Development of an oral treatment that rescues gait ataxia and retinal degeneration in a phenotypic mouse model of familial dysautonomia.

Familial dysautonomia (FD) is a rare neurodegenerative disease caused by a splicing mutation in elongator acetyltransferase complex subunit 1 (ELP1). This mutation leads to the skipping of exon 20 and a tissue-specific reduction of ELP1, mainly in the central and peripheral nervous systems. FD is a complex neurological disorder accompanied by severe gait ataxia and retinal degeneration. There is currently no effective treatment to restore ELP1 production in individuals with FD, and the disease is ultimately fatal. After identifying kinetin as a small molecule able to correct the ELP1 splicing defect, we worked on its optimization to generate novel splicing modulator compounds (SMCs) that can be used in individuals with FD. Here, we optimize the potency, efficacy, and bio-distribution of second-generation kinetin derivatives to develop an oral treatment for FD that can efficiently pass the blood-brain barrier and correct the ELP1 splicing defect in the nervous system. We demonstrate that the novel compound PTC258 efficiently restores correct ELP1 splicing in mouse tissues, including brain, and most importantly, prevents the progressive neuronal degeneration that is characteristic of FD. Postnatal oral administration of PTC258 to the phenotypic mouse model TgFD9;Elp1Δ20/flox increases full-length ELP1 transcript in a dose-dependent manner and leads to a 2-fold increase in functional ELP1 in the brain. Remarkably, PTC258 treatment improves survival, gait ataxia, and retinal degeneration in the phenotypic FD mice. Our findings highlight the great therapeutic potential of this novel class of small molecules as an oral treatment for FD.

Different Purkinje cell pathologies cause specific patterns of progressive gait ataxia in mice.

Gait ataxia is one of the most common and impactful consequences of cerebellar dysfunction. Purkinje cells, the sole output neurons of the cerebellar cortex, are often involved in the underlying pathology, but their specific functions during locomotor control in health and disease remain obfuscated. We aimed to describe the effect of gradual adult-onset Purkinje cell degeneration on gaiting patterns in mice, and to determine whether two different mechanisms that both lead to Purkinje cell degeneration cause different patterns in the development of gait ataxia. Using the ErasmusLadder together with a newly developed limb detection algorithm and machine learning-based classification, we subjected mice to a challenging locomotor task with detailed analysis of single limb parameters, intralimb coordination and whole-body movement. We tested two Purkinje cell-specific mouse models, one involving stochastic cell death due to impaired DNA repair mechanisms (Pcp2-Ercc1-/-), the other carrying the mutation that causes spinocerebellar ataxia type 1 (Pcp2-ATXN1[82Q]). Both mouse models showed progressive gaiting deficits, but the sequence with which gaiting parameters deteriorated was different between mouse lines. Our longitudinal approach revealed that gradual loss of Purkinje cell function can lead to a complex pattern of loss of function over time, and that this pattern depends on the specifics of the pathological mechanisms involved. We hypothesize that this variability will also be present in disease progression in patients, and that our findings will facilitate the study of therapeutic interventions in mice, as subtle changes in locomotor abilities can be quantified by our methods.

Nitrous Oxide-induced Myeloneuropathy Due to Recreational Abuse.

BACKGROUND: The recreational use of nitrous oxide (N2O) has increased in recent years with a noticeable surge in the incidence of nitrous oxide-related myeloneuropathy. OBJECTIVES: To raise awareness of increasing myeloneuropathy due to recreational nitrous oxide misuse in Israel. METHODS: We conducted a case series documenting the clinical and investigative features of eight patients presenting with nitrous oxide-induced myeloneuropathy who were admitted to our departments. RESULTS: Paresthesia was the chief complaint in all patients, with sensory gait ataxia being a common feature, which was often accompanied by Romberg's sign and mild lower limb weakness. Vitamin B12 levels were below the normal range in seven patients, accompanied by elevated homocysteine and methylmalonic acid levels. Magnetic resonance imaging scans revealed hyperintense signals in the dorsal columns of the cervical spine. All patients improved following vitamin B12 injections. CONCLUSIONS: Enhancing awareness, prompting the use of appropriate investigations, and advocating for timely treatment are needed to overcome the risks associated with nitrous oxide misuse.

Consensus Paper: Ataxic Gait.

