Severe Motor Deficits Research Articles

Health characteristics and health care trajectory of polyhandicaped person before and after 1990

IntroductionPolyhandicap is defined as the combination of severe mental impairment and severe motor deficit resulting in reduced mobility and an extreme reduction in autonomy. Over the last 20years, care management for these patients has become more structured, however, their care pathway is not always optimal. ObjectiveTo describe/compare the health characteristics, treatment and history of the care pathways of subjects who received care before and after 1990. MethodMulticentre cross-sectional study, population studied: patients with polyhandicap: (i) causal brain damage<3years, (ii) severe mental impairment, (iii) motor disability, (iv) reduced mobility, (v) extreme restriction of autonomy. Data collected: clinical and medical, care procedures, treatments, history of care pathways. ResultsPatients are divided into 2 groups: 545 patients who received care after 1990 and 330 before 1990. Older patients present more recurrent urinary infections, slow transit, behavioural disorders and pain, and are prescribed a greater number of drugs. For those who received care before 1990, the age of admission to an establishment is lower, with one-third receiving a consultation dedicated to the transition from paediatric to adult teams. Discussion/ConclusionThe care sector for patients with polyhandicap makes it possible to meet their needs throughout their lives, however, there is still progress to be made in terms of formalisation and of coordinating the care pathway in order to facilitate the transition from paediatric to adult services/establishments.

Strabismus Is Correlated with Gross Motor Function in Children with Spastic Cerebral Palsy

ABSTRACTPurpose: To investigate the correlation between clinical features of strabismus and motor dysfunction classified according to the Gross Motor Function Classification System (GMFCS) in patients with spastic cerebral palsy (CP).Methods: In this retrospective, cross-sectional study in single tertiary medical center, 62 patients who are diagnosed with spastic CP who had an ophthalmic examination between 2006 and 2014 were included. Only patients with vision sufficient to fixate were included and patients with restrictive or paralytic strabismus were excluded. The types of CP were classified as diplegia, hemiplegia, or quadriplegia for distribution of motor impairment. The GMFCS was used to grade gross motor dysfunction, which was then classified as mild (grade 1, 2 and 3) or severe (grade 4 and 5) motor impairment. Strabismus was investigated in terms of direction, constancy, and deviation angle. The relationship between strabismus characteristics and the level of GMFCS and type of CP were assessed.Results: Thirty-eight and 24 patients had mild or severe motor deficit, respectively. Forty patients had strabismus, which was more frequent in patients with severe motor impairment.(P = .014) Exotropia and esotropia occurred with similar frequency. Constant and large-angle strabismus was frequently observed in patients with severe motor impairment.(P < .005, 0.027) The topographical subtype of CP was not related to clinical features of strabismus.Conclusions: The prevalence of strabismus is higher in severe motor impairment. The constancy and angle of strabismus was related to the severity of motor impairment while the topographical subtype of CP has no significant relationship.

In vivo nuclear capture and molecular profiling identifies Gmeb1 as a transcriptional regulator essential for dopamine neuron function

Midbrain dopamine (mDA) neurons play a central role in reward signaling and are widely implicated in psychiatric and neurodegenerative disorders. To understand how mDA neurons perform these functions, it is important to understand how mDA-specific genes are regulated. However, cellular heterogeneity in the mammalian brain presents a major challenge to obtaining this understanding. To this end, we developed a virus-based approach to label and capture mDA nuclei for transcriptome (RNA-Seq), and low-input chromatin accessibility (liDNase-Seq) profiling, followed by predictive modeling to identify putative transcriptional regulators of mDA neurons. Using this method, we identified Gmeb1, a transcription factor predicted to regulate expression of Th and Dat, genes critical for dopamine synthesis and reuptake, respectively. Gmeb1 knockdown in mDA neurons resulted in downregulation of Th and Dat, as well as in severe motor deficits. This study thus identifies Gmeb1 as a master regulator of mDA gene expression and function, and provides a general method for identifying cell type-specific transcriptional regulators.

Is segmental muscle strength recovery different in patients with dominant versus non-dominant hemispheric ischemic stroke?

