Cerebellar Cortical Degeneration Research Articles

Cerebellar cortical degeneration in ‘Cirneco dell'Etna’ dog: First case report

AbstractA 4‐month‐old, intact male, Cirneco dell'Etna dog was presented with clinical signs of cerebellar ataxia, hindlimb hypometry and short steps with rapid progression. No findings were obtained from blood examinations, magnetic resonance imaging and cerebrospinal fluid (CSF) examinations and the dog was euthanased when it was not able to walk. Histological examination and immunohistochemical staining of the cerebellum showed multifocal depletion of Purkinje cells, marked increase in cellularity (astrogliosis) and a moderate reduction of the cells of the granule layer and thinning of the molecular layer. This case report describes the first case of cerebellar cortical degeneration in a purebreed Cirneco dell'Etna dog.

Magnetic resonance imaging pattern recognition of metabolic and neurodegenerative encephalopathies in dogs and cats.

Metabolic/neurodegenerative encephalopathies encompass a wide list of conditions that share similar clinical and magnetic resonance imaging (MRI) characteristics, challenging the diagnostic process and resulting in numerous tests performed in order to reach a definitive diagnosis. The aims of this multicentric, retrospective and descriptive study are: (I) to describe the MRI features of dogs and cats with metabolic/neurodegenerative encephalopathies; (II) to attempt an MRI recognition pattern classifying these conditions according to the involvement of grey matter, white matter or both; and (III) to correlate the MRI findings with previous literature. A total of 100 cases were recruited, comprising 81 dogs and 19 cats. These included hepatic encephalopathy (20 dogs and three cats), myelinolysis (five dogs), intoxications (seven dogs and one cat), thiamine deficiency (two dogs and seven cats), hypertensive encephalopathy (three dogs and two cats), neuronal ceroid lipofuscinosis (11 dogs and one cat), gangliosidosis (three dogs and two cats), fucosidosis (one dog), L-2-hydroxyglutaric aciduria (13 dogs and one cat), Lafora disease (11 dogs), spongiform leukoencephalomyelopathy (one dog) and cerebellar cortical degeneration (four dogs and two cats). None of the hepatic encephalopathies showed the previously described T1-weighted hyperintensity of the lentiform nuclei. Instead, there was involvement of the cerebellar nuclei (8/23), which is a feature not previously described. Dogs with myelinolysis showed novel involvement of a specific white matter structure, the superior longitudinal fasciculus (5/5). Thiamine deficiency affected numerous deep grey nuclei with novel involvement of the oculomotor nuclei (3/9), thalamic nuclei, subthalamus and cerebellar nuclei (1/9). Cats with hypertensive encephalopathy had a more extensive distribution of the white matter changes when compared to dogs, extending from the parietal and occipital lobes into the frontal lobes with associated mass effect and increased brain volume. Lysosomal storage disease showed white matter involvement only, with neuronal ceroid lipofuscinosis characterised by severe brain atrophy when compared to gangliosidosis and fucosidosis. All patients with L-2-hydroxyglutaric aciduria had a characteristic T2-weighted hyperintense swelling of the cerebral and cerebellar cortical grey matter, resulting in increased brain volume. Lafora disease cases showed either normal brain morphology (5/11) or mild brain atrophy (6/11). Dogs with cerebellar cortical degeneration had more marked cerebellar atrophy when compared to cats. This study shows the important role of MRI in distinguishing different metabolic/neurodegenerative encephalopathies according to specific imaging characteristics.

Clinical, imaging and histopathological characterization of a series of three cats with cerebellar cortical degeneration

