Subtle Neurological Abnormalities Research Articles

"Progressive myoclonic ataxia and developmental/epileptic encephalopathy associated with a novel homozygous mutation in TCN2 gene".

Transcobalamin II (TCN2) defect is a rare metabolic disorder associated with a range of neurological manifestations, including mild developmental delay, severe intellectual disability, ataxia, and, in some cases, seizures. Cobalamin, an essential nutrient, plays a crucial role in central nervous system myelination. We present a family with an index patient who exhibited progressive neurodevelopmental regression starting at 9 months of age, accompanied by myoclonic seizures, ataxia, and tremor. No significant hematological abnormalities were observed. Exome sequencing analysis identified a novel homozygous mutation, c.3G>A - P(Met1I), affecting the acceptor site of intron 4 of the TCN2 gene (chromosome 22: 31003321, NM_000355.4), leading to likely pathogenic variant potentially affecting translation. Following treatment with hydroxocobalamin, the patient demonstrated partial clinical improvement. He has a sibling with overt hematological abnormalities and subtle neurological abnormalities who is homozygous to the same mutation. Both parents are heterozygous for the same mutation. In infants presenting with unexplained non-specific neurological symptoms, irrespective of classical signs of vitamin B12 deficiency, evaluation for TCN2 defect should be considered. Early diagnosis and appropriate management can lead to favorable outcomes.

Neurological Soft Signs in Schizophrenia, a Picture of the Knowledge in the Last Decade: A Scoping Review.

(1) Background: Neurological Soft Signs (NSS) are subtle neurological abnormalities that are more common in schizophrenia patients than in healthy individuals and have been regularly observed in neuroleptic-naive first-episode patients, supporting the hypothesis that they are an intrinsic component of schizophrenia. (2) Methods: a review of articles published in the last ten years (from January 2013 to January 2023) was carried out on articles published in ScienceDirect and PubMed, by following the PRISMA Statement extension for scoping reviews (PRISMA-ScR), which evaluated the impact of NSS in correlation with the symptomatology, neuroleptic treatment, and the cerebral structural changes of patients with schizophrenia. (3) Results: thirty articles were included, among them twelve included MRI structural evaluation and four studies with a longitudinal design. (4) Conclusions: interest in researching NSS has increased in recent years, but questions remain about their origin and relationship to schizophrenia symptoms, thus this study aims to fill in information gaps in the hope that future research will help provide individualized treatment. It is suggested that NSS in schizophrenia might have an inherited genetic relationship pattern, thus being in line with a trait viewpoint. Most of the research revealed that schizophrenia patients had higher NSS scores than healthy controls, however, they were rather similar to their first-degree relatives, thus, also arguing in favor of a trait perspective. The greatest improvement in scores is seen in those with a remitting course, as shown by declining NSS ratings concurrent with symptomatology.

Different trajectories of neurological soft signs progression between treatment-responsive and treatment-resistant schizophrenia patients

Schizophrenia patients exhibit subtle and non-localizing neurological abnormalities, known as neurological soft signs (NSS). Life-span evidence suggests that NSS vary along the course of schizophrenia. An association between NSS and treatment response has been proposed, suggesting that NSS reflect the underlying neuropathology development in schizophrenia. However, few studies have investigated the relationship between NSS and treatment resistance in first-episode schizophrenia patients. We conducted a longitudinal study on 52 first-episode schizophrenia patients, who were assessed at baseline, the sixth month, and the fifth year using the abridged version of the Cambridge Neurological Inventory. The trajectories of NSS between 29 treatment-responsive patients (with full symptomatic remission) and 23 treatment-resistant patients (who received clozapine) were compared using mixed model ANOVA. We also controlled for the effect of age and estimated IQ, using a mixed ANCOVA model. Although the two schizophrenia groups had comparable NSS at the baseline, their trajectories of NSS differed significantly. Compared with their treatment-responsive counterparts, treatment-resistant schizophrenia patients had worsening of NSS over time. Our findings support the potential utility of NSS in identifying treatment resistance in first-episode schizophrenia. Progressive worsening of NSS in treatment-resistant schizophrenia patients may reflect the development of underlying neuropathology. Further studies using large samples of treatment-resistant schizophrenia patients are needed.

