Georgia state spinal muscular atrophy newborn screening experience: Screening assay performance and early clinical outcomes.

The purpose of this study is to provide the results of the newborn screening (NBS) program for Spinal Muscular Atrophy (SMA) in the state of Georgia to determine disease incidence, time to diagnosis and treatment, and early outcomes. NBS for SMA was performed using real time PCR assays from February 2019 through February 2020 in a pilot phase of screening. This method continued as part of our official state panel, and here we describe the pilot period as well as the first year of standard screening through February 2021. Medical records of infants with a positive NBS were reviewed for time to confirmation and neurologic evaluation, SMN2 copy number, clinical information, and treatment. Descriptive statistics were applied. Of the 301,418 samples screened, there were 15 true positive (eight males) and 24 false positive cases. One patient was missed due to human error early in the pilot phase and presented after symptom onset. The incidence of SMA in Georgia is approximately 1 in 18,840 births per year. After the pilot phase, the false positive rate was found to be so low that all patients who test positive were immediately referred to neurology for further care. Four patients died prior to intervention. Ten patients received intervention. Gene therapy was the preferred treatment. One patient was lost to follow-up; another was clinically followed. In conclusion, trends for treated patients show improved or stable motor function. Long-term follow-up will help determine the durability of treatment.

Possible contribution of cerebellar disinhibition in epilepsy.

OBJECTIVE: We hypothesize that loss of inhibition from the cerebellum can lead to cortical activation and seizures. BACKGROUND: The traditional model for development of seizures purports that the source of seizures is increased electrical activity originating from cerebral cortical neurons. Studies have shown a decrease in inhibition results in a shift of cortical activity to a hyperexcitable state, which may lead to seizures. Interestingly, a 1978 study suggested the term "disorder of disinhibition" as a way to describe epilepsy from studies of chronic cerebellar stimulation. DESIGN/METHODS: Cases and experimental studies in which cerebellar lesions have been implicated in the development of seizures were reviewed. Cases in which cerebellar inhibition has been targeted in the treatment of seizures were also included. Twenty-six studies and case reports are presented for this report. RESULTS: The cases show cerebellar lesions can lead to cortical epileptiform activity. Purkinje cell loss is linked to the occurrence of seizures in animals. The majority of patients with cerebellar lesions were seizure free after complete resection, while less than half of patients were seizure free after partial resection. Novel treatments using deep-brain stimulation targeting cerebellar structures demonstrated therapeutic benefits for seizures. CONCLUSIONS: Although pathophysiology is not well-understood, the cerebellum likely plays an inherent role in inhibiting aberrant cortical epileptogenesis. Cerebellar lesions may cause seizures due to loss of the inhibition of cortical areas or through intrinsic epileptic activity. Treatments enhancing cerebellar stimulation have shown therapeutic benefits in treating seizures, which could potentially provide another avenue for treatment.

Does the addition of integrated cognitive behaviour therapy and motivational interviewing improve the outcomes of standard care for young people with comorbid depression and substance misuse?

OBJECTIVE: To determine whether the addition of cognitive behaviour therapy and motivational interviewing (CBT/MI) to standard alcohol and other drug (AOD) care improves outcomes for young people with comorbid depression and substance misuse. PARTICIPANTS AND SETTING: Participants were young people with comorbid depression (Kessler Psychological Distress Scale score ≥ 17) and substance misuse (mainly alcohol and/or cannabis) seeking treatment at two youth AOD services in Melbourne, Australia. The study was conducted between September 2006 and September 2008. Sixty young people received CBT/MI in addition to standard care (SC) (the SC+CBT/MI group) and 28 received SC only (the SC group). MAIN OUTCOME MEASURES: Depressive symptoms and AOD use in the previous 30 days, measured at baseline and at 3-month and 6-month follow-up. RESULTS: Compared with participants in the SC group, those in the SC+CBT/MI group showed significant reductions in depression and cannabis use and increased social contact and motivation to change substance use at 3-month follow-up. However, at 6-month follow-up, the SC group had achieved similar improvements to the CBT/MI group on these variables. All young people achieved significant improvements in functioning and quality of life variables over time, regardless of treatment group. No changes in AOD use were found in either group at 6-month follow-up. CONCLUSION: The delivery of CBT/MI in addition to SC may achieve accelerated treatment gains in the short term.

Electroencephalography characteristics to predict one-year outcomes in pediatric anti-NMDA receptor encephalitis.