BackgroundNeurological inherited disorders are rare in domestic animals. Cerebellar cortical degeneration remains amongst the most common of these disorders. The condition is defined as the premature loss of fully differentiated cerebellar components due to genetic or metabolic defects. It has been studied in dogs and cats, and various genetic defects and diagnostic tests (including magnetic resonance imaging (MRI)) have been refined in these species. Cases in cats remain rare and mostly individual, and few diagnostic criteria, other than post-mortem exam, have been evaluated in reports with multiple cases. Here, we report three feline cases of cerebellar cortical degeneration with detailed clinical, diagnostic imaging and post-mortem findings.Case presentationThe three cases were directly (siblings, case #1 and #2) or indirectly related (same farm, case #3) and showed early-onset of the disease, with clinical signs including cerebellar ataxia and tremors. Brain MRI was highly suggestive of cerebellar cortical degeneration on all three cases. The relative cerebrospinal fluid (CSF) space, relative cerebellum size, brainstem: cerebellum area ratio, and cerebellum: total brain area ratio, were measured and compared to a control group of cats and reference cut-offs for dogs in the literature. For the relative cerebellum size and cerebellum: total brain area ratio, all affected cases had a lower value than the control group. For the relative CSF space and brainstem: cerebellum area ratio, the more affected cases (#2 and #3) had higher values than the control group, while the least affected case (#3) had values within the ranges of the control group, but a progression was visible over time. Post-mortem examination confirmed the diagnosis of cerebellar cortical degeneration, with marked to complete loss of Purkinje cells and associated granular layer depletion and proliferation of Bergmann glia. One case also had Wallerian-like degeneration in the spinal cord, suggestive of spinocerebellar degeneration.ConclusionOur report further supports a potential genetic component for the disease in cats. For the MRI examination, the relative cerebellum size and cerebellum: total brain area ratio seem promising, but further studies are needed to establish specific feline cut-offs. Post-mortem evaluation of the cerebellum remains the gold standard for the final diagnosis.

Mild Deficits in Fear Learning: Evidence from Humans and Mice with Cerebellar Cortical Degeneration.

Functional brain imaging studies in humans suggest involvement of the cerebellum in fear conditioning but do not allow conclusions about the functional significance. The main aim of the present study was to examine whether patients with cerebellar degeneration show impaired fear conditioning and whether this is accompanied by alterations in cerebellar cortical activations. To this end, a 2 d differential fear conditioning study was conducted in 20 cerebellar patients and 21 control subjects using a 7 tesla (7 T) MRI system. Fear acquisition and extinction training were performed on day 1, followed by recall on day 2. Cerebellar patients learned to differentiate between the CS+ and CS-. Acquisition and consolidation of learned fear, however, was slowed. Additionally, extinction learning appeared to be delayed. The fMRI signal was reduced in relation to the prediction of the aversive stimulus and altered in relation to its unexpected omission. Similarly, mice with cerebellar cortical degeneration (spinocerebellar ataxia type 6, SCA6) were able to learn the fear association, but retrieval of fear memory was reduced. In sum, cerebellar cortical degeneration led to mild abnormalities in the acquisition of learned fear responses in both humans and mice, particularly manifesting postacquisition training. Future research is warranted to investigate the basis of altered fMRI signals related to fear learning.

Quantitative Analysis of Cerebellar Cortical Degeneration Using MRI in Dogs

Quantitative Analysis of Cerebellar Cortical Degeneration Using MRI in Dogs

Rapidly Progressive Cerebellar Ataxia and Dementia due to Cortical Cerebellar and Thalamic Degeneration: A Case Series of Two Autopsy Confirmed Patients (P8-11.016)

<h3>Objective:</h3> To report two patients with sporadic, adult-onset ataxia with a rapidly progressive disease course and extra-cerebellar symptoms resembling prion disease. <h3>Background:</h3> Sporadic, adult-onset cerebellar ataxia is a disease with multiple etiologies. Cortical cerebellar atrophy (CCA), idiopathic late-onset cerebellar ataxia and sporadic adult-onset ataxia of unknown etiology have been used to refer to this disorder. These names describe key features of the disease, including degeneration limited to the cerebellar cortex (with or without secondary involvement of inferior olivary nucleus), slowly progressive ataxia and the absence of a clear etiology. <h3>Design/Methods:</h3> We studied two patients with rapidly progressive cerebellar ataxia and dementia. We performed postmortem evaluation of the brain and whole genome sequencing, as well as analysis of AAGGG pentanucleotide repeat expansion in the <i>RFC1</i>. <h3>Results:</h3> Case 1 was a 36-year-old man with a one-year history of ataxia and dementia. Case 2 was a 41-year-old woman with a 16-month history of ataxia and dementia. Extensive studies on autoimmune etiologies and prion disease were negative in both patients. Pathological findings were consistent with CCA, but there were also degenerative changes in the thalamus of both cases. Immunohistochemistry did not show prion protein deposits. Genetic analyses did not reveal any pathogenic variants associated with cerebellar ataxia or pathologic repeat expansion in the <i>RFC1</i> gene. <h3>Conclusions:</h3> Although the underlying etiology of rapidly progressive CCA is unknown, we propose that the combination of clinical and pathological features of CAA with a short disease course defines a new disease entity, which we refer to as rapidly progressive cerebellar cortical and thalamic degeneration (RPCCAT). <b>Disclosure:</b> Dr. Koga has nothing to disclose. Mr. Ali has nothing to disclose. Matthew Baker has nothing to disclose. Klaas Wierenga has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for BMC Medical Genomics . Dr. Dompenciel has nothing to disclose. Dr. Dickson has nothing to disclose. Dr. Wszolek has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Polish Neurological Society/Via Medica.

