Xp22.3 genomic deletions involving the CDKL5 gene in girls with early onset epileptic encephalopathy

Purpose : Mutations of the X‐linked gene cyclin‐dependent kinase‐like 5 (CDKL5) cause an X‐linked encephalopathy with early onset intractable epilepsy, including infantile spasms and other seizure types, and a Rett syndrome (RTT)–like phenotype. Very limited information is available on the frequency and phenotypic spectrum associated with CDKL5 deletions/duplications. We investigated the role of CDKL5 deletions/duplications in causing early onset intractable epilepsy of unknown etiology in girls. Methods : We studied 49 girls with early onset intractable epilepsy, with or without infantile spasms, and developmental impairment, for whom no etiologic factors were obvious after clinical examination, brain magnetic resonance imaging (MRI) and expanded screening for inborn errors of metabolism. We performed CDKL5 gene mutation analysis in all and multiplex ligation dependent probe amplification assay (MLPA) in those who were mutation negative. Custom Array‐comparative genomic hybridization (CGH), breakpoint polymerase chain reaction (PCR) analysis, and X‐inactivation studies were performed in patients in whom MLPA uncovered a genomic alteration. Results : We found CDKL5 mutations in 8.2% (4 of 49) of patients and genomic deletions in 8.2% (4 of 49). Overall, abnormalities of the CDKL5 gene accounted for 16.3% (8 of 49) of patients. Discussion : CDKL5 gene deletions are an under‐ascertained cause of early onset intractable epilepsy in girls. Genetic testing of CDKL5, including both mutation and deletion/duplication analysis, should be considered in this clinical subgroup.     

CDKL5 alterations lead to early epileptic encephalopathy in both genders

Purpose: Genetic mutations of the cyclin‐dependent kinase‐like 5 gene (CDKL5) have been reported in patients with epileptic encephalopathy, which is characterized by intractable seizures and severe‐to‐profound developmental delay. We investigated the clinical relevance of CDKL5 alterations in both genders. Methods: A total of 125 patients with epileptic encephalopathy were examined for genomic copy number aberrations, and 119 patients with no such aberrations were further examined for CDKL5 mutations. Five patients with Rett syndrome, who did not show methyl CpG‐binding protein 2 gene (MECP2) mutations, were also examined for CDKL5 mutations. Key Findings: One male and three female patients showed submicroscopic deletions including CDKL5, and two male and six female patients showed CDKL5 nucleotide alterations. Development of early onset seizure was a characteristic clinical feature for the patients with CDKL5 alterations in both genders despite polymorphous seizure types, including myoclonic seizures, tonic seizures, and spasms. Severe developmental delays and mild frontal lobe atrophies revealed by brain magnetic resonance imaging (MRI) were observed in almost all patients, and there was no gender difference in phenotypic features. Significance: We observed that 5% of the male patients and 14% of the female patients with epileptic encephalopathy had CDKL5 alterations. These findings indicate that alterations in CDKL5 are associated with early epileptic encephalopathy in both female and male patients.     

Epilepsy in Rett syndrome,and CDKL5‐ and FOXG1‐gene–related encephalopathies

Rett syndrome is an X‐linked neurodevelopmental disorder that manifests in early childhood with developmental stagnation, and loss of spoken language and hand use, with the development of distinctive hand stereotypies, severe cognitive impairment, and autistic features. About 60% of patients have epilepsy. Seizure onset before the age of 3 years is unlikely, and onset after age 20 is rare. Diagnosis of Rett syndrome is based on key clinical elements that identify “typical” Rett syndrome but also “variant” or “atypical” forms. Diagnostic criteria have been modified only slightly over time, even after discovering that MECP2 gene alterations are present in >90% of patients with typical Rett syndrome but only in 50–70% of atypical cases. Over the last several years, intragenic or genomic alterations of the CDKL5 and FOXG1 genes have been associated with severe cognitive impairment, early onset epilepsy and, often, dyskinetic movement disorders, which have variably been defined as Rett variants. It is now clearly emerging that epilepsy has distinctive characteristics in typical Rett syndrome and in the different syndromes caused by CDKL5 and FOXG1 gene alterations. The progressive parting of CDKL5‐ and FOXG1‐gene–related encephalopathies from the core Rett syndrome is reflected by the effort to produce clearer diagnostic criteria for typical and atypical Rett syndrome. Efforts to characterize the molecular pathology underlying these developmental encephalopathies are pointing to abnormalities of telencephalic development, neuronal morphogenesis, maturation and maintenance, and dendritic arborization.     

