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Cerebellar ataxia-predominant multiple system atrophy (MSA-C) and cortical cerebellar atrophy are representative diseases of adult-onset sporadic degenerative ataxia. Both diseases are distinctly different because of α-synuclein pathology. However, it takes approximately 2 years for cerebellar ataxia to progress to concomitant severe autonomic dysfunction in patients with MSA-C. The period of only cerebellar ataxia (mono system atrophy) may extend to more than 10 years. Understanding mono system atrophy is vital for the early diagnosis and drug development for MSA. In this review, we discuss mono system atrophy focusing on the concept and natural history and the possibility of the of early diagnosis and disease-modifying therapy for MSA.

A 51-year-old man with a cerebral lacunar infarction of the midbrain that had occurred two years before, was transferred from a regional psychiatric hospital with chronic progressive psychiatric symptoms including cognitive decline, irritability and hallucinations. Neurological examinations upon admission revealed cerebellar ataxia including dysarthria, ataxic gait and bilateral intention tremor. Brain FLAIR MRI on day 2 revealed abnormal hyperintense lesions in the bilateral insular cortex and temporal pole. Treponemal and non-treponemal specific antibodies were positive in both serum and cerebrospinal fluid (CSF), indicating a diagnosis of neurosyphilis. Treatment with intravenous penicillin (24 × 10 6 units/day × 28 days) improved his psychiatric symptoms, ataxia, imaging abnormalities and inflammatory CSF findings. Cerebellar ataxia is a rare symptom of neurosyphilis. Nonetheless, the possibility of neurosyphilis should be considered if a young adult ataxia accompanied by psychiatric symptoms.

We present the case of a 51-year-old man with a 5-year history of slowly progressive gait ataxia and dysarthria who showed a wide-based gait requiring assistance. The patient's score on the Revised Hasegawa Dementia Scale (HDS-R) was 22/30 and constructional apraxia was also evident. Cerebrospinal fluid analysis showed 3 cells/microl, and the protein concentration was 58 mg/dl. Brain MRI showed no evidence of cerebellar atrophy, and SPECT-eZIS showed no decrease in cerebellar blood flow. However, voxel based morphometry (VBM) and FineSRT revealed cortical cerebellar atrophy and reduced cerebellar blood flow. In addition, the patient tested positive for anti-gliadin (IgA) and anti-SS-A/Ro antibodies, and was thus diagnosed as having autoimmune cerebellar ataxia. The patient showed positive response to intravenous immunoglobulins (IVIg) and regained the ability to walk unassisted. The HDS-R score also improved to 27/30. If cortical cerebellar atrophy can be diagnosed in the early stages in patients with progressive cerebellar ataxia by imaging techniques such as MRI-VBM and FineSRT, and if such patients test positive for anti-gliadin, anti-GAD or anti-thyroid antibodies, it is possible that they have autoimmune cerebellar ataxia. The commencement of immunotherapy including IVIg should be considered in such

A 58-year-old woman began to show ataxia at age 45 and dysarthria at age 56. Neurological examination revealed slurred speech, truncal ataxia, and pyramydal sign. Neither history of alcoholism nor hereditary factors were found. The level of serum ammonia was increased. Brain MRI study showed a high signal intensity in the cerebral peduncle and globus pallidus and mild cerebellar atrophy on T1-weighted image. A portal-systemic shunt due to a shunt vessel was found between the left splenic and kidney veins although she did not show any other symptoms or signs due to liver cirrhosis. Her symptoms dramatically improved by an intravenous administration of branched amino acid. The present case suggests an importance in finding a treatable cerebellar ataxia.

