Non-inferiority Prospective Randomized Trial of Acetazolamide Versus Diazepam in Patients With Continuous Spike and Wave in Sleep (CSWS)/Landau Kleffner Syndrome (LKS)
Phase: PHASE2
Conditions: Landau-Kleffner Syndrome, Status Epilepticus, Electrographic
Sponsor: Mayo Clinic

 
 
Non-inferiority prospective 
randomized trial of 
acetazolamide vs diazepam in 
patients with continuous spike 
and wave in sleep 
(CSWS)/Landau Kleffner 
syndrome (LKS)  
 
NCT# 02904265 
 
January 13, 2017 

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NON-INFERIORITY PROSPECTIVE RANDOMIZED TRIAL OF 
ACETAZOLAMIDE VS DIAZEPAM IN PATIENTS WITH CONTINUOUS 
SPIKE AND WAVE IN SLEEP (CSWS)/LANDAU-KLEFFNER 
SYNDROME (LKS) 
 
Principal Investigator: 
Katherine Nickels, MD 
Department of Pediatric and Adolescent Neurology 
Mayo Clinic, MN 
Supported by: N/A 
 
Study Intervention Provided by: N/A 
 
Sponsor of IND (IDE): N/A 
  
 
Version 5 
January 13, 2017

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TABLE OF CONTENTS 
Page 
PRÉCIS .......................................................................................................................................... 4 
Study Title ................................................................................................................................... 4 
Objectives ................................................................................................................................... 4 
Design and Outcomes ................................................................................................................. 4 
Interventions and Duration ......................................................................................................... 5 
Sample Size and Population........................................................................................................ 5 
STUDY TEAM ROSTER............................................................................................................. 6 
Principal Investigator: Name .................................................................................................... 6 
Co-Investigators: Name............................................................................................................ 6 
PARTICIPATING STUDY SITES ............................................................................................. 7 
1 
Study objectives ..................................................................................................................... 8 
1.1 
Primary Objective ........................................................................................................... 8 
1.2 
Secondary Objectives...................................................................................................... 8 
2 
BACKGROUND AND RATIONALE ................................................................................ 8 
2.1 
Background on Condition, Disease, or Other Primary Study Focus .............................. 8 
2.2 
Study Rationale ............................................................................................................... 9 
3 
STUDY DESIGN ................................................................................................................... 9 
4 
SELECTION AND ENROLLMENT OF PARTICIPANTS .......................................... 10 
4.1 
Inclusion Criteria .......................................................................................................... 10 
4.2 
Exclusion Criteria ......................................................................................................... 11 
4.3 
Study Enrollment Procedures ....................................................................................... 11 
5 
STUDY INTERVENTIONS .............................................................................................. 12 
5.1 
Interventions, Administration, and Duration ................................................................ 12 
5.2 
Handling of Study Interventions ................................................................................... 13 
5.3 
Concomitant Interventions ............................................................................................ 13 
5.3.1 Allowed Interventions ............................................................................................... 13 

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5.3.2 Required Interventions .............................................................................................. 13 
5.3.3 Prohibited Interventions ............................................................................................ 13 
5.4 
Adherence Assessment ................................................................................................. 14 
6 
STUDY PROCEDURES .................................................................................................... 14 
6.1 
Schedule of Evaluations ................................................................................................ 14 
6.2 
Description of Evaluations ............................................................................................ 16 
6.2.1 Screening Evaluation ................................................................................................ 16 
6.2.2 Enrollment, Baseline, and/or Randomization ........................................................... 17 
6.2.3 Follow-up Visits........................................................................................................ 18 
6.2.4 Completion/Final Evaluation .................................................................................... 19 
7 
SAFETY ASSESSMENTS ................................................................................................. 19 
7.1 
Specification of Safety Parameters ............................................................................... 20 
7.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters .... 20 
7.3 
Adverse Events and Serious Adverse Events ............................................................... 20 
7.4 
Reporting Procedures .................................................................................................... 21 
7.5 
Follow-up for Adverse Events ...................................................................................... 21 
7.6 
Safety Monitoring ......................................................................................................... 21 
8 
INTERVENTION DISCONTINUATION........................................................................ 21 
9 
STATISTICAL CONSIDERATIONS .............................................................................. 22 
9.1 
General Design Issues ................................................................................................... 22 
9.2 
Sample Size and Randomization .................................................................................. 22 
9.2.1 Treatment Assignment Procedures ........................................................................... 23 
9.3 
Interim analyses and Stopping Rules ............................................................................ 23 
9.4 
Outcomes ...................................................................................................................... 23 
9.4.1 Primary outcome ....................................................................................................... 23 
9.4.2 Secondary outcomes ................................................................................................. 24 
9.5 
Data Analyses ............................................................................................................... 24 
10 DATA COLLECTION AND QUALITY ASSURANCE ................................................ 24 
10.1 
Data Collection Forms .................................................................................................. 24 
10.2 
Data Management ......................................................................................................... 24 
10.3 
Quality Assurance ......................................................................................................... 24 
10.3.1 
Training ................................................................................................................. 24 
10.3.2 
Quality Control Committee.................................... Error! Bookmark not defined. 

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10.3.3 
Metrics ................................................................... Error! Bookmark not defined. 
10.3.4 
Protocol Deviations ............................................................................................... 24 
10.3.5 
Monitoring ............................................................................................................ 24 
11 PARTICIPANT RIGHTS AND CONFIDENTIALITY ................................................. 25 
11.1 
Institutional Review Board (IRB) Review .................................................................... 25 
11.2 
Informed Consent Forms .............................................................................................. 25 
11.3 
Participant Confidentiality ............................................................................................ 25 
11.4 
Study Discontinuation ................................................................................................... 25 
12 ETHICAL CONSIDERATIONS ....................................................................................... 25 
13 COMMITTEES........................................................................ Error! Bookmark not defined. 
14 PUBLICATION OF RESEARCH FINDINGS ................................................................ 25 
15 REFERENCES .................................................................................................................... 25 
16 SUPPLEMENTS/APPENDICES ...................................................................................... 27 
 
 