Neuropsychological presentation of colpocephaly and porencephaly with symptom onset in adulthood

ABSTRACT Colpocephaly is a form of congenital ventriculomegaly while porencephaly describes any full-thickness defect within the brain which usually presents as a cystic structure. Postulated aetologies include intrauterine/perinatal injuries, genetic disorders, and morphogenesis error. Colopocephaly and porencephaly is typically diagnosed in infancy while diagnosis in adulthood is exceptionally rare. We report a case of co-existence of colpocephaly with porencephaly diagnosed incidentally in a 54-year-old male presenting with subtle cognitive and neurologic abnormalities. Neuropsychological assessment revealed weaknesses in executive functions, processing speed, and language.To our knowledge, this is the only reported case of dual incidental findings of porencephaly and colpocephaly in an adult.

M158. ASSOCIATIONS OF NEUROLOGICAL SOFT SIGNS AND CEREBELLAR-CEREBRAL FUNCTIONAL CONNECTIVITY IN PATIENTS WITH FIRST-EPISODE SCHIZOPHRENIA AND THEIR UNAFFECTED SIBLINGS

BackgroundNeurological softs signs (NSS) are defined as subtle neurological abnormalities with manifestations of motor coordination, sensory integration and disinhibition. Evidence has suggested NSS as one of the most promising endophenotypes for schizophrenia spectrum disorders. Moreover, accumulating evidence also suggest that NSS may be associated with specific functional connectivity. The present study aimed to examine the cerebellar-cerebral resting-state functional connectivity (rsFC) of NSS in patients with first-episode schizophrenia (FES) and their unaffected siblings (SB).MethodsWe administered the abridge version of the Cambridge Neurological Inventory (CNI) to 51 FES patients, 20 unaffected SB, and 50 healthy controls (HC) to assess the severity of NSS. All the participants also underwent a resting-state functional magnetic resonance imaging (MRI) scan. Ten regions of interest (ROIs) in the cerebellum were selected to represent cerebellar motor network (MN) and cerebellar executive control network (EN), which corresponded to the “sensorimotor-cognitive” dichotomy of NSS. rsFC between each ROI and the whole brain voxels were constructed, and the linear regression analysis was conducted to examine the cerebellar-cerebral rsFC patterns of NSS in each group.ResultsRegarding the cerebellar MN, there were positive correlations observed between the rsFC of the cerebellar MN with the default mode network (DMN) and NSS in FES patients group (CNI total score and the motor coordination subscale) and the SB group (CNI total score and the motor coordination and sensory integration subscales). The rsFC of the cerebellar MN and the sensorimotor network were significantly and positively correlated with NSS (CNI total score and the motor coordination and sensory integration subscales) in the SB group.Regarding the cerebellar EN, we found that both the FES and the SB groups exhibited significantly negative correlations between NSS (CNI total score and the motor coordination subscale) and the rsFC of the cerebellar EN with the DMN. Moreover, the rsFC between the cerebellar EN and the sensorimotor network was positively correlated with NSS (CNI total score and the motor coordination and disinhibition subscales) in the SB group.DiscussionWe found inverse correlations between NSS and the rsFC of the cerebellar EN/MN and the DMN in both FES patients and their unaffected SB, suggesting that altered cerebellar-cerebral rsFC between these networks is correlated with the NSS. Moreover, the SB group exhibited a unique correlational pattern that NSS were correlated with the cerebellar-sensorimotor network rsFC, suggesting that such a network connectivity may serve as a potential biomarker for schizophrenia.

Isolated, Subtle Neurological Abnormalities in Mild Cognitive Impairment Types.

