Human chorionic gonadotropin decreases cerebral cystic encephalomalacia and parvalbumin interneuron degeneration in a pro-inflammatory model of mouse neonatal hypoxia-ischemia.

The pregnancy hormone, human chorionic gonadotropin (hCG) is an immunoregulatory and neurotrophic glycoprotein of potential clinical utility in the neonate at risk for cerebral injury. Despite its well-known role in its ability to modulate the innate immune response during pregnancy, hCG has not been demonstrated to affect the pro-degenerative actions of inflammation in neonatal hypoxia-ischemia (HI). Here we utilize a neonatal mouse model of mild HI combined with intraperitoneal administration of lipopolysaccharide (LPS) to evaluate the neuroprotective actions of hCG in the setting of endotoxin-mediated systemic inflammation. Intraperitoneal treatment of hCG shortly prior to LPS injection significantly decreased tissue loss and cystic degeneration in the hippocampal and cerebral cortex in the term-equivalent neonatal mouse exposed to mild HI. Noting that parvalbumin immunoreactive interneurons have been broadly implicated in neurodevelopmental disorders, it is notable that hCG significantly improved the injury-mediated reduction of these neurons in the cerebral cortex, striatum and hippocampus. The above findings were associated with a decrease in the amount of Iba1 immunoreactive microglia in most of these brain regions. These observations implicate hCG as an agent capable of improving the neurological morbidity associated with peripheral inflammation in the neonate affected by HI. Future preclinical studies should aim at demonstrating added neuroprotective benefit by hCG in the context of therapeutic hypothermia and further exploring the mechanisms responsible for this effect. This research is likely to advance the therapeutic role of gonadotropins as a treatment for neonates with neonatal brain injury.

Physician Approaches to the Pharmacologic Treatment of Dystonia in Cerebral Palsy.

Objective: To determine how physicians approach pharmacologic dystonia treatment in people with CP and assess physician readiness to participate in a randomized trial comparing existing pharmacologic dystonia treatments. Methods: We administered a REDCap survey to physician members of the American Academy of Cerebral Palsy and Developmental Medicine and of the Child Neurology Society to assess which pharmacologic agents they use to treat dystonia in CP and their preferred indications and dosing. Results: Of 479 physicians surveyed, 240 (50%) responded. Respondents treated functionally limiting (95%) and generalized (57%) dystonia and most commonly used six medications: baclofen (95%), trihexyphenidyl (79%), gabapentin (67%), carbidopa/levodopa (55%), clonazepam (55%), and diazepam (54%). Baclofen was preferred in people with co-existing spasticity (81%), gabapentin was preferred in people with co-existing pain (49%), and trihexyphenidyl was avoided in people with constipation (34%) or urinary retention (42%). Preferred dosing regimens followed published regimens for dystonia, when available, but otherwise followed published regimens for other CP symptoms (spasticity and seizures). Baclofen was preferred by 64% of respondents as first line treatment, but there was no clear consensus on second or third-line medications. Most respondents (51%) were comfortable randomizing their patients to receive any of the six most commonly used medications used to treat dystonia in CP. Conclusions: This study summarizes current indications and dosing for the six most commonly used medications to treat dystonia in CP as per treating physicians in the US and Canada and also demonstrates physician support for a randomized trial comparing the effectiveness of these treatments.

Mice born preterm develop gait dystonia and reduced cortical parvalbumin immunoreactivity.

Preterm birth leading to cerebral palsy (CP) is the most common cause of childhood dystonia, a movement disorder that is debilitating and often treatment refractory. Dystonia has been typically associated with dysfunction of striatal cholinergic interneurons, but clinical imaging data suggests that cortical injury may best predict dystonia following preterm birth. Furthermore, abnormal sensorimotor cortex inhibition has been found in many studies of non-CP dystonias. To assess the potential for a cortical etiology of dystonia following preterm birth, we developed a new model of preterm birth in mice. Noting that term delivery in mice on a C57BL/6J background is embryonic day 19.1 (E19.1), we induced preterm birth at the limits of pup viability at embryonic day (E) 18.3, equivalent to human 22 weeks gestation. Mice born preterm demonstrate display clinically validated metrics of dystonia during gait (leg adduction amplitude and variability) and also demonstrate reduced parvalbumin immunoreactivity in the sensorimotor cortex, suggesting dysfunction of cortical parvalbumin-positive inhibitory interneurons. Notably, reduced parvalbumin immunoreactivity or changes in parvalbumin-positive neuronal number were not observed in the striatum. These data support the association between cortical dysfunction and dystonia following preterm birth. We propose that our mouse model of preterm birth can be used to study this association and potentially also study other sequelae of extreme prematurity.