The aim of this consensus paper is to discuss the roles of the cerebellum in human gait, as well as its assessment and therapy. Cerebellar vermis is critical for postural control. The cerebellum ensures the mapping of sensory information into temporally relevant motor commands. Mental imagery of gait involves intrinsically connected fronto-parietal networks comprising the cerebellum. Muscular activities in cerebellar patients show impaired timing of discharges, affecting the patterning of the synergies subserving locomotion. Ataxia of stance/gait is amongst the first cerebellar deficits in cerebellar disorders such as degenerative ataxias and is a disabling symptom with a high risk of falls. Prolonged discharges and increased muscle coactivation may be related to compensatory mechanisms and enhanced body sway, respectively. Essential tremor is frequently associated with mild gait ataxia. There is growing evidence for an important role of the cerebellar cortex in the pathogenesis of essential tremor. In multiple sclerosis, balance and gait are affected due to cerebellar and spinal cord involvement, as a result of disseminated demyelination and neurodegeneration impairing proprioception. In orthostatic tremor, patients often show mild-to-moderate limb and gait ataxia. The tremor generator is likely located in the posterior fossa. Tandem gait is impaired in the early stages of cerebellar disorders and may be particularly useful in the evaluation of pre-ataxic stages of progressive ataxias. Impaired inter-joint coordination and enhanced variability of gait temporal and kinetic parameters can be grasped by wearable devices such as accelerometers. Kinect is a promising low cost technology to obtain reliable measurements and remote assessments of gait. Deep learning methods are being developed in order to help clinicians in the diagnosis and decision-making process. Locomotor adaptation is impaired in cerebellar patients. Coordinative training aims to improve the coordinative strategy and foot placements across strides, cerebellar patients benefiting from intense rehabilitation therapies. Robotic training is a promising approach to complement conventional rehabilitation and neuromodulation of the cerebellum. Wearable dynamic orthoses represent a potential aid to assist gait. The panel of experts agree that the understanding of the cerebellar contribution to gait control will lead to a better management of cerebellar ataxias in general and will likely contribute to use gait parameters as robust biomarkers of future clinical trials.

Longitudinally extensive dorsal column spinal cord lesion with sensory ganglionopathy.

We present a case of a 23-year-old woman with a history of celiac disease who presented with a 2-month history of progressive gait unsteadiness and falls. Neurologic examination exhibited preserved motor strength, diffuse areflexia, and ataxic gait. Autoimmune and infectious workups were unremarkable, including vitamin B12. Electrodiagnostic testing showed absent diffuse sensory responses, consistent with sensory ganglionopathy. Total spine magnetic resonance imaging (MRI) revealed a non-enhancing, posterior cord, hyperintense signal from C1-T11. Partial improvement in her sensory ataxia was noted after 6 months of high-dose steroids without dorsal cord signals change on repeat MRI that suggests Wallerian degeneration of sensory axons.

Postoperative Acute-Phase Gait Training Using Hybrid Assistive Limb Improves Gait Ataxia in a Patient with Intradural Spinal Cord Compression Due to Spinal Tumors.

Sensory ataxia due to posterior cord syndrome is a relevant, disabling condition in nontraumatic spinal cord dysfunction. Ataxic gait is a common symptom of sensory ataxia that restricts activities of daily living. A 70-year-old woman with severe sensory disturbance was diagnosed with intradural extramedullary spinal cord tumors found in the thoracic spine region (T8). Surgical management of the tumors was performed. The patient received gait training 20 days after surgery (postoperative acute phase) using a hybrid assistive limb (HAL). HAL is a wearable exoskeleton cyborg that provides real-time assistance to an individual for walking and limb movements through actuators mounted on the bilateral hip and knee joints. Walking ability was assessed using the 10 m walking test, which included evaluating walking speed, step length, and cadence in every session. To evaluate the immediate effects of HAL training, walking speed and step length were measured before and after the training in each session. During the 10 m walking test, gait kinematics and lower muscle activity were recorded using a motion capture system and wireless surface electromyography before the first session and after completion of all HAL sessions. After the HAL training sessions, improvement in the patient's gait performance was observed in the gait joint angles and muscle activity of the lower limb. After 10 training sessions, we observed the following changes from baseline: walking speed (from 0.16 m/s to 0.3 m/s), step length (from 0.19 m to 0.37 m), and cadence (from 50.9 steps/min to 49.1 steps/min). The average standard deviations of the knee (from right, 7.31; left, 6.75; to right, 2.93; p < 0.01, left, 2.63; p < 0.01) and ankle joints (from right, 6.98; left, 5.40; to right, 2.39; p < 0.01, left, 2.18; p < 0.01) were significantly decreased. Additionally, walking speed and step length improved immediately after completing all the HAL training sessions. This suggests that HAL gait training might be a suitable physical rehabilitation program for patients with sensory ataxia causing dysfunctional movement of the lower limb.