Abstract Introduction &amp; objectives: Starting from the well-known functional hemispheric asymmetry and concomitantly, from the clinical findings of practitioners involved in the post-stroke rehabilitation process, the aim of this study was to evaluate whether ischemic stroke in the dominant hemisphere results in more severe initial motor deficit and if its motor recovery is decreased compared to that of the non-dominant hemisphere. Material and method: This was a retrospective study, comprising 39 patients with ischemic stroke in the middle cerebral artery territory, divided into two groups depending on the hemispheric location of the lesion (left/right). They were evaluated for their segmental muscle strength using the Medical Research Council Muscle Strength Grading Scale, both in terms of initial value and evolution between two successive admissions. Results and conclusions: No significant difference was found for motor deficit evaluated on the occasion of the first admission between patients with left-side stroke and those with right-side stroke. Motor recovery was more obvious proximally in the paretic limbs, but without statistical significance. Key words: hemispheric dominance, functional laterality, stroke, motor rehabilitation,

Predicting Functional Impairment in patients with chronic subdural hematoma treated with burr hole Trepanation—The FIT-score

ObjectiveIt remains difficult to estimate prolonged functional impairment in patients with chronic subdural hematoma (cSDH) treated with burr hole trepanation. We aim to establish a score that reliably predicts postoperative functional impairment. Patients and methodsRetrospectively analysis of a prospective institutional database. cSDH patients operated in 2013–2016 were identified. Clinical outcome was dichotomized into presence (modified-Rankin-Scale (mRS) ≥ 2) or absence of functional impairment (mRS 0–1) at discharge and last follow-up. A score was developed, based on the effect sizes of a set of outcome predictors. Its accuracy was tested using Area Under the Receiver-Operating Characteristic (AUROC) curve analysis. The 2017 cohort served for internal validation. ResultsA cohort of 253 patients (mean age 75 years, 75% male) was analyzed, of which 77 patients (30%) remained functionally impaired. In multivariate analysis, severe motor deficits at admission (OR 5.84, 95% CI 2.71–12.59, p < 0.001), age (≥85 years: 5.53, 2.14–14.32, p < 0.0001) and disorientation at admission (2.65, 11.39–5.05, p = 0.003) were associated with persistent functional impairment. Based on those variables, we created the “Functional Impairment after burr hole Trepanation” (FIT-score), which showed an AUROC of 0.77 (95% CI 0.70–0.83) for impairment at discharge and 0.76 (0.70–0.82) for impairment at follow-up. Internal validation confirmed the model with an AUROC of 0.79 (0.68–0.91) at discharge and 0.77 (0.64–91) at follow-up. ConclusionsThe FIT-score is likely to assist the physician when counseling patients and relatives pertaining to the need for postoperative rehabilitation and mid- to long-term supportive home care.

Therapeutic hypothermia attenuates paraplegia and neuronal damage in the lumbar spinal cord in a rat model of asphyxial cardiac arrest

Spinal cord ischemia can result from cardiac arrest. It is an important cause of severe spinal cord injury that can lead to serious spinal cord disorders such as paraplegia. Hypothermia is widely acknowledged as an effective neuroprotective intervention following cardiac arrest injury. However, studies on effects of hypothermia on spinal cord injury following asphyxial cardiac arrest and cardiopulmonary resuscitation (CA/CPR) are insufficient. The objective of this study was to examine effects of hypothermia on motor deficit of hind limbs of rats and vulnerability of their spinal cords following asphyxial CA/CPR. Experimental groups included a sham group, a group subjected to CA/CPR, and a therapeutic hypothermia group. Severe motor deficit of hind limbs was observed in the control group at 1 day after asphyxial CA/CPR. In the hypothermia group, motor deficit of hind limbs was significantly attenuated compared to that in the control group. Damage/death of motor neurons in the lumbar spinal cord was detected in the ventral horn at 1 day after asphyxial CA/CPR. Neuronal damage was significantly attenuated in the hypothermia group compared to that in the control group. These results indicated that therapeutic hypothermia after asphyxial CA/CPR significantly reduced hind limb motor dysfunction and motoneuronal damage/death in the ventral horn of the lumbar spinal cord following asphyxial CA/CPR. Thus, hypothermia might be a therapeutic strategy to decrease motor dysfunction by attenuating damage/death of spinal motor neurons following asphyxial CA/CPR.

