Diazepam for outpatient treatment of nonconvulsive status epilepticus in pediatric patients with Angelman syndrome

Epilepsy & Behavior 82 (2018) 74–80

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Diazepam for outpatient treatment of nonconvulsive status epilepticus in pediatric patients with Angelman syndrome Lila Worden a, Olivia Grocott b, Amanda Tourjee b, Fonda Chan c, Ronald Thibert a,b,⁎ a b c

Department of Pediatric Neurology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, United States Angelman Syndrome Clinic, Massachusetts General Hospital, 175 Cambridge Street Suite 340, Boston, MA 02114, United States Department of Neurology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, United States

a r t i c l e

i n f o

Article history: Received 28 December 2017 Revised 21 February 2018 Accepted 25 February 2018 Available online xxxx Keywords: Nonconvulsive status epilepticus Atypical absence Angelman syndrome Pediatric Benzodiazepine Diazepam

a b s t r a c t Nonconvulsive status epilepticus (NCSE) is present in multiple pediatric neurogenetic syndromes with epileptic encephalopathies. While intravenous (IV) medications are used inpatient for treatment of critical illness-related NCSE, there is no consensus on treatment of ambulatory NCSE. Up to 50% of patients with Angelman syndrome (AS) have NCSE with myoclonic or atypical absence status. Here we report our experience in pediatric patients with AS and NCSE treated outpatient with a tapering course of oral diazepam. We conducted a chart review of 104 patients seen in the Angelman Syndrome Clinic at Massachusetts General Hospital from January 2008 to March 2017, who met the criteria. Response to treatment was defined as cessation of NCSE symptoms with electroencephalogram (EEG) confirmation when possible. Twenty-one patients with NCSE were identified, and 13 patients (9 male) with 25 episodes of NCSE were included. Mean age at NCSE episode was 5 years 4 months (15 months–12 years). Six patients had one episode of NCSE, and 7 patients had recurrent episodes (mean: 2.7; range: 2–4). Median diazepam treatment was 6 days (4–12 days), with a mean dose of 0.32 mg/kg/day divided over 2–3 administrations, decreased every 2 days. Nine episodes required multiple courses; however, oral diazepam alone was ultimately successful in 80% (20/25) of NCSE episodes. Oral diazepam was well-tolerated with no major side effects. A short course of oral diazepam is well-tolerated and effective in patients with AS who have ambulatory NCSE. It may be considered prior to escalating to inpatient care in AS and possibly other epilepsy syndromes. © 2018 Elsevier Inc. All rights reserved.

1. Introduction Nonconvulsive status epilepticus (NCSE) was first described in modern times by W.G. Lennox in patients with chronic epilepsy in 1945 [1], though there is historical evidence of a case description as early as the year 1501 [2]. While initially described in ambulatory patients, NCSE has been increasingly recognized in the critical care setting in patients with encephalopathy. Overall population incidence is estimated at 5.6 to 18.3 per 100,000 persons per year [3]. There is no universally accepted definition for NCSE. One of the most common definitions is a condition of prolonged electrographic seizure activity without convulsions resulting in nonconvulsive clinical symptoms [3]. Many use 30 min of epileptic activity as an operational definition for NCSE in studies, though the time frame is arbitrary. Nonconvulsive status epilepticus was previously divided into complexpartial status epilepticus or absence status epilepticus based on focal or generalized discharges. Some groups advocate for differentiating ⁎ Corresponding author at: Angelman Syndrome Clinic, Massachusetts General Hospital, 175 Cambridge Street Suite 340, Boston, MA 02114, United States. E-mail addresses: [email protected] (L. Worden), [email protected] (A. Tourjee), [email protected] (F. Chan), [email protected] (R. Thibert).

https://doi.org/10.1016/j.yebeh.2018.02.027 1525-5050/© 2018 Elsevier Inc. All rights reserved.

ambulatory or “proper” NCSE from NCSE that occurs in the setting of coma [4,5]; other groups advocate classification of NCSE by etiology, separating those associated with chronic conditions such as epilepsy or neurodegenerative disorders from those associated with acute conditions such as postcardiac arrest, traumatic brain injury, or encephalitis as the morbidity and mortality differ significantly [6]. While there are many iterations of NCSE classification schemes, there is a clear difference in those that are epilepsy-related in the ambulatory setting. In ambulatory patients with NCSE, a preexisting diagnosis of epilepsy is present in 62% of patients, compared with 6% of patients who are comatose or in critical care settings; inversely, mortality is 3–6% for epilepsy-related ambulatory NCSE vs. 27–61% for critical care NCSE in adults [5,7]. While the NCSE literature had been dominated by a relatively recent explosion of critical illness-related NCSE, 50% of NCSE cases occur in patients with epilepsy [3]. Nonconvulsive status epilepticus occurs with increased frequency in certain pediatric genetic epilepsy syndromes or epileptic encephalopathies such as the following: approximately 50% of patients with Angelman syndrome (AS) [8–14], 40% of patients with Dravet syndrome [15,16], 75–85% of patients with Lennox–Gastaut [15,17], and almost all children with Ring Chromosome 20 syndrome [3,18]. Even benign childhood epilepsy syndromes are

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Table 1 Clinical and EEG findings of patients. Pt

Sex AS subtype

Age

Clinical presentation

Trigger

EEG findings with % of EEG with epileptiform discharges

Seizure Treatment treatment

2nd course

1

M

1 year 3 months 1 year 4 months

Somnolent, tremors, decreased social interaction Somnolent, decreased social interaction

