Nitrazepam for the treatment oflennox-gastaut syndrome

Introduction 

Lennox-Gastaut syndrome is a severe age-specific childhood epilepsy syndrome associated with epileptic encephalopathy. Lennox-Gastaut syndrome makes up 5% of all childhood epilepsies [1], [2]. Patients with this syndrome have multiple seizure types, including tonic, atonic, myoclonic, and atypical absence [3]. Tonic seizures are the most characteristic seizure type and often lead to repeated falls (drop seizures), with subsequent injuries. The occurrence of tonic seizures is also associated with poor prognosis for intellectual development [4], [5]. Electroencephalogram (EEG) findings are characteristic and demonstrate less than 2-Hz slow spike-and-wave discharges evident maximally over the anterior head regions [6].

Associated mental retardation is usually static; however, cognitive decline occurs often secondary to poorly controlled seizures (epileptic encephalopathy). It is thought that if seizures can be discontinued, cognitive function may improve. In addition to mental retardation, many patients with Lennox-Gastaut syndrome develop behavioral problems [7]. The progressive intellectual decline in Lennox-Gastaut syndrome is related to seizure burden and cognitive side effects of medication used to treat Lennox-Gastaut syndrome [8]. The serious physical injuries and progressive cognitive decline associated with frequent seizures require aggressive therapy.

Effective treatment includes both pharmacologic and nonpharmacologic options. Antiepileptic drugs are the mainstay of treatment, and include valproate, benzodiazepines, lamotrigine, topiramate, and felbamate. The ketogenic diet may be effective, however, poor compliance and side effects lead to frequent failures [9]. Other nonpharmacologic options include corpus callosum section and vagus nerve stimulation. However, no single treatment is completely effective and polytherapy often leads to disabling side effects.

We report the results of an open-label study of 14 patients with medication-resistant Lennox-Gastaut syndrome treated with nitrazepam.

Materials and methods 

Fourteen patients with medication-resistant Lennox-Gastaut syndrome were enrolled in an open-label compassionate use investigational protocol. Patients were treated prospectively with oral nitrazepam (not U.S. Food and Drug Administration approved) using a compassionate use protocol approved by Cornell University Medical College institutional review board in 1994. Informed consent was obtained before initiating study drug. Hoffman-LaRoche, Inc., provided the study drug in double-scored 5-mg tablets.

Patients were included in the study if they had multiple seizure types, which could include, atonic, tonic, myoclonic, atypical absence, generalized tonic-clonic seizures, and partial seizures, slow spike-and-wave discharges in EEG, and mental retardation. Pre-enrollment EEG/video-EEG studies were performed during the baseline period to confirm the diagnosis of Lennox-Gastaut syndrome and to document seizure count.

Parents and caregivers were requested to keep seizure diaries for seizure counts. Seizure frequency data were obtained from seizure diaries every 2 weeks for the first 2 months, and thereafter every month. Adverse events were also documented at each visit. Patients were excluded from study if parents or caregivers were noncompliant with seizure counts, drug administration, or clinic visits. Physical and neurologic examinations were performed at baseline and during each visit in the open-level phase. Clinical laboratory tests, including antiepileptic drug levels, blood chemistries, and hematology, were performed at baseline and 2 weeks after reaching the maximum dose of nitrazepam.

Nitrazepam was initiated as an oral dose of 0.25 mg/kg/day with increments of 0.25 mg/kg/day made every 2 weeks based on clinical response. During the titration phase, concomitant benzodiazepine, if any, was gradually withdrawn and discontinued.

We compared the 1-month baseline seizure frequency with the median seizure rate reduction during the first 12 months of treatment with nitrazepam. Nonparametric statistical analysis (Wilcoxan matched pairs test) was used because normality of the data could not be assumed.

Results 

Fourteen patients were enrolled in the study over a period of 3 years. There were nine males and five females. The mean age of the patients was 3 years (range = 11 months-8 years). The mean duration of follow-up was 16 months (range = 13-30 months). Daily dosage ranged from 0.25 mg to 3 mg/kg, with a median dose of l.5 mg/kg administered in twice daily dosage.

The following etiologies were observed in these 14 patients: three patients had tuberous sclerosis, five patients had hypoxic-ischemic encephalopathy, one patient had traumatic brain injury, one patient had pachygyria, one patient had Down syndrome, and three patients were cryptogenic (Table 1). Five of 14 patients had a prior history of infantile spasms.