Isolated, subtle neurological abnormalities (ISNA) are commonly seen in aging and have been related to cerebral small vessel disease (SVD) and subcortical atrophy in neurologically and cognitively healthy aging subjects. To investigate the frequency of ISNA in different mild cognitive impairment (MCI) types and to evaluate for each MCI type, the cross-sectional relation between ISNA and white matter hyperintensities (WMH), lacunes, caudate atrophy, and ventricular enlargement. One thousand two hundred fifty subjects with different MCI types were included in the analysis and underwent brain magnetic resonance imaging. WMHs were assessed through two visual rating scales. Lacunes were also rated. Atrophy of the caudate nuclei and ventricular enlargement were assessed through the bicaudate ratio (BCr) and the lateral ventricles to brain ratio (LVBr), respectively. Apolipoprotein E (APOE) genotypes were also assessed. The routine neurological examination was used to evaluate ISNAs that were clustered as central-based signs, cerebellar-based signs, and primitive reflexes. The items of Part-III of the Unified Parkinson's Disease Rating Scale were used to evaluate ISNAs that were clustered as mild parkinsonian signs. Associations of ISNAs with imaging findings were determined through logistic regression analysis. The ISNAs increase with the age and are present in all MCI types, particularly in those multiple domains, and carrying the APOE ϵ4 allele, and are associated with WMH, lacunes, BCr, and LVBr. This study demonstrates that cortical and subcortical vascular and atrophic processes contribute to ISNAs. Long prospective population-based studies are needed to disentangle the role of ISNAs in the conversion from MCI to dementia.

Neurological soft signs and grey matter abnormalities in individuals with ultra-high risk for psychosis.

Neurological soft signs (NSSs), conventionally defined as subtle neurological abnormalities, are frequently found in individuals with schizophrenia. Many neuroimaging studies have also reported that NSSs are associated with grey matter changes in patients with schizophrenia at different stages of the illness. However, these findings may be confounded by the effect of antipsychotic medications, chronicity, and duration of untreated psychosis. Examining NSSs in individuals with ultra-high risk (UHR) for psychosis may help to identify the neuroanatomical substrates of NSSs related to the illness itself and to avoid these potential confounding effects. A sample of 21 individuals with UHR were included in the present study. NSSs were rated using the abridged version of the Cambridge Neurological Inventory. Grey matter volume was assessed using optimized voxel-based morphometry on images acquired by a high-resolution 3-T magnetic resonance imaging scanner. We found that higher NSS scores in individuals with UHR were associated with decreased grey matter volume at the superior and medial frontal cortex, the rectal cortex, the pre- and post-central cortex, the insula, the caudate, and the cerebellum. Our results suggest that these brain structural characteristics may represent the neuroanatomical substrate of NSSs in individuals with UHR. These findings contribute to the understanding of the intrinsic features of psychosis associated with NSSs and may provide insights into pre-schizophrenia pathophysiology.

F125. POOR OUTCOME SCHIZOPHRENIA (KRAEPELINIAN SUB-TYPE): SOCIAL COGNITIVE AND NEURODEVELOPMENTAL MARKERS

BackgroundPoor outcome schizophrenia represents a public health challenge and it asks questions about neurodevelopmental mechanisms by its own. The kraepelinian schizophrenia sub-type, defined by Keefe’s criteria (1987), refers to a very poor prognosis sub-group (severe dysfunction in self-care) on the basis of the longitudinal course of the illness. Studies on kraepelinian sub-group show differences with good outcome patients regarding pre-morbid functioning, negative and disorganized symptoms, impaired performance on specific social cognitive and motor deficits (visual-motor processing, abstraction/flexibility, fine motor dexterity) (Albus and al., 1996; Bralet and al., 2006). Neurological soft signs (NSS) refer to subtle neurological abnormalities comprising deficits in sensory integration, motor coordination and sequencing of complex motor acts. Previous studies showed that NSS scores are correlated to schizophrenia, specifically among patients with poor premorbid functioning and with severe negative and disorganization symptoms. NSS could be a neurodevelopmental marker interesting to detect patients with a risk of poor prognosis. Deficits in theory of mind is correlated with disorganization and poor prognosis. The aim of our study was to explore the association between NSS, Theory of Mind and kraepelinian sub-type in order to understand better the etiopathogenic mechanisms underlying the kraepelinian sub-type.MethodsIn 2016, we recruited 2 samples of 25 schizophrenic patients, kraepelinians and no-kraepelinians, matched on sex, ages (+/- 5 years) and duration of illness (+/- 5 years) from the psychiatric departments in Picardie area (France), according to DSM-IV-TR criteria and using Keefe’s criteria. Several socio-demographical, pharmacological, clinical, cognitive and NNS (with the 3 subscores, sensory integration, motor integration and motor coordination) (Krebs and al., 2000) were collected for each patient. To compare the 2 sub-groups we used bi-variate analysis and multivariate regression analysis (p< 0,05)ResultsResults showed a worse significant NSS score among kraepelinian patients: total score, sensory integration, motor integration, motor coordination, p< 0,0001; there was no link with treatment (equ mg/day chlorpromazine). As well kraepelinians show worse significantly performance at the eye gaze test p<0,001. Multivariate analysis showed that kraepelinian sub-type is more explained significantly by eyes-test, motor integration and disorganization dimensionDiscussionPoor prognosis schizophrenia refers to specific and complex neurodevelopmental mechanisms which could be markers of a poor outcome. We must confirm these results in a larger prospective cohort from UHR and first episode assessing some specific neurodevelopmental markers using NSS and cognitive assessment. As well some specific biological markers and genes implicating in neurodevelopment and glutamatergic system could be studied in these patients. Focusing on these specific markers could contribute to define innovating combinating therapeutic strategies (pharmacological, cognitive remediation and social skills) to avoid poor prognosis.