Recent viral illness and new seizure Recent viral illness and new seizure

–

LGIT

N

LGIT

1 year 11 months

Fatigue

Worsening GI dysfunction

LGIT

DZP 6 day taper starting at 0.26 mg/kg/day divided BID

Ya

1 year 8 months

Atonic seizures

Viral illness

95%, 700 μV frontally predominant generalized spike and wave at 1–2.5 Hz 50%, 700 μV frontally predominant generalized spike and wave at 2–2.5 Hz –

DZP 6 day taper starting at 0.22 mg/kg/day divided BID DZP 9 day taper starting at 0.3 mg/kg/day divided BID

LGIT

Y

1 year 6 months

Pallor, increased drooling, “not himself”

Carnival trip

–

LEV

2 years 7 months

Motor regression, increased seizure frequency, fatigue

–

LEV

2 years 11 months 3 years 4 months

Prolonged postictal period after multiple GTCs

–

N50%, high amplitude frontally predominant generalized spike and wave at 1–1.5 Hzc 80%, 600 μV generalized spike–wave discharges

DZP 6 day taper starting at 0.26 mg/kg/day divided BID Added CLB DZP 9 day taper starting at 0.29 mg/kg/day divided BID Increased LEV DZP 6 day taper starting at 0.57 mg/kg/day divided TID

–

3 years 8 months

Somnolent, motor regression, poor sleep, decreased communication, atonic seizures, increased myoclonus Appeared “off”, dry heaving, myoclonus

4 years 2 months

Fatigue, staring episodes, motor regression, myoclonus

Sleep problems, gastrointestinal illness

5 years 4 months

Staring frequently, myoclonus, increased seizure frequency

Tooth infection

5 years 10 months 6 years 4 months

Somnolent, developmental regression

Aspiration pneumonia

“Behavioral changes” and drop seizures

4 years 4 months

2

M

Deletion

Deletion

3

M

Deletion

4

M

Deletion

5

6

7

8

9

F

M

M

M

F

Deletion

Deletion

Deletion

Deletion

Deletion

–

N95%, 750 μV frontally predominant generalized spike and slow wave discharges at 1.5–2 Hz N90%, 800 μV frontally predominant generalized spike and slow wave discharges at 1.5–2 Hz “Frequent bursts of generalized spike and slow wave activity”c

–

–

–

CLB, VPA

70%, 700 μV generalized spike and wave discharges at 2–2.5 Hz –

CLB, LTG

Decreased CLB dose

–

CLB, LTG

Fatigue, constipation

–

CLB, LEV, LGIT

6 years 1 month

Sleep disturbance

LEV wean

90%, 1000 μV left frontal predominant generalized spike and slow wave at 1.5–2 Hz –

7 years 8 months

Developmental regression, loss of motor skills, poor balance

Allergies

CLB, LEV, LGIT

6 years 0 months

Increased absence seizures

Poor sleep, constipation

50%, 650 μV generalized spike and slow wave discharges at 2–2.5 Hz –

6 years 11 months

Fatigue, malaise, poor balance, decreased social interactions and communication

Recent sinus infection

80%, 3 Hz generalized spike and wave activity

LEV, LGIT, VPA

7 years 1 month

Decreased alertness, increased seizure frequency

–

LCM, LEV, TPM

8 years 9 months

Fatigue, increased seizure frequency

–

N95% frontally predominant generalized spike and wave discharges at 1–2 Hz N95%, 1000 μV generalized spike and wave discharges at 1.5–2 Hz

7 years 4 months

Decreased activity, increased seizure frequency, falling

–

50–60%, 700 μV generalized frontally predominant spike and wave discharges at 2.5–3 Hz

CLB

CLB, LEV

LEV, LGIT, VPA

DZP, LEV, LTG, VPA

CLB, LTG

N

Y

N

DZP 9 day taper starting at 0.38 mg/kg/day divided BID Added LEV DZP 6 day taper starting at 0.25 mg/kg/day divided BID

N

DZP 12 day taper starting at 0.38 mg/kg/day divided BID Transitioned gluten-free, casein-free diet to LGIT DZP 6 day taper starting at 0.45 mg/kg/day divided BID Added LEV and RFM DZP 8 day taper starting at 0.44 mg/kg/day divided TID Increased CLB DZP 8 day taper starting at 0.44 mg/kg/day divided TID

Y

DZP 4 day taper starting at 0.18 mg/kg/day divided BID Increased CLB DZP 6 day taper starting at 0.24 mg/kg/day divided BID

N

Y

Nb

N

Yb

N

DZP 6 day taper starting at 0.36 mg/kg/day divided TID Restarted LGIT DZP 6 day taper starting at 0.23 mg/kg/day divided TID Increased CLB and LEV DZP 6 day taper starting at 0.2 mg/kg/day divided BID Halved carbohydrate allowance of LGIT DZP 6 day taper starting at 0.4 mg/kg/day divided BID Increased LEV dose and halved carbohydrate allowance of LGIT DZP 6 day taper starting at 0.42 mg/kg/day divided BID

N

DZP 4 day taper starting at 0.36 mg/kg/day divided BID Increased baseline DZP dose after taper DZP 12 day taper starting at 0.38 mg/kg/day divided TID Increased LTG dose

Yb

N

N

Y

Yb

Nb

(continued on next page)

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Table 1 (continued) Pt

Sex AS subtype

Age

Clinical presentation

Trigger

EEG findings with % of EEG with epileptiform discharges

Seizure Treatment treatment

2nd course

7 years 4 months

Increased seizure frequency, balance problems

Viral illness

–

LEV

N

10 F

Deletion

11 M

UBE3A 7 years 9 mutation months

–

–

CLB, LEV, LTG

DZP 6 day taper starting at 0.25 mg/kg/day divided TID Increased LEV DZP 6 day taper starting at 0.37 mg/kg/day divided TID