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PRÉCIS 
Electrical status epilepticus in sleep is a pattern on electroencephalogram (EEG) in which 
there is nearly continuous activation of epileptiform discharges in slow-wave sleep. Some 
children, who have a history of normal development, develop language regression with this 
pattern and are diagnosed with Landau-Kleffner syndrome (LKS). Other children, typically with 
a history of developmental delay, seizures, and abnormal neuroimaging, experience global 
regression of skills and are diagnosed with continuous spike and wave in slow wave sleep 
(CSWS). Both disorders are associated with poor developmental outcomes if not aggressively 
treated and represent potentially treatable causes of developmental regression in childhood.  
There is no consensus regarding optimal therapy for these disorders and practice is based on 
small series and expert opinion. One of the agreed upon first line options for these children is 
high-dose diazepam (0.5 mg/kg/day) which is typically effective in treatment of ESES, but has 
significant behavioral and cognitive side effects, necessitating brief, pulsatile, treatment periods. 
Relapse when diazepam is discontinued occurs on over 50% of patients.   
Our group has had success in using acetazolamide, a carbonic anhydrase inhibitor FDA 
approved for the treatment of epilepsy, in children with refractory ESES. We published a case 
series of 6 children treated with acetazolamide for refractory ESES and at initial follow-up 50% 
had significant improvement in their spike-wave index (measure of ESES).  
Acetazolamide is a well-tolerated medication and has minimal side effects compared to 
diazepam and other therapies for ESES. Furthermore, acetazolamide can be used as a chronic, 
rather than intermittent, medication.  There have been no studies comparing the efficacy of 
acetazolamide to diazepam as first line therapy. Our goal is to compare the use of acetazolamide 
versus diazepam as first line therapy for newly diagnosed ESES in a prospective randomized 
non-inferiority trial in pediatric patients in the pediatric epilepsy monitoring unit.  
Study Title  
Non-inferiority prospective randomized trial of acetazolamide (AZM) vs diazepam (DZP) in 
patients with CSWS/LKS 
Objectives  
1)  To establish non-inferiority of acetazolamide compared to diazepam  in children with 
ESES and clinical CSWS/LKS 
2) To demonstrate frequency of ESES relapse in children on long term acetazolamide 
therapy vs pulse diazepam therapy 
Design and Outcomes   
This study will be a prospective randomized study to assess the non-inferiority of 
acetazolamide compared to diazepam as first-line therapy in the treatment of ESES in 

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pediatric patients aged 3 through 12 years old, inclusive, diagnosed with LKS/CSWS. We 
will be assessing medication efficacy through measurement of spike-wave index (SWI) 
and follow-up SWI following intervention, as well as behavioral scales pre- and post-
intervention. Additionally, we will assess the frequency of ESES relapse in children on 
long-term acetazolamide therapy versus pulse diazepam therapy.  
 
Evaluations to be performed include Pediatric Epilepsy Monitoring Unit (PEMU) 
admission for overnight video EEG monitoring, and baseline behavioral assessments 
including the Vineland and Vanderbilt forms once a diagnosis of ESES has been made. 
The subject will then be randomized to either AZM or DZP. The subject will then have 
repeat overnight EEG and behavioral assessments in 4-5 weeks. If there is SWI response, 
the primary neurologist will decide whether to continue or wean the study medication.  If 
there is no response or worsening, then the subject may cross-over to the other 
medication and the EEG and developmental assessments will be repeated after 4-5 
weeks.  
Interventions and Duration  
Interventions to be compared are treatment with acetazolamide versus diazepam. Patients 
will be randomly selected to receive either diazepam 0.5 mg/kg to a maximum dose of 20 
mg by mouth each evening or acetazolamide at an initial dose of 8 to 10 mg/kg/d divided 
BID to a maximum dose of 375 mg BID to be uptitrated to a maximum dose of 11-16 
mg/kg/d divided BID or 750 mg BID. Patients will remain on treatment for 4 to 5 weeks 
duration at which efficacy will be assessed.  If effective, the patient may continue or 
wean the medication at the discretion of the child’s primary neurologist.  If the study 
medication is ineffective, they may opt to cross-over to the other study drug and efficacy 
will be assessed after an additional 4 to 5 weeks. Subjects will be followed clinically for 
6 months following enrollment in the study to assess cognitive and behavioral outcomes 
and to assess for potential relapse of ESES in the follow-up period. 
Sample Size and Population  
The target population is pediatric patients aged 3-12 years, inclusive, with a diagnosis of 
ESES and CSWS/LKS who will be prospectively recruited. Subjects will be recruited 
from our Pediatric Neurology outpatient clinic at Mayo Clinic in Rochester, MN The goal 
number of participants will be 100 patients total. There should be approximately 50 
patients per treatment group (i.e. 50 in AZM group and 50 in DZP group).  
 
After identification of patients who meet study inclusion criteria, randomization to either 
treatment will occur through computer generated randomization. Supervising physician, 
subjects, and families will not be blinded to treatment.  

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STUDY TEAM ROSTER  
Principal Investigator: 
Dr. Katherine Nickels, MD 
 
200 1st Street SW 
 
Rochester, MN 55905 
 
(p) 507-284-0774 
 
(f) 507-284-0727 
 
nickels.katherine@mayo.edu  
Main responsibilities/Key roles: Study design, subject 
recruitment, subject enrollment, manuscript design/editing 
Co-Investigators: 
 
Dr. Anthony Fine, MD 
 
200 1st Street SW 
 
Rochester, MN 55905 
 
(p) 507-284-3351 
 
(f) 507-284-0727 
 
fine.anthony@mayo.edu 
Main responsibilities/Key roles: study design, data collection, 
data analysis, manuscript design/editing 
Dr. Elaine Wirrell, MD 
 
200 1st Street SW 
 
Rochester, MN 55905 
 
(p) 507-284-0774 
 
(f) 507-284-0727 
 
wirrell.elaine@mayo.edu 
Main responsibilities/Key roles: study design, subject 
recruitment, subject enrollment, manuscript design/editing 
Dr. Lily Wong-Kisiel, MD 
 
200 1st Street SW 
 
Rochester, MN 55905 
 
(p) 507-284-0774 
 
(f) 507-284-0727 
 
wongkisiel.lily@mayo.edu   
Main responsibilities/Key roles: study design, subject 
recruitment, subject enrollment, manuscript design/editing 
Dr. Eric Payne, MD 
 
200 1st Street SW 
 
Rochester, MN 55905 
 
(p) 507-284-0774 

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(f) 507-284-0727 
 
payne.eric@mayo.edu 
Main responsibilities/Key roles: study design, subject 
recruitment, subject enrollment, manuscript design/editing 
 
PARTICIPATING STUDY SITES  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1 
STUDY OBJECTIVES 
1.1 Primary Objective 
The primary objective is to evaluate the non-inferiority of acetazolamide versus 
diazepam as the first-line therapy in children with ESES and the clinical diagnosis of 
continuous spike and wave in sleep (CSWS) or Landau-Kleffner syndrome (LKS). We 
hypothesize that there is no difference in the efficacy in acetazolamide compared to 
diazepam when used as the initial therapy in the treatment of ESES.   
 
