Chronic Ataxia Research Articles

Hot cross bun sign in JC-Virus Granule cell neuronopathy in HIV infected patient – a case report

BackgroundJohn Cunningham virus related granule cell neuronopathy (JCV-GCN) is a rare manifestation of the reactivation of infection of the cerebellar granule cells by the JCV, mostly in immunocompromised individuals. The “hot cross bun” (HCB) sign is a cruciform hyperintensity seen in the midpons on T2-weighted and fluid attenuated inversion recovery (FLAIR) sequences on magnetic resonance imaging (MRI) of the brain. An index sub-Saharan Africa report of a case of JCV-GCN with HCB sign follows.Case PresentationA 27-year-old HIV positive female with JCV-GCN was re-evaluated for chronic ataxia complicated by subacute progressive horizontal diplopia. Cerebrospinal fluid (CSF) had trace Mycobacterium tuberculosis (MTB) detected by GeneXpert Mycobacterium Tuberculosis/Rifampicin resistance (MTB/RIF) assay test. Brain MRI revealed diffuse severe cerebellar atrophy with a hot cross bun sign and patchy enhancement contiguous to the cerebellar dentate nuclei bilaterally. She continued Highly Active Antiretroviral Therapy (HAART) pending CSF HIV viral load counts and started standard brain TB local treatment regimen protocols with progressive improvement in limb ataxia.ConclusionsIn conclusion, finding of the HCB sign may be indicative of and aid diagnosis of JCV-GCN in the right clinical context. This could be an important neuroimaging marker in this context, that may radiologically be more evident in later stages of the condition.

Severe, Subacute, Progressive, Sensory Predominant Polyneuropathy in a Patient with Chronic Progressive Cerebellar Ataxia and Antibodies to ITPR-1 (P1-14.013)

Severe, Subacute, Progressive, Sensory Predominant Polyneuropathy in a Patient with Chronic Progressive Cerebellar Ataxia and Antibodies to ITPR-1 (P1-14.013)

Diagnosis of lymphoma based on magnetic resonance imaging, analysis of cerebrospinal fluid, intraocular fluid and fine‐needle aspirate of a uveal mass lesion in a dog

AbstractA 10.5‐year‐old, male, entire labrador retriever dog was presented for chronic progressive ataxia and recent onset of a left‐sided head tilt and salivation. Neurological examination findings were deemed consistent with a multifocal brain and spinal cord neuroanatomic localisation. Ophthalmological examination of the right eye revealed pupil shape abnormality (dyscoria), a pale uveal mass lesion and white cellular sediment in the anterior chamber. Magnetic resonance imaging of the brain, eyes, thoracolumbar and lumbosacral spinal cord and surrounding structures showed multiple lesions affecting the central nervous system (brain), peripheral nervous system (left trigeminal nerve) and right eye. Cerebrospinal fluid, right eye anterior chamber fluid and fine‐needle aspirate biopsy of the uveal mass lesion yielded a cytological diagnosis of lymphoma (suspected large granular lymphocytic). The dog was discharged with palliative treatment and euthanased at home 4 days later. This case report documents the cytological diagnosis of lymphoma in the cerebrospinal fluid, intraocular fluid and fine‐needle aspirate of a uveal mass in a dog.

Clinical variability associated with intronic FGF14 GAA repeat expansion in Japan.

The GAA repeat expansion within the fibroblast growth factor 14 (FGF14) gene has been found to be associated with late-onset cerebellar ataxia. This study aimed to investigate the genetic causes of cerebellar ataxia in patients in Japan. We collected a case series of 940 index patients who presented with chronic cerebellar ataxia and remained genetically undiagnosed after our preliminary genetic screening. To investigate the FGF14 repeat locus, we employed an integrated diagnostic strategy that involved fluorescence amplicon length analysis polymerase chain reaction (PCR), repeat-primed PCR, and long-read sequencing. Pathogenic FGF14 GAA repeat expansions were detected in 12 patients from 11 unrelated families. The median size of the pathogenic GAA repeat was 309 repeats (range: 270-316 repeats). In these patients, the mean age of onset was 66.9 ± 9.6 years, with episodic symptoms observed in 56% of patients and parkinsonism in 30% of patients. We also detected FGF14 repeat expansions in a patient with a phenotype of multiple system atrophy, including cerebellar ataxia, parkinsonism, autonomic ataxia, and bilateral vocal cord paralysis. Brain magnetic resonance imaging (MRI) showed normal to mild cerebellar atrophy, and a follow-up study conducted after a mean period of 6 years did not reveal any significant progression. This study highlights the importance of FGF14 GAA repeat analysis in patients with late-onset cerebellar ataxia, particularly when they exhibit episodic symptoms, or their brain MRI shows no apparent cerebellar atrophy. Our findings contribute to a better understanding of the clinical variability of GAA-FGF14-related diseases.