12 F

Deletion

–

–

CLB, LEV, LTG

DZP 8 day taper starting at 0.22 mg/kg/day divided BID

N

13 M

Deletion

–

–

CLB, CZP, LTG, VPA

DZP 6 day taper starting at 0.25 mg/kg/day divided BID Increased CLB dose

N

Increased seizure frequency, motor regression, decreased communication 8 years 2 Increased seizure frequency, months somnolent, constant postictal mode, “drunk” 12 years Increased frequency of absence 2 months seizures

N

CLB: clobazam, CZP: clonazepam, DZP: diazepam, LEV: levetiracetam, LGIT: low glycemic index treatment, LTG: lamotrigine TPM: topiramate, VPA: valproate. a Three treatment courses. b Failed DZP treatment. c EEG tracing unavailable for primary review; findings per medical records.

affected, as NCSE occurs in approximately half of children with Panayiotopoulos syndrome [19], 3% of patients with absence epilepsy [20], and 6% of patients with juvenile myoclonic epilepsy [21]. Despite the frequency of NCSE in certain epilepsy syndromes, there is no consensus on how to treat it, and while IV benzodiazepines are the first line for critical illness-related NCSE, most agree that there should be less aggressive treatment for outpatients though guidelines on oral treatment are lacking. Recurrent NCSE is frequent in certain genetic epilepsy syndromes. Angelman syndrome is a genetic syndrome characterized by loss of ubiquitin protein ligase E3A (UBE3A) gene on chromosome 15, most frequently from deletion of maternally inherited genes in the 15q11-13 region and may also be due to uniparental disomy, imprinting defect, or mutation of the gene. The prevalence of AS has been estimated at 1 in 10,000 to 40,000 [22–25]. The constellation of features includes intellectual disability, ataxia, spasticity, typical facies, happy demeanors (“happy puppet”), and severe epilepsy. Eighty to 95% of patients with AS develop epilepsy, and NCSE occurs in half of these patients [26,27]. Patients with AS typically have atypical absence or myoclonic type NCSE, described in the literature as having features including decreased alertness, atypical absence status, atonic head drop, hypotonia, and/or myoclonic movements. In this study, we report our experience with a large series of pediatric patients with AS who have had NCSE treated with a tapering course of oral diazepam.

prescribed diazepam dose and duration, changes to antiepileptic treatments, and response to diazepam course. Response to diazepam was defined as a return to baseline and cessation of NCSE symptoms. Electroencephalogram data were reviewed by a second epileptologist (F.C.) for confirmation. This study was approved by the Massachusetts General Hospital Institutional Review Board. 3. Results (Table 1) 3.1. Demographics Twenty-one (20%) out of 104 pediatric patients seen in the Angelman Syndrome Clinic were identified as having NCSE. For analysis of the use of diazepam for NCSE, 5 patients were excluded due to an incomplete medical record, and 3 patients were excluded because they used lorazepam to treat NCSE instead of diazepam. The remaining 13 unique patients were included in this review with a total of 25 episodes of NCSE. Clinical features of NCSE episodes can be found in Table 1. Of the 13 patients with NCSE treated with diazepam, 12 patients had AS due to a maternal deletion, and 1 patient had a UBE3A mutation. Nine patients (69%) were male. The average age at a NCSE episode was 5 years and 4 months, ranging from 1 year and 3 months to 12 years and 2 months (Fig. 1). 3.2. Nonconvulsive status epilepticus episodes

2. Material and methods The medical records of all patients seen in the Angelman Syndrome Clinic at the Massachusetts General Hospital from January 2008 to May 2017 were reviewed. All patients included had genetic confirmation of AS and were less than 18 years old at the time of data collection. Individuals whose primary neurologic care was at an outside institution and individuals lost to follow-up were excluded. A total of 104 pediatric patients who met these criteria were identified. Patients who had an episode of NCSE were identified by the provider (R.T.) and confirmed via electronic medical records. Patients were further excluded if they did not use diazepam in treatment of NCSE or if they had inadequate documentation of symptoms, dose, or response to treatment. Electroencephalograms (EEGs) were reviewed when available; however, a clinical diagnosis of NCSE based on symptomatology and the experience of our epileptologist (R.T.) was accepted when EEG was not obtained (typically because it would have delayed treatment). Electronic medical records were reviewed for patient demographics and molecular subtype of AS. The following information concerning the episodes of NCSE was collected: symptoms at presentation, preceding events, pre- and posttreatment EEG if available, antiepileptic treatments at the time including dietary therapy,

The most common symptom of NCSE was increased seizure frequency or a cluster of seizure activity at the onset, present in 14 of 25 episodes (56%) of NCSE. Small motor movements of eye rolling, eye lid fluttering, and head nods were additionally noted in 5 instances. Altered mental status (decreased alertness, seeming

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

Age of NCSE episodes (years)

Fig. 1. Distribution of ages of NCSE episodes. Median: 5.8 years (IQR: 2.9–7.3 years).

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A

B

Fig. 2. Electroencephalogram sample for Patient 1 during 3rd episode of NCSE. A. Prediazepam treatment EEG showing 2–2.5 Hz, 700 μV frontally predominant generalized spike–wave activity. B. Postdiazepam treatment EEG showing continuous diffuse irregular 5–6 Hz, 200 μV theta slowing and occasional biposterior notched delta activity.

