Clinical usefulness and challenges of instrumented motion analysis in patients with intellectual disabilities.

BACKGROUND: Clinical laboratory testing of locomotor disorders is challenging in patients with intellectual disability (ID). Nevertheless, also in this population gait analysis has substantial value as motor problems are common. To promote its use, adequate protocols need to be developed and the impact on clinical decision making needs to be documented. RESEARCH QUESTION: What is the clinical usefulness of instrumented motion analysis in patients with ID? METHOD: This narrative review consists of three parts. A literature review was performed to describe the gait pattern of patients with ID. Next, benefits and challenges of standard gait analysis protocols are described. Finally, a case of a girl with ID due to genetic cause showing gait abnormalities is discussed. RESULTS: The literature review resulted in 20 studies on "gait" in patients with an "ID", published since August, 1st 2013. Gait deviations were observed in all studies investigating the ID population with an underlying genetic syndrome. Observed gait deviations in the ID population might be attributed to physical characteristics, cognitive components or both. The main goal of clinical gait assessment is the identification of gait deviations and the evaluation of their progress over time, in order to optimize the treatment plan. The choice of adequate method and measurement modalities depends on the clinical goal, the available resources and the abilities of the patient. In the case report we presented, we succeeded in performing an instrumented 3D gait analysis in a girl with severe ID at the ages of 4y4m, 6y0m, 7y2m and 8y2m. Progressive gait deviations were found suggesting a crouch gait pattern was developing. Results of the gait analysis led to the prescription of rigid ankle-foot orthoses. SIGNIFICANCE: Gait analysis has substantial value for patients with ID. Gait analysis allows clinicians to objectify the relationship between physical characteristics and gait features.

Retinal haemorrhages in a university hospital: not always abusive head injury.

Retinal haemorrhages (RH) and subdural haematomas (SDH) are frequently seen in abusive head trauma (AHT). The aim of our study is to show that they are suggestive, but not pathognomonic for AHT. We performed an observational retrospective study on children, aged 1-18 months old, admitted to the Antwerp University Hospital with RH. History, physical examination, medical course, coagulation and metabolic tests, skeletal survey, head circumference, retinal findings, cerebral imaging, and evaluation reports by social services or civil/criminal courts were collected. Twenty-nine children with RH were included. Twenty three of them were found suspect of AHT. Three children of this group showed intraparenchymal haematomas/infarctions, 5 interhemispheric blood, 6 cerebral oedema, 7 ventricle compression, and 4 papilloedema. Seven of the 16 children with diffusion-weighted MRI images showed diffuse lesions. In 2 of the 6 children not suspect for AHT, an aetiology was found. None of the 4 remaining children showed the above-mentioned abnormalities. Three of these 4 cases showed an accelerated growth of the head circumference months before presentation. The majority of the children in all groups showed 'too numerous to count' (>20) RH (12 of the 23 'suspect' children, and 4 of the 6 'non-suspect' children). Results showed no differences between the groups concerning the location, distribution, or size of the RH. Infants with RH and/or SDH are not necessarily victims of AHT. Cerebral imaging and retinal findings can help differentiate suspect from non-suspect cases. Infants with a large head circumference could be predisposed to RH or SDH.

Low-dose fenfluramine significantly reduces seizure frequency in Dravet syndrome: a prospective study of a new cohort of patients.

