Rett Syndrome and Epilepsy: An Update for Child Neurologists

Pediatric Neurology 48 (2013) 337e345

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Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu

Review Article

Rett Syndrome and Epilepsy: An Update for Child Neurologists Alison Dolce MD a, *, Bruria Ben-Zeev MD b, Sakkubai Naidu MD a, c, Eric H. Kossoff MD a a

Johns Hopkins Hospital, Baltimore, Maryland Sheba Medical Center, Tel Hashomer, Tel Aviv, Israel c Kennedy Krieger Institute, Baltimore, Maryland b

article information

abstract

Article history: Received 11 September 2012 Accepted 12 November 2012

Rett syndrome, a neurogenetic disorder predominantly affecting females, has many characteristic features including psychomotor retardation, impaired language development, hand stereotypies, gait dysfunction, and acquired microcephaly. Although each of these features undoubtedly contributes to the morbidity of this neurologic disorder, epilepsy is perhaps one of the most well-described and problematic, affecting as many as 50%-90% of patients. Seizures can often be refractory, requiring polytherapy and consideration of nonpharmacologic management (e.g., ketogenic diets and vagus nerve stimulation). In addition, many nonepileptic symptoms of Rett syndrome can occasionally be difficult to differentiate from seizures making clinical management and family counseling challenging. Our goal in this review is to better define the clinical and electrophysiological aspects of the epilepsy associated with Rett syndrome and provide practical guidance regarding management. Ó 2013 Elsevier Inc. All rights reserved.

Introduction

In 1966, Dr. Andreas Rett [1] described 22 girls with a progressive neurologic syndrome with seizures. Seventeen years later, Hagberg et al. [2] distinguished 35 girls with similar characteristics and imparted the eponym Rett syndrome, along with the first specific diagnostic criteria. These criteria have since been modified and clarified in the Rett Search Consortium in 2010 [3], with some controversy remaining over whether the diagnosis should require acknowledgment of the gene defect [4]. Rett syndrome primarily affects girls with an incidence of approximately 1:10,000-22,000 [5]. It seems to have no proclivity for a particular race or ethnic group. In 1999, loss of function mutations in the gene-encoding methyl-CpGbinding protein 2 (MECP2) at Xq28 were found to be associated with both rare familial cases of Rett syndrome (less than 1%), as well as the more common sporadic (de novo) occurrences of Rett syndrome (>99%) [6]. More recently, mutations in the genes cyclin-dependent kinase-like 5 and forkhead box protein G1 have been reported to resemble * Communications should be addressed to: Dr. A. Dolce; 200 N. Wolfe St.; Suite 2158; Baltimore; MD 21287. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2012.11.001

clinical features of Rett syndrome and are called atypical, variant, or congenital Rett syndrome, although significant differences from Rett syndrome have been documented [7,8]. Clinical features and diagnosis

Rett syndrome is characterized by early normal development with subsequent regression. This pattern is quite unique from most known genetic, chromosomal, and neurodevelopmental disorders. Most children with Rett syndrome are the product of a normal pregnancy and delivery, with apparently normal growth and development for at least the first 6 months of life. In some cases, during early infancy, vague symptoms may be present, including hypotonia, jerkiness in limb movement, and reduced social interaction manifesting as apathy. An early sign of neurologic involvement is deceleration of head growth, which begins between 2-4 months of age before recognition of developmental delay. It is eventually diagnosed as acquired microcephaly. Often beginning around 12-18 months of age, changes occur as arrested cognitive and motor development, as well as loss of acquired verbal skills and stereotyped repetitive hand movements with loss of normal hand function. This nascent developmental regression is sometimes sudden and often rapid, occurring in the time span of

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weeks to months with associated severe sleep disturbances, irritability, and poor eye contact that is occasionally mistaken for autism. This regression is then followed by a more indolent course of neurologic deterioration, often ending with significant motor disability causing some of the adolescent girls to be wheelchair-bound by their teenage years. The disease eventually reaches a plateau of stability. Patients are known to survive into their sixth or seventh decade [9], albeit with substantial physical and cognitive disabilities. Children with Rett syndrome often follow such a discernible course such that four stages of the disease have been proposed, although not all stages are distinct from each other clinically (Figure 1) [10,11]. Epilepsy features Clinical features

Epilepsy is very common in Rett syndrome with frequency ranging from approximately 50%-90% [12,13]. There has been some suggestion that those individuals with seizures and Rett syndrome have a greater overall clinical severity with greater impairment of ambulation, hand use, and communication [14]. All seizure types may be present in Rett syndrome with no characteristic “first seizure” semiology. Compared with the general population, early febrile seizures may be more frequent (12% vs. 2-5% overall) [15]. The most common seizure types reported include complex partial, generalized tonic-clonic, tonic, and myoclonic seizures, with absence and clonic seizures being less frequent [12,16]. Symptomatic focal epilepsy (58%) seems to be more common than generalized epilepsy (38%) [17]. The severity of epilepsy is not significantly correlated with any particular type of seizure [12].

