Inositol 1,4,5-trisphosphate receptor type 1 autoantibody (ITPR1-IgG/anti-Sj)-associated autoimmune cerebellar ataxia, encephalitis and peripheral neuropathy: review of the literature

Abstract

Background: In 2014, we first described novel autoantibodies to the inositol 1,4,5-trisphosphate receptor type 1 (ITPR1-IgG/anti-Sj) in patients with autoimmune cerebellar ataxia (ACA) in this journal. Here, we provide a review of the available literature on ITPR1-IgG/anti-Sj, covering clinical and paraclinical presentation, tumour association, serological findings, and immunopathogenesis.

Methods: Review of the peer-reviewed and PubMed-listed English language literature on ITPR1-IgG/anti-Sj. In addition, we provide an illustrative report on a new patient with ITPR1-IgG-associated encephalitis with cognitive decline and psychosis.

Results: So far, at least 31 patients with serum ITPR1-IgG/anti-Sj have been identified (clinical information available for 21). The most common manifestations were ACA, encephalopathy with seizures, myelopathy, and (radiculo)neuropathy, including autonomic neuropathy. In 45% of cases, an underlying tumour was present, making the condition a facultative paraneoplastic neurological disorder. The neurological syndrome preceded tumour diagnosis in all but one case. In most cases, immunotherapy had only moderate or no effect. The association of ITPR1-IgG/anti-Sj with manifestations other than ACA is corroborated by the case of a 48-year-old woman with high-titre ITPR1-IgG/anti-Sj antibodies and rapid cognitive decline, affecting memory, attention and executive function, and psychotic manifestations, including hallucinations, investigated here in detail. FDG-PET revealed right-temporal glucose hypermetabolism compatible with limbic encephalitis. Interestingly, ITPR1-IgG/anti-Sj mainly belonged to the IgG2 subclass in both serum and cerebrospinal fluid (CSF) in this and further patients, while it was predominantly IgG1 in other patients, including those with more severe outcome, and remained detectable over the entire course of disease. Immunotherapy with intravenous methylprednisolone, plasma exchange, and intravenous immunoglobulins, was repeatedly followed by partial or complete recovery. Long-term treatment with cyclophosphamide was paralleled by relative stabilization, although the patient noted clinical worsening at the end of each treatment cycle.

Conclusions: The spectrum of neurological manifestations associated with ITPR1 autoimmunity is broader than initially thought. Immunotherapy may be effective in some cases. Studies evaluating the frequency of ITPR1-IgG/anti-Sj in patients with cognitive decline and/or psychosis of unknown aetiology are warranted. Tumour screening is essential in patients presenting with ITPR1-IgG/anti-Sj.

Keywords: Anti-Sj; Anti-neuronal autoantibodies; Autoimmune encephalitis; Cancer; Cerebellar ataxia; Cognitive decline; Dementia; IP3R1; Inositol 1,4,5-trisphosphate receptor type 1 antibodies (ITPR1-IgG); InsP3R1; Limbic encephalitis; Medusa head ataxia; Paraneoplastic neurological syndromes; Polyneuropathy; Purkinje cell antibodies.

Fig. 1

ITPR1 protein expression, as detected by immunohistochemistry, in the cerebellum (a), cerebral cortex (b), hippocampus (c), and lateral ventricle wall/basal ganglia (d), together with protein expression scores (e) (modified images from the Human Protein Atlas image database [40]; https://www.proteinatlas.org; licensed under the Creative Commons Attribution-ShareAlike 3.0 International License)

Fig. 2

Binding of ITPR1-IgG/anti-Sj to cerebellar sections (a–c; a: staining of the Purkinje cell layer and the molecular layer; b: staining of axonal cross sections in the cerebellar white matter) and to ITPR1-transfected HEK293 cells (d) but not to mock-transfected HEK293 cells (e). Green fluorescence (FITC) indicates binding of patient IgG; red fluorescence (AF568) indicates binding of patient IgG of the IgG2 subclass; blue fluorescence corresponds to cell nuclei stained by 4′,6-diamidino-2-phenylindole. Note that the vessel-associated staining present in panel (c) is caused by non-specific cross-reactivity of the detection antibody with primate IgG that has penetrated the vessel walls post mortem during preparation of the brain specimen, was therefore present also after incubation of the sections with PBS instead of serum (not shown), and does not indicate the presence of anti-vessel antibodies in our patient; no such cross-reactivity was seen when using another, whole-IgG-specific secondary antibody (a, b)