Clinical and electrophysiological features of SCN8A variants causing episodic or chronic ataxia

Variants in SCN8A are associated with a spectrum of epilepsies and neurodevelopmental disorders. Ataxia as a predominant symptom of SCN8A variation has not been well studied. We set out to investigate disease mechanisms and genotype-phenotype correlations of SCN8A-related ataxia. We collected genetic and electro-clinical data of ten individuals from nine unrelated families carrying novel SCN8A variants associated with chronic progressive or episodic ataxia. Electrophysiological characterizations of these variants were performed in ND7/23cells and cultured neurons. Variants associated with chronic progressive ataxia either decreased Na+ current densities and shifted activation curves towards more depolarized potentials (p.Asn995Asp, p.Lys1498Glu and p.Trp1266Cys) or resulted in a premature stop codon (p.Trp937Ter). Three variants (p.Arg847Gln and biallelic p.Arg191Trp/p.Asp1525Tyr) were associated with episodic ataxia causing loss-of-function by decreasing Na+ current densities or a hyperpolarizing shift of the inactivation curve. Two additional episodic ataxia-associated variants caused mixed gain- and loss-of function effects in ND7/23cells and were further examined in primary murine hippocampal neuronal cultures. Neuronal firing in excitatory neurons was increased by p.Arg1629His, but decreased by p.Glu1201Lys. Neuronal firing in inhibitory neurons was decreased for both variants. No functional effect was observed for p.Arg1913Trp. In four individuals, treatment with sodium channel blockers exacerbated symptoms. We identified episodic or chronic ataxia as predominant phenotypes caused by variants in SCN8A. Genotype-phenotype correlations revealed a more pronounced loss-of-function effect for variants causing chronic ataxia. Sodium channel blockers should be avoided under these conditions. BMBF, DFG, the Italian Ministry of Health, University of Tuebingen.

Superficial siderosis suspected to be related to vertebral fracture and vertebroplasty

Superficial siderosis (SS) of the central nervous system is a rare disorder caused by chronic or recurrent hemorrhages into the subarachnoid space, and subsequent deposition of hemosiderin in the subpial layers of the brain and spinal cord lead to the development of neuronal damage. The diagnosis of SS is typically made by brain imaging and management may include identifying and treating the underlying cause of the bleeding, as well as symptomatic treatment. We present the case of a 79-year-old female with chronic progressive gait ataxia and dysarthria. She was eventually diagnosed with SS probably due to lumbar compression fracture treated with vertebroplasty 6 years ago.

Celiac disease seroprevalence in patients with infertility. A case-control study.

Although most patients with celiac disease (CD) have digestive manifestations, in some of them they may be of extraintestinal (atypical) nature, such as chronic anemia, ataxia, and fertility disorders. To determine the prevalence of CD-related antibodies in Mexican women with fertility disorders. Case-control study of women who attended evaluation for fertility disorders in a specialized center. h-tTG-IgA, gliadin IgA II and gliadin IgG II were quantified; titers > 30 IU were considered positive. One-hundred and seventy-one cases and 171 controls were included; 137 patients (80.1%) had infertility, and 34 (19.9%), sterility. Eight patients (4.6%, 95% CI = 2.3-8.9) had at least one positive marker for CD in comparison with one woman in the control group (0.5%, 95% CI = 0.01-3, p = 0.04, odds ratio = 8.3). Six of the eight patients had unexplained infertility. Up to 4.6% of women with infertility had at least one positive marker for CD. As in other parts of the world, screening for CD could be recommended in women with infertility, especially in those with unexplained infertility.

