Cocaine-related cervical spinal cord infarction: a case report and review of the literature.

STUDY DESIGN: Case report. OBJECTIVES: To report a clinical case of spinal cord infarction due to cocaine use. SETTING: Spinal Center, IRCCS Fondazione S. Lucia, Rome (Italy). CASE PRESENTATION: Two days after recreational use of cocaine, a 27-year-old Caucasic man was admitted to the emergency department for acute cervical pain, weakness in all four limbs, and urinary retention. A cervical spinal magnetic resonance imaging scan, performed after 2 days, showed a "pencil-like" lesion extending from C4 to T1 metamer, compatible with acute ischemia in the anterior spinal artery territory. Other causes of vascular disorders, as well as inflammatory and infectious disorders were ruled out. At admission in our department, the patient had an incomplete tetraplegia at level C6, an indwelling catheter, and was unable to stand and walk. After 3 months of rehabilitation, he had an AIS score D tetraplegia at level C7, was able to stand and walk using parallel bars, and indwelling catheter was replaced by intermittent catheterization. DISCUSSION AND CONCLUSIONS: The etiology of medullary infarction may remain unexplained in nearly 30-40% of cases. Even if rare, cocaine-induced ischemic myelopathy should be considered and ruled out in the differential diagnosis of any acute nontraumatic myelopathy, especially in young patients.

Flumazenil therapy for a gabapentin-induced coma: a case report.

BACKGROUND: Spasticity and neuropathic pain are common in patients after spinal cord injury and negatively affect patients' quality of life. Gabapentin and baclofen are frequently used to treat these conditions. We present a flumazenil-reversed gabapentin-induced coma case, which, to our knowledge, is the second one described in scientific literature. CASE PRESENTATION: A 70-year-old Caucasian man was admitted to our neurorehabilitation ward following a fall with cervical trauma that resulted in immediate tetraplegia. During his stay, he suffered from lower limb pain, both neuropathic and due to severe spasticity. Gradual baclofen and gabapentin administration was prescribed, with reduction in both pain and spasticity. One morning, the patient was found unresponsive, with a Glasgow Coma Score of 3. Head computerized tomography, electrocardiogram, electroencephalogram, vital signs, blood tests, breathing, and blood oxygenation were normal. Renal and liver failure were ruled out. Intravenous 0.25 mg of flumazenil (Anexate) was administered, resulting in complete neurocognitive recovery with a Glasgow Coma Score of 15. DISCUSSION AND CONCLUSIONS: This case report highlights the importance of the individual response to certain pharmacological agents and suggests that further studies need to be conducted both on flumazenil and gabapentin pharmacodynamics to better understand their molecular-receptor activity, and on possible multiple flumazenil mechanisms of action, beyond its classical strict benzodiazepine antagonist action.

Symbitron Exoskeleton: Design, Control, and Evaluation of a Modular Exoskeleton for Incomplete and Complete Spinal Cord Injured Individuals.

In this paper, we present the design, control, and preliminary evaluation of the Symbitron exoskeleton, a lower limb modular exoskeleton developed for people with a spinal cord injury. The mechanical and electrical configuration and the controller can be personalized to accommodate differences in impairments among individuals with spinal cord injuries (SCI). In hardware, this personalization is accomplished by a modular approach that allows the reconfiguration of a lower-limb exoskeleton with ultimately eight powered series actuated (SEA) joints and high fidelity torque control. For SCI individuals with an incomplete lesion and sufficient hip control, we applied a trajectory-free neuromuscular control (NMC) strategy and used the exoskeleton in the ankle-knee configuration. For complete SCI individuals, we used a combination of a NMC and an impedance based trajectory tracking strategy with the exoskeleton in the ankle-knee-hip configuration. Results of a preliminary evaluation of the developed hardware and software showed that SCI individuals with an incomplete lesion could naturally vary their walking speed and step length and walked faster compared to walking without the device. SCI individuals with a complete lesion, who could not walk without support, were able to walk with the device and with the support of crutches that included a push-button for step initiation Our results demonstrate that an exoskeleton with modular hardware and control allows SCI individuals with limited or no lower limb function to receive tailored support and regain mobility.

Neuromuscular Controller Embedded in a Powered Ankle Exoskeleton: Effects on Gait, Clinical Features and Subjective Perspective of Incomplete Spinal Cord Injured Subjects.

