Degenerative Cerebellar Ataxia: Medical Treatment Seo-Young Choi

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Degenerative Cerebellar Ataxia: Medical Treatment

Seo-Young Choi

Department of Neurology, Pusan National University Hospital, Pusan National University School of Medicine and Biomedical Research Institute, Busan, Korea ISSN: 2234-0971 대한안신경의학회지: 제9권 Supplement 1

Clin Neuroophthalmol 9(Suppl 1):S41-44, April 2019

Degenerative cerebellar ataxia:

Medical treatment

Case series Choi Seo-Young

• 100mg/d

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Choi SY • Degenerative Cerebellar Ataxia: Medical Treatment

Clin Neuroophthalmol 9(Suppl 1):S41-44, April 2019 S42 http://neuro-ophthalmology.co.kr

• Methodologic limitation 에 대한 discussion이 대 부분

• ICARS vs. SARA

• ICARS 5 point의 기준= 39점의

• Short 13%

observation period

• Heterogeneity

• 질환별 분석은 없으나, MSA-c 개 인data에서는 ICARS 변화가 거 의 없어 보임

• 2012, Cochrane review

• 2, 4, 4-8 weeks FU

• CBC, electrolyte, LFT, EKG

• mRS

• 3.6 ± 2.3 (range 0.75–9) years from the onset of disease

• followed up for 10.1 ± 3.1 (range 5–16) weeks over the course of their treatment with nilotinib (daily doses of 150–300 mg)

Patient 4

Patient 5

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Degenerative Cerebellar Ataxia: Medical Treatment • ^{Choi SY}

Clin Neuroophthalmol 9(Suppl 1):S41-44, April 2019 http://neuro-ophthalmology.co.kr S43

c-Abl?

• Def: the cellular homolog of the Abelson murine leukemia virus oncogene and belongs to the Abl family of tyrosine kinasepresent in the

cytoplasm and nucleus of the cell

• Expressed in most cells and is part of an intricate network of protein interactions and

phosphorylation events in the cell

• A variety of physiological functions including the regulation of cell growth and motility,

cytoskeleton dynamics, receptor endocytosis, DNA repair, cell survival and autophagy

• 다양한 cell에 서 다양한 기능 을 하고 있음

• CML: chimeric Breakpoint cluster region protein (BCR)- ABL1 fusion gene

• Enhanced protein kinase activity with cell proliferation

❶

❻

❸

❹

❺

• Nilotinib

• Animal model: increased concentrations of dopamine and its metabolites, improved motor behavior

• 실제 dopaminergic neuron 을 살리는(?) 문제에 대해서 는 아직 연구 중

• PD patients: reduced the relative level of phosphorylated (active) c-Abl in the cerebrospinal fluid

• Pagan, F. et al. J Parkinsons Dis, 2016

• 12 patients, 150-300mg/day for 24 weeks

• Motor and cognition improvements

• 1 patient = serious cardiac adverse event

기전?

1. c-Abl inhibits the NR2D subunit of NMDA receptor.

• ↑ the NMDA receptor at the postsynaptic PC → NO release → ↓ presynaptic glutamate release, synaptic plasticity

• possibly enhance the plasticity of the synapse between PC and parallel fibers by restoring the NMDA/NO activity.

2. Reverse the toxic effect of TDP-43

• TDP-43 is involved in the pathogenesis of various neurodegenerative disorders by altering the synaptic function, disruption glutamate homeostasis 3. Restore mGluR1-mediated cerebellar function

• metabotropic glutamate receptor 1 (mGluR1) in postsynaptic PC clears excessive glutamate in the synaptic place and generates slow excitatory postsynaptic potentials

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Choi SY • Degenerative Cerebellar Ataxia: Medical Treatment

Clin Neuroophthalmol 9(Suppl 1):S41-44, April 2019 S44 http://neuro-ophthalmology.co.kr

삼성역학 논문 review

• Indication 을 다 잡아보자.

• MSA C

Multiple systemic atropy

• Definite MSA

• the neuropathologic findings of widespread and abundant CNS alpha-synuclein–positive glial cytoplasmic inclusions (Papp–Lantos inclusions) in association with neurodegenerative changes in striatonigral or olivopontocerebellar structures

• Probable MSA

• A sporadic, progressive, adult (>30 y) onset disease characterized by

• Autonomic failure involving urinary incontinence (inability to control the release of urine from the bladder, with erectile dysfunction in males) or an orthostatic decrease of blood pressure within 3 min of standing by at least 30 mm Hg systolic or 15 mm Hg diastolic AND

• Poorly levodopa-responsive parkinsonism (bradykinesia with rigidity, tremor, or postural instability) OR

• A cerebellar syndrome (gait ataxia with cerebellar dysarthria, limb ataxia, or cerebellar oculomotor dysfunction)

S. Gilman, Neurology 2008

Possible MSA

• A sporadic, progressive, adult (>30 y) onset disease characterized by

• Parkinsonism (bradykinesia with rigidity, tremor, or postural instability) OR

• A cerebellar syndrome (gait ataxia with cerebellar dysarthria, limb ataxia, or cerebellar oculomotor dysfunction) AND

• At least one feature suggesting autonomic dysfunction (otherwise unexplained urinary urgency, frequency or incomplete bladder emptying, erectile dysfunction in males, or significant orthostatic blood pressure decline that does not meet the level required in probable MSA) AND

• At least one of the additional features shown in table 3

S. Gilman, Neurology 2008

Idiopathic cerebellar ataxia

1. Core features

1) Sporadic (negative family history)

2) Cerebellar ataxia with insidious onset in adults (> 30 years old) and a slowly progressive course

3) Cerebellar atrophy (bilateral) on brain CT/MRI 2. Exclusion criteria

1) Multiple system atrophy (probable or possible MSA)

Patients with MRI findings suggestive of MSA are excluded, even if they don't meet the criteria for possible MSA.

2) Hereditary ataxias

Negative for SCA1, 2, MJD/SCA3, 6, 8, 17, 31, or DRPLA by genetic testing 3) Other diseases (no evidence of established or symptomatic causes)

Tumor, Cerebrovascular, Infections, Immune-mediated, Inflammation, Demyelinating, Mitochondrial, Toxic, Metabolic, PSP, CJD, superficial siderosis

Yoshida, et al. JNS 2018