A novel clinicopathologic entity causing rapidly progressive cerebellar ataxia?

Sporadic, adult-onset cerebellar ataxia is a disease with multiple etiologies. In addition to cortical cerebellar atrophy (CCA), which is often used for the pathological diagnosis, other terms such as idiopathic late-onset cerebellar ataxia (ILOCA) and sporadic adult-onset ataxia of unknown etiology (SAOA) have been used to refer to this disorder. These names describe key features of the disease, including degeneration limited to the cerebellar cortex (with or without secondary involvement of inferior olivary nuclei), a slowly progressive ataxia, and absence of a clear etiology, such as multiple system atrophy, as well as paraneoplastic, autoimmune, infectious and inherited ataxias. In this Point of View article, we describe two patients with sporadic, adult-onset ataxia with rapidly progressive disease course in addition to extracerebellar symptoms resembling prion disease, including the reevaluation of one patient who was previously reported. Pathological findings are mostly consistent with CCA, but also have degenerative changes in the thalamus. Whole genome sequencing in two patients with rapidly progressive CCA did not reveal any pathogenic variants associated with cerebellar ataxia. Although the underlying etiology behind rapidly progressive CCA is unknown, we suggest that the unique combination of clinical and pathological features of CAA with a short disease course defines a new disease entity, rapidly progressive cerebellar cortical and thalamic degeneration. This viewpoint article draws attention to this rare sporadic cerebellar ataxia with the hope that highlighting clinical and pathologic findings in a typical case will lead to improved recognition and research.

Cerebellar cortical degeneration with increased phosphorylated neurofilament heavy chain in cerebrospinal fluid in a Holstein calf

Cerebellar cortical degeneration with increased phosphorylated neurofilament heavy chain in cerebrospinal fluid in a Holstein calf

Antisense Oligonucleotide Therapy Targeted Against ATXN3 Improves Potassium Channel-Mediated Purkinje Neuron Dysfunction in Spinocerebellar Ataxia Type 3.

Spinocerebellar ataxia type 3 (SCA3) is the second-most common CAG repeat disease, caused by a glutamine-encoding expansion in the ATXN3 protein. SCA3 is characterized by spinocerebellar degeneration leading to progressive motor incoordination and early death. Previous studies suggest that potassium channel dysfunction underlies early abnormalities in cerebellar cortical Purkinje neuron firing in SCA3. However, cerebellar cortical degeneration is often modest both in the human disease and mouse models of SCA3, raising uncertainty about the role of cerebellar dysfunction in SCA3. Here, we address this question by investigating Purkinje neuron excitability in SCA3. In early-stage SCA3 mice, we confirm a previously identified increase in excitability of cerebellar Purkinje neurons and associate this excitability with reduced transcripts of two voltage-gated potassium (KV) channels, Kcna6 and Kcnc3, as well as motor impairment. Intracerebroventricular delivery of antisense oligonucleotides (ASO) to reduce mutant ATXN3 restores normal excitability to SCA3 Purkinje neurons and rescues transcript levels of Kcna6 and Kcnc3. Interestingly, while an even broader range of KV channel transcripts shows reduced levels in late-stage SCA3 mice, cerebellar Purkinje neuron physiology was not further altered despite continued worsening of motor impairment. These results suggest the progressive motor phenotype observed in SCA3 may not reflect ongoing changes in the cerebellar cortex but instead dysfunction of other neuronal structures within and beyond the cerebellum. Nevertheless, the early rescue of both KV channel expression and neuronal excitability by ASO treatment suggests that cerebellar cortical dysfunction contributes meaningfully to motor dysfunction in SCA3.

Cerebellar Cortical Degeneration in a Cross-Breed Calf

Cerebellar Cortical Degeneration in a Cross-Breed Calf

Late onset of cerebellar cortical degeneration in a Magellanic penguin (Spheniscus magellanicus).