BACKGROUND: Electrographic characteristics (extreme delta brush, posterior dominant rhythm and slow waves) may predict outcomes in anti-NMDA receptor encephalitis (NMDARE). However, whether changes in EEG sleep architecture predict outcomes are unknown. We examine electrophysiological characteristics including sleep architecture in a pediatric NMDARE population and correlate with outcomes at one year. METHODS: Retrospective chart and EEG review was performed in pediatric NMDARE patients at a single center. Patients with first EEGs available within 48 h of admission, prior to treatment, and one-year follow-up data were included. EEGs were independently reviewed by two epileptologists, and a third when disagreement occurred. Clinical outcomes included modified Rankin scale (mRS) at one year. RESULTS: Nine patients (6 females) (range 1.9-16.7 years) were included. Five of nine patients had loss of posterior dominant rhythm (PDR) and three of nine patients had absent sleep architecture. Loss of PDR correlated with a worse mRS score at one year (2.8 versus 0.5, p = 0.038). Loss of PDR and loss of sleep architecture was associated with increased inpatient rehabilitation stay and in higher number of immunotherapy treatments administered. In multivariate analysis, absence of sleep architecture (p = 0.028), absence of PDR (p = 0.041), and epileptiform discharges (p = 0.041) were predictors of mRS at one year. CONCLUSIONS: Loss of normal PDR, absence of sleep architecture, and epileptiform discharges are associated with worse outcomes at one year which has not been reported before. EEG characteristics may help prognosticate in NMDARE. Larger studies are needed to confirm these findings.

The precuneal cortex: anatomy and seizure semiology.

The purpose of this review is to describe the functional anatomy of the precuneal cortex and outline some semiological features of precuneal seizures. The precuneal cortex is a structure that occupies the posterior medial portion of the parietal lobe, and it has broad cortical and subcortical connections. Neuroanatomical tracing, functional imaging, as well as electrical stimulation studies of humans and other primates have elucidated many complex integrative functions of the precuneus including visuo-spatial imagery, sensorimotor functions, and consciousness. Based on the understanding of its functions and connectivity, descriptions of potential seizure semiologies are hypothesized and compared to what is available in the literature. The latter is mostly in the form of case reports or case series. Seizures may involve simple or complex motor or sensory manifestations including abnormal eye movements, visual hallucinations, sensation of motion, or medial temporal-like seizures.

Developing integrated models of care within the youth Alcohol and Other Drug sector.

OBJECTIVE: The aim of this paper is to describe an initiative in Victoria, Australia, aimed at improving the detection and management of co-occurring mental health issues within the youth Alcohol and Other Drug (AOD) sector. CONCLUSIONS: Over the past 4 years, in partnership with local youth AOD services, we have developed a successful service model that addresses co-occurring mental health issues within the youth AOD sector. However, such capacity-building requires the full support of workers and senior management, and a cultural shift whereby the assessment and management of mental health issues are seen as a priority and core service issue. The capacity-building process was facilitated by embedding experienced mental health clinicians within each service to support and implement the initiative. This model offered learning opportunities through the modelling of relevant skills and the provision of 'on-the-job' training. Such approaches demonstrate that integrated models of care can be delivered within youth AOD services, although further research is needed to determine their effectiveness.

Feasibility and acceptability of a mental health screening tool and training programme in the youth alcohol and other drug (AOD) sector.

The high prevalence of co-occurring mental health and substance use disorders in young people is well established. Despite this, there are low rates of detection of co-occurring disorders across alcohol and other drug (AOD) services within Australia. This paper describes the development, implementation and evaluation of a mental health screening tool and training programme within the youth AOD sector. Thirty youth AOD workers received training in mental health screening, and the screening tool was subsequently piloted on 84 young people accessing two youth AOD services. Training was evaluated using measures of the trainee's mental health knowledge, attitudes, skills and confidence in mental health screening at baseline and 12-month follow-up. Feedback from young people supported the feasibility, acceptability and relevance of the screening tool. Evaluation of the associated training programme indicated improvements in AOD workers' mental health knowledge, skills and confidence in mental health screening. These findings provide preliminary evidence of the feasibility and acceptability of the mental health screening tool to young people and the effectiveness of the training package within the youth AOD sector.

Feasibility and outcomes of an innovative cognitive-behavioural skill training programme for co-occurring disorders in the youth alcohol and other drug (AOD) sector.

There are limited treatment options available for young drug users with comorbid mental health problems who present to alcohol and other drug (AOD) services within Australia. While there is some evidence for the use of cognitive-behaviour therapy (CBT) in the treatment of co-occurring disorders, CBT is rarely used to address comorbidity in the AOD sector. This paper describes the development, implementation and evaluation of a brief cognitive-behavioural skills (BCBS) training programme for addressing comorbidity within two youth AOD services in Australia. Ten youth AOD workers completed a 2-day training programme in the BCBS. Training was evaluated using measures of trainees' cognitive-behavioural knowledge, attitudes towards mental health interventions and level of skills and confidence in each of the BCBS pre- and 6 months post-training. The BCBS training had a positive impact on the knowledge, skills and confidence of trainees and was perceived to be highly relevant and appropriate. These findings provide preliminary support for the feasibility and effectiveness of the BCBS training programme for workers within the youth AOD sector.

Utility of gray-matter segmentation of ictal-Interictal perfusion SPECT and interictal 18F-FDG-PET in medically refractory epilepsy.

