Mild Neurological Impairment Research Articles

Clinical Management in Traumatic Brain Injury.

Traumatic brain injury is one of the leading causes of morbidity and mortality worldwide and is one of the major public healthcare burdens in the US, with millions of patients suffering from the traumatic brain injury itself (approximately 1.6 million/year) or its repercussions (2-6 million patients with disabilities). The severity of traumatic brain injury can range from mild transient neurological dysfunction or impairment to severe profound disability that leaves patients completely non-functional. Indications for treatment differ based on the injury's severity, but one of the goals of early treatment is to prevent secondary brain injury. Hemodynamic stability, monitoring and treatment of intracranial pressure, maintenance of cerebral perfusion pressure, support of adequate oxygenation and ventilation, administration of hyperosmolar agents and/or sedatives, nutritional support, and seizure prophylaxis are the mainstays of medical treatment for severe traumatic brain injury. Surgical management options include decompressive craniectomy or cerebrospinal fluid drainage via the insertion of an external ventricular drain. Several emerging treatment modalities are being investigated, such as anti-excitotoxic agents, anti-ischemic and cerebral dysregulation agents, S100B protein, erythropoietin, endogenous neuroprotectors, anti-inflammatory agents, and stem cell and neuronal restoration agents, among others.

The Quality of Life of the Patients with Thoracic Ossification of the Ligamentum Flavum after Surgery Using EQ-5D-5L.

There is a lack of studies on the quality of life (QoL) after posterior laminectomy in patients with thoracic ossification of the ligamentum flavum (TOLF), and risk factors associated with poor prognosis remain controversial. Therefore, the present study was conducted to illustrate the QoL for TOLF patients after surgery and determine its relationship with their demographic, surgery-related, clinical characteristics and imaging data. One hundred and eighteen patients diagnosed with thoracic myelopathy because of TOLF were enrolled in this retrospective study. They all underwent posterior decompressive laminectomy from August 2010 to January 2022. The QoL was evaluated based on the EQ-5D-5L. Collecting gender, age, number of operations, compressed segments, Frankel grade, complications, body mass index (BMI), symptoms and duration, modified Japanese Orthopaedic Association (mJOA) score (preoperative), follow-up time and type of ossification, increased signal on Sagittal T2-weighted Images (ISST2I), occupancy rate and analyzing by Mann-Whitney U-test, Kruskal-Wallis test, the χ2 -test, and logistic regression tests. Average follow-up 70.8 months (18-149), the mean age was 59.74 ± 9.81 years and the mean score for the QoL based on the EQ-5D-5 L and visual analogue scale (VAS) score were 0.71 ± 0.28 and 78.88 ± 10.21 at the final follow-up. Moderate and severe problems were found in the pain/discomfort in 22.0% of the patients. These mobility and usual activities numbers were slightly higher (24.6% and 30.4%, respectively). The mean scores for QoL and VAS were significantly higher in patients with mild and moderate neurological impairment, normal BMI, <60 years of age, no dural tears, symptom relief at hospital discharge, unilateral and bilateral ossification on axial CT scan, ≤ 50% spinal canal occupancy on CT and MRI, and none or fuzzy on ISST2I. QoL after posterior laminectomy in TOLF patients is generally satisfactory compared to preoperative levels. Preoperative mJOA score, Age, comorbid diabetes, the major symptom is activity limitation, BMI, ISST2I, Intraoperative dural tears and spinal canal occupancy rate correlate significantly with the corresponding dimensions and are predictive. Age, spinal canal occupancy rate, ISST2I, preoperative mJOA score, BMI are significantly associated with and have predictive value for overall postoperative QoL.

Developmental outcomes for survivors of placental laser photocoagulation for the management of twin-to-twin transfusion syndrome