Postoperative navigated transcranial magnetic stimulation to predict motor recovery after surgery of tumors in motor eloquent areas

ObjectiveTo know whether motor deficits after tumor surgery are transient is reassuring for the patient and crucial for planning rehabilitation and adjuvant treatment. We analyze the value of postoperative MRI navigated transcranial magnetic stimulation (nTMS) compared to intraoperative MEP monitoring in predicting recovery of motor function. MethodsRetrospective series of nTMS mappings within 14 days after surgery for supratentorial tumors (09/2014–05/2018). All patients with motor deficits of Medical-Research-Council-Grade (MRCS) 0–4- were included. ResultsWe performed nTMS mapping on average 3.8 days after surgery and recorded nTMS MEP in 11 of 13 patients. Motor strength recovered to at least MRCS 4 within one month if postoperative nTMS elicited MEPs (positive predictive value 90.9%). If nTMS did not elicit MEPs, the patient did not recover (negative predictive value 100%). Intraoperative MEP and postoperative nTMS were equally predictive for long-term motor recovery. In cases of intraoperative MEP alteration/signal loss, but a positive postoperative nTMS mapping, 2/3 patients demonstrated a good motor recovery. ConclusionnTMS may predict long-term motor recovery of patients suffering from severe motor deficits directly after resection of tumors located in motor eloquent areas. SignificanceIn cases of intraoperative MEP alterations, postoperative nTMS may clarify the potential for motor recovery.

Individually tailored whole-body vibration training to reduce symptoms of chemotherapy-induced peripheral neuropathy: study protocol of a randomised controlled trial—VANISH

IntroductionChemotherapy-induced peripheral neuropathy (CIPN) is a prevalent and clinically meaningful side effect of cancer treatment. CIPN is induced by neurotoxic agents, causing severe sensory and/or motor deficits, resulting in disability...

Awake craniotomy with transcortical motor evoked potential monitoring for resection of gliomas in the precentral gyrus: utility for predicting motor function.

Resection of gliomas in the precentral gyrus carries a risk of severe motor dysfunction. To prevent permanent, severe postoperative motor dysfunction, reliable intraoperative predictors of postoperative function are required. Since 2005, the authors have removed gliomas in the precentral gyrus with combined functional mapping and estimation of intraoperative voluntary movement (IVM) during awake craniotomy and transcortical motor evoked potentials (MEPs). The purpose of the current study was to evaluate whether intraoperative findings of combined monitoring of IVM during awake craniotomy and transcortical MEP monitoring were useful for predicting postoperative motor function of patients with gliomas in the precentral gyrus. The current study included 30 patients who underwent resection of precentral gyrus gliomas during awake craniotomy from April 2000 to January 2018. All tumors were removed with monitoring of IVM during awake craniotomy and transcortical MEPs. Postoperative motor function was classified as stable or declined, with the extent of decline categorized as mild, moderate, or severe. We defined moderate and severe deficits were those that hindered daily life. In 28 of 30 cases, available waveforms were obtained with transcortical MEPs. The mean extent of resection (EOR) was 93%. Relative to preoperative status, motor function 6 months after surgery was considered stable in 20 patients and was considered to show mild decline in 7, moderate decline in 2, and severe decline in 1. Motor function 6 months after surgery was significantly correlated with IVM (p = 0.0096), changes in transcortical MEPs (decline ≤ or > 50%) (p = 0.0163), EOR, and ischemic lesions on postoperative MRI. Six patients with no change in IVM showed stable motor function 6 months after surgery. Only 2 patients with a decline in IVM and a decline in MEPs ≤ 50% had a decline in motor function 6 months after surgery (18%; 2/11 patients), whereas 11 patients with a decline in IVM and a decline in MEPs > 50% had such a decline in motor function (73%; 8/11 patients) including 2 patients with moderate and 1 with severe deficits. Three patients with moderate or severe motor deficits showed the lowest MEP values (< 100 µV). Combined judgment from monitoring of IVM during awake craniotomy and transcortical MEPs is useful for predicting postoperative motor function during removal of gliomas in the precentral gyrus. Maximum resection was achieved with an acceptable morbidity rate. Thus, these tumors should not be considered unresectable.

