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.

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.

Shared and specific signatures of locomotor ataxia in mutant mice.

Several spontaneous mouse mutants with deficits in motor coordination and associated cerebellar neuropathology have been described. Intriguingly, both visible gait alterations and neuroanatomical abnormalities throughout the brain differ across mutants. We previously used the LocoMouse system to quantify specific deficits in locomotor coordination in mildly ataxic Purkinje cell degeneration mice (pcd; Machado et al., 2015). Here, we analyze the locomotor behavior of severely ataxic reeler mutants and compare and contrast it with that of pcd. Despite clearly visible gait differences, direct comparison of locomotor kinematics and linear discriminant analysis reveal a surprisingly similar pattern of impairments in multijoint, interlimb, and whole-body coordination in the two mutants. These findings capture both shared and specific signatures of gait ataxia and provide a quantitative foundation for mapping specific locomotor impairments onto distinct neuropathologies in mice.

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.

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.

Examination of the effects of coordination and balance problems on gait in ataxic multiple sclerosis patients.

OBJECTIVE: To investigate the effects of coordination and balance problems on gait and plantar pressure distribution in multiple sclerosis patients. METHODS: This was an observational, cross-sectional study. It was conducted at Necmettin Erbakan University between March and December 2017. Twenty-four individuals with coordination problems, 36 individuals with balance problems and 32 healthy individuals were included in the study. The EDSS, Functional Reach Test, Dynamic Gait Index, baropodometry and stabilometry evaluations were performed. RESULTS: There were significant differences between the groups (velocity p=0.000, cadence p=0.000, step width p=0.018, step length p=0.000, foot angle p=0.000). Multiple comparisons demonstrated that the velocities and cadences of the coordination group were lower, while their step widths were found to be higher, compared to the balance group (p=0.012, p=0.004, p=0.017, respectively). In static plantar pressure distribution, lateral forefoot pressure, lateral hindfoot pressure and medial hindfoot pressure were significantly different between the groups (p=0.002, p=0.000, respectively) Multiple comparisons showed that the pressure on the lateral part of the hindfoot in the coordination group was found to be significantly higher compared to the balance group (p=0.002). According to the dynamic plantar pressure distribution, lateral forefoot, medial forefoot, lateral hindfoot and medial hindfoot pressures were significantly different between the groups (p<0.05). CONCLUSION: Coordination and balance problems affect gait and plantar pressure distribution. The identification of these changes will help physiotherapists determine specific therapeutic targets.

Ataxic Gait in Essential Tremor: A Disease-Associated Feature?

Background: While accumulating evidence suggests that balance and gait impairments are commonly seen in patients with essential tremor (ET), questions remain regarding their prevalence, their relationship with normal aging, whether they are similar to the impairments seen in spinocerebellar ataxias, their functional consequences, and whether some ET patients carry greater susceptibility. Methods: We conducted a literature search (until December 2018) on this topic. Results: We identified 23 articles on gait or balance impairments in ET. The prevalence of balance impairment (missteps on tandem walk test) was seven times higher in ET patients than controls. Gait impairments in ET included reduced speed, increased asymmetry, and impaired dynamic balance. While balance and gait problems worsened with age, ET patients were more impaired than controls, independent of age. The pattern of impairments seen in ET was qualitatively similar to that seen in spinocerebellar ataxias. Balance and gait impairments resulted in greater number of near falls in ET patients. Factors associated with balance and gait impairments in ET included age, presence of tremor in midline structures, and cognitive dysfunction. Discussion: Accumulating evidence suggests that balance and gait impairments are common in ET patients and occur to a greater extent in controls. Thus, they represent a disease-associated feature. These impairments, which are qualitatively similar to those seen in spinocerebellar ataxias, are not merely subclinical but result in difficulty performing functional tasks and increase falls risk. A subset of patients is more susceptible to balance and gait impairments. The full spectrum of impairments remains to be characterized.

Vestibular dysfunction in acute traumatic brain injury.

