Bromelain decreases oxidative stress and Neuroinflammation and improves motor function in adult male rats with cerebellar Ataxia induced by 3-acetylpyridine.

Bromelain is a plant-based molecule with antioxidant, antithrombotic, anticancer, and anti-inflammatory properties. Bromelain has been shown to reduce the release of inflammatory cytokines. This study aimed to determine whether bromelain can prevent ataxia in rats caused by 3-acetylpyridine (3-AP). Thirty-six albino rats were divided into the control, 3-AP, and 3-AP + Brom groups. In the 3-AP + Brom group, bromelain was injected intraperitoneally at 40 mg/kg daily for 30 days. Various techniques such as rotarod, electromyography (EMG), elevated plus maze, IHC, and Sholl analysis were used to evaluate the possible effects of bromelain on cerebellar neurons and glial cells. The results demonstrated significant improvements in most of the 3-AP + Brom, including motor coordination, neuromuscular response, anxiety, oxidative capacity, microgliosis, astrogliosis, cell death, and morphological variables compared to the 3-AP group. The mechanism of action of bromelain in restoring cerebellar ataxia needs further investigation, but it may be a candidate to help restore degeneration in animals with ataxia.

Neurologic Deficits Following Oral Misuse of the Nasal Decongestant Propylhexedrine.

INTRODUCTION: Propylhexedrine is an over-the-counter nasal decongestant used recreationally for amphetamine-like effects. Prior reports have associated intravenous misuse with brainstem dysfunction and diplopia. This is a case of propylhexedrine ingestion resulting in neurological impairment with associated MRI findings. CASE REPORT: A 21-year-old man presented with neurologic symptoms after ingesting propylhexedrine extracted from a 250 mg nasal inhaler into a lemon juice solution following recommendations from an online forum. He also followed recommendations to simultaneously ingest 1 g L-arginine to theoretically mitigate the risk of vasoconstriction. He developed flushing and euphoria before falling asleep. He awoke 12 h later with dizziness, intractable vomiting, diplopia, ataxia, dysmetria, and spontaneous horizontal nystagmus. Magnetic resonance imaging (MRI) revealed T2 enhancement concerning for vasogenic edema of the right posterior limbs of the internal capsule extending into the midbrain, cerebellar peduncles, and cerebellar white matter. Workup for primary vascular or autoimmune etiologies was unrevealing. Expanded drug testing was positive for mitragynine and THC. Blood analyzed via liquid chromatography quadrupole time-of-flight mass spectrometry was positive for propylhexedrine. On hospital day 6, the patient was discharged to physical rehabilitation with unresolved dysmetria and ataxia. DISCUSSION: Recreational oral misuse of propylhexedrine may be associated with neurologic injury. MRI findings in this case demonstrated vasogenic edema suggesting vasospasm as a possible etiology. Serum testing confirmed the presence of propylhexedrine. Although testing was also positive for mitragynine and THC, these have not been associated with similar neurologic deficits or MRI findings.

Comprehensive Physiotherapy Rehabilitation in a Patient With Cerebellar Ataxia and Dysphagia: A Case Report Investigating Symptomatology, Management, and Outcomes.

A cerebellar infarct occurs when blood flow to the cerebellum, located in the posterior cranial fossa, is disrupted. This diminished blood supply leads to decreased oxygen delivery, resulting in motor and balance control impairments. One prevalent sign of neurodegenerative diseases is dysphagia, which is typically linked to a higher death rate. No systematic and uniform assessment of dysphagia is used in the clinical care environment of individuals with ataxia. Its effect on the quality of life associated with health in patients is little understood. Therefore, this case report works to address dysphagia in cerebellar ataxia. This case report examines the physiotherapy management of a 41-year-old male who had cerebellar ataxia secondary to an infarct in the bilateral cerebellar hemisphere and vermis. The rehabilitation period lasted for six weeks. On examination, the patient had difficulty swallowing and showed symptoms of cerebellar dysfunctions, such as nystagmus, dyssynergia, dysmetria, and dysdiadochokinesia. Neuro-physiotherapy interventions, like conventional physiotherapy, trunk, and pelvis proprioceptive neuromuscular facilitation (PNF), Kinesio taping for dysphagia, interventions to treat gait, balance training interventions, and Frenkel's exercises were commenced. The outcome measures were evaluated using standardized outcome measures like the Swallowing Quality of Life Scale (SWAL-QOL), Severity of Ataxia Scale (SARA), Trunk Impairment Scale (TIS), Berg Balance Scale (BBS), Barthel Index, and World Health Organization Quality of Life (WHO-QOL). We conclude that a properly structured physiotherapy program subsequently improved the symptoms of patients. Furthermore, it enhanced functional independence, which subsequently improved the patient's quality of life.