Powered exoskeletons are among the emerging technologies claiming to assist functional ambulation. The potential to adapt robotic assistance based on specific motor abilities of incomplete spinal cord injury (iSCI) subjects, is crucial to optimize Human-Robot Interaction (HRI). Achilles, an autonomous wearable robot able to assist ankle during walking, was developed for iSCI subjects and utilizes a NeuroMuscular Controller (NMC). NMC can be used to adapt robotic assistance based on specific residual functional abilities of subjects. The main aim of this pilot study was to analyze the effects of the NMC-controlled Achilles, used as an assistive device, on chronic iSCI participants' performance, by assessing gait speed during 10-session training of robot-aided walking. Secondary aims were to assess training impact on participants' motion, clinical and functional features and to evaluate subjective perspective in terms of attitude towards technology, workload, usability and satisfaction. Results showed that 5 training sessions were necessary to significantly improve robot-aided gait speed on short paths and consequently to optimize HRI. Moreover, the training allowed participants who initially were not able to walk for 6 minutes, to improve gait endurance during Achilles-aided walking and to reduce perceived fatigue. Improvements were obtained also in gait speed during free walking, thus suggesting a potential rehabilitative impact, even if Achilles-aided walking was not faster than free walking. Participants' subjective evaluations indicated a positive experience.

Functional Changes of Mentalizing Network in SCA2 Patients: Novel Insights into Understanding the Social Cerebellum.

In recent years, increasing evidence of the cerebellar role in social cognition has emerged. The cerebellum has been shown to modulate cortical activity of social brain regions serving as a regulator of function-specific mentalizing and mirroring processes. In particular, a mentalizing area in the posterior cerebellum, specifically Crus II, is preferentially recruited for more complex and abstract forms of social processing, together with mentalizing cerebral areas including the dorsal medial prefrontal cortex (dmPFC), the temporo-parietal junction (TPJ), and the precuneus. In the present study, the network-based statistics approach was used to assess functional connectivity (FC) differences within this mentalizing cerebello-cerebral network associated with a specific cerebellar damage. To this aim, patients affected by spinocerebellar ataxia type 2 (SCA2), a neurodegenerative disease specifically affecting regions of the cerebellar cortex, and age-matched healthy subjects have been enrolled. The dmPFC, left and right TPJ, the precuneus, and the cerebellar Crus II were used as regions of interest to construct the mentalizing network to be analyzed and evaluate pairwise functional relations between them. When compared with controls, SCA2 patients showed altered internodal connectivity between dmPFC, left (L-) and right (R-) TPJ, and right posterior cerebellar Crus II.The present results indicate that FC changes affect a function-specific mentalizing network in patients affected by cerebellar damage. In particular, they allow to better clarify functional alteration mechanisms driven by the cerebellar damage associated with SCA2 suggesting that selective cortico-cerebellar functional disconnections may underlie patients' social impairment in domain-specific complex and abstract forms of social functioning.

Gait training with Achilles ankle exoskeleton in chronic incomplete spinal cord injury subjects.

Powered exoskeletons (EXOs) have emerged as potential devices for Spinal Cord Injury (SCI) to support the intervention of physical therapists during therapy (rehabilitation EXOs) as well as to assist lower limb motion during the daily life (assistive EXOs). Although the ankle is considered a key joint for gait restoration after SCI, very few ankle exoskeletons were developed and tested in incomplete SCI (iSCI) population. Among those, the Achilles ankle exoskeleton is the only one embedding a Controller inspired by the neuromuscular system (NeuroMuscular Controller, NMC). In a previous study we demonstrated that a period dedicated to train iSCI subjects in using the Achilles EXO as an assistive aid, improved robot-aided walking speed and surprisingly also generated a positive trend in free walking speed on long and short distances thus suggesting a possible unexpected rehabilitation effect. To further investigate this result, a case-control longitudinal study was conducted in the present work. The aim of this study was to test the hypothesis that Achilles-aided training could improve performance of free walking of chronic iSCI people more than conventional intensity-matched gait rehabilitation. Before and after conventional and robot-aided rehabilitation a number of variables were analyzed, including spatiotemporal parameters, joint kinematics, ground reaction forces, muscle force, spasticity and its related symptoms, balance and personal experience about the training. Results showed that only the NMC-controlled Achilles training allowed participants to significantly walk faster, with a longer step length and a reduced gait cycle time. A slight force and spasticity improvements were also experienced. In terms of subjects' personal experience, Achilles training was perceived more interesting and less physically demanding than conventional rehabilitation.

The Implementation of Predictions During Sequencing.

