Severe Cerebellar Ataxia Research Articles

Acute Cerebellar Ataxia in a Pediatric Case of Lyme Disease and a Review of Literature

A broad range of neurologic disorders have been described in children with Lyme disease, of which peripheral facial nerve palsy and aseptic meningitis are among the most common. In contrast, there are few reports of cerebellar involvement in pediatric Lyme disease patients. We report the case of a 5-year-old girl seropositive for antibodies against the causative Lyme disease pathogen Borrelia burgdorferi presenting with severe acute cerebellar ataxia from the in southern coast of Anatolia (Mediterranean region).

Methoxetamine associated reversible cerebellar toxicity: Three cases with analytical confirmation

Context. There have been recent concerns about increasing use and accessibility of methoxetamine, a ketamine derivative. Few data are available to describe the clinical features associated with methoxetamine exposure. We report three cases that presented to hospital with acute neurological toxicity associated with analytically confirmed methoxetamine exposure. Case details. A 19-year-old male presented with severe truncal ataxia, nystagmus, incoordination and reduced conscious level several hours after nasal insufflation of what was initially thought to be ketamine. Features of cerebellar toxicity persisted for 3–4 days before gradual recovery. Two more patients aged 17 and 18 years presented with severe cerebellar ataxia, imbalance and reduced conscious level 40 minutes after nasal insufflation of methoxetamine (MXE). Both had slurred speech, incoordination and cerebellar ataxia that resolved within 24 hours. Serum methoxetamine concentrations were 0.24 mg/L, 0.45 mg/L and 0.16 mg/L, respectively, and no other drugs were identified on an extended toxicological screen. Discussion. Methoxetamine may cause rapid onset of neurological impairment, characterised by acute cerebellar toxicity. Spontaneous recovery was observed, but the duration of recovery may extend to several days. Presentation with an acute cerebellar toxidrome should alert clinicians to the possibility of methoxetamine exposure.

Surgical treatment of intraventricular ependymomas and subependymomas

Background and purposeThe aim of the study was to present our experience in the surgical treatment of intraventricular ependymomas and subependymomas with special consideration to the evaluation of the surgical outcome and risk of tumour recurrence. Material and methodsWe report a series of 36 consecutive patients treated surgically for intraventricular ependymoma or subependymoma in the years 1992–2008. There were 26 lateral ventricle and 10 fourth ventricle tumours. Complete resection was achieved in 19 patients while the remaining 17 patients underwent either subtotal or partial resection. Histopathological evaluation revealed ependymoma, subependymoma and anaplastic ependymoma in 20, 11 and 5 cases, respectively ResultsEight patients died after surgery due to postoperative brain injury. Five patients were severely disabled postoperatively: one patient developed hemiparesis, three patients presented adynamic syndrome, and one patient developed severe cerebellar ataxia subsequent to vermis injury. All patients with posterior fossa tumours presented with lower cranial nerve deficit. Seventeen patients received radiotherapy postoperatively. There were five recurrent tumours during follow-up; three patients underwent subsequent reoperation. Importantly, five patients with supratentorial tumours and a history of incomplete resection with postoperative radiotherapy had no tumour recurrence in over 10 years’ follow-up. ConclusionsIntraventricular ependymomas and subependymomas still remain a surgical challenge due to a relatively high incidence of incomplete tumour resections and/or permanent neurological complications associated with their removal. Still, even incomplete tumour removal with subsequent radiotherapy facilitates long-term progression-free survival in some cases.

Paraneoplastic cerebellar degeneration in Hodgkin′s lymphoma

Paraneoplastic cerebellar degeneration (PCD) is a rare disorder presenting typically with acute or subacute severe cerebellar ataxia. PCD is most commonly associated with small cell lung cancer followed by adenocarcinoma of breast and ovary, and Hogdkin's lymphoma. We report a case of a 54-year-old male with acute-onset pancerebellar syndrome with underlying Hodgkin's lymphoma. A high index of suspicion of PCD resulted in arriving at an early diagnosis of underlying Hodgkin's disease. The patient was managed with six cycles of chemotherapy, which resulted in clinical stabilization and reversal of magnetic resonance imaging abnormalities. Antitumor therapy appears to have a significant impact on reversing PCD and hence early diagnosis and intervention for the primary remains the corner stone in stabilizing the neurological condition.