Patient-Friendly Summary of the ACR Appropriateness Criteria®: Ataxia-Child

Not being able to move in a coordinated fashion is referred to as ataxia. Signs of ataxia include clumsiness, unsteady gait, nystagmus, and dysdiadochokinesis (inability to perform rapid alternating movements like foot tapping). Ataxia may be genetic or acquired, such as from illness or trauma. Acute onset ataxia develops within hours or days. In children with acute ataxia and no recent history of trauma, MRI head without and with contrast, MRI head without contrast, or CT head without contrast are usually appropriate. MRA head and/or neck, MRI spine, and CTA head and/or neck may be appropriate. For acute ataxia (following traumatic head or neck injury), MRI head without contrast or CT head without contrast are usually appropriate. MRA head and/or neck and CTA head and/or neck may be appropriate. For recurrent ataxia (episodes of ataxia followed by relatively symptom-free periods), MRI head without contrast is usually appropriate. MRI spectroscopy head or MRI head without and with contrast may be appropriate. For chronic progressive ataxia (symptoms typically appear and increase in severity over at least two months), MRI head without and with contrast or MRI head without contrast are usually appropriate. MRI complete spine without or with/without contrast, and CT head without contrast may be appropriate. For chronic nonprogressive ataxia (symptoms typically appear in first year of life, last more than two months, and do not change in severity), MRI head without contrast is usually appropriate. MRI complete spine without contrast and CT head without contrast may be appropriate.

Episodic ataxia type 2: a clinical, genetic and radiological study of 10 patients

To describe a series of patients with episodic ataxia type 2 (EA2), attending to epidemiological, clinical, radiological, and therapeutic variables. Retrospective revision of patients with molecular diagnosis of EA2 (CACNA1A mutations), between 1988 and 2022. Information achieved from the database of our Movement Disorders clinic. A descriptive statistical analysis was made. Ten patients from five families were analyzed (six women). Median age at diagnosis was 37.5 years-old, with a median diagnostic delay of 20 years. 70% reported familial history of CACNA1A associated symptoms, although 50% presented migraine, epilepsy, dystonia, or neuropsychiatric alterations. Two heterozygous consanguineous patients had homozygotic descendance with infant mortality due to early-onset epileptic encephalopathy type 42. Five pathogenic/probably pathogenic CACNA1A variants were detected. 80% of patients had episodic triggers, being stress the most common. Episodes had a weekly frequency before treatment initiation. Six patients developed chronic ataxia (one patient demand gait support). 50% of patients with neuroimaging presented cerebellar atrophy. Acetazolamide were initiated in 80%, and 75% of them showed improvement of episodic symptoms. Nephrolithiasis was the most frequent side effect. EA2 has a great intrafamilial and interfamilial phenotypic variability. The most frequent phenotype were weekly episodes of unsteadiness, several hours of length, stress as the main trigger, chronic ataxia and gaze-evoked nystagmus. Acetazolamide is effective, although complications are usual. Neurologist must be alert as diagnostic delay is constant.

Rehabilitation in Ataxia

Ataxic disorders are numerous and relatively uncommon. They can result in lesions in the cerebellum, spinal cord, thalamic nuclei, vestibular nuclei, cerebral white matter and sensory pathways. Ataxia can be acute, subacute or chronic onset and progressive in nature. As pharmacological treatment, especially in chronic and progressive ataxia, is efficient nor is generally effective in treating various issues, rehabilitation has an important role to play in alleviating symptoms and quality of life. Various rehabilitation strategies such as conventional physical and occupational therapy, gait training and coordination therapy have been used for a long time. In the last 3–4 decades, there has been an addition in the armamentarium of rehabilitation with the use of non-invasive brain stimulation, virtual reality, body weight support treadmill training and robotic gait training to improve various aspects of the illness. The current evidence with rehabilitation strategies is also insufficient, so further longitudinal studies with bigger sample size and specific goal-directed therapies are the need of the hour.

C1 Cervical Stenosis Causing Chronic Neck Pain and Ataxia: The Importance of Physical Examination and Radiographic Imaging.