Traumatic brain injury (TBI) is the commonest cause of disability in under-40-year-olds. Vestibular features of dizziness (illusory self-motion) or imbalance which affects 50% of TBI patients at 5 years, increases unemployment threefold in TBI survivors. Unfortunately, vestibular diagnoses are cryptogenic in 25% of chronic TBI cases, impeding therapy. We hypothesized that chronic adaptive brain mechanisms uncouple vestibular symptoms from signs. This predicts a masking of vestibular diagnoses chronically but not acutely. Hence, defining the spectrum of vestibular diagnoses in acute TBI should clarify vestibular diagnoses in chronic TBI. There are, however, no relevant acute TBI data. Of 111 Major Trauma Ward adult admissions screened (median 38-years-old), 96 patients (87%) had subjective dizziness (illusory self-motion) and/or objective imbalance were referred to the senior author (BMS). Symptoms included: feeling unbalanced (58%), headache (50%) and dizziness (40%). In the 47 cases assessed by BMS, gait ataxia was the commonest sign (62%) with half of these cases denying imbalance when asked. Diagnoses included BPPV (38%), acute peripheral unilateral vestibular loss (19%), and migraine phenotype headache (34%), another potential source of vestibular symptoms. In acute TBI, vestibular signs are common, with gait ataxia being the most frequent one. However, patients underreport symptoms. The uncoupling of symptoms from signs likely arises from TBI affecting perceptual mechanisms. Hence, the cryptogenic nature of vestibular symptoms in TBI (acute or chronic) relates to a complex interaction between injury (to peripheral and central vestibular structures and perceptual mechanisms) and brain-adaptation, emphasizing the need for acute prospective, mechanistic studies.

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.

Clinical Study on 3 Patients with Infarction of the Vermis/Tonsil in the Cerebellum.

BACKGROUND: Infarction of the vermis and the tonsil in the cerebellum presents as truncal and gait ataxia. Acute rotatory vertigo is often present in infarction of the nodulus in the caudal vermis, which is closely associated with the vestibular pathway, but is minor in infarction of the rostral vermis. The rostral vermis receives input from the dorsal spinocerebellar tract (DSCT) which conveys unconsciousness proprioceptive signals from the ipsilateral lower trunk and leg. The present study investigated the characteristics of infarction of the vermis and the tonsil. PATIENTS AND METHODS: Neuroradiological findings of 3 patients whose lesions were located in the vermis or the tonsil were analyzed. RESULTS: All lesions were located in the anterior lobe in the rostral vermis, the nodulus in the caudal vermis, or the tonsil. Truncal and gait ataxia were exhibited by 3 patients. Rotatory vertigo was exhibited by 2 patients whose lesions were located in the nodulus and the tonsil, but absent in a patient with infarction of the anterior lobe. Lateropulsion opposite the lesion was apparent in a patient with infarction of the tonsil. Gaze-evoked nystagmus was observed in 2 patients with infarction of the nodulus and the tonsil. CONCLUSIONS: The tonsil and the nodulus were considered to have a close relationship with the vestibular pathway. Absence of rotatory vertigo indicated impairment of the DSCT. Our data suggested that the cause of truncal and gait ataxia differed between the rostral vermis and the caudal vermis/tonsil.

Characteristics of ataxic gait in familial dysautonomia patients.

INTRODUCTION AND OBJECTIVES: Progressive ataxic gait is a common symptom in individuals with Familial Dysautonomia (FD). At least 50% of adults with FD require assistance with walking. Our aims were to describe the medical condition of individuals with FD (ii) compare their gait characteristics to healthy individuals, and (iii) assess correlations between gait measures, presence of unstable gait pattern and frequency of falls. METHODS: Twelve subjects with FD (7 males, age 25.3±10.6 years) and 16 healthy participants (6 males, age 35.9±11.9 years) were recruited. Gait kinematics, gait symmetry, dynamic muscle activity, and foot deep vibration sensation were recorded. RESULTS: Ataxic gait degrees were: severe (6 out of 12), moderate (4 out of 12) and low (2 out of 12). The number of falls correlated with base width asymmetry. Crouch gait was noted in 3 out of 12 of the subjects. CONCLUSIONS: In-depth quantitative gait analysis of individuals with FD revealed ataxic gait. The ataxic pattern might be a result of combined neurological deficiencies and osseous deformities. Increasing the base of support of patients with FD might increase the symmetry of the base width during gait and decrease the number of falls. Additionally, perturbation treatment and dynamic balance exercises may be recommended in order to improve compensatory strategies. Future investigation of this population should include quantification of osseous rotations of the lower limb in order to fully understand its effect on their gait pattern and falls.

Psychometric properties of outcome measures evaluating decline in gait in cerebellar ataxia: A systematic review.

