Electrical Status Epilepticus in Sleep Clinical Trial
Official title:
Electrical Status Epilepticus in Sleep: Response of Neuropsychological Deficits and Epileptiform Activity to Clobazam Treatment
Electrical status epilepticus in sleep (ESES) is a pattern of abnormal discharges in the
electroencephalogram (EEG). Children who have this pattern present seizures and
neuropsychological regression. There are no studies that systematically evaluate the
response of abnormal discharges in the EEG, seizures and neuropsychological regression to
different antiepileptic treatments. Therefore, treatment strategies in ESES are not based on
scientific evidence. High-dose benzodiazepines such as diazepam (valium) have been reported
to improve the severe EEG abnormalities of patients with ESES in the short-term. But the
long-term response of seizures and neuropsychological regression has not been systematically
studied. Clobazam is a benzodiazepine derivative with antiepileptic properties. The
pharmacologic properties of clobazam make of this drug a particularly useful option in ESES:
in patients with ESES the alpha-2 subunit of the GABA receptor is preferentially
up-regulated and clobazam may have a higher affinity for this particular subunit, so
investigators expect a higher effect of this drug on ESES patients than with other
benzodiazepines (Loddenkemper et al, in preparation). The aim of our study is to objectively
evaluate the response to clobazam treatment of neuropsychological deficits, seizures and
abnormal discharges in the EEG in patients with ESES. Clobazam treatment is used in routine
clinical practice and investigators will objectively quantify its effect.
Our working hypothesis is that high-dose clobazam treatment may control the abnormal
epileptiform discharges in the EEG in patients with ESES. The reduction in abnormal
epileptiform discharges may lead to an improvement in neuropsychological deficits and
seizures. The predicted improvement in seizures and neuropsychological function would lead
to a better quality of life in these patients.
- A. RESEARCH METHODS
Study design. Investigators will perform a prospective descriptive cohort study with
historical controls.
Participating institutions. Children's Hospital Boston (PI: Tobias Loddenkemper) and
Children's Hospital Colorado (PI: Kevin Chapman).
Patients. Investigators will enroll patients with ESES studied at our centers and treated
with high-dose clobazam treatment as decided by the clinical epileptologist.
The diagnosis of ESES will be confirmed based on neuropsychological regression in at least
one domain of development, the presence of seizures that appear in an age-related manner and
the presence in the EEG of the ESES pattern (Loddenkemper, et al. 2011a).
Contact with the patients. Once that the potential candidate is recognized (patient with
ESES, a change in medication regimen is decided that includes initiation of clobazam), the
research team will contact the primary epileptologist. The primary epileptologist will
contact the patient in order to check whether the family and/or patient would like to be
contacted for this research protocol. If the patient agrees to be contacted, the research
team will contact the patient in order to propose them to participate in the study.
EEG assessment. Investigators will assess the epileptiform activity in the long-term
monitoring unit before and after treatment for every patient.Assessment of clinical data.
The clinical charts of the patients included in the study will be collected reviewed for
relevant clinical information. This information will be updated and complemented with the
patient and/or the family during the admissions for long-term monitoring. Assessment of
neuropsychological data: A battery of neuropsychological tests will be performed by
board-certified clinical neuropsychologists to obtain information regarding cognitive
abilities.
Safety measures. Investigators will continuously monitor patients for adverse effects during
hospitalization and provide them with contact information for continuous report of possible
adverse effects. Potential risk to subjects. As subjects will be using a FDA-approved drug
for the treatment of epilepsy their risk will be the same as in routine clinical care. There
will not be risks associated with the specific use of clobazam as it is routinely used for
clinical care and the decision to use it or not will depend on the primary provider and not
on the research team. Other potential risks are related with the loss of privacy and
confidentiality. Investigators will develop mechanisms to ensure protection of patients'
privacy and confidentiality.
Quality control method. Investigators will perform quality control measures every 5
collected patients at Children's Hospital Boston. Additionally, independent medical
monitoring will be implemented.
- B. STATISTICAL ANALYSIS
Calculation of the sample size. Our previous study with diazepam treatment (Sánchez
Fernández, et al. in press-a) found that the difference in epileptiform activity before and
after treatment was of around 30%. There are no other data available on the quantification
of the response of epileptiform activity to antiepileptic treatment.
- C. PLANS FOR MISSING DATA
Recruitment of patients. Patients with ESES frequently belong to the category of patients
that are not able to understand the study protocol both because of their age and because of
neuropsychological regression. Their families and/or caretakers will decide in most cases
about study enrollment and the patient consent/assent will be looked for when
developmentally possible. Although studies with patients with severe developmental delays
pose significant challenges, the burden of participating in the study will not be
significantly different from the burden of normal clinical care. Additionally this study
will be performed at centers that are familiar with the care of patients with severe
developmental delay.
Sample size. Power calculation for the proposed study is challenging due to the novel
approach. Our preliminary data, however, strongly favor feasibility and completion.
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Observational Model: Cohort, Time Perspective: Prospective