Barry S. Russman

Practice Parameter: Diagnostic assessment of the child with cerebral palsy Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society

Objective: The Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society develop practice parameters as strategies for patient management based on analysis of evidence. For this parameter the authors reviewed available evidence on the assessment of a child suspected of having cerebral palsy (CP), a nonprogressive disorder of posture or movement due to a lesion of the developing brain. Methods: Relevant literature was reviewed, abstracted, and classified. Recommendations were based on a four-tiered scheme of evidence classification. Results: CP is a common problem, occurring in about 2 to 2.5 per 1,000 live births. 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 MRI preferred to CT (Level A). Metabolic and genetic studies should not be routinely obtained in the evaluation of the child with CP (Level B). If the clinical history or findings on neuroimaging do not determine a specific structural abnormality or if there are additional and atypical features in the history or clinical examination, metabolic and genetic testing should be considered (Level C). Detection of a brain malformation in a child with CP warrants consideration of an underlying genetic or metabolic etiology. Because the incidence of cerebral infarction is high in children with hemiplegic CP, diagnostic testing for coagulation disorders should be considered (Level B). However, there is insufficient evidence at present to be precise as to what studies should be ordered. An EEG is not recommended unless there are features suggestive of epilepsy or a specific epileptic syndrome (Level A). Because 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 (Level A). Conclusions: Neuroimaging results in children with CP are commonly abnormal and may help determine the etiology. Screening for associated conditions is warranted as part of the initial evaluation.

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.

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. Muscle Nerve 50: 477–487, 2014

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 ones thinking about this disease group.

Cerebral palsy: A rational approach to a treatment protocol, and the role of botulinum toxin in treatment

Cerebral palsy (CP) is characterized by aberrant control of movement or posture and appears early in life secondary to central nervous system damage. The symptoms of CP fallinto four groups: Symptoms due to loss of selective motor control; symptoms due to abnormal muscle tone; symptoms due to imbalance between muscle agonists and antagonists; and symptoms due to impaired balance. The goals of treatment are to maximize function and minimize the development of hoint conrtacture and other secondary porblems. Development of a tratment plan begins with hte deginition of obhectiones and consideration of the effects of gtrowth and development on the patients abilities. The role of botulinum toxin in CP treatment has grown in recent years. The patient who could benefit most from botulin toxin treatment is one who is hypertonic and whose abnormal muscle tone is interfering with function, or who is expected to develop joint contracture with growth because of this abnormal tone. By altering this muscle tone, function can be enhanced or additional therapeutic modalities can be employed. Assessing treatment outcomes for BTX injection involves the same set of questions and measurements as for other types of treatments and depends on the careful definition of treatment objectives beforehand. ©1997 John Wiley & Sons, Inc. Spasticity: Etiology, Evaluation, Management, and the Role of Botulinum Toxin Type A, MF Brin, editor. Muscle Nerve 1997;20(suppl):S181‐S193.

Comparing botulinum toxin A with casting for treatment of dynamic equinus in children with cerebral palsy

The purpose of this study was to compare the cumulative efficacy (three treatment sessions) of botulinum toxin A (BTX‐A) alone, casting alone, and the combination of BTX‐A and casting in the management of dynamic equinus in ambulatory children with spastic cerebral palsy (CP). Thirty‐nine children with spastic CP (mean age 5y 10mo, range 3 to 9y) were enrolled in the study. A multicenter, randomized, double blind, placebo‐controlled prospective study was used. Children were randomly assigned to one of three treatment groups: BTX‐A only (B), placebo injection plus casting (C), or BTX‐A plus casting (B+C). The dosage for the BTX‐A injections was 4U/kg per extremity. Assessments were performed at baseline, 3,6,7.5, and 12 months with a total of three treatments administered after the evaluations at baseline, 3, and 6 months. Primary outcome measures were ankle kinematics, velocity, and stride length. Secondary outcome measures were ankle spasticity, strength, range of motion, and ankle kinetics. Group B made no significant change in any variable at any time. Groups C and B+C demonstrated significant improvements in ankle kinematics, spasticity, passive range of motion, and dorsiflexor strength. Results of this 1‐year study indicate that BTX‐A alone provided no improvement in the parameters measured in this study, while casting and BTX‐A/casting were effective in the short‐ and long‐term management of dynamic equinus in children with spastic CP.