The primary objective will be measured using the spike wave index (SWI), a measure 
of percentage of seconds containing a potentially epileptiform discharge (spikes and/or 
sharp waves) during slow wave sleep (Galanopoulou 2000). Baseline SWI prior to 
initiation of therapy will be compared to post-treatment SWI. The SWI will act as an 
electrographic measure of intervention.  Additional measures to assess clinical change 
will be the Vineland and Vanderbilt behavioral scales which we will use to compare 
baseline behavior/attention to post-treatment behavior/attention.  
1.2 Secondary Objectives 
The secondary objectives are to assess the frequency of clinical and electrographic 
relapse of ESES in children treated with long-term acetazolamide versus pulse diazepam 
therapy.  
2 
BACKGROUND AND RATIONALE  
2.1 Background on Condition, Disease, or Other Primary Study Focus 
The electroclinical syndromes of continuous spike and wave in slow wave sleep 
(CSWS) and Landau-Kleffner syndrome (LKS) are seen only in the pediatric population. 
Children affected are typically between the ages of 3 to 12 years of age with a peak onset 
of 5 to 7 years. It is felt that the continuous activation of epileptiform discharges (ESES) 
leads to developmental regression and loss of previously acquired skills. In  LKS, speech 
and language can be most severely affected and children will often develop an auditory 
agnosia. CSWS is associated with global regression of skills and higher seizure burden.  
In addition to the loss of skills, there are  behavioral abnormalities seen, including 
hyperactivity, inattention, aggressiveness, and autistic-like behaviors. The pattern of 
ESES is felt to self-resolve by adolescence in the majority of children.  However, the 
developmental milestones lost and behavioral effects will remain. Prior studies have 
shown that longer duration of ESES and earlier onset of ESES are associated with poorer 
cognitive outcomes, highlighting the need for early recognition and initiation of therapy 
(Rossi 1999, Scholtes 2005).  
 
There is no consensus regarding optimal therapy for these disorders and practice is 
based on small series and expert opinion. Therapies that are trialed in ESES include the 
antiepileptic medications, immunomodulatory therapies (steroids, IVIG, plasma 
exchange), dietary therapy (ketogenic diet, modified Atkins diet), and surgery (multiple 
subpial transections, lesionectomy/lobectomy). Therapy choice varies by institution and 

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anecdotal evidence.  
 
Acetazolamide is a well-tolerated medication and has minimal side effects compared to 
benzodiazepines and other therapies for ESES (Fine 2015, Veggiotti 2012). Furthermore, 
acetazolamide can be used as a chronic, rather than intermittent, medication.   
 
There have been no studies comparing the efficacy of acetazolamide to diazepam as 
first line therapy. Our goal is to compare the use of acetazolamide versus diazepam as 
first line therapy for newly diagnosed ESES in a prospective randomized non-inferiority 
trial in pediatric patients in the pediatric epilepsy monitoring unit. 
2.2 Study Rationale 
One of the agreed upon first line options for these children is high-dose diazepam (0.5 
mg/kg/day) which is typically effective in treatment of ESES, but has significant 
behavioral and cognitive side effects, necessitating brief, pulsatile, treatment periods 
(DeNegri 1995, Francois 2014, Sanchez-Fernandez 2013). Relapse when diazepam is 
discontinued occurs on over 50% of patients (Inustuka 2006).   
 
Our group has had success in using acetazolamide, a carbonic anhydrase inhibitor FDA 
approved for the treatment of epilepsy, in children with refractory ESES. The use of 
acetazolamide by our epilepsy group was inspired by a previous publication by Dr. 
Wirrell on the use of sulthiame, another carbonic anhydrase inhibitor used in the 
treatment of epilepsy, in the treatment of a child with CSWS (Wirrell 2006). However, 
sulthiame has been associated with lower cognitive performance at higher doses and this 
medication is not available in the US (Wirrell 2008).  
 
The antiepileptic properties of carbonic anhydrase inhibitors are felt to be related to pH 
shifts caused changes in HCO3- and CO2 in the neuronal environment. There are over 13 
known carbonic anhydrase isoforms with 11 found in the brain. Acetazolamide is a 
membrane permeable sulfonamide carbonic anhydrase inhibitor. The exact mechanism as 
an anticonvulsant has not been clearly elucidated (Ruusuvuori 2014). In vitro studies 
suggest that acetazolamide may alter the GABAA receptor dependent 
HCO3 efflux in the maintenance of epileptiform events and use of AZM in in vitro 
studies can reduce epileptiform discharges by reducing neuronal synchronization (Hamidi 
2015).  
 
We published a retrospective case series of 6 children treated with acetazolamide for 
refractory ESES and at initial follow-up 50% had significant improvement in their spike-
wave index (measure of ESES) (Fine 2015). SWI reduction was maintained in 50% of 
these children. In our unpublished data from that study, 2 additional children who did not 
meet our inclusion criteria for analysis had initial spike wave improvement when initiated 
on AZM for ESES recurrence.  
 
3 
STUDY DESIGN 
This study will be a prospective randomized open-label non-inferiority study comparing 

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acetazolamide to diazepam when used as the first line therapy in pediatric patients for the 
treatment of ESES. We hypothesize that there is no difference in the efficacy of 
acetazolamide compared to diazepam, which is the typical agreed upon first line therapy, 
in the treatment of the ESES disorders of CSWS/LKS. To determine the efficacy of these 
medications, we will be evaluating the spike-wave indices (SWI) which is a measure of 
ESES, as well as developmental assessments with Vanderbilt and Vineland 
questionnaires. We will additionally be evaluating for the frequency of ESES relapse in 
children on long-term acetazolamide therapy compared to diazepam therapy.  
 
 The study population will be pediatric patients with epilepsy aged 3 to 12 years, 
inclusive, with a diagnosis on EEG of ESES and a clinical diagnosis of CSWS/LKS. This 
specific age range has been chosen as this is the typical range of age of onset of ESES 
(Nickels 2008). Our target sample size will be 100 total patients recruited from Mayo 
Clinic Rochester We aim to randomize approximately 50 subjects to receive AZM and 50 
subjects to receive DZP.  
 
