INTRODUCTION

Infantile epileptic encephalopathies are a group of epilepsies presenting in infancy and characterized by pharmacoresistant seizures, cognitive impairment, and a spectrum of psychiatric and behavioral disorders. Epileptic encephalopathies are defined by “the notion that the epileptic activity itself may contribute to severe cognitive and behavioral impairments above and beyond what might be expected from the underlying pathology alone, and that these can worsen over time. These impairments may be global or more selective and they may occur along a spectrum of severity” (1,2).

Conjoint efforts of clinicians and the spectacular advances of molecular biology tools with massive parallel sequencing technologies have allowed the identification of causal genes in some of these infantile epileptic encephalopathies such as Dravet syndrome or epilepsy of infancy with migrating focal seizures and the description of new genetic syndromes as for patients with PCDH19 or CDKL5 mutations. The recent discoveries of causal genes in this group contribute to the term genetic epilepsies as suggested by the revised terminology of the International League Against Epilepsies (ILAE) and emphasize the key role of these genes in the abnormalities (2).

This chapter focuses on some monogenic genetic epilepsy syndromes of interest for paediatric neurologists and summarizes the impact of gene discovery on diagnosis, genetic counseling, and mechanisms, paving the future way for personalized therapies.

DRAVET SYNDROME

Dravet syndrome (DS) was first described by C. Dravet in 1978 under the terminology of severe myoclonic epilepsy in infancy (SMEI) (3). DS was recognized as an epileptic syndrome in 1989 by the Commission on Classification and Terminology of the International League Against Epilepsy (ILAE) and in the “revised terminology and concepts for organization of seizures and epilepsies” proposed in 2010 (1,2). DS is characterized by febrile and afebrile, generalized and unilateral, clonic or tonic–clonic seizures, which occur in the first year of life in an otherwise normal infant and are later associated with myoclonus, atypical absences, and focal seizures. Seizures are resistant to antiepileptic drugs (AEDs). Developmental delay becomes apparent during the second year and is followed later on by definite cognitive impairment and personality disorders (4). Some patients are considered to have a borderline form of the syndrome (severe myoclonic epilepsy borderline). They present the main clinical features of DS, but myoclonic seizures and atypical absences are not observed. Other patients present with a sole seizure type tonic–clonic seizure; they were described as “childhood epilepsy with intractable grand mal seizures” (5) and “severe idiopathic generalised epilepsy of infancy with generalized tonic–clonic seizures” (ICEGTC) (6).

Clinical and EEG Features

The course of epilepsy in DS can be divided into three stages (Figure 26.1).

The first or “febrile stage” usually lasts from seizure onset until the age of 12 to 15 months. Seizure onset is always before age 1 year and often between 3 and 9 months. The first seizure is usually febrile (70% of patients) with fever related to febrile illness or vaccination, which are both frequent at this age. Typically, the seizure is convulsive, clonic with a focal onset, and invading one side of the body (hemiclonic). The seizure is usually long-lasting, more than 15 minutes, and can evolve into status epilepticus (SE). Neurologic examination and brain imaging (MRI) are normal. This first seizure is often considered a complicated febrile seizure and the diagnosis of DS is rarely suspected. However, the young age of onset should suggest the diagnosis and physicians should institute a close follow-up of such patients. The seizures often recur within a few weeks despite the use of antiepileptic drugs (4). They can be febrile or not, brief, or long-lasting. This sequence is highly pathognomonic and should not be wrongly considered as recurrent complicated febrile seizures. During this stage, the background EEG activity in wakefulness and the organization of sleep are normal (4). Paroxysmal activities are rare and 25% of the patients can present generalized spike-waves (SWs) induced by intermittent photic stimulation (7,8). The diagnosis should be highly suspect at this stage, especially in case of alternating hemiclonic seizures (4,8).

FIGURE 26.1 EEG and clinical stages in patients with Dravet syndrome.

