Longitudinal timed function tests in Duchenne muscular dystrophy: ImagingDMD cohort natural history.

INTRODUCTION: Tests of ambulatory function are common clinical trial endpoints in Duchenne muscular dystrophy (DMD). Using these tests, the ImagingDMD study has generated a large data set that can describe the contemporary natural history of DMD in 5-12.9-year-olds. METHODS: Ninety-two corticosteroid-treated boys with DMD and 45 controls participated in this longitudinal study. Participants performed the 6-minute walk test (6MWT) and timed function tests (TFT: 10-m walk/run, climbing 4 stairs, supine to stand). RESULTS: Boys with DMD had impaired functional performance even at 5-6.9 years old. Boys older than 7 had significant declines in function over 1 year for 10-m walk/run and 6MWT. Eighty percent of participants could perform all functional tests at 9 years old. TFTs appear to be slightly more responsive and predictive of disease progression than the 6MWT in 7-12.9 year olds. DISCUSSION: This study provides insight into the contemporary natural history of key functional endpoints in DMD. Muscle Nerve 58: 631-638, 2018.

Multicenter prospective longitudinal study of magnetic resonance biomarkers in a large duchenne muscular dystrophy cohort.

OBJECTIVE: The aim of this study was to describe Duchenne muscular dystrophy (DMD) disease progression in the lower extremity muscles over 12 months using quantitative magnetic resonance (MR) biomarkers, collected across three sites in a large cohort. METHODS: A total of 109 ambulatory boys with DMD (8.7 ± 2.0 years; range, 5.0-12.9) completed baseline and 1-year follow-up quantitative MR imaging (transverse relaxation time constant; MRI-T2 ), MR spectroscopy (fat fraction and (1) H2 O T2 ), and 6-minute walk test (6MWT) measurements. A subset of boys completed additional measurements after 3 or 6 months. RESULTS: MRI-T2 and fat fraction increased significantly over 12 months in all age groups, including in 5- to 6.9-year-old boys. Significant increases in vastus lateralis (VL) fat fraction were observed in 3 and 6 months. Even in boys whose 6MWT performance improved or remained stable over 1 year, significant increases in MRI-T2 and fat fraction were found. Of all the muscles examined, the VL and biceps femoris long head were the most responsive to disease progression in boys with DMD. INTERPRETATION: MR biomarkers are responsive to disease progression in 5- to 12.9-year-old boys with DMD and able to detect subclinical disease progression in DMD, even within short (3-6 months) time periods. The measured sensitivity of MR biomarkers in this multicenter study may be critically important to future clinical trials, allowing for smaller sample sizes and/or shorter study windows in this fatal rare disease.

Mutations in γ adducin are associated with inherited cerebral palsy.

OBJECTIVE: Cerebral palsy is estimated to affect nearly 1 in 500 children, and although prenatal and perinatal contributors have been well characterized, at least 20% of cases are believed to be inherited. Previous studies have identified mutations in the actin-capping protein KANK1 and the adaptor protein-4 complex in forms of inherited cerebral palsy, suggesting a role for components of the dynamic cytoskeleton in the genesis of the disease. METHODS: We studied a multiplex consanguineous Jordanian family by homozygosity mapping and exome sequencing, then used patient-derived fibroblasts to examine functional consequences of the mutation we identified in vitro. We subsequently studied the effects of adducin loss of function in Drosophila. RESULTS: We identified a homozygous c.1100G>A (p.G367D) mutation in ADD3, encoding gamma adducin in all affected members of the index family. Follow-up experiments in patient fibroblasts found that the p.G367D mutation, which occurs within the putative oligomerization critical region, impairs the ability of gamma adducin to associate with the alpha subunit. This mutation impairs the normal actin-capping function of adducin, leading to both abnormal proliferation and migration in cultured patient fibroblasts. Loss of function studies of the Drosophila adducin ortholog hts confirmed a critical role for adducin in locomotion. INTERPRETATION: Although likely a rare cause of cerebral palsy, our findings indicate a critical role for adducins in regulating the activity of the actin cytoskeleton, suggesting that impaired adducin function may lead to neuromotor impairment and further implicating abnormalities of the dynamic cytoskeleton as a pathogenic mechanism contributing to cerebral palsy.

Ataluren treatment of patients with nonsense mutation dystrophinopathy.