“postictal” or “off”, poor communication) was reported in 13 (52%), fatigue or somnolence was reported in 10 (40%), motor or developmental regression was noted in 8 (32%), and tremors or myoclonus was noted in 6 (24%) cases. Duration of NCSE symptoms ranged from 1 day to 1 month prior to treatment (duration estimates available in 17 of 25 episodes of NCSE). Triggers were identified in 14 out of 25 episodes of NCSE; 9 of which were infection-related (primarily viral respiratory illnesses, but also gastrointestinal illness, sinusitis, and pneumonia); 2 were triggered by antiepileptic medication tapers; 1 was triggered by poor sleep and constipation; 1 was triggered by seasonal allergies; and 1 was triggered by a trip to a carnival.

Patients were on an average of 1.9 (range: 0–4) antiepileptic treatments at the time of the NCSE episode, and three episodes occurred while on no antiepileptic treatments. Six patients had a single episode of NCSE; 7 patients had repeated episodes, with an average of 2.7 episodes (range: 2–4 episodes). Those who had a single episode had an average age of 7 years 7 months (range: 2 years 11 months– 12 years 2 months) at the time of their episode, compared with 4 years 7 months (range: 1 year 3 months–8 years 9 months) for those with repeated episodes. Seven of twelve patients (58%) with maternal deletions had recurrent episodes, and the one patient with a UBE3A mutation had only a single episode. 3.3. Electroencephalogram findings

Table 2 Example diazepam taper starting at 0.3 mg/kg/day for a 30-kg child.

AM Noon PM

Day 1

Day 2

Day 3

Day 4

3 mg 3 mg 3 mg

3 mg 3 mg 3 mg

3 mg

3 mg

3 mg

3 mg

Day 5

Day 6

3 mg

3 mg

Electroencephalograms were obtained before diazepam treatment in 14 of 25 cases of NCSE and were available for primary review in 12 cases. All tracings demonstrated high-voltage, frontally predominant, slow spike and wave discharges comprising 50% or more of the record. Maximum amplitudes ranged from 600 to 1000 μV at frequencies of 1.5–3 Hz. The percentage of the record containing discharges

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ranged from 50 to 95%. All were bi-frontally predominant spike and wave discharges. One subject had asymmetric discharges, with higher amplitudes over the left hemisphere, and the others all had no significant amplitude asymmetries. Seven of 25 episodes had a posttreatment EEG within 3 months showing resolution of the NCSE; 5 of 7 EEGs were after diazepam only; and 2 of 7 EEGs were after diazepam and steroid treatment (Fig. 2). 3.4. Treatment and side effects Diazepam courses lasted a median of 6 days, but ranged from 4 to 12 days. Initial diazepam dosing ranged from 0.18 to 0.57 mg/kg/day divided over 2 or 3 administrations per day. The average starting dose was 0.32 mg/kg/day. There were multiple patients who needed more than 1 treatment course to return to baseline: 5 episodes needed 2 treatment courses, and 1 episode required 3 courses. Oral diazepam was ultimately successful in cessation of NCSE symptoms in 80% (20/25) of cases. Five NCSE events in 3 patients did not respond to oral diazepam. Patient 5 responded to oral prednisone therapy during both episodes after failing diazepam treatment, requiring hospitalization for one of the episodes. Patient 8 required inpatient hospitalization for both episodes: he was treated with therapeutic coma for the first episode and IV steroids followed by a prolonged steroid taper during the second episode. Episodes in patient 9 additionally responded to highdose IV steroids. Overall, 12% (3/25) of episodes required hospitalization, whereas 22/25 (88%) episodes did not require hospitalization. Side effects were reported in a minority of cases. Patient 7 had continued intermittent seizures and nasal congestion that resolved with the addition of an allergy medication. Patient 5 (second NCSE episode) and patient 3 reported fatigue during treatment, though notably patient 5 did not benefit from the diazepam taper and required a course of oral steroids for resolution. No patient suffered from serious adverse events such as respiratory depression or aspiration. 4. Discussion We have highlighted 13 patients with AS who have been treated with brief courses of oral diazepam for 25 episodes of NCSE. Our study is the first to detail dosing parameters for an oral benzodiazepine course for pediatric patients in treatment of NCSE. The treatment was overall successful 80% of the time. Most patients responded to the initial course of diazepam, but some needed a second course of treatment immediately following the first if there was only a partial response. There was no relationship between duration of symptoms and those who responded to the initial course of diazepam (range: 1 day to 2 weeks) compared with those who required a second course of diazepam (range: 1 day to 2 weeks) or those who failed to clinically improve with diazepam (range: 2 days to 1 month). Seven patients had more than 1 episode of NCSE, and six continued to be responsive to diazepam in later courses. Our data underscore the tendency for a subset of patients with AS to have recurrent episodes of NCSE, which has been reported to a lesser degree in other studies of AS [12]. The difference could be explained by the current study being undertaken in a specialty referral center with a larger population experiencing potentially more severe baseline seizure severity, as the majority (7/12) of the patients in this cohort with AS from maternal deletions had more than 1 episode of NCSE. Additionally, seizure severity in patients with AS tends to improve after puberty [9,10,13,26,28]. Likewise, we did not have any patients with NCSE reported above the age of 12 years. Diazepam courses ranged from 0.18 to 0.57 mg/kg/day divided over 2–3 administrations per day for the initial dosing. The dose range was generous but allowed for ease of administration given the available medication forms (1 mg/mL solution; or 2, 5, or 10 mg tablets). Despite the large dose range, diazepam was tolerated at every dose with minimal side effects of fatigue reported in 2 of 25 cases. Respiratory depression and aspiration, due to excessive sedation, are serious

