Diagnosis and management of Cornelia de Lange syndrome: first international consensus statement.

Cornelia de Lange syndrome (CdLS) is an archetypical genetic syndrome that is characterized by intellectual disability, well-defined facial features, upper limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in any one of seven genes, all of which have a structural or regulatory function in the cohesin complex. Although recent advances in next-generation sequencing have improved molecular diagnostics, marked heterogeneity exists in clinical and molecular diagnostic approaches and care practices worldwide. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria, both for classic CdLS and non-classic CdLS phenotypes, molecular investigations, long-term management and care planning.

Predictors of employment for adults with intellectual and developmental disabilities participating in a postsecondary transition program in the United States.

BACKGROUND: Previous research has shown that post-secondary collegiate vocational educational programs often have positive effects on employment outcomes for young adults with intellectual and developmental disabilities. AIMS: Using secondary data of a program in the United States collected over several years, we examined which intervention components of a postsecondary education transition program predicted subsequent employment for young adults with intellectual and developmental disabilities. MATERIALS & METHODS: The sample consisted of 56 individuals that participated in a transition-services collegiate program; Crossing Points, University of Alabama. RESULTS: Results were able to robustly indicate that acquiring job-specific skills was a much better predictor than global measures of intellectual or adaptive behaviour. Additionally, survival curve analyses as an innovative approach to this population showed that there was a positive relation between the number of job-specific training sessions and eventual community employment. DISCUSSION: Results are discussed in relation to a historical parallel movement to expand inclusion of students with intellectual and developmental disabilities in the least restrictive educational setting for primary and secondary public education years. CONCLUSION: In conclusion, the results of the current study suggest positive findings with job-skills training both specific and general.

Validation of the triple timed up-and-go test in Lambert-Eaton myasthenia.

INTRODUCTION: There are no validated, practical, and quantitative measures of disease severity in Lambert-Eaton myasthenia (LEM). METHODS: Data from the Effectiveness of 3,4-Diaminopyridine in Lambert-Eaton Myasthenic Syndrome (DAPPER) trial were analyzed to assess triple timed up-and-go (3TUG) reproducibility and relationships between 3TUG times and other measures of LEM severity. RESULTS: The coverage probability technique showed ≥0.90 probability for an acceptable 3TUG difference of ≤0.2, indicating that it is reproducible in LEM patients. The correlation between 3TUG times and lower extremity function scores was significant in subjects who continued and in those who were withdrawn from 3,4-diaminopyridine free base. Worsening patient-reported Weakness Self-Assessment Scale and Investigator Assessment of Treatment Effect scores corresponded with prolongation of 3TUG times. DISCUSSION: The 3TUG is reproducible, demonstrates construct validity for assessment of lower extremity function in LEM patients, and correlates with changes in patient and physician assessments. These findings, along with prior reliability studies, indicate 3TUG is a valid measure of disease severity in LEM.

3,4-diaminopyridine base effectively treats the weakness of Lambert-Eaton myasthenia.

INTRODUCTION: 3,4-diaminopyridine has been used to treat Lambert-Eaton myasthenia (LEM) for 30 years despite the lack of conclusive evidence of efficacy. METHODS: We conducted a randomized double-blind placebo-controlled withdrawal study in patients with LEM who had been on stable regimens of 3,4-diaminopyridine base (3,4-DAP) for ≥ 3 months. The primary efficacy endpoint was >30% deterioration in triple timed up-and-go (3TUG) times during tapered drug withdrawal. The secondary endpoint was self-assessment of LEM-related weakness (W-SAS). RESULTS: Thirty-two participants were randomized to continuous 3,4-DAP or placebo groups. None of the 14 participants who received continuous 3,4-DAP had > 30% deterioration in 3TUG time versus 72% of the 18 who tapered to placebo (P < 0.0001). W-SAS similarly demonstrated an advantage for continuous treatment over placebo (P < 0.0001). Requirement for rescue and adverse events were more common in the placebo group. DISCUSSION: This trial provides significant evidence of efficacy of 3,4-DAP in the maintenance of strength in LEM. Muscle Nerve 57: 561-568, 2018.

Assessing wandering risk among individuals with Alzheimer's disease and dementia: a pilot study.