Persistent motor dysfunction despite homeostatic rescue of cerebellar morphogenesis in the Car8 waddles mutant mouse

BackgroundPurkinje cells play a central role in establishing the cerebellar circuit. Accordingly, disrupting Purkinje cell development impairs cerebellar morphogenesis and motor function. In the Car8wdl mouse model of hereditary ataxia, severe motor deficits arise despite the cerebellum overcoming initial defects in size and morphology.MethodsTo resolve how this compensation occurs, we asked how the loss of carbonic anhydrase 8 (CAR8), a regulator of IP3R1 Ca2+ signaling in Purkinje cells, alters cerebellar development in Car8wdl mice. Using a combination of histological, physiological, and behavioral analyses, we determined the extent to which the loss of CAR8 affects cerebellar anatomy, neuronal firing, and motor coordination during development.ResultsOur results reveal that granule cell proliferation is reduced in early postnatal mutants, although by the third postnatal week there is enhanced and prolonged proliferation, plus an upregulation of Sox2 expression in the inner EGL. Modified circuit patterning of Purkinje cells and Bergmann glia accompany these granule cell adjustments. We also find that although anatomy eventually normalizes, the abnormal activity of neurons and muscles persists.ConclusionsOur data show that losing CAR8 only transiently restricts cerebellar growth, but permanently damages its function. These data support two current hypotheses about cerebellar development and disease: (1) Sox2 expression may be upregulated at sites of injury and contribute to the rescue of cerebellar structure and (2) transient delays to developmental processes may precede permanent motor dysfunction. Furthermore, we characterize waddles mutant mouse morphology and behavior during development and propose a Sox2-positive, cell-mediated role for rescue in a mouse model of human motor diseases.

Intraoperative neurophysiological monitoring for intradural extramedullary spinal tumors: predictive value and relevance of D-wave amplitude on surgical outcome during a 10-year experience.

OBJECTIVEThe purpose of this study was to evaluate the technical feasibility, accuracy, and relevance on surgical outcome of D-wave monitoring combined with somatosensory evoked potentials (SSEPs) and motor evoked potentials (MEPs) during resection of intradural extramedullary (IDEM) spinal tumors.METHODSClinical and intraoperative neurophysiological monitoring (IONM) data obtained in 108 consecutive patients who underwent surgery for IDEM tumors at the Institute for Scientific and Care Research "ASMN" of Reggio Emilia, Italy, were prospectively entered into a database and retrospectively analyzed. The IONM included SSEPs, MEPs, and-whenever possible-D-waves. All patients were evaluated using the modified McCormick Scale at admission and at 3, 6, and 12 months of follow-up .RESULTSA total of 108 patients were included in this study. A monitorable D-wave was achieved in 71 of the 77 patients harboring cervical and thoracic IDEM tumors (92.2%). Recording of D-waves in IDEM tumors was significantly associated only with a preoperative deeply compromised neurological status evaluated using the modified McCormick Scale (p = 0.04). Overall, significant IONM changes were registered in 14 (12.96%) of 108 patients and 9 of these patients (8.33%) had permanent loss of at least one of the 3 evoked potentials. In 7 patients (6.48%), the presence of an s18278 caudal D-wave was predictive of a favorable long-term motor outcome even when the MEPs and/or SSEPs were lost during IDEM tumor resection. However, in 2 cases (1.85%) the D-wave permanently decreased by approximately 50%, and surgery was definitively abandoned to prevent permanent paraplegia. Cumulatively, SSEP, MEP, and D-wave monitoring significantly predicted postoperative deficits (p = 0.0001; AUC = 0.905), with a sensitivity of 85.7% and a specificity of 97%. Comparing the area under the receiver operating characteristic curves of these tests, D-waves appeared to have a significantly greater predictive value than MEPs and especially SSEPs alone (0.992 vs 0.798 vs 0.653; p = 0.023 and p < 0.001, respectively). On multiple logistic regression, the independent risk factors associated with significant IONM changes in the entire population were age older than 65 years and an anterolateral location of the tumor (p < 0.0001).CONCLUSIONSD-wave monitoring was feasible in all patients without severe preoperative motor deficits. D-waves demonstrated a statistically significant higher ability to predict postoperative deficits compared with SSEPs and MEPs alone and allowed us to proceed with IDEM tumor resection, even in cases of SSEP and/or MEP loss. Patients older than 65 years and with anterolateral IDEM tumors can benefit most from the use of IONM.