BackgroundFetoscopic laser coagulation of placental anastomoses reverses the pathological process in twin-to-twin transfusion syndrome, thereby increasing survival, but there are a paucity of studies addressing long-term neurodevelopmental outcome of survivors. This study aimed to ascertain the presence of neurodevelopmental disabilities in child survivors of monochorionic pregnancies managed by placental laser photocoagulation in the Australian state of Victoria.MethodsAll pregnancies undergoing placental laser photocoagulation with the Victorian Fetal Therapy Service between 2006–2017 were included. Information on each surviving child, including demographics, perinatal course, and developmental progress was collected from parents, and consent was sought to complete the Child Behaviour Checklist. Interviewers evaluated whether this information was consistent with a diagnosis of any of 14 neurodevelopmental conditions. A three-tiered outcome measure was allocated for each child: (1) unimpaired or developmentally normal, (2) mild or moderate neurological impairment, or (3) severe neurological impairment. Clinical predictors for adverse outcome were identified.ResultsOf 116 pregnancies (113 twin, 3 triplet), 96 (83%) resulted in 1 + surviving fetuses. 57/113 (50%) twin pregnancies resulted in 2 survivors, 36 (32%) in 1 survivor, and 20 (18%) in no survivors. Of the 235 fetuses, 154 (65.5%) survived to follow-up. Survival increased from 59% in 2006–2008 to 73% in 2015–2017. 90/154 (58%) survivors were followed up at a mean age of 7.5 [SD 3.0] years. Based on parental interview and Child Behaviour Checklist data, 28/90 (31%) participants were assessed as having neurodevelopmental impairment, 27 of mild-moderate severity and 1 severe. Speech/language disorders, attention deficit (hyperactivity) disorders, and fine motor impairment were most common. Neonatal length of stay conferred the highest risk of impairment.ConclusionSubstantial variation exists between fetal therapy services in the type and length of neonatal follow-up following fetoscopic laser coagulation, contributing to a lack of data on long-term outcomes. The findings from this study support increasingly urgent calls to undertake systematic and sustained follow-up of fetoscopic laser coagulation survivors until school age. Information from this study may assist parents in their decision-making when offered fetal surgery. Importantly, it highlights a group for targeted surveillance and early intervention.

5607225 ADDITION OF THERAPEUTIC PLASMA EXCHANGE TO RED CELL EXCHANGE IMPROVES OUTCOMES OF FAT EMBOLISM SYNDROME IN SICKLE CELL DISEASE

Background: Fat embolism syndrome (FES) is a severe but possibly underdiagnosed complication of sickle cell disease (SCD) associated with very high mortality and morbidity. It is the result of extensive bone marrow necrosis that leads to release of large amounts of fat droplets in the systemic circulation. These not only cause mechanical obstruction of the microvasculature but also act as a substrate for the generation of various pro-inflammatory cytokines that contribute to the development of multiorgan failure. FES predominantly affects non-homozygous patients and those with a previously mild course of their illness. Immediate red cell exchange (RCE) can be life-saving and it is currently the treatment of choice. However, despite its increasing use in recent years, mortality remains substantial while a large number of survivors is left with significant neurocognitive impairment. With that in mind, we have previously advocated the addition of therapeutic plasma exchange (TPE) to RCE in order to address the inflammatory environment and potentially improve outcomes. Aims: To compare outcomes from FES using standard treatment with RCE and combination of RCE and TPE. Methods: A systematic review of all cases published since 2012 where RCE was employed was performed, and outcomes were compared to cases where a combination of RCE and TPE was used. Results: The systematic review of the literature identified 39 cases treated with RCE since 2012. Mortality was 21%, 33% of patients were left with severe and 13% with mild neurological impairment while only 33% made a complete recovery (CR). We are aware (publications/ personal communication) of 11 cases (separate from the previous 39) treated with combination of RCE and TPE worldwide (8 UK, 2 Canada, 1 USA). 9 patients were adults and 2 patients were children. 5 patients had homozygous Hb SS disease, 5 Hb SC and 1 Hb Sβ+. All patients, irrespective of genotype, had previously a mild course of their illness. The number of TPE procedures performed varied greatly between cases (1-10). There was 1 death (9%), 2 patients (18%) suffered mild/moderate neurological impairment and 8 patients (73%) achieved CR. Both patients reported as suffering mild/moderate neurological impairment are patients who developed the complication recently, have fully recovered cognition but are still in rehabilitation improving from generalised weakness resulting from prolonged hospitalisation and are very likely to achieve CR eventually. One more 13-year old patient (not included in this analysis as the final outcome is yet unknown) is currently recovering in hospital having recently suffered severe FES with multiorgan failure requiring extracorporeal membrane oxygenation now extubated, recovering organ function and able to communicate appropriately. Interestingly, 2 patients had a cytotoxic lesion of the corpus callosum (CLOCC) on brain imaging. This further highlights the role of the inflammatory environment in the pathophysiology of FES as CLOCCs are known to be the result of direct cytotoxicity from proinflammatory cytokines, especially IL-1 and IL-6. TPE was well tolerated with no associated adverse events. Conclusion: These early data suggest a clear benefit from this approach, and as TPE is a low risk intervention, we recommend its addition to RCE as standard management for FES in SCD. Reference 1. Tsitsikas DA, Vize J, Abukar J. Fat Embolism Syndrome in Sickle Cell Disease. J Clin Med. 2020 Nov 8;9(11):3601.