An 8-year-old female Magellanic penguin (Spheniscus magellanicus) started to show epilepsy-like seizures. Subsequent magnetic resonance imaging (MRI) examinations did not reveal any responsible lesions. The neurological symptoms worsened at the age of 10. This penguin became recumbent and died 6 months later after the apparition of the recumbency. At necropsy, only multiple yellowish necrotic lesions in the air sacs and lungs were found. Histopathological evaluation of the brain showed a marked loss of Purkinje cells and many hypertrophied parvalbumin-positive basket/stellate cells were seen in the cerebellar cortex. Calbindin immunohistochemistry demonstrated disrupted arrangement of dendrites in the Purkinje cells. This case was diagnosed as cerebellar cortical degeneration with a very late onset and a slow progression in a Magellanic penguin.

A RARE CASE OF PARANEOPLASTIC NEUROLOGICAL SYNDROME ASSOCIATED WITH ADENOCARCINOMA OF THE LUNG

SESSION TITLE: Lung Cancer 1 SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/09/2018 01:15 PM - 02:15 PM INTRODUCTION: Paraneoplastic neurologic syndromes (PNS) are rare but clinically important complications of malignancy. These syndromes occur in approximately 0.01% of cancer patients, although more frequently in those with lung cancer, specifically small cell carcinoma. The neurologic syndromes are extensive and may present as encephalomyelitis, cerebellar cortical degeneration, peripheral neuropathy, neuopsoclonus-myoclonus, and retinopathy[1]. CASE PRESENTATION: A 76-year old woman with a recent diagnosis of well differentiated adenocarcinoma, mixed acinar and micropapillary, KRAS p.Gly12Val tumor marker positive, type lung cancer, presented with shortness of breath and altered mental status. According to family she was becoming progressively confused for the prior six weeks, displaying “hyper-somnolence” and speaking “with her eyes closed”. Neurological exam was significant for lethargy, confusion, and incoherent speech. Admission labs showed elevated WBC count 15.7; lactate 0.8. Chest X-ray showed patchy opacities bilaterally, and mild pulmonary congestion. CT scan of her brain was negative for acute pathology. Brain MRI was negative for metastatic disease. Empiric treatment for pneumonia was initiated based on x-ray findings. During her hospital stay, patient remained minimally communicative and unable to follow commands. VEEG was unremarkable. CSF analysis showed 5 WBC, no RBC, with 48% lymphocytes, and 48% monocytes. CSF cytology was negative for malignant cells. Elevated protein was measured at 81 mg/dL. CSF PCR was negative for VZV, HSV, and West Nile Virus. Paraneoplastic encephalitis was suspected due to lack of alternative etiologies for the patient’s symptoms. Treatment with IVIG and high-dose solumedrol was initiated. Ultimately, the paraneoplastic antibody panel resulted with type I anti-neuronal nuclear antibody (ANNA-1) titer of 1:512, Anti-Hu AB titer of 1:32, and anti-recoverin titer of 1:1. DISCUSSION: Paraneoplastic neurologic syndromes are rare clinical syndromes, resulting from the remote effect of a tumor on the nervous system, associated 95% of the time with small cell lung cancer [2]. Our patient’s manifestation of PNS with lung adenocarcinoma is extremely rare. Due to the very low incidence of non-small cell lung cancer associated with PNS, her diagnosis of lung adenocarcinoma was not believed to be contributory to her change in mental status. However, discovery of well characterized onconeural proteins such anti-Hu antibodies in the CSF, made a diagnosis of a PNS highly likely. CONCLUSIONS: Our case demonstrates that lung adenocarcinoma can play a role in the development of paraneoplastic neurologic syndrome and should be considered in the setting of a patient with altered mental status without other cause. Reference #1: Miyamoto, K., et al., A case of paraneoplastic syndrome accompanied by two types of cancer. J Neurol Neurosurg Psychiatry, 2002. 72(3): p. 408-9. Reference #2: Kanaji, N., et al., Paraneoplastic syndromes associated with lung cancer. World J Clin Oncol, 2014. 5(3): p. 197-223. DISCLOSURES: No relevant relationships by Scott Ferrara, source=Web Response No relevant relationships by eman rashed, source=Web Response No relevant relationships by Peter Rattner, source=Web Response No relevant relationships by Michael Silverberg, source=Web Response

Microstructural MRI Basis of the Cognitive Functions in Patients with Spinocerebellar Ataxia Type 2