C1 Cervical Stenosis Causing Chronic Neck Pain and Ataxia: The Importance of Physical Examination and Radiographic Imaging.

Long-Surviving Adult Siblings With Joubert Syndrome Harboring a Novel Compound Heterozygous CPLANE1 Variant.

Background and ObjectivesWe describe 2 long-surviving siblings with a mild phenotype of Joubert syndrome (JBTS) harboring a novel compound heterozygous missense variant in the CPLANE1 gene.MethodsTargeted sequencing data of 2 middle-aged siblings (sister and brother) with JBTS were analyzed.ResultsThe patients were older than 60 years and presented with an inborn facial anomaly and ataxia, accompanied by a molar tooth sign on brain MRI. The male patient showed mild intellectual disability, abnormal eye movements, and progressive gait disturbance. Targeted sequencing revealed a compound heterozygous missense variant of CPLANE1 p.Arg1193Cys_Gln1223Pro; c.3577C>T_3668A>C. Multiple in silico assays predicted that the missense sites were pathogenic.DiscussionThe phenotype-genotype correlation of CPLANE1 remains controversial, although many cases have been previously reported in children and young adults. Our study revealed a novel pathogenic variant of CPLANE1 in patients, confirming the role of this gene in JBTS, thus providing an opportunity for neurologists to recognize JBTS as a differential diagnosis for chronic progressive ataxia in an aging society.

BREAST CANCER ASSOCIATED ANTI YO-ANTIBODY MEDIATED PARANEOPLASTIC CEREBELLAR DEGENERATION: CASE SERIES AND REVIEW OF LITERATURE

Paraneoplastic cerebellar degeneration (PCD) is a rare immune mediated disorder characterized by progressive cerebellar ataxia in presence of onconeural antibodies which occurs due to an indirect effect of underlying malignancy i.e. small cell lung cancer (SCLC), breast and gynecologic cancer, and Hodgkin lymphoma. In about 50% of patients neurological manifestation of Paraneoplastic cerebellar degeneration occurs prior to detection of carcinoma. Anti-Yo Antibody is the commonest antibody present in patients with Paraneoplastic cerebellar degeneration which is associated with breast carcinoma. We describe 3 female patients with anti YO antibody mediated PCD with breast cancer. One patient had a previous diagnosis of breast cancer with post mastectomy status one year back. Two of them presented with ataxia and on further examination, breast lump was found. All three patients had symmetrical ataxia with one patient had severely debilitating ataxia and was not able to walk unassisted. Magnetic resonance imaging brain showed cerebellar atrophy in two patients while one patient had normal MRI. Anti- YO antibody was strongly positive in all the three patients. All patients were given immunotherapy (corticosteroids in 2, Intravenous immunoglobulin in 1) with 1 patient showed modest improvement These case highlights the need to consider for workup for paraneoplastic cerebellar degeneration in female patients presenting with subacute to chronic progressive ataxia, so that the tumors can be detected and treated in early stage with a good outcome.

RFC1 repeat expansions: A recurrent cause of sensory and autonomic neuropathy with cough and ataxia.

Ataxia and cough are rare features in hereditary sensory and autonomic neuropathies (HSAN), a group of diseases of mostly unknown genetic cause. Biallelic repeat expansions in RFC1 are associated with cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS). This study aimed to investigate the prevalence of RFC1 repeat expansions in a cohort of HSAN patients. After unremarkable whole-exome sequencing (WES) analysis, we performed repeat-primed PCR to detect intronic RFC1 expansions in 12 HSAN families, who all presented with chronic cough. In these patients, 75% carried biallelic expansions of the pathogenic AAGGG motif. Compared with RFC1-/- cases, RFC1+/+ cases presented more consistently with positive sensory and autonomic symptoms. Afferent ataxia was more severe in the RFC1+/+ cohort and cerebellar ataxia was a common feature (21%). We demonstrate that RFC1 is a frequent cause of (WES-negative) HSAN with chronic cough and ataxia. The diagnostic yield of RFC1 repeat-primed PCR was surprisingly high, given that HSAN is genetically poorly understood. This combination of HSAN, ataxia, and chronic cough symptoms represents a new nosological entity within the neuropathy-ataxia spectrum.