Caregiver descriptions of dystonia in cerebral palsy.

OBJECTIVE: To determine how caregivers describe dystonia in people with cerebral palsy (CP). METHODS: In this prospective cohort study, paper surveys were administered to caregivers between September 7, 2021 and October 28, 2021 during CP Center visits at a large tertiary care center. Caregivers were asked to describe involuntary movements triggered by voluntary movement or triggered by tactile stimulation in the people with CP they cared for. Their CP Center medical provider separately assessed people with CP for dystonia. Movement features described exclusively by caregivers of people with CP and dystonia were determined using conventional content analysis. RESULTS: 113 caregivers responded on behalf of 56 people with and 57 people without dystonia. If caregivers noted that both voluntary movement and tactile stimulation triggered involuntary movements, that had a 92% positive predictive value for a dystonia diagnosis. Movement features exclusively described in people with CP and dystonia included: (1) stiffening, tensing, or tightening (15% of respondents); (2) involvement of the head (10%), torso (5%), or feet (5%); and (3) triggers of stretching (12.5%), excitement (5%), or transfers (5%). INTERPRETATION: In addition to a thorough exam, asking caregivers of people with CP to describe involuntary movements triggered by voluntary movement or tactile stimulation may inform clinical dystonia diagnosis.

Upper Extremity Dystonia Features in People With Spastic Cerebral Palsy.

Background and Objectives: Dystonia in cerebral palsy (CP) is debilitating and common, but underdiagnosed, especially when coexistent with spasticity. With dedicated research-based assessment, dystonia is found in most people with spastic CP but is only clinically diagnosed in the minority. To begin addressing the high rates of dystonia underdiagnosis in this population, we determined the key feature experts use to assess upper extremity dystonia in people with spastic CP. Methods: In this prospective cohort study, 3 pediatric movement disorder specialists assessed upper extremity dystonia in neurologic examination videos of people with spastic CP and isolated periventricular leukomalacia (PVL) on brain MRI (i.e., those with a brain injury pattern typical for spastic CP). Dystonia severity was rated using the 10-point Global Dystonia Severity Rating Scale, first by each expert independently and then again after consensus-building discussion. Conventional content analysis of these discussions revealed salient features ("codes") that experts used to assess upper extremity dystonia. Code frequency distributions were compared between dystonia severity categories using χ2 tests. Results: We identified 96 people with spastic CP with isolated PVL on brain MRI seen in the St. Louis Children's Hospital CP Center between 2005 and 2018. Of them, 26 people were able and willing to be recorded while doing a standardized set of upper extremity examination maneuvers (age 4-25 years; 28% nonambulatory, 77% White). When assessing their videos, experts cited the "hand" less often and "shoulder" more often with increasing dystonia severity (p < 0.005, χ2 test). "Mirror movements" and the "hand open/close" examination maneuver were cited significantly more frequently in videos when experts were attempting to distinguish between no dystonia and mild dystonia (p < 0.005). Discussion: Expert clinicians use distinct movement features to assess upper extremity dystonia in people with spastic CP and PVL. Attention to involuntary shoulder (vs hand) movements can help gauge dystonia severity. Differentiation between mirror movements and dystonia, particularly during the hand open/close examination maneuver, may help identify mild dystonia. These results can help guide upper extremity dystonia assessment in people with spastic CP, thus potentially helping mitigate dystonia underdiagnosis.

SIGnature Libraries: A roadmap for the formation of special interest group libraries.

