Severe Cerebellar Ataxia Research Articles

IELSG38: phase II trial of front-line chlorambucil plus subcutaneous rituximab induction and maintenance in mucosa-associated lymphoid tissue lymphoma.

The IELSG38 trial was conducted to investigate the effects of subcutaneous (SC) rituximab on the complete remission (CR) rate and the benefits of SC rituximab maintenance in patients with extranodal marginal zone lymphoma (MZL) who received front-line treatment with chlorambucil plus rituximab. Study treatment was an induction phase with oral chlorambucil 6 mg/m2/day on weeks 1-6, 9-10, 13-14, 17-18, and 21-22, and intravenous rituximab 375 mg/m2 on day 1 of weeks 1-4, and 1,400 mg SC on weeks 9, 13, 17, and 21. Then, a maintenance phase followed with rituximab administered at 1,400 mg SC every two months for two years. Of the 112 patients enrolled, 109 were evaluated for efficacy. The CR rates increased from 52% at the end of the induction phase to 70% upon completion of the maintenance phase. With a median follow-up of 5.8 years, the 5-year event-free, progression-free, and overall survival rates were 87% (95% CI: 78-92), 84% (95% CI: 75-89), and 93% (95% CI: 86-96), respectively. The most common grade ≥3 toxicities were neutropenia (33%) and lymphocytopenia (16%). Six patients experienced treatment-related serious adverse events, including fever of unknown origin, sepsis, pneumonia, respiratory failure, severe cerebellar ataxia, and fatal acute myeloid leukemia. The trial showed that SC rituximab did not improve the CR rate at the conclusion of the induction phase, which was the main endpoint. Nevertheless, SC rituximab maintenance might have facilitated long-term disease control, potentially contributing to enhanced event-free and progression-free survival.

Severe Hypomagnesemia-induced Cerebellar Ataxia after Major Gastrointestinal Cancer Surgeries: A Report of Two Cases

Severe Hypomagnesemia-induced Cerebellar Ataxia after Major Gastrointestinal Cancer Surgeries: A Report of Two Cases

Teaching NeuroImages: The dentate sign in subacute cerebellar ataxia

A 79-year-old woman developed infectious periaortitis after an abdominal aortic aneurysm repair. A month later, she exhibited vertigo, dysarthria, and unsteady gait, progressing to inability to stand, painful paresthesia, and disorientation. Her examination showed dysmetria, dysdiadochokinesia, and severe cerebellar ataxia. She underwent extensive laboratory investigations, including autoimmune and paraneoplastic panels. Prominent dentate hyperintensity on T2-weighted and fluid-attenuated inversion recovery sequences had been overlooked (figure). The cerebellar syndrome, and the abnormal dentate signal, resolved within 15 days from discontinuing metronidazole. Besides encephalopathy and polyneuropathy, metronidazole can induce subacute cerebellar ataxia by selectively affecting the dentate nucleus.1,2 Recognizing this imaging hallmark identifies a reversible iatrogenic complication and prevents unnecessary testing.

Anti-GAD65 Antibody-Associated Autoimmune Encephalitis With Predominant Cerebellar Involvement Following Toripalimab Treatment: A Case Report of a Novel irAE of Toripalimab

Toripalimab (Junshi Bioscience Co., Ltd) is a new immune checkpoint inhibitor (ICI) that targets programmed cell death protein 1 (PD-1) in various cancers, including metastatic melanoma. No neurological immune-related adverse events (n-irAEs) of toripalimab have been reported, except for neuromuscular involvement. We report a case of a 63-year-old woman who presented with severe vertigo, vomiting, nystagmus, cerebellar ataxia, and cognitive impairment after toripalimab treatment for metastatic melanoma. Compared with the concomitant cognitive dysfunction and a pathological reflex involving the cerebral cortex, the signs and symptoms of cerebellar involvement were much more prominent. Anti-glutamic acid decarboxylase 65 (anti-GAD65) antibody was positive in both serum and cerebrospinal fluid (CSF). After intravenous immunoglobulin (IVIG) and methylprednisolone (IVMP) administration, the symptoms of vertigo and vomiting resolved, with cognitive impairment and cerebellar ataxia remaining. This is the first report of autoimmune encephalitis (AIE) as an n-irAE of toripalimab.