Birth

When present, the course and severity of epilepsy in Rett syndrome is often variable; however, literature suggests that there are some clear patterns over the age spectrum. Most seizures appear between 2-5 years of age (median onset is 4 years), with a very small percentage occurring after the age of 10 years [15,18,19]. The onset of epilepsy generally correlates with clinical stages 2-3, that is, the rapid destructive and plateau stage (Figure 1) [20]. The severity of epilepsy often tends to decline after adolescence, with decreased seizure frequency and overall less secondarily generalized seizures, even in those patients who were previously considered quite intractable [12,19]. Although there are several possible atypical variants of Rett syndrome, we will briefly only mention the early seizure variant (Hanefeld variant). This particular variant is characterized by early onset of seizures, often before 5 months of age, which precedes any developmental regression. Infantile spasms may be prominent, as may refractory myoclonic epilepsy [21]. The early onset of seizures is subsequently followed by a more established Rett syndrome clinical picture. Mutations in cyclin-dependent kinase-like 5 may be recognized in those patients with Rett syndrome phenotype if they do not have an identifiable mutation in MECP2 [7,15]. Prognosis

There is no clear consensus with regard to whether an earlier onset of seizures portends a poorer prognosis in Rett syndrome. Steffenburg et al. [12] have suggested that early onset of seizures can be associated with more seizure types, more intractable epilepsy, and status epilepticus. Nissenkorn et al. [15] reported that onset after age 5 years is a good prognostic factor for well-controlled seizures, whereas an

NORMAL DEVELOPMENT

6 mo

1 yr

STAGE 1 – EARLY ONSET Decreased head growth Hypotonia/delays in gross motor skills Loss of hand skills/speech; Less eye contact, social interaction & interest in toys

2 yr

3 yr

4 yr

5 yr

10 yr

>20 yrs

STAGE 3 – PLATEAU Seizures are usually prominent Autonomic dysfunction Behavior may improve Increased eye contact/hand use Many people with Rett Syndrome remain in this stage for the entirety of their lives.

STAGE 2 – RAPID DESTRUCTIVE Autistic features, intellectual disability Decreased head growth more apparent Respiratory abnormalities Hand stereotypies, motor dysfunction

STAGE 4 – LATE MOTOR DETERIORATION Decrease/loss of mobility Spasticity/Dystonia Communication/hand skills generally stable Scoliosis Figure 1. Onset and progression: four stages of classic Rett syndrome.

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earlier onset is a risk factor for development of electrical status epilepticus of sleep [15]. Other authors have reported that early-onset epilepsy did not have a negative effect on the long-term course of Rett syndrome [22]. Although there has been some suggestion that the presence of microcephaly is a risk factor for epilepsy and its severity [12], others have found no clear correlation [14,18]. Additionally, there seems to be no significant difference in epilepsy among different ethnic groups with Rett syndrome [14]. Signs or symptoms that predate the development of seizures in Rett syndrome are not clearly defined. Using data extracted from the Australian Rett Syndrome Database, Jian et al. [23] suggested that possible predictive factors may include developmental problems appearing in the first 10 months of life and absence of walking. Certain types of mutations in MECP2 have been reported to confer different susceptibility to seizures [14]. Nonepileptic events

Despite its frequent presence as part of the syndrome, epilepsy can be difficult to fully characterize as many of the other signature manifestations in Rett syndrome may easily be mistaken as having epilepsy by both parents and professionals. One particular study found that only one third of parent-reported seizure behaviors were actually temporally associated with epileptiform abnormalities [14]. The myriad of behaviors that may be inappropriately classified as ictal events include hand stereotypies, breath-holding and cyanosis, hyperventilation, staring, unusual eye movements (oculogyric movements, blinking episodes), oral facial dyskinesias, unwarranted bouts of laughing or screaming, and motor abnormalities (tremor, dystonia, jerking, spasticity, and episodic atonia) [24]. Perhaps even more important to note is that epileptiform activity on electroencephalography (EEG) is frequent and occurs without any clear evidence of corresponding clinical seizures [25]. Chaotic breathing patterns are a common manifestation in Rett syndrome and are only present in the waking state, with consistently normal breathing patterns in sleep. Several authors have found that background EEG activity may slow into the delta range (1-4 Hz) during episodes of apnea or hyperventilation, but there is generally no epileptiform correlate [26,27]. Similarly, Ben-Zeev et al. [28] reported four girls with Rett syndrome who had frequent episodes of unilateral hand tapping (initially considered as stereotypy) that were found to be synchronous with onset of contralateral central spikes on EEG. This behavior did not respond to acute or long-term anticonvulsant medications and partially remitted spontaneously after a few months. This further elucidates the often confusing clinical features in Rett syndrome and the difficulty in distinguishing epileptic from nonepileptic events [28]. EEG findings

Despite the prevalence of epilepsy in Rett syndrome, there have been relatively few reports of the characteristic EEG findings in these patients. EEG is an important diagnostic tool in children with Rett syndrome because it allows for the distinction between true seizures and nonepileptic behavioral characteristics, as described previously. Given

