Effects of cerebellar transcranial magnetic stimulation on ataxias: A randomized trial.

INTRODUCTION: Cerebellar ataxia remains a neurological symptom orphan of treatment interventions, despite being prevalent and incapacitating. We aimed to study, in a double-blind design, whether cerebellar modulation could improve ataxia. METHODS: We included patients with diagnosis of spinocerebellar ataxia type 3, multiple systems atrophy cerebellar type, or post-lesion ataxia. Patients received five sessions each of sham and active cerebellar 1 Hz deep repetitive transcranial magnetic stimulation in randomized order. Our primary outcome was the decrease in the Scale for the Assessment and Rating of Ataxia when comparing phases (active x sham). Secondary outcomes measures included the International Cooperative Ataxia Rating Scale, and other motor, cognitive, and quality of life scales. This study was registered at clinicaltrials.gov (protocol NCT03213106). RESULTS: Twenty-four patients aged 29-74 years were included in our trial. After active stimulation, the Scale for the Assessment and Rating of Ataxia score was significantly lower than the score after sham stimulation [median (interquartile range) of 10.2 (6.2, 16.2) versus 12.8 (9.6, 17.8); p = 0.002]. The International Cooperative Ataxia Rating Scale score also improved after active stimulation versus sham [median (interquartile range) of 29.0 (21.0, 43.5) versus 32.8 (22.0, 47.0); p = 0.005]. Other secondary outcomes were not significantly modified by stimulation. No patient presented severe side effects, and nine presented mild and self-limited symptoms. CONCLUSIONS: Our protocol was safe and well-tolerated. These findings suggest that cerebellar modulation may improve ataxic symptom and provide reassurance about safety for clinical practice.

Multiple system atrophy: Building a global community - 30years of advocacy efforts.

Multiple system atrophy (MSA) is a rare, progressive and ultimately fatal neurodegenerative disease with no known cause and no available disease modifying treatment. Known previously by various names including Shy-Drager Syndrome, olivopontocerebellar atrophy (OPCA) and striatonigral degeneration, MSA can be classified simultaneously as a movement disorder, an autonomic disorder, a cerebellar ataxia and an atypical parkinsonian disorder. Despite scholarly attempts to better describe the disease, awareness among medical practitioners about multiple system atrophy as a diagnostic possibility has been slow to catch on. As a result, patients often go undiagnosed for many years or are largely misdiagnosed as Parkinson's disease. The non-homogeneous clinical presentation of MSA and years of confusing nomenclature have all contributed to a lack of awareness of the disease among healthcare professionals as well as the public. This lack of awareness has amplified the unmet needs of MSA patients and other stakeholders. Since the 1980s there has been a growing advocacy effort directed at this rare disease from advocacy groups, grassroots supporters, healthcare professionals and research networks. These stakeholders are beginning to unite their efforts and attack the disease from a global perspective in the hopes of improving outcomes for MSA patients in the future.

[Case of anti-TPO/gliadin antibody-positive cerebellar atrophy that responded to intravenous immunoglobulin therapy begun 16 years after onset].

We present a case of slowly progressive gait ataxia with a 16-year history in an 87-year-old woman. In 1994 she became aware of a slight unsteadiness while walking and cortical cerebellar atrophy was diagnosed. She had no familial history of neurological disorders. In 2007, idiopathic thrombocytopenic purpura (ITP) was diagnosed. The symptoms gradually worsened, and she was admitted in 2010 because she could not walk without support. MRI voxel-based morphometry (VBM) imaging showed atrophy of the entire cerebellum, and SPECT using eZIS showed reduced perfusion in the same regions. Her blood was positive for both anti-TPO antibody (42 IU/ml) and anti-gliadin antibody (20.2 EU). We therefore diagnosed autoimmune cerebellar atrophy. The patient showed a positive response to intravenous immunoglobulins (IVIg) and regained the ability to walk unassisted. Her posture and gait disturbance scores on the International Cooperative Ataxia Rating Scale had improved from 20 to 9. Even 16 years after onset, intravenous immunoglobulins were effective. In cases of prolonged disease, immunotherapy can be effective in autoimmune cerebellar atrophy and should not be excluded from the treatment choices.