Deletion of CHD8 in cerebellar granule neuron progenitors leads to severe cerebellar hypoplasia, ataxia, and psychiatric behavior in mice

CHD8 is a candidate gene for autism spectrum disorders and neurological development delay. It has been reported to be essential for neurogenesis in the cerebral cortex, but the function of CHD8 in cerebellum has not been comprehensively investigated. The potential relationship of cerebellum dysplasia with psychiatric disorders in patients with CHD8 mutations is still not clear. In this study, we establish different conditional knockout mouse models to investigate the roles of CHD8 in cerebellar development. Mice with neural stem cell-specific Chd8 deletion exhibit significant reduction of cerebellum volume and no layering structure is detected. Genetic deletion of Chd8 in cerebellar granule neuron progenitors (GNPs) leads to cerebellar hypoplasia, absent of proliferation layer and ectopic of Purkinje neuron. However, no substantial cerebellar dysplasia is detected in mice with Purkinje neuron- or oligodendrocyte-specific Chd8 ablation. Single-cell RNA sequencing indicates that ribosome-related genes and pathways are most significantly disrupted in GNPs, indicating the potential mechanism. Importantly, in addition to the ataxia phenotype, mice with GNP-specific Chd8 ablation present a neuropsychiatric phenotype in three-chamber and light/dark tests. Taken together, our results provide insights not only into the function of CHD8 in cerebellar development, but also the pathogenesis of neuropsychiatric disorders in patients with CHD8 mutations.

Necessary treatment of brain metastases in poor‐performance status patients: for all, for no one, or for whom?

AbstractThe optimum treatment of brain metastases (BRM) in people with poor performance status remains to be ascertained. We aimed to report our reviewed 10‐year stereotactic radiosurgery experience of poor performance status patients with BRM treated at a single institution. Between June 2000 and December 2009, the study participants included 22 consecutive individuals with severe hemiparesis or cerebellar ataxia and stereotactic radiosurgery‐irradiated BRM. The mean follow‐up period was 26 months. Most of the patients were women, aged <65 years and diagnosed with solitary brain metastasis. Extracranial metastases were present in 45% of the patients. A total of 13 individuals (59%) died within 2 months after therapy, and nine patients (41%) died at a much later period. The overall median survival was 2 months, and the 2‐year and 5‐year crude survival rates were 41% and 14%, respectively. Short survival was not predominant after therapy in this limited experience, and the observed prolonged survival suggests that stereotactic radiosurgery still represents a valuable treatment option for poor performance status individuals with BRM.

Recurrent severe and long‐lasting cerebellar ataxia attacks in adult‐onset neuronal intranuclear inclusion disease

AbstractNeuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disease that is characterized by eosinophilic hyaline intranuclear inclusions. NIID presents highly variable clinical manifestations such as dementia, ataxia, convulsion, neuropathy, and autonomic dysfunction. A 60‐year‐old woman developed recurrent severe cerebellar ataxia (SARA score: 30/40 points). She was diagnosed with adult‐onset NIID by a characteristic brain diffusion‐weighed imaging hyperintensity lesion in subcortical white matter and intranuclear inclusion bodies in a skin biopsy. Her ataxia was more severe and lasted longer (additional 19 days) than a previous case, although she showed remarkable improvement.

Ablation of polyamine catabolic enzymes provokes Purkinje cell damage, neuroinflammation, and severe ataxia