INTRODUCTION: Dystrophinopathy is a rare, severe muscle disorder, and nonsense mutations are found in 13% of cases. Ataluren was developed to enable ribosomal readthrough of premature stop codons in nonsense mutation (nm) genetic disorders. METHODS: Randomized, double-blind, placebo-controlled study; males ≥ 5 years with nm-dystrophinopathy received study drug orally 3 times daily, ataluren 10, 10, 20 mg/kg (N=57); ataluren 20, 20, 40 mg/kg (N=60); or placebo (N=57) for 48 weeks. The primary endpoint was change in 6-Minute Walk Distance (6MWD) at Week 48. RESULTS: Ataluren was generally well tolerated. The primary endpoint favored ataluren 10, 10, 20 mg/kg versus placebo; the week 48 6MWD Δ=31.3 meters, post hoc P=0.056. Secondary endpoints (timed function tests) showed meaningful differences between ataluren 10, 10, 20 mg/kg, and placebo. CONCLUSIONS: As the first investigational new drug targeting the underlying cause of nm-dystrophinopathy, ataluren offers promise as a treatment for this orphan genetic disorder with high unmet medical need.

Skeletal muscles of ambulant children with Duchenne muscular dystrophy: validation of multicenter study of evaluation with MR imaging and MR spectroscopy.

PURPOSE: To validate a multicenter protocol that examines lower extremity skeletal muscles of children with Duchenne muscular dystrophy (DMD) by using magnetic resonance (MR) imaging and MR spectroscopy in terms of reproducibility of these measurements within and across centers. MATERIALS AND METHODS: This HIPAA-compliant study was approved by the institutional review boards of all participating centers, and informed consent was obtained from each participant or a guardian. Standardized procedures with MR operator training and quality assurance assessments were implemented, and data were acquired at three centers by using different 3-T MR imaging instruments. Measures of maximal cross-sectional area (CSAmax), transverse relaxation time constant (T2), and lipid fraction were compared among centers in two-compartment coaxial phantoms and in two unaffected adult subjects who visited each center. Also, repeat MR measures were acquired twice on separate days in 30 boys with DMD (10 per center) and 10 unaffected boys. Coefficients of variation (CVs) were computed to examine the repeated-measure variabilities within and across centers. RESULTS: CSAmax, T2 from MR imaging and MR spectroscopy, and lipid fraction were consistent across centers in the phantom (CV, <3%) and in the adult subjects who traveled to each site (CV, 2%-7%). High day-to-day reproducibility in MR measures was observed in boys with DMD (CSAmax, CV = 3.7% [25th percentile, 1.3%; 75th percentile, 5.1%]; contractile area, CV = 4.2% [25th percentile, 0.8%; 75th percentile, 4.9%]; MR imaging T2, CV = 3.1% [25th percentile, 1.2%; 75th percentile, 4.7%]; MR spectroscopy T2, CV = 3.9% [25th percentile, 1.5%; 75th percentile, 5.1%]; and lipid fraction, CV = 4.7% [25th percentile, 1.0%; 75th percentile, 5.3%]). CONCLUSION: The MR protocol implemented in this multicenter study achieved highly reproducible measures of lower extremity muscles across centers and from day to day in ambulatory boys with DMD.

Definition and classification of hyperkinetic movements in childhood.

Hyperkinetic movements are unwanted or excess movements that are frequently seen in children with neurologic disorders. They are an important clinical finding with significant implications for diagnosis and treatment. However, the lack of agreement on standard terminology and definitions interferes with clinical treatment and research. We describe definitions of dystonia, chorea, athetosis, myoclonus, tremor, tics, and stereotypies that arose from a consensus meeting in June 2008 of specialists from different clinical and basic science fields. Dystonia is a movement disorder in which involuntary sustained or intermittent muscle contractions cause twisting and repetitive movements, abnormal postures, or both. Chorea is an ongoing random-appearing sequence of one or more discrete involuntary movements or movement fragments. Athetosis is a slow, continuous, involuntary writhing movement that prevents maintenance of a stable posture. Myoclonus is a sequence of repeated, often nonrhythmic, brief shock-like jerks due to sudden involuntary contraction or relaxation of one or more muscles. Tremor is a rhythmic back-and-forth or oscillating involuntary movement about a joint axis. Tics are repeated, individually recognizable, intermittent movements or movement fragments that are almost always briefly suppressible and are usually associated with awareness of an urge to perform the movement. Stereotypies are repetitive, simple movements that can be voluntarily suppressed. We provide recommended techniques for clinical examination and suggestions for differentiating between the different types of hyperkinetic movements, noting that there may be overlap between conditions. These definitions and the diagnostic recommendations are intended to be reliable and useful for clinical practice, communication between clinicians and researchers, and for the design of quantitative tests that will guide and assess the outcome of future clinical trials.