Natural History of Adult Patients with GM2 Gangliosidosis.

OBJECTIVE: GM2 gangliosidoses are lysosomal diseases due to biallelic mutations in the HEXA (Tay-Sachs disease [TS]) or HEXB (Sandhoff disease [SD]) genes, with subsequent low hexosaminidase(s) activity. Most patients have childhood onset, but some experience the first symptoms during adolescence/adulthood. This study aims to clarify the natural history of adult patients with GM2 gangliosidosis. METHODS: We retrospectively described 12 patients from a French cohort and 45 patients from the literature. RESULTS: We observed 4 typical presentations: (1) lower motoneuron disorder responsible for proximal lower limb weakness that subsequently expanded to the upper limbs, (2) cerebellar ataxia, (3) psychosis and/or severe mood disorder (only in the TS patients), and (4) a complex phenotype mixing the above 3 manifestations. The psoas was the first and most affected muscle in the lower limbs, whereas the triceps and interosseous were predominantly involved in the upper limbs. A longitudinal study of compound motor action potentials showed a progressive decrease in all nerves, with different kinetics. Sensory potentials were sometimes abnormally low, mainly in the SD patients. The main brain magnetic resonance imaging feature was cerebellar atrophy, even in patients without cerebellar symptoms. The prognosis was mainly related to gait disorder, as we showed that beyond 20 years of disease evolution, half of the patients were wheelchair users. INTERPRETATION: Improved knowledge of GM2 gangliosidosis in adults will help clinicians achieve correct diagnoses and better inform patients on the evolution and prognosis. It may also contribute to defining proper outcome measures when testing emerging therapies. ANN NEUROL 2020;87:609-617.

The Efficacy and Safety of Transcranial Direct Current Stimulation for Cerebellar Ataxia: a Systematic Review and Meta-Analysis.

A promising new approach, transcranial direct current stimulation (tDCS) has recently been used as a therapeutic modality for cerebellar ataxia. However, the strength of the conclusions drawn from individual studies in the current literature may be constrained by the small sample size of each trial. Following a systematic literature retrieval of studies, meta-analyses were conducted by pooling the standardized mean differences (SMDs) using random-effects models to assess the efficacy of tDCS on cerebellar ataxia, measured by standard clinical rating scales. Domain-specific effects of tDCS on gait and hand function were further evaluated based on 8-m walk and 9-hole peg test performance times, respectively. To determine the safety of tDCS, the incidences of adverse effects were analyzed using risk differences. Out of 293 citations, 5 randomized controlled trials involving a total of 72 participants with cerebellar ataxia were included. Meta-analysis indicated a 26.1% (p = 0.003) improvement in ataxia immediately after tDCS with sustained efficacy over months (28.2% improvement after 3 months, p = 0.04) when compared with sham stimulation. tDCS seems to be domain-specific as the current analysis suggested a positive effect on gait (16.3% improvement, p = 0.04) and failed to reveal differences for hand function (p = 0.10) with respect to sham. The incidence of adverse events in tDCS and sham groups was similar. tDCS is an effective intervention for mitigating ataxia symptoms with lasting results that can be sustained for months. This treatment shows preferential effects on gait ataxia and is relatively safe.

Double Vision and Gait Ataxia in an Immunocompetent 9-Year-Old Girl With Intracranial Phaeohyphomycosis.

ABSTRACT: A 9-year-old girl presented with morning headaches associated with vomiting, gait ataxia, and facial and ocular motor nerve palsies. Her initial imaging was concerning for demyelinating disease. After extensive infectious and rheumatologic workup returned negative, she was treated twice with intravenous immunoglobulin and intravenous steroids with near-complete resolution each time. She returned, however, with worsening neurologic deficits and imaging revealing focal ischemic infarction in the brainstem as well as new-onset hydrocephalus. A multispecialty workup was initiated without conclusive diagnosis. A novel, noninvasive test for plasma cell-free DNA established a diagnosis of Cladophialophora bantiana that was confirmed and validated by a brain biopsy taken during a clinical decompensation. Treatment was initiated with systemic voriconazole and intraventricular amphotericin B.