Biallelic loss of function variants in ATP1A2 cause hydrops fetalis, microcephaly, arthrogryposis and extensive cortical malformations

The Na+/K+- ATPase acts as an ion pump maintaining the essential plasma membrane potential in all mammalian cell types, and is essential for many cellular functions. There are four α isoforms (α1, α2, α3 and α4) with distinct expression patterns, kinetic properties and substrate affinity. The α2-isoform is encoded by ATP1A2 and evidence supports its utmost importance in Cl− homeostasis in neurons, and in the function of respiratory neurons at birth. Monallelic pathogenic variants in ATP1A2 are associated with familial hemiplegic migraine type 2 (FHM2) and on rare occasions with alternating hemiplegia of childhood 1 (AHC1). To date, no instances of biallelic loss of function variants have been reported in humans. However, Atp1a2 homozygous loss of function knockout mice (α2−/− mice) show severe motor deficits, with lack of spontaneous movements, and are perinatally lethal due to absent respiratory activity. In this report we describe three newborns from two unrelated families, who died neonatally, presenting in utero with an unusual form of fetal hydrops, seizures and polyhydramnios. At birth they had multiple joint contractures (e.g. arthrogryposis), microcephaly, malformations of cortical development, dysmorphic features and severe respiratory insufficiency. Biallelic loss of function variants in ATP1A2, predicted to be pathogenic were found on whole exome sequencing. We propose that this is a distinctive new syndrome caused by complete absence of Na+/K+- ATPase α2-isoform expression.

Circuit Dysfunction in SOD1-ALS Model First Detected in Sensory Feedback Prior to Motor Neuron Degeneration Is Alleviated by BMP Signaling.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease for which the origin and underlying cellular defects are not fully understood. Although motor neuron degeneration is the signature feature of ALS, it is not clear whether motor neurons or other cells of the motor circuit are the site of disease initiation. To better understand the contribution of multiple cell types in ALS, we made use of a Drosophila Sod1G85R knock-in model, in which all cells harbor the disease allele. End-stage dSod1G85R animals of both sexes exhibit severe motor deficits with clear degeneration of motor neurons. Interestingly, earlier in dSod1G85R larvae, motor function is also compromised, but their motor neurons exhibit only subtle morphological and electrophysiological changes that are unlikely to cause the observed decrease in locomotion. We analyzed the intact motor circuit and identified a defect in sensory feedback that likely accounts for the altered motor activity of dSod1G85R We found cell-autonomous activation of bone morphogenetic protein signaling in proprioceptor sensory neurons which are critical for the relay of the contractile status of muscles back to the central nerve cord, completely rescues early-stage motor defects and partially rescue late-stage motor function to extend lifespan. Identification of a defect in sensory feedback as a potential initiating event in ALS motor dysfunction, coupled with the ability of modified proprioceptors to alleviate such motor deficits, underscores the critical role that nonmotor neurons play in disease progression and highlights their potential as a site to identify early-stage ALS biomarkers and for therapeutic intervention.SIGNIFICANCE STATEMENT At diagnosis, many cellular processes are already disrupted in the amyotrophic lateral sclerosis (ALS) patient. Identifying the initiating cellular events is critical for achieving an earlier diagnosis to slow or prevent disease progression. Our findings indicate that neurons relaying sensory information underlie early stage motor deficits in a Drosophila knock-in model of ALS that best replicates gene dosage in familial ALS (fALS). Importantly, studies on intact motor circuits revealed defects in sensory feedback before evidence of motor neuron degeneration. These findings strengthen our understanding of how neural circuit dysfunctions lead to neurodegeneration and, coupled with our demonstration that the activation of bone morphogenetic protein signaling in proprioceptors alleviates both early and late motor dysfunction, underscores the importance of considering nonmotor neurons as therapeutic targets.