Role of child neurologists and neurodevelopmentalists in the diagnosis of cerebral palsy: A survey study.

OBJECTIVE: To contextualize the role of child neurologists and neurodevelopmentalists (CNs/NDDs) in cerebral palsy (CP) care, we review the changing landscape of CP diagnosis and survey stakeholder CNs/NDDs regarding their roles in CP care. METHODS: The optimal roles of the multiple specialties involved in CP care are currently unclear, particularly regarding CP diagnosis. We developed recommendations regarding the role of CNs/NDDs noting (1) increasing complexity of CP diagnosis given a growing number of genetic etiologies and treatable motor disorders that can be misdiagnosed as CP and (2) the views of a group of physician stakeholders (CNs/NDDs from the Child Neurology Society Cerebral Palsy Special Interest Group). RESULTS: CNs/NDDs felt that they were optimally suited to diagnose CP. Many (76%) felt that CNs/NDDs should always be involved in CP diagnosis. However, 42% said that their patients with CP were typically not diagnosed by CNs/NDDs, and 18% did not receive referrals to establish the diagnosis of CP at all. CNs/NDDs identified areas of their expertise critical for CP diagnosis including knowledge of the neurologic examination across development and early identification of features atypical for CP. This contrasts with their views on CP management, where CNs/NDDs felt that they could contribute to the medical team, but were necessary primarily when neurologic coexisting conditions were present. DISCUSSION: Given its increasing complexity, we recommend early referral for CP diagnosis to a CN/NDD or specialist with comparable expertise. This contrasts with current consensus guidelines, which either do not address or do not recommend specific specialist referral for CP diagnosis.

Modeling disease trajectory in Duchenne muscular dystrophy.

OBJECTIVE: To quantify disease progression in individuals with Duchenne muscular dystrophy (DMD) using magnetic resonance biomarkers of leg muscles. METHODS: MRI and magnetic resonance spectroscopy (MRS) biomarkers were acquired from 104 participants with DMD and 51 healthy controls using a prospective observational study design with patients with DMD followed up yearly for up to 6 years. Fat fractions (FFs) in vastus lateralis and soleus muscles were determined with 1H MRS. MRI quantitative T2 (qT2) values were measured for 3 muscles of the upper leg and 5 muscles of the lower leg. Longitudinal changes in biomarkers were modeled with a cumulative distribution function using a nonlinear mixed-effects approach. RESULTS: MRS FF and MRI qT2 increased with DMD disease duration, with the progression time constants differing markedly between individuals and across muscles. The average age at half-maximal muscle involvement (µ) occurred 4.8 years earlier in vastus lateralis than soleus, and these measures were strongly associated with loss-of-ambulation age. Corticosteroid treatment was found to delay µ by 2.5 years on average across muscles, although there were marked differences between muscles with more slowly progressing muscles showing larger delay. CONCLUSIONS: MRS FF and MRI qT2 provide sensitive noninvasive measures of DMD progression. Modeling changes in these biomarkers across multiple muscles can be used to detect and monitor the therapeutic effects of corticosteroids on disease progression and to provide prognostic information on functional outcomes. This modeling approach provides a method to transform these MRI biomarkers into well-understood metrics, allowing concise summaries of DMD disease progression at individual and population levels. CLINICALTRIALSGOV IDENTIFIER: NCT01484678.

Variability and minimum detectable change for walking energy efficiency variables in children with cerebral palsy.