An overview of early-onset cerebellar ataxia: a practical guideline.

Early onset ataxias (EOAs) are a heterogeneous group of rare neurological disorders that not only involve the central and peripheral nervous system but also involve other organs. They are mainly manifested by degeneration or abnormal development of the cerebellum occurring before the age of 25 years and typically the pattern of inheritance is autosomal recessive.The diagnosis of autosomal recessive cerebellar ataxias (ARCAs) is confirmed by the clinical, laboratory, electrophysiological examination, neuroimaging findings, and mutation analysis when the causative gene is detected. Correct diagnosis is crucial for appropriate genetic counseling, estimating the prognosis, and, in some cases, pharmacological intervention. The wide variety of genotypes with a heterogeneous phenotypic manifestation makes the diagnostic work-up challenging, time-consuming, and expensive, not only for the clinician but also for the children and their parents. In this review, we focused on the step-by-step approach in which cerebellar ataxia is a prominent sign. We also outline the most common disorders in ataxias with early-onset manifestations.

Long-Term Follow-Up before and during Riluzole Treatment in Six Patients from Two Families with Spinocerebellar Ataxia Type 7.

BACKGROUND: Currently no curative treatment exists for spinocerebellar ataxias (SCAs). Riluzole repurposing was proposed as a symptomatic treatment in different types of cerebellar ataxia. We report a long-term-follow up under riluzole treatment in SCA type 7. METHODS: Six patients received Riluzole 50 mg twice daily on a compassionate use program for a mean of 4.8 years (range 3.5-9). We measured ataxia onset and progression through the Scale for the Assessment and Rating of Ataxia (SARA), and collected extensive ophthalmological data before and after Riluzole treatment. Electrocardiogram and laboratory profile for drug safety were performed every six months. RESULTS: Riluzole treatment showed no effect on visual function in two patients with an advanced retinal damage. Improvements of visual function occurred in four patients followed by ophthalmologic stability up to 5 years after starting treatment. Two patients had a less steep deterioration of ataxia after treatment compared to pre-treatment, during the first 2,5 years of therapy. One showed soon after therapy an improvement of the SARA score, and then overall stability lasting 3,5 years, followed by ataxia worsening. One visually impaired patient without neurological impairment did not worse until the last visit after 3,5 years of follow-up. The remaining 2 patients showed an improvement of SARA scores soon after therapy, and an overall stability lasting respectively 5 and 3 years. No adverse event was registered during the observation period. DISCUSSION: This study suggests a possible beneficial action of Riluzole in SCA7 and provides a detailed description of the ophthalmologic profile of these patients.

External Laryngeal Tremor in Adult-Onset Alexander Disease: A Case Report.

Introduction: Alexander disease is caused by mutations in GFAP, the glial fibrillary acidic protein gene. External laryngeal tremor has not been reported in adult-onset Alexander disease (AOAxD). The aims of this work were to report one such case and to review the literature on palatopharyngeal tremor and AOAxD. Case Presentation: A 43-year-old man experienced involuntary movements at the front of his neck. Continuous, rhythmic vertical movements of the laryngeal skeleton, soft palate and tongue, and lower limb dysmetria were observed. The pathogenic GFAP variant c.994G>A; p.(Glu332Lys) was found. MRI demonstrated spinal cord and medulla oblongata atrophy and hyperintensities at the cerebellum and cerebral white matter. Conclusion: External laryngeal, palatopharyngeal tremor and cerebellar ataxia constituted a mild phenotype, as expected from this variant, herein reported in isolation for the third time. Imaging was consistent with AOAxD, including the so-called tadpole sign. Additional studies are necessary to define this infrequent disease.

Recent advances in diagnosis of immune-mediated cerebellar ataxias: novel concepts and fundamental questions on autoimmune mechanisms.