 The study location will be the inpatient Pediatric Epilepsy Monitoring Unit (PEMU). 
This is where the consent process, overnight EEG, randomization, behavioral 
assessments, and monitoring for side effects will occur. Additional evaluations may occur 
at visits with the subjects’ primary neurologist/epileptologist in the outpatient Pediatric 
Neurology clinic. The location will be the inpatient PEMU at Mayo Clinic Rochester, St. 
Marys Campus.  
 The entire study is expected to last approximately 3 years in duration (subject 
enrollment, data acquisition, data analysis, and manuscript preparation). For each 
individual participant, the approximate duration of the study is 6 months, including 
follow-up period.  
 
 The interventions to be performed include the prescription of either acetazolamide or 
diazepam after randomization (randomization to be performed by computer generated 
randomization program). There will be no blinding of the prescribing epileptologist, 
patient, or caregiver. Medication will be dispensed by the inpatient pharmacy while the 
subject is in the inpatient PEMU and then will be dispensed via the outpatient pharmacy 
on hospital dismissal. Medications will be given orally (PO).  
 
4 
SELECTION AND ENROLLMENT OF PARTICIPANTS  
4.1 Inclusion Criteria  
Subjects must meet all of the following inclusion criteria to participate in this study: 
• Child aged 3-12 years of age, inclusive. 
• ESES and clinical CSWS/LKS defined by all of the following (confirmed during 
inpatient PEMU evaluation): 
o SWI ≥50% during first hour of sleep 
o Bilateral synchrony of discharges during sleep 
o Clinical evidence of behavior and/or academic regression 

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o Daytime SWI ≤20% 
4.2 Exclusion Criteria  
All candidates for study enrollment meeting any of the following exclusion criteria at 
baseline evaluation will be excluded from study participation.  
• Previous treatment with benzodiazepine or acetazolamide for ESES 
• Current treatment with carbamazepine, phenytoin, oxcarbazepine, phenobarbital, 
vigabatrin  
• AED medication changes over the month prior to enrollment 
• Epileptic encephalopathy other than CSWS/LKS 
• Prior serious adverse reaction to benzodiazepines or acetazolamide 
• Sulfa allergy 
• Progressive underlying neurologic condition 
• Frequent seizures that would prevent the patient from maintaining a stable dose of 
medications 
• Female subjects who have begun menstruation (given risk of pregnancy) 
4.3 Study Enrollment Procedures  
• 
Candidates for study recruitment will be identified and informed of the study 
at the outpatient Pediatric Neurology appointment. At that time, the outpatient 
neurologist/epileptologist can inform the attending epileptologist on the 
PEMU service that there is a potential study candidate. Potential subjects will 
then be monitored in the PEMU, according to standard practice, and if ESES 
is confirmed on overnight EEG then the study will be further discussed and 
subjects will be consented.   
• 
Candidates who are ineligible for study enrollment and/or those who chose to 
not participate in this study will be documented in our “Screening Log.”  
• 
Once eligibility for enrollment in this study with confirmation of ESES is 
performed, then consent of the subject/parent will occur. We have prepared 
signed informed consent documents which will be discussed with 
subject/caregivers and signed by parents/caregivers. We additionally will have 
informed assent for children who are unable to adequately provide informed 
consent.   
• 
Medication randomization will occur after consent process is performed. 
Subjects will be entered into a spreadsheet which contains computer generated 
randomization and assigns the subject to either the AZM or DZP group. No 
blinding will occur.  

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5 
STUDY INTERVENTIONS  
5.1 Interventions, Administration, and Duration  
The intervention to be performed in this study is the randomization to receive either 
diazepam or acetazolamide. Subjects will also undergo behavioral rating scales at 
baseline, at 4-5 weeks following medication initiation, and potentially at 8-10 weeks if 
they cross-over to the other medication. 
The dosing of diazepam is 0.5 mg/kg to a maximum dose of 20 mg by mouth (PO) each 
evening. At hospital discharge, the subject will be given a prescription at their target dose 
which will be dispensed by the outpatient pharmacy. 
Potential side effects of diazepam include agitation, sedation, mood changes. If there is 
concern for medication toxicity or side effects, the dose of diazepam can be reduced at 
the attending neurologist/epileptologist’s discretion.  The side effects experienced and 
new dose must be clearly documented.  
Diazepam is a medication in the benzodiazepine class that is FDA approved for the 
treatment of epilepsy in children down to 6 months of age. The dosing used in the 
treatment of ESES is higher than typically used in the treatment of epilepsy.  However, 
this regimen and dose is well-agreed upon in the epilepsy literature and is in line with our 
standard of care in the treatment of this syndrome (Inutsuka 2006, Kramer 2009, Nickels 
2008, Sanchez Fernandez 2014)  
The dosing of acetazolamide will be 8-10 mg/kg up to a maximum dose of 375 mg by 
mouth (PO) divided twice daily X 1 week, then increased to 11-16 mg/kg to a maximum 
dose of 750 mg by mouth divided twice daily thereafter. At hospital discharge, the 
subject will be given a prescription and instructions for titration to goal dose, which will 
be dispensed by the outpatient pharmacy. 
Potential side effects of acetazolamide include decreased appetite, nausea, diarrhea, 
paresthesias (tingling in hands, feet, around mouth), funny taste to carbonated beverages, 
and risk of kidney stones (in combination with certain medications). If there is concern 
for medication toxicity or side effects, then the dose of acetazolamide can be reduced at 
the attending neurologist/epileptologist’s discretion.  The side effects experienced and 
new dose must be clearly documented. 
Acetazolamide is a sulfonamide carbonic anhydrase inhibitor that is FDA approved in the 
treatment of epilepsy in patients 12 years and older. It is approved for the treatment of 
multiple epilepsy types. While it is has not been FDA approved to be used in children, 
there are multiple reports in the literature regarding its successful and safe use (Irahara 
2011, Go 2009, Vradkar 2003, Katayama 2002). Additionally, the use of acetazolamide 
in the treatment of ESES has been studied previously and is in line with our standard of 
care in the treatment of this syndrome (Pisani 1995, Fine 2015).  

