Achtnichts, L

Beiser, I

Bertschi, M

Gschwind, M

Nedeltchev, K

Schegk, E.

English

E. Schegk

I. Beiser

L. Achtnichts

K. Nedeltchev

M. Bertschi

M. Gschwind

Crossref

Untreated anti-Ca/ARHGAP26 autoantibody-associated cerebellar ataxia progressing over 27 years

Bern Open Repository and Information System (BORIS)

Vol:.(1234567890)Journal of Neurology (2023) 270:3258–3260https://doi.org/10.1007/s00415-023-11632-21 3LETTER TO THE EDITORSUntreated anti‑Ca/ARHGAP26 autoantibody‑associated cerebellar ataxia progressing over 27 yearsE. Schegk2 · I. Beiser1 · L. Achtnichts1 · K. Nedeltchev1 · M. Bertschi1 · M. Gschwind1,3 Received: 5 December 2022 / Revised: 16 February 2023 / Accepted: 17 February 2023 / Published online: 1 March 2023 © The Author(s) 2023Dear Sirs,Autoantibodies against the RhoGTPase-activating protein 26 (ARHGAP26) and autoantibody-associated cerebellar ataxia were first described in 2010 [1]. We present a case of anti-Ca-associated cerebellar ataxia with Parkinson-like traits and a so far never described very slow progression over 27 years without treatment, therefore, broadening clinical presentation by parkinsonian features.A 79-year-old farmer presented to our department with a movement disorder that had been slowly progressing over a time span of 27 years.His neurologic history started in 1992, when the so far healthy patient in his mid-50 s received neurologic work-up for the first time because of involuntary movements that had started 2 years before (first in the right arm, then leg, and after 6 months also in left arm and leg). He then fur-ther complained about myoclonic jerks triggered by targeted movements and a freezing gait with consecutive falls, he also described an incapacity of unclasping objects, which led to broken cups. Laboratory testing showed normal find-ings, notably normal ceruloplasmin levels, and a normal infectiology work-up. Oligoclonal bands in the cerebro-spinal fluid (CSF) were positive. Electroencephalography and motor evoked potentials were normal. No autonomic neuropathy was found. Brain MRI displayed frontoparietal cortical atrophy, MRI of the cervical spine was normal. Single-photon emission computed tomography (SPECT) and positron emission tomography (PET) of the brain were normal. Consequently, our patient had been diagnosed with multiple system atrophy of the olivo-ponto-cerebellar sub-type (MSA OPC), and treatment with selegiline and levo-dopa/benserazide was established.In 1996, freezing of gait and falls had improved under dopaminergic treatment, whereas the myoclonic jerks had worsened. He furthermore suffered from a repeated loss of consciousness under orthostatic conditions. Clinical exami-nation revealed slight stammering, a positive palmomen-tal reflex more pronounced right than left and myoclonic jerks when the right limbs were passively flexed. He showed intention myoclonus in the finger-nose and heel-shin test. A rebound was seen in the upper extremities. No signs of cog-nitive decline or apraxia were documented. The brain MRI confirmed atrophy of both cerebrum and cerebellum. Levo-dopa/benserazide was continued, Selegiline was tapered.During the following 20 years after this initial evaluation, no neurologic follow-up would take place until the patient was admitted to our department because of an acute wors-ening of his myoclonic jerks. He now reported that the pre-viously documented gait freezing with postural imbalance was accompanied by morning stiffness, hypomimia, hypo-phonia, and dysarthria, cognitive decline with forgetfulness and involuntary loss of urine. Clinical examination showed a slowed and depressed patient, with saccadic eye movements, hypometric saccades, rigidity of the left arm and both legs, resting tremor of all limbs, predominant at the left hand, irregular posture tremor of the hands, with re-emerging as well as stimulus sensitive myoclonic jerks of all limbs and apraxia. Laboratory testing showed a urinary tract infection, it was treated with Ceftriaxone 2 g/d for 2 days.The debilitating jerks improved partially under clon-azepam 0.25 mg/d. Levodopa test showed only minimal improvement from 42 to 39 points (MDS-UPDRS III), mainly in the upper extremities, whereas the marked axial symptoms were unchanged. Electrophysiological testing was normal. A new brain MRI revealed frontoparietal cortical atrophy but no atrophy of the basal ganglia or the cerebellum  * M. Gschwind  markus.gschwind@ksa.ch1 