Neurological soft signs in patients with schizophrenia: current knowledge and future perspectives in the post-genomics era

Neurological soft signs (NSS), minor and subtle neurological abnormalities in sensory integration and motor performance that are not part of a properly defined neurological syndrome, have been consistently observed in patients with schizophrenia. The prevalence estimates of NSS in patients with schizophrenia have been reported to be higher than in healthy subjects. Current evidence suggests that NSS are an integral part of the disease and cannot be fully explained by the exposure to antipsychotic medication, as they are already present in treatment-naive patients. NSS have been associated with cardinal features of the disorder such as cognitive impairment, psychopathological severity, or functional outcome. The increased prevalence of NSS and/or related motor precursors has been described at different stages of development (infancy, childhood, adolescence) in those subjects who later developed schizophrenia. Evidence from family and twin studies indicates that genetic factors play an important role in the emergence of NSS, and some authors have already suggested that such neurological anomalies are suitable endophenotypes for schizophrenia. Some genetic association studies based on a candidate gene approach have already reported the association of genetic variants with the severity of NSS. This non-systematic review describes the potential relevance of NSS 1) in the understanding of schizophrenia as a neurodevelopmental disorder, 2) as outcome predictors, 3) as biological markers during several stages of development, and 4) as a candidate (endo)phenotype for genetic analyses. Likewise, the possibilities afforded by the advances in high-throughput techniques in genomic analysis are also discussed. Keywords: genome-wide association studies; motor function; sensory integration; endophenotype (Published: 8 July 2016) Citation: Translational Developmental Psychiatry 2016, 4 : 30071 - http://dx.doi.org/10.3402/tdp.v4.30071

Association of Cortical Thickness and Neurological Soft Signs in Patients with Chronic Schizophrenia and Healthy Controls

Background: Neurological soft signs (NSS), i.e. subtle neurological abnormalities, have been frequently found in schizophrenia. Neuroimaging studies in schizophrenia have shown abnormal cortical thickness changes across the cortical mantle. However, few studies have examined relationships between NSS and cortical thickness abnormalities in schizophrenia. Method: A sample of 18 patients with chronic schizophrenia and 20 age-matched healthy controls were included. Cortical thickness was assessed on high-resolution 3-tesla magnetic resonance imaging by using FreeSurfer software and NSS were rated on the Heidelberg Scale. Results: Significant negative correlations between NSS and cortical thickness were found in the prefrontal, inferior temporal, superior parietal, postcentral, and supramarginal cortices in the schizophrenia patients. In the controls, however, this negative correlation was found in the anterior cingulate, pericalcarine and superior/middle temporal regions. Conclusion: Our results not only confirmed the association between NSS and cortical thickness in chronic schizophrenia but also indicated that patients and controls have different anatomical substrates of NSS.

Nerological Soft Signs in HIV-associated Neurocognitive Disorder: a Clinical Marker?