Objective: "SIGnature Libraries" channel the dynamism of academic society-based special interest groups (SIG) to systematically identify and provide user-oriented access to essential literature for a subspecialty field in a manner that keeps pace with the field's continuing evolution. The libraries include literature beyond clinical trial data to encompass historical context, diagnostic conceptualization, and community organization materials to foster a holistic understanding of how neurologic conditions affect individuals, their community, and their lived experience. Methods: Utilizing a modified-Delphi approach, Child Neurology Society's Cerebral Palsy (CP) SIG (n = 75) administered two rounds of literature submissions and ratings. A final review by an 11-member international advisory group determined threshold ratings for resource inclusion and the library's final structure. Results: Seventy-nine articles were submitted for the first Delphi round and 22 articles for the second Delphi round. Survey response rates among SIG members were 29/75 for the first round and 24/75 for the second round. The advisory board added additional articles in the final review process in view of the overall project goal. A total of 60 articles were included in the final library, and articles were divided into seven sections and stratified by rating scores. A process for ongoing revisions of the library was determined. The library will be published on the Child Neurology Society website and made publicly accessible. Conclusions: The CP SIGnature Library offers learners an unprecedented resource that provides equitable access to latest consensus guidelines, existing seminal datasets, up-to-date review articles, and other patient care tools. A distinctive feature of the library is its intentional large scope and depth, presented in a stratified fashion relative to the consensus-determined importance of each article. Learners can efficiently navigate the library based on individual interests and goals, and the library can be used as core curriculum for CP education.

Current Practices in the Evaluation of Global Developmental Delay/Intellectual Disability: A Nationwide Survey of Child Neurologists.

Background and Objectives: Global developmental delay/intellectual disability (GDD/ID) are among the most common neurologic conditions evaluated by child neurologists in the United States. No recent neurology-specific guidelines for GDD/ID diagnostic evaluation exist, which could lead to practice variability. We assessed current practices in GDD/ID diagnostic evaluation among US child neurologists, including drivers of exome sequencing (ES). Methods: A 19-item online anonymous survey was distributed between April 2021 and September 2021 to 953 eligible child neurologists by email and/or online platforms through the American Academy of Neurology and Child Neurology Society. Multinomial logistic regression was used to determine the predictors of sending ES as a part of GDD/ID diagnostic evaluation. Results: Of 172 unique respondents, 69.2% reported almost always obtaining a chromosomal microarray while 10.5% reported almost always pursuing ES. However, 65.1% identified ES as a first-tier diagnostic test for GDD/ID. Clinical practice demographics independently associated with a higher likelihood of pursuit of ES were more years of experience (p = 0.002) and more people with GDD/ID in one's practice (p < 0.001). Inclusion of brain MRI, EEG, and metabolic laboratory values as part of GDD/ID diagnostic evaluation varied widely. Modalities to screen for treatable disorders (ES or metabolic laboratory values) were reported to be consistently used by only 24.8% of respondents. Respondents identified key barriers to the pursuit of ES including the need for genetics referral/genetic counseling and insurance coverage/out-of-pocket cost. Discussion: Among US child neurologists, there is marked practice variability in GDD/ID diagnostic evaluation across multiple types of testing, raising concern for disparities in care. There is a widespread lack of screening for treatable causes of ID, which may lead to missed diagnoses and avoidable morbidity. Despite most respondents' support for ES as a first-tier diagnostic test for GDD/ID, only a small minority routinely pursue ES as a part of their evaluation. Provider-level factors (years of experience, percent of patients with GDD/ID) and system-level barriers (access to genetics expertise, lack of insurance coverage) were determinants of the frequency of use of ES. These findings suggest the need for updated consensus guidelines and advocacy/education to improve child neurologists' ability to pursue ES for GDD/ID.

Clinical actionability of genetic findings in cerebral palsy.

Background and objectives: Single gene mutations are increasingly recognized as causes of cerebral palsy (CP) phenotypes, yet there is currently no standardized framework for measuring their clinical impact. We evaluated Pathogenic/Likely Pathogenic (P/LP) variants identified in individuals with CP to determine how frequently genetic testing results would prompt changes in care. Methods: We analyzed published P/LP variants in OMIM genes identified in clinical (n = 1,345 individuals) or research (n = 496) cohorts using exome sequencing of CP patients. We established a working group of clinical and research geneticists, developmental pediatricians, genetic counselors, and neurologists and performed a systematic review of existing literature for evidence of clinical management approaches linked to genetic disorders. Scoring rubrics were adapted, and a modified Delphi approach was used to build consensus and establish the anticipated impact on patient care. Overall clinical utility was calculated from metrics assessing outcome severity if left untreated, safety/practicality of the intervention, and anticipated intervention efficacy . Results: We found 140/1,841 (8%) of individuals in published CP cohorts had a genetic diagnosis classified as actionable , defined as prompting a change in clinical management based on knowledge related to the genetic etiology. 58/243 genes with P/LP variants were classified as actionable; 16 had treatment options targeting the primary disease mechanism , 16 had specific prevention strategies , and 26 had specific symptom management recommendations. The level of evidence was also graded according to ClinGen criteria; 44.6% of interventions had evidence class "D" or below. The potential interventions have clinical utility with 97% of outcomes being moderate-high severity if left untreated and 62% of interventions predicted to be of moderate-high efficacy . Most interventions (71%) were considered moderate-high safety/practicality . Discussion: Our findings indicate that actionable genetic findings occur in 8% of individuals referred for genetic testing with CP. Evaluation of potential efficacy , outcome severity , and intervention safety / practicality indicates moderate-high clinical utility of these genetic findings. Thus, genetic sequencing to identify these individuals for precision medicine interventions could improve outcomes and provide clinical benefit to individuals with CP. The relatively limited evidence base for most interventions underscores the need for additional research.