BACKGROUND: We examined a screening instrument to assess risk for wandering among individuals with Alzheimer's disease and dementia according to caregiver informants. METHODS: Pilot data were collected on the Risk of Wandering (RoW) screening instrument by 48 responses from an online survey using the Alzheimer's Association Trial Match system. RESULTS: Results indicated acceptable evidence of the internal consistency of scores for the data obtained, α = 0.81. Receiver operating characteristic curve results indicated acceptable evidence of the screening instrument scores' ability to discriminate between individuals who eloped and those who did not wander off, AUC = 0.72, P = 0.003. CONCLUSIONS: A cut-off score for future use is suggested along with directions for future research. The development of a screening instrument would appear to be preferable to restricting the movement of these individuals or unnecessarily invading their privacy through monitoring devices while simultaneously balancing the desire to prevent distress, serious injury, or death.

Acute Stroke Despite Dabigatran Anticoagulation Treated with Idarucizumab and Intravenous Tissue Plasminogen Activator.

Dabigatran is a direct thrombin inhibitor used to reduce the risk of stroke in patients with nonvalvular atrial fibrillation. For patients who present with an acute stroke despite dabigatran therapy, clinical data on the use of intravenous tissue plasminogen activator (IV-tPA) is limited. There is an anticipated increased risk of symptomatic intracranial hemorrhage (sICH) when using IV-tPA in patients on dabigatran therapy. In 2015, the humanized monoclonal antibody fragment idarucizumab was approved for rapid (minutes) reversal of anticoagulant effects of dabigatran. Dabigatran reversal with idarucizumab before administration of IV-tPA might reduce the risk of sICH. We report a case of a 69-year-old stroke patient on dabigatran for paroxysmal atrial fibrillation who presented with an initial National Institutes of Health Stroke Scale (NIHSS) of 12. There was no early evidence of ischemic stroke or hemorrhage on head computed tomography, and coagulation studies implied therapeutic dabigatran levels. After controlling blood pressure, dabigatran was reversed with idarucizumab, and IV-tPA was administrated beginning 197 minutes after he was last seen at his baseline. Subsequent brain magnetic resonance imaging showed 2 punctate infarcts in the left temporal lobe and occipital lobe with no evidence of hemorrhage. The patient was discharged with an NIHSS of 1. Telephone follow-up 2 months later indicated that he was at his prestroke baseline, except for a complaint of worsened short-term memory. Idarucizumab reversal of dabigatran may reduce the risk of sICH and should be considered for acute stroke patients arriving in the IV-tPA time window.

Health care provider responses to initial parental reports of autism spectrum disorder symptoms: results from a nationally representative sample.

BACKGROUND: Health care provider (HCP) responses to initial parental report of autism spectrum disorder (ASD) symptoms were examined in relation to latency to diagnosis and child chronological age at diagnosis. METHOD: Secondary data analyses were conducted for a sample of 1384 parents of children with ASD utilizing data from the National Survey of Children with Special Health Care Needs (NS-CSHCN, 2009-2010 National Survey of Children with Special Health Care Needs, 2009) and the Centers for Disease Control and Prevention Pathways to Diagnosis and Services (CDC PDS, Survey of pathways to diagnosis and services, 2011). RESULTS: Approximately 44% of the sample experienced predominantly delayed HCP responses, 38% experienced predominantly proactive responses, while the remaining 18% experienced a relatively even mix of delayed and proactive responses across HCPs. With regard to outcomes correlated with the type of HCP response, individuals exposed to proactive HCPs were diagnosed with ASD almost a year earlier for child chronological age than individuals exposed to mixed HCPs. This difference increased beyond a year between individuals receiving proactive HCPs versus individuals experiencing delayed HCPs. Finally, after controlling for socioeconomic status, parent-reported severity of ASD symptoms, and age at time of referral, proactive HCP was correlated with decreased time to diagnosis from parental first report of ASD symptoms. CONCLUSIONS: Results are discussed with regard to increasing proactive HCP responses to parental first concerns of ASD symptomology versus a mix or delayed responses.

Myasthenia gravis and related disorders: Pathology and molecular pathogenesis.