For individuals with neuromuscular disorders, the assessment of walking energy efficiency is useful as a clinical outcome measure. Issues surrounding data collection methodology, normalization of the data, and variability and clinical utility of energy efficiency data preclude universal application. This study examined the variability and the clinical utility of velocity, energy efficiency index (EEI), gross cost, and net nondimensional cost (NNcost) in children and adolescents with spastic diplegic cerebral palsy (CP) in Gross Motor Function Classification System (GMFCS) levels I to III. The energy efficiency of walking was evaluated in 23 children and adolescents (12 males, 11 females, mean age 11y 3mo [SD 3y 5mo]; range 7-17y). Day-to-day variability was similar for all energy efficiency variables, with no significant differences in magnitude of variability between GMFCS levels. Correlations between EEI and gross cost and EEI and NNcost were fairly good (r=0.65, p<0.001, and r=0.74, p<0.001 respectively). However, only gross cost and NNcost discriminated between GMFCS levels in children with CP. Gross cost required the greatest amount of change to be considered clinically significant, whereas NNcost and EEI required a similar amount of change. For cohorts of children with CP who are evaluated over time, NNcost is the best normalization method as it reduces the variability between participants of different ages, height, and weight while evaluating only the amount of energy used to ambulate.

Continuous intrathecal baclofen infusion for intractable spastic cerebral palsy--is it worth it?

This Practice Point commentary discusses a recent paper by Hoving et al., who compared the cost-effectiveness of continuous intrathecal baclofen infusion (CIBI) with that of 'standard care' in children with cerebral palsy whose abnormal muscle tone was interfering with function and/or quality of life. The current management of severe spasticity and dystonia in cerebral palsy consists of oral medications, botulinum toxin, selective dorsal rhizotomy, orthopedic surgery, and/or CIBI. CIBI is the treatment of choice for patients whose severely abnormal tone is interfering with their care, comfort, and/or quality of life. The added cost of care associated with the use of CIBI for 1 year is nearly twice that of standard care. However, on the basis of their cost-effectiveness analysis, which took into consideration the improvement in quality of life, Hoving et al. concluded that the added expense is cost-effective. Although this prospective study lasted for only 1 year and included only 15 patients, the conclusions are similar to those based on previously published results.

Skeletal muscle magnetic resonance biomarkers correlate with function and sentinel events in Duchenne muscular dystrophy.

OBJECTIVE: To provide evidence for quantitative magnetic resonance (qMR) biomarkers in Duchenne muscular dystrophy by investigating the relationship between qMR measures of lower extremity muscle pathology and functional endpoints in a large ambulatory cohort using a multicenter study design. METHODS: MR spectroscopy and quantitative imaging were implemented to measure intramuscular fat fraction and the transverse magnetization relaxation time constant (T2) in lower extremity muscles of 136 participants with Duchenne muscular dystrophy. Measures were collected at 554 visits over 48 months at one of three imaging sites. Fat fraction was measured in the soleus and vastus lateralis using MR spectroscopy, while T2 was assessed using MRI in eight lower extremity muscles. Ambulatory function was measured using the 10m walk/run, climb four stairs, supine to stand, and six minute walk tests. RESULTS: Significant correlations were found between all qMR and functional measures. Vastus lateralis qMR measures correlated most strongly to functional endpoints (|ρ| = 0.68-0.78), although measures in other rapidly progressing muscles including the biceps femoris (|ρ| = 0.63-0.73) and peroneals (|ρ| = 0.59-0.72) also showed strong correlations. Quantitative MR biomarkers were excellent indicators of loss of functional ability and correlated with qualitative measures of function. A VL FF of 0.40 was an approximate lower threshold of muscle pathology associated with loss of ambulation. DISCUSSION: Lower extremity qMR biomarkers have a robust relationship to clinically meaningful measures of ambulatory function in Duchenne muscular dystrophy. These results provide strong supporting evidence for qMR biomarkers and set the stage for their potential use as surrogate outcomes in clinical trials.

Two-Year Longitudinal Changes in Lower Limb Strength and Its Relation to Loss in Function in a Large Cohort of Patients With Duchenne Muscular Dystrophy.

OBJECTIVE: The main objective of this study was to examine the effect of disease on strength in two functionally important lower limb muscles for a period of 2 yrs in children with Duchene muscular dystrophy. DESIGN: Seventy-seven Duchene muscular dystrophy children participated in this study. Plantar flexors, knee extensors, strength, and performance on timed tests (6-min walk, 4-stairs, 10-m walk, supine-up) were assessed yearly for 2 yrs. Multivariate normal regression was used to assess changes in strength over time in the Duchene muscular dystrophy group. Spearman correlations were computed to examine relationship between strength and function. RESULTS: Normalized plantar flexor and knee extensor strength showed a significant decrease (P < 0.05) over 2 yrs, with larger declines in knee extensor. At baseline, knee extensor strongly correlated with performance on timed tests. However, plantar flexor strength was found to be a stronger predictor of loss in ambulatory function. Modest correlations (r = 0.19-0.34) were found between the decline in strength and functional performance over 2 yrs. CONCLUSIONS: This study describes the loss of lower limb strength in a large cohort of Duchene muscular dystrophy children for 2 yrs. The findings support that lower limb strength alone cannot account for the decline in performance on functional tests, and the role of other contributing factors, such as compensatory strategies, should be considered.