A recurrent de novo missense mutation in UBTF causes developmental neuroregression.

UBTF (upstream binding transcription factor) exists as two isoforms; UBTF1 regulates rRNA transcription by RNA polymerase 1, whereas UBTF2 regulates mRNA transcription by RNA polymerase 2. Herein, we describe 4 patients with very similar patterns of neuroregression due to recurrent de novo mutations in UBTF (GRCh37/hg19, NC_000017.10: g.42290219C > T, NM_014233.3: c.628G > A) resulting in the same amino acid change in both UBTF1 and UBTF2 (p.Glu210Lys [p.E210K]). Disease onset in our cohort was at 2.5 to 3 years and characterized by slow progression of global motor, cognitive and behavioral dysfunction. Notable early features included hypotonia with a floppy gait, high-pitched dysarthria and hyperactivity. Later features included aphasia, dystonia, and spasticity. Speech and ambulatory ability were lost by the early teens. Magnetic resonance imaging showed progressive generalized cerebral atrophy (supratentorial > infratentorial) with involvement of both gray and white matter. Patient fibroblasts showed normal levels of UBTF transcripts, increased expression of pre-rRNA and 18S rRNA, nucleolar abnormalities, markedly increased numbers of DNA breaks, defective cell-cycle progression, and apoptosis. Expression of mutant human UBTF1 in Drosophila neurons was lethal. Although no loss-of-function variants are reported in the Exome Aggregation Consortium (ExAC) database and Ubtf-/- is early embryonic lethal in mice, Ubtf+/- mice displayed only mild motor and behavioral dysfunction in adulthood. Our data underscore the importance of including UBTF E210K in the differential diagnosis of neuroregression and suggest that mainly gain-of-function mechanisms contribute to the pathogenesis of the UBTF E210K neuroregression syndrome.

Middle-age-onset cerebellar ataxia caused by a homozygous TWNK variant: a case report.

BACKGROUND: The TWNK gene encodes the twinkle protein, which is a mitochondrial helicase for DNA replication. The dominant TWNK variants cause progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3, while the recessive variants cause mitochondrial DNA depletion syndrome 7 and Perrault syndrome 5. Perrault syndrome is characterized by sensorineural hearing loss in both males and females and gonadal dysfunction in females. Patients with Perrault syndrome may present early-onset cerebellar ataxia, whereas middle-age-onset cerebellar ataxia caused by TWNK variants is rare. CASE PRESENTATION: A Japanese female born to consanguineous parents presented hearing loss at age 48, a staggering gait at age 53, and numbness in her distal extremities at age 57. Neurological examination revealed sensorineural hearing loss, cerebellar ataxia, decreased deep tendon reflexes, and sensory disturbance in the distal extremities. Laboratory tests showed no abnormal findings other than a moderate elevation of pyruvate concentration levels. Brain magnetic resonance imaging revealed mild cerebellar atrophy. Using exome sequencing, we identified a homozygous TWNK variant (NM_021830: c.1358G>A, p.R453Q). CONCLUSIONS: TWNK variants could cause middle-age-onset cerebellar ataxia. Screening for TWNK variants should be considered in cases of cerebellar ataxia associated with deafness and/or peripheral neuropathy, even if the onset is not early.

Transient Neurological Symptoms Preceding Cerebellar Ataxia with Glutamic Acid Decarboxylase Antibodies.

A prompt diagnosis and treatment of patients with autoimmune cerebellar ataxia (CA) with antibodies against glutamic acid decarboxylase (GAD-Abs) may lead to a better prognosis. Herein, we report prodromal transient neurological symptoms that should raise clinical suspicion of CA with GAD-Abs. We initially identified a 70-year-old man who presented a first acute episode of vertigo, diplopia, and ataxia lasting 2 weeks. Two months later, he experienced a similar episode along with new-onset gaze-evoked nystagmus. After 4 months, downbeat nystagmus, left limb dysmetria, and gait ataxia progressively appeared, and an autoimmune CA was diagnosed based on the positivity of GAD-Abs in serum and cerebrospinal fluid (CSF). We searched retrospectively for similar presentations in a cohort of 31 patients diagnosed with CA and GAD-Abs. We found 11 (35.4%) patients (all women, median age 62 years; 8/11 [72.7%] with autoimmune comorbidities) with transient neurological symptoms antedating CA onset by a median of 3 months, including vertigo in 9 (81.8%; described as paroxysmal in 8) and fluctuating diplopia in 3 (27.3%) patients. The identification of transient neurological symptoms of unknown etiology, such as paroxysmal vertigo and fluctuating diplopia, should lead to GAD-Abs testing in serum and CSF, especially in patients with autoimmune comorbidities.