Interventional and preventive effects of aripiprazole and ceftriaxone used alone or in combination on oxaliplatin-induced tactile and cold allodynia in mice

Background and purposeChemotherapy-induced peripheral neuropathy (CIPN) is a pharmacoresistant neurological complication induced by some antitumor drugs. This study aimed to assess antiallodynic properties of aripiprazole and ceftriaxone used alone or in combination to attenuate neuropathic pain related to CIPN caused by oxaliplatin. MethodsNeuropathic pain was induced in mice by a single intraperitoneal dose of oxaliplatin (10 mg/kg). Aripiprazole and ceftriaxone were used in a single- or repeated dosing protocol. Their antiallodynic activity was assessed using von Frey and cold plate tests on the day of oxaliplatin injection and after 7 days. The influence of aripiprazole and ceftriaxone on animals’ locomotor activity and motor coordination was also assessed. ResultsSingle-dose and repeated-dose aripiprazole 10 mg/kg and ceftriaxone 200 mg/kg used alone and in combination attenuated early-phase and late-phase tactile allodynia in oxaliplatin-treated mice. Repeated administrations of ceftriaxone 200 mg/kg prevented the development of late-phase tactile allodynia. Both drugs showed no antiallodynic properties in the cold plate test. Single-dose aripiprazole 1 and 10 mg/kg but not its repeated administration significantly decreased locomotor activity of oxaliplatin-treated mice. Single-dose aripiprazole 1 and 10 mg/kg, aripiprazole 1 mg/kg + ceftriaxone 50 mg/kg and aripiprazole 1 mg/kg + ceftriaxone 200 mg/kg impaired motor coordination in the rotarod test. ConclusionsIn mice, neither ceftriaxone nor aripiprazole attenuated cold allodynia. Ceftriaxone alone could attenuate tactile allodynia caused by oxaliplatin without inducing motor adverse effects. Although the administration of aripiprazole reduced tactile allodynia, this effect seems to be limited considering severe motor deficits induced by this drug.

Progressively disrupted somatodendritic morphology in dopamine neurons in a mouse Parkinson's model.

Parkinson's disease is characterized by the progressive loss of dopamine neurons in the substantia nigra, leading to severe motor deficits. Although the disease likely begins to develop years before observable motor symptoms, the specific morphological and functional alterations involved are poorly understood. MitoPark mice lack the gene coding for mitochondrial transcription factor A specifically in dopamine neurons, which over time produces a progressive decline of neuronal function and related behavior that phenotypically mirrors human parkinsonism. Our previous work identified a progressive decrease in cell capacitance in dopamine neurons from MitoPark mice, possibly suggesting reduced membrane surface area. We therefore sought to identify and quantify somatodendritic parameters in this model across age. We used whole-cell patch clamp and fluorescent labeling to quantify somatodendritic morphology of single, neurobiotin-filled dopamine neurons in acutely isolated brain slices from MitoPark mice. We found that MitoPark mice exhibit an adult-onset, age-dependent reduction of neuritic branching and soma size in dopamine neurons. This decline proceeds similarly in MitoPark mice of both sexes, but does not begin until after the age that early decrements in ion channel physiology and behavior have previously been observed. A progressive and severe decline in somatodendritic morphology occurs prior to cell death, but is not responsible for the subtle decrements observable in the earliest stages of neurodegeneration. This work could help identify the ideal time window for specific treatments to halt disease progression and avert debilitating motor deficits in Parkinson's patients. © 2018 International Parkinson and Movement Disorder Society.

The presence of depression in de novo Parkinson's disease reflects poor motor compensation.