Department of Neurology, Cantonal Hospital Aarau, Tellstrasse 25, CH-5011 Aarau, Switzerland2 Department of Neurology, University Hospital and University of Berne, Berne, Switzerland3 Department of Neurology, Geneva University Hospitals and University of Geneva, Geneva, Switzerland3259Journal of Neurology (2023) 270:3258–3260 1 3and no signs of normal pressure hydrocephalus (Fig. 1). Neuropsychologic testing revealed an unspecific, mild cog-nitive impairment (verbal learning weakness).CSF was unchanged with a normal cell count, but positive oligoclonal bands. For that reason, we also searched for an autoimmune or paraneoplastic process. The panel of anti-neuronal autoantibodies (anti-Hu, -Ri, -Yo, -amphiphysin, -CV2, -Ma, -Ta/Ma2, -Sox1, -Tr, -Zic4, -NMDA-R, -VGCC, -VGKC, -LGI1, -CASPR2, -GAD) was negative, as were rheumatic antibodies (ANA, ANCA, rheumatoid factor). A whole-body FDG-PET/CT was normal, giving no evidence for a neoplastic process.Results from cell-based indirect immunofluorescence on monkey cerebellum arrived after the patient had been discharged. Rho GTPase-activating protein 26 had been detected (Titer 1:1000, considered highly significant), consistent with autoantibody-associated cerebellar ataxia. Unfortunately, the patient later refused further follow-up.This patient, diagnosed 27 years ago with a multisystem atrophy of the olivo-ponto-cerebellar subtype in 1993, and found to have ARHGAP26 autoantibody-associated cere-bellar ataxia today, showed a very slow evolution. Interest-ingly, the parkinsonian motor symptoms were predominant with freezing, falls, and fluctuating myoclonic jerks. There was autonomic dysregulation but there were no pyramidal signs. Anti-ARHGAP26 antibodies bind to all structures of Purkinje cells. They are also detectable in a subset of neurons in the hippocampus [2]. Involvement of the basal ganglia, which could have explained the extrapyramidal signs of our patient, was, to our knowledge, never described.From today’s retrospective perspective, the patient’s symptomatology and neuroimaging is not completely con-sistent with the diagnosis of olivo-ponto-cerebellar atrophy. Especially, in the initial description, there was no ataxia or cerebellar dysarthria described; instead, involuntary jerks and signs of dysautonomia are present. The cerebellar syn-drome would seem to correspond to a cognitive affective syndrome, but this syndrome is not specific for cerebellar damage in the absence of clear neurological signs that would depose cerebellar damage. Only frontoparietal but not cer-ebellar atrophy is reported in the first MRI, and SPECT and PET scans were judged unremarkable. In the 1996, MRI both frontoparietal atrophy and cerebellar atrophy were found, however, other markers of OPCA such as atrophy of middle cerebellar peduncles were not. We underline that we referred the historic medical documentation of that time. From today’s perspective, we might, therefore, better describe our patient as an unusual case of movement dis-order with the presence of anti-ARHGAP26 autoantibody-associated cerebellar ataxia, in which, however, olivo-ponto-cerebellar atrophy may be one of the diagnostic hypotheses considered.So far, a total of ten cases of anti-ARHGAP26 autoanti-body-associated cerebellar ataxia have been published, five among them of possible paraneoplastic origin [3–6]. The dis-ease mostly manifests relatively subacute within a few days [1, 3, 4]. However, in some cases, symptoms included dizzi-ness, ataxia, dysarthria [6], behavioral changes [7], and cog-nitive decline [5] over several months to years until the diag-nosis could be made. The long-term course of the disease is largely unknown. In one patient, diagnosed after 18 years of disease onset [3], treatment with valproate (because of an initially suspected myoclonic epilepsy) resulted in a 5-year remission. Another patient showed limited benefit after immunosuppressive therapy right after disease onset, but no benefit from escalated immune therapy at a later stage [4], contrasting to a third patient who reported transient benefit from intravenous methylprednisolone 19 years after disease onset [5]. The rate of progression may, therefore, be a source of heterogeneity for this autoantibody.Patients with cerebellar dysfunction may struggle with depression, limitations in cognitive ability and slowed reac-tion time, known as the cerebellar cognitive affective syn-drome [2, 6–8], which