Table 1. Patient characteristics

	No.	Age	Gender	Etiology	Seizure types	Neuroimaging
	1	2 yr	F	Cryptogenic	ATA, AT, CP	Atrophy, calcification
	2	11 mo	M	Cryptogenic	ATA, AT	Calcification
	3	8 yr	M	Tuberous sclerosis	ATA, GTC, CP	Cortical tubers
	4	3 yr	M	Tuberous sclerosis	ATA, AT, CP	Multiple cortical hamartoma
	5	2 yr	M	Down syndrome	AT, GTC	Diffuse atrophy
	6	4 yr	F	Cryptogenic	T, ATA	Mild atrophy
	7	2 yr	F	Cryptogenic	AT, ATA	Mild atrophy
	8	8 yr	M	Birth asphyxia	GTC, MY, AT, T	Atrophy, C: C Section
	9	2 yr	M	Cryptogenic	T, AT, GTC	Severe atrophy
	10	3 yr	F	Cryptogenic	T, ATA	Diffuse atrophy
	11	3 yr	M	Tuberous sclerosis	ATA, AT, CP	Cortical tubers
	12	3 yr	M	Cryptogenic	ATA, AT, GTC	Diffuse atrophy and left porencephalic cyst
	13	4 yr	M	Birth asphyxia	GTC, ATA, T	Severe atrophy
	14	2 yr	F	Traumatic brain injury	T, GTC	Severe atrophy

Abbreviations:AT=AtonicATA=Atypical absenceCP=Complex partialGTC=Generalized tonic-clonicMY=MyoclonicT=Tonic

The median seizure rate reduction during the first 12 months of treatment with nitrazepam was 41% (P = 0.001). Two patients became seizure free, five patients demonstrated at least 50% reduction in seizure rate, six patients had at least 25% seizure rate reduction, and one patient did not respond (Table 2). All seizure types were reduced by nitrazepam. The sample size was too small to determine if any particular seizure type was more affected than any other.

Table 2. Reduction in seizure frequency

	Patient No.	Baseline Sz Frequency	Median Sz Over 12 mo on NZP	%Sz Red12 mo postNZP Therapy
	1	>100	73	27%
	2	23	16	30%
	3	>127	97	23%
	4	>200	>200	0%
	5	23	11	52%
	6	45	33	27%
	7	93	63	32%
	8	23	0	100%
	9	>215	>111	48%
	10	78	37	52%
	11	>179	>106	40%
	12	>35	19	46%
	13	28	1	96%
	14	>117	64	45%

These patients also demonstrate behavioral problems, such as hyperactivity and aggression. Their only hope lies in better understanding of the pathophysiology of Lennox-Gastaut syndrome. Abbreviations:NZP=NitrazepamRed=ReductionSz=Seizure frequency

Response to nitrazepam usually occurred within 6 weeks of initiating treatment. One patient had complete cessation of seizures after 3 weeks of initiating treatment. Another patient became seizure free after 3 months of treatment. These two patients remain seizure free on nitrazepam monotherapy at 18-month and 2-year follow-up, respectively.

Common adverse events included sedation in six children (40%) and drooling in nine patients (60%). These side effects diminished over time, and no patient discontinued treatment because of these side effects. No treatment-related deaths occurred in these patients. Seven of 14 patients (50%) remained on nitrazepam for 4 years or longer. One patient was discontinued because of lack of response after a 2-month trial. Seven patients were gradually withdrawn off the drug because of decreased availability of the drug in the past year.

Drug levels of concomitantly used antiepileptic drugs were not altered by the use of nitrazepam. No alteration in blood chemistries or hepatic function occurred in any patient.

Discussion 

Children with the Lennox-Gastaut syndrome continue to have seizures throughout their lives. The seizure frequency is high, and seizures are difficult to control. The morbidity associated with Lennox-Gastaut syndrome leads to a significant burden on society and caregivers. Unfortunately, safe and effective treatment is not available. Valproate and benzodiazepines have been the mainstay of treatment for many years [10]. Confirming the efficacy and safety of available agents are important because few effective agents are available for patients with Lennox-Gastaut syndrome.

Nitrazepam is an orally administered benzodiazepine with a half-life of 8–19 hours. The drug is rapidly absorbed from the gastrointestinal tract and is partially metabolized in the liver and is excreted in the urine and feces [11], [12], [13]. Nitrazepam has demonstrated a broad spectrum of activity as an antiepileptic drug in animal models of epilepsy against seizures induced by maximal electroshock and metrazol [11], [12], [13]. Nitrazepam is not available in the United States and its use requires investigational new drug license through institutional review boards. Since 1963, nitrazepam has been studied under a variety of protocols and has demonstrated activity against many seizure types. The majority of these studies have been in adults with a variety of epilepsy syndromes.

The most common adverse events evident in these studies included drowsiness, increased oral secretions, and ataxia [14]. These side effects were usually dose related and decreased with dose reduction. Ataxia is a commonly reported side effect of benzodiazepines, however, we did not observe this in our small cohort of patients.

