Brain & Development xxx (2014) xxx–xxx www.elsevier.com/locate/braindev
Case report
Nocturnal frontal lobe epilepsy in mucopolysaccharidosis Paolo Bonanni a,⇑, Anna Volzone a, Giovanna Randazzo a, Lisa Antoniazzi a, Angelica Rampazzo b, Maurizio Scarpa b, Lino Nobili c a
Epilepsy and Clinical Neurophysiology Unit, IRCCS “E. Medea”, Conegliano, TV, Italy b Department of Paediatrics, University of Padova, Italy c “Claudio Munari” Epilepsy Surgery Centre, Niguarda Ca’Granda Hospital, Milan, Italy
Received 25 July 2013; received in revised form 5 December 2013; accepted 11 December 2013
Abstract Nocturnal frontal lobe epilepsy (NFLE) is an epileptic syndrome that is primarily characterized by seizures with motor signs occurring almost exclusively during sleep. We describe 2 children with mucopolysaccharidosis (MPS) who were referred for significant sleep disturbance. Long term video-EEG monitoring (LT-VEEGM) demonstrated sleep-related hypermotor seizures consistent with NFLE. No case of sleep-related hypermotor seizures has ever been reported to date in MPS. However, differential diagnosis with parasomnias has been previously discussed. The high frequency of frontal lobe seizures causes sleep fragmentation, which may result in sleep disturbances observed in at least a small percentage of MPS patients. We suggest monitoring individuals with MPS using periodic LT-VEEGM, particularly when sleep disorder is present. Moreover, our cases confirm that NFLE in lysosomal storage diseases may occur, and this finding extends the etiologic spectrum of NFLE. Ó 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. Keywords: Sleep disturbances; Epilepsy; Mucopolysaccharidosis
1. Introduction Nocturnal frontal lobe epilepsy (NFLE) is an epileptic syndrome primarily characterized by seizures that occur almost exclusively during sleep. Seizures are characterized by autonomic activation and bizarre motor behaviour of increasing complexity and duration; they range from simple and brief stereotyped motor events to paroxysmal arousals and major attacks [1,2]. The ictal signs associated with these seizures suggest that frontal lobes may be involved. ⇑ Corresponding author. Address: Epilepsy and Clinical Neurophysiology Unit, IRCCS E. Medea, Via Costa Alta 37, Conegliano 31015, TV, Italy. Tel.: +39 0438 414347; fax: +39 0438 410101. E-mail address:
[email protected] (P. Bonanni).
NFLE is a heterogeneous disorder with onset during infancy or childhood [3]; it may present in sporadic and familial forms, induce various seizure types, and be drug resistant in approximately 30% of patients. Symptomatic aetiology is present only in 13% of NFLE patients and most NFLE cases remain cryptogenic [1]. The majority of symptomatic patients experience symptoms due to focal cortical dysplasia [2]. Only 1 case with aspartylglucosaminuria and NFLE has been reported to date [4]. We describe 2 patients with mucopolysaccharidosis (MPS) who were referred for significant sleep disturbance. Long term video-EEG monitoring (LT-VEEGM) of these patients demonstrated sleeprelated hypermotor seizures consistent with NFLE.
0387-7604/$ - see front matter Ó 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.braindev.2013.12.002
Please cite this article in press as: Bonanni P et al. Nocturnal frontal lobe epilepsy in mucopolysaccharidosis. Brain Dev (2014), http:// dx.doi.org/10.1016/j.braindev.2013.12.002
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2. Case reports 2.1. Case 1 Patient 1 was carried to term over the course of a normal pregnancy. After 1 year of age, the patient experienced psychomotor retardation, hyperactivity, coarse facial features, joint stiffness and macrosomia. At the age of 29 months, a genetic diagnosis of MPS type II was made. Electroencephalogram (EEG) showed spike–wave (SW) complexes over frontal regions. At 5.1 years the Stanford–Binet scale showed a mental age of 4.5 (IQ of 87). MRI, performed almost yearly between the ages 3 and 10 years, showed mild diffuse brain atrophy. At the age of 8 years, the child received enzyme replacement therapy with Idursulfase, but this did not halt the neurological progression. At the age of 7 years, the patient suddenly presented with frontal non-convulsive status epilepticus (NCSE). Disappearance of ictal EEG activity was observed after ethosuximide therapy. At the age of 10 years, significant sleep disorder and behavioural regression appeared. According to the patient’s parents, sleep was disturbed by short episodes of sudden wakening with vocalizations, and chaotic motor activity. These episodes recurred several times a night. To better understand the origin of the patient’s sleep disorder, LT-VEEGM (2 nights) was performed. Because of significant hyperactivity, leads were positioned only for scalp EEG, surface