Clinical features of early myoclonic encephalopathy caused by a CDKL5 mutation

BackgroundCDKL5 deficiency is caused by mutations in the cyclin-dependent kinase-like 5 (CDKL5) gene and clinically manifests often in females as drug-resistant intractable epilepsy and severe psychomotor retardation.Case reportWe report the case of a girl with a CDKL5 mutation born at 39 weeks without neonatal asphyxia. She developed epilepsy at age 1 month with myoclonus of the face and limbs, and non-rhythmic and irregular opsoclonus. She developed tonic seizures and epileptic spasms at 6 months of age and was diagnosed with symptomatic West syndrome and underwent adrenocorticotropic hormone therapy but her seizures were refractory. At the age of 4, she was introduced to our hospital and development was at 2 months of age. We diagnosed her with early myoclonic encephalopathy (EME) due to the remaining suppression-burst pattern observed on an electroencephalogram and her symptoms since onset were mainly myoclonus. At 14 years of age, mutational analysis revealed a CDKL5 mutation (c.380A > G:p.His127Arg). She was diagnosed with epileptic encephalopathy exhibiting clinical features of early myoclonic epilepsy caused by CDKL5 deficiency.ConclusionsEarly onset epilepsy with severe psychomotor retardation without a known etiology may be caused by a mutation in CDKL5. More research investigating a genotype-phenotype correlation of CDKL5 mutations is necessary because clinical severity may be associated with the location and type of mutations.     

Characteristic phasic evolution of convulsive seizure in PCDH19‐related epilepsy

PCDH19‐related epilepsy is a genetic disorder that was first described in 1971, then referred to as “epilepsy and mental retardation limited to females”. PCDH19 has recently been identified as the responsible gene, but a detailed characterization of the seizure manifestation based on video‐EEG recording is still limited. The purpose of this study was to elucidate features of the seizure semiology in children with PCDH19‐related epilepsy. To do this, ictal video‐EEG recordings of 26 convulsive seizures in three girls with PCDH19‐related epilepsy were analysed. All seizures occurred in clusters, mainly during sleep accompanied by fever. The motor manifestations consisted of six sequential phases: “jerk”, “reactive”, “mild tonic”, “fluttering”, “mild clonic”, and “postictal”. Some phases were brief or lacking in some seizures, whereas others were long or pronounced. In the reactive phase, the patients looked fearful or startled with sudden jerks and turned over reactively. The tonic and clonic components were less intense compared with those of typical tonic‐clonic seizures in other types of epilepsy. The fluttering phase was characterised initially by asymmetric, less rhythmic, and less synchronous tremulous movement and was then followed by the subtle clonic phase. Subtle oral automatism was observed in the postictal phase. The reactive, mild tonic, fluttering and mild clonic phases were most characteristic of seizures of PCDH19‐related epilepsy. Ictal EEG started bilaterally and was symmetric in some patients but asymmetric in others. It showed asymmetric rhythmic discharges in some seizures at later phases. The electroclinical pattern of the phasic evolution of convulsive seizure suggests a focal onset seizure with secondary generalisation. Based on our findings, we propose that the six unique sequential phases in convulsive seizures suggest the diagnosis of PCDH19‐related epilepsy when occurring in clusters with or without high fever in girls. [Published with video sequences online]     

CDKL5 gene-related epileptic encephalopathy: electroclinical findings in the first year of life