Most of our patients were severely retarded and nonambulatory, therefore ataxia was not observed. We titrated the dose of nitrazepam slowly, therefore, patients’ tolerance was better and they did not develop ataxia. The forementioned side effects are also observed with use of other benzodiazepines and are not unique to nitrazepam. Rare instances of sudden death have been reported in children on nitrazepam, attributed to aspiration secondary to increased pooling of oral secretions [15]. More recently, Rintahaka et al. [16] reported a higher mortality in children with epilepsy taking nitrazepam in comparison to epileptic children not taking nitrazepam. No deaths occurred in our patients who were followed for up to 5 years. This outcome may be a result of the small sample size of our study. Drooling was the second most common side effect reported in our study. Two patients developed aspiration pneumonia that was effectively treated with antibiotics. Six of 14 patients in our study had previously tried and failed other FDA-approved benzodiazepines, including clonazepam and lorazepam. Nitrazepam was initiated because of continuous intractable seizures. Five of these patients had decreased seizures on nitrazepam.

Despite reports of rapid development of tolerance with benzodiazepines, seven of our patients (50%) remained on nitrazepam for 4 years or longer. Attempts at tapering nitrazepam resulted in worsening of seizures in two patients. Nitrazepam taper was not attempted in the other five patients.

No organ failures have been reported with nitrazepam use. Elevation of liver enzymes has been reported in patients receiving polydrug therapy [14]. We did not observe any clinically significant elevations of liver enzymes, or alteration of other laboratory parameters in our patients.

To our knowledge, six clinical trials of nitrazepam in children with symptomatic generalized epilepsy have been published. Most recently, Chamberlain [17] reported efficacy of nitrazepam in 10 children with Lennox-Gastaut syndrome. Two (20%) of 10 children had complete cessation of seizures, four children had partial response, and four children did not respond. Millichap and Ortiz [18] reported complete cessation of seizures in 27 (75%) of 36 children. Gibbs and Anderson [19] reported improvement in four (18%) of 22 patients. Liske and Forster [12] reported a greater than 25% improvement in 30 (60%) of 50 patients. In the only controlled study, Dreifuss et al. [20], in a comparative trial of nitrazepam and corticotrophin in patients with previously untreated patients with infantile spasms, reported similar response in both groups (more than 75% reduction in 50% of the children). However, side effects and treatment discontinuation was significantly greater in the corticotrophin-treated group. This finding suggests that nitrazepam is likely safer and better tolerated than corticotrophin.

Infantile spasms is a closely related syndrome and many patients with infantile spasms evolve into Lennox-Gastaut syndrome [2], [8]. Treatment strategies and rationale are often similar.

Results of our prospective study indicate that nitrazepam is an effective and safe benzodiazepine for the treatment of Lennox-Gastaut syndrome, with more than 50% reduction in seizure frequency in seven (60%) patients. Dramatic improvement (90% reduction in seizure frequency) was observed in two of 14 patients. Sedation and pooling of secretions were observed frequently but were less noticeable with slow titration of the dosage.

New antiepileptic medications, such as lamotrigine, felbamate, and topiramate, have also demonstrated efficacy in the treatment of Lennox-Gastaut syndrome [21], [22], [23], [24]. The higher incidence of rash in children taking lamotrigine, particularly in combination with valproate, is problematic and limits its use. However, with recently revised recommendation of dose escalation the incidence of rash may decrease. The hepatotoxicity and aplastic anemia associated with felbamate use has significantly limited its use [25]. Preliminary experience with topiramate use in children with Lennox-Gastaut syndrome has been encouraging [26], [27]. Vagus nerve stimulation has also been found to reduce seizures in patients with Lennox-Gastaut syndrome. Hosain et al. [28] reported a median seizure rate reduction of 52% with the use of vagus nerve stimulation after 6 months of treatment.

This study leads us to conclude that nitrazepam is an effective adjunctive antiepileptic drug for patients with refractory Lennox-Gastaut syndrome with mixed seizures. Unlike other benzodiazepines its tolerability and efficacy was retained over time. Nitrazepam may be the optimal benzodiazepine for patients with Lennox-Gastaut syndrome. It is widely available in Europe and other North American countries, although it is not FDA-approved for use in the United States, and should serve as a valuable agent for treatment of the mixed seizures of Lennox-Gastaut syndrome.

Despite the low prevalence of Lennox-Gastaut syndrome (4%-5%), it constitutes a major burden of intractable epilepsies of childhood. Open-label trials of newer pharmacologic agents and other treatment modalities may further contribute to the management and understanding of the pathophysiology of Lennox-Gastaut syndrome. Continued research toward better understanding of this syndrome should be a priority.