Top Ten Articles on Developmental Disabilities
September 19, 2008
Gordon Worley, MD, Gregory Liptak, MD
10a. Morgan AT, Vogel AP. Intervention for dysarthria associated with acquired brain injury in children and adolescents. Cochrane Database Syst Rev. 2008 Jul 16;(3):CD006279.
BACKGROUND: The term 'acquired brain injury' (ABI) incorporates a range of aetiologies including cerebrovascular accident, brain tumour and traumatic brain injury. ABI is a common cause of disability in the paediatric population, and dysarthria is a common and often persistent sequelae associated with ABI in children. OBJECTIVES: To assess the efficacy of intervention delivered by Speech and Language Pathologists/Therapists targeting dysarthric speech in children resulting from acquired brain injury. SEARCH STRATEGY: We searched CENTRAL (Issue 4, 2006), MEDLINE (1966 to 02/2007), CINAHL (1982 to 02/2007), EMBASE (1980 to 02/2007), ERIC (1965 to 02/2007), Linguistics Abstracts Online (1985 to 02/07), PsycINFO (1872 to 02/2007). Additional references were also sought from reference lists studies. SELECTION CRITERIA: The review considered randomised controlled trials (RCTs) and quasi-experimental design studies of children aged 3-16 years with acquired dysarthria grouped by aetiology (e.g., brain tumour, traumatic brain injury, cerebrovascular accident). DATA COLLECTION AND ANALYSIS: Each author independently assessed the titles and abstracts for relevance (100% inter-rater reliability) and the full text version of all potentially relevant articles was obtained. No studies met inclusion criteria. MAIN RESULTS: Of 2091 titles and abstracts identified, full text versions of only three (Morgan 2007; Murdoch 1999; Netsell 2001) were obtained. 2088 were excluded, largely on the basis of not including dysarthria, being diagnostic or descriptive papers, and for concerning adults rather than children. Morgan 2007 and Murdoch 1999 were excluded for not employing RCT or quasi-randomised methodology; Netsell 2001 on the basis of being a theoretical review paper, rather than an intervention study. Five references were identified and obtained from the bibliography of the Murdoch 1999 paper. All were excluded due to including populations without ABI, adults with dysarthria, or inappropriate design. Thus, no studies met inclusion criteria. AUTHORS' CONCLUSIONS: The review demonstrates a critical lack of studies, let alone RCTs, addressing treatment efficacy for dysarthria in children with ABI. Possible reasons to explain this lack of data include i) a lack of understanding of the characteristics or natural history of dysarthria associated with this population; ii) the lack of a diagnostic classification system for children precluding the development of well targeted intervention programs; and iii) the heterogeneity of both the aetiologies and resultant possible dysarthria types of paediatric ABI. Efforts should first be directed at modest well-controlled studies to identify likely efficacious treatments that may then be trialed in multi-centre collaborations using quasi-randomised or RCT methodology.
10b. Watemberg N, Waiserberg N, Zuk L, Lerman-Sagie T. Developmental coordination disorder in children with attention-deficit-hyperactivity disorder and physical therapy intervention. Dev Med Child Neurol. 2007 Dec;49(12):920-5.
Although physical therapy (PT) is effective in improving motor function in children with developmental coordination disorder (DCD), insufficient data are available on the impact of this intervention in children with combined attention-deficit-hyperactivity disorder (ADHD) and DCD. This prospective study aimed to establish the prevalence of DCD among a cohort of patients with ADHD, characterize the motor impairment, identify additional comorbidities, and determine the role of PT intervention on these patients. DCD was detected in 55.2% of 96 consecutive children with ADHD (81 males, 15 females), mostly among patients with the inattentive type (64.3% compared with 11% of those with the hyperactive/impulsive type, p < 0.05). Mean age was 8 years 4 months (SD 2 y). Individuals with both ADHD and DCD more often had specific learning disabilities (p=0.05) and expressive language deficits (p=0.03) than children with ADHD only. Twenty-eight patients with ADHD and DCD randomly received either intensive group PT (group A, mean age 9 y 3 mo, SD 2 y 3 mo) or no intervention (group B, mean age 9 y 3 mo, SD 2 y 2 mo). PT significantly improved motor performance (assessed by the Movement Assessment Battery for Children; p=0.001). In conclusion, DCD is common in children with ADHD, particularly of the inattentive type. Patients with both ADHD and DCD are more likely to exhibit specific learning disabilities and phonological (pronunciation) deficits. Intensive PT intervention has a marked impact on the motor performance of these children.
