# A challenging case of cerebellar ataxia associated with oro facial dominant chorea

Alexane Larget, Marie Rafiq, Raquel Barbosa, Fabrice Bonneville, Chloé Bost, Margherita Fabbri, Clémence Leung, Hélène Mirabel, Emilie Rigal Milongo, Jérémie Pariente, et al.

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To cite this version:

Alexane Larget, Marie Rafiq, Raquel Barbosa, Fabrice Bonneville, Chloé Bost, et al. A challenging case of cerebellar ataxia associated with oro facial dominant chorea. Parkinsonism & Related Disorders, 2025, 132, pp.107189. 10.1016/j.parkreldis.2024.107189. hal-05035144

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# A challenging case of cerebellar ataxia associated with oro facial dominant chorea

Alexane Larget<sup>a</sup>, Marie Rafiq<sup>a,e,f,g</sup>, Raquel Barbosa<sup>a,e</sup>, Fabrice Bonneville<sup>b,e,f</sup>, Chloé Bost<sup>c,d,f</sup>, Margherita Fabbri<sup>a,e</sup>, Clémence Leung<sup>a</sup>, Hélène Mirabel<sup>a,f,g</sup>, Emilie Rigal Milongo<sup>h</sup>, Jérémie Pariente<sup>a,e,f,g</sup>, Fabienne Ory-Magne<sup>a,e,f,g,*</sup>

## ARTICLE INFO

### Keywords:

- Autoantibodies

- Cerebellar ataxia

- Chorea

- Encephalitis

- GAD65 autoimmunity

- Glutamic acid decarboxylase

## 1. Case description

An 87-year-old man presented to our department complaining of episodic, non-disabling movements of the face and tongue for one year. With the exception of late-onset type 2 diabetes, his medical history was unremarkable, as was his family history. He had never received any other treatment, particularly neuroleptics. According to the patient and his family these movements initially occurred once a day, for a few hours, without trigger, and remained limited to the face. After three months, the episodes became more frequent and balance gradually deteriorated. After six months, the movements were permanent, more pronounced and socially disabling, but still limited to the face. While he was still able to walk unaided, he began to fall, fortunately without consequence. Over the next three months, his symptoms worsened, his balance deteriorated and he had to use two walking canes to get around. He found it increasingly difficult to swallow, and suffered rapid and significant weight loss (15 kg) (see Table 1, Fig. 1).

After 9 months of symptom progression, his first neurological

examination revealed upper and lower limb dysmetria, an ataxic gait (difficulty walking in tandem and staggering, broad-based sustentation polygon) and a severe cerebellar dysarthria (see video). In addition, he had choreic movements predominantly of the face with marked involvement of the tongue, but also more discreetly in the upper limbs. The rest of the examination was unremarkable (no oculomotor disorders, no parkinsonian syndrome, no pyramidal syndrome). Although he appeared impulsive and with an exaltation of mood and familiarity, his general cognitive performance was preserved (Mini-Mental State Examination at 27/30, no praxis disorder, RL/RI-16 episodic memory test normal). His cognitive assessment revealed only abnormalities in visual memory and mental flexibility (DMS48 with immediate recognition at 33/48 (−4.6 DS) and delayed recognition at 25/48 (−10.25 DS)).

On this path the following investigations were carried out: a) Laboratory tests (complete blood count, CRP, chemistry metabolic panel for liver and kidney function, coagulation panel, lipid panel, thyroid panel, anticardiolipid and β2-GP1 antibodies, DNA double strand Ab, antibody tests for celiac disease, TPO antibody, vitamins tests including thiamine,

<footnote><sup>a</sup> Department of Neurology, University Hospital of Toulouse, Toulouse, France</footnote>

<footnote><sup>b</sup> Department of Neuroradiology, University Hospital of Toulouse, Toulouse, France</footnote>

<footnote><sup>c</sup> INSERM U1043 – CNRS UMR 5282, INFINITY, France</footnote>

<footnote><sup>d</sup> Laboratoire d'Immunologie, Institut Fédératif de Biologie, CHU de Toulouse, France</footnote>