CASPR2-IgG-associated autoimmune seizures.

This study was undertaken to report clinical presentations and outcomes of CASPR2-IgG-associated seizures. Mayo Clinic Neuroimmunology database was queried to identify CASPR2-IgG-seropositive (CASPR2-IgG+) patients evaluated at our institution (2009-2019). Of the 53 CASPR2-IgG+ patients (titer ≥ 1:10), 20had seizures (38%). All seizure patients were male, with median onset age of 68years. Eighteen (90%) had seizures at initial presentation. One patient was found to have malignancy (colon adenocarcinoma). Two patients had coexisting LGI1-IgG. Twelve patients had archived sera, which on titration had CASPR2-IgG titers ≥ 1:100. Fifteen patients (75%) met criteria for autoimmune encephalitis. Patients most commonly presented with focal onset, nonmotor seizures with impaired awareness (n=14, 70%). Eleven patients also had focal motor and/or sensory seizures as one of the seizure semiologies. The majority of patients (n=11, 55%) developed generalized tonic-clonic seizures during their disease course. Seizure clusters occurred in 12 patients. In addition to seizures, patients developed cognitive disturbance (n=16, 80%), episodic emotional lability (n=13, 65%), paroxysmal dizziness (n=9, 45%), episodic ataxia (n=6, 30%), and chronic ataxia (n=9, 45%). Only three patients (15%) had coexisting peripheral nervous system involvement. Frontotemporal or temporal ictal and/or interictal electroencephalographic abnormalities were present among nine patients, and three had multifocal epileptiform abnormalities. Eight patients (40%) had medial temporal T2/fluid-attenuated inversion recovery hyperintensity on brain magnetic resonance imaging. Elevated cerebrospinal fluid protein and/or lymphocytic pleocytosis was present in most cases (13/14, 93%). Thirteen patients reached seizure freedom following initiation of antiseizure medication (ASM; n=4) or a combination of immunotherapy and ASM (n=9). Median duration of follow-up was 25months (range = 2-136months). CASPR2-IgG evaluation should be considered among older male patients with new onset focal seizures and impaired awareness often occurring in clusters with/without features of encephalitis. Coexisting neurological manifestations, including episodic emotional lability, ataxia, and paroxysmal dizziness, also aid in the diagnosis.

Combined Genome, Transcriptome and Metabolome Analysis in the Diagnosis of Childhood Cerebellar Ataxia.

Ataxia in children is a common clinical sign of numerous neurological disorders consisting of impaired coordination of voluntary muscle movement. Its most common form, cerebellar ataxia, describes a heterogeneous array of neurologic conditions with uncountable causes broadly divided as acquired or genetic. Numerous genetic disorders are associated with chronic progressive ataxia, which complicates clinical management, particularly on the diagnostic stage. Advances in omics technologies enable improvements in clinical practice and research, so we proposed a multi-omics approach to aid in the genetic diagnosis and molecular elucidation of an undiagnosed infantile condition of chronic progressive cerebellar ataxia. Using whole-exome sequencing, RNA-seq, and untargeted metabolomics, we identified three clinically relevant mutations (rs141471029, rs191582628 and rs398124292) and an altered metabolic profile in our patient. Two POLR1C diagnostic variants already classified as pathogenic were found, and a diagnosis of hypomyelinating leukodystrophy was achieved. A mutation on the MMACHC gene, known to be associated with methylmalonic aciduria and homocystinuria cblC type, was also found. Additionally, preliminary metabolome analysis revealed alterations in our patient’s amino acid, fatty acid and carbohydrate metabolism. Our findings provided a definitive genetic diagnosis reinforcing the association between POLR1C mutations and hypomyelinating leukodystrophy and highlighted the relevance of multi-omics approaches to the disease.

From Genotype to Phenotype: Expanding the Clinical Spectrum of CACNA1A Variants in the Era of Next Generation Sequencing.