Spinal muscular atrophy: clinical classification and disease heterogeneity.

The clinical classification of spinal muscular atrophy, caused by deletion of the survival motor neuron 1 gene (SMN1), is based on age at onset and maximum function achieved. Evidence suggests that maximum function achieved is more closely related to life expectancy than age at onset. Therefore, it is important to wait for a period before assigning a patient to 1 of 5 classes of the disorder. Several diseases result from degeneration of the anterior horn cell but are not caused by SMN1. The classification for these conditions is evolving. This article offers an attempt at organizing one's thinking about this disease group.

Safety and Efficacy of Repeat Open-Label AbobotulinumtoxinA Treatment in Pediatric Cerebral Palsy.

This was a prospective, repeat-treatment, open-label study (NCT01251380) of abobotulinumtoxinA for the management of lower limb spasticity in children who had completed a double-blind study. Children (2-17 years) received injections into the gastrocnemius-soleus complex, and other distal and proximal muscles as required (maximum total dose per injection cycle: 30 U/kg or 1000U). A total of 216 of the 241 double-blind patients entered the extension study and 207 received ≥1 open label injection into the gastrocnemius-soleus; 17-24% of patients also had injections into the hamstrings. The most frequent adverse events were related to common childhood infections and the most frequent treatment-related adverse event was injection site pain (n = 10). There was no evidence of a cumulative effect on adverse events. Sustained significant clinical improvements in muscle tone (Modified Ashworth Scale), spasticity (Tardieu Scale), overall clinical benefit (Physicians Global Assessment), and goal attainment (Goal Attainment Scale) were also observed across treatment cycles.

AbobotulinumtoxinA (Dysport®) Improves Function According to Goal Attainment in Children With Dynamic Equinus Due to Cerebral Palsy.

This secondary analysis of a large (n = 241), randomized, double-blind study evaluated the efficacy of 2 doses of abobotulinumtoxinA + standard of care (SOC) versus placebo + SOC in enabling children with dynamic equinus due to cerebral palsy to achieve their functional goals using Goal Attainment Scaling. Most parents/caregivers selected goals targeting aspects of gait improvement as most relevant. Mean (95% confidence interval) Goal Attainment Scaling T scores at week 4 were higher for both abobotulinumtoxinA groups versus placebo (treatment difference vs placebo: 10 U/kg/leg: 5.32 [2.31, 8.32], P = .0006, and 15 U/kg/leg 4.65 [1.59, 7.71], P = .0031). Superiority of both abobotulinumtoxinA doses versus placebo was maintained at week 12. Best goal attainment T scores were higher in the abobotulinumtoxinA groups versus placebo for the common goals of improved walking pattern, decreased falling, decreased tripping, and improved endurance. These findings demonstrate that single injections of abobotulinumtoxinA (10 and 15 U/kg/leg) significantly improved the ability of pediatric cerebral palsy patients to achieve their functional goals.

AbobotulinumtoxinA for Equinus Foot Deformity in Cerebral Palsy: A Randomized Controlled Trial.