Primary and secondary CoQ10 deficiencies in humans

CoQ(10) deficiencies are clinically and genetically heterogeneous. This syndrome has been associated with five major clinical phenotypes: (1) encephalomyopathy, (2) severe infantile multisystemic disease, (3) cerebellar ataxia, (4) isolated myopathy, and (5) nephrotic syndrome. In a few patients, pathogenic mutations have been identified in genes involved in the biosynthesis of CoQ(10) (primary CoQ(10) deficiencies) or in genes not directly related to CoQ(10) biosynthesis (secondary CoQ(10) deficiencies). Respiratory chain defects, ROS production, and apoptosis variably contribute to the pathogenesis of primary CoQ(10) deficiencies.

Clinical Course of Patients with Familial Early-Onset Alzheimer’s Disease Potentially Lacking Senile Plaques Bearing the E693Δ Mutation in Amyloid Precursor Protein

Background/Aims: Oligomeric amyloid β (Aβ) is currently considered to induce Alzheimer’s disease (AD). We examined 2 patients with familial AD who possessed the Osaka (E693Δ) mutation in amyloid precursor protein. To the best of our knowledge, these patients are the first AD cases presumably affected with Aβ oligomers in the absence of senile plaques, and they support the Aβ oligomer hypothesis. Methods: We evaluated the clinical course, neuropsychological data, cerebrospinal fluid biomarker levels, magnetic resonance imaging (MRI) scans, fluorodeoxyglucose-positron emission tomography (PET) scans, and Pittsburgh compound B (PiB)-PET images of these patients. Results: In the early stages, these patients developed memory disturbances in a similar rate to patients with sporadic AD. Despite their memory disturbances, both patients showed only limited brain atrophy on MRI and little amyloid accumulation on PiB-PET. Subsequent to the development of memory disturbances, both patients suffered from motor dysfunction, probably due to cerebellar ataxia, and, within a few years, the patients fell into an apallic state. Conclusions: Familial AD patients with Osaka (E693Δ) mutation show severe dementia, cerebellar ataxia, and gait disturbances.

A new phenotype of mitochondrial disease characterized by familial late-onset predominant axial myopathy and encephalopathy

Axial myopathy is a rare neuromuscular disease that is characterized by paraspinal muscle atrophy and abnormal posture, most notably camptocormia (also known as bent spine). The genetic cause of familial axial myopathy is unknown. Described here are the clinical features and cause of late-onset predominant axial myopathy and encephalopathy. A 73-year-old woman presented with a 10-year history of severe paraspinal muscle atrophy and cerebellar ataxia. Her 84-year-old sister also developed late-onset paraspinal muscle atrophy and generalized seizures with encephalopathy. Computed tomography showed severe atrophy and fatty degeneration of their paraspinal muscles. Their mother and maternal aunt also developed bent spines. The existence of many ragged-red fibers and cytochrome c oxidase-negative fibers in the biceps brachii muscle of the proband indicated a mitochondrial abnormality. No significant abnormalities were observed in the respiratory chain enzyme activities; however, the activities of complexes I and IV were relatively low compared with the activities of other complexes. Sequence analysis of the mitochondrial DNA from the muscle revealed a novel heteroplasmic mutation (m.602C>T) in the mitochondrial tRNAPhe gene. This familial case of late-onset predominant axial myopathy and encephalopathy may represent a new clinical phenotype of a mitochondrial disease.

Astrocyte Dysfunction Associated with Cerebellar Attrition in a Nijmegen Breakage Syndrome Animal Model

Nijmegen breakage syndrome (NBS) is a genomic instability disorder caused by hypomorphic mutations in the Nbs1 gene. When Nbs1 is conditionally inactivated in the central nervous system of mice (Nbs1-CNS-Δ), they suffer from severe cerebellar atrophy, ataxia, and white matter damage. Here, we show that conditional inactivation of the murine Nbs1 gene has a profound effect on the integrity and the functionality of the glial cells, which suggests their crucial role in the pathogenesis of NBS. Interestingly, in Nbs1-CNS-Δ mice, the dramatic reduction in the numbers of Purkinje and granule cells was also linked to a reduction of microglial cells but not to astrocytes (GFAP+), suggesting an impairment in astrocytic functionality. Nbs1 levels were dramatically reduced in adult astrocyte isolated from Nbs1-CNS-Δ mice, suggesting a major role in cerebellar pathology. In order to investigate the effect of Nbs1 deletion on astrocyte activity, we investigated glutamine synthetase levels in astrocyte and discovered 40% reduction as compared to WT. Furthermore, we found a significant reduction in the secretion of neurotrophic factors, such as brain-derived neurotrophic factor and neurotrophin 3. Understanding the contribution of malfunctioning astrocytes to the etiology of NBS can elucidate a hitherto unknown aspect of this disorder.