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5.2 Handling of Study Interventions  
The medication will be provided by the outpatient pharmacy at Mayo Clinic Rochester. 
Subjects/caregivers may wish to have their outpatient prescription filled at a local 
pharmacy. The cost of the medications to be used in this study will not be paid for 
through research funds, since the treatment using either medication is in line with our 
standard of care in the treatment of this syndrome. Medication will be dispensed to the 
subject and payment will be the subject/caregiver responsibility.  
5.3 Concomitant Interventions 
5.3.1 Allowed Interventions 
• Subjects may receive their prescribed seizure rescue medications as needed (i.e. 
diazepam rectal gel, diazepam buccal solution, lorazepam buccal solution, 
midazolam intranasal solution, clonazepam tablets, etc.) 
• 
Subjects may take their previously prescribed antiepileptic therapy, provided that 
the there are no dose adjustments made prior to, during, or after the enrollment 
period.  
 
5.3.2 Required Interventions  
• Baseline overnight EEG in the PEMU 
• Baseline Vineland scale 
• Baseline Vanderbilt Parent scale 
• Follow-up PEMU stay or ambulatory 24-hour EEG at 4-5 weeks post medication 
initiation (and at 8-10 weeks if cross-over) 
• Follow-up Vineland scale at 4-5 weeks post medication initiation (and at 8-10 
weeks if cross-over) 
• Follow-up Vanderbilt Parent scale at 4-5 weeks post medication initiation (and at 8-
10 weeks if cross-over) 
 
5.3.3  Prohibited Interventions 
• The use of the following antiepileptic agents is prohibited during this study, due 
to known exacerbation of ESES associated with these medications:  
o oxcarbazepine,  
o carbamazepine,  
o phenytoin,  
o phenobarbital,  
o vigabatrin,  

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5.4 Adherence Assessment  
Adherence to the study regimen will be defined as those study participants who complete 
both baseline EEG and behavioral scales and post-intervention EEG and behavioral 
scales. As medication will be dispensed to subjects, we cannot ensure medication 
compliance. If participants do not complete the follow-up testing, then they will be 
considered withdrawn from this study and their information will not be analyzed. 
Adherence will need to be 100% to all required study interventions in order for subjects 
to count towards data analysis.  
 
6 
STUDY PROCEDURES 
6.1 
Schedule of Evaluations 
1) Part 1 
a. Patients with suspected CSWS/LKS will have education regarding syndrome, 
treatment, and possible enrollment into study discussed prior to PEMU admission 
b. Patient will be admitted to Pediatric Epilepsy Monitoring Unit (PEMU) for 
overnight admission to confirm presence of ESES, consistent with standard 
practice of care 
c. After confirmation of ESES on EEG, parental consent and child assent will be 
completed (day 2 of admission) by the supervising consultant on the PEMU 
service to provide clinical care 
d. Patients meeting above inclusion/exclusion criteria with be randomly selected to 
receive either: 
i. Diazepam 0.5 mg/kg to a maximum dose of 20 mg by mouth each 
evening, or 
ii. Acetazolamide 8-10 mg/kg  to a maximum dose of 375 mg by mouth 
divided twice daily X 1 week, then increase to 11-16 mg/kg to a maximum 
dose of 750 mg by mouth divided twice daily thereafter 
e. Randomization will be completed through computer program.  Patient/family and 
consenting provider will not be blinded to treatment. 
f. Vanderbilt and Vineland assessments will be completed at the time of enrollment 
to assess focus, attention, and behavior (day 2 of PEMU admission, prior to 
discharge) 
i. Should the scoring on Vanderbilt Parent scales rate positive then a 
Vanderbilt Teacher scale will be sent home with the family 
ii. Vanderbilt Teacher scale will be mailed back to study staff for scoring 
iii. If both Parent and Teacher scales are positive then a referral to Child 
Psychiatry will be offered to family 

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g. The first hour of overnight sleep EEG will be independently reviewed by 2 
pediatric epileptologists, blinded to history and treatment for confirmation for 
research.  
i. They will determine SWI (calculated as percent of time containing spike 
wave discharge during the first hour of sleep) 
ii. They will document presence of bilateral synchronous discharges 
2) Part 2 
a. All other medications will be held at steady doses from 1 month prior to 
enrollment and continue at steady doses until return admission to PEMU for 
overnight EEG. 
b.  Rescue medication can be given as needed for breakthrough seizures 
c. Study medications (diazepam or acetazolamide) can be reduced by the attending 
epileptologist if the child is experiencing unacceptable side effects. 
 
3) Part 3 
a. Patient will return to PEMU for overnight EEG 4-5 weeks after initial assessment, 
consistent with current standard of care. An alternative option will be to undergo 
24-hour ambulatory EEG with outpatient follow-up visit following EEG. 
b. On the day of admission/return visit: 
i. Vanderbilt and Vineland assessments will be completed at the time of 
admission to assess focus, attention, and behavior  
1. Should the scoring on Vanderbilt Parent scales rate positive then a 
Vanderbilt Teacher scale will be sent home with the family 
2. Vanderbilt Teacher scale will be mailed back to study staff for 
scoring 
3. If both Parent and Teacher scales are positive then a referral to 
Child Psychiatry will be offered to family 
ii. Parents will be questioned on whether they perceive the child’s regression 
as improved, worse, or no change 
iii. Presence of side effects will be determined based: medication reduced, 
medication stopped, full medication course completed 
c. The first hour of the overnight sleep EEG will be reviewed by the supervising 
consultant on the PEMU service to provide clinical care 
i. Improvement will be defined as 
1. Mild improvement: decrease in SWI by 20-49% 
2. Significant improvement: decrease in SWI by ≥50% 
ii. If no improvement in EEG seen, the patient will be crossed over to the 
other medication 
iii. If improvement in EEG is seen, continuation or weaning of 
benzodiazepine or acetazolamide will be completed at the primary 
neurologist’s discretion 

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iv. The patient will be monitored clinically for signs or relapse and, if they 
occur, readmitted to PEMU for confirmation of recurrence of ESES. 
 