Introduction With the introduction of antiretroviral treatment, the survival rates of Human Immunodeficiency virus (HIV) patients have improved significantly. However, the incidence of HIV- associated neurocognitive disorders (HAND) gained importance and represents actually a significant public health problem. Neurological soft signs (NSS) refers to subtle neurological abnormalities in motor and sensory performance. The presence of these symptoms has been widely described in patients with mental diseases like Schizophrenia or Alzheimer’s Disease, but have not been studied in HAND despite its known subcortical physiopathology. Objectives To study the prevalence HAND in a Chilean cohort of HIV patients and describe its association to NSS. Methods HIV patients without history of head injury trauma or opportunistic infections of the CNS were recruited from the HIV clinic, underwent a thorough clinical interview and neuropsychological testing. Healthy controls were recruited from the community. All participants were assessed with the Heidelberger NSS scale. HAND was diagnosed using NIMH and NINDS criteria. Results Until now, 35 HIV+ patients and 18 controls completed the described assessment. 11 patients were cognitive healthy, 11 with Asymptomatic Neurocognitive Impairment (ANI) and 13 with Mild Neurocognitive Disorder (MND). NSS total score differed significantly between groups (F= 2,92 (DF=3), p ANI, MND and Cognitive healthy HIV>MND. Discussion Our data supports the use of NSS as a marker of HAND. It should be considered in the clinical examination of HIV patients.

Signes neurologiques mineurs dans la schizophrénie précoce

Neurological soft signs (NSS) are subtle neurological abnormalities that cannot be linked to the achievement of a specific region of the central nervous system and which are not part of a particular neurological syndrome. These signs are observed in the case of diseases supporting the neurodevelopmental model such as schizophrenia in general and its early form defined notably by an age of onset of less than 18 years. Indeed, the NSS belong to a set of clinical, cognitive, electrophysiological and neuroanatomical markers reflecting neurodevelopmental brain abnormalities in patients with schizophrenia. The objectives of our study were to determine the prevalence, the scores, and the nature of neurological soft signs (NSS) in adolescent patients suffering from early onset schizophrenia diagnosis in comparison to healthy controls, and to explore the correlations between NSS and the demographic, clinical and therapeutic features of these patients. Twelve adolescents were recruited in the Child Psychiatry Department at the Razi Hospital (Tunisia), with the diagnosis of schizophrenia according to the DSM-IV supplemented by the Kiddie SAD PL. They were matched by age and educational level with twelve healthy controls without psychiatric family or personal history. The clinical status of the patients was assessed using the Positive and Negative Syndrome Scale (PANSS). Neurological soft signs (NSS) were rated with the Neurological Soft Signs Examination (NSSE) by Krebs et al. (2000) for the two groups. This scale is composed of 23 items exploring motor coordination, motor integrative function, sensory integration, involuntary movements and quality of lateralization. The mean age of our population was 14.7 years. The average age of onset of the disease was 12.2 years. The sex-ratio was 1.4. Educational level was 7.4 years. The PANSS mean total score was 74.3. The mean daily dose, in chlorpromazine equivalents, was 523.9 mg/day. Four patients received a strict monotherapy of antipsychotics, while the other patients were receiving an association of two neuroleptics. The prevalence of NSS was 100% (cut-off point=11) with a mean total score of 29.3±4.1. The highest score was for the motor coordination (10.1). As for the control group, the mean total score was 7±1.3. A highly significant difference was found between patients and controls for all sub-scores of NSS. Negative correlations were found in patients, between age and neurological soft signs total score (P=0.05; r=-0.57) and also with sensory integration score (P=0.04; r=-0.58). The NSS total score was also correlated with low educational level (P=0.03; r=-0.61). There was no correlation between neurological soft signs scores and PANSS scores or the daily dose of antipsychotics. The prevalence and NSS scores are high among young people with early onset schizophrenia diagnosis illustrating the existence of structural abnormalities of the brain, themselves consequences of early neurodevelopmental disturbances, which would support the neurodevelopmental hypothesis concerning this pathology.