BACKGROUND: Although botulinum toxin is a well-established treatment of focal spasticity in cerebral palsy, most trials have been small, and few have simultaneously assessed measures of muscle tone and clinical benefit. METHODS: Global, randomized, controlled study to assess the efficacy and safety of abobotulinumtoxinA versus placebo in cerebral palsy children with dynamic equinus foot deformity. Patients were randomized (1:1:1) to abobotulinumtoxinA 10 U/kg/leg, 15 U/kg/leg, or placebo injections into the gastrocnemius-soleus complex (1 or both legs injected). In the primary hierarchical analysis, demonstration of benefit for each dose required superiority to placebo on the primary (change in Modified Ashworth Scale from baseline to week 4) and first key secondary (Physician's Global Assessment at week 4) end points. RESULTS: Two hundred and forty-one patients were randomized, and 226 completed the study; the intention to treat population included 235 patients (98%). At week 4, Modified Ashworth Scale scores significantly improved with abobotulinumtoxinA; mean (95% confidence interval) treatment differences versus placebo were -0.49 (-0.75 to -0.23; P = .0002) for 15 U/kg/leg and -0.38 (-0.64 to -0.13; P = .003) for 10 U/kg/leg. The Physician's Global Assessment treatment differences versus placebo of 0.77 (0.45 to 1.10) for 15 U/kg/leg and 0.82 (0.50 to 1.14) for 10 U/kg/leg were also significant (both Ps < .0001). The most common treatment-related adverse event was muscular weakness (10 U/Kg/leg = 2; placebo = 1). CONCLUSIONS: AbobotulinumtoxinA improves muscle tone in children with dynamic equinus resulting in an improved overall clinical impression and is well tolerated.

A phase 1 trial of riluzole in spinal muscular atrophy.

BACKGROUND: Severe spinal muscular atrophy (SMA) (Werdnig-Hoffmann disease, acute SMA, and SMA I) is a disease of the motor neuron characterized by onset before 6 months of age, failure ever to achieve sitting without support, and a life expectancy of 2 years or less. There is no known treatment for SMA, and, until recently, no therapeutic trials have been attempted. There is reason to believe that glutamate, an excitatory neurotransmitter, enhances programmed cell death of anterior horn cells. Riluzole, a glutamate inhibitor, has been shown to slow the rate of decline in patients with amyotrophic lateral sclerosis, another form of motor neuron disease. OBJECTIVES: To determine whether a glutamate inhibitor might be tolerated by infants with SMA and, furthermore, whether this medication could have a positive effect on life expectancy. DESIGN: Subjects with homozygous deletions of the survival motor neuron gene were recruited from pediatric neuromuscular clinics and randomized in a 2:1 ratio, 2 riluzole to 1 placebo. Neurologic examination was performed at the first visit by one of the investigators. Complete blood count, hepatic and renal screens, and urinalysis were performed at baseline, 2 weeks, 1 month, 2 months, 3 months, 6 months, and 9 months after drug or placebo was started. An electrocardiogram was done at baseline, 3 months, 6 months, and 12 months. Treatment was stopped after 9 months, and blood work was repeated at 12 months. Treatment was reinstituted at 1 year if requested by the parents. The enrollment goal was 30 patients; however, support from the pharmaceutical company was withdrawn when Rhone-Poulenc Rorer was taken over by Aventis. The investigational review boards of the participating centers approved the protocol and consent forms. RESULTS: Seven patients received riluzole and 3 received placebo medication. All 3 patients in the placebo group died (mean age, 9 months). Three of 7 who received active drug are still living at ages 513 years, 4 years, and 30 months. None of the 10 subjects experienced adverse effects or changes in laboratory test results. None showed any change in motor abilities. CONCLUSIONS: Riluzole appears to be safe in young children. This was a limited study with insufficient power to show a difference between the 2 groups. Because there is a suggestion of possible benefit in treated subjects, we recommend further study of riluzole in pediatric patients with SMA.

Evaluation of the child with cerebral palsy.

Cerebral palsy (CP) is a common problem, occurring in about 2 to 2.5 per 1000 live births. The diagnosis of CP is based upon a history of abnormal motor development that is not progressive coupled with an examination (e.g. hypertonicity, increased reflexes, clonus) "placing" the lesion in the brain. In order to establish that a brain abnormality exists in children with CP that may, in turn, suggest an etiology and prognosis, neuroimaging is recommended with magnetic resonance imaging preferred to computed tomography. Metabolic and genetic studies should be obtained if there are atypical features in the history or on the examination. Detection of a brain malformation in a child with CP might suggest an underlying genetic or metabolic etiology. As cerebral infarction is high in children with hemiplegic CP, diagnostic testing for coagulation disorders should be considered. However, there is insufficient evidence at present to be precise as to what studies should be ordered. An electroencephalogram is not recommended unless there are features suggestive of epilepsy or a specific epileptic syndrome. As children with CP may have associated deficits of mental retardation, ophthalmologic and hearing impairments, speech and language disorders and oral-motor dysfunction, screening for these conditions should be part of the initial assessment.