<footnote><sup>e</sup> INSERM, Toulouse Neuroimaging Center, UMR, 1214, Toulouse, France</footnote>

<footnote><sup>f</sup> Centre de référence constitutif des syndromes paranéoplasiques et encéphalites auto-immunes, Centre Hospitalier de Toulouse, Toulouse, France</footnote>

<footnote><sup>g</sup> Neurosmart, Neurologie Structure Maladies Rares, CHU de Toulouse, France</footnote>

<footnote><sup>h</sup> Clinique Saint Exupéry, Toulouse, France</footnote>

<footnote>* Corresponding author. Department of Neurology, University Hospital of Toulouse, Toulouse, France
E-mail address: ory.f@chu-oulouse.fr (F. Ory-Magne).</footnote>
<table><caption>**Table 1**
Differential diagnosis of chorea regarding the body distribution (* particularly in elderly).</caption><thead><tr><th>Body distribution</th><th>Differential diagnosis</th></tr></thead><tbody><tr><td>Forehead</td><td>Huntington disease*</td></tr><tr><td>Orobuccolingual</td><td>Tardive chorea*<br>Acquired hepatocerebral degeneration<br>Chorea-acanthocytosis<br>Lesch-Nyhan syndrome<br>PKAN<br>Lubag disease<br>Paraneoplastic*</td></tr><tr><td>Hemichorea</td><td>Structural lesion*<br>Nonketonic hyperglycemia*<br>Polycythemia vera*<br>Other*</td></tr></tbody></table>

pyridoxine, folate and cobalamin) which were unremarkable; b) A search for active infectious diseases including HIV, HBV, HCV, Lyme borreliosis, brucellosis and CMV, VZV, EBV was negative; c) A cerebrospinal fluid (CSF) examination showed a normal cell count, normal total protein and mild hyperglycorrhachia at 4,23 mmol per litre (reference range 2.22–3.89) with the same oligoclonal profile in blood and CSF; d) Brain MRI (Figure A, B) showed only mild age-related cortico-subcortical atrophy and periventricular and centropontine unspecific FLAIR hyperintensities. There was no cerebellar atrophy; e) To exclude body neoplastic lesions, he underwent a thoraco-abdomino-pelvic CT scan and a body PET scan, which were normal; f) A genetic test to rule out Huntington's disease (HD) found 17/11 CAG repeats.

At that time, after eliminate differential diagnosis of chorea in the elderly (Table), our main hypothesis was autoimmune encephalitis due to a complex movement disorder (ataxia combined with chorea) associated with visual recognition memory impairment and marked weight loss. GAD65-antibodies (GAD-Ab) were found in the blood (over 2000 IU/mL, a titer confirmed twice, ELISA RSR Ltd GADAb). A high GAD-Ab titer (23,22 IU/ml, cut-off 5 IU/ml) in the CSF was confirmed by ELISA, with compatible fluorescence of the cytoplasm of cells in the cerebellar layer of monkey cerebellum slices (INOVA REF.504225) (Figure B). No other antibodies were detected.

He was treated with a combination of immunoglobulins (0.4 g/kg/day i.v.) and steroids (methylprednisolone hemisuccinate, 1 g/day i.v.) for 5 days once a month. In combination low-dose tetrabenazine (50 mg daily) reduced disabling choreic movements (see video). After 6 months of treatment, the choreic movements and dysarthria had disappeared, while his dysmetria had improved markedly. The cerebellar ataxia also improved. Although the falls have not recurred, the patient still requires a walking stick. He does not wish to have his cognitive performance

assessed. Biologically, GAD-Ab persists in the blood and CSF.

## 2. Discussion

This case extends the clinical spectrum of anti-GAD antibodies beyond the classic “anti-GAD antibody spectrum disorders”, which include stiff person syndrome, cerebellar ataxia, autoimmune epilepsy, limbic encephalitis, progressive encephalomyelitis with rigidity and myoclonus, and eye movement disorders [1–3]. Although a few cases have already suggested that the autoimmune neurological spectrum of GAD may extend to focal or generalized chorea [4], no dominant oro-facial involvement has been reported.