Transmission of the rare HRAS mutation (c. 173C &gt; T; p.T58I) further illustrates its attenuated phenotype

Costello syndrome was delineated based on its distinctive phenotype including severe failure-to-thrive with macrocephaly, characteristic facial features, hypertrophic cardiomyopathy, papillomata, malignant tumors, and cognitive impairment. Heterozygous germline mutations in the proto-oncogene HRAS cause Costello syndrome, and its inheritance pattern would thus be autosomal dominant. With exception of two instances of parental mosaicism, one presumed gonadal and the other proven somatic mosaicism for the p.G12S change, all published cases resulted from de novo mutations, typically arising in the paternal germline. More than 90% of these mutations affect the glycine residues in position 12 or 13, and result in a gain-of-function of the altered protein. A rare heterozygous HRAS alteration (c.173C > T; p.T58I) associated with an attenuated phenotype was previously reported in one patient. We identified two additional individuals with this mutation, father and son. Further studies supported origin of the alteration in the grand-paternal germline. Transmission of the mutation underscores its attenuated phenotype compatible with reproduction. We reviewed the phenotype in the newly identified individuals (Patient 1, 2) and include updated information on the first previously reported individual with HRAS p.T58I (Patient 3). Macrocephaly was present in all three. Cardiac findings included hypertrophic cardiomyopathy with double-chambered right ventricle; or mitral valve prolapse in one patient each. While subtle neurologic abnormalities or developmental delay were present in all, only one showed significant cognitive and functional impairment. None developed papillomata or a malignant tumor. Genetic counseling for Costello syndrome needs to take into consideration the particular HRAS mutation.

Venous haemangioma of the mandibular division of the trigeminal nerve

To present a rare cause of facial pain, and the differential diagnosis of a lesion of the mandibular division of the trigeminal nerve. A 19-year-old woman presented to a tertiary referral skull base centre with right periorbital pain and a progressive, right-sided deficit of the mandibular division of the trigeminal nerve. Clinical examination revealed right-sided hypoaesthesia in the mandibular division of the trigeminal nerve dermatome, mild trismus and some wasting of the right masseter muscle. Computed tomography and magnetic resonance imaging scans revealed a small area of mildly enhancing soft tissue centred within the foramen ovale, with concentric enlargement. Surgery was undertaken via an infratemporal fossa (Fisch) type D approach. A vascular lesion was found filling the foramen ovale, with no obvious nerve separate from the lesion. The lesion was removed en bloc. Histopathological analysis demonstrated a venous haemangioma within the nerve. Facial pain is common, and may be wrongly attributed to trigeminal neuralgia. A thorough clinical examination must be performed to identify subtle neurological abnormalities, and appropriate imaging undertaken to exclude rare causes, such as this venous haemangioma of the mandibular division of the trigeminal nerve.

Screening for Mild Traumatic Brain Injury in the Presence of Psychiatric Comorbidities

Chapman JC, Andersen AM, Roselli LA, Meyers NM, Pincus JH. Screening for mild traumatic brain injury in the presence of psychiatric comorbidities. Objective To determine whether or not a battery of neurobehavioral tests, the Brief Objective Neurobehavioral Detector (BOND), could detect mild traumatic brain injury (mTBI) among a group of psychiatric inpatients with numerous substance-related and medical comorbidities. The 16-item BOND is comprised of neurologic examination tasks and has been shown to correlate with radiologic and cognitive findings in previous studies. Design Masked comparison. Setting Inpatient psychiatric unit at the Veterans Affairs Medical Center in Washington, DC. Participants Patients (N=51) sequentially admitted for suicidal ideation in the context of various psychiatric disorders. Interventions No intervention. Main Outcome Measure BOND total and subtest scores. Results Forty-three patients were eligible and analyzed. Twenty-seven had sustained an mTBI in the distant past, and 16 had never sustained a traumatic brain injury (TBI) (non-TBI group). On average, the mTBI group demonstrated a significantly greater number of abnormal subtests on the BOND (mean, 7.22) than did the non-TBI group (mean, 4.50; P=.003). Although the BOND significantly correlated with the presence of mTBI, it did not correlate with any of the psychiatric, substance-related, or medical comorbidities. Multiple regressions indicated that the BOND total score was not explained by age, posttraumatic stress disorder diagnosis, or any combination of the psychiatric, substance-related, or medical comorbidities. High rates of sensitivity (70%) and specificity (69%) were found. Conclusions The results of this pilot study suggest that the inexpensive, brief, and objective BOND instrument may be a useful screening tool for the detection of subtle neurologic brain abnormalities after mTBI, even in the presence of substantial comorbidities.