Cerebellar ataxia often results in impairment in ambulation secondary to gait pattern dysfunction and compensatory gait adjustments. Pharmaceutical and therapy-based interventions with potential benefit for gait in ataxia are starting to emerge, however evaluation of such interventions is hampered by the lack of outcome measures that are responsive, valid and reliable for measurement of gait decline in cerebellar ataxia. This systematic review aimed for the first time to evaluate the psychometric properties of gait and walking outcomes applicable to individuals with cerebellar ataxia. Only studies evaluating straight walking were included. A comprehensive search of three databases (MEDLINE, CINAHL and EMBASE) identified 53 studies meeting inclusion criteria. Forty-nine were rated as 'poor' as assessed by the COnsensus-based Standards for the selection of health Measurement INstruments checklist. The primary objective of most studies was to explore changes in gait related to ataxia, rather than to examine psychometric properties of outcomes. This resulted in methodologies not specific for psychometric assessment. Thirty-nine studies examined validity, 11 examined responsiveness and 12 measured reliability. Review of the data identified double and single support and swing percentage of the gait cycle, velocity, step length and the Scale for Assessment and Rating of Ataxia (SARA) gait item as the most valid and responsive measures of gait in cerebellar ataxia. However, further evaluation to establish their reliability and applicability for use in clinical trials is clearly warranted. We recommend that inter-session reliability of gait outcomes should be evaluated to ensure changes are reflective of intervention effectiveness in cerebellar ataxia.

A systematic review of the gait characteristics associated with Cerebellar Ataxia.

BACKGROUND: Cerebellar Ataxias are a group of gait disorders resulting from dysfunction of the cerebellum, commonly characterised by slowly progressing incoordination that manifests as problems with balance and walking leading to considerable disability. There is increasing acceptance of gait analysis techniques to quantify subtle gait characteristics that are unmeasurable by current clinical methods This systematic review aims to identify the gait characteristics able to differentiate between Cerebellar Ataxia and healthy controls. METHODS: Following systematic search and critical appraisal of the literature, gait data relating to preferred paced walking in Cerebellar Ataxia was extracted from 21 studies. A random-effect model meta-analysis was performed for 14 spatiotemporal parameters. Quality assessment was completed to detect risk of bias. RESULTS: There is strong evidence that compared with healthy controls, Cerebellar Ataxia patients walk with a reduced walking speed and cadence, reduced step length, stride length, and swing phase, increased walking base width, stride time, step time, stance phase and double limb support phase with increased variability of step length, stride length, and stride time. CONCLUSION: The consensus description provided here, clarifies the gait pattern associated with ataxic gait disturbance in a large cohort of participants. High quality research and reporting is needed to explore specific genetic diagnoses and identify biomarkers for disease progression in order to develop well-evidenced clinical guidelines and interventions for Cerebellar Ataxia.

Use of dynamic movement orthoses to improve gait stability and trunk control in ataxic patients.

BACKGROUND: Patients with cerebellar ataxia show increased upper body movements, which have an impact on balance and walking. AIM: In this study, we investigated the effect of using dynamic movement orthoses (DMO), designed as elastic suits, on trunk motion and gait parameters. DESIGN: Longitudinal uncontrolled study. SETTING: Outpatient rehabilitation unit. POPULATION: Eleven patients (7 men, 4 women; mean age: 49.9±9.5 years) with degenerative cerebellar ataxia were enrolled in this study. METHODS: Linear overground gait of patients was recorded by means of an optoelectronic gait analysis system before DMO use (DMO-) and during DMO use (DMO+). Time-distance parameters, lower limb joint kinematics, body sway, trunk oscillations, and gait variability (coefficient of variation [CV]) were recorded. Patient satisfaction with DMO device was measured using Quebec user evaluation of satisfaction with assistive technology. RESULTS: When using the DMO, patients showed a significant decrease in stance phase duration, double support phase duration, swing phase CV, pelvic range of motion (ROM), body sway, and trunk ROMs. A significant increase was observed in the swing phase duration and knee joint ROM. Out of 11 patients, 10 were either quite satisfied (8 points) or very satisfied (2 points) with the assistive device. CONCLUSIONS: The DMO reduce the upper body motion and in improve balance-related gait parameters. CLINICAL REHABILITATION IMPACT: We propose use of DMO as an assistive/rehabilitative device in the neurorehabilitation of cerebellar ataxia to improve the trunk control and gait stability. DMO may be considered a prototype that can be modified in terms of material characteristics, textile layers, elastic components, and diagonal and lateral seams.