Aim Cyclin‐dependent kinase‐like 5 (CDKL5) gene abnormalities cause an early‐onset epileptic encephalopathy. We performed video‐electroencephalography (video‐EEG) monitoring early in the course of CDKL5‐related epileptic encephalopathy in order to examine the early electroclinical characteristics of the condition. Method We used video‐EEG to monitor six infants (five females, one male) with CDKL5‐related epileptic encephalopathy (five mutations; one deletion), at ages 45 days to 12 months and followed them up to the ages of 14 months to 5 years (mean age 23mo). We focused our analysis on the first year of life. The results were evaluated against those of a comparison group of nine infants (aged below 1y) with epileptic encephalography who had tested negative for CDKL5 mutations and deletions. Results One infant exhibited normal background activity, three exhibited moderate slowing, and two exhibited a suppression burst pattern. Two participants had epileptic spasms and four had a stereotyped complex seizure pattern, which we defined as a ‘prolonged’ generalized tonic–clonic event consisting of a tonic–tonic/vibratory contraction, followed by a clonic phase with series of spasms, gradually translating into repetitive distal myoclonic jerks. Seizure duration ranged from 2 to 4 minutes. The EEG correlate of each clinical phase included an initial electrodecremental event (tonic vibratory phase), irregular series of sharp waves and spike slow waves (clonic phase with series of spasms), and bilateral rhythmic sharp waves (time locked with myoclonus). Interpretation Infants with CDKL5‐related early epileptic encephalopathy can present in the first year of life with an unusual electroclinical pattern of ‘prolonged’ generalized tonic–clonic seizures.     

The three stages of epilepsy in patients with CDKL5 mutations

Mutations in the X-linked cyclin-dependent kinase-like 5 ( CDKL5 ) gene are responsible for a severe encephalopathy with early epilepsy. So far, the electroclinical phenotype remains largely unknown and no clear genotype–phenotype correlations have been established.
Purpose: To characterize the epilepsy associated with CDKL5 mutations and to look for a relationship between the genotype and the course of epilepsy.
Methods : We retrospectively analyzed the electroclinical phenotypes of 12 patients aged from 2.5 to 19 years diagnosed with pathogenic CDKL5 mutations and one patient with a novel intronic sequence variation of uncertain pathogenicity and examined whether the severity of the epilepsy was linked to the type and location of mutations.
Results : The epilepsy course reveals three successive stages: (Stage I) early epilepsy (onset 1–10 weeks) with normal interictal electroencephalogram (EEG) (10/13) despite frequent convulsive seizures; (Stage II) epileptic encephalopathy with infantile spasms (8/8) and hypsarrhythmia (8/8). At the age of evaluation, seven patients were seizure free and six had developed refractory epilepsy (stage III) with tonic seizures and myoclonia (5/6).
  Interestingly, the patients carrying a CDKL5 mutations causing a truncation of the catalytic domain tended to develop a more frequent refractory epilepsy than patients with mutations located downstream (4/6, 66.6% versus 1/6, 16%) although, these trends are not yet significant.
Discussion : Our data contribute to a better definition of the epileptic phenotype in CDKL5 mutations, and might give some clues to a potential relationship between the phenotype and the genotype in these patients.     

Phenotypic manifestations between male and female children with CDKL5 mutations

BackgroundCyclin-dependent kinase-like 5 (CDKL5), which maps to chromosome Xp22.13 and contains 20 coding exons, has been recognized as the gene responsible for early-onset epileptic encephalopathy (EoEE). A retrospective study is carried out to analyze potential genotypic and phenotypic differences between male and female patients with CDKL5 mutations.Materials and methodsTargeted next-generation DNA sequencing was employed to search for mutations in patients with cryptogenic EE. A total of 44 patients with EoEE/infantile spasms (ISs)/West syndrome were enrolled for pathogenic mutation screening. The clinical phenotypes of patients with CDKL5 mutations were analyzed and compared with those of 166 published cases.ResultsOne novel and three recurrent mutations were found in four enrolled patients (two boys and two girls). One female patient had partial seizures during the early infantile period and epileptic spasms and tonic seizures several weeks thereafter. The other female patient had IS with hypsarrhythmia. The two male patients had IS without typical hypsarrhythmia and were bedridden. Brain MRIs of the male patients revealed brain atrophy and white matter hyperintensity. The female patients exhibited autistic features with hand stereotypies.ConclusionOur study highlights that both girls and boys with IS harbor CDKL5 mutations. Male children with CDKL5 mutations demonstrate a higher frequency of infantile spasms and brain atrophy, whereas female children often exhibit atypical Rett syndrome with EoEE. In addition, male children have a more severe phenotype than female children.     