Abstract 225: Late Awakening In Comatose Survivors Of Out-of-hospital Cardiac Arrest

Background: Despite advanced neuroprognostication using neuron-specific enolase, electroencephalogram and brain imaging, prediction of neurological outcome in comatose survivors of out-of-hospital cardiac arrest (OHCA) remain challenging and early discontinuation of postresuscitation treatment may be harmful for patients with delayed awakening. Hypothesis: Significant proportion of comatose survivors of OHCA may regain consciousness only after discharge from intensive care unit (ICU). Methods: Consecutive comatose survivors of OHCA admitted to our ICU between January 1, 2003 and December 31, 2021 were investigated. Cerebral performance category (CPC) was used for evaluation of neurological recovery. CPC 1 indicated complete recovery, CPC 2 mild neurological impairment, CPC 3 severe neurological impairment and CPC 4 vegetative state. Results: A total of 1098 patients (63 + 14 years, 79% (864 of 1098) men) were enrolled. OHCA was witnessed in 88% (966 of 1098), basic life support was performed in 57% 630 of 1098), delay to emergency team arrival was 7.5 + 5.3 minutes and initial shockable rhythm was present in 77%. (851 of 1098). Reestablishment of spontaneous circulation (ROSC) was obtained after 12.9 + 11.8 minutes of advanced life support. Coronary angiography was performed in 74% (822 of 1098) and percutaneous coronary intervention in 52% (567 of 1098). Mechanical circulatory support was used in 16% (175 of 1098) and hypothermia (32-34 C) in 85% (940 of 1098). Among 740 patients who survived to ICU discharge on day 7 (median), 272 patients (36.8%) of patients remained in CPC 3-4 ( Figure). Among these 272 patients, CPC 1-2 at hospital discharge was documented in 19.9%. (54 patients). Conclusion: Almost 20% of comatose survivors of OHCA without neurological recovery at ICU discharge may ultimately regain consciousness. This argues against premature withdrawal of care in step down units and normal wards.

Exploration of the Severity of Hepatic Encephalopathy Deterioration Process Through Dynamics of the EEG Band Power time series.

Cirrhosis is a liver disease that could impair the functionality of the neural system, limiting cognitive processes and reduce mobility, possibly because alterations on dynamics of neural communications. In this study the dynamics of band power fluctuations on ß and γ bands were studied on three groups: control, patients with cirrhosis and patients diagnosed with minimal hepatic encephalopathy. EEG signals were recorded on an oddball paradigm and analyzed to obtain the latency and amplitude of the P300 wave and Detrended Fluctuation Analysis (DFA) exponent values over ß and γ band power time series for each channel. As expected, the latency of the P300 wave was significantly different for control subjects ( ). Amplitudes were not as different, but they tend to decrease for cirrhosis and minimal hepatic encephalopathy groups. DFA exponent values also tends to describe a more regular process and seems to be related with presence of symptoms of hepatic encephalopathy. These subtle changes could be produced by the mechanisms of a mild neurological impairment and be used, if it is confirmed, as an index to evaluate such deterioration.

Preoperative Magnetic Resonance Imaging Signal Intensity Classification Is Associated With Clinical Presentation and Surgical Outcomes in Myelopathy Caused by Thoracic Ossification of Ligamentum Flavum: A Multicenter Study.

