Acute Cerebellar Inflammation and Related Ataxia: Mechanisms and Pathophysiology

Abstract

The cerebellum governs motor coordination and motor learning. Infection with external microorganisms, such as viruses, bacteria, and fungi, induces the release and production of inflammatory mediators, which drive acute cerebellar inflammation. The clinical observation of acute cerebellitis is associated with the emergence of cerebellar ataxia. In our animal model of the acute inflammation of the cerebellar cortex, animals did not show any ataxia but hyperexcitability in the cerebellar cortex and depression-like behaviors. In contrast, animal models with neurodegeneration of the cerebellar Purkinje cells and hypoexcitability of the neurons show cerebellar ataxia. The suppression of the Ca2+-activated K+ channels in vivo is associated with a type of ataxia. Therefore, there is a gap in our interpretation between the very early phase of cerebellar inflammation and the emergence of cerebellar ataxia. In this review, we discuss the hypothesized scenario concerning the emergence of cerebellar ataxia. First, compared with genetically induced cerebellar ataxias, we introduce infection and inflammation in the cerebellum via aberrant immunity and glial responses. Especially, we focus on infections with cytomegalovirus, influenza virus, dengue virus, and SARS-CoV-2, potential relevance to mitochondrial DNA, and autoimmunity in infection. Second, we review neurophysiological modulation (intrinsic excitability, excitatory, and inhibitory synaptic transmission) by inflammatory mediators and aberrant immunity. Next, we discuss the cerebellar circuit dysfunction (presumably, via maintaining the homeostatic property). Lastly, we propose the mechanism of the cerebellar ataxia and possible treatments for the ataxia in the cerebellar inflammation.

Immune-Triggered Forms of Plasticity Across Brain Regions

“…Despite the difficulty in interpreting the biological significance of behaviors, learning, and cognition, the interaction of immune cells with neurons is a quite important feature of brain functioning. The immune-triggered plasticity and related meta-plasticity are expected to be involved in psychiatric disorders evoked by aberrant immunity, specifically at the stage of neurodevelopment and maturation of brain vasculatures (Hopkins and Rothwell, 1995 ; Gilmore et al, 2004 ; Choi et al, 2016 ; Menard et al, 2017 ; Greene et al, 2018 ; Nie et al, 2018 ; Segawa et al, 2021 ; Parvez and Ohtsuki, 2022 ). It is also plausible that brain immunity, such as microglia or disease-associated macrophages in the brain, may have an “immune-memory” in the ways of responses against immune stimulants via an inflammatory mediator signaling and plasticity.…”

Diagnosing viral encephalitis and emerging concepts

“…Common clinical syndromes include limbic encephalitis, brainstem encephalitis, cerebellitis, and deep gray matter encephalitis. Information obtained using selected references [22–31]. Specifics of each clinical syndrome can be found in Table 1.…”

“…Brainstem encephalitis presents with cranial nerve deficits and/or ataxia and can be seen with enteroviruses [25][26][27]; mimics include neuromyelitis optica (NMO), Listeria monocytogenes, brucellosis, and autoimmune encephalitis [9]. Cerebellitis has predilection in children and manifests with acute cerebellar symptoms; it is observed with VZV or as a postinfectious autoimmune complication [28][29][30]. Deep gray matter encephalitis presents with impaired consciousness and/or extrapyramidal symptoms and can be seen with respiratory viruses, JEV, and WNV [31].…”

“…Information obtained using selected references [22–31].BMT, bone marrow transplant; CMV, cytomegalovirus; EBV, Epstein--Barr virus; EV, enterovirus; FLAIR, fluid attenuated inversion recovery; HHV, human herpesvirus; HSCT, hematopoietic stem cell transplant; HSV, herpes simplex virus; JEV, Japanese encephalitis virus; LOC, level of consciousness; VZV, varicella zoster virus; WNV, West Nile virus.aRhombencephalitis refers specifically to inflammation of the medulla, pons, and cerebellum, while brainstem encephalitis is inflammation of the midbrain through medulla.bRespiratory viruses encompass adenoviruses, influenza A/B, parainfluenza, and respiratory syncytial virus.…”

“…Information obtained using selected references [22–31].BMT, bone marrow transplant; CMV, cytomegalovirus; EBV, Epstein--Barr virus; EV, enterovirus; FLAIR, fluid attenuated inversion recovery; HHV, human herpesvirus; HSCT, hematopoietic stem cell transplant; HSV, herpes simplex virus; JEV, Japanese encephalitis virus; LOC, level of consciousness; VZV, varicella zoster virus; WNV, West Nile virus.…”