d. The first hour of the overnight sleep EEG will be reviewed by 2 pediatric 
epileptologists, blinded to history and treatment for confirmation for research 
4) Part 4 
a. For those who crossover to the other medication, the patient will return to PEMU 
for overnight EEG 4-5 weeks after previous assessment or undergo 24-hour 
outpatient ambulatory EEG followed by outpatient return visit, consistent with the 
current practice of care 
b. On the day of admission to the PEMU/or return visit: 
i. Vanderbilt and Vineland assessments will be completed at the time of 
admission to assess focus, attention, and behavior 
1. Should the scoring on Vanderbilt Parent scales rate positive then a 
Vanderbilt Teacher scale will be sent home with the family 
2. Vanderbilt Teacher scale will be mailed back to study staff for 
scoring 
3. If both Parent and Teacher scales are positive then a referral to 
Child Psychiatry will be offered to family 
ii. Parents will be questioned on whether they perceive the child’s regression 
as improved, worse, or no change 
iii. Presence of side effects will be determined based: medication reduced, 
medication stopped, full medication course completed 
c. The first hour of the EEG will be reviewed by the supervising consultant on the 
PEMU service to provide clinical care 
i. Improvement will be defined as  
1. Mild improvement: decrease in SWI by 20-49% 
2. Significant improvement: decrease in SWI by ≥50% 
ii. Additional medication management will be completed at the primary 
neurologist’s discretion 
d. The first hour of the overnight sleep EEG will be reviewed by 2 pediatric 
epileptologists, blinded to history and treatment for confirmation for research 
6.2 Description of Evaluations  
6.2.1 Screening Evaluation 
Screening   
Potential candidates will be identified in the outpatient Child Neurology clinic. At 
that time, this study may be discussed with subjects and their families as an 
introduction; however, screening will not take place until admission to the PEMU 
occurs.  
 

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Once potential candidates are admitted to the PEMU, they will undergo overnight 
EEG as part of their evaluation for ESES (routine standard of care for children with 
suspected ESES). If an ESES pattern is identified and other inclusion criteria are met, 
then the study will be discussed and consenting will occur.  
 
Overnight EEG must be performed at the time of study enrollment for a subject to 
participate in this study.  
 
Consenting Procedure 
Informed consent will take place after identification of eligible candidates via 
screening EEG. All study staff will be able to consent participants into the study. The 
informed consent will be signed by the parents/guardians after the consent procedure. 
An assent form is also available for children who can participate in the assent process. 
Once consent is obtained, this document will be scanned into the electronic medical 
record (EMR) and a copy of the signed consent will be kept in a locked cabinet with 
other confidential study materials.  
  
6.2.2 Enrollment, Baseline, and/or Randomization 
Enrollment 
Enrollment date in this study will be considered when the candidate/proxy has signed 
informed consent after meeting inclusion criteria.  
 
Baseline Assessments 
Following enrollment in this study, participants and parents will complete baseline 
behavioral assessments (on Day 2 of PEMU admission). These assessments include 
the Vanderbilt Assessment Scales (National Institute for Children’s Health Quality), a 
measure of childhood behavior, primarily used to rate the symptoms of ADHD 
(attention deficit hyperactivity disorder), but also measures symptoms of oppositional 
defiant disorder, conduct disorder, depression, and anxiety. An additional assessment 
is the Vineland Adaptive Behavioral Scale (Pearson), which measures 
communication, social skills, motor skills, daily living skills, and adaptive living 
skills. 
 
If scores on the Vanderbilt Parent Informant scales rate positive then Teacher scales 
will be sent home with families to be mailed back to study staff. If both scales rate 
positive, then a referral to Child Psychiatry will be offered.  
 
Randomization 
Following enrollment, the subjects will be assigned a study number. This number will 
then be entered into a computer program which will then randomize them to receive 
either of the 2 study medications (AZM or DZP). 
 
Randomization must occur following enrollment in this study at the time of initial 
EEG. 
 

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6.2.3 Follow-up Visits 
• Visit 2 (4-5 weeks after enrollment/initial assessment): 
o Return to PEMU for overnight EEG or 24-hour outpatient ambulatory 
EEG followed by outpatient return visit, according to standard practice 
of care  
o On the day of admission/or outpatient return visit: 
 Vanderbilt and Vineland assessments will be completed  
 Should the scoring on Vanderbilt Parent scales rate positive 
then a Vanderbilt Teacher scale will be sent home with the 
family 
 Vanderbilt Teacher scale will be mailed back to study staff for 
scoring 
 If both Parent and Teacher scales are positive then a referral to 
Child Psychiatry will be offered to family 
 Parents will be questioned on whether they perceive the child’s 
regression as improved, worse, or no change 
 Evaluation of side-effects 
o The first hour of the overnight sleep EEG will be reviewed by the 
supervising consultant on the PEMU service to provide clinical care 
 Improvement will be defined as 
• Mild improvement: decrease in SWI by 20-49% 
• Significant improvement: decrease in SWI by ≥50% 
 If no improvement in EEG seen, the patient will be crossed 
over to the other medication 
 If improvement in EEG is seen, continuation or weaning of 
benzodiazepine or acetazolamide will be completed at the 
primary neurologist’s discretion 
 The patient will be monitored clinically for signs of relapse 
and, if they occur, readmitted to PEMU for confirmation of 
recurrence of ESES, according to standard practice of care. 
o The first hour of the overnight sleep EEG will be reviewed by 2 
pediatric epileptologists, blinded to history and treatment for 
confirmation for research 
• Visit 3 ( 8-10 weeks after enrollment) 
o For those who crossover to the other medication, the patient will return 
to PEMU for overnight EEG or undergo 24-hour outpatient 
ambulatory EEG followed by an outpatient return visit, according to 
standard practice of care.  
o On the day of admission/or outpatient return visit: 
 Vanderbilt and Vineland assessments will be completed 

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 Should the scoring on Vanderbilt Parent scales rate positive 
then a Vanderbilt Teacher scale will be sent home with the 
family 
 Vanderbilt Teacher scale will be mailed back to study staff for 
scoring 
 If both Parent and Teacher scales are positive then a referral to 
Child Psychiatry will be offered to family 
 Parents will be questioned on whether they perceive the child’s 
regression as improved, worse, or no change 
 Evaluation of side-effects 
o The first hour of the EEG will be reviewed by the supervising 
consultant on the PEMU service to provide clinical care 
 Improvement will be defined as  
• Mild improvement: decrease in SWI by 20-49% 
• Significant improvement: decrease in SWI by ≥50% 
 Additional medication management will be completed at the 
primary neurologist’s discretion 
o The first hour of the overnight sleep EEG will be reviewed by 2 
pediatric epileptologists, blinded to history and treatment for 
confirmation for research 
6.2.4 Completion/Final Evaluation 
Participants will have completed the study investigations following either visit 2 or 3. 
They will have regular follow-up with their primary neurologist/epileptologist for 
continued medication management following study completion at the discretion of 
their primary neurologist.  
 