REM Sleep Behaviour Disorder in Older Individuals

Rapid eye movement (REM) sleep behaviour disorder (RBD) is a sleep disorder in which patients appear to be enacting their dreams while in REM sleep. The behaviours are typically violent, in association with violent dream content, so serious harm can be done to the patient or the bed partner. The disorder predominantly affects older adults, and has an estimated prevalence in adults of 0.4-0.5%. However, the frequency is much higher in certain neurodegenerative diseases, especially Parkinson's disease, dementia with Lewy bodies and multiple systems atrophy. RBD can occur in the absence of diagnosed neurological diseases (the 'idiopathic' form), although patients with this form of RBD may have subtle neurological abnormalities and often ultimately develop a neurodegenerative disorder. Data from animal models and cases of RBD developing after brainstem (pontine tegmentum, medulla) lesions have led to the understanding that RBD is caused by a lack of normal REM muscle atonia and a lack of normal suppression of locomotor generators during REM sleep. Clonazepam is used as first-line therapy for RBD and melatonin as second-line therapy, although evidence for both of these interventions comes from uncontrolled case series. Because the risk of injury to the patient or the bed partner is high, interventions to improve the safety of the sleep environment are also often necessary. This review describes the epidemiology, pathophysiology and treatment of RBD.

Considerations on the Impact of Hepatic Encephalopathy Treatments in the Pretransplant Setting

Hepatic encephalopathy (HE) is a common complication of acute and chronic liver disease associated with exposure of brain tissue to excessive levels of ammonia produced by intestinal bacteria. Clinical manifestations range from subtle neurologic abnormalities to coma. Because development of HE can reduce survival probability, guidelines for evaluating patients for liver transplantation suggest that patients who develop HE should be considered for transplantation. Various patient factors before transplantation, including the presence of HE and reduced nutritional status, may increase the risk of poor outcomes after transplantation. Therefore, effective management of HE before transplantation, while minimizing the potential impact of negative predictive factors, may improve transplantation outcomes. The most common HE treatments are directed toward reducing systemic ammonia levels, thereby reducing brain exposure to this neurotoxin. The administration of nonabsorbable disaccharides is considered as a first-line therapy for HE, and the antibiotics neomycin and metronidazole are frequently administered, despite a lack of clinical data supporting their efficacy. These agents are associated with adverse events that may reduce nutritional status in patients awaiting transplantation and could contribute to poor posttransplantation outcomes. The nonsystemic antibiotic rifaximin has demonstrated efficacy for the treatment of HE and has a favorable safety profile. Given these data, nonsystemic antibiotics may also provide a safe and effective option for treating HE in the pretransplant setting. This article reviews treatments for HE and the potential impact these treatments may have on pretransplantation status of patients awaiting liver transplantation and on posttransplantation outcomes.

Hippocampal malrotation in pediatric patients with epilepsy associated with complex prefrontal dysfunction

The cognitive consequences of hippocampal malrotation (HIMAL) were investigated in a matched control study of children with epilepsy. Seven children with HIMAL were compared on a range of memory and attention tasks with 21 control children with epilepsy without temporal role pathology and 7 children with epilepsy and magnetic resonance imaging (MRI)-documented hippocampal sclerosis. In addition, in a statistical morphometric analysis, MRI studies from four children with HIMAL were compared to similar images of 20 age-matched typically developing control children. Although the task battery was sensitive to the memory deficit of the children with hippocampal sclerosis, it did not reveal memory impairment in the patients with HIMAL. In contrast, the patients with HIMAL were impaired on the attentionally more demanding dual tasks, compared to both the control and the hippocampal sclerosis group. The structural MRI analysis revealed morphometric abnormalities in the tail of the affected hippocampus, the adjacent neocortex, and the ipsilateral medial thalamus. The basal forebrain was bilaterally affected. Abnormalities in remote cortex were found in the ipsilateral temporal lobe, the contralateral anterior cingulate gyrus, and bilateral in the dorsolateral and lateral-orbitofrontal prefrontal cortex. Because the prefrontal cortical regions have been shown to be active during dual-task performance, the MRI results converge with the neuropsychological findings of impairment on these tasks. We conclude that HIMAL had no direct memory repercussions, but was secondary to subtle but widespread neurologic abnormalities that also affected morphology and functioning of the prefrontal cortex.