A case of neuro-Behçet's disease manifested as chronic progressive cerebellar ataxia is reported. A 56-year-old woman had suffered from recurrent oral aphthous ulcers, genital ulcers and polyarthritis since her late twenties. At age 53, she noticed small stepped-gait; at age 55, she developed scanning speech, a wide-based gait and memory disturbance. On admission she had oral aphthous ulcers, scarring of genital ulcers and polyarthralgia. A neurological examination revealed memory disturbance, saccadic eye movement, scanning speech, a slow tongue wiggle, moderate limb and truncal ataxia and moderate hyperreflexia in four limbs without pathological reflexes. Relevant laboratory examination data showed a positive HLA-B51. The cerebrospinal fluid (CSF) had a mild elevation of the cell counts and the amounts of protein. Brain magnetic resonance imaging showed mild atrophy of the cerebellum and brainstem. Fluoro-2-deoxyglucose-positron emission tomography showed a decreased glucose metabolism in the cerebellum and brainstem. Methylprednisolone pulse therapy (1 g x 3 days) followed by oral corticosteroids (50 mg/day) with gradual tapering markedly alleviated the cerebellar ataxia. The presence of oral and genital ulcers and CSF pleocytosis as well as effectiveness of corticosteroids in relieving the neurologic symptoms suggested neuro-Behçet's disease. We propose the existence of a new subtype of neuro-Behçet's disease characterized by chronic progressive cerebellar involvement possibly due to microvasculitis for which corticosteroids may be effective.

A 39-year-old man with episodic ataxia with nystagmus (EA-2) was reported. He showed intermittent cerebellar dysfunction, i.e., ataxia, nystagmus, dysarthria and vertigo, since he was 10 years old. Although this attack lasted for several hours, he was normal with exception of interictal nystagmus. His parents and sister showed no episodic ataxia. We ruled out the diseases, which may cause episodic ataxia, such as multiple sclerosis, vascular disorders, metabolic disorders and congenital anomalies. He was released from the attack by treatment with acetazolamide. EA-2 has been associated with mutations in the alpha 1A-voltage dependent calcium channel gene (CACNL1A4), which is also affected in familial hemiplegic migraine (FMH) and spinocerebellar ataxia type 6 (SCA6). In EA-2, frame-shift mutation leading to premature stop and splice-site mutation leading to truncated, non-functional channel protein have been reported. However, our patient did not have the mutations in the CACNL1A4 gene that were previously reported. In addition, our patient did not have an expanded CAG allele in the CACNL1A4 gene which is responsible for SCA6. Further examination is required to address whether a new mutation exists in the CACNL1A4 gene in our patient.

We reported a girl with "prolonged" cerebellar ataxia for whom steroid was effective. At the age of 9 months, she developed gait disturbance, tremor and abnormal eye movements following exanthema subitum. Her symptoms were prolonged for more than 4 months and she was admitted to our hospital. The symptoms were successfully suppressed with repeated ACTH treatment but recurred in a few weeks after cessation of the therapy. Steroid was also effective but reduction of the dosage resulted in worsening of symptoms. Immunological mechanism was suspected for her disorder because of her response to steroid and ACTH.

Paroxysmal cerebellar ataxia (PCA) is a specific disease which exhibits spasmodic cerebellar ataxia but rarely shows abnormal neurological findings in the intermission. Verger first described an isolated case. Subsequent reports of the disease included mostly cases with autosomal dominant inheritance, but the reports have been limited to about 20 families. Although both the lesion and the cause have not been clearly identified, since Vighetto et al. demonstrated the atrophy of the anterosuperior region of the cerebellar vermis using magnetic resonance imaging (MRI), the lesion of PCA captured the attention of researchers. The patient was a 40-year-old male, who exhibited spasmodic inarticulation and dizziness during walking when he was 10 years old. The symptoms gradually became aggravated in both frequency and duration. Abnormal findings were observed by electroencephalography and Hydantol F was given with no successful effect. The results of a CT scan of the head revealed no abnormality, whereas those of MRI revealed the atrophy in the folia of anterosuperior region of the cerebellar vermis by MRI as in the case of Vighetto et al., and PCA was suspected. Findings from positron emission tomography (PET) for the first time disclosed the abnormality in the cerebellar vermis and brainstem, and suggested an organic disorder in the cerebellar vermis and a functional abnormality in the cerebellum and brainstem. Since the report by Griggs et al., it has been known that acetazolamide is effective for PCA although the pharmacological mechanism is not yet clear. In our present case, the attack was improved in both frequency and duration by the administration of acetazolamide, and the effectiveness of acetazolamide in the patient was confirmed.(ABSTRACT TRUNCATED AT 250 WORDS)