BACKGROUND AND PURPOSE: Dravet syndrome (DS) is a severe, drug-resistant epilepsy. Fenfluramine has been reported to have a long-term clinically meaningful anticonvulsive effect in patients with DS. METHODS: This prospective, open-label study assessed the safety and effectiveness of low-dose fenfluramine in a new cohort of patients with DS. Following a 3-month baseline period, fenfluramine was added to each patient's current antiepileptic drug regimen at a dose of 0.25-1.0 mg/kg/day (max. 20 mg/day). The incidence of major motor seizures (tonic, clonic, tonic-clonic, atonic and myoclonic seizures lasting >30 s) in both the baseline and treatment periods was assessed via a seizure diary. Periodic echocardiographic examinations during the treatment period were used to assess cardiovascular safety. RESULTS: Nine patients (aged 1.2-29.8 years) enrolled in the study and were treated with fenfluramine for a median duration of 1.5 (range, 0.3-5.1) years. Median frequency of major motor seizures was 15.0/month in the baseline period. All patients demonstrated a reduction in seizure frequency during the treatment period with a median reduction of 75% (range, 28-100%). Seven patients (78%) experienced a ≥50% reduction in major motor seizure frequency. The most common adverse events were somnolence (n = 5) and anorexia (n = 4). No evidence of cardiac valvulopathy or pulmonary hypertension was observed. CONCLUSIONS: The effectiveness and safety of low-dose fenfluramine as an add-on therapy for DS in this new prospective cohort supports previous findings.

Retrospective evaluation of low long-term efficacy of antiepileptic drugs and ketogenic diet in 39 patients with CDKL5-related epilepsy.

OBJECTIVE: Mutations in the CDKL5 gene cause an early-onset epileptic encephalopathy. To date, little is known about effective antiepileptic treatment in this disorder. METHOD: Accordingly, the aim of this retrospective study was to explore the role of different antiepileptic drugs (AEDs) and the ketogenic diet (KD) in the treatment of this rare genetic disorder. We evaluated the efficacy in 39 patients with CDKL5 mutations at 3, 6 and 12 months after the introduction of each treatment. One patient was lost to follow-up after 6 and 12 months. RESULTS: The responder rate (>50% reduction in seizure frequency) to at least one AED or KD was 69% (27/39) after 3 months, 45% (17/38) after 6 months and 24% (9/38) after 12 months. The highest rate of seizure reduction after 3 months was reported for FBM (3/3), VGB (8/25), CLB (4/17), VPA (7/34), steroids (5/26), LTG (5/23) and ZNS (2/11). Twelve patients (31%) experienced a seizure aggravation to at least one AED. Most patients showed some but only initial response to various AEDs with different modes of actions. SIGNIFICANCE: Considering both age-related and spontaneous fluctuation in seizure frequency and the unknown impact of many AEDs or KD on cognition, our data may help defining realistic treatment goals and avoiding overtreatment in patients with CDKL5 mutations. There is a strong need to develop new treatment strategies for patients with this rare mutation.

Analysis of FOXG1 Is Highly Recommended in Male and Female Patients with Rett Syndrome.

We screened a cohort of 5 male and 20 female patients with a Rett spectrum disorder for mutations in the coding region of FOXG1, previously shown to cause the congenital variant of Rett syndrome. Two de novo mutations were identified. The first was a novel missense mutation, p.Ala193Thr (c.577G>A), in a male patient with congenital Rett syndrome, and the second was the p.Glu154GlyfsX301 (c.460dupG) truncating mutation in a female with classical Rett syndrome, a mutation that was previously reported in an independent patient. The overall rate of FOXG1 mutations in our cohort is 8%. Our findings stress the importance of FOXG1 analysis in male patients with Rett syndrome and in female patients when mutations in the MECP2 and CDKL5 genes have been excluded.

Clinical spectrum of early-onset epileptic encephalopathies associated with STXBP1 mutations.