Assessing quantitative EEG spectrograms to identify non‐epileptic events

Aims. To evaluate the sensitivity and specificity of quantitative EEG (QEEG) spectrograms in order to distinguish epileptic from non‐epileptic events. Methods. Seventeen patients with paroxysmal non‐epileptic events, captured during EEG monitoring, were retrospectively assessed using QEEG spectrograms. These patients were compared to a control group of 13 consecutive patients (ages 25‐60 years) with epileptic seizures of similar semiology. Assessment of raw EEG was employed as the gold standard against which epileptic and non‐epileptic events were validated. QEEG spectrograms, available using Persyst 12 EEG system integration software, were each assessed with respect to their usefulness to distinguish epileptic from non‐epileptic seizures. The given spectrogram was interpreted as indicating a seizure if, at the time of the clinically identified event, it showed a visually significant change from baseline. Results. Eighty‐two clinically identified paroxysmal events were analysed (46 non‐epileptic and 36 epileptic). The “seizure detector trend analysis” spectrogram correctly classified 33/46 (71%) non‐epileptic events (no seizure indicated during a clinically identified event) vs. 29/36 (81%) epileptic seizures (seizure indicated during a clinically identified event) (p=0.013). Similarly, “rhythmicity spectrogram”, FFT spectrogram, “asymmetry relative spectrogram”, and integrated‐amplitude EEG spectrogram detected 28/46 (61%), 30/46 (65%), 22/46 (48%) and 27/46 (59%) non‐epileptic events vs. 27/36 (75%), 25/36 (69%), 25/36 (69%) and 27/36 (75%) epileptic events, respectively. Conclusions. High sensitivities and specificities for QEEG seizure detection analyses suggest that QEEG may have a role at the bedside to facilitate early differentiation between epileptic seizures and non‐epileptic events in order to avoid unnecessary administration of antiepileptic drugs and possible iatrogenic consequences.     

Persistent frequent subclinical seizures and memory impairment after clinical remission in smoldering limbic encephalitis

Aim. To delineate a possible correlation between clinical course and EEG abnormalities in non‐infectious “smoldering” limbic encephalitis. Methods. Long‐term clinical data, including video‐EEG monitoring records, were analysed in two patients. Results. The two patients were positive for anti‐voltage‐gated potassium channel complex antibody and unspecified antineuronal antibody, respectively. The latter patient had small cell lung carcinoma. Both patients had memory impairment and clinical seizures. EEG showed frequent subclinical seizure patterns in the bilateral temporal regions. Subclinical seizure patterns and memory impairment persisted over one to two years after clinical seizure remission. Therapy (prednisolone and chemoradiation in the two patients, respectively) resulted in decreased occurrence of subclinical seizure patterns and memory improvement. Conclusions. EEG seizure patterns may persist years after clinical seizure remission in “smoldering” limbic encephalitis and lead to memory impairment.     

Biallelic SZT2 variants in a child with developmental and epileptic encephalopathy

Developmental and epileptic encephalopathy is a group of conditions characterized by the co‐occurrence of epilepsy and intellectual disability, in which there is additional developmental impairment independent of epileptic activity. Biallelic variants of SZT2, a known seizure threshold regulator gene, have been linked to a wide spectrum of clinical features, ranging from severe intellectual disability with refractory seizures to mild intellectual disability without seizures. Here, we describe a child with developmental and epileptic encephalopathy whose genetic testing led to the identification of novel biallelic variants of SZT2, a paternally inherited c.2798C>T, p.(Ser933Phe) variant and a maternally inherited c.4549C>T, p.(Arg1517Trp) variant. Our patient showed common clinical and radiographic features among patients with SZT2‐related encephalopathy. However, neonatal‐onset seizures and suppression‐burst EEG activity, not previously associated with SZT2‐related encephalopathy, were observed in this case. Although the seizures were controlled with carbamazepine, the developmental consequences remained profound, suggesting that the developmental impairments might be attributed to a direct effect of the SZT2 variants rather than the epileptic activity. We propose that SZT2 variants should be regarded among those that are believed to cause neonatal‐onset developmental and epileptic encephalopathy with a suppression‐burst pattern on EEG.     