9. Montes G, Halterman JS. Association of childhood autism spectrum disorders and loss of family income. Pediatrics. 2008 Apr;121(4):e821-6.
BACKGROUND: Parents of children with autism have significant out-of-pocket expenditures related to their child's care. The impact of having a child with autism on household income is not known. OBJECTIVE: The purpose of this work was to estimate the loss of household income associated with childhood autism using a nationally representative sample. METHODS: Parents of 11,684 children enrolled in kindergarten to eighth grade were surveyed by the National Household Education Survey-After School Programs and Activities in 2005. An autism spectrum disorder was defined as an affirmative response to the questions, "has a health professional told you that [child] has any of the following disabilities? 1) autism? 2) pervasive developmental disorder or PDD?" There were 131 children with autism spectrum disorder in the sample and 2775 children with other disabilities. We used ordinal logistic regression analyses to estimate the expected income of families of children with autism given their education level and demographic characteristics and compared the expected income with their reported income. RESULTS. Both having a child with autism spectrum disorder and having a child with other disabilities were associated with decreased odds of living in a higher income household after controlling for parental education, type of family, parental age, location of the household, and minority ethnicity. The average loss of annual income associated with having a child with autism spectrum disorder was $6200 or 14% of their reported income. CONCLUSION: Childhood autism is associated with a substantial loss of annual household income. This likely places a significant burden on families in the face of additional out-of-pocket expenditures.
8. Morrow EM et al. Identifying Autism Loci and Genes by Tracing Recent Shared Ancestry. Science 11 July 2008:Vol. 321. no. 5886, pp. 218 - 223.
To find inherited causes of autism-spectrum disorders, we studied families in which parents share ancestors, enhancing the role of inherited factors. We mapped several loci, some containing large, inherited, homozygous deletions that are likely mutations. The largest deletions implicated genes, including PCDH10 (protocadherin 10) and DIA1 (deleted in autism1, or c3orf58), whose level of expression changes in response to neuronal activity, a marker of genes involved in synaptic changes that underlie learning. A subset of genes, including NHE9 (Na+/H+ exchanger 9), showed additional potential mutations in patients with unrelated parents. Our findings highlight the utility of "homozygosity mapping" in heterogeneous disorders like autism but also suggest that defective regulation of gene expression after neural activity may be a mechanism common to seemingly diverse autism mutations.
[This study has several implications. First, autism has several recessive causes. Second, it reinforces our understanding that autism has many different causes. Third, although autism has diverse causes, many of the genes found focus on a common cellular mechanism, specifically the way that neurons make connections in response to learning. Finally, many of the mutations do not seem to completely remove a gene, but instead affect the on/off switches that control when and where the genes are expressed. This is important because it is probably easier to affect an on/off switch than to replace an entire gene.]
7. Brooke BS, Habashi JP, Judge DP, Patel N, Loeys B, Dietz HC 3rd. Angiotensin II blockade and aortic-root dilation in Marfan's syndrome. N Engl J Med. 2008 Jun 26;358(26):2787-95.
BACKGROUND: Progressive enlargement of the aortic root, leading to dissection, is the main cause of premature death in patients with Marfan's syndrome. Recent data from mouse models of Marfan's syndrome suggest that aortic-root enlargement is caused by excessive signaling by transforming growth factor beta (TGF-beta) that can be mitigated by treatment with TGF-beta antagonists, including angiotensin II-receptor blockers (ARBs). We evaluated the clinical response to ARBs in pediatric patients with Marfan's syndrome who had severe aortic-root enlargement. METHODS: We identified 18 pediatric patients with Marfan's syndrome who had been followed during 12 to 47 months of therapy with ARBs after other medical therapy had failed to prevent progressive aortic-root enlargement. The ARB was losartan in 17 patients and irbesartan in 1 patient. We evaluated the efficacy of ARB therapy by comparing the rates of change in aortic-root diameter before and after the initiation of treatment with ARBs. RESULTS: The mean (+/-SD) rate of change in aortic-root diameter decreased significantly from 3.54+/-2.87 mm per year during previous medical therapy to 0.46+/-0.62 mm per year during ARB therapy (P < 0.001). The deviation of aortic-root enlargement from normal, as expressed by the rate of change in z scores, was reduced by a mean difference of 1.47 z scores per year (95% confidence interval, 0.70 to 2.24; P < 0.001) after the initiation of ARB therapy. The sinotubular junction, which is prone to dilation in Marfan's syndrome as well, also showed a reduced rate of change in diameter during ARB therapy (P < 0.05), whereas the distal ascending aorta, which does not normally become dilated in Marfan's syndrome, was not affected by ARB therapy. CONCLUSIONS: In a small cohort study, the use of ARB therapy in patients with Marfan's syndrome significantly slowed the rate of progressive aortic-root dilation. These findings require confirmation in a randomized trial.