Optimal control mechanisms require prediction capabilities. If one cannot predict the consequences of a motor act or behavior, one will continually collide with walls or become a social pariah. "Looking into the future" is thus one of the most important prerequisites for smooth movements and social interactions. To achieve this goal, the brain must constantly predict future events. This principle applies to all domains of information processing, including motor and cognitive control, as well as the development of decision-making skills, theory of mind, and virtually all cognitive processes. Sequencing is suggested to support the predictive capacity of the brain. To recognize that events are related, the brain must discover links among them in the spatiotemporal domain. To achieve this, the brain must often hold one event in working memory and compare it to a second one, and the characteristics of the two must be compared and correctly placed in space and time. Among the different brain structures involved in sequencing, the cerebellum has been proposed to have a central function. We have suggested that the operational mode of the cerebellum is based on "sequence detection" and that this process is crucial for prediction. Patterns of temporally or spatially structured events are conveyed to the cerebellum via the pontine nuclei and compared with actual ones conveyed through the climbing fibers olivary inputs. Through this interaction, data on previously encountered sequences can be obtained and used to generate internal models from which predictions can be made. This mechanism would allow the cerebellum not only to recognize sequences but also to detect sequence violations. Cerebellar pattern detection and prediction would thus be a means to allow feedforward control based on anticipation. We will argue that cerebellar sequencing allows implementation of prediction by setting the correct excitatory levels in defined brain areas to implement the adaptive response for a given pattern of stimuli that embeds sufficient information to be recognized as a previously encountered template. Here, we will discuss results from human and animal studies and correlate them with the present understanding of cerebellar function in cognition and behavior.

Structural cerebellar correlates of cognitive functions in spinocerebellar ataxia type 2.

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disease involving the cerebellum and characterized by a typical motor syndrome. In addition, the presence of cognitive impairment is now widely acknowledged as a feature of SCA2. Given the extensive connections between the cerebellum and associative cerebral areas, it is reasonable to hypothesize that cerebellar neurodegeneration associated with SCA2 may impact on the cerebellar modulation of the cerebral cortex, thus resulting in functional impairment. The aim of the present study was to investigate and quantitatively map the pattern of cerebellar gray matter (GM) atrophy due to SCA2 neurodegeneration and to correlate that with patients' cognitive performances. Cerebellar GM maps were extracted and compared between SCA2 patients (n = 9) and controls (n = 33) by using voxel-based morphometry. Furthermore, the relationship between cerebellar GM atrophy and neuropsychological scores of the patients was assessed. Specific cerebellar GM regions were found to be affected in patients. Additionally, GM loss in cognitive posterior lobules (VI, Crus I, Crus II, VIIB, IX) correlated with visuospatial, verbal memory and executive tasks, while additional correlations with motor anterior (V) and posterior (VIIIA, VIIIB) lobules were found for the tasks engaging motor and planning components. Our results provide evidence that the SCA2 neurodegenerative process affects the cerebellar cortex and that MRI indices of atrophy in different cerebellar subregions may account for the specificity of cognitive symptomatology observed in patients, as result of a cerebello-cerebral dysregulation.

Severe 5,10-methylenetetrahydrofolate reductase deficiency: a rare, treatable cause of complicated hereditary spastic paraplegia.

BACKGROUND AND PURPOSE: Juvenile- or adult-onset forms of severe 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency manifesting as complicated hereditary spastic paraplegia have rarely been described. METHODS: Two siblings with mental retardation developed a progressive spastic paraparesis in their late teens. Their diagnostic assessment included extensive neurophysiologic, neuroimaging and metabolic studies. RESULTS: Brain magnetic resonance imaging showed occipital white matter alterations, and electromyography documented a mixed polyneuropathy. Severe hyperhomocisteinemia (>150 µmol/L) associated with the characteristic amino acid profile suggested a diagnosis of severe MTHFR deficiency, confirmed by MTHFR direct sequencing. Treatment with betaine and vitamins benefitted patients' symptoms and diagnostic features. CONCLUSIONS: Severe MTHFR deficiency can be a rare, treatable cause of autosomal recessive complicated hereditary spastic paraplegia. Its screening should be part of the diagnostic flowchart for these disorders.

Transcranial cerebellar direct current stimulation: Effects on brain resting state oscillatory and network activity.