electromyography (EMG) of the right and left deltoid muscles, electrocardiogram and abdominal pneumogram. During sleep, EEG showed spikes and sharp waves that were often repetitive over the frontal regions (Fig. 1A). Sleep was disturbed by frequent attacks of hyperkinetic automatism involving the inferior limbs (mainly pedalling), autonomic changes (mainly hyperventilation and tachycardia starting soon after the beginning of clinical motor signs), vocalization, frightened expression, and tonic/ dystonic posturing of the left leg and foot (Fig. 2A). Ictal semiology was highly stereotyped. The duration was 12–15 s. At the end of each episode the patient was awake and required a number of minutes to fall back to sleep. Ictal EEG was partially obscured by movement artefacts; however, clinical seizures were often preceded by diffuse attenuated EEG activity and followed by rhythmic slow wave activity at 4–6 Hz over the frontal regions. In addition to these episodes, which we called major, we observed briefer attacks (duration of 3–8 s) that were characterized only by the latter part of major attacks (abrupt wakening, vocalization, frightened expression and tonic posturing of the left leg and foot). The occurrence of motor symptoms of varying complexity during sleep was separately assessed by
distinguishing between major and minor attacks. We were able to count 269 attacks (1 every 2–5 min) throughout the night: 159 were major attacks, and 110 were minor attacks. Paroxysmal episodes often occurred with periodic repetition. The numerousness of episodes produced fragmented sleep, in which it was difficult to recognize discrete sleep stages. Antiepileptic treatment with clobazam and carbamazepine completely controlled seizure recurrence, and the quality of sleep and behaviour were significantly improved. 2.2. Case 2 Pregnancy and delivery were without complications. At the age of 3 years, a diagnosis of MPS-IIIA was suspected in this male patient on the basis of clinical phenotype (developmental delay during the 2nd year of age and facial dysmorphisms). The diagnosis was subsequently genetically confirmed. MRI, performed at 3 and 9 years, showed mild diffuse brain atrophy. Our observation occurred at age 11; profound cognitive impairment, impaired speech development, hearing loss, uncontrollable hyperactivity and sleep disturbance were present. According to the parents, sleep was disturbed by short episodes characterized by sudden wakening and chaotic motor activity. These episodes recurred several times each night. Two nights of LT-VEEGM were performed. Because of significant hyperactivity, leads were placed only on the scalp for EEG and the right and left deltoid muscles for surface EMG. During sleep, EEG showed spike and SW activity mainly over the frontal regions (Fig. 1B). Moreover, sleep was disturbed by frequent stereotyped attacks characterized by motor automatism (mainly pedalling), rotation of the trunk, vocalization and frightened expression (Fig. 2B). Paroxysmal episodes occurred throughout the night, often with a periodic repetition. Major attacks were 5–15 s in duration. Ictal EEG was obscured by movement artefacts. Additionally, we observed briefer attacks (1–3 s in duration) that were characterized only by some jerks of the legs; this was similar to the initial part of the major attacks. In 1 night, we were able to count 18 major attacks and 56 minor attacks. During the second night of monitoring, 10 mg of clobazam were administered, and the number of the seizures was significantly reduced. However, because of significant sedation and unsteadiness of the patient, clobazam was stopped after a few days. The parents refused other antiepileptic treatments for the patient. 3. Discussion We describe 2 MPS patients referred for significant sleep disorder that was characterized by sudden
Please cite this article in press as: Bonanni P et al. Nocturnal frontal lobe epilepsy in mucopolysaccharidosis. Brain Dev (2014), http:// dx.doi.org/10.1016/j.braindev.2013.12.002
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Fig. 1. EEG during sleep. Part A: patient 1 at age 11 years; Part B: patient 2 at age 11 years. In both patients, spikes and spike and waves over frontal regions. LD = left deltoid; RD = right deltoid; sec = second.
Fig. 2. Video-EEG monitoring during sleep. Part A: patient 1 during a major attack of 15 s in duration, 1: patient 1 is sleeping; 2–8: abrupt arousal with pedalling and vocalization; 9–15: grimacing and tonic/dystonic posturing of the left leg and foot; 16,17: end of the seizure; Part B: patient 2 during a major seizure of 10 s in duration, 1: patient 2 is sleeping; 2–6: repetitive flexion and extension of the legs and vocalization; 7–15: rotation of the trunk and pedalling; 16: end of the attack.