OBJECTIVES: Heterozygous mutations in STXBP1, encoding the syntaxin binding protein 1, have recently been identified in Ohtahara syndrome, an epileptic encephalopathy with very early onset. In order to explore the phenotypic spectrum associated with STXBP1 mutations, we analyzed a cohort of patients with unexplained early-onset epileptic encephalopathies. METHODS: We collected and clinically characterized 106 patients with early-onset epileptic encephalopathies. Mutation analysis of the STXBP1 gene was done using sequence analysis of the exon and intron-exon boundaries and multiplex amplification quantification to detect copy number variations. RESULTS: We identified 4 truncating mutations and 2 microdeletions partially affecting STXBP1 in 6 of the 106 patients. All mutations are predicted to abolish STXBP1 function and 5 mutations were proven to occur de novo. None of the mutation-carrying patients had Ohtahara syndrome. One patient was diagnosed with West syndrome at disease onset, while the initial phenotype of 5 further patients did not fit into a specific recognized epilepsy syndrome. Three of these patients later evolved to West syndrome. All patients had severe to profound mental retardation, and ataxia or dyskinetic movements were present in 5 patients. CONCLUSION: This study shows that mutations in STXBP1 are not limited to patients with Ohtahara syndrome, but are also present in 10% (5/49) of patients with an early-onset epileptic encephalopathy that does not fit into either Ohtahara or West syndrome and rarely in typical West syndrome. STXBP1 mutational analysis should be considered in the diagnostic evaluation of this challenging group of patients.

Multiplex ligation-dependent probe amplification to detect subtelomeric rearrangements in routine diagnostics.

Subtelomeric rearrangements are believed to be responsible for 5-7% of idiopathic mental retardation cases. Due to the relative complexity and high cost of the screening methods used till now, only preselected patient populations including mostly the more severely affected cases have been screened. Recently, multiplex ligation-dependent probe amplification (MLPA) has been adapted for use in subtelomeric screening, and we have incorporated this technique into routine diagnostics of our laboratory. Since the evaluation of MLPA as a screening method, we tested 275 unselected patients with idiopathic mental retardation and detected 12 possible subtelomeric aberrations: a der(11)t(11;20)(qter;qter), a 19pter duplication, a der(18)t(18;10)(qter; pter), a 15qter deletion, a 8pter deletion, a 6qter deletion, a der(X)t(X;1)(pter;qter), a der(X)t(X;3)(pter;pter), a 5qter duplication, a 3pter deletion, and two 3qter duplications. The patients can be subdivided into two groups: the first containing de novo rearrangements that are likely related to the clinical presentation of the patient and the second including aberrations also present in one of the parents that may or may not be causative of the mental retardation. In our patient cohort, five (1.8%) subtelomeric rearrangements were de novo, three (1.1%) rearrangements were familial and suggestively disease causing, and four (1.5%) were possible polymorphisms. This high frequency of subtelomeric abnormalities detected in an unselected population warrants further investigation about the feasibility of routine screening for subtelomeric aberrations in mentally retarded patients.

Botulinum toxin type A in the treatment of children and adolescents with an acquired brain injury.

PRIMARY OBJECTIVE: To describe clinical experience using botulinum toxin type A (BTX-A) in children with acquired brain injury. RESEARCH DESIGN: Single centre, open label, pilot study. METHODS AND PROCEDURES: Twenty-one patients were randomized to three groups according to impairment severity and treatment objectives. EXPERIMENTAL INTERVENTIONS: Group 1: Spastic quadriparesis patients with impaired consciousness treated with the primary goal of improving comfort and well-being; Group 2: Patients with upper limb spasticity treated with the primary goal of improving arm functioning; Group 3: Lower limb spasticity patients treated with the primary goal of improving leg function. OUTCOMES AND RESULTS: Baseline, 1, 3 and 5-month post-treatment assessments were carried out using joint goniometry, Modified Ashworth Scale and video-observations. All groups demonstrated initial improvements, with patients in Group 2 showing a positive effect at least 5 months post-treatment. CONCLUSIONS: With a good outlining of treatment goals, BTX-A is an effective therapy for brain injury patients.

Liver transplantation using cavoportal transposition: an effective treatment in patients with complete splanchnic venous thrombosis.

Complete venous thrombosis of the splanchnic system remains a major challenge in liver transplantation surgery. Some of these patients have been treated successfully by multivisceral transplantation. Cavoportal transposition is another alternative to treat these patients. We reviewed our single-center experience with this technique. Five patients with operatively confirmed complete splanchnic thrombosis were transplanted with the cava portal transposition technique. All survived the procedure; 60% survived long term. This technique is a useful salvage procedure in moribund patients with diffuse portal thrombosis who would otherwise rapidly succumb.