Sex differences in quadrupedal walking gaits of Uner Tan syndrome cases, healthy humans and nonhuman primates.

BACKGROUND: Uner Tan syndrome (UTS) cases with habitual quadrupedal locomotion (QL), impaired intelligence, and dysarthric or no speech predominantly use lateral sequence (LS) gait like nonprimates rather than the predominantly diagonal sequence (DS) gait of nonhuman primates. However, these studies neglected possible sex-related differences in these gait types. OBJECTIVES: (1) To assess the possible sex-related gait types in UTS cases, healthy infants and adults with requested QL, and the nonhuman primates. (2) To test the hypothesis that sex differences may exist in quadrupedal walking gaits in UTS cases, healthy humans, and nonhuman primates. METHODS: The UTS cases were filmed, the other study groups were taken from public open 'youtube' videos, which were used to assess the walking gait types as DS and LS. The right and left hind-limb phase values were calculated separately for males and females to allow a possible sex difference in walking gaits to be determined. RESULTS: Females predominantly used DS gait, contrary to males with predominantly LS gait. CONCLUSIONS: Consistent with the working hypothesis, the results suggested a biological sex-related trend in preferred walking gaits exists in all of the human and nonhuman primates using QL.

Progression of Gait Ataxia in Patients with Degenerative Cerebellar Disorders: a 4-Year Follow-Up Study.

In the present study, the progression of gait impairment in a group of patients with primary degenerative cerebellar ataxias was observed over a period of 4 years. A total of 30 patients underwent an initial gait analysis study, and thereafter only 12 were evaluated because they completed the 2- and 4-year follow-up evaluations. Time-distance parameters, trunk and joint range of motion (RoM), and variability parameters (e.g., coefficients of variation) were measured at the baseline and at each follow-up evaluation. The scale for the assessment and rating of ataxia (SARA) was used to evaluate disease severity. We found a significant increase in the SARA score at both the 2- and 4-year follow-up evaluations. Almost all the gait variables changed significantly only at the 4-year follow-up. Particularly, we found a significant decrease in the step length and in the hip, knee, and ankle joint RoM values and noted a significant increase in the trunk rotation RoM and stride-to-stride and step length variability. Furthermore, a significant difference in ankle joint RoM was found between spinocerebellar ataxia and sporadic adult-onset ataxia patients, with the value being lower in the former group of patients. Our findings suggest that patients with degenerative cerebellar ataxias exhibit gait decline after 4 years from the baseline. Moreover, patients try to maintain an effective gait by adopting different compensatory mechanisms during the course of the disease in spite of disease progression.

Memory deficits, gait ataxia and neuronal loss in the hippocampus and cerebellum in mice that are heterozygous for Pur-alpha.

Pur-alpha is a highly conserved sequence-specific DNA and RNA binding protein with established roles in DNA replication, RNA translation, cell cycle regulation, and maintenance of neuronal differentiation. Prior studies have shown that mice lacking Pur-alpha (-/-) display decreased neurogenesis and impaired neuronal differentiation. We sought to examine for the first time, the behavioral phenotype and brain histopathology of mice that are heterozygous (+/-) for Pur-alpha. Standardized behavioral phenotyping revealed a decreased escape response to touch, limb and abdominal hypotonia, and gait abnormalities in heterozygous Pur-alpha (+/-) mice, compared to wild-type (+/+) littermates. Footprint pattern analyses showed wider-based steps, increased missteps and more outwardly rotated hindpaws in heterozygous Pur-alpha (+/-) mice, suggestive of cerebellar pathology. The Barnes maze and novel object location testing revealed significant memory deficits in heterozygous Pur-alpha mice, suggestive of hippocampal pathology. Quantitative immunohistochemical assays of the vermal region of the cerebellum and CA1-3 regions of the hippocampus revealed reduced numbers of neurons in general, as well as reduced numbers of Pur-alpha+-immunopositive neurons and dendrites in heterozygous Pur-alpha mice, compared to wild-type littermates. Past studies have implicated mutations in Pur-alpha in several diseases of brain development and neurodegeneration. When combined with these new findings, the Pur-alpha heterozygous knockout mice may provide an animal model to study mechanisms of and treatments for Pur-alpha-related cognitive deficiencies and neuropathology.