ACR Appropriateness Criteria® Dizziness and Ataxia: 2023 Update.

Diagnostic evaluation of a patient with dizziness or vertigo is complicated by a lack of standardized nomenclature, significant overlap in symptom descriptions, and the subjective nature of the patient's symptoms. Although dizziness is an imprecise term often used by patients to describe a feeling of being off-balance, in many cases dizziness can be subcategorized based on symptomatology as vertigo (false sense of motion or spinning), disequilibrium (imbalance with gait instability), presyncope (nearly fainting or blacking out), or lightheadedness (nonspecific). As such, current diagnostic paradigms focus on timing, triggers, and associated symptoms rather than subjective descriptions of dizziness type. Regardless, these factors complicate the selection of appropriate diagnostic imaging in patients presenting with dizziness or vertigo. This document serves to aid providers in this selection by using a framework of definable clinical variants. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

Reversible encephalitis-like episodes in fragile X-associated tremor/ataxia syndrome: a case report.

BACKGROUND: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by CGG repeat expansion of FMR1 gene. Both FXTAS and neuronal intranuclear inclusion disease (NIID) belong to polyglycine diseases and present similar clinical, radiological, and pathological features, making it difficult to distinguish these diseases. Reversible encephalitis-like attacks are often observed in NIID. It is unclear whether they are presented in FXTAS and can be used for differential diagnosis of NIID and FXTAS. CASE PRESENTATION: A 63-year-old Chinese male with late-onset gait disturbance, cognitive decline, and reversible attacks of fever, consciousness impairment, dizziness, vomiting, and urinary incontinence underwent neurological assessment and examinations, including laboratory tests, electroencephalogram test, imaging, skin biopsy, and genetic test. Brain MRI showed T2 hyperintensities in middle cerebellar peduncle and cerebrum, in addition to cerebellar atrophy and DWI hyperintensities along the corticomedullary junction. Lesions in the brainstem were observed. Skin biopsy showed p62-positive intranuclear inclusions. The possibilities of hypoglycemia, lactic acidosis, epileptic seizures, and cerebrovascular attacks were excluded. Genetic analysis revealed CGG repeat expansion in FMR1 gene, and the number of repeats was 111. The patient was finally diagnosed as FXTAS. He received supportive treatment as well as symptomatic treatment during hospitalization. His encephalitic symptoms were completely relieved within one week. CONCLUSIONS: This is a detailed report of a case of FXTAS with reversible encephalitis-like episodes. This report provides new information for the possible and rare features of FXTAS, highlighting that encephalitis-like episodes are common in polyglycine diseases and unable to be used for differential diagnosis.

A novel MT-ATP6 variant associated with complicated ataxia in two unrelated Italian patients: case report and functional studies.

BACKGROUND: MT-ATP6 is a mitochondrial gene which encodes for the intramembrane subunit 6 (or A) of the mitochondrial ATP synthase, also known asl complex V, which is involved in the last step of oxidative phosphorylation to produce cellular ATP through aerobic metabolism. Although classically associated with the NARP syndrome, recent evidence highlights an important role of MT-ATP6 pathogenic variants in complicated adult-onset ataxias. METHODS: We describe two unrelated patients with adult-onset cerebellar ataxia associated with severe optic atrophy and mild cognitive impairment. Whole mitochondrial DNA sequencing was performed in both patients. We employed patients' primary fibroblasts and cytoplasmic hybrids (cybrids), generated from patients-derived cells, to assess the activity of respiratory chain complexes, oxygen consumption rate (OCR), ATP production and mitochondrial membrane potential. RESULTS: In both patients, we identified the same novel m.8777 T > C variant in MT-ATP6 with variable heteroplasmy level in different tissues. We identifed an additional heteroplasmic novel variant in MT-ATP6, m.8879G > T, in the patients with the most severe phenotype. A significant reduction in complex V activity, OCR and ATP production was observed in cybrid clones homoplasmic for the m.8777 T > C variant, while no functional defect was detected in m.8879G > T homoplasmic clones. In addition, fibroblasts with high heteroplasmic levelsof m.8777 T > C variant showed hyperpolarization of mitochondrial membranes. CONCLUSIONS: We describe a novel pathogenic mtDNA variant in MT-ATP6 associated with adult-onset ataxia, reinforcing the value of mtDNA screening within the diagnostic workflow of selected patients with late onset ataxias.