BackgroundPolyamine catabolism plays a key role in maintaining intracellular polyamine pools, yet its physiological significance is largely unexplored. Here, we report that the disruption of polyamine catabolism leads to severe cerebellar damage and ataxia, demonstrating the fundamental role of polyamine catabolism in the maintenance of cerebellar function and integrity.MethodsMice with simultaneous deletion of the two principal polyamine catabolic enzymes, spermine oxidase and spermidine/spermine N1-acetyltransferase (Smox/Sat1-dKO), were generated by the crossbreeding of Smox-KO (Smox−/−) and Sat1-KO (Sat1−/−) animals. Development and progression of tissue injury was monitored using imaging, behavioral, and molecular analyses.ResultsSmox/Sat1-dKO mice are normal at birth, but develop progressive cerebellar damage and ataxia. The cerebellar injury in Smox/Sat1-dKO mice is associated with Purkinje cell loss and gliosis, leading to neuroinflammation and white matter demyelination during the latter stages of the injury. The onset of tissue damage in Smox/Sat1-dKO mice is not solely dependent on changes in polyamine levels as cerebellar injury was highly selective. RNA-seq analysis and confirmatory studies revealed clear decreases in the expression of Purkinje cell-associated proteins and significant increases in the expression of transglutaminases and markers of neurodegenerative microgliosis and astrocytosis. Further, the α-Synuclein expression, aggregation, and polyamination levels were significantly increased in the cerebellum of Smox/Sat1-dKO mice. Finally, there were clear roles of transglutaminase-2 (TGM2) in the cerebellar pathologies manifest in Smox/Sat1-dKO mice, as pharmacological inhibition of transglutaminases reduced the severity of ataxia and cerebellar injury in Smox/Sat1-dKO mice.ConclusionsThese results indicate that the disruption of polyamine catabolism, via coordinated alterations in tissue polyamine levels, elevated transglutaminase activity and increased expression, polyamination, and aggregation of α-Synuclein, leads to severe cerebellar damage and ataxia. These studies indicate that polyamine catabolism is necessary to Purkinje cell survival, and for sustaining the functional integrity of the cerebellum.

Severe Cerebellar Degeneration and Chiari I Malformation - Speculative pathophysiology based on a systematic review.

Symptomatic Chiari Type I Malformation (CM) is treated with posterior fossa decompression with or without duroplasty. We have noticed some cases with concomitant severe cerebellar ataxia due to cerebellar atrophy. The aim of this study is to review the literature of CM associated with severe cerebellar atrophy and discuss its potential physiopathology. A systematic literature review in the Pubmed Database was performed using the following key-terms: "cerebellar atrophy Chiari", and "cerebellar degeneration Chiari". Articles reporting the presence of cerebellar degeneration/atrophy associated with CM were included. We found only six studies directly discussing the association of cerebellar atrophy with CM, with a total of seven cases. We added one case of our own practice for additional discussion. Only speculative causes were described to justify cerebellar atrophy. The potential causes of cerebellar atrophy were diffuse cerebellar ischemia from chronic compression of small vessels (the most mentioned speculative cause), chronic raised intracranial pressure due to CSF block, chronic venous hypertension, and association with platybasia with ventral compression of the brainstem resulting in injury of the inferior olivary nuclei leading to mutual trophic effects in the cerebellum. Additionally, it is not impossible to rule out a degenerative cause for cerebellar atrophy without a causative reason. Severe cerebellar atrophy is found in some patients with CM. Although chronic ischemia due to compression is the most presumed cause, other etiologies were proposed. The real reasons for cerebellar degeneration are not known. Further studies are necessary.

A preventable ataxia: Cerebrotendinous xanthomatosis

Cerebrotendinous xanthomatosis is an autosomal recessive inborn error of metabolism that is an often missed but treatable cause of hereditary ataxia. We report a case of cerebrotendinous xanthomatosis (CTX) that was diagnosed only after the development of cognitive decline and adult onset ataxia in a 35-year-old man. He had poor scholastic performance in childhood followed by gradually progressive cognitive decline. He presented to us with severe cerebellar ataxia and oculomotor apraxia. The key features that led to the diagnosis of CTX were the history of cataracts in childhood and Achilles tendon xanthoma. His brain magnetic resonance imaging showed characteristic features of CTX, and the diagnosis was confirmed by demonstrating the mutation in exon 2 of the CYP27A1 gene. The recognition of CTX earlier could have prevented his significant disabilities. The definitive treatment is oral chenodeoxycholic acid, which will prevent the accumulation of the cholestanol, which is thought to be responsible for the neurotoxicity.