potential adverse effects but were not seen in our study. While there is a large dosing range, doses used in this study were comparable with the total daily doses which are used in a single administration for rectal diazepam in status epilepticus, and which are generally well tolerated. Additionally, patients with NCSE presenting with somnolence and increased seizures may be at higher risk of aspiration from NCSE than from diazepam itself as their alertness is improved with treatment. The most common course was a 6-day taper starting with 0.2–0.4 mg/kg/day divided two or three times per day and decreasing the number of administrations every 2 days (Table 2). In half the episodes of NCSE, there were simultaneous changes made to the antiepileptic regimen consisting of increased doses or addition of medication, or carbohydrate restriction for patients on a low glycemic index diet. This was primarily done to have increased seizure protection after diazepam was discontinued, as the effects of these changes are not present immediately. The diazepam courses were most often prescribed alone when it was the first NCSE episode (in 6 of 10 instances of diazepam taper alone). While it makes evaluation of diazepam more difficult, changing baseline antiepileptic treatment to provide more consistent seizure control is critical in these patients, the majority of whom have refractory seizures at baseline, especially if there is not a clearly identified transient trigger. Overall, NCSE occurred in 21 out of 104 (20%) patients in our cohort from the Angelman Syndrome Clinic. The average prevalence reported in the literature is 50% (range: 22–90%; median: 50%) among 7 previously published case series with a range of 8–36 patients with AS [8–14]. Our reported prevalence is lower for multiple potential reasons. As a referral center for AS, a large portion of our patients have local care for most of their neurology needs, and diagnosis and management of NCSE would not always fall under our care. Notably, however, it is reported that NCSE is likely underrecognized outside of a specialty center, including delay in diagnosis within 24 h of presentation to an emergency room for mental status changes [29]. Identification of behavioral change in patients with AS or other genetic encephalopathies who have preexisting intellectual disability and behavior problems is even more difficult. Additionally, those who have primary management at our referral center may be less likely to be on carbamazepine or phenobarbital, which have been commonly prescribed and associated with seizure exacerbation in patients with AS, so it is possible that the prevalence of NCSE is lower at our center than elsewhere [30]. In sum, it leads us to believe that the current incidence of NCSE in the general AS population is likely closer to previously reported studies. Despite the concept that ambulatory NCSE is common in many epilepsy syndromes, there are no treatment guidelines apart from consensus that treatment should be less aggressive than treatment of NCSE from acute causes due to significantly lower mortality and morbidity. In fact, many studies report no long-term cognitive or behavioral effects with typical absence status epilepticus in pediatric and adult patients [31–34] or in adults with complex partial status [29,35]. However, the literature is lacking studies relevant to children with genetic epilepsy syndromes or epileptic encephalopathies who have baseline developmental delay and behavioral change, and who may be more significantly impaired. For example, Hoffmann-Riem and colleagues [17] found that NCSE confers an odds ratio of 25 for severe intellectual disability in children with Lennox–Gastaut syndrome. In our study, developmental or motor regression was a presenting symptom in one-third of patients, and Ohtsuka and colleagues [11] had noted the potential for prolonged or permanent regression in similar patients, though data are limited by lack of formal, longitudinal neurodevelopmental assessments. Notably, Angelman-associated NCSE is generally atypical absence or myoclonic status, which historically has a worse response to benzodiazepine treatment and increases the risk of a prolonged episode [36,37]. Anecdotally, we have seen similar improvements in symptoms in children with b50% of the EEG comprising generalized spike–wave discharges, though this was difficult to quantify.

L. Worden et al. / Epilepsy & Behavior 82 (2018) 74–80

While “aggressive” treatment is not typically recommended for ambulatory NCSE, there are no clinical trials supporting any single treatment regimen. Benzodiazepines have been the most studied, and IV and oral benzodiazepines remain the first line therapy [38–40]. Intravenous benzodiazepines have been used with good success in various types of NCSE, including typical absence status [41,42], simple partial status [42], and complex partial status [43]. In the short term, Hopp and colleagues showed that a favorable response to an IV benzodiazepine trial is linked with increased survival and functional recovery at discharge [44]. The most frequently recommended doses of IV benzodiazepine in the literature are lorazepam, of 0.1 mg/kg up to 2-4 mg, or 10 mg of diazepam though specific weight-based dosing of diazepam is not discussed for children [45–48]. Multiple reports discuss the possibility of using oral benzodiazepines as first line in NCSE; however, there are no clear recommendations for oral therapy [39,40,49–51]. Oral therapy has a distinct advantage over IV therapy in accessibility and lack of painful IV placement, which is important for patients with baseline neurocognitive impairments and who may have additional functional difficulties with ongoing NCSE. Ohtsuka and colleagues report one case of NCSE in AS who was treated with high-dose oral diazepam at 5 mg/day for 7 days at the age of 19 months, though the mg/kg dose is not described [11]. In the same study, 3 of 5 episodes of NCSE were abated with clonazepam, suggesting that alternative benzodiazepines may be equally effective. Lastly, oral clobazam has been recommended to treat multiple types of NCSE in children with epilepsy syndromes [39,49,51] and has demonstrated effectiveness in a small series of adults [38]. While other benzodiazepines have been successful, diazepam has the benefit of a longer half-life than lorazepam due to active metabolites (44–100 h compared with 16–18 h) [52], widespread availability, and low cost. It is also the preferred benzodiazepine in certain other epileptic encephalopathies such as continuous spike and wave of sleep [53]. Because of these reasons and our history of success in NCSE treatment, diazepam is the preferred medication at our institution. Following benzodiazepines, IV valproic acid has been shown to be helpful in multiple other cases of NCSE, including myoclonic and absence status, and is suggested as a second line therapy by some, though this is debated [49,54–58]. It has been effective in cases of genetic epileptic encephalopathies, as well as in both AS [11] and Rett syndrome [59]. Daily use of valproic acid has been found to cause an increase in tremor and difficulty ambulating in the population with AS, making it a viable option in NCSE but not as a prolonged outpatient treatment [60]. Alternative oral therapies are limited to case studies, but oral levetiracetam [61,62] and initiation of the ketogenic or modified Atkins diet [63], or the low glycemic index diet [64] have also shown some success in NCSE treatment and may be applied to an outpatient setting. The main limitation of this study is the inability to confirm NCSE by EEG in all cases. Nonconvulsive status epilepticus was confirmed electrographically in 56% of NCSE episodes. The remainder did not have EEGs prior to treatment. While NCSE was not electrographically confirmed in these patients, the clinical constellation of symptoms in patients with AS should raise high suspicion for NCSE, and the episodes were diagnosed clinically as such by an epileptologist with expertise in the field (R.T.). In the 11 instances of NCSE without electrographic confirmation, 4 occurred in patients who previously had NCSE with EEG confirmation. Additionally, 10 of the 11 episodes without EEG confirmation responded clinically to oral diazepam, supporting NCSE as the likely etiology since additional benzodiazepine improved their symptoms instead of worsening them, as might be expected if there was an alternative cause such as illness or poor sleep. Likewise, only a minority of patients had EEGs soon after their diazepam course, so we do not have electrographic confirmation of cessation of NCSE; however, response to antiepileptic medications, not just electrographically but also clinically, has been suggested by others as an important criterion of NCSE [6]. While this descriptive retrospective study is limited, it is a helpful starting point for future investigations regarding the treatment of