Retrospective Cohort Study. To explore whether classification of the increased signal intensity (ISI) on magnetic resonance imaging (MRI) correlates with clinical presentations and outcomes in symptomatic thoracic ossification of ligamentum flavum (T-OLF) patients. All patients with symptomatic T-OLF who underwent laminectomy at four institutions were reviewed. The ISI on preoperative T2-weighted MRI was divided into 3 groups, Grade 0, none; Grade 1, light (obscure); and Grade 2, intense (bright). Neurological function before surgery and at follow-up was evaluated by the revised Japanese Orthopedic Association (JOA) score. Patients' demographics, clinical manifestations, and surgical outcomes were compared. A total of 94 patients were involved. Preoperative MRI showed 32 patients in Grade 0, 39 patients in Grade 1, and 23 patients in Grade 2. Low extremities numbness, weakness, and clinical signs were less frequent in Grade 0 patients. The grade of ISI was correlated with the duration of symptoms and cord compression. Grade 0 patients had a better preoperative JOA score than those with ISI changes, while Grade 2 patients showed worse neurological recovery, longer duration of operation, more intraoperative blood loss, and a higher incidence of perioperative complications. The classification of ISI is an effective parameter for preoperatively assessing cord compression, clinical severity, and surgical outcomes in T-OLF patients. Grade 0 patients have relatively mild neurological impairment but are more likely to be misdiagnosed. Grade 2 indicates the worst clinical impairment and neurological recovery, and implies a risky and challenging surgery.

Paroxysmal tonic upgaze in a child with SCN8A-related encephalopathy.

Pathogenic variants in the SCN8A gene have been associated with a broad phenotypic spectrum, ranging from benign familial infantile seizures to severe, early-onset developmental and epileptic encephalopathy. This spectrum also includes an "intermediate phenotype" characterized by different degrees of cognitive disability, mild neurological impairment, and therapeutically manageable epilepsy. We report on a child harbouring a de novo, novel SCN8A deletion, whose clinical picture is consistent with an SCN8A-related "intermediate phenotype". This patient's peculiar feature is the occurrence of paroxysmal tonic upgaze (PTU), a non-epileptic disorder consisting of sustained conjugate upward deviation of the eyes, with neck flexion, and downbeat saccades. PTU has been described in otherwise healthy children, as well as in a few genetic syndromes, but has never been observed in SCN8A-related phenotypes. This report, therefore, adds a new symptom to the spectrum of movement disorders associated with SCN8A-related developmental and epileptic encephalopathy. In this short communication, we provide video-EEG documentation of PTU and seizures, and discuss the challenging differential diagnosis between the two symptoms.

Fat Embolism Syndrome in Sickle Cell Disease.

Fat embolism syndrome is a devastating complication of sickle cell disease resulting from extensive bone marrow necrosis and associated with high mortality rates, while survivors often suffer severe neurological sequelae. Despite that, the syndrome remains under-recognised and under-diagnosed. Paradoxically, it affects exclusively patients with mild forms of sickle cell disease, predominantly HbSC and HbSβ+. A significant number of cases occur in the context of human parvovirus B19 infection. We provide here a brief summary of the existing literature and describe our experience treating 8 patients in our institution. One patient had HbSS, 6 HbSC and 1 HbSβ+. All patients developed type I respiratory failure and neurological involvement either at presentation or within the first 72 h. The most striking laboratory abnormality was a 100-fold increase of the serum ferritin from baseline. Seven patients received emergency red cell exchange and 1 simple transfusion. Two patients (25%) died, 2 patients (25%) suffered severe neurological impairment and 1 (12%) mild neurological impairment on discharge, while 3 (38%) patients made a complete recovery. With long-term follow-up, 1 patient with severe neurological impairment and one patient with mild neurological impairment made dramatic improvements, making the long-term complete recovery or near complete recovery rate 63%. Immediate red cell exchange transfusion can be lifesaving and should be instituted as soon as the syndrome is suspected. However, as the outcomes remain unsatisfactory despite the increasing use of red cell exchange, we suggest additional therapeutic measures such as therapeutic plasma exchange and pre-emptive transfusion for high risk patients.

Fatigue in patients with hereditary neuropathy with liability to pressure palsies.

ObjectiveHereditary Neuropathy with Liability to Pressure Palsies (HNPP) is caused by a heterozygous deletion of peripheral myelin protein‐22 (PMP22) gene resulting in focal sensorimotor deficits. Our lab has identified a disruption of myelin junctions in excessively permeable myelin that impairs action potential propagation. This mechanism is expected to cause fatigue in patients with HNPP. Therefore, the objective was to characterize fatigue in patients with HNPP and determine the relationship of fatigue to nerve pathology, disability, and quality of life.MethodsNine females with HNPP participated in a single visit that included genotyping, nerve conduction studies, neurological exam, quantitative magnetic resonance imaging, and a physical therapy exam incorporating upper and lower extremity function and survey measures of fatigue. This visit was followed by 2 weeks of ecological momentary assessment (wrist‐worn device) that captured fatigue ratings five times per day.ResultsParticipants demonstrated mild neurological impairment (CMTNS: 5.7 ± 2.8), yet reported high fatigue levels (average fatigue intensity over 2 weeks: 5.9 out of 10). Higher fatigue levels were associated with poorer quality of life and more pain. Higher fatigue was associated with significantly greater distal nerve proton density changes on peripheral nerve MRI, which is in line with hyper‐permeable myelin in HNPP.InterpretationFatigue is common and severe among patients with HNPP whose disabilities are minimal by conventional outcome measures. Therapeutic interventions targeting fatigue have the potential to improve quality of life and may serve as a robust outcome measure to show longitudinal changes for patients with HNPP.