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disease involving the cerebellum. The particular atrophy pattern results in some typical clinical features mainly including motor deficits. In addition, the presence of cognitive impairments, involving language, visuospatial and executive functions, has been also shown in SCA2 patients and it is now widely accepted as a feature of the disease. The aim of the study is to investigate the microstructural patterns and the anatomo-functional substrate that could account for the cognitive symptomatology observed in SCA2 patients. In the present study, diffusion tensor imaging (DTI) based-tractography was performed to map the main cerebellar white matter (WM) bundles, such as Middle and Superior Cerebellar Peduncles, connecting cerebellum with higher order cerebral regions. Damage-related diffusivity measures were used to determine the pattern of pathological changes of cerebellar WM microstructure in patients affected by SCA2 and correlated with the patients’ cognitive scores. Our results provide the first evidence that WM diffusivity is altered in the presence of the cerebellar cortical degeneration associated with SCA2 thus resulting in a cerebello-cerebral dysregulation that may account for the specificity of cognitive symptomatology observed in patients.

Genome sequencing reveals a splice donor site mutation in the SNX14 gene associated with a novel cerebellar cortical degeneration in the Hungarian Vizsla dog breed.

BackgroundCerebellar cortical degeneration (CCD) is an increasingly recognised neurodegenerative disease process affecting many dog breeds. Typical presentation consists of a progressive cerebellar ataxia, with a variable age at onset and rate of progression between different breeds. Cerebellar histopathological findings typically consist of primary Purkinje neuronal degeneration and loss, with variable secondary depletion of the granular and molecular cell layers. Causative genes have been identified associated with CCD in several breeds, allowing screening for selective breeding to reduce the prevalence of these conditions. There have been no previous reports of CCD in Hungarian Vizslas.ResultsTwo full-sibling Hungarian Vizsla puppies from a litter of nine presented with a history of progressive ataxia, starting around three months of age. Clinical signs included marked hypermetric and dysmetric ataxia, truncal sway, intention tremors and absent menace responses, with positional horizontal nystagmus in one dog. Routine diagnostic investigations were unremarkable, and magnetic resonance imaging performed in one dog revealed mild craniodorsal cerebellar sulci widening, supportive of cerebellar atrophy. Owners of both dogs elected for euthanasia shortly after the onset of signs. Histopathological examination revealed primary Purkinje neuron loss consistent with CCD. Whole genome sequencing was used to successfully identify a disease-associated splice donor site variant in the sorting nexin 14 gene (SNX14) as a strong causative candidate. An altered SNX14 splicing pattern for a CCD case was demonstrated by RNA analysis, and no SNX14 protein could be detected in CCD case cerebellum by western blotting. SNX14 is involved in maintaining normal neuronal excitability and synaptic transmission, and a mutation has recently been found to cause autosomal recessive cerebellar ataxia and intellectual disability syndrome in humans. Genetic screening of 133 unaffected Hungarian Vizslas revealed the presence of three heterozygotes, supporting the presence of carriers in the wider population.ConclusionsThis is the first report of CCD in Hungarian Vizsla dogs and identifies a highly associated splice donor site mutation in SNX14, with an autosomal recessive mode of inheritance suspected.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-016-0433-y) contains supplementary material, which is available to authorized users.

Conditioning and aversion to toxic Solanum bonariense ("naranjillo") leaves in calves

ABSTRACT: Solanum bonariense is a perennial poisonous shrub that induces cerebellar cortical degeneration when eaten by cattle. The aim of this research was to outline a protocol to induce a conditioned aversion to this plant. During the pre-conditioning period ten calves (126±12kg BW) were maintained at half of their normal energy intake with lucerne hay and water ad libitum, to stimulate consumption of S. bonariense. Every two days they were offered 100g ofS. bonariense leaves for 5 minutes. Calves began eating the target plant on day 10 and consumed all the plant material on day 12. The conditioning period began after each calf consumed the entire amount of S. bonariense for three consecutive sessions. Five animals were randomly selected for conditioning, and after ingestion ofS. bonariense they were dosed by oral gavage with lithium chloride (LiCl) at 200mg kg-1 BW (treated group), while the other five received a similar volume of water by oral gavage (control group). After 2 doses of LiCl the treated group ate no S. bonariense while the control group consumed the entire 100g. We confirmed that LiCl is a powerful tool to induce conditioned aversions against S. bonariense in calves, which persists for at least 3 months.