Generation of induced pluripotent stem cells from skin fibroblasts of a patient with olivopontocerebellar atrophy.

Generation of induced pluripotent stem (iPS) cells from somatic cells of patients represents a powerful tool for disease modeling, and they may have a wide range of applications in cell therapies. Olivopontocerebellar atrophy (OPCA) is a rare and debilitating neurologic disease of insidious onset, characterized by atrophy of the cerebellum pons and inferior olivary nuclei with concomitant ambulation deficits and dyscoordination. Here, we report the generation of iPS cells from skin fibroblasts of a 56-year-old female patient with familial OPCA. OPCA is classified in the autosomal dominant ataxia that is also named spinocerebellar ataxia (SCA) 7. The disease allele of SCA7 gene of the patient contains 45 CAG trinucleotide repeats, the number of which is larger than the normal repeat number (4 to 36 CAG repeats). The OPCA-iPS cells were generated via ectopic expression of four transcription factors: OCT4, SOX2, KLF4 and c-MYC. The OPCA-iPS cells expressed the pluripotency markers, and they can be differentiated into various somatic cell types in vitro and in vivo. Furthermore, the iPS cells also can be committed to differentiate into neural cells. Therefore, the OPCA-iPS cells offer an unprecedented cell model to investigate disease mechanisms, discover novel drugs, and develop new therapies for OPCA.

Clinical study of transplantation of neural stem cells in therapy of inherited cerebellar atrophy.

OBJECTIVE: To study the clinical effect of neural stem cell transplantation in the treatment of inherited cerebellar atrophy (CA). METHODS: The cells from human fetal cerebellum (8-10 weeks of gestation) were grown and expanded in vitro. The cultured neurospheres were then planted into the dentate nuclei of patients by stereo tactic operation. Totally, 12 patients (7 males and 5 females with age ranging 22-62 years, mean 43 years) were treated by this operation from August 2006 to August 2008. RESULTS: The cells of fetal cerebellum were expanded by 10(7) folds in undifferentiated state in the culture. After the operation, no rejection was detected. Follow up, the effective rates were 58.3% after 3 months, 75.0% after 6 months, and 66.7% for 12-24 months (mean 18 months). CONCLUSION: The transplantation of in vitro cultured neural stem cell is a feasible and effective treatment for inherited CA, but the long term effectiveness need to be taken in consideration.

Various methods of Purkinje cells transplantation and their functional response in Lurcher mutant mice.

Embryonic cerebellum was transplanted to adult Lurcher mutant mice affected with hereditary olivocerebellar degeneration and with resulting cerebellar ataxia. Grafts were applied as solid pieces of tissue or as cell suspensions. The aim was to replace Purkinje cells lost by the neurodegeneration with embryonic cells and to observe the effect on motor symptoms of cerebellar ataxia. Success rate of the two methods was also compared. Motor skills were tested before and in week intervals after the transplantation. The results were compared with sham-operated controls. When the solid graft was transplanted, the success rate was two times higher as compared with the cell suspension method. Fibre sprouting and cell migration from the graft to the host tissue was observed. Insignificant amelioration of motor skills was found in mice after the solid cerebellar tissue transplantation, while the cell suspension application had no effect.

[Diagnosis and therapy of multiple system atrophy]. / Diagnostik und Therapie der Multisystematrophie.

Numerous studies of the past years have established the clinical features, course and neuropathology characterizing multiple system atrophy (MSA). Clinically, two motor subtypes can be classified based on the predominance of a parkinsonian syndrome refractory to L-dopa and cerebellar ataxia. 80% of the cases involve MSA-P (the parkinsonian variant of MSA) and 20% MSA-C (cerebellar variant of MSA). Virtually all of these patients show disturbances of autonomic and urogenital function, half of the patients also exhibit pyramidal signs. Neuropathologically, MSA-C is based on an olivopontocerebellar atrophy (OPCA) and MSA-P on striatonigral degeneration (SND). However, a combination of OPCA and SND pathologies is observed in most cases. Recent evidence suggests that a key pathogenetic role may be played by glial alpha synuclein-containing inclusion bodies, which might lead to neuronal dysfunction and ultimately to cell loss. There is no therapy known to be effective in treating the motor disorders of MSA-C. By contrast, L-dopa replacement is at least transiently effective in about 30% of patients with MSA-P. Currently, initial efforts are being undertaken throughout Europe to develop neuroprotective solutions. Experiments are underway to test whether neurotransplantation by striatal grafting is a suitable method for inducing a clinically relevant response to L-dopa. Neurologically, the options for treating orthostatic hypertension and urogenital disorders are often overlooked.