Subtle neurological and metabolic abnormalities in an Opa1 mouse model of autosomal dominant optic atrophy

The ubiquitously expressed gene OPA1 is the main disease causing gene for autosomal dominant optic atrophy (ADOA). These patients present with bilateral reduction in visual acuity, central visual field defects and impaired color vision, secondary to the progressive loss of retinal ganglion cells (RGCs) and subsequent degeneration of the optic nerve. Up to now, it is not clear why a mutation in a ubiquitously expressed gene affects only RGCs and the optic nerve. Twenty-two-month-old Opa1 animals underwent a full examination following the Shirpa protocol. Weight, food intake and life span were monitored. Rotarod treadmill experiments were performed to assess neuromuscular function. Limb skeletal muscle was evaluated morphologically, mitochondrial cytochrome c oxidase (COX) activity was studied histochemically and mtDNA integrity was determined by long-range PCR. The Shirpa test showed that 33% of the Opa1 mice suffered from tremor and 52% of the Opa1 animals showed an abnormal clutching reflex. Control animals performed well in the accelerating Rotarod treadmill experiment whereas the Opa1 mice performed significantly worse. Skeletal muscle fibers were morphologically normal, had normal COX activity and showed no evidence of secondary mtDNA damage in contrast to patients with syndromic ADOA. We also found a highly significant difference in body weight. Our results demonstrate that OPA1 mutations affect not only RGCs but also other tissues and cell types, though to a lesser extent. In particular we found deficits in both neuromuscular and metabolic function. We therefore want to encourage clinicians to be vigilant about to extra-ocular manifestations in ADOA patients.

Subtle Neurological Abnormalities as Risk Factors for Cognitive and Functional Decline, Cerebrovascular Events, and Mortality in Older Community-Dwelling Adults

Subtle, but clinically detectable, neurological abnormalities (SNAs) are associated with impaired physical performance in elderly persons without overt neurological diseases. We investigated whether SNAs were prospectively associated with cognitive and functional status, death, and cerebrovascular events (CVEs) in older community-dwelling individuals. In participants without history of stroke, parkinsonism and dementia, or cognitive impairment, a score (N(SNA)) was obtained by summing SNAs detected with a simple neurological examination. Cognitive status and disability were reassessed 4 years later, and deaths and CVEs were documented over 8 years. Of 506 participants free of neurological diseases (mean [SEM] age, 71.9 [0.3] years; 42% were men), 59% had an N(SNA) of 1 or more (mean [SEM], 1.1 [0.06]; range, 0-8). At baseline, the N(SNA) increased with age and with declining cognitive and physical performance, depressive symptoms, and disability, after adjusting for several covariates, but did not increase with falls and urinary incontinence. The N(SNA) prospectively predicted worsening cognitive status and disability, adjusting for demographics and for baseline comorbidity and cognitive and physical performance. The mortality rates were 22.6, 23.3, 23.9, 58.6, and 91.9 per 1000 person-years in participants with an N(SNA) of 0, 1, 2, 3, and 4 or higher, respectively. Compared with an N(SNA) of less than 3, having an N(SNA) of 3 or higher was associated with an increased adjusted risk of death (hazard ratio, 1.77; 95% confidence interval [CI], 1.25-2.74) and of CVE (hazard ratio, 1.94; 95% CI, 1.07-3.54) over 8 years. In this sample of older community-dwelling persons without overt neurological diseases, multiple SNAs were associated with cognitive and functional decline and independently predicted mortality and CVEs.