Role of fragile X messenger ribonucleoprotein 1 in the pathophysiology of brain disorders: a glia perspective.

Fragile X messenger ribonucleoprotein 1 (FMRP) is a widely expressed RNA binding protein involved in several steps of mRNA metabolism. Mutations in the FMR1 gene encoding FMRP are responsible for fragile X syndrome (FXS), a leading genetic cause of intellectual disability and autism spectrum disorder, and fragile X-associated tremor-ataxia syndrome (FXTAS), a neurodegenerative disorder in aging men. Although FMRP is mainly expressed in neurons, it is also present in glial cells and its deficiency or altered expression can affect functions of glial cells with implications for the pathophysiology of brain disorders. The present review focuses on recent advances on the role of glial subtypes, astrocytes, oligodendrocytes and microglia, in the pathophysiology of FXS and FXTAS, and describes how the absence or reduced expression of FMRP in these cells can impact on glial and neuronal functions. We will also briefly address the role of FMRP in radial glial cells and its effects on neural development, and gliomas and will speculate on the role of glial FMRP in other brain disorders.

Fragile X-associated tremor/ataxia syndrome treated with multitarget deep brain stimulation.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive hereditary neurodegenerative disorder which causes intention tremor and cerebellar ataxia. It typically affects the ageing population. Deep brain stimulation (DBS) is widely accepted in the treatment of common movement disorders and has been trialled in treating rare and complex neurodegenerative disorders. We report a case of a man in his 40s with a long history of tremor affecting his hands. MRI brain revealed high T2 signal in the middle cerebellar peduncles. Genetic testing revealed FMR1 premutation confirming the diagnosis of FXTAS. Subsequently, he was treated with multitarget DBS of the ventralis intermediate nucleus and ventralis oralis posterior nuclei bilaterally, with excellent neurological function at 9 years follow-up. This case suggests multitarget DBS for FXTAS with neurophysiology-guided DBS programming can provide excellent long-term tremor suppression in selected patients.

4-Hydroxybenzoic acid rescues multisystemic disease and perinatal lethality in a mouse model of mitochondrial disease.

Coenzyme Q (CoQ) deficiency syndrome is conventionally treated with limited efficacy using exogenous CoQ10. Poor outcomes result from low absorption and bioavailability of CoQ10 and the clinical heterogenicity of the disease. Here, we demonstrate that supplementation with 4-hydroxybenzoic acid (4HB), the precursor of the benzoquinone ring in the CoQ biosynthetic pathway, completely rescues multisystemic disease and perinatal lethality in a mouse model of CoQ deficiency. 4HB stimulates endogenous CoQ biosynthesis in tissues of Coq2 mutant mice, normalizing mitochondrial function and rescuing cardiac insufficiency, edema, and neurodevelopmental delay. In contrast, exogenous CoQ10 supplementation falls short in fully restoring the phenotype. The treatment is translatable to human use, as proven by in vitro studies in skin fibroblasts from patients with pathogenic variants in COQ2. The therapeutic approach extends to other disorders characterized by deficiencies in the production of 4HB and early steps of CoQ biosynthesis and instances of secondary CoQ deficiency.

Phenotypic analysis of ataxia in spinocerebellar ataxia type 6 mice using DeepLabCut.

This study emphasizes the benefits of open-source software such as DeepLabCut (DLC) and R to automate, customize and enhance data analysis of motor behavior. We recorded 2 different spinocerebellar ataxia type 6 mouse models while performing the classic beamwalk test, tracked multiple body parts using the markerless pose-estimation software DLC and analyzed the tracked data using self-written scripts in the programming language R. The beamwalk analysis script (BAS) counts and classifies minor and major hindpaw slips with an 83% accuracy compared to manual scoring. Nose, belly and tail positions relative to the beam, as well as the angle at the tail base relative to the nose and tail tip were determined to characterize motor deficits in greater detail. Our results found distinct ataxic abnormalities such as an increase in major left hindpaw slips and a lower belly and tail position in both SCA6 ataxic mouse models compared to control mice at 18 months of age. Furthermore, a more detailed analysis of various body parts relative to the beam revealed an overall lower body position in the SCA684Q compared to the CT-longQ27PC mouse line at 18 months of age, indicating a more severe ataxic deficit in the SCA684Q group.