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NCSE in a more structured manner, including pre- and postdiazepam treatment EEGs and more strict dosing guidelines. Alternative oral benzodiazepines such as lorazepam, clonazepam, and clobazam have some evidence of potential effectiveness, and ideally, IV and oral benzodiazepine administration may be directly compared in the future. 5. Conclusion In conclusion, we present 25 episodes of NCSE in 13 pediatric patients with AS who were treated with a brief tapering course of oral diazepam. This treatment was well-tolerated and was successful in treating NCSE symptoms in 80% of patients. Additionally, 88% of episodes did not require hospitalization. It should be considered as a first line therapy for NCSE in AS, though future prospective studies are needed to make more definitive conclusions. Future studies may also support more widespread use in other chronic epilepsy syndromes with frequent NCSE, prior to considering IV approaches. Declarations of interest None. Acknowledgments We would like to acknowledge all the families and patients who have visited the Angelman Syndrome Clinic at the Massachusetts General Hospital. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. References [1] Lennox W. The treatment of epilepsy. Med Clin North Am 1945;29:1114–28. [2] Wolf P, Trinka E, Bauer G. Absence status epilepticus: the first documented case? Epilepsia 2007. https://doi.org/10.1111/j.1528-1167.2007.01334.x. [3] Walker M, Cross H, Smith S, Young C, Aicardi J, Appleton R, et al. Status epilepticus: Epilepsy Research Foundation. Epileptic Disord 2005;7:253–96. [4] Bauer G, Trinka E. Nonconvulsive status epilepticus and coma. Epilepsia 2010;51: 177–90. https://doi.org/10.1111/j.1528-1167.2009.02297.x. [5] Fernández-Torre JL, Rebollo M, Gutiérrez A, López-Espadas F, Hernández-Hernández MA. Nonconvulsive status epilepticus in adults: electroclinical differences between proper and comatose forms. Clin Neurophysiol 2012. https://doi.org/10.1016/j. clinph.2011.06.020. [6] Sutter R, Semmlack S, Kaplan PW. Nonconvulsive status epilepticus in adults — insights into the invisible; 2016. https://doi.org/10.1038/nrneurol.2016.45. [7] Shneker BF, Fountain NB. Assessment of acute morbidity and mortality in nonconvulsive status epilepticus. Neurology 2003;61:1066–73. [8] Galván-Manso M, Campistol J, Conill J, Sanmartí FX. Analysis of the characteristics of epilepsy in 37 patients with the molecular diagnosis of Angelman syndrome. Epileptic Disord 2005;7(1):19–25. [9] Laan LAEM, Renier WO, Arts WFM, Buntinx IM, Stroink H, Beuten P, et al. Evolution of epilepsy and EEG findings in Angelman syndrome. Epilepsia 1997;38:195–9. https://doi.org/10.1111/j.1528-1157.1997.tb01097.x. [10] Matsumoto A, Kumagai T, Miura K, Miyazaki S, Hayakawa C, Yamanaka T. Epilepsy in Angelman syndrome associated with chromosome 15q deletion. Epilepsia 1992;33: 1083–90. https://doi.org/10.1111/j.1528-1157.1992.tb01763.x. [11] Ohtsuka Y, Kobayashi K, Yoshinaga H, Ogino T, Ohmori I, Ogawa K, et al. Relationship between severity of epilepsy and developmental outcome in Angelman syndrome. Brain and Development 2005;27:95–100. https://doi.org/10.1016/j.braindev.2003. 09.015. [12] Uemura N, Matsumoto A, Nakamura M, Watanabe K, Negoro T, Kumagai T, et al. Evolution of seizures and electroencephalographical findings in 23 cases of deletion type Angelman syndrome. Brain and Development 2005. https://doi.org/10.1016/j. braindev.2004.01.009. [13] Valente KD, Koiffmann CP, Fridman C, Varella M, Kok F, Andrade JQ, et al. Epilepsy in patients with angelman syndrome caused by deletion of the chromosome 15q11-13. Arch Neurol 2006;63:122–8. https://doi.org/10.1001/archneur.63.1.122. [14] Viani F, Romeo A, Viri M, Mastrangelo M, Lalatta F, Selicorni A, et al. Seizure and EEG patterns in Angelman's syndrome. J Child Neurol 1995;10:467–71. https://doi.org/ 10.1177/088307389501000609. [15] Arzimanoglou A, Guerrini R, Aicardi J. Status epilepticus. In: Arzimanoglou A, Guerrini R, Aicardi J, editors. Aicardi's epilepsy child. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2004. p. 241–61.