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that the EEG result can often be floridly abnormal in Rett syndrome, pediatric neurologists may need to consider more prolonged video EEG monitoring in many cases to aid in correlating clinical events with electrographic changes and improve diagnostic accuracy. In an abstract by Sousa et al. [29], four girls with confirmed Rett syndrome who presented with subtle nonconvulsive status epilepticus were studied. All patients were young and presented with episodes of behavioral arrest, cyanosis, hand manipulations, and episodes of hyperventilation. Surprisingly, their EEG results were characterized by continuous epileptiform activity in centroparietal and temporal areas (two patients), generalized ictal theta activity (one patient), and ictal generalized delta activity (one patient) [29]. This further emphasizes the importance of correlation of clinical and EEG findings and additionally calls to attention that the diagnosis of nonconvulsive status epilepticus in Rett syndrome can be difficult to identify and may easily go unrecognized as stereotypical behavior. The EEG findings in Rett syndrome often assume stereotypical patterns that similarly progress through the four clinical stages of the disease [5,30-32]; however, these abnormalities are not diagnostic for Rett syndrome [33]. The most common EEG findings are summarized in Figure 2, with images shown in Figure 3. Many authors have suggested that EEG abnormalities often parallel the disease course with a decline in seizure burden and EEG abnormalities with advancing age [30,31]. Very early in the disease the EEG is almost invariably normal; however, sometime after 2-4 years of age, all girls with Rett syndrome have development of an abnormal EEG result [34]. In an attempt to associate clinical staging with EEG abnormalities, the following EEG characteristics have been described. Stage 1dEarly Onset (6-18 months)

Because seizures are not a prominent feature in this stage, EEG scans may not be obtained. Early EEG results typically tend to be normal. However, in some cases slowing of the posterior background rhythm and background activity during wakefulness may be noted [35]. Stage 2dRapid Destructive (18 months-3 years)

If not present in stage 1, background activity slowing is now characteristically seen during wakefulness. Rolandic spikes (focal spikes in the centrotemporal regions) may be seen as the first EEG abnormality, often continuing into stage 3. Because this pattern is found during drowsiness and increased during sleep, the EEG may initially resemble that of benign epilepsy with centrotemporal spikes [15]. This early involvement of the motor cortex in the disease process of Rett syndrome interestingly correlates with the onset of motor abnormalities. Sleep features may be well developed in patients younger than 2.5 years of age [35]; however, with clinical progression, poorly developed or absent sleep spindles may be seen. Such sleep abnormalities continue as the child ages, with perhaps more severe disturbances observed in both nonrapid and rapid eye movement stages. Sleep in general seems to augment epileptiform activity in many patients [35].

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Birth

NORMAL DEVELOPMENT

6 mo STAGE 1 – EARLY ONSET EEG is normal or shows occipital background activity slowing in the awake state 1 yr

2 yr

3 yr

4 yr

5 yr

10 yr

>20 yrs

STAGE 2 – RAPID DESTRUCTIVE STAGE 3 – PLATEAU Focal spike or sharp waves occurring at centroSlowing of background activity, temporal locations (Rolandic spikes) in sleep & absence of non-REM sleep, awake state-this pattern can persist into stage 3; multifocal epileptiform Loss of non-REM sleep discharges, generalized slow spike-wave & rhythmic bursts of delta over central regions in sleep & awake. Epilepsy is often prominent. STAGE 4 – LATE MOTOR DETERIORATION Marked slowing of background activity with delta rhythms, multifocal epileptiform activity in awake state, generalized slow spike-wave activity in sleep, rhythmic theta activity in central/frontal-central regions. The EEG may have an absence of epileptiform abnormalities. Figure 2. Characteristic EEG findings in the four stages of classic Rett syndrome.

Stage 3dPlateau (2-10 years)

Seizure burden is prominent during this stage. Sleep patterns continue to be abnormal with absence of vertex transients, and sleep spindles in non-REM sleep and waking background activity remains slowed. During this period a unique pattern of bilaterally synchronous bursts of pseudoperiodic delta activity and generalized rhythmic spike discharges are seen most prominently during sleep (possibly from a subcortical origin) [34]. Stage 4dLate Motor Deterioration (>10 years)

Slowing of the background activity remains a characteristic feature on EEG. Additional patterns noted include multifocal spike or sharp wave discharges in the waking state, as well as generalized slow spike-wave activity during sleep. During this clinical stage, despite the persistence of epileptiform abnormalities on EEG, clinical seizures are generally no longer a prominent feature. Some patients in this stage may have near-normal activity when awake and asleep on their EEG scans [36]. Slow theta rhythms (4-6 Hz) over the central region or vertex may become a prominent feature on EEG [30]. It has been suggested that this rhythm is evidence of hyperexcitability of the motor or sensorimotor region and the presence of a disinhibited, dysfunctional motor cortex owing to the primary frontal lobe dysfunction [30,36]. Association between genotype and phenotype

