Electrical Status Epilepticus in Sleep: Response of Neuropsychological Deficits and Epileptiform Activity to Clobazam Treatment
Condition: Electrical Status Epilepticus in Sleep
MeSH terms: Status Epilepticus
Study type: Observational [Patient Registry]

Summary: 
      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.
    

Detailed description: 
      - 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.
    

Intervention name(s): ESES treated with clobazam
Intervention type(s): Drug
Intervention description(s): The patients that will participate in the protocol will be those that are administered for clinical reasons oral clobazam.
Intervention MeSH terms: Clobazam
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Investigators will enroll patients with ESES studied at our centers and treated with
        high-dose clobazam treatment as decided by the clinical epileptologist. Patients with ESES
        are monitored once or twice a year in the long-term electroencephalogram monitoring unit to
        assess epileptiform activity. Patients with very active discharges and neuropsychological
        regression require a change in their treatment regimen. If the treating epileptologist
        decides that high-dose cloblazam treatment is indicated for clinical reasons, then the
        patient will be offered to participate in the study. The research team will not be
        responsible for or influence the treatment decisions in any way.
      
Keywords: Electrical status epilepticus in sleep; Continuous spikes and waves during sleep; Children; Electroencephalogram; Neuropsychology; Development; Antiepileptic drugs; Clobazam; Seizures