Elavl3 is essential for the maintenance of Purkinje neuron axons

Neuronal Elav-like (nElavl or neuronal Hu) proteins are RNA-binding proteins that regulate RNA stability and alternative splicing, which are associated with axonal and synaptic structures. nElavl proteins promote the differentiation and maturation of neurons via their regulation of RNA. The functions of nElavl in mature neurons are not fully understood, although Elavl3 is highly expressed in the adult brain. Furthermore, possible associations between nElavl genes and several neurodegenerative diseases have been reported. We investigated the relationship between nElavl functions and neuronal degeneration using Elavl3−/− mice. Elavl3−/− mice exhibited slowly progressive motor deficits leading to severe cerebellar ataxia, and axons of Elavl3−/− Purkinje cells were swollen (spheroid formation), followed by the disruption of synaptic formation of axonal terminals. Deficit in axonal transport and abnormalities in neuronal polarity was observed in Elavl3−/− Purkinje cells. These results suggest that nElavl proteins are crucial for the maintenance of axonal homeostasis in mature neurons. Moreover, Elavl3−/− mice are unique animal models that constantly develop slowly progressive axonal degeneration. Therefore, studies of Elavl3−/− mice will provide new insight regarding axonal degenerative processes.

Cerebellar Purkinje cell degeneration in a mule foal (Equus mulus mulus)

A case of a mule foal with cerebellar Purkinje cell degeneration is described. A one-day-old mule foal was presented with lateral recumbency, obtunded mentation, poor metabolic status (general weakness, congestive...

Is stereotactic radiosurgery of brain metastases in patients with poor performance status worthwhile?

192 Background: Performance status is a consistent predictor of outcome in people with advanced disease. Variable prognosis has not led to the exclusion of patients with Karnofsky performance scores of < 70 from treatment of brain metastases (BRM) with stereotactic radiosurgery (SRS). The role of SRS for BRM in individuals with poor performance status (PPS) has not been elucidated to date. To better understand the prognostic utility of SRS in this particular patient cohort, we assessed the longevity periods of our treated PPS subjects with BRM. Methods: A retrospective review of patients with BRM treated by SRS during a 10-year period (2000-2009) identified 22 adult individuals with PPS; PPS was defined by the presence of severe hemiparesis or cerebellar ataxia. The primary endpoint of the analysis was survival because of some limitations in the obtained data. The mean follow-up was 26 months (range: < 1 to 144 months). Results: The mean age was 55.8 years, and the majority of the subjects were female. Most of the patients were younger and diagnosed with solitary brain metastasis. The synchronous primary malignant tumor was not yet under control in a third of the patients, and extracranial metastases were noted in 45% of the subjects. Thirteen people (59%) died within two months after therapy, and nine patients (41%) lived for two years or longer. The overall crude survival rates at 1 year and 5 years were 41% and 18%, respectively. Treatment response information was not available in the short-survival group because of early demise. Intracranial tumor control was achieved in the long-term survivors, considering that BRM progression requiring repeat SRS was not observed in any instance. Characterization of the two groups with different longevities was not possible. Conclusions: Early mortality was not predominant in this limited experience, and the observed prolonged survival suggests that SRS still represents a valuable treatment option for individuals with PPS and BRM.

Exome Sequencing Identifying Dual Mutations in Calcium Signaling Genes GNAO1 and ATP2B3 in a Patient with Early Infantile Epileptic Encephalopathy

Early infantile epileptic encephalopathy (EIEE) is an age-dependent epileptic encephalopathy. It occurs early in life with various types of seizures, especially tonic spasms and its overall prognosis is poor. We report a 5-year-old boy with EIEE, severe developmental delay, intractable epilepsy, and congenital cerebellar ataxia. His infantile spasms were treated successfully with ACTH, but he later developed intractable focal seizures. Whole exome sequencing revealed a maternally inherited missense mutation in the ATP2B3 gene (c.3338C > T/p.T1113M) and a de novo missense mutation in the GNAO1 gene (c.133G > C/p.G45R). Both genes are associated with calcium signaling pathways. The ATP2B3 gene is associated with intracellular calcium clearance, resulting in abnormal calcium homeostasis and X-linked spinocerebellar ataxia-1. The GNAO1 gene is associated with G protein signaling, affecting calcium signaling, and EIEE. Both mutations are related to maintain cellular calcium homeostasis, but the phenotype was not significantly more severe than those which have been reported.