Ancient founder mutation in RUBCN: a second unrelated family confirms Salih ataxia (SCAR15).

BACKGROUND: Homozygous frameshift mutation in RUBCN (KIAA0226), known to result in endolysosomal machinery defects, has previously been reported in a single Saudi family with autosomal recessive spinocerebellar ataxia (Salih ataxia, SCAR15, OMIM # 615705). The present report describes the clinical, neurophysiologic, neuroimaging, and genetic findings in a second unrelated Saudi family with two affected children harboring identical homozygous frameshift mutation in the gene. It also explores and documents an ancient founder cerebellar ataxia mutation in the Arabian Peninsula. CASE PRESENTATION: The present family has two affected males (aged 6.5 and 17 years) with unsteady gait apparent since learning to walk at 2.5 and 3 years, respectively. The younger patient showed gait ataxia and normal reflexes. The older patient had saccadic eye movement, dysarthria, mild upper and lower limb and gait ataxia (on tandem walking), and enhanced reflexes in the lower limbs. Cognitive abilities were mildly impaired in the younger sibling (IQ 67) and borderline in the older patient (IQ 72). Nerve conduction studies were normal in both patients. MRI was normal at 2.5 years in the younger sibling. Brain MRI showed normal cerebellar volume and folia in the older sibling at the age of 6 years, and revealed minimal superior vermian atrophy at the age of 16 years. Autozygome and exome analysis showed both affected have previously reported homoallelic mutation in RUBCN (NM_014687:exon18:c.2624delC:p.A875fs), whereas the parents are carriers. Autozygosity mapping focused on smallest haplotype on chromosome 3 and mutation age analysis revealed the mutation occurred approximately 1550 years ago spanning about 62 generations. CONCLUSIONS: Our findings validate the slowly progressive phenotype of Salih ataxia (SCAR15, OMIM # 615705) by an additional family. Haplotype sharing attests to a common founder, an ancient RUBCN mutation in the Arab population.

Movement disorder in a patient with Human Immunodeficiency Virus on an anti-retroviral therapy: A Case Report.

Human Immunodeficiency Virus associated neurocognitive dysfunction can present as a case of movement disorder in a patient with prolonged antiretroviral therapy. Diagnosis was made after ruling out space occupying lesions, nutritional deficiencies and infectious causes through brain imaging and cerebrospinal fluid analysis. With multidisciplinary care and change of antiretroviral therapy to drugs with higher cerebrospinal fluid penetration, symptoms of the patient improved over a span of six months. Delayed neurological damage due to Human Immunodeficiency Virus can present with isolated cerebellar symptoms.

A man in his sixties with gait ataxia, dysarthria and mild cognitive impairment. / En mann i 60-årene med gangvansker, dysartri og lett kognitiv svikt.

BACKGROUND: Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) syndrome is an immune-mediated, treatable and inflammatory CNS disease first reported by Pittock et al. (2010). CASE PRESENTATION: We describe a 66-year-old man with previous history of diabetes, atrial fibrillation and hypertension, who was admitted to hospital with reduced general condition. He had experienced dizziness and unstable gait for a year, and had been periodically confused, especially in the previous month. MR imaging showed characteristic punctuate and curvilinear gadolinium enhancements in the pons. Our patient was diagnosed with CLIPPERS and was given corticosteroid treatment, initially methylprednisolone intravenously and then prednisone orally. Other differential diagnoses, such as CNS lymphoma, high-grade glioma, CNS vasculitis, neurosarcoidosis, demyelinating disease, Bickerstaff brainstem encephalitis, and acute disseminated encephalomyelitis were ruled out. The patient's condition improved dramatically after corticosteroid treatment. INTERPRETATION: In 2017, the diagnostic criteria for CLIPPERS were published. Based on these criteria we were able to diagnose this patient with possible CLIPPERS, consistent with clinical symptoms, MRI findings, absence of better explanations for the condition, and clinical and radiological improvement after treatment with corticosteroids. An unequivocal diagnosis of CLIPPERS can only be established by characteristic pathological findings.