Epilepsy severity is considered to be a major contributor to the general severity of Rett syndrome phenotype [37]. In

several studies, seizures tended to occur earlier in patients with the Rett syndrome phenotype that did not have clearly identifiable MECP2 mutations. Seizures in the first year of life occurred in only 4% of all girls with Rett syndrome studied, with only 20% of them carrying the MECP2 mutation [38]. The rarity of MECP2 mutations in girls with seizure onset during the first year of life was confirmed also by Jian et al. [23]. MECP2 mutations are spread across the gene and can be described according to the specific protein function related to their location. Although there are more than 300 different mutations described so far in the MECP2 gene, 60% of the classical cases carry one of eight hot spot mutations. The most prevalent in most cohorts are p.T158M and p.R168X. Most studies investigating genotype-phenotype relationships in Rett syndrome compare between cohorts with specific hot spot mutations and rarely relate to the other less common mutations. Few studies take into account mutation location in relation to the protein functional regions. Severe mutations such as large deletions, early truncating, and missense in the methyl binding domain (MBD) or the nuclear localizing segment were found to present with earlier or more severe epilepsy, whereas a milder mutation (late truncating or C-terminal deletions) had a protective effect on epilepsy onset [18,23,39,40]. A recent U.S. study on 493 patients found significantly more epilepsy in patients with the missense MBD-related mutations: p.T158M mutation (74%) and p.R106W (78%), whereas patients with p.R255X or p.R306C had lower occurrence of seizures (49%) [14]. A tendency to higher prevalence of the p.T158M mutation in drug-resistant epilepsy was also described by Buoni et al [41]. The

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Figure 3. Typical EEG findings in different stages of Rett syndrome.

localization of this missense mutation in the MBD region, affecting interaction with chromatin, might explain its severe effect on the general phenotype, including epilepsy [14,23,38,39,41]. However, no correlations between genotype and phenotype were found in large Australian, Italian, Israeli, and British cohorts [15,17,37,41].

An international cohort of patients with Rett syndrome with large-scale deletions was recently investigated; these patients have the most severe phenotype in general, and epilepsy severity according to three severity scales is a major contributor to their generally worse severity [37]. Interestingly, in a smaller group of large-scale deletions,

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although epilepsy tended to be more severe, the onset was later than in other mutations [18]. The discrepancies between different cohorts as related to the effect of specific mutations on epilepsy clinical parameters may be explained by the different X inactivation status in patients with similar mutations. The correspondence between brain and lymphocytes is unclear, but because brain tissue is unavailable, studies used the lymphocyte X inactivation ratios for phenotype genotype correlations. Skewed inactivation was a protective factor for early seizure onset and seizure rate in two studies on the basis of the Australian database [23,29]. Recently, polymorphisms in the BDNF gene were shown to associate independently with epilepsy in Rett syndrome [15,39,42,43]. BDNF has a special role in the pathophysiology of Rett syndrome because it is one of the major genes upregulated by MECP2 [44]. Increasing BDNF levels in MECP2 mutant mice was shown to improve disease phenotype [45,46]. Therefore it is not surprising that the Val/Val polymorphism, present in 20% of the general population and responsible for higher BDNF synaptic secretion, was associated with overall decreased disease severity and later seizure onset in a large Australian-Israeli cohort of girls with the p.R168X mutation [42]. In the Israeli cohort of patients with Rett syndrome, this polymorphism was found as the only parameter influencing seizure onset in patients with different mutations [15]. These data are contradicted in a French cohort, finding the opposite correlation [39] while being supported by an Italian cohort analyzing a possible Rett syndrome variant with preserved speech (Zappella variant) [43].

Epilepsy treatment

Despite some investigation into appropriate seizure therapy in Rett syndrome, there are no definitive recommendations at this time, and therefore the choice of the ideal first anticonvulsant drug remains unclear. Additionally, because epilepsy can often be quite severe, with up to 50% having intractable seizures, polytherapy may be necessary to provide symptomatic relief [15]. Krajnc et al. [19] reported the need for three or more drugs in 18.5% of patients with Rett syndrome. Jian et al. [40] similarly reported 19% requiring three or more anticonvulsants in the first month of their study. Anticonvulsants

There are a limited number of reports specifically addressing the anticonvulsant treatment of epilepsy in Rett syndrome, and of those available, most are small series with a limited number of subjects and multiple different anticonvulsants being used (Table 1). Given that both partial and generalized seizures may be present in Rett syndrome, drugs selected for use in the literature are often those considered to have broad-spectrum efficacy. Common drugs reported in clinical practice as first- or second-line monotherapy for Rett syndrome include valproate and lamotrigine. Valproate appears to be the most typically reported anticonvulsant for Rett syndrome at this time. Some authors have reported a 75% rate of seizure freedom with valproate as first monotherapy, whereas others found only 6% to be seizure free [13,19]. In the study by Nissenkorn

Table 1. Anticonvulsant drugs reported in the treatment of epilepsy in Rett syndrome

Anticonvulsant

No. of Individuals

Author, Years Reported

Monotherapy vs. Polytherapy

>50% Seizure Reduction

Valproate

8 16 4 15 15 4 3 1 2 4 1 3 8 2 5 3 2 2 4 2 2 1 1

Krajnc, 2011 [19] Huppke, 2007 [13] Krajnc, 2011 [19] Huppke, 2007 [13] Huppke, 2007 [13] Krajnc, 2011 [19] Huppke, 2007 [13] Stenbom, 1998 [48] Stenbom, 1998 [48] Uldall, 1993 [47] Huppke, 2007 [13] Krajnc, 2011 [19] Specchio, 2010 [50] Goyal, 2004 [49] Goyal, 2004 [49] Krajnc, 2011 [19] Krajnc, 2011 [19] Huppke, 2007 [13] Huppke, 2007 [13] Krajnc, 2011 [19] Huppke, 2007 [13] Krajnc, 2011 [19] Huppke, 2007 [13]