The second stage (12–15 months to 5 years) is characterized by the onset of various seizure types, the beginning of cognitive slowing, and the appearance of gait disturbance. Fever sensitivity remains frequent and, in addition, exercise and external heat can trigger seizures. Pattern sensitivity can also occur at this stage. Various seizure types appear: atypical absences, focal seizures, brief myoclonic seizures, or myoclonic nonconvulsive status described as “obtundation status” (status with consciousness impairment of variable intensity) (4,8). From the second to the fifth year and in almost half the patients, we observe a progressive slowing of the background activity and an increase of paroxysmal anomalies, which are generalized, focal, and multifocal (7,9). The photosensitivity becomes more evident. Eye closure and fixation of patterns can elicit symptomatic or asymptomatic discharges (7,10). Sleep is still well structured with persistence or increase of the anomalies of the wakefulness. Neurologic signs are observed with variable frequencies at this stage: gait delay and gait disturbances in 80%, and moderate pyramidal signs from 50% to 80% (4,8,9).

The third stage is reported in the literature as the “stabilization stage.” This stabilization is not synonymous to improvement but to the chronicity of this syndrome. The seizures tend to decrease but remain pharmacoresistant, and only a few patients become seizure-free despite polytherapies. Nocturnal seizures become predominant with a decrease in convulsive diurnal seizures (4,8,11). Fever sensitivity persists at this stage. At long-term follow-up, the background activity can continue to slow, with an increase of theta activities in the central regions and vertex. The paroxysmal abnormalities can persist or decrease in 19% to 25% of patients, as well as the photosensitivity (11). The organization of sleep remains normal in 70% of patients. The cognitive delay is generally reported after 4 years of age and stabilizes after the age of 6 to 7 years. The decline in the developmental quotient is constant, although variable, and it results from the slowing and stagnation of the psychomotor development rather than from a neurologic regression (12). Patients often present behavior problems with hyperactivity (4,8,12) and autistic features are frequently reported (13).

Etiologies

DS is the prototype of monogenic epilepsy and 80% of patients with DS carry a mutation in SCN1A (14–16). This gene is located on 2q24.3, codes for the α1 subunit of the sodium channel gene, and is required for the initiation and propagation of action potentials. Mutations of SCN1A were first discovered in the epilepsy syndrome of “genetic (previously generalised) epilepsy with febrile seizure plus” (GEFS+) (17). More than 900 mutations have been associated with DS and randomly distributed across the protein. Most mutations are de novo and around 5% to 10% are inherited (15,16). Correlations between phenotypes and genotypes have been studied by different authors but no consensus has been reached (18–20). In addition, intrafamilial clinical variability in epilepsy phenotype was reported, showing the same mutation (21–24). These cases could suggest the presence of other modifying factors such as genes or environmental influences.

Research aimed at identifying mutations in other genes in the remaining 15% to 20% of SCN1A-negative-DS patients has been successful to some extent. Protocadherin 19 (PCDH19) mutations (on chromosome Xq22) were first reported in SCN1A-negative patients (25). Authors reported familial and de novo point mutations in PCDH19 in 13 females presenting a clinical picture similar to Dravet syndrome (25). In another study, 7 (37%) of the 19 patients with SCN1A-negative SMEI were found to have PCDH19 mutations (26). These authors suggest that PCDH19 might account for 5% of DS. The phenotype of these patients differs slightly from the DS typical picture because of later onset, recurrent cluster of brief seizures, a less frequent status epilepticus, and finally a less severe cognitive outcome in some patients (25–27).

Other genes have been reported in a few patients with DS negative for SCN1A as GABRG2, SCN1B, and CHD2 (28–30). However, these patients often do not fulfill the whole criteria for DS, and more patients should be reported in order to draw a clear phenotype.

Genetic Diagnosis and Counseling

Although reported in 80% of patients with DS, SCN1A abnormalities are not exclusively causal of DS, and patients with typical DS might be negative for SCN1A mutations or deletions. SCN1A abnormality can help to confirm the diagnosis that is mainly based on electroclinical features. Finding a mutation would confirm an epilepsy related to SCN1A and help to end large etiologic work up, but might leave the evolution open to either a GEFS+ or a DS, or even to an “unaffected”carrier status in a familial case (21,22).

SCN1A abnormality is usually de novo but might be inherited in almost 10% of patients from one of the parents in autosomal-dominant mode (15,16,21,22). The risk of familial recurrence is 50% when a parent presents the mutation. However, recurrent cases with mutation reported as de novo in the proband might recur in a sibling because of parental germinal mosaicism (31,32). Genetic counseling should consider this risk and inform the families even when their child with DS has de novo mutation. Antenatal diagnosis can be proposed.