Coenzyme Q and mitochondrial disease

Coenzyme Q(10) (CoQ(10)) is an essential electron carrier in the mitochondrial respiratory chain and an important antioxidant. Deficiency of CoQ(10) is a clinically and molecularly heterogeneous syndrome, which, to date, has been found to be autosomal recessive in inheritance and generally responsive to CoQ(10) supplementation. CoQ(10) deficiency has been associated with five major clinical phenotypes: (1) encephalomyopathy, (2) severe infantile multisystemic disease, (3) cerebellar ataxia, (4) isolated myopathy, and (5) nephrotic syndrome. In a few patients, pathogenic mutations have been identified in genes involved in the biosynthesis of CoQ(10) (primary CoQ(10) deficiencies) or in genes not directly related to CoQ(10) biosynthesis (secondary CoQ(10) deficiencies). Respiratory chain defects, ROS production, and apoptosis contribute to the pathogenesis of primary CoQ(10) deficiencies. In vitro and in vivo studies are necessary to further understand the pathogenesis of the disease and to develop more effective therapies.

Late onset and rapid progression of cerebellar abiotrophy in a domestic shorthair cat

A two-year-old male domestic shorthair cat was seen because of sudden onset of incoordination and tremors that had rapidly worsened over five days. Neurological examination revealed severe cerebellar ataxia, intention tremors and bilaterally decreased menace response. Blood work evaluation included a complete cell blood count (CBC), serum biochemistry profile, urinalysis, faecal flotation, cerebrospinal fluid (CSF) analysis and retroviral testing. Except for testing positive for feline immunodeficiency virus (FIV) antibodies, all other results were within the normal range. The patient was euthanased two days later because of progression of clinical signs, and a necropsy was performed. Histologically, lesions were limited to the cerebellum and consistent with cerebellar abiotrophy. No secondary diseases that could explain the rapid development of clinical signs were found. It was considered unlikely that cerebellar degeneration was related to FIV positivity, as virus invasion of the central nervous system (CNS) is mainly limited to the cerebral cortex. This case report is the first to describe late onset and rapid progression cerebellar abiotrophy in a cat.

Conditional inactivation of the NBS1 gene in the mouse central nervous system leads to neurodegeneration and disorganization of the visual system

Nijmegen breakage syndrome (NBS) is a genomic instability disease caused by hypomorphic mutations in the NBS1 gene encoding the Nbs1 (nibrin) protein. Nbs1 is a component of the Mre11/Rad50/Nbs1 (MRN) complex that acts as a sensor of double strand breaks (DSBs) in the DNA and is critical for proper activation of the broad cellular response to DSBs. Conditional disruption of the murine ortholog of the human NBS1, Nbs1, in the CNS of mice was previously reported to cause microcephaly, severe cerebellar atrophy and ataxia. Here we report that conditional targeted disruption of the murine NBS1 gene in the CNS results in mal-development, degeneration, disorganization and dysfunction of the murine visual system, especially in the optic nerve. Nbs1 deletion resulted in reduced diameters of Nbs1-CNS-Δ eye and optic nerve. MRI analysis revealed defective white matter development and organization. Nbs1 inactivation altered the morphology and organization of the glial cells. Interestingly, at the age of two-month-old the levels of the axonal guidance molecule semaphorin-3A and its receptor neuropilin-1 were up-regulated in the retina of the mutant mice, a typical injury response. Electroretinogram analysis revealed marked reduction in a- and b-waves, indicative of decreased retinal function. Our study points to a novel role for Nbs1 in the development, organization and function of the visual system.

Diffusion-weighted Magnetic Resonance Imaging of a Severe Heat Stroke Patient Complicated with Severe Cerebellar Ataxia

A 78-year-old woman was admitted for severe heat stroke with brain damage. She was unconscious on arrival at the emergency room. Her armpit temperature was 42.0 degrees C and blood pressure was 76/25 mmHg. She was rapidly cooled and given intensive treatment. On magnetic resonance imaging, T1- and T2-weighted images showed no significant signals, but diffusion-weighted images demonstrated localized symmetrical injuries of the cerebellum and thalami. She gradually became conscious, but severe cerebellar ataxia persisted.