Please cite this article in press as: Bonanni P et al. Nocturnal frontal lobe epilepsy in mucopolysaccharidosis. Brain Dev (2014), http:// dx.doi.org/10.1016/j.braindev.2013.12.002
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awakenings and chaotic motor activity. LT-VEEGM was performed and motor manifestations of varying complexity and duration were recorded only during sleep in both patients. All attacks, major and minor, were highly stereotyped for both patients. Ictal EEGs in both patients was obscured by movement artefacts, while interictal EEGs showed epileptiform abnormalities over the frontal regions. Differential diagnosis of abnormal paroxysmal motor events in sleep presents a difficult challenge for clinicians [5], particularly when patients have a neurodegenerative disorder such as MPS. Bizarre clinical features of hyperkinetic seizures in NFLE result in frequent misdiagnoses of pseudoseizures or parasomnias [5,6]. Universally accepted diagnostic criteria are lacking for NFLE. Analysis of video-polysomnographic recordings of attacks is the only way to distinguish sleep-related hypermotor seizures from sleep disorders [5]. In our 2 MPS patients, nocturnal episodes with bizarre motor manifestations were highly stereotyped, brief and occurred throughout the night, often with periodic repetition. They were also characterized by motor (mainly bipedal) automatisms, tonic/dystonic posturing, and clearly asymmetrical movements. On the basis of these clinical characteristics, we diagnosed NFLE in both patients. Epilepsy and sleep disturbance are common disorders in patients with MPS. In MPS II, seizures are present in 13–34% of patients, and the age of onset is approximately 10 years [7,8]. Seizures are considered to be an early clinical marker of central nervous system involvement in MPS II [7]. Myoclonic, absence, generalized tonic clonic seizures, and NCSE, are the most common types of seizure [7,8]. In MPS IIIA, seizures are present in 66% of patients and the age of onset is approximately 11 years. Seizures in MPS IIIA are usually well controlled by medication [9]. Our 2 patients demonstrate that sleep-related hypermotor seizures may be part of the spectrum of the epileptic phenotype in MPS. Sleep disturbances are common in both MPS II and MPS IIIA; more than 80% of these patients are affected [10,7]. Commonly reported sleep problems include frequent waking, settling difficulties, and night wandering [10,7]. Sleep apnoea is well described as a cause of sleep disturbance in MPS II [11]. However, in our 2 patients, we have shown that the cause of sleep disorder was nocturnal epilepsy. The high frequency of seizures per night produced significant sleep fragmentation with disorganized sleep stages. During the day, both patients exhibited significantly hyperactive behaviour and shortened attention span; this was likely due to excessive diurnal somnolence. In patient 1, antiepileptic drug treatment
with clobazam and carbamazepine completely controlled seizure recurrence, with marked improvements in sleep and behaviour quality. In patient 2, clobazam, administered on the 2nd day of the long term videoEEG monitoring, reduced the number of epileptic seizures. Therefore, our experience demonstrates that NFLE may be part of the epileptic phenotype of MPS and that sleep disturbance, which is very frequent and disabling in MPS, may be caused by sleep-related hypermotor seizures. These seizures may be easily treated with low dose carbamazepine and clobazam. We suggest monitoring individuals with MPS using periodic LT-VEEGM, particularly when sleep disorder is present. Moreover, our cases confirm that NFLE may occur in lysosomal storage diseases [4], and our findings extend the etiologic spectrum of NFLE. References [1] Provini F, Plazzi G, Tinuper P, Vandi S, Lugaresi E, Montagna P. Nocturnal frontal lobe epilepsy. A clinical and polygraphic overview of 100 consecutive cases. Brain 1999;122:1017–31. [2] Nobili L, Francione S, Mai R, Cardinale F, Castana L, Tassi L, et al. Surgical treatment of drug-resistant nocturnal frontal lobe epilepsy. Brain 2007;130:561–73. [3] Zucconi M, Ferini-Strambi L. NREM parasomnias: arousal disorders and differentiation from nocturnal frontal lobe epilepsy. Clin Neurophysiol 2000;111(Suppl. 2):S129–35. [4] Ambrosetto G, Santucci M. Sleep-related hypermotor seizures in aspartylglucosaminuria: a case report. Epilepsia 2009;50:1638–40. [5] Tinuper P, Provini F, Bisulli F, Vignatelli L, Plazzi G, Vetrugno R, et al. Movement disorders in sleep: guidelines for differentiating epileptic from non-epileptic motor phenomena arising from sleep. Sleep Med Rev 2007;11:255–67. [6] Derry CP, Harvey AS, Walker MC, Duncan JS, Berkovic SF. NREM arousal parasomnias and their distinction from nocturnal frontal lobe epilepsy: a video EEG analysis. Sleep 2009;32:1637–44. [7] Holt J, Poe MD, Escolar ML. Early clinical markers of central nervous system involvement in mucopolysaccharidosis type II. J Pediatr 2011;159:320–6. [8] Bonanni P, Gubernale M, Martinez F, Randazzo G, Milantoni L, Martinuzzi A, et al. Non-convulsive status epilepticus of frontal origin in mucopolysaccharidosis type II successfully treated with ethosuximide. Dev Med Child Neurol 2012;54:961–4. [9] Valstar MJ, Neijs S, Bruggenwirth HT, Olmer R, Ruijter GJ, Wevers RA, et al. Mucopolysaccharidosis type IIIA: clinical spectrum and genotype–phenotype correlations. Ann Neurol 2010;68:876–87. [10] Fraser J, Wraith JE, Delatycki MB. Sleep disturbance in mucopolysaccharidosis type III (Sanfilippo syndrome): a survey of managing clinicians. Clin Genet 2002;62:418–21. [11] Lin HY, Chen MR, Lin CC, Chen CP, Lin DS, Chuang CK, et al. Polysomnographic characteristics in patients with mucopolysaccharidosis. Pediatr Pulmonol 2010;45:1205–12.
Please cite this article in press as: Bonanni P et al. Nocturnal frontal lobe epilepsy in mucopolysaccharidosis. Brain Dev (2014), http:// dx.doi.org/10.1016/j.braindev.2013.12.002