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L. Worden et al. / Epilepsy & Behavior 82 (2018) 74–80

[16] Mulley JC, Scheffer IE, Petrou S, Dibbens LM, Berkovic SF, Harkin LA. SCN1A mutations and epilepsy. Hum Mutat 2005;25:535–42. https://doi.org/10.1002/ humu.20178. [17] Hoffmann-Riem M, Diener W, Benninger C, Rating D, Unnebrink K, Stephani U, et al. Nonconvulsive status epilepticus–a possible cause of mental retardation in patients with Lennox-Gastaut syndrome. Neuropediatrics 2000;31:169–74. https://doi.org/ 10.1055/s-2000-7456. [18] Inoue Y, Fujiwara T, Matsuda K, Kubota H, Tanaka M, Yagi K, et al. Ring chromosome 20 and nonconvulsive status epilepticus. A new epileptic syndrome. Brain 1997;120: 939–53. https://doi.org/10.1093/brain/120.6.939. [19] Panayiotopoulos CP. Panayiotopoulos syndrome: a common and benign childhood epileptic syndrome. London: John Libbey & Company Ltd.; 2002. [20] Knake S, Rosenow F, Vescovi M, Oertel WH, Mueller HH, Wirbatz A, et al. Incidence of status epilepticus in adults in Germany: a prospective, population-based study. Epilepsia 2001;42:714–8. https://doi.org/10.1046/j.1528-1157.2001.01101.x. [21] Dziewas R, Kellinghaus C, Lüdemann P. Nonconvulsion status epilepticus in patients with juvenile myoclonic epilepsy: types and frequencies. Seizure 2002;11:335–9. https://doi.org/10.1053/seiz.2001.0611. [22] Buckley RH, Dinno N, Weber P. Angelman syndrome are the estimates too low. Am J Med Genet 1998;80:385–90. [23] Clayton-Smith J. Clinical research on Angelman syndrome in the United Kingdom: observations on 82 affected individuals. Am J Med Genet 1993;46:12–5. https://doi.org/10.1002/ajmg.1320460105. [24] Kyllerman M. On the prevalence of Angelman syndrome. Am J Med Genet 1995;59: 405 author reply 403-404 https://doi.org/10.1002/ajmg.1320590331. [25] Petersen MB, Brøndum-Nielsen K, Hansen LK, Wulff K. Clinical, cytogenetic, and molecular diagnosis of Angelman syndrome: estimated prevalence rate in a Danish county. Am J Med Genet 1995;60:261–2. https://doi.org/10.1002/ajmg.1320600317. [26] Pelc K, Boyd SG, Cheron G, Dan B. Epilepsy in Angelman syndrome. Seizure 2008. https://doi.org/10.1016/j.seizure.2007.08.004. [27] Thibert RL, Larson AM, Hsieh DT, Raby AR, Thiele EA. Neurologic manifestations of Angelman syndrome. Pediatr Neurol 2013. https://doi.org/10.1016/j.pediatrneurol. 2012.09.015. [28] Buntinx IM, Hennekam RCM, Oebele F, Stroink H, Beuten J, Mangelschots K, et al. Clinical profile of Angelman syndrome at different ages. Am J Med Genet 1995; 183:176–83. [29] Kaplan PW. Nonconvulsive status epilepticus in the emergency room. Epilepsia 1996;37:643–50. [30] Thibert RL, Conant KD, Braun EK, Bruno P, Said RR, Nespeca MP, et al. Epilepsy in Angelman syndrome: a questionnaire-based assessment of the natural history and current treatment options. Epilepsia 2009. https://doi.org/10.1111/j.1528-1167. 2009.02108.x. [31] Dodrill CB, Wilensky AJ. Intellectual impairment as an outcome of status epilepticus. Neurology 1990;40:23–7. [32] Guberman A, Cantu-Reyna G, Stuss D, Broughton R. Nonconvulsive generalized status epilepticus: clinical features, neuropsychological testing, and long-term follow-up. Neurology 1986;36:1284–91. [33] Kaplan PW. Prognosis in nonconvulsive status epilepticus. Epileptic Disord 2000;2:185–93. [34] Krumholz A. Epidemiology and evidence for morbidity of nonconvulsive status epilepticus. J Clin Neurophysiol 1999;16:314–22 [discussion 353]. [35] Cockerell OC, Walker MC, Sander JW, Shorvon SD. Complex partial status epilepticus: a recurrent problem. J Neurol Neurosurg Psychiatry 1994;57(7):835. [36] Espay AJ, Andrade DM, Wennberg RA, Lang AE. Atypical absences and recurrent absence status in an adult with Angelman syndrome due to the UBE3A mutation. Epileptic Disord 2005;7(3):227–30. [37] Garmel GM, Jacobs AK, Eilers MA. Tonic status epilepticus: an unusual presentation of unresponsiveness. Ann Emerg Med 1992;21:223–7. https://doi.org/10.1016/ S0196-0644(05)80172-6. [38] Gastaut H, Tinuper P, Aguglia U, Lugaresi E. Treatment of certain forms of status epilepticus by means of a single oral dose of clobazam. Rev Electroencephalogr Neurophysiol Clin 1984;14:203–6. [39] Walker MC. Diagnosis and treatment of nonconvulsive status epilepticus. CNS drugs 2001;15:931–9. [40] Walker MC. Treatment of nonconvulsive status epilepticus. Int Rev Neurobiol 2007. https://doi.org/10.1016/S0074-7742(06)81019-6.