Reliability and Validity of the English Version of the AOSpine PROST (Patient Reported Outcome Spine Trauma).

Multicenter validation study. The aim of this study was to translate and adapt the AOSpine PROST (Patient Reported Outcome Spine Trauma) into English, and test its psychometric properties among North-American spine trauma patients. In the absence of an outcome instrument specifically designed and validated for traumatic spinal column injury patients, it is difficult to measure the effect size of various treatment options. The AOSpine Knowledge Forum Trauma initiated a project and developed the AOSpine PROST consisting of 19 items. Patients were recruited from two level-1 North-American trauma centers. For concurrent validity, next to AOSpine PROST also 36-item Short-Form Health Survey (SF-36) was filled out by patients. Patient characteristics were analyzed using descriptive statistics. Floor and ceiling effects as well as the number of inapplicable and missing questions were analyzed for content validity. Cronbach α and item-total correlation coefficients (ITCCs) were calculated for internal consistency. Spearman correlation tests were performed within AOSpine PROST items and in correlation to SF-36. Test-retest reliability was assessed using intraclass correlation coefficients (ICCs). Factor analysis was performed to explore any dimensions within AOSpine PROST. The AOSpine PROST was translated adapted into English using established guidelines. Of 196 enrolled patients, 162 (82.7%) met the inclusion criteria and provided sufficient data. Content validity showed good results, and no floor and ceiling effects were seen. The internal consistency was excellent (Cronbach α = 0.97; ITCC 0.50-0.90) as well as test-retest reliability (ICC = 0.97). Spearman correlations were good (0.29-0.85). The strongest correlations of AOSpine PROST with SF-36 were seen with the physical components (0.69-0.82; P < 0.001). Factor analysis revealed two possible dimensions (Eigen values >1), explaining 75.7% of variance. The English version of AOSpine PROST showed very good validity and reliability. It is considered as a valuable tool, and has the potential to contribute to the reduction of ongoing controversies in spine trauma care. 2.

Comparative Effectiveness of Different Combinations of Treatment Interventions in Patients with Stroke at the Convalescence Stage Based on the Markov Decision Process.

Objective The objective of this study was to compare the effectiveness of different combinations of interventions in patients with stroke at the convalescence stage based on the electronic health records (EHRs) by using the Markov decision process (MDP) theory and explore the feasibility of the Markov model in the real-world study (RWS). Methods Screening was conducted for patients with stroke at the convalescence stage who were admitted to the Third Affiliated Hospital of Zhejiang Chinese Medical University from January 2012 to January 2017 based on the EHRs. The relevant clinical data were extracted, and the appropriate conversion was made (state-action-reward) according to the Markov model. The transformed data were analysed and solved by the MDP to obtain the best interventions for patients with various stroke recovery periods. Results 926 patients with stroke at the convalescence stage were initially selected. And according to the inclusion exclusion criteria, 854 patients were screened. Through the MDP, we obtained the following results: (1)when the patients with stroke at the convalescence stage have a medical history, but no complications, and mild neurological impairment, ≥66-year- and 18–45-year-old patients are advised to choose acupuncture treatment. 46–65-year-old patients are advised to choose rehabilitation treatment. When patients with moderate to severe neurological impairment, patients are advised to choose rehabilitation, Chinese herbal decoction, and acupuncture combined therapy. (2) Without complications or medical history, patients who are ≥ 66 years old are recommended to choose rehabilitation treatment when the nerve function impairment is mild; rehabilitation and acupuncture treatment are recommended when moderate and severe injuries are caused. (3) The combination of rehabilitation, Chinese herbal decoction, and acupuncture treatment is recommended for patients with phlegm and blood stasis. Acupuncture treatment is recommended for patients with mild impairment of nerve function in qi deficiency and blood stasis type. Rehabilitation, Chinese herbal decoction, and acupuncture treatment are recommended for moderate-severe injuries. Conclusions The MDP makes it possible to study the effectiveness of various treatment methods in stroke patients who are at the convalescence stage. Further exploratory studies using MDP theory in other areas in which complex interventions are common would be worthwhile.