Disorders affecting the presynaptic, synaptic, and postsynaptic portions of the neuromuscular junction arise from various mechanisms in children and adults, including acquired autoimmune or toxic processes as well as genetic mutations. Disorders include autoimmune myasthenia gravis associated with acetylcholine receptor, muscle specific kinase or Lrp4 antibodies, Lambert-Eaton myasthenic syndrome, nerve terminal hyperexcitability syndromes, Guillain Barré syndrome, botulism, organophosphate poisoning and a number of congenital myasthenic syndromes. This review focuses on the various molecular and pathophysiological mechanisms of these disorders, characterization of which has been crucial to the development of treatment strategies specific for each pathogenic mechanism. In the future, further understanding of the underlying processes may lead to more effective and targeted therapies of these disorders. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis.

The tipping point: Value differences and parallel dorsal-ventral frontal circuits gating human approach-avoidance behavior.

Excessive avoidance and diminished approach behavior are both prominent features of anxiety, trauma and stress related disorders. Despite this, little is known about the neuronal mechanisms supporting gating of human approach-avoidance behavior. Here, we used functional magnetic resonance imaging (fMRI) to track dorsal anterior cingulate and medial prefrontal (dACC/dmPFC) activation along an approach-avoidance continuum to assess sensitivity to competing appetitive and aversive contingencies and correspondence with behavior change. Behavioral and fMRI experiments were conducted using a novel approach-avoidance task where a monetary reward appeared in the presence of a conditioned stimulus (CS), or threat, that signaled increasing probability of unconditioned stimulus (US) delivery. Approach produced the reward or probabilistic US, while avoidance prevented US delivery, and across trials, reward remained fixed while the CS threat level varied unpredictably. Increasing the CS threat level (i.e., US probability) produced the desired approach-avoidance transition and inverted U-shaped changes in decision times, electrodermal activity and activation in pregenual ACC, dACC/dmPFC, striatum, anterior insula and inferior frontal regions. Conversely, U-shaped changes in activation were observed in dorsolateral and ventromedial prefrontal cortex and bimodal changes in the orbitofrontal and ventral hippocampus. These new results show parallel dorsal-ventral frontal circuits support gating of human approach-avoidance behavior where dACC/dmPFC signals inversely correlate with value differences between approach and avoidance contingencies while ventral frontal signals correlate with the value of predictable outcomes. Our findings provide an important bridge between basic research on brain mechanisms of value-guided decision-making and value-focused clinical theories of anxiety and related interventions.

Predictors of Elopement Exhibited by School-Aged Children With Special Health Care Needs: Towards the Development of a Screening Instrument for Elopement.

Elopement exhibited by school-aged children with special health care needs is a relatively low frequency problem behavior with the potential for severe negative consequences for the child and family. Using data from the Centers for Disease Control and Prevention (CDC) Survey of Pathways to Diagnosis and Services, our results represent one of the first empirical studies of variables that may be associated with children with special health care needs engaging in elopement. Using data from a nationally representative sample of children with special health care needs, our results revealed two variables that were statistically significant predictors of parent-reported elopement in the past year: (1) the child's chronological age, and (2) the presence of an autism spectrum disorder (ASD) diagnosis. We found that the likelihood of an elopement event was inversely related to age, but positively associated with the presence of an ASD diagnosis. Using parent-response items from the CDC data set, we selected a set of questions to screen for risk of elopement and analyzed their psychometric properties. We discuss the need for future research to validate this screening instrument for school-aged youth with special health care needs. Our study provides an initial psychometric analysis to support a potential screening instrument for elopement events among school-aged youth that needs to be validated by a longitudinal study of its predictive validity.

Limited utility of current MRI criteria for distinguishing multiple sclerosis from common mimickers: primary and secondary CNS vasculitis, lupus and Sjogren's syndrome.

