Abstracts

Rationale: CDKL5 is now a well-known genetic cause for EIEE (early infantile epileptic encephalopathy). It is a gene carried on the X chromosome. It has complex interactions with other genes including MECP2, the gene associated with Rett syndrome. CDKL5 patients most often present with atypical Rett. Most mutations are de novo, however, inheritance via germ-line mosacisim is thought to occur and recurrence of the mutation within single families has been reported. In more severe mutations, such as the one we report here, the DNA encodes a frameshift mutation with loss of function. Seizure control in CDKL5 patients with EIEE may be very challenging. Seizures usually start within the first 5 months of life. They may be startle induced and may be of multiple types, the most common of which are tonic, myoclonic and focal onset. Approximately 50-70% of patients develop infantile spasms. Here, we describe a treatment strategy for treating CDKL5 patients with clusters of seizures who have become tolerant to anti-epileptic medications, in particular, benzodiazepines. Methods: A female infant (born prematurely at 36 weeks gestational age) presented at 2 months of age with spells concerning for seizures. Initial EEG showed subtle interictal left fronto-central sharp waves and small spikes. The ictal EEG was relatively unremarkable with generalized high amplitude slow waves with attenuation. Semiology was bilateral lateral arm tonic extension and usually rightward eye deviation, followed by myoclonic jerks. The seizures were brief (duration of 30 seconds to 3 minutes) and occurred in clusters. Initial treatment was with fosphenytoin, phenobarbital, and leviteracetam. Our patient developed a significant skin allergy to phenobarbital. Increasing doses of leviteracetam to 80 mg/kg/day were ineffective. Oxcarbazepine was titrated to the highest effective dose, but was limited due to hyponatremia. Topiramate was initially effective, but it caused significant metabolic acidosis. Lacosamide had no significant effect. Clobazam was started but also with a dose limitation for worsening hypotonia. Ketogenic diet and hemp oil were tried for approximately one month, but neither seemed beneficial for our patient. Due to parental concerns, VNS and vigabatrin have been discussed but have not been used to date. Results: Aside from a slightly premature birth, our patient seemed to be a normal, healthy, well-developing infant. Over a period of 2 months after seizure onset, she became profoundly hypotonic and encephalopathic. Reflux and poor feeding leading to g-tube placement. Initial studies including serum amino acids, urine organic acids, serum lactate and ammonia, and microarray were negative. MRI was negative for lesion. SPECT was done but did not show a definite seizure focus. The GeneDx EpiXpanded panel revealed the previously unreported heterozygous pathogenic variant c693delA: p.Ser232LeufsX4. This knowledge led to a change in treatment strategy. Because CDKL5 patients are known to have very brief "honeymoon" periods with medications, longer acting medications were used as daily therapy. Bolus oral or enteral valproic acid (20 mg/kg) and levetiracetam (40 mg/kg) has been used effectively to seizure clusters . Prolonged seizures have been aborted successfully with intranasal midazolam. At the age of 6 months, our patient has several days seizure-free and clusters are aborted with sparing use of valproic acid and levetiracetam Conclusions: CDKL5 mutations can cause severe early infantile epileptic encephalopathy with intractable refractory epilepsy. Using medications with longer half -lives may be most effective for baseline seizure control. Clusters may be aborted with large doses of medications with short-onset and time to peak. Funding: None