Outcome

In adolescence and adulthood, seizure frequency tends to progressively decrease and to occur mainly during night time (4,11,33). Fever sensitivity might persist but convulsive status epilepticus, photosensitivity, and pattern stimulation tend to decrease. The motor abilities are usually reduced, due to a combination of neurologic signs: ataxia, tremor, and clumsiness of fine movements and skeletal abnormalities (kypho-scoliosis), leading to a peculiar posture named “a crouch gait” (34). The decline in the developmental quotient is constant, although variable in different studies (12,35). This decline is not due to a regression as in neurodegenerative diseases (12). Nonetheless, a few patients have normal intellectual abilities after the age of 6 (36,37).

Behavioral disorders are frequently observed, most often hyperactivity, attention deficit, opposing and provocative behavior, and poor danger awareness (4,12,35,37). Autism should be explored and might be underdiagnosed in this population (13).

Feeding difficulties are frequently reported with anorexia and weight loss, and some patients require transitory tube feeding.

Treatment of Patients With DS

The management of patients with DS includes the treatment of seizures and the management of comorbidities.

Antiepileptic Drugs (AEDs)

Valproate (VPA) is usually the first AED prescribed after the first long-lasting seizure. It is usually associated as the next step to benzodiazepines (BDZs); the most commonly used are clonazepam (CZP) and clobazam (CLB).

Stiripentol (STP) is an orphan drug with a paediatric AMM for DS. It is used as adjunctive therapy with VPA and CLB for refractory generalized tonic–clonic seizures in patients with DS (38). Topiramate (TPM) is useful in controlling convulsive and focal seizures (39,40). Ketogenic diet (KD) showed efficacy in patients with DS (41,42). Other AEDs might be used as possible adjunctive therapy: levetiracetam, ethosuximide, zonisamide, and bromide. Patients with DS are not candidates for respective epilepsy surgery. Vagus nerve stimulation might reduce seizure rate, improving the quality of life (43).

Some AEDs might worsen seizures: carbamazepine (CBZ) and lamotrigine (LTG) for convulsive and myoclonic seizures, or phenytoin (PHT) and vigabatrin for myoclonic jerks (44).

Two AEDs, fenfluramine and cannabidiol, have obtained the designation as orphan drugs for DS with ongoing trials to confirm the efficacy and safety.

Management of Comorbidities

Besides pharmacoresistant seizures, patients with DS, as for other infantile epileptic encephalopathies, present with various comorbidities that should be evaluated and treated. Cognitive evaluations should individuate delayed milestones and organize the appropriate educative and rehabilitation program for each child. Management of behavioral disorders and psychologic support is warranted for all children with DS with follow up during childhood and throughout adolescence and adulthood (45). Treatments for hyperactive behavior can include, in addition to educational therapy, drugs such as methylphenidate. Patients with DS usually present with sleep disorders, induced in part by nocturnal/sleep seizures. The prescription of melatonin as sleep inducers is useful. Feeding difficulties are frequently reported by carers of patients with anorexia and weight loss. This problem is often exacerbated by AEDs; in some patients, decreasing the AED doses can be helpful. The involvement of a nutritionist in the general management of patients with feeding problems should be encouraged. Furthermore, other specific care includes speech therapy, physiotherapy, and psychomotricity for the motor impairment, as well as orthopaedic follow-up for kyphoscoliosis and foot deformities, especially in adult life (34).

EPILEPSY IN PATIENTS WITH PCDH19 MUTATIONS

Introduction

PCDH19 is expressed in the developing brain and is postulated to be involved in establishing neuronal connections and signal transduction at the synaptic membrane level (46) and molecular specification of neurons in the cerebral cortex (47). It has been associated with “epilepsy and mental retardation limited to females,” in females with sporadic Dravet-like syndrome, and the spectrum has extended to focal epilepsy.

Clinical Features

Epilepsy and Mental Retardation Limited to Females (EFMR)

Protocadherin 19 (PCDH19) female-limited epilepsy, PCDH19-FE, also known as epilepsy and mental retardation limited to females (EFMR) is an infantile onset epilepsy syndrome with or without intellectual disability (ID) and autism. EFMR was first described in a large family in which 15 females, related through normal fathers and affected mothers, had an epilepsy of early onset associated with mental retardation (48). This unusual inheritance pattern was called X-linked inheritance with male sparing (49). Affected girls appeared normal until 4 to 18 months of age, when they began to have focal and generalized seizures that gradually increased in frequency and were accompanied by developmental regression. In most patients, the frequency of seizures declined by the age of 2 to 3 years, but cognitive development remained markedly impaired, ranging from profound to slight delay. None presented with motor delay (48).