Transcranial cerebellar direct current stimulation (tcDCS) can offer new insights into the cerebellar function and disorders, by modulating noninvasively the activity of cerebellar networks. Taking into account the functional interplay between the cerebellum and the cerebral cortex, we addressed the effects of unilateral tcDCS (active electrode positioned over the right cerebellar hemisphere) on the electroencephalographic (EEG) oscillatory activity and on the cortical network organization at resting state. Effects on spectral (de)synchronizations and functional connectivity after anodal and cathodal stimulation were assessed with respect to a sham condition. A lateralized synchronization over the sensorimotor area in gamma band, as well as an increase of the network segregation in sensory-motor rhythms and a higher communication between hemispheres in gamma band, were detected after anodal stimulation. The same measures after cathodal tcDCS returned responses similar to the sham condition.

Microstructural MRI Basis of the Cognitive Functions in Patients with Spinocerebellar Ataxia Type 2.

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disease involving the cerebellum. The particular atrophy pattern results in some typical clinical features mainly including motor deficits. In addition, the presence of cognitive impairments, involving language, visuospatial and executive functions, has been also shown in SCA2 patients and it is now widely accepted as a feature of the disease. The aim of the study is to investigate the microstructural patterns and the anatomo-functional substrate that could account for the cognitive symptomatology observed in SCA2 patients. In the present study, diffusion tensor imaging (DTI) based-tractography was performed to map the main cerebellar white matter (WM) bundles, such as Middle and Superior Cerebellar Peduncles, connecting cerebellum with higher order cerebral regions. Damage-related diffusivity measures were used to determine the pattern of pathological changes of cerebellar WM microstructure in patients affected by SCA2 and correlated with the patients' cognitive scores. Our results provide the first evidence that WM diffusivity is altered in the presence of the cerebellar cortical degeneration associated with SCA2 thus resulting in a cerebello-cerebral dysregulation that may account for the specificity of cognitive symptomatology observed in patients.

Neural substrates of motor and cognitive dysfunctions in SCA2 patients: A network based statistics analysis.

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disease characterized by a progressive cerebellar syndrome, which can be isolated or associated with extracerebellar signs. It has been shown that patients affected by SCA2 present also cognitive impairments and psychiatric symptoms. The cerebellum is known to modulate cortical activity and to contribute to distinct functional networks related to higher-level functions beyond motor control. It is therefore conceivable that one or more networks, rather than isolated regions, may be dysfunctional in cerebellar degenerative diseases and that an abnormal connectivity within specific cerebello-cortical regions might explain the widespread deficits typically observed in patients. In the present study, the network-based statistics (NBS) approach was used to assess differences in functional connectivity between specific cerebellar and cerebral "nodes" in SCA2 patients. Altered inter-nodal connectivity was found between more posterior regions in the cerebellum and regions in the cerebral cortex clearly related to cognition and emotion. Furthermore, more anterior cerebellar lobules showed altered inter-nodal connectivity with motor and somatosensory cerebral regions. The present data suggest that in SCA2 a cerebellar dysfunction affects long-distance cerebral regions and that the clinical symptoms may be specifically related with connectivity changes between motor and non-motor cerebello-cortical nodes.

DJ-1 modulates mitochondrial response to oxidative stress: clues from a novel diagnosis of PARK7.

DJ-1 mutations are associated to early-onset Parkinson's disease and accounts for about 1-2% of the genetic forms. The protein is involved in many biological processes and its role in mitochondrial regulation is gaining great interest, even if its function in mitochondria is still unclear. We describe a 47-year-old woman affected by a multisystem disorder characterized by progressive, early-onset parkinsonism plus distal spinal amyotrophy, cataracts and sensory-neural deafness associated with a novel homozygous c.461C>A [p.T154K] mutation in DJ-1. Patient's cultured fibroblasts showed low ATP synthesis, high ROS levels and reduced amount of some subunits of mitochondrial complex I; biomarkers of oxidative stress also resulted abnormal in patient's blood. The clinical pattern of multisystem involvement and the biochemical findings in our patient highlight the role for DJ-1 in modulating mitochondrial response against oxidative stress.

Myotonic dystrophy type 1: role of CCG, CTC and CGG interruptions within DMPK alleles in the pathogenesis and molecular diagnosis.