Myoclonus and Dystonia as Recurrent Presenting Features in Patients with the SCA21-Associated TMEM240 p.Pro170Leu Variant.

Background: Spinocerebellar ataxia 21 (SCA21) is a rare neurological disorder caused by heterozygous variants in TMEM240. A growing, yet still limited number of reports suggested that hyperkinetic movements should be considered a defining component of the disease. Case Series: We describe two newly identified families harboring the recurrent pathogenic TMEM240 p.Pro170Leu variant. Both index patients and the mother of the first proband developed movement disorders, manifesting as myoclonic dystonia and action-induced dystonia without co-occurring ataxia in one case, and pancerebellar syndrome complicated by action-induced dystonia in the other. We reviewed the literature on TMEM240 variants linked to hyperkinetic disorders, comparing our cases to described phenotypes. Discussion: Adding to prior preliminary observations, our series highlights the relevance of hyperkinetic movements as clinically meaningful features of SCA21. TMEM240 mutation should be included in the differential diagnosis of myoclonic dystonia and ataxia-dystonia syndromes.

Mitochondrial dysfunction in Fragile X syndrome and Fragile X-associated tremor/ataxia syndrome: prospect use of antioxidants and mitochondrial nutrients.

Fragile X syndrome (FXS) is a genetic disorder characterized by mutation in the FMR1 gene, leading to the absence or reduced levels of fragile X Messenger Ribonucleoprotein 1 (FMRP). This results in neurodevelopmental deficits, including autistic spectrum conditions. On the other hand, Fragile X-associated tremor/ataxia syndrome (FXTAS) is a distinct disorder caused by the premutation in the FMR1 gene. FXTAS is associated with elevated levels of FMR1 mRNA, leading to neurodegenerative manifestations such as tremors and ataxia.Mounting evidence suggests a link between both syndromes and mitochondrial dysfunction (MDF). In this minireview, we critically examine the intricate relationship between FXS, FXTAS, and MDF, focusing on potential therapeutic avenues to counteract or mitigate their adverse effects. Specifically, we explore the role of mitochondrial cofactors and antioxidants, with a particular emphasis on alpha-lipoic acid (ALA), carnitine (CARN) and Coenzyme Q10 (CoQ10). Findings from this review will contribute to a deeper understanding of these disorders and foster novel therapeutic strategies to enhance patient outcomes.

Detrusor Sphincter Dyssynergia.

Detrusor sphincter dyssynergia (DSD) is defined as a detrusor contraction concurrent with an involuntary contraction of the urethral and/or periurethral striated muscles typically occurring in a patient with a spinal cord lesion above the sacral cord. Consequently, high urethral closure pressures during the detrusor contraction leads to high intravesical voiding pressure and large postvoid residuals, which can lead to significant complications in up to 50% of patients if DSD is not treated and followed-up regularly. DSD treatment options are centered around symptomatic management rather that addressing the underlying causative mechanisms.

Multifeature quantitative motor assessment of upper limb ataxia including drawing and reaching.

OBJECTIVE: Voluntary upper limb movements are an ecologically important yet insufficiently explored digital-motor outcome domain for trials in degenerative ataxia. We extended and validated the trial-ready quantitative motor assessment battery "Q-Motor" for upper limb movements with clinician-reported, patient-focused, and performance outcomes of ataxia. METHODS: Exploratory single-center cross-sectional assessment in 94 subjects (46 cross-genotype ataxia patients; 48 matched controls), comprising five tasks measured by force transducer and/or position field: Finger Tapping, diadochokinesia, grip-lift, and-as novel implementations-Spiral Drawing, and Target Reaching. Digital-motor measures were selected if they discriminated from controls (AUC >0.7) and correlated-with at least one strong correlation (rho ≥0.6)-to the Scale for the Assessment and Rating of Ataxia (SARA), activities of daily living (FARS-ADL), and the Nine-Hole Peg Test (9HPT). RESULTS: Six movement features with 69 measures met selection criteria, including speed and variability in all tasks, stability in grip-lift, and efficiency in Target Reaching. The novel drawing/reaching tasks best captured impairment in dexterity (|rho9HPT| ≤0.81) and FARS-ADL upper limb items (|rhoADLul| ≤0.64), particularly by kinematic analysis of smoothness (SPARC). Target hit rate, a composite of speed and endpoint precision, almost perfectly discriminated ataxia and controls (AUC: 0.97). Selected measures in all tasks discriminated between mild, moderate, and severe impairment (SARA upper limb composite: 0-2/>2-4/>4-6) and correlated with severity in the trial-relevant mild ataxia stage (SARA ≤10, n = 20). INTERPRETATION: Q-Motor assessment captures multiple features of impaired upper limb movements in degenerative ataxia. Validation with key clinical outcome domains provides the basis for evaluation in longitudinal studies and clinical trial settings.