A novel pathogenic mechanism for cerebellar lesions produced by Solanum bonariense in cattle.

Intoxication with Solanum bonariense in cattle causes cerebellar cortical degeneration with perikaryal vacuolation, axonal swelling, and death primarily of Purkinje cells, with accumulation of electron-dense residual storage bodies in membrane-bound vesicles. The pathogenesis of this disease is not fully understood. Previously, we proposed that inhibition of protein synthesis in Purkinje cells among other altered metabolic pathways could lead to cytoskeletal alterations, subsequently altering cell-specific axonal transport. In the present study, immunohistochemical and histochemical methods were used to identify neuronal cytoskeletal alterations and axonal loss, demyelination, and astrogliosis in the cerebellum of intoxicated bovines. Samples of cerebellum from 3 natural and 4 experimental cases and 2 control bovines were studied. Immunoreactivity against neurofilament (NF)-200KDa confirmed marked loss of Purkinje neurons, and phospho-NF protein, β-tubulin, and affinity reaction against phalloidin revealed an altered perikaryal distribution of neuronal cytoskeletal proteins in the remaining Purkinje cells in intoxicated cattle. Reactive astrogliosis in every layer of the cerebellar cortex was also observed with anti-glial fibrillary acidic protein immunohistochemistry. In affected cattle, demyelination and axonal loss in the cerebellar white matter, as well as basket cell loss were demonstrated with Klüver-Barrera and Bielschowsky stains, respectively. Based on these results, we propose that neuronal cytoskeletal alterations with subsequent interference of the axonal transport in Purkinje cells may play a relevant role in the pathogenesis of this neurodegenerative disorder, and also that demyelination and axonal loss in the cerebellar white matter, as well as astrogliosis in the gray matter, likely occur secondarily to Purkinje cell degeneration and death.

Spontaneous poisoning by Solanum subinerme Jack as a cause of cerebellar cortical degeneration in cattle

The present work reports cerebellar degeneration in cattle associated with the ingestion of Solanum subinerme in northern Brazil. The main clinical signs were periodic crises with loss of balance, falls, opisthotonus, and nystagmus. The histological lesions consisted of diffuse vacuolation of the perikaryon of the Purkinje neurons, followed by the loss of these cells and their substitution by Bergman glia. It is concluded that S. subinerme is another species of Solanum that causes cerebellar degeneration in cattle.

Case report: simultaneous occurrence of multifocal cortical hypoplasia and degeneration in the cerebellum and systematic cerebrovascular intimal fibroelastosis in a calf

The etiology of cerebellar hypoplasia is often uncertain in one litter or single animals. A spontaneous case of cerebellar cortical hypoplasia and degeneration with a topographic difference in the involvement of lesions is herein described in a 6-month-old female Japanese Shorthorn calf with a history of neurologic signs beginning at birth. The calf was euthanatized because of unfavorable prognosis. The most significant gross lesions were present in the cerebellum, where the cerebellar folia of the vermis and flocculonodular lobe were smaller in size than normal. Upon histopathologic examination of the cerebellum, the whole rostral vermis, some lobules of the caudal vermis, and the whole flocculonodular lobe displayed bilaterally symmetric cortical hypoplasia characterized by narrowing of the molecular layer, absence of Purkinje cells, and hypocellularity of the granular layer. Additional intracerebellar findings consisted of a varying degree of Purkinje cell loss leaving empty baskets in some folia of the well-developed lobules at the caudal vermis and the presence of areas displaying bilateral myelin deficiency in association with spongy vacuolar changes in the deep cerebellar nuclei. Other significant findings included an ischemic cell change of the cerebrocortical pyramidal neurons in the Sylvian gyrus of the left parietal lobe and systematic intimal fibroelastic hyperplasia similar to arterio(lo)sclerosis in the cerebral and cerebellar blood vessels. These histopathologic evidences raise one possibility that a putative chronic hypoxemia due to systematic cerebrovascular alteration might have been implicated in the development of multifocal cerebellar cortical hypoplasia and degeneration in this calf, though final affirmation of this notion should await further investigations of similar or identical cases.