Oculopalatal tremor and severe late-onset cerebellar ataxia

Following four recurrent bleedings of a mesencephalic cavernoma within 10 years (figure 1A), a 62-year-old woman demonstrated left kinetic cerebellar syndrome. She then developed oculopalatal tremor (OPT) associated with bilateral inferior olive hyperintensity (figure 1B). Gamma knife radiation was performed, but she developed severe cerebellar ataxia. OPT secondary to brainstem strokes and …

Selective regulation of spontaneous activity of neurons of the deep cerebellar nuclei by N‐type calcium channels in juvenile rats

The cerebellum coordinates movement and maintains body posture. The main output of the cerebellum is formed by three deep nuclei, which receive direct inhibitory inputs from cerebellar Purkinje cells, and excitatory collaterals from mossy and climbing fibres. Neurons of deep cerebellar nuclei (DCN) are spontaneously active, and disrupting their activity results in severe cerebellar ataxia. It is suggested that voltage-gated calcium channels make a significant contribution to the spontaneous activity of DCN neurons, although the exact identity of these channels is not known. We sought to delineate the functional role and identity of calcium channels that contribute to pacemaking in DCN neurons of juvenile rats. We found that in the majority of cells blockade of calcium currents results in avid high-frequency bursting, consistent with the notion that the net calcium-dependent current in DCN neurons is outward. We showed that the bursting seen in these neurons after block of calcium channels is the consequence of reduced activation of small-conductance calcium-activated (SK) potassium channels. With the use of selective pharmacological blockers we showed that L-, P/Q-, R- and T-type calcium channels do not contribute to the spontaneous activity of DCN neurons. In contrast, blockade of high-threshold N-type calcium channels increased the firing rate and caused the cells to burst. Our results thus suggest a selective coupling of N-type voltage-gated calcium channels with calcium-activated potassium channels in DCN neurons. In addition, we demonstrate the presence of a cadmium-sensitive calcium conductance coupled with SK channels, that is pharmacologically distinct from L-, N-, P/Q-, R- and T-type calcium channels.

Hipomielinización central, hipogonadismo hipogonadotrófico e hipodontia: una nueva forma de leucodistrofia

To report one patient with slowly progressive encephalopathy, ataxia, central hypomyelination, hypodontia and hypogonadotropic hypogonadism, the 4H syndrome. This clinical picture has been described recently and there are only four patients reported previously. A girl with a previously normal early psychomotor development, presented a slowly progressive deterioration since 15 months of age. Now, she is 14 years old, and has a severe cerebellar ataxia, with tremor and dysmetria. She can't neither walk nor remain standing alone. She has lost the sphincter control and has an immature expressive language. She has no puberal development and definitive hypodontia of upper central incisors. The brain magnetic resonance imaging shows a diffuse hypomyelination, that is confirmed with diffusion and spectroscopy studies. The hypomyelinating leukoencephalopathies are disorders with abnormally low amount of myelin. The diagnosis is difficult in most of the patients. The hypomyelinating leukoencephalopathies include classic disorders and new leukoencephalopathies, described in the past few years.

Locomotor Training Using Body-Weight Support on a Treadmill in Conjunction With Ongoing Physical Therapy in a Child With Severe Cerebellar Ataxia

This case report describes the effects of locomotor training using body-weight support (BWS) on a treadmill and during overground walking on mobility in a child with severe cerebellar ataxia who was nonambulatory. To date, no studies have examined the efficacy of this intervention in people with cerebellar ataxia. The patient was a 13-year-old girl who had a cerebellar/brainstem infarct 16 months before the intervention. Her long-term goal was to walk independently in her home with a walker. Locomotor training using a BWS system both on the treadmill and during overground walking was implemented 5 days a week for 4 weeks in a clinic. Locomotor training using BWS on a treadmill was continued 5 days a week for 4 months at home. Prior to training, she was able to take steps on her own with the help of another person, but did not take full weight on her feet or walk on a regular basis. At 6 months, she walked for household distances. Prior to training, her Pediatric Functional Independence Measure scores were 3 (moderate assistance) for all transfers, 2 (maximal assistance) for walking, and 1 (total assistance) for stairs. At 6 months, her scores were 6 (modified independence) for transfers, 5 (supervision) for walking, and 4 (minimal assistance) for stairs. Prior to training, she was unable to take independent steps during treadmill walking; at 6 months, all of her steps were unassisted. Locomotor training using BWS on a treadmill in conjunction with overground gait training may be an effective way to improve ambulatory function in individuals with severe cerebellar ataxia, but the intensity and duration of training required for functionally significant improvements may be prolonged.