M M M M M M M M P* P* M Py Pz M P* Py M M M M M M M

7/8 5/13 3/4 10/14 9/14 2/4 1/2 0/1 1/2 4/4 0/1 3/3 4/8 2/2 5/5 2/3 1/2 1/1 2/4 2/2 1/2 1/1 1/1

Carbamazepine Sulthiame Lamotrigine

Levetiracetam

Topiramate

Phenobarbital Primidone Vigabatrin Clobazam

(87.5%) (38%) (75%) (71%) (64%) (50%) (50%) (0%) (50%) (100%) (0%) (100%) (50%)z (100%) (100%) (67%) (50%) (100%) (50%) (100%) (50%) (100%) (100%)

Abbreviations: M ¼ Monotherapy P ¼ Polytherapy * The indication for polytherapy was not clearly defined. y Polytherapy was generally used in those in whom two different monotherapies failed. z All patients were receiving concomitant antiseizure therapy before initiation of levetiracetam. Four of eight (50%) were seizure free; the remaining four patients had a reported marked reduction in frequency and duration of seizures, but the percent of seizure reduction was not specified.

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et al. [15], valproate was the most prevalently used anticonvulsant with a reported effectiveness (>50% reduction in seizure frequency) in 59% of the patients. This study also suggested that valproate is beneficial in the treatment of electrical status epilepticus of sleep in Rett syndrome because it decreased the epileptic activity to less than 25% of slow wave sleep in five of 10 patients [15]. Contrarily, Huppke et al. [13] found poor response to valproate monotherapy; they reported monotherapy with carbamazepine as providing a 56% rate of seizure freedom [13]. The effects of lamotrigine as an add-on drug have been described by Uldall et al. [47] as producing a 50%-77% reduction in seizure frequency in four patients with Rett syndrome. These girls also reportedly had improvement in their general well-being and alertness [47]. Krajnc et al. [19] reported a 50% seizure-free rate in their study. Additionally, Stenbom et al. [48] reported positive effects of lamotrigine on seizure frequency; however, the effects noticed were inconsistent between cases. Newer anticonvulsants have been used in limited studies to date. Goyal et al. [49] reported a 50%-75% reduction in seizure frequency (along with improvements in respiratory abnormalities) in seven patients with Rett syndrome treated with topiramate (two of them as monotherapy). The effect of levetiracetam was evaluated in the treatment of drug-resistant Rett syndrome by Specchio et al. [50] with an 84.5% reduction in the mean monthly number of seizures after 3 months and 92.9% after 6 months. In addition, their results indicated that levetiracetam may be more effective in the treatment of myoclonic and focal seizures specifically compared with other seizure types [50]. For resistant cases, polytherapy may at times be necessary. From the report by Huppke et al. [13], anticonvulsant polytherapy after an ineffective monotherapy resulted in a 50% reduction of seizure frequency in 42% of patients with Rett syndrome and a seizure-free interval of more than 6 months in 40% of patients. There are no studies that have evaluated the necessary length of time needed to continue anticonvulsant therapy. Given that many patients in later life have minimal seizure burden, it may perhaps be reasonable to consider lowering and even discontinuing treatment when patients have been seizure free for some time and when they are older. At our centers, we have circumstantial evidence of good responses to levetiracetam, lamotrigine, and topiramate. We also use valproate; however, the side effects can sometimes be problematic. Many children require two anticonvulsants for optimal seizure control. Ketogenic diet

There are three reports in the literature describing the positive effects of the classical ketogenic diet on seizure frequency and behavior in Rett syndrome. In 1986, Haas et al. [51] described seven girls with Rett syndrome and refractory epilepsy who were treated with the ketogenic diet (five of whom were able to tolerate the diet for periods of at least 3-6 months). Four of the five girls had a reduction of seizures of at least 50%, with all five having some variable degree of improvement in social behavior and psychomotor function [51]. Liebhaber et al. [52] described one girl with refractory epilepsy who was treated with the ketogenic diet

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for 4 years with a resultant 70% reduction in seizures, as well as improvements in social contact, language, and behavior. In a case report by Giampietro et al. [53], the benefit of the ketogenic diet was described in a 10-year-old girl with atypical Rett syndrome and intractable seizures. With implementation of a ketogenic diet, she had a decrease in seizure frequency and improvement in communication with family members [53]. As a result of this research, the consensus statement by the International Ketogenic Diet Study Group listed Rett syndrome as a condition in which the ketogenic diet has been reported as “probably” particularly beneficial because of at least two publications describing excellent benefit with the ketogenic diet [54]. Many children with Rett syndrome are fed with gastrostomy tubes, also making them good potential candidates for dietary therapy because they can be easily started on the ketogenic diet without compliance issues. At Johns Hopkins Hospital, Rett syndrome is one of the fastest growing subpopulations being treated with the ketogenic diet, especially if the patients have gastrostomy tubes. Vagus nerve stimulation