Rolling mouse Nagoya (RMN), an ataxia mutant mouse, is adequate to checking up the efficacy of drugs on the ataxic movement disorders. The effects of some drugs on the ataxia of RMN were investigated by open field study. The drugs administered to RMN were as follows: TRH, FLA-63, DL-threo-DOPS, phenoxybenzamine and propranolol. Ataxic gait of RMN were remarkably improved by TRH, but remained unchanged by other drugs. The pretreatments with FLA-63, DOPS and phenoxybenzamine were not influenced to the antiataxic effects of TRH, while the pretreatment with propranolol increased the antiataxic effect of TRH in RMN. These results suggest that mechanism of the improvement of ataxic gait by TRH may not be sufficiently explained through only changing norepinephrine metabolism.

Histidyl-proline diketopiperazine (HPD) is the active metabolite deriving from thyrotropin-releasing hormone (TRH). However, its regional distribution in the central nervous system is quite different from TRH. Above all, it is to be noted that cerebellum is one of the richest region of HPD. In rat cerebellum, for example, the concentration of HPD is 20 times higher than that of TRH. This indicates the probable action of HPD within cerebellar system. Recently, a fascinating hypothesis has been proposed by Prasad et al that some activities of TRH are based on its conversion to HPD. The purpose of this experiment is to clarify whether the hypothesis may also be appropriate for the action in the cerebellar system. Twenty four Wistar rats treated with 3-acetylpyridin (3-AP) intraperitoneally were used in our experiment. Before 3-AP administration, those rats were conditioned by electric stimulation to run forward. The 3-AP treated rat is established so as to make an ataxic rat along with a selective degeneration of the inferior olive nucleus. Those ataxic rats were divided into 3 groups according to the test drugs, that is, the group of HPD, TRH (5 mumole/kg each), and saline [the same volume (3.6 ml/kg)] control. Eight rats of each group received an intraperitoneal injection once a day from 5th to 9th day after 3-AP treatment. The behavioral tests were carried out at the 5th, 7th, and 9th day after 3-AP treatment. The ataxic gaits were observed every 30 minutes over 4 hours in succession.(ABSTRACT TRUNCATED AT 250 WORDS)

Two cases of Vogt-Koyanagi-Harada disease with rare neurological complications were reported, which are one case with vestibular and cerebellar ataxia, and one with multiple cranial nerve palsies. The first case, a 32-year-old man, was admitted to our ophthalmologic department because of visual impairment. Two weeks later, he complained of gait disturbance. Limb and truncal ataxia, vestibular dysfunction and perceptive deafness were observed. Ophthalmologic examination revealed typical findings of Vogt-Koyanagi-Harada disease. CSF showed elevated protein and mononuclear pleocytosis. After treatment with oral steroid therapy, vestibular and cerebellar ataxia, and visual impairment improved. The second case, a 22-years-old man, showed the VIIth, VIIIth, IXth, and Xth cranial nerve palsies with visual impairment, and he was diagnosed to have cranial nerve palsies associated with Vogt-Koyanagi-Harada disease. After steroid therapy, there was a marked clinical improvement. Vogt-Koyanagi-Harada disease is an autoimmune disease against the melanocytes and involving tissues containing melanocytes such as uvea, meningea, skin and inner ear, etc.. Neurological complications except for meningitis and perceptive deafness have been rarely reported in Japan. Related to the present cases, possible pathogenesis was discussed.