Clinical effects of elastic bandage on neurogenic orthostatic hypotension.

Neurogenic orthostatic hypotension (OH) often causes troublesome symptoms such as dizziness, syncope and falling, interfering active daily life or various therapies in rehabilitation. Nonpharmacologic measures for treating patients with OH include wearing elastic leotard, head-up tilting at night, etc. Elastic garment or antigravity suits is certainly effective, but it may be uncomfortable and not practical. Although elastic bandage (EB) bound on the lower limbs has been thought to be useful, there is few clinical report about its beneficial evidence. We investigated short-term clinical effects of commercially available EB on OH, and estimated the mechanism of its effectiveness by measuring some blood pressure-related humoral variables in neurodegenerative patients with OH.

The treatment of spinocerebellar ataxias: facts and hypotheses.

Actual therapeutic assays in spinocerebellar ataxias, i.e. in Friedreich's ataxia (FA) and olivopontocerebellar atrophy (OPCA) are discussed in relation to (i) the serotoninergic theory; (ii) the excitotoxic action of glutamate; and (iii) cerebrospinal fluid thiamine deficiency in ataxic patients. Data from the literature show that neurochemical deficiencies arising from cerebellar damage in both FA and OPCA patients are multiple. Assays of replacement and neuroprotective therapeutics with a single drug have produced controversial data or mildly effective results. Consequently, it is hypothesized that a drug cocktail, i.e. L-5-hydroxytryptophan, thiamine and amantadine hydrochloride, would be more beneficial. This cocktail proved to be useful in open studies, improving respiratory disorders in FA patients. More powerful inhibitors of N-methyl-D aspartate receptor channels should be tried initially in animal experiments.

Autoantibodies to glutamate receptor subunit GluR2 in nonfamilial olivopontocerebellar degeneration.

We describe a 63-year-old man with a 5-year history of progressive sporadic olivopontocerebellar atrophy (OPCA) who exhibits high serum titers of IgM autoantibodies to the neuronal glutamate receptor subunit GluR2. Immunohistochemistry revealed intense staining of mouse cerebellar Purkinje cells and cells in the pontine nuclei and olivary complex. Glutamate receptor currents were activated in a subset of cultured mouse neurons by an anti-GluR2 IgM fraction, and they were blocked by the competitive AMPA-type glutamate receptor antagonist CNQX and by a synthetic peptide to a specific epitope region of GluR2 (AA 369-393). The patient was treated with nine courses of plasmapheresis with little improvement of symptomatology. However, IgM titers to GluR2 decreased approximately 8-fold and the serum functional activity decreased proportionally. These findings may suggest a role for autoimmunity to glutamate receptors in the pathophysiology of certain forms of progressive nervous system degeneration.

Transcranial magnetic stimulation in multiple system and late onset cerebellar atrophies.

Central motor conduction time (CMCT) after transcranial magnetic stimulation (TMS) of the cortex, electromyography and nerve conduction velocity were performed in 24 patients with multiple system (MSA) and late onset cerebellar atrophy (LOCA) (often olivopontocerebellar atrophy--OPCA -). CMCT was abnormal in 7 patients with OPCA and one with LOCA. CMCT abnormalities (43% of cases) and increased threshold (68%) were more often found within OPCA group than in another multisystem atrophy and LOCA. Reduction in amplitude of the response after TMS was significantly correlated with cerebral hemispheres's atrophy. Increased threshold was correlated with upper vermal hemisphere atrophy and enlargement of the fourth ventricle. Electrophysiologic signs of mixed peripheral neuropathy were found in 8 patients. TMS abnormalities were not related to peripheral nerve involvement. Marked variation in CMCT suggests heterogeneity in these diseases. However, the percentage of CMCT abnormalities in OPCA group suggests that TMS seems to play a role in the neurophysiological diagnosis of these heterogeneous disorders.