There is one published case series describing the effects of vagus nerve stimulation (VNS) on epilepsy in Rett syndrome [55]. Seven females with Rett syndrome, in all of whom at least two trials of anticonvulsants had failed before they received VNS, were evaluated. Six of the seven girls, after 1 year of VNS therapy, had at least a 50% reduction in seizure frequency (four had at least a 90% reduction at 1 year). Additionally, two patients who kept follow-up at 2 years had maintained more than a 90% reduction in seizure frequency. In all of the girls, the VNS was well tolerated with no surgical complications and a parental report of increased alertness. Although there was concern that use of a VNS may affect the already compromised autonomic functions in these girls, the authors suggested that VNS therapy was well tolerated, with no patients having exacerbations of their baseline breathing abnormalities. Decreased appetite was reported in two patients; however, it was believed this was more likely part of the natural history of Rett syndrome because these symptoms did not resolve with reductions in VNS stimulation parameters. In an abstract by Topcu et al. [56], two of three patients with Rett syndrome who underwent implantation of a VNS were described as having a 25%-30% reduction in seizure frequency (as well as decreased seizure severity and duration). Additionally, both girls showed improvement in eye contact and decreased stereotypies. Additional treatment considerations

Certain anticonvulsants are more commonly associated with decreased bone mineral density and fracture risk if treated for a prolonged period of time [57,58]. Physicians need to take into consideration that children with Rett syndrome are at a higher risk of osteopenia and have been reported to have a fracture rate nearly four times that of the general population [59]. Leonard et al. [60] studied valproate and the risk of fracture in Rett syndrome reporting a threefold increase in risk of fracture if valproate was used

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for more than 1 year (on its own or in combination with other anticonvulsants). They found no additional increase in risk of fracture for medications such as vigabatrin, topiramate, benzodiazepines, or lamotrigine; however, they reported that carbamazepine may be slightly protective for fracture when used for longer than 2 years. The authors were unable to report whether the effects of valproate in Rett syndrome are of comparable consequence in children with other causes of epilepsy [60]. These findings support the need for nutritional, physical, and medical interventions, as well as potential routine checking of bone mineral density in individuals with Rett syndrome. Physicians may consider an anticonvulsant drug for associated comorbidities of Rett syndrome. Medications such as lamotrigine, valproate and topiramate may have additional benefit for the common behavioral abnormalities of Rett syndrome (e.g., screaming, self-injury) [48,61,62]. Conclusions

Epilepsy is a prominent symptom in Rett syndrome and substantially contributes to the morbidity of the disease. Although seizures are not part of the diagnostic criteria for Rett syndrome, epilepsy affects 50%-90% of patients and is part of the severity scale in Rett syndrome [12,13]. Despite its high prevalence, it is still difficult to predict which patients are more prone to development of early seizures and, of those, who will have easily treatable seizures versus intractability. Recognizing typical clinical and EEG patterns may be useful in diagnosis and management, but again these findings are not pathognomonic. Although a bias may exist, given that those children with good seizure control may be inherently underreported, epilepsy can often be quite severe, with evidence suggesting that up to 50% become recalcitrant [15]. The limited data available on the treatment of epilepsy in Rett syndrome would suggest that broad-spectrum anticonvulsants such as valproate and lamotrigine are commonly used, yet topiramate and levetiracetam may hold promise as well. Given the often refractory nature of this condition, physicians should begin to consider the ketogenic diet and VNS earlier in the clinical course because they might be helpful. Future controlled, longterm studies on all therapies for epilepsy in Rett syndrome would be beneficial to further support their implementation. Useful websites for parents

http://www.rettsyndrome.org http://www.ninds.nih.gov/disorders/rett/detail_rett.htm http://www.nichd.nih.gov/health/topics/rett_syndrome.cfm References [1] Rett A. On an unusual brain atrophy syndrome in hyperammonemia in childhood. Wien Med Wochenschr 1966;116: 723e6. [2] Hagberg B, Aicardi J, Dias K, Ramos O. A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett’s syndrome: Report of 35 cases. Ann Neurol 1983;14: 471e9. [3] Neul JL, Kaufmann WE, Glaze DG, et al. Rett syndrome: Revised diagnostic criteria and nomenclature. Ann Neurol 2010;68: 944e50.