[Mouse models of Marfan syndrome have identified over-expression of latent transforming growth factor-$ binding protein. Studies of diabetics with nephropathy have shown that angiotensin-receptor blockers lower these levels. This preliminary report suggests that blocking angiotensin II type 1 receptors will benefit young patients with severe Marfan's syndrome. This exiting finding is preliminary and will require confirmation. However, it shows how research from multiple fields can be synthesized to address a serious chronic condition in children.]
6. Wasdell MB, Jan JE, Bomben MM, Freeman RD, Rietveld WJ, Tai J, Hamilton D, Weiss MD. A randomized, placebo-controlled trial of controlled release melatonin treatment of delayed sleep phase syndrome and impaired sleep maintenance in children with neurodevelopmental disabilities. J Pineal Res. 2008 Jan;44(1):57-64.
The purpose of this study was to determine the efficacy of controlled-release (CR) melatonin in the treatment of delayed sleep phase syndrome and impaired sleep maintenance of children with neurodevelopmental disabilities including autistic spectrum disorders. A randomized double-blind, placebo-controlled crossover trial of CR melatonin (5 mg) followed by a 3-month open-label study was conducted during which the dose was gradually increased until the therapy showed optimal beneficial effects. Sleep characteristics were measured by caregiver who completed somnologs and wrist actigraphs. Clinician rating of severity of the sleep disorder and improvement from baseline, along with caregiver ratings of global functioning and family stress were also obtained. Fifty-one children (age range 2-18 years) who did not respond to sleep hygiene intervention were enrolled. Fifty patients completed the crossover trial and 47 completed the open-label phase. Recordings of total night-time sleep and sleep latency showed significant improvement of approximately 30 min. Similarly, significant improvement was observed in clinician and parent ratings. There was additional improvement in the open-label somnolog measures of sleep efficiency and the longest sleep episode in the open-label phase. Overall, the therapy improved the sleep of 47 children and was effective in reducing family stress. Children with neurodevelopmental disabilities, who had treatment resistant chronic delayed sleep phase syndrome and impaired sleep maintenance, showed improvement in melatonin therapy.
5. Eyre JA, Smith M, Dabydeen L, Clowry GJ, Petacchi E, Battini R, Guzzetta A, Cioni G. Is hemiplegic cerebral palsy equivalent to amblyopia of the corticospinal system? Ann Neurol. 2007 Nov;62(5):493-503.
OBJECTIVE: Subjects with severe hemiplegic cerebral palsy have increased ipsilateral corticospinal projections from their noninfarcted cortex. We investigated whether their severe impairment might, in part, be caused by activity-dependent, competitive displacement of surviving contralateral corticospinal projections from the affected cortex by more active ipsilateral corticospinal projections from the nonaffected cortex, thereby compounding the impairment. METHODS: Transcranial magnetic stimulation (TMS) characterized corticospinal tract development from each hemisphere over the first 2 years in 32 healthy children, 14 children with unilateral stroke, and 25 with bilateral lesions. Magnetic resonance imaging and anatomic studies compared corticospinal tract growth in 13 patients with perinatal stroke with 46 healthy subjects. RESULTS: Infants with unilateral lesions initially had responses after TMS of the affected cortex, which became progressively more abnormal, and seven were eventually lost. There was associated hypertrophy of the ipsilateral corticospinal axons projecting from the noninfarcted cortex. Magnetic resonance imaging and anatomic studies demonstrated hypertrophy of the corticospinal tract from the noninfarcted hemisphere. TMS findings soon after the stroke did not predict impairment; subsequent loss of responses and hypertrophy of ipsilateral corticospinal axons from the noninfarcted cortex predicted severe impairment at 2 years. Infants with bilateral lesions maintained responses to TMS from both hemispheres with a normal pattern of development. INTERPRETATION: Rather than representing "reparative plasticity," increased ipsilateral projections from the noninfarcted cortex compound disability by competitively displacing surviving contralateral corticospinal projections from the infarcted cortex. This may provide a pathophysiological explanation for why signs of hemiplegic cerebral palsy appear late and progress over the first 2 years of life.