was also found in our patient. He also displayed deficits in verbal learning and recall, which was previously described in anti-ARHGAP26 antibody-positive patients [4, 6] and is consistent with limbic system involve-ment. ARHGAP26 is expressed in a subset of neurons in the hippocampus, which could explain those symptoms.Fig. 1  New brain MRI of the patient. Sagittal MRI-images (MPRAGE) and axial FLAIR-weighted images of our patient show-ing frontoparietal cortical atrophy and cerebellar, vermis-accentuated atrophy3260 Journal of Neurology (2023) 270:3258–32601 3Our case illustrates that anti-ARHGAP26 antibody-pos-itive patients can present a very slow subacute evolution. However, to date, we cannot exclude that the anti-ARH-GAP26 antibody was in fact an accidental finding and not causally related to the patient’s condition. During the last 20 years, major advances in knowledge about autoimmune and paraneoplastic cerebellar ataxias have been made, and many new antibodies have been characterized [9]. The addi-tional clinical description of our patient is, therefore, highly valuable, all the more as he was diagnosed by an expert in the field 27 years ago.Supplementary Information The online version contains supplemen-tary material available at https:// doi. org/ 10. 1007/ s00415- 023- 11632-2.Author contributions ES drafted and revised the manuscript and con-tributed the video. IB drafted the manuscript and treated the patient. LA drafted the manuscript and treated the patient. KN revised the manuscript and contributed important knowledge, MB diagnosed the patient, drafted and revised the manuscript and contributed the video, MG wrote and revised the manuscript, contributed the illustration and supervised the study.Data availability No consent was given for public data sharing. Data are available from the corresponding author on reasonable request.Declarations Conflicts of interest None of the authors have anything to declare re-lated to this project.Ethical approval This report conforms to the Declaration of Helsinki, and explicit written consent was obtained from the patient.Open Access This article is licensed under a Creative Commons Attri-bution 4.0 International License, which permits use, sharing, adapta-tion, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.References 1. Jarius S, Wandinger KP, Horn S, Heuer H, Wildemann B (2010) A new Purkinje cell antibody (anti-Ca) associated with subacute cerebellar ataxia: immunological characterization. J Neuroinflam-mation 7:21 2. Jarius S, Wildemann B (2015) “Medusa head ataxia”: the expand-ing spectrum of Purkinje cell antibodies in autoimmune cerebel-lar ataxia. Part 2: Anti-PKC-gamma, anti-GluR-delta2, anti-Ca/ARHGAP26 and anti-VGCC. J Neuroinflammation 12:167 3. Jarius S, Martinez-Garcia P, Hernandez AL et al (2013) Two new cases of anti-Ca (anti-ARHGAP26/GRAF) autoantibody-associ-ated cerebellar ataxia. J Neuroinflammation 10:7 4. Doss S, Numann A, Ziegler A et al (2014) Anti-Ca/anti-ARH-GAP26 antibodies associated with cerebellar atrophy and cogni-tive decline. J Neuroimmunol 267:102–104 5. Wallwitz U, Brock S, Schunck A, Wildemann B, Jarius S, Hoff-mann F (2017) From dizziness to severe ataxia and dysarthria: New cases of anti-Ca/ARHGAP26 autoantibody-associated cer-ebellar ataxia suggest a broad clinical spectrum. J Neuroimmunol 309:77–81 6. Bartels F, Pruss H, Finke C (2018) Anti-ARHGAP26 autoanti-bodies are associated with isolated cognitive impairment. Front Neurol 9:656 7. Jarius S, Wildemann B, Stocker W, Moser A, Wandinger KP (2015) Psychotic syndrome associated with anti-Ca/ARHGAP26 and voltage-gated potassium channel antibodies. J Neuroimmunol 286:79–82 8. Schmahmann JD (2004) Disorders of the cerebellum: ataxia, dys-metria of thought, and the cerebellar cognitive affective syndrome. J Neuropsychiatry Clin Neurosci 16:367–378 9. Muniz-Castrillo S, Vogrig A, Ciano-Petersen NL, Villagran-Gar-cia M, Joubert B, Honnorat J (2022) Novelties in autoimmune and paraneoplastic cerebellar ataxias: twenty years of progresses. Cerebellum 21:573–591

Untreated anti-Ca/ARHGAP26 autoantibody-associated cerebellar ataxia progressing over 27 years.

https://boris.unibe.ch/189669/1/Schegk__2023__Untreated_anti-Ca.pdf

Untreated anti-Ca/ARHGAP26 autoantibody-associated cerebellar ataxia progressing over 27 years.

Abstract

Similar works

Full text

Available Versions

Crossref

Bern Open Repository and Information System (BORIS)