Clinical experience with levetiracetam in childhood epilepsy: an add-on and mono-therapy trial.

We examined the efficacy, optimum dosage and adverse effects of levetiracetam in two prospective trials in children with epilepsy. In the add-on trial, 67 children between 6 months and 16 years were included. In the mono-therapy trial, 10 children between 4 years and 16 years were included. Levetiracetam was titrated up to an optimal dosage for every individual patient, depending on efficacy and tolerability, and reflecting clinical practice. The range of dosages used was between 12 and 62 mg/kg/day, with a median of 33 mg/kg/day. Overall, 20 weeks after the start of levetiracetam, there was a median seizure reduction of 60% (add-on trial 50%; mono-therapy trial 81%). Levetiracetam was equally effective for partial and generalized seizures. Side effects were less common in the mono-therapy trial. Tiredness (7.8%) and aggressiveness (5%) were the most common side effects, and were dose-related, but were no reason to discontinue levetiracetam. In 25% of the children, a positive effect was seen on behaviour and/or alertness. This could not be related directly to seizure control. Overall, these two clinical trials confirm that levetiracetam is a broad spectrum anti-epileptic drug with a favourable safety profile. The positive effect on behaviour needs further quantitative study.

De novo KCNQ2 mutations in patients with benign neonatal seizures.

Benign familial neonatal convulsions (BFNC) are characterized by unprovoked seizures during the first weeks of life with spontaneous remission after a few months. Mutations have been identified in the voltage-gated potassium ion channels KCNQ2 and KCNQ3. The authors performed a mutation analysis of KCNQ2 and KCNQ3 in six patients of whom four had no family history of neonatal seizures. The authors identified three KCNQ2 mutations in four patients that all arose de novo.

A deletion in SCN1B is associated with febrile seizures and early-onset absence epilepsy.

Generalized epilepsy with febrile seizures plus (GEFS+) is a clinically and genetically heterogeneous syndrome with childhood onset, characterized by febrile seizures (FS) and a variety of afebrile epileptic seizure types. The authors performed a mutational analysis of SCN1B on 74 unrelated probands with GEFS+, FS, or FS plus (FS+). In a family with FS+ and early-onset absence epilepsy, a mutation was identified that predicts a deletion of five amino acids in the extracellular immunoglobulin-like domain of SCN1B and potential loss of function. SCN1B mutations are associated with GEFS+ and may have a role in the elicitation of absence seizures.

Anti-epileptogenesis research: the clinical relevance.

In recent years, different research lines have examined the epileptogenic process in order to understand the different stages in this process, and with the hope that early recognition and intervention could prevent chronic epilepsy in patients with epileptic seizures. In animals, acquired epilepsy is studied most commonly with kindling models, status epilepticus models and traumatic brain injury models. Molecular genetic studies substantially help to understand age-specific channel and receptor abnormalities. Major progress has been made in recent years and we are now waiting for the first large scale multi-center clinical trials that test the possible anti-epileptogenic properties of anti-epileptic drugs or other compounds in well defined patient groups. In clinical practice, a structured diagnostic work-up in all patients with recurrent seizures is a first and necessary step in the recognition of patients at risk for developing chronic and refractory epilepsy.

Effect of levetiracetam in refractory childhood epilepsy syndromes.

In this open-label add-on study of levetiracetam in refractory childhood epilepsy syndromes, we studied the effect of a rapid introduction of levetiracetam on the total seizure frequency in 21 children, known to have partial and generalized seizures. Starting dosage was 10 mg/kg/day, increased every 4th day by 10 mg/kg up to a maximum of 60 mg/kg/day, depending on efficacy and tolerability. In this highly refractory population, 47% showed a seizure frequency reduction of more than 50%. Levetiracetam was effective both in partial and generalized seizures, with a significant effect on myoclonic seizures. Only mild side-effects were observed in four of 21 children, at a dosage of more than 40 mg/kg/day.