Brain Region Size Differences Associated With Dystonia in People With Cerebral Palsy Born Premature.

BACKGROUND: Dystonia in cerebral palsy (CP) is classically associated with deep gray matter injury at term gestation, but the patterns of injury associated with dystonia following premature birth are unclear. We examined whether there were brain regional size differences associated with dystonia in people with CP born premature. METHODS: In this retrospective cohort study, we identified subjects with CP born premature (<37 weeks gestational age) seen at a tertiary care CP center between February 1, 2017, to February 1, 2021, who had T1-weighted brain magnetic resonance imaging (MRI) done between ages one and five years available in the clinical record. We measured the following on these brain MRI images per the 2013 Kidokoro criteria: interhemispheric distance, biparietal width, lateral ventricle diameter, transcerebellar diameter, deep gray matter area, and corpus callosum thickness. We then compared the sizes of these structures between those with and without dystonia correcting for gestational age at birth and gross motor functional ability (univariate general linear models). RESULTS: Fifty-five subjects met the inclusion and exclusion criteria. Interhemispheric distance was significantly greater in those with dystonia, suggesting decreased cortical volume (P = 0.005). There was no significant difference in the other measured structures between those with and without dystonia, including deep gray matter area. CONCLUSIONS: Increased interhemispheric distance, not measures of deep gray matter size, correlate with the presence of dystonia in people with CP born premature.

Chronic striatal cholinergic interneuron excitation induces clinically-relevant dystonic behavior in mice.

Dystonia is common, debilitating, often medically refractory, and difficult to diagnose. The gold standard for both clinical and mouse model dystonia evaluation is subjective assessment, ideally by expert consensus. However, this subjectivity makes translational quantification of clinically-relevant dystonia metrics across species nearly impossible. Many mouse models of genetic dystonias display abnormal striatal cholinergic interneuron excitation, but few display subjectively dystonic features. Therefore, whether striatal cholinergic interneuron pathology causes dystonia remains unknown. To address these critical limitations, we first demonstrate that objectively quantifiable leg adduction variability correlates with leg dystonia severity in people. We then show that chemogenetic excitation of striatal cholinergic interneurons in mice causes comparable leg adduction variability in mice. This clinically-relevant dystonic behavior in mice does not occur with acute excitation, but rather develops after 14 days of ongoing striatal cholinergic interneuron excitation. This requirement for prolonged excitation recapitulates the clinically observed phenomena of a delay between an inciting brain injury and subsequent dystonia manifestation and demonstrates a causative link between chronic striatal cholinergic interneuron excitation and clinically-relevant dystonic behavior in mice. Therefore, these results support targeting striatal ChIs for dystonia drug development and suggests early treatment in the window following injury but prior to dystonia onset. One Sentence Summary: Chronic excitation of dorsal striatal cholinergic interneuron causes clinically-relevant dystonic phenotypes in mice.

Spared nerve injury causes motor phenotypes unrelated to pain in mice.

