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Preventive Antiepileptic Treatment in Tuberous Sclerosis Complex

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Jozwiak S, Słowińska M, Borkowska J, Sadowski K, Łojszczyk B, Domańska-Pakieła D, et al. Preventive Antiepileptic Treatment in Tuberous Sclerosis Complex: A Long-Term, Prospective Trial. Pediatric Neurology 2019;101:18–25. https://doi.org/10.1016/j.pediatrneurol.2019.07.008.
Publication Type
Commentary by: 
Karen L. Skjei, MD, ABPN, ABCN
Director, Clinical Neurophysiology
Associate Chief, Epilepsy
Associate Professor, Neurology
Division of Pediatric Neurology

Epileptogenesis, the development of epilepsy, is a process of progressive alterations in neuronal excitability and interconnectivity before the first spontaneous seizure occurs. Some evidence suggests that early intervention, in the form of initiation of antiseizure medications prior to onset of clinical seizures, may disrupt this process.
Epilepsy is a common feature of tuberous sclerosis complex (TSC), occurring in 70-90% of TSC patients, often presenting within the first year of life. Early onset of seizures and drug-resistant epilepsy are predictive of intellectual disability, seen in 40-70% of TSC patients.

In 2006, the authors initiated a prospective, unblinded trial involving early initiation of vigabatrin, prior to clinical seizure onset, in patients with TSC. Serial electroencephalograms (EEGs) were performed every 4-6 weeks on 14 infants diagnosed with TSC prenatally or within the first 2 months of life. Teatment with vigabatrin (100-150 mg/kg/day) was initiated within a week of the first appearance of epileptiform discharges. If no clinical seizures appeared by age 24 months, vigabatrin was discontinued. As a control group, they compared a previous cohort, including 31 infants managed according to standard epilepsy guidelines, with initiation of vigabatrin within a week of when seizures were reported by caregivers or noted by medical professionals. Both the early treatment group and the control groups included patients with TSC1 and TSC2 mutations, as well as patients in whom genetic testing was not performed or in whom no mutation was identified.

Initial results, presented in 2011, suggested that early initiation of vigabatrin decreased neurodevelopmental impairmenets at age 24 months. This study looks at longer term outcomes, after a minimum of 5 years follow-up (median duration of follow-up about 8 years in both groups). All 14 patients in the early treatment group were included. Three patients from the standard treatment cohort were lost to follow-up and data was unavailable on another 3, decreasing the control group to 25.

Their results are striking. Half of patients in the early treatment group (50%) never experienced a clinical seizure, vs. only one patient of 25 (5%) in the control group (p=0.001). While the rate of drug-resistance and seizure remission were similar between both groups, the median intelligence quotient (IQ) in the early treatment group was an astounding 94 vs. 46 in the standard group (p < 0.03). Only 3 of the 14 patients in the early treatment group (21%) developed intellectual disability, versus 18 (72%) in the control group. And none in the early treatment group vs 3 (12%) in the control group had profound intellectual disability.

The authors mentioned several of the limitations to this study, including the small number of subjects, the open label design, and the fact that the two groups were not followed in parallel.
Another significant limitation of this study was that only 10 of the 14 infants in the early treatment group actually received vigabatrin before 24 months of age (the age when vigabatrin was discontinued if no clinical seizures appeared.) One patient developed EEG abnormalities at 29 months of life and was started on vigabatrin, and 3 of the 14 patients (21%) in the treatment group never developed any EEG abnormalities or seizures despite not having received any treatment. In comparison, however, only 1 of 25 patients (4%) in the control group remained seizure free.

This intent to treat approach used by the authors and the asymmetry between treatment and control group could be argued to have artifically inflated their good outcomes. When the patients who did not receive early vigabatrin (i.e. before 24 months of age) were excluded from the analysis, only 3 of the remaining 10 patients (30%) never went on to develop clinical seizures, as compared to 50% using the intent to treat analysis. While 30% is still markedly improved from the 1 patient (4%) of the control group who did not develop seizures, it is also within range of that seen in some other TSC cohorts that did not receive early treatment. The median age at seizure onset among those who developed epilepsy was similar between groups (6 months among those who received early treatment vs 7.5 among controls).
Interestingly, the percentage of patients who developed epilepsy who continued to have active seizures at the end of the study was higher in the group that received early treatment (5 of 7, 71%) than among the standard group (11 of 24, 46%), as was the median number of antiseizure medications used in those patients (4 in the early treatment group vs 3 in the standard group). Regarding neurodevelopmental outcomes, while the results were less dramatic than with the intent to treat analysis, still only 3 of the 10 patients (30%) who actually received the early treatment developed intellectual disabilities, notably lower than 18 of 25 (72%) in the control group. And the median IQ of the preventative group remained stable (91 vs 94) when the patients who didn’t receive treatment were excluded.

This long-term follow-up study looking at the neurodevelopmental outcomes in TSC patients treated with vigabatrin at onset of epileptiform abnormalities increases our anticipation for the results of the completed randomized control trial, EPISTOP, and raises the question whether similar prophylactic treatment in other epilepsy syndromes could improve outcomes.
Article Abstract:
Background- Drug-resistant epilepsy is the main risk factor for future intellectual disability in patients with tuberous sclerosis complex. Clinical epileptic seizures are often preceded by electroencephalographic changes, which provide an opportunity for preventive treatment. We evaluated the neuropsychologic and epilepsy outcomes at school age in children with tuberous sclerosis complex who received preventive antiepileptic treatment in infancy.

Methods- The authors performed a prospective, nonrandomized clinical trial with 14 infants diagnosed with tuberous sclerosis complex in whom serial electroencephalographic recordings were performed and preventive treatment with vigabatrin initiated when active epileptic discharges were detected. An age-matched control group consisted of 31 infants with tuberous sclerosis complex in whom treatment with vigabatrin was given only after onset of clinical seizures. Results of clinical assessment of epilepsy and cognitive outcomes were analyzed

Results- All patients in the preventive group (n = 14) and 25 of 31 patients in the standard treatment group were followed through minimum age five years, median 8.8 and 8.0 years in the preventive and standard groups, respectively. The median intelligence quotient was 94 for the preventive group when compared with 46 for the standard group (P < 0.03). Seven of 14 patients (50%) in the preventive group never had a clinical seizure when compared with one of 25 patients (5%) in the standard treatment group (P = 0.001).

Conclusions- This study provides evidence that preventive antiepileptic treatment in infants with tuberous sclerosis complex improves long-term epilepsy control and cognitive outcome at school age.

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