De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy.

Severe myoclonic epilepsy of infancy (SMEI) is a rare disorder that occurs in isolated patients. The disease is characterized by generalized tonic, clonic, and tonic-clonic seizures that are initially induced by fever and begin during the first year of life. Later, patients also manifest other seizure types, including absence, myoclonic, and simple and complex partial seizures. Psychomotor development stagnates around the second year of life. Missense mutations in the gene that codes for a neuronal voltage-gated sodium-channel alpha-subunit (SCN1A) were identified in families with generalized epilepsy with febrile seizures plus (GEFS+). GEFS+ is a mild type of epilepsy associated with febrile and afebrile seizures. Because both GEFS+ and SMEI involve fever-associated seizures, we screened seven unrelated patients with SMEI for mutations in SCN1A. We identified a mutation in each patient: four had frameshift mutations, one had a nonsense mutation, one had a splice-donor mutation, and one had a missense mutation. All mutations are de novo mutations and were not observed in 184 control chromosomes.

Infantile demyelinating neuropathy associated with a de novo point mutation on Ser72 in PMP22 and basal lamina onion bulbs in skin biopsy.

Codon 72 has been designated as a hot spot for distinct missense mutations in the peripheral myelin protein 22 (PMP22) gene. Ser72Leu substitution was associated with Dejerine-Sottas syndrome (DSS) in four patients and with congenital hypomyelination neuropathy (CHN) in one patient. Our objective was to report one other DSS patient with Ser72Leu substitution in PMP22 and to concurrently illustrate how less invasive procedures such as skin biopsy could provide a rapid and reliable alternative to conventional sural nerve biopsy for the characterization of histophenotypic features. A skin biopsy was carried out in a 2 4/12-year-old girl with muscle atrophy, hypotonia and weakness, as well as generalized areflexia and absent sensory and motor nerve responses. Standard electron microscope techniques were used. PMP22 was screened by automated direct nucleotide sequencing analysis. Morphological examination revealed basal lamina onion bulbs surrounding a de- or hypomyelinated axon in all nerve bundles. Mutation analysis demonstrated a missense point mutation in codon 72 of the PMP22 gene leading to a Ser72Leu substitution. Further genotype-phenotype correlations will have to determine whether morphologically distinct phenotypes can be correlated with specific mutations. For this purpose, cutaneous nerve bundles could serve as an alternative tool to help identify and classify subtypes in this heterogeneous syndrome.

Encephalomyelitis-associated antimyelin autoreactivity induced by streptococcal exotoxins.

OBJECTIVE: After implicating Streptococcus pyogenes as causing acute disseminated encephalomyelitis (ADEM) in a child, we wanted to prove that in vivo activation of autoreactive T lymphocytes by superantigens of this Streptococcus contributed to the dramatic demyelination. BACKGROUND: ADEM is a demyelinating disorder of the CNS sharing many similarities with MS. Demyelination in MS is considered to be the result of an autoimmune process mediated by autoreactive T lymphocytes with specificity for myelin antigens. METHODS: Phenotypic analysis and proliferation assays on blood monocytes, as well as isolation of myelin basic protein (MBP)-reactive T-cell lines/clones; and TCR repertorium analysis by PCR-ELISA and cytokine production. RESULTS: 1) The blood T-cell receptor (TCR) repertoire was compatible with in vivo expansion induced by S. pyogenes exotoxins. 2) TCR expression analysis indicated clonal expansion of CD8+ MBP-reactive T cells, suggesting in vivo activation. MBP-reactive T cells showed crossreactivity to S. pyogenes supernatant and exotoxins. 3) Cytokine mRNA quantification of the mononuclear cells revealed a Th2-biased profile. CONCLUSION: In vivo exposure to S. pyogenes may have induced activation of pathogenic myelin reactive T cells, contributing to the dramatic inflammatory demyelination.