MRI evidence of white matter damage in a mouse model of Nijmegen breakage syndrome

Nijmegen breakage syndrome (NBS) is a genomic instability disease caused by hypomorphic mutations in the NBS1 gene encoding the Nbs1 (nibrin) protein. Nbs1 is a component of the Mre11/Rad50/Nbs1 (MRN) complex that acts as a sensor of double strand breaks (DSBs) in the DNA and is critical for proper activation of the broad cellular response to DSBs. Conditional disruption of the murine ortholog of NBS1, Nbn, in the CNS of mice was previously reported to cause microcephaly, severe cerebellar atrophy and ataxia. In this study we used MRI to study the brain morphology and organization of Nbn deleted mice. Using conventional T2-weighted magnetic resonance, we found that the brains of the mutant mice (Nbs1-CNS-del) were significantly smaller than those of the wild-type animals, with marked mal-development of the cerebellum. Region of interest analysis of the T2 maps revealed significant T2 increase in the areas of white matter (corpus callosum, internal capsule and midbrain), with minor changes, if any, in gray matter. Diffusion tensor imaging (DTI) data confirmed that fractional anisotropy values were significantly reduced in these areas, mainly due to increased radial diffusivity (water diffusion perpendicular to neuronal fibers). Biochemical analysis showed low and dispersed staining for MBP and GalC in Nbs1-CNS-del brains, indicating defects in myelin formation and oligodendrocyte development. Myelin index and protein levels were significantly reduced in these brains. Our results point to a novel function of Nbs1 in the development and organization of the white matter.

BDNF transgene improves ataxic and motor behaviors in stargazer mice

The stargazer ( stg) mouse exhibits severe cerebellar ataxia, abnormal motor behavior, and absence epilepsy. Selective failure of cerebellar brain-derived neurotrophic factor (BDNF) expression is one of the molecular defects in stg mutant. To determine the in vivo effect of BDNF replacement on cerebellar function, we generated a double mutant line of stg–BDNF mice by crossbreeding BDNF-overexpressing transgenics with stg mutants. Significant upregulation of BDNF mRNA and protein levels was confirmed in the double mutant cerebellum. Gross examination showed less severe ataxia with normal cerebellar cytoarchitecture in stg–BDNF mice than the original stg mice. Behavioral characterization of stg–BDNF mice revealed significantly improved performance in swimming test and footprint analysis compared to stg mice. These results provide in vivo evidence for the correlation of the cerebellar BDNF levels to the ataxia and motor behaviors of stg mice.

Motor and cognitive deficits in the heterozygous leaner mouse, a Ca v2.1 voltage-gated Ca 2+ channel mutant

The leaner mutation in mice affects the Ca v2.1 voltage-gated calcium channel α 1A-subunit gene ( Cacna1a), causing a reduction in calcium currents predominantly in Purkinje cells. This reduction in calcium currents causes severe progressive cerebellar ataxia, beginning around postnatal day 10, in homozygous leaner mice ( tg la / tg la ), while their heterozygous littermates ( tg la /+) present no obvious behavioral deficits. In humans, heterozygous mutations in the Cacna1a orthologous gene produce a broad range of neurological manifestations. To evaluate the phenotypic status of the tg la /+ animals, we assessed motor performance and cognition, at different ages, in these mutant mice. We were able to observe age-dependent impairment in motor and cognitive tasks; balance and motor learning deficits were found in demanding tasks on the rotarod and on the hanging wire test, while spatial learning and memory impairment was observed in the Morris water maze. Progressive dysfunction in escape reflexes, indicative of neurological impairment, was also present in tg la /+ animals. Although not presenting major motor alterations, tg la /+ mice show age-dependent motor and cognitive deficits.

Features of probable multiple system atrophy patients identified among 4770 patients with parkinsonism enrolled in the multicentre registry of the German Competence Network on Parkinson’s disease

We identified 221 patients with probable multiple system atrophy (MSA) among 4770 patients enrolled in the multicentre registry of the German Competence Network on Parkinson's disease (PD) according to the established consensus criteria to characterize their clinical presentation. Analyses of more than 100 recorded clinical items revealed several specifics: I) 50% of patients with probable MSA had asymmetry of symptoms at disease onset and tremor at rest was present in 25%; II) a positive response to levodopa was recorded in 51% of patients identified initially with severe autonomic failure and cerebellar ataxia; III) a positive family history was recorded in 11% (n = 23), two of these patients were identified with spinocerebellar ataxia type 3 (SCA3). Thus asymmetry of symptoms, tremor at rest and a positive response to levodopa are not as specific for idiopathic PD as believed previously. Patients with SCA3 may present with the clinical features of MSA.