Ion channel dysfunction is a key pathological substrate of episodic neurological disorders. A classical gene associated to paroxysmal movement disorders is CACNA1A, which codes for the pore-forming subunit of the neuronal calcium channel P/Q. Non-polyglutamine CACNA1A variants underlie familial hemiplegic ataxia type 1 (FHM1) and episodic ataxia type 2 (EA2). Classical paroxysmal manifestations of FHM1 are migraine attacks preceded by motor aura consisting of hemiparesis, aphasia, and disturbances of consciousness until coma. Patients with EA2 suffer of recurrent episodes of vertigo, unbalance, diplopia, and vomiting. Beyond these typical presentations, several reports highlighted manifold clinical features associated with P/Q channelopathies, from chronic progressive cerebellar ataxia to epilepsy and psychiatric disturbances. These manifestations may often outlast the burden of classical episodic symptoms leading to pitfalls in the diagnostic work-up. Lately, the spreading of next generation sequencing techniques linked de novo CACNA1A variants to an even broader phenotypic spectrum including early developmental delay, autism spectrum disorders, epileptic encephalopathy, and early onset paroxysmal dystonia. The age-dependency represents a striking new aspect of these phenotypes und highlights a pivotal role for P/Q channels in the development of the central nervous system in a defined time window. While several reviews addressed the clinical presentation and treatment of FHM1 and EA2, an overview of the newly described age-dependent manifestations is lacking. In this Mini-Review we present a clinical update, delineate genotype-phenotype correlations as well as summarize evidence on the pathophysiological mechanisms underlying the expanded phenotype associated with CACNA1A variants.

Neurological syndromes of celiac disease

Celiac disease is an autoimmune disease in people with a genetic predisposition resulting from the consumption of gluten proteins from wheat, rye, barley and characterized by inflammation of the mucous membrane of the small intestine and atrophy of the villi. Neuropathy, migraine, chronic cerebellar ataxia and fibromyalgia are the most common extraintestinal celiac disease syndromes. The study of small nerve fibers is necessary for painful celiac disease syndromes such as gluten neuropathy and fibromyalgia, as well as for gluten autonomic neuropathy. The study of antineuronal antiganglioside antibodies is necessary for such lesions of both the central and peripheral nervous systems as gluten neuropathy and gluten cerebellar ataxia. A gluten-free diet directly affects the disappearance of headache attacks or a decrease in their frequency and intensity. There is little research on the effect of a gluten-free diet on headache risk.

Ayurvedic management in a chronic spinocerebellar ataxia and progressive improvement in scale for assessment and rating of ataxia score – An interrupted time series case report

Spinocerebellar Ataxias (SCAs) are a highly heterogenous group of disorders that often present as progressive incoordination of walking. Studies are underway globally to find a cure for this genetic disease. Although there are a few Ayurveda case studies reported in SCA, time series reporting of a case has not been done till date. In the present study, a case of SCA was admitted in the IPD, thrice in the period March 2019 to October 2020. The duration of therapy was around two months in each admission. Treatments that aim at arresting the progress of disease such as Nasya (~nasal therapy), Basti (~medicated enema), and Rasayana (~rejuvenative) and that strengthen musculoskeletal system such as Abhyanga (~external oleation) and Churna pinda sweda (~bolus fomentation) were done. The interrupted time series analysis was done with the help of Scale for Assessment and Rating of Ataxia (SARA) score on March 29, 2019, May 27, 2019, January 9, 2020, March 5, 2020, August 14, 2020, and October 13, 2020 and it showed progressive improvement with each admission.

CANVAS: a late onset ataxia due to biallelic intronic AAGGG expansions

The ataxias are a group of disorders that manifest with balance, movement, speech and visual problems. They can arise due to dysfunction of the cerebellum, the vestibular system and/or the sensory neurons. Genetic defects are a common cause of chronic ataxia, particularly common are repeat expansions in this group of conditions. Co-occurrence of cerebellar ataxia with neuropathy and vestibular areflexia syndrome has been termed CANVAS. Although CANVAS is a rare syndrome, on discovery of biallelic expansions in the second intron of replication factor C subunit 1 (RFC1) gene, we and others have found the phenotype is broad and RFC1 expansions are a common cause of late-onset progressive ataxia.We aim to provide a review and update on recent developments in CANVAS and populations, where the disorder has been reported. We have also optimised a protocol for RFC1 expansion screening which is described herein and expanded phenotype after analysing late-onset ataxia patients from around the world.