[We know that kittens who are deprived of vision develop progressive loss of responsiveness by the primary visual cortex. This study provides evidence that similar activity-dependent changes occur in the brains of children who are developing hemiplegia following a prenatal/perinatal stroke. The current dogma is that cerebral palsy results from "a nonprogressive lesion of the brain." This study refutes that dogma. In addition, it suggests that post natal interventions (like constraint therapy, TMS and electrical stimulation of muscles) could enhance the competitive ability of a damaged corticospinal system and mitigate the consequences of the lesion-just like "patching" of the good eye in children developing amblyopia can improve vision.]
4. Chapman DA, Scott KG, Stanton-Chapman TL. Public health approach to the study of mental retardation. Am J Ment Retard. 2008 Mar;113(2):102-16.
We applied a public health approach to the study of mental retardation by providing a basic descriptive epidemiological analysis using a large statewide linked birth and public school record database (N = 327,831). Sociodemographic factors played a key role across all levels of mental retardation. Birthweight less than 1000 g was associated with the highest individual-level risk, but the impact varied considerably, depending on maternal educational level. Low maternal education was associated with the largest effects at the population level for mild and moderate/severe mental retardation. Focusing exclusively on specific biomedical causes is of little use in developing public health plans; a broader biosocial perspective reflecting the interactive complexity of the risk factors comprising the various etiological patterns is needed.
[It is not good in terms of health or longevity to be poor, of color or uneducated. This study demonstrates the effect of social factors on intelligence. Will poverty and poor education always be with us, or can we intervene on a national or global scale to improve the plight of individuals at social disadvantage? And if we do, what effect will that have on outcomes like intelligence?]
3. Kirton A, Chen R, Friefeld S, Gunraj C, Pontigon AM, Deveber G. Contralesional repetitive transcranial magnetic stimulation for chronic hemiparesis in subcortical paediatric stroke: a randomised trial. Lancet Neurol. 2008 Jun;7(6):507-13.
BACKGROUND: Arterial ischaemic stroke (AIS) can cause disabling hemiparesis in children. We aimed to test whether contralesional, inhibitory repetitive transcranial magnetic stimulation (rTMS) could affect interhemispheric inhibition to improve hand function in chronic subcortical paediatric AIS. METHODS: Patients were eligible for this parallel, randomised trial if they were in the SickKids Children's Stroke Program and had subcortical AIS more than 2 years previously, had transcallosal sparing, were more than 7 years of age, had hand motor impairment, had no seizures or dyskinesia, and were taking no drugs that alter cortical excitability. Patients were paired for age and weakness and were randomised within each pair to sham treatment or inhibitory, low-frequency rTMS over contralesional motor cortex (20 min, 1200 stimuli) once per day for 8 days. An occupational therapist did standardised tests of hand function at days 1 (baseline), 5, 10, and 17 (1 week post-treatment), and the primary outcomes were changes in grip strength and the Melbourne assessment of upper extremity function (MAUEF) between baseline and day 10. Patients, parents, and occupational therapists were blinded to treatment allocation. Analysis was per protocol. FINDINGS: Ten patients with paediatric stroke were enrolled (median age 13.25 [IQR 10.08-16.78] years, mean time post-stroke 6.33 [SD 3.56] years): four with mild weakness, two with moderate weakness, and four with severe weakness. A repeated-measures ANOVA showed a significant interaction between time and the effect of treatment on grip strength (p=0.03). At day 10, grip strength was 2.28 (SD 1.01) kg greater than baseline in the rTMS group and 2.92 (1.20) kg less than baseline in the sham group (p=0.009). Benefits in mean grip strength persisted at day 17 (2.63 [0.56] kg greater than baseline with rTMS and 1.00 [0.70] kg less than baseline with sham treatment; p=0.01). Day 10 MAUEF score improved by more in the rTMS group than in the sham group (7.25 [3.8] vs 0.79 [1.3] points greater than baseline; p=0.002), but this benefit did not persist to day 17. Function of the unaffected hand remained stable. rTMS was well tolerated with no serious adverse events. INTERPRETATION: Contralesional inhibitory rTMS was safe and feasible for patients with paediatric subcortical AIS, and seemed to improve hand function in patients with hemiparesis. Further studies are required to confirm the potential role of rTMS in paediatric neurorehabilitation.