Immune-mediated cerebellar ataxias (IMCAs) represent a group of disorders in which the immune system targets mainly the cerebellum and related structures. We address fundamental questions on the diagnosis and immunological pathogenesis of IMCAs, as illuminated by recent advances in the field. Various types of IMCAs have been identified, including post-infectious cerebellitis, Miller Fisher syndrome, gluten ataxia, paraneoplastic cerebellar degeneration (PCD), opsoclonus and myoclonus syndrome, and anti-GAD ataxia. In some cases, identification of several well-characterized autoantibodies points to a specific etiology in IMCAs and leads to a firm diagnosis. In other cases, various autoantibodies have been reported, but their interpretation requires a careful consideration. Indeed, some autoantibodies have only been documented in a limited number of cases and the causal relationship is not established. In order to facilitate an early treatment and prevent irreversible lesions, new entities have been defined in recent years, such as primary autoimmune cerebellar ataxia (PACA) and latent autoimmune cerebellar ataxia (LACA). PACA is characterized by autoimmune features which do not align with traditional etiologies, while LACA corresponds to a prodromal stage. LACA does not imply the initiation of an immunotherapy but requires a close follow-up. Concurrently, accumulation of clinical data has led to intriguing hypotheses regarding the mechanisms of autoimmunity, such as a pathogenesis of autoimmunity against synapses (synaptopathies), and the vulnerability of the entire nervous system when the immunity targets ion channels and astrocytes. The development of PCD in patients treated with immune-checkpoint inhibitors suggests that molecular mimicry specifically determines the direction of autoimmunity, and that the strength of this response is modulated by co-signaling molecules that either enhance or dampen signals from the antigen-specific T cell receptor.

Effects of Anodal tDCS Applied Over the Cerebellum Combined with Physical Therapy on Center of Gravity Sway in a Patient with Cerebellar Ataxia: A Single-Case Study.

Damage to the cerebellum results in dysfunctional standing postural control. Patients with cerebellar ataxia have a larger sway in the center of gravity (COG) while standing. Transcranial direct current stimulation (tDCS) has been applied in the rehabilitation of patients with central nervous system disorders; however, its effect on COG sway in patients with cerebellar ataxia remains unknown. We aimed to confirm the effects of anodal cerebellar tDCS (ctDCS) combined with physical therapy on COG sway in a patient with cerebellar ataxia using a retrospective ABA single-case study design. This study involved a patient with left cerebellar hemorrhage. Walking and postural balance rehabilitation were conducted in phase A. Anodal ctDCS was combined with the walking and postural balance rehabilitation in phase B. We measured COG sway in the open- and closed-eyes standing conditions daily throughout all the phases. In the open-eyes standing condition, there was no significant change in COG sway in phase B. Conversely, in the closed-eyes standing condition, the circumferential area, total sway path length, and anteroposterior sway path length decreased in phase B. No change was observed in the mediolateral sway path length. The combination of anodal ctDCS and physical therapy may decrease COG sway in patients with cerebellar ataxia in the closed-eyes standing condition, and its effect may be greater in the anteroposterior direction.

[Two patients of immunotherapy-responsive autoimmune cerebellar ataxia fulfilled with criteria of multiple system atrophy].

We report two patients with autoimmune cerebellar ataxia who fulfilled the diagnostic criteria of multiple system atrophy (MSA) and responded to immunotherapies. Patient 1 was a 72-year-old man who was diagnosed with clinically probable MSA according to Movement Disorder Society criteria. Patient 2 was a 68-year-old man who was diagnosed with clinically established MSA according to Movement Disorder Society criteria. Both patients showed cerebellar ataxia, autonomic dysfunction, and pyramidal tract signs; however, they also had atypical clinical features. Patient 1 exhibited self-|limiting mild improvement of clinical symptoms and had inflammatory findings in his cerebrospinal fluid. Patient 2 showed a rapidly progressive clinical course. We therefore examined anti-neuronal antibodies using tissue-based immunohistochemical assays with frozen rat cerebellum sections. We detected autoantibodies that mainly reacted with the cytoplasm of Purkinje cells. The two patients then underwent immunotherapies, which led to substantial improvements in their clinical symptoms. Our findings indicate that some patients with autoimmune cerebella ataxia have clinical features that resemble MSA, and respond well to immunotherapies.

Gait rhythm analysis as a new continuous scale for cerebellar ataxia: Power law and lognormal components represent the ataxic gait quantity.