Potential Prodromal Digital Postural Sway Markers for Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS) Detected via Dual-Tasking and Sensory Manipulation.

FXTAS is a neurodegenerative disorder occurring in some Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene premutation carriers (PMCs) and is characterized by cerebellar ataxia, tremor, and cognitive deficits that negatively impact balance and gait and increase fall risk. Dual-tasking (DT) cognitive-motor paradigms and challenging balance conditions may have the capacity to reveal markers of FXTAS onset. Our objectives were to determine the impact of dual-tasking and sensory and stance manipulation on balance in FXTAS and potentially detect subtle postural sway deficits in FMR1 PMCs who are asymptomatic for signs of FXTAS on clinical exam. Participants with FXTAS, PMCs without FXTAS, and controls underwent balance testing using an inertial sensor system. Stance, vision, surface stability, and cognitive demand were manipulated in 30 s trials. FXTAS participants had significantly greater total sway area, jerk, and RMS sway than controls under almost all balance conditions but were most impaired in those requiring vestibular control. PMCs without FXTAS had significantly greater RMS sway compared with controls in the feet apart, firm, single task conditions both with eyes open and closed (EC) and the feet together, firm, EC, DT condition. Postural sway deficits in the RMS postural sway variability domain in asymptomatic PMCs might represent prodromal signs of FXTAS. This information may be useful in providing sensitive biomarkers of FXTAS onset and as quantitative balance measures in future interventional trials and longitudinal natural history studies.

Sensory ataxic polyneuropathy unmasking late-onset urea cycle defect.

A 63-year-old man with type 2 diabetes mellitus, alcohol consumption in moderation, and three episodes of hepatic encephalopathy presented with symmetrical lower limb distal weakness, sensory ataxia, thickened palpable nerves, mood disturbances for seven years, and a family history of schizophreniform disorders. Nerve conduction studies showed demyelinating sensorimotor polyradiculoneuropathy. CSF analysis showed mild albumino-cytological dissociation. MRI brain and lumbosacral plexus showed thickened fifth cranial nerves and lumbosacral roots. He was treated with steroids for a provisional diagnosis of chronic inflammatory polyneuropathy and became encephalopathic. EEG showed triphasic waves. Serum ammonia was 201 micrograms/dL. Further evaluation suggested ornithine transcarbamylase (OTC) deficiency. The patient underwent hemodialysis with a low protein diet, rifaximin, and sodium benzoate, with subsequent recovery.

Predictors of Clinically Important Neuroimaging Findings in Children Presenting Pediatric Emergency Department.

OBJECTIVE: The aim of the study is to evaluate predictors of clinically important neuroimaging results, that is, computed tomography and magnetic resonance imaging in children in an academic pediatric emergency department (PED) from 2015 to 2019. METHODS: This study was conducted in an academic PED. The patient's demographic and clinical characteristics of PED visits and neuroimaging findings requested at the PED were recorded for January 1, 2015, to December 31, 2019. In addition, descriptive statistics and logistic regression analyses were conducted. We described and determined the predictors of clinically important neuroimaging findings in children. RESULTS: Clinically important neuroimaging findings were detected in patients with blurred vision ( P = 0.001), ataxia ( P = 0.003), unilateral weakness ( P = 0.004), and altered level of consciousness ( P = 0.026). Clinically important neuroimaging was found 9.4 times higher in patients with altered level of consciousness, 7.4 times higher in patients with focal weakness, 4.6 times higher in patients with blurred vision, and 3.5 times more in patients presenting with ataxia. CONCLUSIONS: Advanced neuroimaging, especially for selected patients in PED, can improve the quality of health care for patients. On the other hand, irrelevant neuroimaging findings can lead physicians away from prompt diagnosis and accurate management. According to our study, advanced neuroimaging can be performed in the early period for both diagnosis and early treatment, especially in selected patients with ataxia, blurred vision, altered consciousness, and unilateral weakness. In other cases, clinicians may find more supporting evidence.