Cognitive and functional impairment, and perception of illness in acute stroke patients

Aim of the studyObjectives Stroke, the leading cause of death and disability in Indonesia, has a substantial impact on patients’ life. However, only a few studies have assessed the psychological functioning in stroke patients. This study contributes to the need to map out psychological functioning in stroke patients by assessing their illness perception.Subject or material and methodsMethods This is a cross-sectional, descriptive-analytical study. We used a structured questionnaire which consists of a standardized collection of socio-demographic and clinical characteristics, brain CT-scan results, the severity of neurological deficit using NIH Stroke Scale (NIHSS), cognitive assessment tests, as well as Brief Illness Perception Questionnaire (BIPQ) as an instrument to assess illness perception.ResultsResults There were 56 stroke patients recruited as participants. The average age was 55.34 + 10.25, with 30.4 % had formal education less than 9-year compulsory education. Cognitive impairment in 64.3% of subjects was associated with lower coherence (p&lt;0.005). Subjects with higher education had higher personal control, treatment control and coherence (p &lt; 0.05). Subjects with mild neurological impairment had lower treatment control and coherence (p &lt; 0.05).DiscussionStroke patients with mild neurologic impairment at discharge had a more positive perception on the timeline, personal and treatment control.ConclusionsStroke patients with mild neurological impairment who had been discharged had a more positive perception on the timeline, personal and treatment control. Cognitive impairment is associated with lower coherence, which underlines the importance of establishing the cognitive baseline before assessing illness perception in stroke patients.

LIMB GIRDLE MUSCULAR DYSTROPHIES: P.167TRAPPC11-opathies: an emerging phenotype of muscle-eye-brain-liver

Transport protein particle complex (TRAPPC) is involved in endoplasmic reticulum to Golgi transportation. In humans, TRAPPC11 protein is a part of the complex III and its mutations are associated with problems in trafficking of protein to the cell membrane with secretory deficits and its defects can inhibit of glycosylation of alpha-DG. Disorders linked to mutations of proteins of TRAPPC have recentlybeen called TRAPPopathies. TRAPPC11 mutations have been associated and limb-girdle muscular dystrophy (LGMD), congenital muscular dystrophy (CMD) and hepatomegaly with steatosis and ocular involvement (alacrima, catharatas). We described 4 patients with congenital microcephaly, strabismus, moderate to mild proximal weakness, hyperckemia, hypertransaminemia, movement disorders (hyperkinesia, stereotypia, chorea, athetosis) and increase neurological impairment after of infectious insult. Three of them are gipsy. All had intellectual disability. Two patients suffered epilepsy. Muscle biopsy showed reduction of alpha dystroglycan inmunofluorescence. Exome sequencing of majory patients identified homozygous mutation (c.1287+5G>A) in TRAPPC11 gene. One of them had a compound heterozygous mutation in TRAPPC11 gene, one of them was the previously described (c.1287 +5G>A) and the second mutation (c.3379_3380insT) has not been reported before. TRAPPC11-opathies should be considered in the diagnosis of children with proximal weakness, hypotonia, hyperckemia and extramuscular manifestations such as cognitive impairment, epilepsy, movement disorders, eye and liver involvement. We concluded that TRAPPC11-opathies have a phenotype that can be called "phenotype muscle-eye-brain-liver". Interestingly, all of our cases had an increase in neurological affections after an infectious insult indicating that TRAPPC11 plays a physiological role in multiple systems in humans including metabolic system.

