of medications such as phenytoin, and carbamazepine have been unable to control seizure attacks. With current advancements in medicine immunomodulators combined with steroids have shown improvements in these patients, a study done by Byers et al. [12] showed response with lamotrigine for patients with the CACNA1A variant to be effective, in our patient acetazolamide was added in combination with levetiracetam daily and the rest of anticonvulsants have been stopped. Our patient is observed every week and first week of treatment, the mother reports not having noticed any seizure attacks.

The prognosis of epileptic encephalopathies is still guarded poor in several research articles published by different scholars. Although few cases to date are reported to be treated and achieved desirable seizure control, the authors have suggested early diagnosis is crucial for the outcome of these patients.

Epileptic encephalopathies are mostly resistant to anticonvulsants. It is challenging for clinicians in resource-limited settings to deal with this devastating neurological disease. Hence, an early index of suspicion is necessary for children having refractory seizures and to perform appropriate tests such as EEG and genetic studies which will help guide the course of treatment.

Ethical approval is not required for this study in accordance with local or national guidelines. Written informed consent was obtained from the parent/legal guardian of the patient for publication of the details of their medical case and any accompanying images.

The authors declare no conflicts of interests.

There was no funding for writing this manuscript.

Hilary Chipongo wrote the manuscript. Ronald Mclarty conceptualized the original manuscript. Samina Chaki reviewed the patient’s records.

All data generated or analyzed during this study are included in this published article. Further inquiries can be directed to the corresponding author.