Should a participant choose to withdraw from this study, then no additional 
evaluations or interventions are required for research. They should continue to be 
seen by their primary neurologist regarding further management.  
 
Following study termination, continued care and management, including evaluation 
for concerns of possible relapse of ESES, will be provided by the primary 
neurologist/epileptologist.   
7 
SAFETY ASSESSMENTS  
Intervention 
Potential adverse 
experience 
Criteria for 
modification of 
intervention 
Electroencephalogram 
• Scalp irritation 
• Evidence of skin 
irritation 
Acetazolamide 
• Gastrointestinal upset 
• Frequent diarrhea, 

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concern for 
dehydration 
• Decreased appetite 
• Weight loss 
• Rash, Stevens-Johnson 
syndrome 
• New rash not felt 
to be due to other 
causes (such as 
atopic dermatitis) 
Diazepam 
• Behavior/mood change 
• Violent/aggressive 
behaviors 
• Sleep disturbance 
• Insomnia/excessive 
sedation 
 
 
7.1 Specification of Safety Parameters 
Subject safety will be monitored at inpatient PEMU visits. Additionally, subjects/families 
will be instructed on potential side effects of medication and if concern for medication 
side effects or toxicity will be instructed to inform study staff immediately.  
 
For example, if a new rash is noted, the patient will be advised to see his/her primary care 
physician and the primary neurologist/epileptologist will be notified if the rash is not felt 
to be due to atopic dermatitis.   
7.2 Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters 
Subject safety will be monitored at inpatient PEMU visits. Additionally, subjects/families 
will be instructed on potential side effects of medication and if concern for medication 
side effects or toxicity will be instructed to inform study staff immediately.  
7.3 Adverse Events and Serious Adverse Events  
Potential adverse events that can occur in this study are medication side effects, 
worsening of clinical seizures, and worsening of ESES. These are potential events that 
can occur in the routine treatment of a child with ESES regardless of being included in 
this study.  
Potential side effects of diazepam include sedation, mood changes, and agitation. 
Potential side effects of acetazolamide include decreased appetite, nausea, diarrhea, 
paresthesias (tingling in hands, feet, around mouth), funny taste to carbonated beverages, 
and risk of kidney stones (in combination with certain medications), rash, and Stevens 
Johnson syndrome. If there is concern for medication toxicity or side effects, then the 
doses of diazepam or acetazolamide can be reduced or discontinued at the attending 
epileptologist’s discretion. 
Adverse events will be logged in our event log that will be maintained as part of our data 
collection. Adverse events that are deemed serious will be immediately reported to the Principal 
Investigator who will determine the appropriate steps and with forward the event on to our IRB 
for documentation.  

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There should be no potential serious adverse events (SAE) directly related to  
participating in this study as the interventions to be performed are the same as those 
performed in a routine PEMU visit including the use of overnight EEG, administration of 
benzodiazepines, and administration of antiepileptic medications. The only intervention 
that is not routinely performed in the PEMU are the administration of behavioral rating 
scales. 
7.4 Reporting Procedures 
All serious adverse events or events that are felt to be outside the expected potential 
adverse experiences that a subject may encounter by taking part in this study will be 
reported to the PI by study staff within 24 hours (Sunday-Thursday) or 48 hours (Friday-
Saturday). The PI will then investigate the event and log the event with the IRB of record.  
7.5 Follow-up for Adverse Events 
All AE/SAEs will be followed through to resolution or until the investigators attribute the 
AE/SAEs to a cause other than the study drugs or assesses them as chronic or stable. This 
period may go beyond the proposed study/follow-up period for an individual subject.  
7.6 
Safety Monitoring 
Safety monitoring will be performed per our DSMP plan. The PI will oversee subject 
safety and reporting any unexpected AE to the IRB. All AEs will be documented in our 
collection logs.  
8 
INTERVENTION DISCONTINUATION  
Potential reasons for individual study discontinuation include: 
 Voluntary subject withdrawal 
 Adverse medication effects necessitating withdrawal 
 Worsening of ESES requiring deviation from study protocol 
 Worsening of ESES requiring use of alternative therapy 
 Worsening of seizures requiring change in other anti-seizure medications 
 No follow up EEG 
 No follow up behavioral scales 
 
Following discontinuation, if for reasons of medication toxicity or worsening of ESES 
then the subjects will continue to be followed (with permission) and be seen by their 
attending Pediatric Neurologist for continued management of their ESES. If the subject 
agrees, then information may be collected such as interventions performed at that time 
and in the future (i.e. future EEGs, medication interventions, etc.). Additional 
information to be collected on subjects who withdraw from this study include 
cognitive/behavioral outcomes on those not treated with diazepam or acetazolamide and 
those treated with brief courses of either/both medications.  

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9 
STATISTICAL CONSIDERATIONS  
9.1 General Design Issues  
Our statistical hypothesis is that there is no difference in the efficacy of acetazolamide 
compared to diazepam in the treatment of CSWS/LKS.  
 
We have chosen a non-inferiority study as our study design. The reason being that we 
believe that acetazolamide is “not inferior” to diazepam, “our standard,” in the treatment 
of ESES. Acetazolamide may have benefits over diazepam in that the side effect profile 
is better tolerated in children. Additionally, it is a medication that can be used for long-
term rather than short cycles. 
 
9.2 Sample Size and Randomization 
Sample size calculations 
-Sample size, n, based on formula: 
n = f(α, β) × [πs × (100 − πs) + πe × (100 − πe)] / (πs − πe − d)2 
Test Significance level , alpha (one-sided): 0.05 
Power (1-beta): 80% (0.8) 
Non-inferiority limit, d: 0.15 (15%) 
Percentage ‘success’ in control group (diazepam): 30%-50% (based on literature) 
Percentage ‘success’ in experimental group (acetazolamide): 50% (based on our prior review) 
n= 48-276 (based on 30-50% success rate in diazepam “control” group) 
 (i.e. 24 – 138 per group) 
 
-Two test group of equivalence in proportions (large equal n’s) 
Test Significance level , alpha (one-sided): 0.05 
Standard proportion, πs: 0.5 (50% expected response rate to diazepam) 
Equivalence limit difference, πT  - πs, Δ0: 0.2 (20% difference limit) 
Test expected proportion, πT : 0.5 (50% expected response rate to acetazolamide) 
Expected difference, πT  - πs, Δ1 : 0.0 

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Power (1-beta): 80% (0.8) 
n per group : 78 subjects 
Numbers needed to treat (NNT) analysis: 
Percentage of patients who experienced side effect on diazepam in literature: 25% 
Percentage of patients who experienced side effects on acetazolamide in our review: 0% 
Absolute risk reduction: 33.33% 
NNT: 3 
95%CI (2.3-4.4) 
 
9.2.1 Treatment Assignment Procedures 
Subjects will be randomized to either AZM or DZP therapy after study enrollment. 
Randomization will occur via computer generated program which will assign the 
study medication. Neither the participants nor the study investigator will be blinded to 
the study medication being administered. There will be no stratification.  
9.3 Interim analyses and Stopping Rules 
No interim analyses are planned.  
 