We estimated the severity of cerebellar ataxia by analyzing gait rhythm. We measured the step times in patients with pure cerebellar ataxia and healthy controls and then analyzed the distribution of the ratios of adjacent times. Gait rhythm displayed the best adaptation when expressed as the sum of the power law and lognormal distributions in both groups, and the groups could be distinguished by the exponent of the power law distribution, reflecting the fractal property of gait rhythm. Gait rhythm might reflect different features of impairment in patients with cerebellar ataxia, making it a useful continuous scale for cerebellar ataxia.

Might patients with cerebellar ataxia benefit from the Computer Assisted Rehabilitation ENvironment (CAREN)? A pilot study focusing on gait and balance.

Introduction: Ataxia is a neurological symptom that causes decreased balance, loss of coordination, and gait alterations. Innovative rehabilitation devices like virtual reality (VR) systems can provide task-oriented, repetitive and intensive training with multisensorial feedback, thus promoting neuroplastic processes. Among these VR technologies, the Computer Assisted Rehabilitation ENvironment (CAREN) associates a split belt treadmill on a 6-degrees of freedom platform with a 180° VR screen and a Vicon motion capture system to monitor patients' movements during training sessions. Methods: Eight patients affected by cerebellar ataxia were enrolled and received 20 sessions of CAREN training in addition to standard rehabilitation treatment. Each patient was evaluated at the beginning and at the end of the study with 3D gait analysis and clinical scales to assess balance, gait function and risk of falls. Results: We found improvements in kinematic, kinetic, and electromyographic parameters (as per pre-post- CAREN training), as well as in clinical outcomes, such as balance and risk of falls in ataxic patients. In addition, we found that trunk rotation improved, after CAREN intervention, approximating to the normative values. Discussion: Our results suggested that CAREN might be useful to improve specific biomechanical parameters of gait in ataxic patients.

Acute Cerebellitis and Obstructive Hydrocephalus: An Unseen Neurological Complication After Surgical Repair for Tetralogy of Fallot.

Acute cerebellitis with obstructive hydrocephalus post-Tetralogy of Fallot surgery is extremely rare but can present aggressively in pediatric cases. Early diagnosis is critical for prompt medical and surgical intervention. We report a fatal case in a 7-year-old boy post-surgery, where neurological symptoms rapidly progressed, leading to drowsiness and intermittent response to commands. Despite initial computed tomography scans showing no abnormality, subsequent scans revealed cerebellitis and hydrocephalus. Treatment with steroids, antibiotics, and cerebrospinal fluid drainage was unsuccessful, and the condition's etiology remained unclear despite negative serological tests and cultures. This highlights the challenge of diagnosing and treating acute cerebellitis, especially when no specific cause is found and when deterioration is swift. The role of opioids in pediatric patients and their potential association with neurosurgical complications is also discussed, prompting further inquiry into postoperative symptoms and opioid-related risks in susceptible individuals.

Phenotypic variability related to dominant UCHL1 mutations: about three families with optic atrophy and ataxia.

INTRODUCTION: Ubiquitin C-terminal hydrolase L1 (UCHL1) has been associated with a severe, complex autosomal recessive spastic paraplegia (HSP79) [1] [2] [3] [4]. More recently, UCHL1 loss of function (LoF) variants have been associated to an autosomal dominant disease characterized by late-onset spastic ataxia, neuropathy, and frequent optic atrophy [5]. METHODS: Routine clinical care whole-genome (WGS) and exome (ES) sequencing. RESULTS: We present three families with autosomal dominant UCHL1-related disorder. The clinical phenotype mainly associated optic atrophy, mixed cerebellar and sensory ataxia, and possible hearing loss. We delineated two major phenotypes, even within the same family: (1) juvenile severe optic atrophy followed by a later-onset ataxia, or (2) late-onset ataxia with asymptomatic or mild optic atrophy. The families harboured three novel heterozygous variants in UCHL1: two loss of function (p.Lys115AsnfsTer40; c.171_174 + 7del11), and one missense (p.Asp176Asn) involving the catalytic site of the protein and potentially altering the adjacent splice site. DISCUSSION: We confirm the existence of dominantly inherited UCHL1 pathogenic variants. We describe a considerable intrafamilial phenotypic variability, with two main phenotypes. Optic atrophy was consistently present, but with varying degrees of severity. Neither delayed motor or intellectual development, nor dysmorphic features were part of the dominant phenotype in comparison with the autosomal recessive form. The molecular mechanism appears to be haploinsufficiency. UCHL1 monoallelic variants should therefore be considered in any case of early-onset optic atrophy or in late-onset complex ataxic syndrome with asymptomatic optic atrophy.