Selective rescue of heightened anxiety but not gait ataxia in a premutation 90CGG mouse model of Fragile X-associated tremor/ataxia syndrome.

A CGG-repeat expansion in the premutation range in the Fragile X mental retardation 1 gene (FMR1) has been identified as the genetic cause of Fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset neurodegenerative disorder that manifests with action tremor, gait ataxia and cognitive impairments. In this study, we used a bigenic mouse model, in which expression of a 90CGG premutation tract is activated in neural cells upon doxycycline administration-P90CGG mouse model. We, here, demonstrate the behavioural manifestation of clinically relevant features of FXTAS patients and premutation carrier individuals in this inducible mouse model. P90CGG mice display heightened anxiety, deficits in motor coordination and impaired gait and represent the first FXTAS model that exhibits an ataxia phenotype as observed in patients. The behavioural phenotype is accompanied by the formation of ubiquitin/FMRpolyglycine-positive intranuclear inclusions, as another hallmark of FXTAS, in the cerebellum, hippocampus and amygdala. Strikingly, upon cessation of transgene induction the anxiety phenotype of mice recovers along with a reduction of intranuclear inclusions in dentate gyrus and amygdala. In contrast, motor function deteriorates further and no reduction in intranuclear inclusions can be observed in the cerebellum. Our data thus demonstrate that expression of a 90CGG premutation expansion outside of the FMR1 context is sufficient to evoke an FXTAS-like behavioural phenotype. Brain region-specific neuropathology and (partial) behavioural reversibility make the inducible P90CGG a valuable mouse model for testing pathogenic mechanisms and therapeutic intervention methods.

Acute Neurologic Disorder from an Inhibitor of Fatty Acid Amide Hydrolase.

BACKGROUND: A decrease in fatty acid amide hydrolase (FAAH) activity increases the levels of endogenous analogues of cannabinoids, or endocannabinoids. FAAH inhibitors have shown analgesic and antiinflammatory activity in animal models, and some have been tested in phase 1 and 2 studies. In a phase 1 study, BIA 10-2474, an orally administered reversible FAAH inhibitor, was given to healthy volunteers to assess safety. METHODS: Single doses (0.25 to 100 mg) and repeated oral doses (2.5 to 20 mg for 10 days) of BIA 10-2474 had been administered to 84 healthy volunteers in sequential cohorts; no severe adverse events had been reported. Another cohort of participants was then assigned to placebo (2 participants) or 50 mg of BIA 10-2474 per day (6 participants). This report focuses on neurologic adverse events in participants in this final cohort. A total of 4 of the 6 participants who received active treatment consented to have their clinical and radiologic data included in this report. RESULTS: An acute and rapidly progressive neurologic syndrome developed in three of the four participants starting on the fifth day of drug administration. The main clinical features were headache, a cerebellar syndrome, memory impairment, and altered consciousness. Magnetic resonance imaging showed bilateral and symmetric cerebral lesions, including microhemorrhages and hyperintensities on fluid-attenuated inversion recovery and diffusion-weighted imaging sequences predominantly involving the pons and hippocampi. One patient became brain dead; the condition of two patients subsequently improved, but one patient had residual memory impairment, and the other patient had a residual cerebellar syndrome. One patient remained asymptomatic. CONCLUSIONS: An unanticipated severe neurologic disorder occurred after ingestion of BIA 10-2474 at the highest dose level used in a phase 1 trial. The underlying mechanism of this toxic cerebral syndrome remains unknown.

Neurologic Deficits in Patients With Newly Diagnosed Celiac Disease Are Frequent and Linked With Autoimmunity to Transglutaminase 6.