拡散テンソル画像が病態理解に有用であった両側性小脳性運動性失調で発症した中脳正中部梗塞の1例

An 85-year-old woman with hypertension was admitted with a sudden onset of gait disturbance and dysarthria. On admission, the patient showed severe bilateral cerebellar ataxia with moderate right medial longitudinal fasciculus (MLF) syndrome. Magnetic resonance (MR) imaging showed an acute infarction in the lower and medial part of midbrain. Diffusion tensor imaging (DTI) started from both cerebellar peduncles revealed that the lesion of the acute infarction matched the decussation of superior cerebellar peduncle where crossing of tract was seen and a part of its tract was interrupted at the site. Interruption of the cerebellum red nuclear path at the medial part of midbrain was considered to be the reason for bilateral cerebellar ataxia and visualization of cerebellum red nuclear path by DTI can give better understanding of the neurological symptom.

Early‐onset Behr syndrome due to compound heterozygous mutations in OPA1

SummaryBehr syndrome is an early‐onset and severe syndromic optic atrophy which is probably heterogeneous. Recently, a heterozygous mutation in OPA1 was reported in an adult‐onset Behr‐like syndrome. Heterozygous mutations in OPA1 are the main causes of autosomal dominant optic atrophy (DOA). As many as 20% of patients with DOA exhibit extra‐ocular signs including deafness, external ophthalmoplegia, ataxia, peripheral neuropathy and, myopathy. Aside from these autosomal dominant forms, only few syndromic cases have so far been linked to compound heterozygous OPA1 mutations suggestive of either recessive or semi‐dominant inheritance. However, the clinical spectrum of these emerging double‐mutant OPA1‐related disorders remains to be characterized. We report on four children affected with Behr syndrome associated with compound heterozygous OPA1 mutations. These children were similarly affected with an early‐onset neurological syndrome associating a severe optic atrophy (4/4), cerebellar ataxia (4/4), peripheral neuropathy (4/4), digestive involvement (2/4) and deafness (1/4). This report confirms the importance of searching an OPA1 compound heterozygosity in paediatric cases of syndromic optic neuropathy.

Inferior cerebellar hypoplasia resembling a Dandy-Walker-like malformation in purebred Eurasier dogs with familial non-progressive ataxia: a retrospective and prospective clinical cohort study.

Cerebellar malformations can be inherited or caused by insults during cerebellar development. To date, only sporadic cases of cerebellar malformations have been reported in dogs, and the genetic background has remained obscure. Therefore, this study`s objective was to describe the clinical characteristics, imaging features and pedigree data of a familial cerebellar hypoplasia in purebred Eurasier dogs. A uniform cerebellar malformation characterized by consistent absence of the caudal portions of the cerebellar vermis and, to a lesser degree, the caudal portions of the cerebellar hemispheres in association with large retrocerebellar fluid accumulations was recognized in 14 closely related Eurasier dogs. Hydrocephalus was an additional feature in some dogs. All dogs displayed non-progressive ataxia, which had already been noted when the dogs were 5 – 6 weeks old. The severity of the ataxia varied between dogs, from mild truncal sway, subtle dysmetric gait, dysequilibrium and pelvic limb ataxia to severe cerebellar ataxia in puppies and episodic falling or rolling. Follow-up examinations in adult dogs showed improvement of the cerebellar ataxia and a still absent menace response. Epileptic seizures occurred in some dogs. The association of partial vermis agenesis with an enlarged fourth ventricle and an enlarged caudal (posterior) fossa resembled a Dandy-Walker-like malformation in some dogs. Pedigree analyses were consistent with autosomal recessive inheritance.

The natural history of cerebellar degeneration of Niemann-Pick C mice monitored in vitro.