[Following a stroke, mutifocal, bihemispheric changes occur in brain activity; some of these changes, rather than being functionally advantageous, may be maladaptive and impair recovery. Inhibition of the unaffected motor cortex with rTMS has shown positive results in adults who have had strokes. Although rTMS is not yet ready for the "big time" (as an established clinical procedure), this study provides hope for the future treatment of strokes in children.]
2. Downs J, Bebbington A, Woodhead H, Jacoby P, Jian L, Jefferson A, Leonard H. Early determinants of fractures in Rett syndrome. Pediatrics. 2008 Mar;121(3):540-6.
OBJECTIVES: The goals were to compare the fracture incidence in Rett syndrome with that in the general population and to investigate the impact of genotype, epilepsy, and early motor skills on subsequent fracture incidence in girls and young women with Rett syndrome. METHODS: The Australian Rett syndrome study, a population-based study operating since 1993, investigated Australian subjects with Rett syndrome born since 1976. The 234 (81.2%) of 288 verified cases in the Australian Rett syndrome database in 2004 whose families had completed follow-up questionnaires and provided information about fracture history were included in the analyses. The main outcomes were fracture incidence in the Rett syndrome population and fracture risk according to genotype, presence of epilepsy, and early motor profile. RESULTS: Fracture incidence in this cohort was 43.3 episodes per 1000 person-years, nearly 4 times greater than the population rate. Risk was increased specifically in cases with p.R270X mutations and in cases with p.R168X mutations. Having epilepsy also increased fracture risk, even after adjustment for genotype. CONCLUSIONS: Girls and young women with Rett syndrome are at increased risk of fracture. Those with mutations found previously to be more severe and those with epilepsy have an increased propensity toward fractures. Improved understanding of the risk factors for fracture could contribute to better targeting of interventions to decrease fracture incidence in this vulnerable population.
[Osteopenia and increased fractures occur in children with a variety of developmental disabilities, including cerebral palsy and epilepsy. This study highlights the risks in girls/women who have Rett syndrome. As individuals with disabilities live longer, we need to prevent and manage conditions associated with increased longevity, such as osteoporosis and fractures, in order to optimize their health and well-being.]
1. Dabydeen L, Thomas JE, Aston TJ, Hartley H, Sinha SK, Eyre JA. High-energy and -protein diet increases brain and corticospinal tract growth in term and preterm infants after perinatal brain injury. Pediatrics. 2008 Jan;121(1):148-56.
OBJECTIVE: Our hypothesis was that infants with perinatal brain injury fail to thrive in the first postnatal year because of increased energy and protein requirements from deficits that accumulated during neonatal intensive care. Our aim was to assess whether dietary energy and protein input was a rate-limiting factor in brain and body growth in the first year after birth. METHODS: We conducted a prospective, double-blind and randomized, 2-stage group sequential study and controlled for gestation, gender, and brain lesion. Neonates with perinatal brain damage were randomly allocated to receive either a high- (120% recommended average intake) or average (100% recommended average intake) energy and protein diet. The study began at term and continued for 12 months. Three-day dietary diaries estimated energy and protein intake. The primary outcome measure was growth of occipitofrontal circumference. Other measures were growth of axonal diameters in the corticospinal tract, which were estimated by using transcranial magnetic stimulation, weight gain, and length. RESULTS: The study was terminated at the first analysis when the 16 subjects had completed the protocol, because the predetermined stopping criterion of >1 SD difference in occipitofrontal circumference at 12 months' corrected age in those receiving the higher-energy and -protein diet had been demonstrated. Axonal diameters in the corticospinal tract, length, and weight were also significantly increased. CONCLUSIONS: These data support our hypothesis that infants with significant perinatal brain damage have increased nutritional requirements in the first postnatal year and suggest that decreased postnatal brain growth may exacerbate their impairment. There are no measures of cognitive ability at 12 months of age, and whether there will be any improvement in the status of these children, therefore, remains to be shown.