[41] Schwartz MS, Scott DF. Isolated petit-mal status presenting de novo in middle age. Lancet 1971;298:1399–401. https://doi.org/10.1016/S0140-6736(71)90672-6. [42] Thomas P, Zifkin B, Migneco O, Lebrun C, Darcourt J, Andermann F. Nonconvulsive status epilepticus of frontal origin. Neurology 1999;52 [1174 LP-1174]. [43] Tomson T, Svanborg E, Wedlund JE. Nonconvulsive status epilepticus: high incidence of complex partial status. Epilepsia 1986;27:276–85. [44] Hopp JL, Sanchez A, Krumholz A, Hart G, Barry E. Nonconvulsive status epilepticus: value of a benzodiazepine trial for predicting outcomes. Neurologist 2011;17: 325–9. https://doi.org/10.1097/NRL.0b013e31822f688c. [45] Maganti R, Gerber P, Drees C, Chung S. Nonconvulsive status epilepticus. Epilepsy Behav 2008;12:572–86. https://doi.org/10.1016/j.yebeh.2007.12.002. [46] Osorio I, Reed RC, Peltzer JN. Refractory idiopathic absence status epilepticus: a probable paradoxical effect of phenytoin and carbamazepine. Epilepsia 2000;41: 887–94. https://doi.org/10.1111/j.1528-1157.2000.tb00258.x. [47] Tomson T, Lindbom U, Nilsson BY. Nonconvulsive status epilepticus in adults: thirtytwo consecutive patients from a general hospital population. Epilepsia 1992;33: 829–35. https://doi.org/10.1111/j.1528-1157.1992.tb02190.x. [48] Thomas P, Beaumanoir A, Genton P, Dolisi C, Chatel M. “De novo” absence status of late onset: report of 11 cases. Neurology 1992;42:104–10. [49] Akman CI. Nonconvulsive status epilepticus and continuous spike and slow wave of sleep in children. Semin Pediatr Neurol 2010. https://doi.org/10.1016/j.spen. 2010.06.009. [50] Galimi R. Nonconvulsive status epilepticus in pediatric populations: diagnosis and management. Minerva Pediatr 2012;64:347–55. [51] Korff CM, Nordli DR. Diagnosis and management of nonconvulsive status epilepticus in children. Nat Clin Pract Neurol 2007;3:505–16. https://doi.org/ 10.1038/ncpneuro0605. [52] Lexicomp. Pediatric and neonatal Lexi-drugs online. Wolters Kluwer Clin Drug Information, Inc.http://online.lexi.com, Accessed date: 11 February 2018. [53] Sánchez Fernández I, Chapman K, Peters JM, Klehm J, Jackson MC, Berg AT, et al. Treatment for continuous spikes and waves during sleep (CSWS): survey on treatment choices in North America. Epilepsia 2014;55:1099–108. https://doi.org/ 10.1111/epi.12678. [54] Giroud M, Gras D, Escousse A, Dumas R, Venaud G. Use of injectable valproic acid in status epilepticus. Drug Investig 1993;5:154–9. https://doi.org/10.1007/ BF03258440. [55] Narayanan JT, Murthy JMK. Nonconvulsive status epilepticus in a neurological intensive care unit: profile in a developing country. Epilepsia 2007;48:900–6. https://doi.org/10.1111/j.1528-1167.2007.01099.x. [56] Hovinga CA, Chicella MF, Rose DF, Eades SK, Dalton JT, Phelps SJ. Use of intravenous valproate in three pediatric patients with nonconvulsive or convulsive status epilepticus. Ann Pharmacother 1999;33:579–84. https://doi.org/10.1345/aph.18349. [57] Kaplan PW. Intravenous valproate treatment of generalized nonconvulsive status epilepticus. Clin Electroencephalogr 1999;30:1–4. [58] Yu KT, Mills S, Thompson N, Cunanan C. Safety and efficacy of intravenous valproate in pediatric status epilepticus and acute repetitive seizures. Epilepsia 2003;44: 724–6. https://doi.org/10.1046/j.1528-1157.2003.41302.x. [59] Nissenkorn A, Gak E, Vecsler M, Reznik H, Menascu S, Ben Zeev B. Epilepsy in Rett syndrome — the experience of a National Rett Center. Epilepsia 2010;51:1252–8. https://doi.org/10.1111/j.1528-1167.2010.02597.x. [60] Shaaya EA, Grocott OR, Laing O, Thibert RL. Seizure treatment in Angelman syndrome: a case series from the Angelman Syndrome Clinic at Massachusetts General Hospital. Epilepsy Behav 2016;60:138–41. https://doi.org/10.1016/j.yebeh.2016.04.030. [61] Alehan F, Ozcay F, Haberal M. The use of levetiracetam in a child with nonconvulsive status epilepticus. J Child Neurol 2008;23(3):331. https://doi.org/10.1177/ 0883073807309237. [62] Trabacca A, Profice P, Costanza MC, Gesualdi M, De Rinaldis M. Levetiracetam in nonconvulsive status epilepticus in childhood: a case report. J Child Neurol 2007; 22:639–41. https://doi.org/10.1177/0883073807302612. [63] Kumada T, Miyajima T, Kimura N, Saito K, Shimomura H, Oda N, et al. Modified Atkins diet for the treatment of nonconvulsive status epilepticus in children. J Child Neurol 2010;25:485–9. https://doi.org/10.1177/0883073809347597. [64] Martikainen MH, Paivarinta M, Jaaskelainen S, Majamaa K, Martikainen MHPMJSMK. Successful treatment of POLG-related mitochondrial epilepsy. Epileptic Disord 2012; 14:438–41.