Depression frequently accompanies Parkinson’s disease and often precedes the onset of motor symptoms. This study aimed to evaluate the impact of depression on motor compensation in patients with de novo Parkinson’s disease. This retrospective cohort study analyzed data from 474 non-demented patients with de novo Parkinson’s disease (mean age, 64.6±9.8 years; 242 men) who underwent both dopamine transporter PET scan and depression assessment using the Beck Depression Inventory at baseline. Patients were classified into tertiles by Beck Depression Inventory score. At baseline, high-tertile group (Beck Depression Inventory score ≥15, n = 157) showed more severe motor deficits and lower cognitive function than low-tertile group (Beck Depression Inventory score ≤7, n = 158, P = 0.034 and P = 0.008, respectively). Greater motor deficits in high-tertile group than low-tertile group remained significant after controlling for dopamine transporter binding in the posterior putamen, as well as other confounding variables. During follow-up of a median duration of 47 months, high-tertile group received higher levodopa-equivalent doses for symptom control than did low-tertile group after controlling for age, gender, and initial motor deficit severity. These results demonstrate that depression in de novo Parkinson’s disease is associated with motor deficit severity at baseline and dose of PD medications during follow-up, suggesting that the presence of depression in de novo Parkinson’s disease represents poor motor compensation.

CONGENITAL MUSCULAR DYSTROPHIES: P.323Review of the natural history of mental development in Fukuyama congenital muscular dystrophy patients, based on a written questionnaire from their families

Fukuyama congenital muscular dystrophy (FCMD) is characterized by brain malformation caused by abnormal neurocyte migration, and presents with eye manifestations. Ninety percent of FCMD patients have the homozygote insertional mutation of the founder haplotype, and show typical progression of motor functional deficits. However, many patients with a heterozygote mutation show more severe motor and mental functional deficits. Although many prior reports on FCMD patients focused on the natural history of motor development, very few have referenced mental development. We surveyed 49 families of FCMD patients, who belonged to a patient's association, using a descriptive questionnaire. We classified our questions into 4 categories: 1) motor development, 2) social skills, 3) living skills and 4)language development. Forty-nine answers were collected, the median patient age was 7 years (range: 1.3 to 36 years). Twenty-eight patients had the homozygote mutation, 11 the heterozygote, and there was no answer for the other. All motor development milestones were delayed in all patients. Even though 80% of patients achieved single word communication, verbal development reflecting when the necessity for verbal communication arose, yielded a low evaluation in the social skill category. All patients achieved the skills needed for meal consumption more easily than other living skills such as changing their clothes. Many patients never obtained independent gait, while upper limb motions varied among patients. Furthermore, these motor function level affected their mental development. Communication with the others was also found to be an important factor for encouraging mental development. This study is a rare study focusing on the details of the mental development of FCMD. This survey is anticipated to help the families of FCMD patients as they strive to stimulate the development of their children.

Current concepts in the neuropathogenesis of mucolipidosis type IV.

Mucolipidosis type IV (MLIV) is an autosomal recessive, lysosomal storage disorder causing progressively severe intellectual disability, motor and speech deficits, retinal degeneration often culminating in blindness, and systemic disease causing a shortened lifespan. MLIV results from mutations in the gene MCOLN1 encoding the transient receptor potential channel mucolipin-1. It is an ultra-rare disease and is currently known to affect just over 100 diagnosed individuals. The last decade has provided a wealth of research focused on understanding the role of the enigmatic mucolipin-1 protein in cell and brain function and how its absence causes disease. This review explores our current understanding of the mucolipin-1 protein in relation to neuropathogenesis in MLIV and describes recent findings implicating mucolipin-1's important role in mechanistic target of rapamycin and TFEB (transcription factor EB) signaling feedback loops as well as in the function of the greater endosomal/lysosomal system. In addition to addressing the vital role of mucolipin-1 in the brain, we also report new data on the question of whether haploinsufficiency as would be anticipated in MCOLN1 heterozygotes is associated with any evidence of neuron dysfunction or disease. Greater insights into the role of mucolipin-1 in the nervous system can be expected to shed light not only on MLIV disease but also on numerous processes governing normal brain function. This article is part of the Special Issue "Lysosomal Storage Disorders".