The epileptology of GNB5 encephalopathy

Pathogenic variants in GNB5 cause an autosomal recessive neurodevelopmental disorder with neonatal sinus bradycardia. Seizures or epilepsy occurred in 10 of 22 previously reported cases, including 6 children from one family. We delineate the epileptology of GNB5 encephalopathy. Our nine patients, including five new patients, were from seven families. Epileptic spasms were the most frequent seizure type, occurring in eight of nine patients, and began at a median age of 3 months (2 months to 3 years). Focal seizures preceded spasms in three children, with onset at 7 days, 11 days, and 4 months. One child presented with convulsive status epilepticus at 6 months. Three children had burst suppression on electroencephalography (EEG), three had hypsarrhythmia, and one evolved from burst suppression to hypsarrhythmia. Background slowing was present in all after age 3 years. Magnetic resonance imaging (MRI) showed cerebral atrophy in one child and cerebellar atrophy in another. All nine had abnormal development prior to seizure onset and ultimately had profound impairment without regression. Hypotonia was present in all, with contractures developing in two older patients. All individuals had biallelic pathogenic variants in GNB5, predicted by in silico tools to result in protein truncation and loss‐of‐function. GNB5 developmental and epileptic encephalopathy is characterized by epileptic spasms, focal seizures, and profound impairment.     

Epileptic seizures and headache/migraine: A review of types of association and terminology

PurposeThere are different possible temporal associations between epileptic seizures and headache attacks which have given rise to unclear or controversial terminologies. The classification of the International League Against Epilepsy does not refer to this type of disorder, while the International Classification of Headache Disorders (ICHD-2) defines three kinds of association: 1. migraine-triggered seizure (“migralepsy”), 2. hemicrania epileptica, and 3. post-ictal headache.MethodsWe performed an extensive review of the literature, not including “post-ictal” and “inter-ictal” headaches.ResultsOn the basis of well-documented reports, the following clinical entities may be identified: (A) “epileptic headache (EH)” or “ictal epileptic headache (IEH)”: in this condition headache (with or without migrainous features) is an epileptic manifestation per se, with onset, and cessation if isolated, coinciding with the scalp or deep EEG pattern of an epileptic seizure. EH maybe followed by other epileptic manifestations (motor/sensory/autonomic); this condition should be differentiated from “pure” or “isolated” EH, in which headache/migraine is the sole epileptic manifestation (requiring differential diagnosis from other headache forms). “Hemicrania epileptica” (if confirmed) is a very rare variant of EH, characterized by ipsilateral location of headache and ictal EEG paroxysms. (B) “Pre-ictal migraine” and “pre-ictal headache”: when a headache attack is followed during, or shortly after, by a typical epileptic seizure. The migraine attack may be with or without aura, and its seizure-triggering role (“migraine-triggered seizure”) is still a subject of debate. A differentiation from occipital epilepsy is mandatory. The term “migralepsy” has not been used uniformly, and may therefore led to misinterpretation.ConclusionsOn the basis of this review we suggest definitions and a terminology which may become the basis of a forthcoming classification of headaches associated with epileptic seizures.     