Four additional unrelated families with EFMR were reported (50). All affected females had seizures at some stage at a mean age of seizure onset of 14 months (range 6 to 36 months). The seizures were triggered by fever in 63% of patients. The seizures were polymorphous and included tonic–clonic (26), focal (11), absence (5), tonic (4), atonic (3), and myoclonic (4) seizures. The seizures ceased at a mean age of 12 years. Development was variable but most reported patients (67%) had intellectual disability. Psychiatric features were prominent with autism spectrum disorders and behavioral problems (50). Females with EFMR showed mutations in PCDH19, which was established as the causal gene in this group (51).

Patients With PCDH19 Mutations and Dravet Syndrome-Like Phenotype

In a series of 40 patients with DS negative to SCN1A, Depienne et al reported PCDH19 familial and de novo point mutations in 13 females (25). In another study, 7 (37%) of the 19 sporadic patients with SCN1A-negative DS were found to have PCDH19 mutations (26). These authors suggest that PCDH19 might account for 5% of DS. Patients with PCDH19 mutations present differences with the classical phenotype of DS, mainly a later onset of epilepsy, predominantly focal and less polymorphous seizures, less status epilepticus with seizures occurring in clusters, and finally a better seizure outcome with long periods of seizure freedom between the clusters (25–27,52,53). Both phenotypes, patients with PCDH19 and DS mutations, share early onset in infancy or early childhood, persistent high sensitivity to fever, and various degrees of mental delay and psychiatric and behavioral disorders (52).

Electroclinical Features

A detailed description of seizures semiology was reported in 34 female patients with PCDH19 mutations (91% were de novo) (53). Clusters of focal febrile and afebrile seizures had occurred in all patients, at a mean age of 10 months. The predominant ictal sign was fearful screaming. Seizures on video-EEG showed a stereotyped pattern with both focal and generalized seizures, the latter consisting of absences and myoclonus. Ictal EEG during focal seizures showed a major involvement of the frontotemporal regions, suggesting an epileptogenic dysfunction involving the frontotemporal limbic system. Status epilepticus occurred in 30% of patients.

PCDH19 shares some similarities with SCN1A regarding its wide phenotypic spectrum that encompasses epilepsies with febrile seizures, normal intellect, and severe epileptic encephalopathies. PCDH19 mutations occur predominantly in females.

Gene and Mechanisms

Since the PCDH19 gene is subject to X inactivation, hemizygous-transmitting males likely have a homogeneous population of PCDH19-negative cells, whereas affected females are likely to be mosaic, comprising a mixed population of PCDH19-negative and PCDH19-wild type cells. This might explain the unaffected status of hemizygous males and the affected status of females with tissue mosaicism in females. One male patient presented with mosaic PCDH19, and like a heterozygous female presented the DS phenotype (25). This mechanism, termed cellular interference, is a major issue for genetic counseling in patients with PCDH19 (25,27).

The study of transcriptomes of PCDH19-FE and control primary skin fibroblasts showed a dysregulation in some proteins involved in the metabolism of steroids, mainly AKR1C3 (54). AKR1C1-3 encode steroid hormone-metabolizing enzymes whose key products include allopregnanolone and estradiol. Concordantly, the blood levels of allopregnanolone were also reduced in patients with PCDH19 mutations. This study suggested that the deficiency of neurosteroid allopregnanolone, one of the most potent GABA receptor modulators, may contribute to PCDH19-FE and opened possible opportunities for targeted therapy (54).

Treatment

There are no specific treatments for this rare epilepsy and future studies based on the input mechanisms due to the gene alteration are expected. In some patients showing a phenotype similar to DS, the same AEDs used in DS are prescribed with some efficacy (valproate, clobazam, and stiripentol). It is often difficult to control the occurrence of clusters during febrile illness, and rescue therapy with benzodiazepine are usually used. A tailored rehabilitation program with a multidsciplinary team encompassing a child psychiatrist is often needed for patients with ASD and ID (55).

EPILEPSY OF INFANCY WITH MIGRATING FOCAL SEIZURES

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