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Review
. 2019;17(1):33-58.
doi: 10.2174/1570159X16666180917105033.

Immune-mediated Cerebellar Ataxias: Practical Guidelines and Therapeutic Challenges

Affiliations
Review

Immune-mediated Cerebellar Ataxias: Practical Guidelines and Therapeutic Challenges

Hiroshi Mitoma et al. Curr Neuropharmacol. 2019.

Abstract

Immune-mediated cerebellar ataxias (IMCAs), a clinical entity reported for the first time in the 1980s, include gluten ataxia (GA), paraneoplastic cerebellar degenerations (PCDs), antiglutamate decarboxylase 65 (GAD) antibody-associated cerebellar ataxia, post-infectious cerebellitis, and opsoclonus myoclonus syndrome (OMS). These IMCAs share common features with regard to therapeutic approaches. When certain factors trigger immune processes, elimination of the antigen( s) becomes a priority: e.g., gluten-free diet in GA and surgical excision of the primary tumor in PCDs. Furthermore, various immunotherapeutic modalities (e.g., steroids, immunoglobulins, plasmapheresis, immunosuppressants, rituximab) should be considered alone or in combination to prevent the progression of the IMCAs. There is no evidence of significant differences in terms of response and prognosis among the various types of immunotherapies. Treatment introduced at an early stage, when CAs or cerebellar atrophy is mild, is associated with better prognosis. Preservation of the "cerebellar reserve" is necessary for the improvement of CAs and resilience of the cerebellar networks. In this regard, we emphasize the therapeutic principle of "Time is Cerebellum" in IMCAs.

Keywords: Cerebellar ataxias; anti-GAD65Ab-associated cerebellar ataxia; gluten ataxia; immune-mediated cerebellar ataxias; immunotherapy; opsoclonus myoclonus syndrome; paraneoplastic cerebellar degeneration; post-infectious cerebellitis; prognosis; therapy; treatment..

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Figures

Fig. (1)
Fig. (1)
Classification of immune-mediated cerebellar ataxias (IMCAs). (The color version of the figure is available in the electronic copy of the article).
Fig. (2)
Fig. (2)
(A) Clinical time-course is classified into six patterns; (a) full recovery type, (b) partial recovery type, (c) stabilization type, (d) relapse type, (e) gradually progressive type, and (f) rapidly progressive type. Triangles: time of commencement of immunotherapy. Possible clinical courses for each subtype are schematically indicated below. Black: common course, gray: occasional course, light gray: rare course. PCI: post-infectious cerebellitis, OMS: opsoclonus myoclonus syndrome, GA: gluten ataxia, PCD: paraneoplastic cerebellar degeneration, Anti-GAD: anti-GAD65Ab-associated CA. (B) Schematic diagram of decline of cerebellar function and the concept of “restorable stage” and “cerebellar reserve”. Proper therapies can restore cerebellar function in patients with the cerebellum at the “restorable stage”, meaning the presence of sufficient cerebellar functional reserve. (The color version of the figure is available in the electronic copy of the article).
Fig. (3)
Fig. (3)
A schematic diagram of the neural circuitry and cellular reserves underlying cerebellar reserve. (A) A schematic diagram of the neural circuitry in the cerebellar cortex. PC: Purkinje cell, GC: granule cell, IN: molecular layer interneurons; Golgi: Golgi cells; MF: mossy fibers, PF: parallel fibers, CF: climbing fibers. Two cellular mechanisms constitute the cerebellar reserve; (1) Multiple forms of synaptic plasticity and (2) Convergence and divergence of mossy fiber inputs. When one microzone is pathologically impaired, the reserve makes it possible to substitute this function with another microzone. LTD: long-term depression, LTP: long-term potentiation, RP: rebound potentiation. Excitatory neurons are shown with a white soma, whereas inhibitory neurons are shown with a black soma. (B) Pathology of excitotoxicity, which causes increased calcium entry. The extracellular invasion, excitotoxicity, is characterized by enhancement through microglia-induced neuroinflammation in a positive-feedback fashion. The excitotoxicity in turn forms a chained cascade leading to lethal statuses (indicated by yellow boxes); (1) oxidative stress, (2) ER stress, and 3) DNA damage. Importantly, the cells are protected against these stresses by (1) antioxidant agents and (2) ER chaperon, ubiquitin-dependent proteasome, and autophagy (indicated by blue boxes). Thus, the lethal statuses, which are beyond these protective capacities, elicit cell death. The protective capacities consist of cellular reserve, cellular ability for compensation and restoration. Glut: glutamate. (The color version of the figure is available in the electronic copy of the article).

References

    1. Hadjivassiliou M. Immune-mediated acquired ataxias. Handb. Clin. Neurol. 2012;103:189–199. [http://dx.doi.org/10.1016/B978-0-444-51892-7.00011-5]. [PMID: 21827889]. - PubMed
    1. Hadjivassiliou M., Grünewald R.A., Chattopadhyay A.K., Davies-Jones G.A., Gibson A., Jarratt J.A., Kandler R.H., Lobo A., Powell T., Smith C.M. Clinical, radiological, neurophysiological, and neuropathological characteristics of gluten ataxia. Lancet. 1998;352(9140):1582–1585. [http://dx.doi.org/10.1016/S0140-6736(98)05342-2]. [PMID: 9843103]. - PubMed
    1. Graus F., Delattre J.Y., Antoine J.C., Dalmau J., Giometto B., Grisold W., Honnorat J., Smitt P.S., Vedeler Ch., Verschuuren J.J., Vincent A., Voltz R. Recommended diagnostic criteria for paraneoplastic neurological syndromes. J. Neurol. Neurosurg. Psychiatry. 2004;75(8):1135–1140. [http://dx.doi.org/10.1136/jnnp. 2003.034447]. [PMID: 15258215]. - PMC - PubMed
    1. Dalmau J., Rosenfeld M.R. Paraneoplastic syndromes of the CNS. Lancet Neurol. 2008;7(4):327–340. [http://dx.doi.org/10.1016/ S1474-4422(08)70060-7]. [PMID: 18339348]. - PMC - PubMed
    1. Ducray F., Demarquay G., Graus F., Decullier E., Antoine J.C., Giometto B., Psimaras D., Delattre J.Y., Carpentier A.F., Honnorat J. Seronegative paraneoplastic cerebellar degeneration: the PNS Euronetwork experience. Eur. J. Neurol. 2014;21(5):731–735. [http://dx.doi.org/10.1111/ene.12368]. [PMID: 24471811]. - PubMed