Long-term performance of show-jumping horses and relationship with severity of ataxia and complications associated with myeloencephalopathy caused by equine herpes virus-1.

BACKGROUND: Equine herpesvirus myeloencephalopathy (EHM) has severe impact on the sport horse population. OBJECTIVE: Study the influence of EHM on the likelihood of affected horses to return to their previous performance and investigate the association of clinical variables with prognosis. ANIMALS: Twenty-six horses positive for equine herpesvirus type 1 (EHV-1) were admitted to a veterinary teaching hospital (VTH) during a natural EHM outbreak at an international jumping event. METHODS: Data collected from the VTH, the International Equestrian Federation, and surveys completed by the riders and horse owners were retrospectively analyzed. RESULTS: Horses affected by EHM had 68% chance of returning to exercise, and 52.9% were able to achieve their preoutbreak performance level. Horses with an ataxia grade at admission ≥4/5 had an increased fatality rate (P < .05) and 10% chance of reaching their preoutbreak performance level. None of the horses with both vascular and urinary complications returned to their previous performance level. Finally, horses vaccinated against EHV-1 and those with urinary complications had a 71.4% and 43.7% fatality rate, respectively. CONCLUSIONS AND CLINICAL IMPORTANCE: Horses affected by EHM were able to return to their previous performance levels, but certain clinical variables were negatively associated with postoutbreak performance. Ataxia grade upon admission and the development of systemic signs of vasculitis and urinary complications were potential poor prognostic indicators in sport horses. Variables linked to fatality included prior vaccination against EHV-1, ataxia grade upon admission, and the development of urinary complications.

Immune Ataxias: The Continuum of Latent Ataxia, Primary Ataxia and Clinical Ataxia.

The clinical category of immune-mediated cerebellar ataxias (IMCAs) is now recognized after 3 decades of clinical and experimental research. The cerebellum gathers about 60% of neurons in the brain, is enriched in numerous plasticity mechanisms, and presents a large variety of antigens at the neuroglial level: ion channels and related proteins, synaptic adhesion/organizing proteins, transmitter receptors, and glial cells. Cerebellar circuitry is especially vulnerable to immune attacks. After the loss of immune tolerance, IMCAs present in an acute or subacute manner with various combinations of a vestibulocerebellar syndrome (VCS), a cerebellar motor syndrome (CMS), and a cerebellar cognitive affective syndrome/Schmahmann's syndrome (CCAS/SS). IMCAs include gluten ataxia (GA), post-infectious cerebellitis (PIC), Miller Fisher syndrome (MFS), paraneoplastic cerebellar degeneration (PCD), opsoclonus myoclonus syndrome (OMS), anti-glutamic acid decarboxylase (anti-GAD) ataxia, and glial fibrillary acidic protein (GFAP) astrocytopathy (GFAP-A). In addition, multiple sclerosis (MS), acute disseminated encephalomyelitis (ADEM), Behçet disease, and collagen-vascular disorders may also present with cerebellar symptoms when lesions involve cerebellar afferences/efferences. Patients whose clinical profiles do not fit with IMCAs are now gathered in the group of primary autoimmune cerebellar ataxias (PACAs). Latent auto-immune cerebellar ataxia (LACA) refers to a clinical stage with a slow progressive course and a lack of obvious auto-immune background. At a pre-symptomatic stage, patients remain asymptomatic, whereas at the prodromal stage aspecific symptoms occur, announcing the symptomatic neuronal loss. LACA corresponds to a time-window where an intervention could lead to preservation of plasticity mechanisms. Patients may evolve from LACA to PACA and typical IMCAs, highlighting a continuum. Immune ataxias represent a model to elucidate the sequence of events leading to destruction of cerebellar neuronal reserve and develop novel strategies aiming to restore plasticity mechanisms.