Niemann-Pick type C (NPC) disease is a fatal hereditary lysosomal lipid storage disease caused by mutations in NPC1 or NPC2. It is still unknown how this disorder evokes clinical signs. Typically, patients develop severe cerebellar ataxia due to progressive Purkinje cell loss. Hitherto, in vitro studies did not allow monitoring the natural process of NPC-associated Purkinje cell degeneration. Aim of this study was to evaluate whether organotypic slice cultures are usable to monitor the natural process of NPC-associated Purkinje-cell degeneration. We used organotypic cerebellar slice cultures of a well-established NPC mouse model to display the natural history of cerebellar degeneration in vitro and cultivated them for a prolonged time period of 6 weeks for the first time. Moreover we tested several therapeutic candidates and evaluated their effect on Purkinje-cell survival. Our approach proves that it is possible to monitor and to prevent NPC-related Purkinje cell death reliably in vitro. This is beneficial because in vivo Purkinje cell loss directly translates into clinical signs. Thus, therapeutically interesting compounds can be tested in vitro, not only to correct biochemical abnormalities, but also to show the likelihood of a compound to prevent ataxia. As to be expected from the results of previous animal experiments, 2-hydroxypropyl-β-cyclodextrin rescued Purkinje cells. We also discovered that 3-methyladenine preserved Purkinje cell numbers by adjusting the autophagic flux in NPC slices. We provide evidence that cerebellar slice cultures are a powerful in vitro tool to study NPC-associated Purkinje cell death in an organotypic setting.

Focused cerebellar laser light induced hyperthermia improves symptoms and pathology of polyglutamine disease SCA1 in a mouse model.

Spinocerebellar ataxia 1 (SCA1) results from pathologic glutamine expansion in the ataxin-1 protein (ATXN1). This misfolded ATXN1 causes severe Purkinje cell (PC) loss and cerebellar ataxia in both humans and mice with the SCA1 disease. The molecular chaperone heat-shock proteins (HSPs) are known to modulate polyglutamine protein aggregation and are neuroprotective. Since HSPs are induced under stress, we explored the effects of focused laser light induced hyperthermia (HT) on HSP-mediated protection against ATXN1 toxicity. We first tested the effects of HT in a cell culture model and found that HT induced Hsp70 and increased its localization to nuclear inclusions in HeLa cells expressing GFP-ATXN1[82Q]. HT treatment decreased ATXN1 aggregation by making GFP-ATXN1[82Q] inclusions smaller and more numerous compared to non-treated cells. Further, we tested our HT approach in vivo using a transgenic (Tg) mouse model of SCA1. We found that our laser method increased cerebellar temperature from 38 to 40°C without causing any neuronal damage or inflammatory response. Interestingly, mild cerebellar HT stimulated the production of Hsp70 to a significant level. Furthermore, multiple exposure of focused cerebellar laser light induced HT to heterozygous SCA1 transgenic (Tg) mice significantly suppressed the SCA1 phenotype as compared to sham-treated control animals. Moreover, in treated SCA1 Tg mice, the levels of PC calcium signaling/buffering protein calbindin-D28k markedly increased followed by a reduction in PC neurodegenerative morphology. Taken together, our data suggest that laser light induced HT is a novel non-invasive approach to treat SCA1 and maybe other polyglutamine disorders.

Identification of saccadic components in spinocerebellar ataxia applying an independent component analysis algorithm

Anomalies in the oculomotor system are well known symptoms in different neurodegenerative diseases. It has been found that patients suffering from severe spino cerebellar ataxia type 2 show deterioration in the main parameters used to describe saccadic movements, specifically the slowing of horizontal saccadic eye movements. Besides, a combination of two components, named pulse and step, constitutes an accepted model of the saccadic generation system. In the present work, independent component analysis is applied in order to separate both pulse and step components, revealing significant differences in several parameters related to the morphology of these components between patients and control responses. Ten electro-oculographic records of spino cerebellar ataxia type 2 patients and ten control subjects were processed with the proposed algorithm with the aim of obtaining a correct diagnosis. The results obtained from these real experiments reveal the validity of the proposed approach as a classification tool for the diagnosis of this disease.