Most animal models of neuropathic pain use targeted nerve injuries quantified with motor reflexive measures in response to an applied noxious stimulus. These motor reflexive measures can only accurately represent a pain response if motor function in also intact. The commonly used spared nerve injury (SNI) model, however, damages the tibial and common peroneal nerves that should result in motor phenotypes (i.e., an immobile or "flail" foot) not typically captured in sensory assays. To test the extent of these issues, we used DeepLabCut, a deep learning-based markerless pose estimation tool to quantify spontaneous limb position in C57BL/6J mice during tail suspension following either SNI or sham surgery. Using this granular detail, we identified the expected flail foot-like impairment, but we also found SNI mice hold their injured limb closer to the body midline compared to shams. These phenotypes were not present in the Complete Freunds Adjuvant model of inflammatory pain and were not reversed by multiple analgesics with different mechanisms of action, suggesting these SNI-specific phenotypes are not directly related to pain. Together these results suggest SNI causes previously undescribed phenotypes unrelated to altered sensation that are likely underappreciated while interpreting preclinical pain research outcomes.

Uncertainties regarding cerebral palsy diagnosis: opportunities to operationalize the consensus definition.

Background and Objectives: Cerebral palsy (CP), the most common motor disability of childhood, is variably diagnosed. We hypothesized that child neurologists and neurodevelopmentalists, often on the frontlines of CP diagnosis in North America, harbor uncertainties regarding the practical application of the most recent CP consensus definition from 2006. Methods: We conducted a cross-sectional survey of child neurologists and neurodevelopmentalists at the 2022 Child Neurology Society Annual Meeting. Attendees were provided the 2006 CP consensus definition and asked whether they had any uncertainties about the practical application of the definition across four hypothetical clinical vignettes. Results: Of 230 attendees, 164 responded to the closing survey questions (71%). 145/164 (88%) expressed at least one uncertainty regarding the clinical application of the 2006 definition. Overwhelmingly, these areas of uncertainty focused on: 1) Age, both with regards to the minimum age of diagnosis and the maximum age of brain disturbance or motor symptom onset, (67/164, 41%), and 2) Interpretation of the term "non-progressive" (48/164, 29%). The vast majority of respondents (157/164, 96%) answered 'Yes' to the question: Do you think we should revise the 2006 consensus definition of CP? Discussion: We propose that the uncertainties we identified could be addressed by operationalizing the 2006 consensus definition to support a more uniform CP diagnosis. To address the most common CP diagnostic uncertainties we identified, we propose 3 points of clarification based on the available literature: 1) Motor symptoms/signs should be present by 2 years old; 2) CP can and should be diagnosed as early as possible, even if activity limitation is not yet present, if motor symptoms/signs can be reasonably predicted to yield activity limitation (e.g. by using standardized examination instruments, Brain MRI, and a suggestive clinical history); and 3) The clinical motor disability phenotype should be non-progressive through 5 years old. We anticipate that operationalizing the 2006 definition of CP in this manner could clarify the uncertainties we identified among child neurologists and neurodevelopmentalists and reduce the diagnostic variability that currently exists.

The Role of Child Neurologists in the Management of Motor Disability in Cerebral Palsy: Establishing the Path Forward.

BACKGROUND: Cerebral palsy (CP) is the most common motor disability of childhood, and yet the role of child neurologists and neurodevelopmentalists (CN/NDDs) in the management of children with CP is unclear. Although previous surveys showed that CN/NDDs believe they are uniquely expert in CP motor phenotyping and should be involved in CP management, others have demonstrated that training in CP management among CN/NDD residency programs is inadequate. METHODS: In this article, we surveyed a group of CN/NDDs at the Child Neurology Society Cerebral Palsy Special Interest Group meeting on January 27, 2022. Questions addressed provider comfort with CP tone management including motor phenotyping, pharmacologic and surgical management, barriers and solutions to improving practice, and the use of systems-based care. RESULTS: Responses from 42 participants demonstrated that CN/NDDs lack experience with CP tone management, with 48% and 58% of respondents reporting little to no experience in pharmacologic or surgical management, respectively. Primary barriers identified to improving comfort with CP tone management included lack of knowledge and ineffective treatment options, while most solutions centered on improving collaborations between CN/NDDs and other specialties. Only 50% of respondents reported currently using systems-based care in the management of patients with CP. CONCLUSIONS: An interdisciplinary, systems-based care model would allow for collaboration and knowledge sharing between involved specialties and provide high-value goal-directed care to maximize the functional outcomes for every individual with CP.

Studies of CP Prevalence: Disparities in Authorship, Citations, and Geographic Location.