BACKGROUND & AIMS: Celiac disease is an autoimmune disorder induced by ingestion of gluten that affects 1% of the population and is characterized by gastrointestinal symptoms, weight loss, and anemia. We evaluated the presence of neurologic deficits and investigated whether the presence of antibodies to Transglutaminase 6 (TG6) increases the risk of neurologic defects in patients with a new diagnosis of celiac disease. METHODS: We performed a prospective cohort study at a secondary-care gastroenterology center of 100 consecutive patients who received a new diagnosis of celiac disease based on gastroscopy and duodenal biopsy. We collected data on neurologic history, and patients were evaluated in a clinical examination along with magnetic resonance imaging of the brain, magnetic resonance (MR) spectroscopy of the cerebellum, and measurements of antibodies against TG6 in serum samples. The first 52 patients recruited underwent repeat MR spectroscopy at 1 year after a gluten-free diet (GFD). The primary aim was to establish if detection of antibodies against TG6 can be used to identify patients with celiac disease and neurologic dysfunction. RESULTS: Gait instability was reported in 24% of the patients, persisting sensory symptoms in 12%, and frequent headaches in 42%. Gait ataxia was found in 29% of patients, nystagmus in 11%, and distal sensory loss in 10%. Sixty percent of patients had abnormal results from magnetic resonance imaging, 47% had abnormal results from MR spectroscopy of the cerebellum, and 25% had brain white matter lesions beyond that expected for their age group. Antibodies against TG6 were detected in serum samples from 40% of patients-these patients had significant atrophy of subcortical brain regions compared with patients without TG6 autoantibodies. In patients with abnormal results from MR spectroscopy of the cerebellum, those on the GFD had improvements detected in the repeat MR spectroscopy 1 year later. CONCLUSIONS: In a prospective cohort study of patients with a new diagnosis of celiac disease at a gastroenterology clinic, neurologic deficits were common and 40% had circulating antibodies against TG6. We observed a significant reduction in volume of specific brain regions in patients with TG6 autoantibodies, providing evidence for a link between autoimmunity to TG6 and brain atrophy in patients with celiac disease. There is a need for early diagnosis, increased awareness of the neurologic manifestations among clinicians, and reinforcement of adherence to a strict GFD by patients to avoid permanent neurologic disability.

The Responsiveness of Triaxial Accelerometer Measurement of Gait Ataxia Is Higher than That of the Scale for the Assessment and Rating of Ataxia in the Early Stages of Spinocerebellar Degeneration.

We reported previously that the average medial-lateral gait amplitude while walking on a straight path determined using triaxial accelerometers fixed on the middle of the upper back may be a quantitative and concise indicator for the severity of cerebellar ataxia. Considering that gait ataxia is a typical initial symptom in a variety of spinocerebellar degeneration (SCD), we aimed to develop quantitative biomarkers for cerebellar ataxia as metric variables. We used triaxial accelerometers to analyze gait parameters in 14 patients with SCD at 3 points over 3 years (at baseline, 1.5 years and 3 years). Analysis of covariance (ANCOVA) models adjusted for the baseline scores were used to estimate sample sizes. The mean medial-lateral amplitude (ML) gained by a triaxial accelerometer fixed on upper back could detect the each 1.5-year change. In the 14 patients, the mean ML(m) was 0.032 ± 0.007(SD) at entry, 0.037 ± 0.008 after 1.5-year follow, and 0.042 ± 0.020 after 3-year follow. In contrast, SARA gait scores were 2.9, 2.9, and 3.0, respectively. The responsiveness of the quantitative evaluation of gait ataxia by triaxial accelerometers is higher than that of the SARA within a 1.5-year follow-up period. Gait analysis by triaxial accelerometers will be complementary to the evaluation of scales like SARA in the assessment of clinical severity of SCD patients in early stage.

A case of methylprednisolone treatment for metronidazole-induced encephalopathy.

BACKGROUND: Metronidazole, a common antimicrobial agent, can induce encephalopathy in rare cases. After discontinuing metronidazole, most patients show clinical improvement. However, in the face of deteriorating conditions, there have done not to have reports of effective drug treatment. CASE PRESENTATION: A 57-year-old man was admitted to our hospital due to dysarthria and ataxic gait after taking metronidazole at the dose of about 32 g for 20 days. Neurological examination showed that his upward and outward movements of bilateral eyeballs were limited, and horizontal and vertical nystagmus were noted. The brain magnetic resonance imaging showed hyper-intensities in the bilateral cerebellar dentate nuclei, medulla oblongata, midbrain and red nuclei in T2W and FLAIR images. However, the patient's clinical symptoms worsened after drug cessation. High-dose intravenous methylprednisolone pulse therapy was applied, and this led to a drastic improvement of his symptoms and signs. CONCLUSIONS: In our case, we suggest that early methylprednisolone intervention can prevent the progression of metronidazole-induced encephalopathy and accelerate neurological recovery. We infer that the progression of encephalopathy is related to the delayed toxicity caused by high dose or concentration of metronidazole.