Experience in a short-term trial with 4-Aminopyridine in cerebellar ataxia

4-Aminopyridine (4-AP) is a reversible blocker of voltagegated potassium channels. Its slow release form has been approved for symptomatic treatment of gait disorder in multiple sclerosis [2]. In a number of small studies, 4-AP and the related compound 3,4-diaminopyridine (3,4-AP) improved downbeat nystagmus and reduced attack frequency in episodic ataxia [9]. In addition, 4-AP decreased gait variability in patients with chronic cerebellar ataxia of different origin [7, 8]. Chronic treatment with 3,4-AP had beneficial effects in a mouse model of spinocerebellar ataxia type 1 (SCA1) [3]. We here report our clinical experiences with 4-AP in 16 patients with chronic cerebellar ataxia. As 4-AP is thought to exert its effect on ataxia by interfering with the activity of cerebellar Purkinje neurons, we treated patients with SCA1, SCA3, SCA6 and sporadic adult-onset ataxia of unknown origin (SAOA), as well as one with a POLG mutation. These disorders are characterized by prominent cerebellar cortical degeneration with Purkinje cell involvement. Three centers participated in the observations. After giving informed consent, 16 patients were treated with the slow release form of 4-AP (Fampyra , 2 9 10 mg/day). Nine of the patients were female. Three patients were diagnosed SCA1, three SCA6, two SCA3, one genetically nonidentified autosomal dominant cerebellar ataxia, one POLG mutation and six of them a SAOA. Age was 60 ± 11.3 years (mean ± SD), disease duration 16.3 ± 17.1 years. To assess the severity of ataxia, we used the Scale for the Assessment and Rating of Ataxia (SARA) [5]. In addition, patients underwent three timed coordination tests, the 8 m walk (8 MW), the 9-hole pegboard (9HPT), and the speech rate test (PATA rate). Performance in these tests allows calculating the SCA Functional Index (SCAFI) [6]. Results of the timed tests are expressed as Z scores. Neurological symptoms other than ataxia were assessed with the Inventory of Non-Ataxia Signs (INAS) [4]. Patients estimated their health-related quality of life on the visual analogue scale of the EQ-5D (EQ-VAS) [1]. Assessments were done at baseline, 4 h and 14 days after treatment. Although two patients discontinued 4-AP due to side effects, the compound was generally well tolerated. This view is also supported by the trend towards an improvement of the EQ-VAS after 14 days. In the remaining 14 patients, SARA (range: 0–40) improved from 14.3 ± 4.7 to 13.0 ± 4.6 points after 4 h (n = 11) and to 13.7 ± 4.6 points after 14 days (n = 14), but these differences failed I. Giordano (&) H. Jacobi M. Minnerop T. Klockgether Department of Neurology, University Hospital of Bonn, Sigmund-Freud-Strase 25, 53105 Bonn, Germany e-mail: ilaria_anna.giordano@ukb.uni-bonn.de

Magnetic resonance imaging and brainstem auditory evoked responses in the diagnosis of cerebellar cortical degeneration in american staffordshire terriers

The aim of the study was to determine the diagnostic usefulness of magnetic resonance imaging (MRI) and brainstem auditory evoked responses (BAER) in dogs suspected of having cerebellar cortical degeneration (CCD). In the years 2009-2011, six dogs with suspected CCD were examined. Both MRI and BAER examinations revealed abnormalities in all dogs (100%). By MRI, T2-weighted midsagittal images revealed an increased amount of cerebrospinal fluid (CSF) surrounding the cerebellum within the sulci of the folia in all dogs (100%). In 4 out of the 6 dogs (66.66%), cerebellar hypoplasia was more visible in the region of the dorsal cerebellar lobules. In 5 out of the 6 dogs (83.33%), the fourth ventricle was enlarged. In our studies, the brain to cerebellum ratio evaluated on the midsagittal image was 11.93%, in comparison to 14.9% in normal dogs. By BAER examination, the amplitude of the first and second waves was diminished and III-V interlatency was prolonged in 5 out of the 6 dogs (83.33%). In one out of the 6 dogs (16.67%), only the III-V interlatency was prolonged. In one dog (16.67%), somato-nervous deafness in the left ear was detected, whereas in the right ear the III-V interlatency was prolonged. MRI of the cerebellum is a reliable method for the antemortem diagnosis of CCD in American Staffordshire terriers, as is BAER examination. BAER is an objective diagnostic tool, which - along with other diagnostic modalities - can be helpful in the assessment, management and follow-up of dogs with cerebellar abiotrophy. It proved to be useful in determining the severity of neurological lesions in comparison to MRI findings, as well as in assessing the prognosis.