C-54 Neuropsychological Testing Profiles of Rare Conditions: A Case of Twin-to-Twin Transfusion Syndrome (TTTS) in a “Donor” Twin

Abstract Objective TTTS is a rare condition occurring in approximately 5-15% of monochorionic twins (sharing a single placenta), in which there is an abnormal arterio-venous connection resulting in excess blood flow to one fetus (“recipient”) and too little to the other (“donor”) (Graeve et al., 2012). Consequently, the “donor” develops in low amniotic fluid, while the “recipient” develops in high amniotic fluid. Neurologic and cardiogenic abnormalities have been identified in the neonatal period and in the long-term for both twins (Wagner, Repke, &amp; Ural, 2013). In terms of neurodevelopmental morbidities, 11.6% of children (age 6) endure mild neurologic impairment and 8.9% experience severe neurologic impairment (Graeve et al., 2012). Methods The present case involves a 7-year-old, right-handed, single female with a medical history of TTTS (“donor”) referred for neuropsychological testing to explore challenges with learning, attention, memory, reading, and spelling. Upon initial neuropsychological consultation, there were suspected neurodevelopmental optometric deficits, so the patient was also referred for ocular/vision testing. This revealed a significant convergence insufficiency/binocular dysfunction (eye teaming), ocular motor dysfunction (tracking), and visual disturbance (visual sensory overload) deficiencies. Results Neuropsychological testing revealed a neurodevelopmental disorder characterized by a language learning disability with mixed-dyslexia, ADHD - combined type, an executive functioning disorder, and neuro-optometric deficiencies interfering with neurocognitive functioning. Conclusion The present case provided further evidence of long-term neurodevelopmental sequelae associated with TTTS (“donor”). Neuropsychological testing elucidated the severity and type of neurodevelopmental impairments and was instrumental in the patient receiving an Individualized Education Program (IEP), which incorporated the accommodations contained in the neuropsychological diagnostic report.

Who will benefit more from low-dose alteplase in acute ischemic stroke?

Controversy persists over the benefits of low-dose versus standard-dose intravenous alteplase for the treatment of acute ischemic stroke. We sought to determine individual patient factors that contribute to the risk-benefit balance of low-dose alteplase treatment. Observational study using data from the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED), an international, randomized, open-label, blinded-endpoint trial that assessed low-dose (0.6 mg/kg) versus standard-dose (0.9 mg/kg) intravenous alteplase in acute ischemic stroke patients. Logistic regression models were used to estimate the benefit of good functional outcome (scores 0 or 1 on the modified Rankin scale at 90 days) and risk (symptomatic intracerebral hemorrhage), under both regimens for individual patients. The net advantage for low-dose, relative to standard-dose, alteplase was calculated by dividing excess benefit by excess risk according to a combination of patient characteristics. The algorithms were externally validated in a nationwide acute stroke registry database in South Korea. Patients with an estimated net advantage from low-dose alteplase, compared with without, were younger (mean age of 66 vs. 75 years), had lower systolic blood pressure (148 vs. 160 mm Hg), lower National Institute of Health Stroke Scale score (median of 8 vs. 16), and no atrial fibrillation (10.3% vs. 97.4%), diabetes mellitus (19.2% vs. 22.4%), or premorbid symptoms (defined by modified Rankin scale = 1) (16.3% vs. 37.8%). Use of low-dose alteplase may be preferable in acute ischemic stroke patients with a combination of favorable characteristics, including younger age, lower systolic blood pressure, mild neurological impairment, and no atrial fibrillation, diabetes mellitus, or premorbid symptoms.

Comprehensive Genetic Characterization of Mitochondrial Ca2+ Uniporter Components Reveals Their Different Physiological Requirements In Vivo

SummaryMitochondrial Ca2+ uptake is an important mediator of metabolism and cell death. Identification of components of the highly conserved mitochondrial Ca2+ uniporter has opened it up to genetic analysis in model organisms. Here, we report a comprehensive genetic characterization of all known uniporter components conserved in Drosophila. While loss of pore-forming MCU or EMRE abolishes fast mitochondrial Ca2+ uptake, this results in only mild phenotypes when young, despite shortened lifespans. In contrast, loss of the MICU1 gatekeeper is developmentally lethal, consistent with unregulated Ca2+ uptake. Mutants for the neuronally restricted regulator MICU3 are viable with mild neurological impairment. Genetic interaction analyses reveal that MICU1 and MICU3 are not functionally interchangeable. More surprisingly, loss of MCU or EMRE does not suppress MICU1 mutant lethality, suggesting that this results from uniporter-independent functions. Our data reveal the interplay among components of the mitochondrial Ca2+ uniporter and shed light on their physiological requirements in vivo.