Prospective Analysis of Strength in Spinal Muscular Atrophy

Spinal muscular atrophy is a genetic disorder of the motor neurons that causes profound hypotonia, severe weakness, and often fatal restrictive lung disease. Patients with spinal muscular atrophy present a spectrum of disease from the most severe infantile-onset type, called Werdnig-Hoffmann disease (type 1), associated with a mortality rate of up to 90%, to a late-onset mild form (type 3), wherein patients remain independently ambulatory throughout adult life. Although many clinicians agree that patients with spinal muscular atrophy lose motor abilities with age, it is unknown whether progressive weakness occurs in all patients with spinal muscular atrophy. We present here results of the first prospective study of muscle strength in patients with spinal muscular atrophy. There was no loss in muscle strength as determined by a quantitative muscle test during the observation period. However, motor function diminished dramatically in some patients with spinal muscular atrophy. Explanations for this loss of function could not be determined from our data. Decrease in motor function could be caused by factors other than loss of strength. Therefore, it is not clear from our results whether spinal muscular atrophy is a neurodegenerative disease. We conclude that treatment trials in spinal muscular atrophy should be designed with consideration of the natural history of strength and motor function in this disorder. (J Child Neurol 2000;15:97-101).

A placebo-controlled trial of gabapentin in spinal muscular atrophy

OBJECTIVE To evaluate the efficacy of gabapentin in increasing muscle strength of patients with spinal muscular atrophy (SMA). BACKGROUND Preclinical data in experimental models of motor neuron disease suggest a neuroprotective effect of gabapentin. METHODS Gabapentin (1200 mg), or placebo, was administered three times daily in a randomized, double-blind trial for 12 months. The primary outcome measure was the average percent change from baseline, based on the measurement of strength in four muscles (elbow flexion and hand grip bilaterally) for each patient. Drug efficacy was examined by comparing the percent change in strength for patients on drug vs. placebo. Secondary efficacy variables included: forced vital capacity (FVC), SMA functional rating scale (SMAFRS), and mini-Sickness Impact Profile (SIP). RESULTS Eighty-four patients, with type II or III SMA, were enrolled at eight sites across the United States. There were no differences in baseline features. There was no difference between the placebo and drug groups in any outcome measure. CONCLUSIONS This study demonstrates the feasibility of this trial design and provides data for the design of future clinical trials in SMA.

Spinal Muscular Atrophy: New Thoughts on the Pathogenesis and Classification Schema

We have established the first prospective, collaborative study of spinal muscular atrophy, the second most common neuromuscular disease of childhood. One hundred and forty-one patients have been evaluated on at least four occasions over a 3-year period. The patients have been grouped by age of onset, as well as by function at the time of initial evaluation. The muscle strength of 96 patients aged 5 years or older was evaluated at 6-month intervals using a fixed myometry system. The new observations made are: (1) The present classification schema is not valid; for example, 49 patients with onset of weakness before 6 months of age (type I or Werdnig-Hoffmann disease), whose life span is said to be only 2 to 4 years, participated in the study and are 4 months to 31 years of age. (2) Thirty-seven patients were evaluated over an 18-month period. None lost strength during this time but four lost function. Although the period of observation was short, the results suggest that the loss of function in patients with spinal muscular atrophy might be explained by a process other than cell death that allows patient strength to be maintained and simultaneously prevents the motor unit from achieving its normal adult potential. (J Child Neurol 1992;7:347-353).

Functional classification and orthopaedic management of spinal muscular atrophy

The majority of patients with chronic infantile and juvenile forms of spinal muscular atrophy survive to adult life. Forty-four patients have been reviewed at an average of 17 years after diagnosis. The subdivision of patients into four groups, based on the maximal physical function developed by the individual, correlates well with the onset and severity of secondary deformity of the limbs and spine. This information allows anticipation of the problems and plans for their treatment to be made from early childhood. After analysis of the orthotic and surgical treatment received by these patients, a specific programme of care is recommended for each of the functional groups.