We aimed to characterize the existing knowledge of cerebral palsy (CP) prevalence globally and identify any existing publication disparities that may impact our understanding of the global burden of CP. To identify existing publications on CP prevalence, PubMed and Web of Science were searched in May 2021 with the following strategy: "cerebral palsy"[title] AND (rate OR prevalence OR epidemiology). This search yielded 2720 results on PubMed and 2314 on Web of Science. Studies published in English, Spanish, or Japanese and which were available in full text were included. Studies that did not report a CP prevalence statistic were excluded. We identified 94 studies meeting inclusion and exclusion criteria. Of 94 studies, 69 (73.4%) studies came from Europe, North America, and Australia with the remaining 25 (26.6%) from Asia, the Middle East, and Africa. No studies from Latin America were identified. CP prevalence estimates ranged from 0.8 to 4.4 per 1000 live births. Studies from Europe are cited more than studies from other regions, ranging from 7.61 citations/year since publication for European studies to 2.1 citations/year for Middle Eastern studies. Studies from Western countries are written almost exclusively by Western authors (99.69%-100%), while studies from Africa consist of a lower proportion of African authors (31.06%). Our results highlight geographical disparities in our knowledge of CP epidemiology. Existing literature from Latin America, Asia, Africa, and the Middle East are relatively undercited by the field. To better grasp the true impact of CP globally, we must support institutions and researchers in underrepresented regions of the world.

Determinants of gait dystonia severity in cerebral palsy.

AIM: To determine the movement features governing expert assessment of gait dystonia severity in individuals with cerebral palsy (CP). METHOD: In this prospective cohort study, three movement disorder neurologists graded lower extremity dystonia severity in gait videos of individuals with CP using a 10-point Likert-like scale. Using conventional content analysis, we determined the features experts cited when grading dystonia severity. Then, using open-source pose estimation techniques, we determined gait variable analogs of these expert-cited features correlating with their assessments of dystonia severity. RESULTS: Experts assessed videos from 116 participants (46 with dystonia aged 15 years [SD 3] and 70 without dystonia aged 15 years [SD 2], both groups ranging 10-20 years old and 50% male). Variable limb adduction was most commonly cited by experts when identifying dystonia, comprising 60% of expert statements. Effect on gait (regularity, stability, trajectory, speed) and dystonia amplitude were common features experts used to determine dystonia severity, comprising 19% and 13% of statements respectively. Gait variables assessing adduction variability and amplitude (inter-ankle distance variance and foot adduction amplitude) were significantly correlated with expert assessment of dystonia severity (multiple linear regression, p < 0.001). INTERPRETATION: Adduction variability and amplitude are quantifiable gait features that correlate with expert-determined gait dystonia severity in individuals with CP. Consideration of these features could help optimize and standardize the clinical assessment of gait dystonia severity in individuals with CP.

Dystonia in individuals with spastic cerebral palsy and isolated periventricular leukomalacia.

AIM: To determine the prevalence of dystonia in individuals with periventricular leukomalacia (PVL) and spastic cerebral palsy (CP), but without basal ganglia and thalamic injury (BGTI) on brain magnetic resonance imaging (MRI). METHOD: This was a retrospective study of individuals with spastic CP and PVL on MRI evaluated between 2005 and 2018 in a CP center. Individuals with non-PVL brain lesions on MRI, including BGTI, were excluded. Dystonia was assessed via blinded review of neurological exam videos by pediatric movement disorders specialists. RESULTS: Eighty-five participants (45 males, 40 females; mean age at videotaping 12 years [standard deviation 5 years 6 months], range 4-26 years) met inclusion and exclusion criteria. Of these participants, 50 (59%) displayed dystonia in their exam videos. The most common locations of dystonia were the fingers and hip adductors. The prevalence of dystonia was unaffected by the gestational age or severity of PVL, and was affected by Gross Motor Function Classification System level. INTERPRETATION: Dystonia is common in individuals with spastic CP and PVL, even without BGTI on MRI. Our findings suggest vigilance for dystonia in individuals with spastic CP should remain high, even without MRI evidence of BGTI. WHAT THIS PAPER ADDS: Individuals with spastic cerebral palsy and isolated periventricular leukomalacia on magnetic resonance imaging commonly display dystonia. Common sites of dystonia are in the fingers and hip adductors.

Under-recognition of leg dystonia in people with cerebral palsy.