We particularly showed that anti-GAD antibody encephalitis can occur at any age, although the mean age at diagnosis is 52.9 years [5] and that chorea can occur in a patient with anti-GAD antibody encephalitis. While chorea has never been reported before, it is important to note that chorea could be associated with gait ataxia, which may define a new overlapping syndrome associated with anti-GAD antibodies. These overlapping presentations are common, especially in cerebellar ataxia. There are no clear explanations for such a broad phenotype in anti-GAD antibody encephalitis. Differences in epitope recognition may explain some cases as patients with epilepsy showed more reactivity to the C-terminal domain of the enzyme than patients with stiff-person syndrome, cerebellar ataxia and limbic encephalitis [6]. A recent study suggested the concomitant presence of anti-GAD antibodies and other pathogenic antibodies (anti-GABAAR, anti-GABAAPR, anti-gephyrin or anti-GlyR) which vary according to clinical presentation [7] which can be excluded in our case.

As the patient had no other causes of chorea (and in particular no antidopaminergic drugs or HD regarding their main oral distribution), the imputability of anti-GAD antibodies in this clinical presentation was retained. We did not identify any other antibodies and particularly no anti-IgLON5-Abs, anti-CRMP5-Abs, anti-Neurexin-3α or anti-NMDAR-Abs which are most often described in antibody encephalitis with choreic movements [5,8]. GAD antibodies were detected using the 2 reference detection techniques (DOT and immunoelectrofluorescence). Furthermore, the evolution of his choreic movements followed the course of his cerebellar symptoms. Both were subacute and both responded positively to immunotherapy. The latter can be safely considered as anti-GAD ataxia in this case as the serum anti-GAD Abs were above 2000 IU/mL and were also found in the CSF. He had no specific MRI abnormalities. While mild cerebellar atrophy can be observed [9], neuroimaging studies show normal findings in 39 % of cases [10].

The number of pathologies responsible for choreic movements is vast. Etiological research requires, in particular, a characterisation of the evolution over time and an exhaustive neurological examination.

<figure><img src="image_5.png" /><figcaption>**Fig. 1.** Brain MRI and antibody fluorescence image</figcaption></figure>

Legend Brain MRI with axial FLAIR images reveal only mild and unspecific hyperintensities (A, B) and fluorescence of the cytoplasm of cells in the cerebellar layer of monkey cerebellum slices labelling GAD65 expression (C).
The distribution of the movements must also be taken into account: while the list of causes of generalized chorea is long, the orofacial involvement is more specific for certain diagnoses (Table). The number of possible diagnoses is further reduced in the elderly, and is limited to iatrogenic causes (neuroleptics or related drugs) and autoimmune diseases, even if Huntington's disease cannot be formally excluded.

### 3. Conclusion

This case extends the clinical spectrum of GAD65-Abs encephalitis. This heterogeneity of GAD-Ab syndromes may be related to different antigenic targets. It highlights the importance of considering this diagnosis even in elderly patients with chorea, especially with associated cerebellar ataxia, to allow early initiation of treatments.

### CRediT authorship contribution statement

**Alexane Larget:** Writing – review & editing, Writing – original draft, Validation, Formal analysis, Conceptualization.
**Marie Rafiq:** Writing – review & editing, Visualization, Validation.
**Raquel Barbosa:** Writing – review & editing, Visualization, Fabrice Bonneville: Writing – review & editing, Visualization, Investigation.
**Chloé Bost:** Writing – review & editing, Validation, Investigation.
**Margherita Fabbri:** Writing – review & editing, Validation.
**Clémence Leung:** Writing – review & editing, Validation.
**Hélène Mirabel:** Investigation.
**Emilie Rigal Milongo:** Investigation.
**Jérémie Pariente:** Writing – review & editing, Validation.
**Fabienne Ory-Magne:** Writing – review & editing, Writing – original draft, Validation, Methodology, Investigation, Conceptualization.

### Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

### Acknowledgements

We thank the patient who gave his written authorization to the

videotape and its diffusion for medical purpose.

## Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.parkreldis.2024.107189.

### References

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