[4] Naidu S, Johnston MV. Neurodevelopmental disorders: Clinical criteria for Rett syndrome. Nat Rev Neurol 2011;7:312e4. [5] Hagberg B, Hanefeld F, Percy A, Skjeldal O. An update on clinically applicable diagnostic criteria in Rett syndrome. Comments to Rett Syndrome Clinical Criteria Consensus Panel Satellite to European Paediatric Neurology Society Meeting, Baden Baden, Germany, 11 September 2001. Eur J Paediatr Neurol 2002;6: 293e7. [6] Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY. Rett syndrome is caused by mutation in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet 1999; 23:185e8. [7] Bahi-Buisson N, Nectoux J, Rosas-Vargas H, et al. Key clinical features to identify girls with CDKL5 mutations. Brain 2008;131: 2647e61. [8] Ariani F, Hayek G, Rondinella D, et al. FOXG1 is responsible for the congenital variant of Rett syndrome. Am J Hum Genet 2008;83: 89e93. [9] Chahrour M, Zoghbi HY. The story of Rett syndrome: From clinic to neurobiology. Neuron 2007;56:422e37. [10] Hagberg B. Clinical manifestations and stages of Rett syndrome. Ment Retard Dev Disabil Res Rev 2002;8:61e5. [11] Hagberg B, Witt-Engerstrom I. Rett syndrome: A suggested staging system for describing impairment profile with increasing age towards adolescence. Am J Med Genet 1986;1:47e59. [12] Steffenburg U, Hagberg G, Hagberg B. Epilepsy in a representative series of Rett syndrome. Acta Paediatr 2001;90:34e9. [13] Huppke P, Kohler K, Brockmann K, Stettner GM, Gartner J. Treatment of epilepsy in Rett syndrome. Eur J Paediatr Neurol 2007;11: 10e6. [14] Glaze DG, Percy AK, Skinner S, et al. Epilepsy and the natural history of Rett syndrome. Neurology 2010;74:909e12. [15] Nissenkorn A, Gak E, Vecsler M, Reznik H, Menascu S, Ben Zeev B. Epilepsy in Rett syndromedThe experience of a National Rett Center. Epilepsia 2010;51:1252e8. [16] Nieto-Barrera M, Nieto-Jimenez M, Diaz F, et al. Clinical course of epileptic seizures in Rett’s syndrome. Rev Neurol 1999;28: 449e53. [17] Cardoza B, Clarke A, Wilcox J, et al. Epilepsy in Rett syndrome: Association between phenotype and genotype, and implications for practice. Seizure 2011;20:646e9. [18] Pintaudi M, Caleva MG, Vignoli A, et al. Epilepsy in Rett syndrome: Clinical and genetic features. Epilepsy Behav 2010;19:296e300. [19] Krajnc N, Zupancic N, Orazem J. Epilepsy treatment in Rett syndrome. J Child Neurol 2011;26:1429e33. [20] Glaze DG, Frost JD Jr, Zoghbi HY, Percy AK. Rett’s syndrome. Correlation of electroencephalographic characteristics with clinical staging. Arch Neurol 1987;44:1053e6. [21] Hanefeld F. The clinical pattern of the Rett syndrome. Brain Dev 1985;7:320e5. [22] Skjeldal OH, Christen HJ, Hagne I, Hanefeld F, Hagberg B. Early seizure onset in Rett syndrome. Eur Child Adolesc Psychiatry 1997; 6:40e1. [23] Jian L, Nagarajan L, de Klerk N, et al. Predictors of seizure onset in Rett syndrome. J Pediatr 2006;149:542e7. [24] Glaze DG, Schultz RJ, Frost JD. Rett syndrome: Characterization of seizures versus non-seizures. Electroencephalogr Clin Neurophysiol 1998;106:79e83. [25] Glaze DG. Neurophysiology of Rett Syndrome. Ment Retard Dev Disabil Res Rev 2002;8:66e71. [26] Cirignotta F, Lugaresi E, Montagna P. Breathing impairment in Rett syndrome. Am J Med Genet Suppl 1986;1:167e73. [27] Glaze DG, Frost JD Jr, Zoghbi HY, Percy AK. Rett’s syndrome: Characterization of respiratory patterns and sleep. Ann Neurol 1987;21:377e82. [28] Ben-Zeev B, Nissenkorn A, Blatt I. Hand stereotypies, partial motor seizures or giant evoked potentials-a newly described phenomena in Rett syndrome. Abstract 1.092, 2010, American Epilepsy Society Annual Meeting. [29] Sousa PS, Machado FC, Caboclo LO. Nonconvulsive status epilepticus in Rett syndrome: clinical and EEG presentation. Epilepsia 2005;46(Suppl 8):156. Abstract No 2.196. [30] Niedermeyer E, Naidu SB, Plate C. Unusual EEG theta rhythms over central region in Rett syndrome: Considerations of the underlying dysfunction. Clin Electroencephalogr 1997;28:36e43.