Dentatorubral-pallidoluysian atrophy: a rare cause of epilepsy, ataxia and chorea.

A 34-year-old woman presented with insidious onset and gradually progressive cerebellar ataxia over 10 years, with generalised convulsions. On examination, there were myoclonic jerks, choreiform movements and cerebellar syndrome. Her family history suggested an autosomal dominant inheritance with anticipation. Genetic analysis for trinucleotide repeat disorders led to a diagnosis of dentatorubral-pallidoluysian atrophy (60 CAG repeats in the atrophin-1 gene). This rare spinocerebellar ataxia should be considered in the differential diagnosis of inherited ataxia when combined with seizures and chorea. Other features suggesting a repeat expansion disorder are variable phenotypes within the same family and possible anticipation.

Streamlined two-step fragment analysis PCR and exome sequencing of RFC1 for diagnostic testing of suspected CANVAS patients.

Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is caused by biallelic pathogenic expansions, or compound heterozygosity with other pathogenic variants in the RFC1 gene. CANVAS is estimated to be underdiagnosed, both because of the lack of formal diagnostic criteria and molecular challenges that translate to lesser access and high cost of routine testing. Our aim was to address the need for making CANVAS genetic testing routine, by designing a streamlined two-step PCR consisting of a short-allele screening PCR and a confirmatory PCR with fragment capillary electrophoresis detection. Exome sequencing of RFC1 was additionally foreseen to resolve potential compound heterozygosity cases. Specificity of our approach was evaluated using ataxia patients with known non-CANVAS diagnoses, and optimized using Southern blot confirmed CANVAS patients. We evaluated our approach by testing patients consecutively referred for clinically suspected CANVAS using first the two-step PCR, followed by exome sequencing. Our approach was able to accurately identify negative and confirm positive cases in prospectively collected suspected CANVAS patients presenting with at least three typical clinical signs. The proposed testing approach provides an alternative method able to clearly distinguish between CANVAS negative and positive cases and can be easily incorporated into the genetic diagnostic laboratory workflow.

COVID-19-Associated Cerebellar Ataxia: A Case Series.

COVID-19-associated cerebellar ataxia has rarely been reported and its clinical characteristics remain understudied. This study aims to report patients with COVID-19-associated cerebellar ataxia from our institution. COVID-19-associated cerebellar ataxia was diagnosed based on the prodromal COVID-19 infection and the exclusion of other causes. This study provides a summary of the patients' clinical presentations, neuroimaging features, and the results of anti-cerebellar antibody examinations. Our study included 11 patients and 4 were male. The median onset age was 38 years. Five patients also demonstrated signs of encephalopathy. Brain magnetic resonance imaging (MRI) was either unremarkable (n = 6) or showed bilateral cerebellar lesions (n = 5), which were typically transient, although brain atrophy could be observed later in the disease course. Anti-Homer-3 and anti-Yo antibodies were each detected in one patient, respectively. All patients received immunotherapy and nine improved. Compared with the late-onset group, individuals who exhibited ataxia earlier following COVID-19 onset (interval<5 days) were significantly younger [median age 18 (15.5-31) vs. 53.5 (44-64.8) years, p = 0.009] and more likely to present with encephalopathy (5/5 vs. 0/6, p = 0.002).They also experienced more severe symptoms [median modified Rankin scale (mRS) score at zenith 5 (5-5) vs. 2 (1.75-2.75), p = 0.017] and had a less favorable prognosis [median mRS score at the last follow-up 4 (2-5) vs. 1 (0-1.25), p = 0.009]. COVID-19-associated cerebellar ataxia can appear with encephalopathy. Brain MRI may show transient bilateral cerebellar lesions and brain atrophy later. Patients who exhibited ataxia earlier following COVID-19 were younger, had more severe symptoms and poorer outcomes.

Cerebellar form of multiple system atrophy: A case report.

Multiple system atrophy is a form of synucleinopathy with an unknown etiology that causes progressive neurodegeneration. It may affect the cerebellum, autonomic nerves, and pyramidal and extrapyramidal systems. We present the case of a 51-year-old man who was hospitalized for recurrent balance problems and dizziness. Cranial magnetic resonance imaging showed the "hot cross bun" sign of the pons with major atrophy of the cerebellum. The cerebellar form of probable multiple system atrophy was the final diagnosis.