BACKGROUND: Magnetic resonance imaging (MRI) criteria play an important role in making an earlier diagnosis of multiple sclerosis (MS) in patients presenting with clinically isolated syndrome. OBJECTIVE: The objective of this paper is to determine whether MRI criteria may be used to distinguish MS from primary and secondary central nervous system (CNS) vasculitis, lupus, and Sjogren's syndrome. METHODS: MRI criteria were applied retrospectively to images for patients with clinically definite MS (CDMS), primary CNS vasculitis, secondary CNS vasculitis, and autoimmune disorders including systemic lupus erythematosus (SLE) and Sjogren's syndrome. Classical statistics and Bayesian analyses were performed. RESULTS: Overall modified Barkhof's MRI criteria were statistically significant in distinguishing CDMS (60%) from SLE/Sjogren's syndrome (17%, p = 0.0173) but not in distinguishing CDMS from primary CNS vasculitis (50%, p = 0.7376) or secondary CNS vasculitis (58%, p = 1.0000). Four of the five other MRI criteria tested were demonstrated to be superior to modified Barkhof's criteria in predicting MS: nine or more T2 lesions (a component of Barkhof's criteria), one or more ovoid periventricular T2 lesions, one or more perpendicular periventricular T2 lesions, and one or more T2 lesions larger than 6 mm. CONCLUSIONS: MRI criteria, including the modified Barkhof's criteria, were unsuccessful in distinguishing MS from primary CNS vasculitis or secondary CNS vasculitis and mildly successful in distinguishing MS from SLE/Sjogren's syndrome.

Assistive technology as a predictor of general or alternate assessment among elementary-aged students with autism spectrum disorders.

The No Child Left Behind Act of 2001 specifically mandates that all students participate in the general assessment process or some form of alternate assessment as a measure of school accountability for student academic progress. Although levels of communication difficulties, intellectual impairment, and specific diagnoses such as autism spectrum disorders (ASDs) are correlated with increased probability of participating in alternate assessment methods, very little empirical research has focused on identifying predictors for students' assessment modality. Archival data from the Special Education Elementary Longitudinal Study (SEELS; 2005) were used to examine variables that predict whether elementary school students with ASD participated in the general or alternate assessment. Results indicated that receptive and expressive communication abilities appear to influence participation in the general vs. alternate assessment in tandem with access to assistive technology. Students with ASDs were approximately 2.71 times more likely to participate in the general assessment when they had access to assistive technology. Next, we performed a second, follow-up analysis for only ASD students with communication problems. The odds ratio value increased to 14.9 indicating that ASD students with communication problems that had access to assistive technology were almost 15 times more likely to participate in the general assessment than students with communication problems without access to assistive technology.

Intravenous immunoglobulin is safe and effective in controlling pre-existing paraneoplastic neuromuscular diseases in cancer patients treated with immune checkpoint inhibitors: two case reports and literature review.

Immune checkpoint inhibitors cause rare but potentially fatal neuromuscular complications, leading to a concern to use these agents in cancer patients with pre-existing autoimmune or inflammatory neuromuscular diseases. We report two such patients with paraneoplastic dermatomyositis and "seronegative" paraneoplastic demyelinating neuropathy, respectively, who have been successfully treated with immune checkpoint inhibitor monotherapy as well as maintenance intravenous immunoglobulin. While controlling the paraneoplastic or autoimmune neuromuscular diseases, the use of intravenous immunoglobulin did not compromise the anti-cancer effect of immune checkpoint inhibitor.

Precision targeting of autoantigen-specific B cells in muscle-specific tyrosine kinase myasthenia gravis with chimeric autoantibody receptor T cells.

Muscle-specific tyrosine kinase myasthenia gravis (MuSK MG) is an autoimmune disease that causes life-threatening muscle weakness due to anti-MuSK autoantibodies that disrupt neuromuscular junction signaling. To avoid chronic immunosuppression from current therapies, we engineered T cells to express a MuSK chimeric autoantibody receptor with CD137-CD3ζ signaling domains (MuSK-CAART) for precision targeting of B cells expressing anti-MuSK autoantibodies. MuSK-CAART demonstrated similar efficacy as anti-CD19 chimeric antigen receptor T cells for depletion of anti-MuSK B cells and retained cytolytic activity in the presence of soluble anti-MuSK antibodies. In an experimental autoimmune MG mouse model, MuSK-CAART reduced anti-MuSK IgG without decreasing B cells or total IgG levels, reflecting MuSK-specific B cell depletion. Specific off-target interactions of MuSK-CAART were not identified in vivo, in primary human cell screens or by high-throughput human membrane proteome array. These data contributed to an investigational new drug application and phase 1 clinical study design for MuSK-CAART for the treatment of MuSK autoantibody-positive MG.

Introduction to the Special Section: Translating Advanced Quantitative Techniques for Single-Case Experimental Design Data.