Comprehensive Genetic Characterisation of Mitochondrial Ca2+ Uniporter Components Reveals Their Different Physiological Requirements in Vivo

Mitochondrial Ca2+ uptake is an important mediator of metabolism and cell death. Identification of components of the highly conserved mitochondrial Ca2+ uniporter has opened it up to genetic analysis in model organisms. Here, we report a comprehensive genetic characterisation of all known uniporter components conserved in Drosophila. While loss of pore-forming MCU or EMRE abolishes fast mitochondrial Ca2+ uptake, this results in only mild phenotypes when young, despite shortened lifespans. In contrast, loss of the MICU1 gatekeeper is developmental lethal, consistent with unregulated Ca2+ uptake. Mutants for the neuronally-restricted regulator MICU3 are viable with mild neurological impairment. Genetic interaction analyses reveal that MICU1 and MICU3 are not functionally interchangeable. More surprisingly, loss of MCU or EMRE does not suppress MICU1 mutant lethality, suggesting that this results from uniporter-independent functions. Our data interrogates the interplay between components of the mitochondrial Ca2+ uniporter, and sheds light on their physiological requirements in vivo.

Neural correlates of fatigue in multiple sclerosis: a combined neurophysiological and neuroimaging approach (R1).

The present study is aimed at further exploring structural and functional correlates of fatigue in Relapsing- Remitting Multiple Sclerosis (RRMS) patients by using a combined approach by means of transcranial magnetic stimulation (TMS) and a Diffusion Tensor Imaging (DTI). The physiopathology of fatigue in MS is still poorly understood, although a variety of pathogenic mechanisms has been proposed. Our working hypothesis is that diffuse microstructural white matter damage may subtend the cortico-subcortical functional disconnection described in patients with MS and fatigue. We enrolled 30 RRMS patients (mean age 39±13; age range 24-63 years) with mild neurological impairment Expanded Disability Status Scale <3.5, divided into two groups on the basis of their fatigue severity scale (FSS) scoring (cutoff ≥ 4). All the patients underwent a neurological evaluation, a brain MRI acquisition (including DTI study) and a neurophysiological assessment by means of TMS in a pre-movement facilitation paradigm. Our data showed a significant mean diffusivity (MD) increase (p=0.036) in left thalamo-frontal reconstructions in the MS patients with fatigue compared to those classified as non-fatigued. Moreover, significant correlations were observed between FSS scale and MD as well as planar coefficient (CP) values extracted from frontal-thalamic connections bilaterally. Instead, the pre-movement facilitation showed a significant difference between the groups with particular regard to the Reaction Time- MEP50ms amplitude (p=0.03). Our work confirms that fatigue is associated with a disruption of brain networks involved in motor preparation processes, depending on several frontal-thalamic pathways. Such findings can have an important role when dealing with fatigue management in MS patients and could be eventually used as prognostic marker of MS course.

Alteration of brain network topology in HIV-associated neurocognitive disorder: A novel functional connectivity perspective.

HIV is capable of invading the brain soon after seroconversion. This ultimately can lead to deficits in multiple cognitive domains commonly referred to as HIV-associated neurocognitive disorders (HAND). Clinical diagnosis of such deficits requires detailed neuropsychological assessment but clinical signs may be difficult to detect during asymptomatic injury of the central nervous system (CNS). Therefore neuroimaging biomarkers are of particular interest in HAND. In this study, we constructed brain connectivity profiles of 40 subjects (20 HIV positive subjects and 20 age-matched seronegative controls) using two different methods: a non-linear mutual connectivity analysis approach and a conventional method based on Pearson's correlation. These profiles were then summarized using graph-theoretic methods characterizing their topological network properties. Standard clinical and laboratory assessments were performed and a battery of neuropsychological (NP) tests was administered for all participating subjects. Based on NP testing, 14 of the seropositive subjects exhibited mild neurologic impairment. Subsequently, we analyzed associations between the network derived measures and neuropsychological assessment scores as well as common clinical laboratory plasma markers (CD4 cell count, HIV RNA) after adjusting for age and gender. Mutual connectivity analysis derived graph-theoretic measures, Modularity and Small Worldness, were significantly (p < 0.05, FDR adjusted) associated with the Executive as well as Overall z-score of NP performance. In contrast, network measures derived from conventional correlation-based connectivity did not yield any significant results. Thus, changes in connectivity can be captured using advanced time-series analysis techniques. The demonstrated associations between imaging-derived graph-theoretic properties of brain networks with neuropsychological performance, provides opportunities to further investigate the evolution of HAND in larger, longitudinal studies. Our analysis approach, involving non-linear time-series analysis in conjunction with graph theory, is promising and it may prove to be useful not only in HAND but also in other neurodegenerative disorders.