Myotonic dystrophy type 1 (DM1) is a multisystem neuromuscular disease caused by a CTG triplet expansion in the 3'-untranslated region (3'-UTR) of DMPK gene. This CTG array is usually uninterrupted in both healthy and DM1 patients, but recent studies identified pathological variant expansions containing unstable CCG, CTC and CGG interruptions with a prevalence of 3-5% of cases. In this review, we will describe the clinical, molecular and genetic issues related to the occurrence of variant expansions associated with DM1. Indeed, the identification of these complex DMPK alleles leads to practical consequences in DM1 genetic counseling and testing, because these exams can give false negative results. Moreover, DM1 patients carrying interrupted alleles can manifest either additional atypical neurological symptoms or, conversely, mild, late-onset forms. Therefore, the prognosis of the disease in these patients is difficult to determine because of the great uncertainty about the genotype-phenotype correlations. We will discuss the putative effects of the variant DM1 alleles on the pathogenic disease mechanisms, including mitotic and meiotic repeats instability and splicing alteration typical of DM1 tissues. Interruptions within the DMPK expanded alleles could also interfere with the chromatin structure, the transcriptional activity of the DM1 locus and the interaction with RNA CUG-binding proteins.

Hereditary spastic paraplegia: Novel mutations and expansion of the phenotype variability in SPG56.

We describe a novel sporadic case of SPG56, a rare complicated form of HSP, that expands the clinical and molecular spectrum of the disease, being associated to novel mutations in CYP2U1 and showing as novel feature dorsal hydromyelia at spinal cord MRI. The patient presented an early-onset, slowly progressive paraparesis associated with mild mental retardation. Neurological assessments included the Spastic Paraplegia Rating Scale (SPRS), Mental Deterioration Battery (MDB), and Wechsler Adult Intelligence Scale (WAIS), neurophysiological and neuroimaging studies. Targeted next-generation sequencing panels for the whole set of genes associated with HSP were performed in the probands and her relatives. Neuroimaging studies showed dorsal hydromyelia but no brain MRI abnormalities. Targeted next-generation identified two novel mutations: the c.5C > A/p.S2* on the maternal allele in compound heterozygosity with the paternally-inherited c.1288+5G > C in CYP2U1. Both mutations predict early protein truncation and a loss of function. So far, only few SPG56 cases have been reported. This case, expands and further characterize the clinical and molecular spectrum of SPG56. In this regard, in consideration of the putative gene function in neurodevelopment, we suggest a causal association between CYP2U1 mutations and hydromyelia in our patient.

Myotonic dystrophy type 1 and de novo FSHD mutation double trouble: a clinical and muscle MRI study.

Here we describe the first case of myotonic dystrophy type 1 (DM1) associated with facio-scapulo-humeral dystrophy (FSHD). From a clinical point of view, the patient displayed a pattern of muscle involvement reminiscent of both disorders, including hand-grip myotonia, facial, axial and distal limbs muscle weakness as well as a bilateral winged scapula associated with atrophy of the pectoralis major muscle and lumbar lordosis; pelvic muscles were mostly spared. An extensive muscle MRI assessment including neck, shoulder, abdominal, pelvic and lower limb muscles documented radiological features typical of DM1 and FSDH. Molecular genetic studies confirmed that the proband carried both a pathologically expanded DMPK allele, inherited from his father, and a de novo shortened D4Z4 repeat fragment at 4q35 locus.

Muscle MRI in female carriers of dystrophinopathy.

BACKGROUND AND PURPOSE: Duchenne muscular dystrophy carriers represent a rare condition that needs to be recognized because of the possible implications for prenatal diagnosis. Muscle biopsy is currently the diagnostic instrument of choice in sporadic patients. We wanted to verify whether muscle magnetic resonance imaging (MRI) could identify a pattern of involvement suggestive of this condition and whether it was similar to that reported in Duchenne and Becker muscular dystrophy. METHODS: Evaluation of pelvic and lower limb MRI scans of 12 dystrophinopathy carriers was performed. RESULTS: We found a frequent involvement of the quadratus femoris, gluteus maximus and medius, biceps femoris long head, adductor magnus, vasti and paraspinal muscles, whilst the popliteus, iliopsoas, recti abdominis, sartorius, and gracilis were relatively spared. Asymmetry was a major feature on MRI; it could be detected significantly more often than with sole clinical examination and even in patients without weakness. CONCLUSIONS: The pattern we describe here is similar to that reported in Duchenne and Becker muscular dystrophy, although asymmetry represents a major distinctive feature. Muscle MRI was more sensitive than clinical examination for detecting single muscle involvement and asymmetry. Further studies are needed to verify the consistency of this pattern in larger cohorts and to assess whether muscle MRI can improve diagnostic accuracy in carriers with normal dystrophin staining on muscle biopsy.