A. Dolce et al. / Pediatric Neurology 48 (2013) 337e345 [31] Niedermeyer E, Rett A, Renner H, Murphy M, Naidu S. Rett syndrome and the electroencephalogram. Am J Med Genet Suppl 1986;1:195e9. [32] Trauner DA, Haas RH. Electroencephalographic abnormalities in Rett syndrome. Pediatr Neurol 1987;3:331e4. [33] Moser SJ, Weber P, Lutschg J. Rett syndrome: Clinical and electrophysiologic aspects. Pediatr Neurol 2007;36:95e100. [34] Hagne I, Witt-Engerstrom I, Hagberg B. EEG development in Rett syndrome. A study of 30 cases. Electroencephalogr Clinical Neurophysiol 1989;72:1e6. [35] Garofalo EA, Drury I, Goldstein GW. EEG abnormalities aid diagnosis of Rett syndrome. Pediatr Neurol 1988;4:350e3. [36] Glaze DG. Neurophysiology of Rett syndrome. J. Child Neurol 2005; 20:740e6. [37] Bebbington A, Anderson A, Ravine D, et al. Investigating genotypephenotype relationships in Rett syndrome using an international data set. Neurology 2008;70:868e75. [38] Charman T, Neilson TC, Mash V, et al. Dimensional phenotypic analysis and functional categorisation of mutations reveal novel genotype-phenotype associations in Rett syndrome. Eur J Hum Genet 2005;13:1121e30. [39] Nectoux P, Bahi-Buisson N, Guellec I, et al. The p.Val66Met polymorphism in the BDNF gene protects against early seizures in Rett syndrome. Neurology 2008;70:2145e51. [40] Jian L, Nagarajan L, de Klerk N, Ravine E, Christodoulou J, Leonard H. Seizures in Rett syndrome: An overview from a oneyear calendar study. Eur J Paediatr Neurol 2007;11:310e7. [41] Buoni S, Zannolli R, Felice CD, et al. Drug-resistant epilepsy and epileptic phenotype-EEG association in MECP2 mutated Rett syndrome. Clin Neurophysiol 2008;119:2455e8. [42] Ben Zeev B, Bebbington A, Ho G, et al. The common BDNF polymorphism may be a modifier of disease severity in Rett syndrome. Neurology 2009;72:1242e7. [43] Buoni S, Zannolli R, De Felice C, et al. EEG features and epilepsy in MECP2-mutated patients with the Zappella variant of Rett syndrome. Clin Neurophysiol 2010;121:652e7. [44] Charcour M, Jung SY, Shaw C, et al. MeCP2, a key contributor to neurological disease, activates and represses transcription. Science 2008;320:1224e9. [45] Ogier M, Wang H, Hong E, Wang Q, Greenberg ME, Katz DM. Brainderived neurotrophic factor expression and respiratory function improve after ampakine treatment in a mouse model of Rett syndrome. J Neurosci 2007;27:10912e7. [46] Larimore JL, Chapleau CA, Kudo S, Theibert A, Percy AK, PozzoMiller L. Bdnf overexpression in hippocampal neurons prevents

[47] [48]

[49]

[50]

[51]

[52] [53]

[54]

[55] [56]

[57]

[58] [59] [60] [61]

[62]

345

dendritic atrophy caused by Rett-associated MECP2 mutations. Neurobiol Dis 2009;34:199e211. Uldall P, Hansen FJ, Tonnby B. Lamotrigine in Rett syndrome. Neuropediatrics 1993;24:339e40. Stenbom Y, Tonnby B, Hagberg B. Lamotrigine in Rett syndrome: Treatment experience from a pilot study. Eur Child Adolesc Psychiatry 1998;7:49e52. Goyal M, O’Riordan MA, Wiznitzer M. Effect of topiramate on seizures and respiratory dysrhythmia in Rett syndrome. J Child Neurol 2004;19:588e91. Specchio N, Balestri M, Striano P, et al. Efficacy of levetiracetam in the treatment of drug-resistant Rett syndrome. Epilepsy Res 2010; 88:112e7. Haas RH, Rice MA, Trauner DA, Merritt TA. Therapeutic effects of a ketogenic diet in Rett syndrome. Am J Med Genet Suppl 1986;1: 225e46. Liebhaber GM, Riemann E, Baumeister FA. Ketogenic diet in Rett syndrome. J Child Neurol 2003;18:74e5. Giampietro PF, Schowalter DB, Merchant S, Campbell LR, Swink T, Roa BB. Widened clinical spectrum of the Q128P MECP2 mutation in Rett syndrome. Childs Nerv Syst 2006;22:320e4. Kossoff EH, Zupec-Kania BA, Amark PE, et al. Optimal clinical management of children receiving the ketogenic diet: Recommendations of the International Ketogenic Diet Study Group. Epilepsia 2009;50:304e17. Wilfong AA, Schultz RJ. Vagus nerve stimulation for treatment of epilepsy in Rett syndrome. Dev Med Child Neurol 2006;48:683e6. Topcu M, Yalnizoglu D, Turanli G, et al. Vagus nerve stimulation in children with Rett syndrome. Abstract No 2.298, 2008, American Epilepsy Society Annual Meeting, Souverein PC, Webb DJ, Weil JG, Van Staa TP, Egberts AC. Use of antiepileptic drugs and risk of fractures: case-control study among patients with epilepsy. Neurology 2006;66:1318e24. Vestergaard P, Reinmark L, Mosekilde L. Fracture risk associated with use of antiepileptic drugs. Epilepsia 2004;45:1330e7. Downs J, Bebbington A, Woodhead H, et al. Early determinants of fractures in Rett syndrome. Pediatrics 2008;121:540e6. Leonard H, Downs J, Jian L, et al. Valproate and risk of fracture in Rett syndrome. Arch Dis Child 2010;95:444e8. Comai S, Tau M, Pavlovic Z, Gobbi G. The psychopharmacology of aggressive behavior: A translational approach: Part 2: Clinical studies using atypical antipsychotics, anticonvulsants, and lithium. J Clin Psychopharmacol 2012;32:237e60. Kumandas S, Caksen H, Ciftci A, Ozturk M, Per H. Lamotrigine in two cases of Rett syndrome. Brain Dev 2001;23:240e2.