Historic, clinical, and prognostic features of epileptic encephalopathies caused by CDKL5 mutations

Mutations within the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene are important causes of early-onset epileptic encephalopathies. We sought to determine the historic, clinical, and prognostic features of epilepsy secondary to CDKL5 mutations. We performed retrospective chart reviews of children at our institution with epilepsy and CDKL5 mutations. Six children were identified. One manifested a deletion in exons 10-15 of the CDKL5 gene, another manifested a single base-pair duplication in exon 3, and the rest manifested base-pair exchanges. The mean age of seizure onset was 1.8 months (range, 1-3 months). Although the majority (4/6, 67%) presented with partial-onset seizures, all children developed infantile spasms. All children demonstrated developmental delay and visual impairment. Although such mutations are X-linked, two children were boys. They did not present with more severe phenotypes than their female counterparts. Despite trials of antiepileptic drugs (mean, 5; range, 3-7), steroids/adrenocorticotropic hormone (4/6; 67%), and the ketogenic diet (6/6; 100%), all children manifested refractory seizures at last follow-up. Although no treatment eliminated seizures, topiramate, vigabatrin, and the ketogenic diet were most helpful at reducing seizure frequency.     

Measurable outcomes for pediatric epileptic encephalopathy: a single‐center experience with corticosteroid therapy

Objective: Corticosteroids are commonly used to treat refractory epilepsy in children, but the heterogeneity of the population and lack of standardized outcome measures have limited understanding of their effectiveness. We conducted a single‐center study of corticosteroids for epileptic encephalopathy to (a) identify domains for measurement and estimate potential effect sizes, (b) characterize heterogeneity, and (c) identify outcomes that may need better tools for measurement. Methods: In this retrospective single‐center cohort study, children with epileptic encephalopathy (excluding infantile spasms) were treated with a standardized course of oral dexamethasone or IV methylprednisolone. Long‐term video electroencephalography (EEG) was assessed via novel ordinal scales for five features: seizure semiology/burden, epileptiform activity, slowing, organization, and sleep architecture. We abstracted parental assessment of functional domains (i.e., cognition) from the medical records. Pre‐treatment and post‐treatment EEG features, functional domains, and treatment regimens were compared. Results: Thirty‐five children with refractory epilepsy were included. Overall, 16/35 (46%) of individuals had a >50% reduction in seizure frequency from the pre‐treatment EEG to the initial post‐treatment EEG. In particular, tonic seizures (in a subset of 23 children) were reduced (24‐hour tonic seizure count pre‐treatment was 8 [4‐13] and 3 [1‐5] post‐treatment EEG#1, p=0.04). For follow‐up post‐treatment EEGs, there was: (1) better formation of sleep spindles (37% normal pre‐treatment to 63% normal post‐treatment; p=0.04); and (2) improvement in parental reported cognition (in 43%). Improved cognition was the only outcome that differed between the dexamethasone and methylprednisolone treated groups (58% for dexamethasone [n=11/19] vs. 25% for methylprednisolone [n=4/16]; p=0.03). Significance: Large studies should be powered to detect reductions in seizures (particularly tonic as we identified a 2.6‐fold reduction), improved EEG organization, and improved sleep architecture (21 percentage points). Cognitive improvements following steroid treatment, reported by parents, should be quantified and fully characterized in future work.     

Developmental and epileptic encephalopathies: recognition and approaches to care

The term “developmental and epileptic encephalopathy” (DEE) refers to when cognitive functions are influenced by both seizure and interictal epileptiform activity and the neurobiological process behind the epilepsy. Many DEEs are related to gene variants and the onset is typically during early childhood. In this setting, neurocognition, whilst not improved by seizure control, may benefit from some precision therapies. In patients with non‐progressive diseases with cognitive impairment and co‐existing epilepsy, in whom the epileptiform activity does not affect or has minimal effect on function, the term “developmental encephalopathy” (DE) can be used. In contrast, for those patients with direct impact on cognition due to epileptic or epileptiform activity, the term “epileptic encephalopathy” (EE) is preferred, as most can revert to their normal or near normal baseline cognitive state with appropriate intervention. These children need aggressive treatment. Clinicians must tailor care towards individual needs and realistic expectations for each affected person; those with DE are unlikely to gain from aggressive antiseizure medication whilst those with EE will gain. Patients with DEE might benefit from a precision medicine approach in order to reduce the overall burden of epilepsy.