The articles in this special section offer strategies to single-case experimental design (SCED) researchers to interpret their outcomes, communicate their results, and compare the results using common, quantitative results. Advancing quantitative methods applied to SCED data will facilitate communication with scientists and other professionals that do not typically interpret graphed data of the dependent variable. Horner and Ferron aptly note that innovative statistical procedures are improving the precision and credibility of SCED research as disseminate our findings to an increasingly diverse audience. This special section promotes the translation of these quantitative methods to encourage their adoption in research using single case experimental designs.

Enrichment of serum IgG4 in MuSK myasthenia gravis patients.

Muscle-specific kinase (MuSK) myasthenia gravis (MG) is a neuromuscular autoimmune disease belonging to a growing group of IgG4 autoimmune diseases (IgG4-AIDs), in which the majority of pathogenic autoantibodies are of the IgG4 subclass. The more prevalent form of MG with acetylcholine receptor (AChR) antibodies is caused by IgG1-3 autoantibodies. A dominant role for IgG4 in autoimmune disease is intriguing due to its anti-inflammatory characteristics. It is unclear why MuSK autoantibodies are predominantly IgG4. We hypothesized that MuSK MG patients have a general predisposition to generate IgG4 responses, therefore resulting in high levels of circulating IgG4. To investigate this, we quantified serum Ig isotypes and IgG subclasses using nephelometric and turbidimetric assays in MuSK MG and AChR MG patients not under influence of immunosuppressive treatment. Absolute serum IgG1 was increased in both MuSK and AChR MG patients compared to healthy donors. In addition, only MuSK MG patients on average had significantly increased and enriched serum IgG4. Although more MuSK MG patients had elevated serum IgG4, for most the IgG4 serum levels fell within the normal range. Correlation analyses suggest MuSK-specific antibodies do not solely explain the variation in IgG4 levels. In conclusion, although serum IgG4 levels are slightly increased, the levels do not support ubiquitous IgG4 responses in MuSK MG patients as the underlying cause of dominant IgG4 MuSK antibodies.

Cerebral venous sinus thrombosis presenting with auditory hallucinations and illusions.

OBJECTIVE: Cerebral venous sinus thrombosis may present with seizures or neuropsychiatric symptoms, but does not typically present with hallucinations. We present a case of venous thrombosis of the right sigmoid and transverse sinuses that presented with auditory hallucinations and illusions. METHODS: We describe a 45-year-old woman with a history of myasthenia gravis, stable on oral prednisone and monthly intravenous immunoglobulin infusions, who started on a progesterone/estrogen combination contraceptive pill for menorrhagia 3 weeks before admission and presented with symptoms of headache, fever, and auditory hallucinations and illusions. RESULTS: The patient's cerebrospinal fluid showed lymphocytic pleocytosis. Two electroencephalograms showed significant right temporal lobe slowing. Magnetic resonance venogram of the brain showed venous sinus thrombosis of the right sigmoid and transverse sinuses. Magnetic resonance imaging showed a cortical venous infarct in the right middle temporal gyrus. The patient's auditory hallucinations and illusions resolved spontaneously weeks after presentation. CONCLUSIONS: This case suggests that auditory hallucinations and illusions should be added to the already broad spectrum of presenting features of cerebral venous sinus thrombosis. The nondominant right middle temporal gyrus may play a role in such auditory hallucinations.

Optimal number of baseline sessions before changing phases within single-case experimental designs.

Recommendations vary considerably for the minimum or optimal number of baseline sessions to conduct within single-case experimental design clinical analyses or research studies. We examined the optimal number of baseline sessions that produced minimal bias. First, we examined the relation between the number of baseline sessions and the degree of bias in calculating estimates of treatment effect size. As the number of baseline sessions increased, the bias in effect size estimates decreased, r = -0.36, p < 0.001. s, we examined what would be the minimum number of baseline sessions associated with varying levels of bias. Bias of approximately ten percent was associated with four to five baseline sessions. Bias of about five percent was associated with six to seven baseline sessions. Third, we examined the relation between standard deviation and varying levels of bias. As the number of baseline sessions increases, the standard deviation for the phase decreased, r = -0.89, p < 0.001. Fourth, we examined what value of standard deviation in the baseline phase was associated with equal to or more than five versus ten percent bias. When considering five or ten percent bias, the optimal level of standard deviation was 0.59 or less.