PURPOSE: We present a method of gray-matter segmentation of functional neuroimaging for localization of seizure onset zone (SOZ) in epilepsy surgery. 18F-FDG-PET hypometabolism and ictal SPECT hyperperfusion may correspond to SOZ. We hypothesize that limiting functional images to gray matter improves identification of small, subtle, or obscure cortical volumes of 18F-FDG-PET hypometabolism and eliminates hyperperfused seizure propagation pathways within white matter in ictal perfusion SPECT. METHODS: Twenty-five adult and pediatric patients age 2-48 years with epilepsy surgery evaluations consisting of MRI, 18F-FDG-PET, ictal and interictal perfusion SPECT, and intracranial EEG (iEEG) monitoring were selected. MRI gray matter segmentation was used to identify cortical regions in coregistered 18F-FDG-PET and Ictal-Interictal SPECT Analysis by SPM (ISAS) as volumes of interest (VOI). VOIs in 18F-FDG-PET and SPECT perfusion clusters were compared to iEEG localization. The level of VOI concordance between two modalities was recorded as the same subgyrus (highest concordance), gyrus, sublobe, lobe, hemisphere, or no concordance. RESULTS: With segmentation, 84% (21/25) of cases had at least one area identified on 18F-FDG-PET scan concordant with iEEG SOZ at sublobar or higher levels, and 72% (18/25) of cases had subgyral concordance with iEEG SOZ. Without segmentation, 60% (15/25) of cases had at least one area in 18F-FDG-PET scan concordant with iEEG SOZ at sublobar or higher levels, and 32% (8/25) with subgyral concordance. 83% (10/12) of seizure free patients had subgyral concordance on segmented 18F-FDG-PET. Both segmented and nonsegmented ictal-interictal SPECT perfusion clusters had 56% (14/25) of cases with at least sublobar concordance. Subgyral concordance was achieved by 28% (7/25) of segmented and 20% (5/25) of nonsegmented SPECTs. DISCUSSION: Segmented 18F-FDG-PET scans frequently result in high correspondence to iEEG onset zones with localizations exactly concordant with iEEG SOZ- more than twice as often as without segmentation. Segmentation allows for the identification of small or subtle areas of hypometabolism that are often unappreciated or are obscured by normally hypometabolic white matter. Segmentation of ictal-interictal SPECT clusters did not significantly increase localization with iEEG SOZ over nonsegmented clusters.

Verbal memory, learning, and executive functioning among adolescent inhalant and cannabis users.

OBJECTIVE: Inhalant use is a common form of drug misuse among young adolescents. However, very little is known about how chronic inhalant misuse affects cognition. Several studies have examined cognitive deficits among inhalant users, but no study has thoroughly addressed the confounding issues frequently associated with inhalant users (e.g., polysubstance use). The aim of the current study was to examine possible deficits in memory, learning, and executive components of memory (interference susceptibility) among young, regular inhalant users relative to a statistically equivalent drug-using control group (primarily cannabis users) and a community control group. METHOD: Three groups of 21 young people (aged 13-24 years) were recruited: an inhalant- using group, a drug-using control group, and a community control group. The inhalant and drug-using controls were matched at the group level on demographic, clinical, and substance use measures. All three groups were statistically equivalent on age, sex, and education. The Rey Auditory Verbal Learning Test was used to assess memory, learning, and interference susceptibility. RESULTS: Community controls performed significantly better than both drug-using groups, while inhalant users were more susceptible to proactive interference relative to drug-using controls. CONCLUSIONS: Difficulty in successful proactive interference resolution demonstrated by the inhalant group may relate to inhalant-specific deficits in executive functioning. These findings raise important questions regarding the hypothesized toxicity of inhalants and of substance-specific cognitive deficits among regular adolescent substance users. Future studies should consider using more specific, experimental probes of cognitive functioning to identify potentially subtle changes among substance-using adolescents.

Early intervention in first-episode psychosis--the impact of a community development campaign.

OBJECTIVE: Substantial delays in providing access to treatment in first-episode psychosis have been well documented. The present study examines the impact of strategies aimed at improving access and reducing delays. METHOD: A pilot community education campaign was conducted with the aim of reducing the duration of untreated psychosis (DUP) in a geographically defined intervention sector located in the northwestern region of Melbourne, Australia. Utilising a quasi-experimental design, a comparison sector with similar demographics was selected from another part of the north-western region. A mobile early detection team and the same treatment system served both sectors. RESULTS: While there was no significant difference between the mean DUP for intervention and comparison sectors, the distributional features of DUP between the two regions were significantly different. In the intervention sector, disproportionately more cases with very long DUP were detected. When a small number of outliers were removed, the mean and median DUP in the intervention sector was reduced. CONCLUSION: These findings highlight the complexity of treatment access and delay and suggest that efforts to reduce DUP may have two effects, not one. Firstly, a different sample of cases is treated through the detection of hidden "long DUP" cases that otherwise may have remained untreated. Secondly, the DUP for the remainder may indeed be reduced. More research with larger samples and more potent campaign strategies is clearly required. It may also be worth considering whether there is a safe and ethical way to undertake a RCT of early versus delayed antipsychotic treatment to perhaps settle the DUP debate once and for all.