Objective: To determine the rates of clinical under-documentation of leg dystonia in people with cerebral palsy (CP). Methods: In this prospective cohort study, we identified independently ambulatory people age 10-20yo with CP-associated spasticity seen in a tertiary care CP center between 1/1/20 to 11/4/21. Three pediatric movement disorders specialists assessed gait videos from these visits for leg dystonia using the Global Dystonia Rating Scale. We compared the gold standard expert consensus assessment for each patient with the clinical documentation of dystonia during a contemporaneous CP Center clinic visit and also with dystonia documentation longitudinally in their medical record. Results: Of 116 people with CP-associated spasticity assessed in this study, 70 were found to have leg dystonia in their gait videos. Only 13% of these 70 individuals (n=9/70) had leg dystonia documented in their contemporaneous CP Center clinic visit, even though they were assessed during this visit by clinicians well-trained in CP and dystonia assessment. Even with repeated assessment, only 54% (n=38/70) of these individuals had leg dystonia documented in their medical record. Conclusions: Leg dystonia is clinically under-documented in people with CP-associated spasticity, even when these people are evaluated by well-trained clinicians. Longitudinal evaluation and vigilance for leg dystonia is critical to address this diagnostic gap.

Molecular Diagnostic Yield of Exome Sequencing and Chromosomal Microarray in Cerebral Palsy: A Systematic Review and Meta-analysis.

Importance: There are many known acquired risk factors for cerebral palsy (CP), but in some cases, CP is evident without risk factors (cryptogenic CP). Early CP cohort studies report a wide range of diagnostic yields for sequence variants assessed by exome sequencing (ES) and copy number variants (CNVs) assessed by chromosomal microarray (CMA). Objective: To synthesize the emerging CP genetics literature and address the question of what percentage of individuals with CP have a genetic disorder via ES and CMA. Data Sources: Searched articles were indexed by PubMed with relevant queries pertaining to CP and ES/CMA (query date, March 15, 2022). Study Selection: Inclusion criteria were as follows: primary research study, case series with 10 or more nonrelated individuals, CP diagnosis, and ES and/or CMA data used for genetic evaluation. Nonblinded review was performed. Data Extraction and Synthesis: Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were used for assessing data quality and validity. Data were extracted by a single observer. Main Outcomes and Measures: A separate meta-analysis was performed for each modality (ES, CMA). The primary outcome was proportion/molecular diagnostic yield (number of patients with a discovered genetic disorder divided by the total number of patients in the cohort), evaluated via meta-analysis of single proportions using random-effects logistic regression. A subgroup meta-analysis was conducted, using risk factor classification as a subgroup. A forest plot was used to display diagnostic yields of individual studies. Results: In the meta-analysis of ES yield in CP, the overall diagnostic yield of ES among the cohorts (15 study cohorts comprising 2419 individuals from 11 articles) was 23% (95% CI, 15%-34%). The diagnostic yield across cryptogenic CP cohorts was 35% (95% CI, 27%-45%), compared with 7% (95% CI, 4%-12%) across cohorts with known risk factors (noncryptogenic CP). In the meta-analysis of CMA yield in CP, the diagnostic yield of CMA among the cohorts (5 study cohorts comprising 294 individuals from 5 articles) was 5% (95% CI, 2%-12%). Conclusions and Relevance: Results of this systematic review and meta-analysis suggest that for individuals with cryptogenic CP, ES followed by CMA to identify molecular disorders may be warranted.

Impact of the COVID-19 Pandemic on the Behavioral Health of People With Intellectual and Developmental Disabilities.

OBJECTIVE: The authors examined how the COVID-19 pandemic affected the behavioral health of people with intellectual and developmental disabilities (IDD). METHODS: A modified version of the Coronavirus Health Impact Survey-Adapted for Autism and Related Neurodevelopmental Conditions was sent to the authors' clinical networks and IDD-affiliated organizations from March to June 2021. RESULTS: In total, 437 people with IDD or their caregivers responded to the survey. Diagnoses included intellectual disability (51%) and autism spectrum disorder (48%). More than half (52%) of respondents reported worsened mental health. Losing access to services correlated with declining mental health. Interventions suggested to improve behavioral health included more time with friends and family (68%), more time outdoors (61%), and access to community activities (59%). CONCLUSIONS: COVID-19 affected the behavioral health of individuals with IDD. Survey results highlight the opportunity to leverage physical activity and pandemic-safe social supports as accessible means to mitigate gaps in services.