Human menstrual blood-derived stem cells promote functional recovery in a rat spinal cord hemisection model

Spinal cord injury (SCI) is associated with a dismal prognosis including severe voluntary motor and sensory deficits in the presence of the current therapies, thus new and efficient treatment strategies are desperately required. Along with several advantages, such as easy accessibility, high-yield, potential of enormous proliferation, menstrual blood-derived mesenchymal stem cells (MenSCs) have been proposed as a promising strategy in regeneration medicine. In this study, the MenSCs were transplanted into incomplete thoracic (T10) spinal cord injury (SCI) rats, all rats were sacrificed at 7, 14, and 28 days after surgery. Based on the results, we found that MenSCs transplantation improved the hind limb motor function. Besides, H&E staining showed that MenSCs treatment markedly reduced cavity formation in the lesion site. Furthermore, treatment by MenSCs showed more MAP2-positive mature neurons, as well as axonal regeneration manifested by NF-200 and less expression of chondroitin sulfate proteoglycans (CSPGs) than the non-treatment in the lesion site. Additionally, immunofluorescence, Western blot, and qRT-PCR methods showed that levels of brain-derived neurotrophic factor (BDNF) were significantly higher in the injured spinal cord after implantation of MenSCs. Results of qRT-PCR indicated that inflammatory factors, including TNF-α and IL-1β were inhibited after MenSCs transplantation. The improved motor function of hind limb and the increased cell body area of motor neurons were suppressed by blocking of the BDNF-TrkB signaling. It was eventually revealed that MenSCs implantation had beneficial therapeutic effects on the rehabilitation of the rat spinal cord hemisection model, mainly by enhancing the expression of BDNF. MenSCs transplantation may provide a novel therapeutic strategy for patients with SCI in the future.

Effect of Dextroamphetamine on Poststroke Motor Recovery

Data from animal models show that the administration of dextroamphetamine combined with task-relevant training facilitates recovery after focal brain injury. Results of clinical trials in patients with stroke have been inconsistent. To collect data important for future studies evaluating the effect of dextroamphetamine combined with physiotherapy for improving poststroke motor recovery and to test the efficacy of the approach. This pilot, double-blind, block-randomized clinical trial included patients with cortical or subcortical ischemic stroke and moderate or severe motor deficits from 5 rehabilitation hospitals or units. Participants were screened and enrolled from March 2001 through March 2003. The primary outcome was assessed 3 months after stroke. Study analysis was completed December 31, 2015. A total of 1665 potential participants were screened and 64 were randomized. Participants had to begin treatment 10 to 30 days after ischemic stroke. Data analysis was based on intention to treat. Participants were allocated to a regimen of 10 mg of dextroamphetamine (n = 32) or placebo (n = 32) combined with a 1-hour physical therapy session beginning 1 hour after drug or placebo administration every 4 days for 6 sessions in addition to standard rehabilitation. The primary outcome was the difference between groups in change in Fugl-Meyer motor scores from baseline to 3 months after stroke (intention to treat with dextroamphetamine). Secondary exploratory measures included the National Institutes of Health Stroke Scale, Canadian Neurological Scale, Action Research Arm Test, modified Rankin Scale score, Functional Independence Measure, Ambulation Speed and Distance, Mini-Mental State Examination, Beck Depression Inventory, and Stroke Impact Scale. Among the 64 patients randomized to dextroamphetamine vs placebo (55% men; median age, 66 years; age range, 27-91 years), no overall treatment-associated difference in the mean (SEM) change in Fugl-Meyer motor scores from baseline to 3 months after stroke was noted (-18.65 [2.27] points with dextroamphetamine vs -20.83 [2.94] points with placebo; P = .58). No overall treatment-associated differences in any of the study's secondary measures and no differences in subgroups based on stroke location or baseline severity were found. No adverse events were attributed to study treatments. Treatment with dextroamphetamine combined with physical therapy did not improve recovery of motor function compared with placebo combined with physical therapy as assessed 3 months after hemispheric ischemic stroke. The studied treatment regimen was safe. ClinicalTrials.gov identifier: NCT01905371.