Potential reasons for stopping this study include: 
 Slow subject accrual 
 Loss of subject follow up 
 High attrition rate 
 Significant number of adverse events  
9.4 Outcomes  
9.4.1 Primary outcome   
The primary outcome measure is the non-inferiority of acetazolamide compared to 
diazepam as first-line therapy in ESES.  
 
This will be measured using EEG data (SWI measurement) recorded at baseline and 
compared to the EEG data recorded at PEMU visit 2 (and if applicable visit 3). 
 
This will also be measured clinically using the behavioral scales (Vineland and 
Vanderbilt) recorded at baseline and compared to the subsequent scales completed at 
PEMU visit 2 (and if applicable visit 3).  

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9.4.2 Secondary outcomes   
The secondary outcome is the frequency of relapse of ESES that occurs in children on 
long-term acetazolamide therapy compared to short-cycle diazepam. This information 
will be obtained from the EEG data and the behavioral data and will be obtained from 
information seen from baseline, visit 2, visit 3, and in the follow-up period.  
9.5 Data Analyses 
Data analyses will be performed with the assistance of a Health Sciences Research 
Statistician at Mayo Clinic in Rochester.  
10 
DATA COLLECTION AND QUALITY ASSURANCE 
10.1 Data Collection Forms 
Data will be collected and entered into one standardized form. Subjects will be assigned a 
study ID and demographic information will be entered into a data collection form (i.e. 
RedCap). For confirmation of ESES and SWI, 2 pediatric epileptologists who will be 
blinded to subjects’ diagnosis and intervention will be asked to review EEG with only the 
Study ID as the identifier. Epileptologists will be able to enter the interpretation of EEG 
into the collection sheet by using subject study ID but will not be able to enter or see 
other identifying information. The remainder of data collection will be entered by other 
study staff who do not need to be blinded to therapy.  
 
Confidentiality of the data will be maintained as this data collection tool will be password 
protected and only study staff will have access. All study information will be kept in a 
folder on a secure, password protected server as well.  
10.2 Data Management  
Mayo Clinic Rochester investigators will be involved in data collection.  
Data collection will occur in a centralized form where all study investigators can access. 
One such possibility is RedCap where users can log-in securely and enter data.  
10.3 Quality Assurance  
10.3.1 
Training 
All study staff have undergone Human Subjects Protection training.  
10.3.2 Protocol Deviations 
Protocol deviations will be documented and submitted to the IRB of record for 
review.  
10.3.3 Monitoring 
Protocol compliance will be monitored by the PI. The PI will receive monthly updates 
from investigators regarding protocol compliance and any data quality concerns.  

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11 
PARTICIPANT RIGHTS AND CONFIDENTIALITY  
11.1 Institutional Review Board (IRB) Review 
This protocol and the informed consent document (uploaded separately) and any 
subsequent modifications will be reviewed and approved by the IRB or ethics committee 
responsible for oversight of the study.  The consent form should be separate from the 
protocol document.  
11.2 Informed Consent Forms 
A signed consent form will be obtained from each participant.   For participants who 
cannot consent for themselves, such as those with a legal guardian (e.g. person with 
power of attorney), this individual must sign the consent form. The consent form will 
describe the purpose of the study, the procedures to be followed, and the risks and 
benefits of participation. A copy will be given to each participant or legal guardian and 
this fact will be documented in the participant’s record.  
11.3 Participant Confidentiality  
Any data, forms, reports, video recordings, and other records will be identified only by a 
participant identification number to maintain confidentiality.  All records will be kept in a 
password protected server.  All computer entry and networking programs will be done 
using participant IDs only.  
11.4 Study Discontinuation  
The study may be discontinued at any time by the IRB, the OHRP, the FDA, or other 
government agencies as part of their duties to ensure that research participants are 
protected.  
12 
ETHICAL CONSIDERATIONS 
This study is being conducted under the guiding ethical principles of respect for persons, 
beneficence, and justice as set forth in the report of The National Commission for the 
Protection of Human Subjects of Biomedical and Behavioral Research titled “Ethical 
Principles and Guidelines for the Protection of Human Subjects of Research,” also known 
as “The Belmont Report.” 
13 
PUBLICATION OF RESEARCH FINDINGS 
Information regarding this study will be available publically on Clinicaltrials.gov. Study 
information will be updated regarding subject enrollment and preliminary information as 
available on this website. The data obtained from this study will be published for the 
scientific community. 
14 
REFERENCES 
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status epilepticus in slow-wave sleep. Epilepsia. 2015 Sep;56(9):e134-8.  
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diazepam for electrical status epilepticus during slow wave sleep in children. Pediatr 
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5. Go T. Effect of antiepileptic drug polytherapy on urinary pH in children and young 
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2008 Jun;15(2):50-60.  
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Kothare SV, Riviello JJ Jr, Loddenkemper T. Long-term response to high-dose 
diazepam treatment in continuous spikes and waves during sleep. Pediatr Neurol. 
2013 Sep;49(3):163-170. 
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Loddenkemper T. Treatment for continuous spikes and waves during sleep (CSWS): 
survey on treatment choices in North America. Epilepsia. 2014 Jul;55(7):1099-108. 
15. Scholtes FB, Hendriks MP, Renier WO. Cognitive deterioration and electrical status 
epilepticus during slow sleep. Epilepsy Behav. 2005 Mar;6(2):167-73. 
16. Varadkar S, Duncan JS, Cross JH. Acetazolamide and autosomal dominant nocturnal 
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syndrome): an update. Epileptic Disord. 2012 Mar;14(1):1-11. 
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15 
SUPPLEMENTS/APPENDICES