
==== Front
Mol Psychiatry
Mol Psychiatry
Molecular Psychiatry
1359-4184
1476-5578
Nature Publishing Group UK London

38321121
2436
10.1038/s41380-024-02436-5
Correspondence
Depression with anti-myelin antibodies in the cerebrospinal fluid
http://orcid.org/0000-0001-7322-1195
Endres Dominique dominique.endres@uniklinik-freiburg.de

1
Berninger Lea 1
Glaser Cornelia 2
http://orcid.org/0000-0002-0911-5758
Hannibal Luciana 3
Berger Benjamin 45
http://orcid.org/0000-0001-9863-317X
Nickel Kathrin 1
http://orcid.org/0000-0002-0263-4360
Runge Kimon 1
Reisert Marco 67
Urbach Horst 8
http://orcid.org/0000-0002-2550-9132
Domschke Katharina 1
http://orcid.org/0000-0001-7729-2759
Venhoff Nils 2
http://orcid.org/0000-0002-8283-7976
Prüss Harald 910
http://orcid.org/0000-0002-2274-5447
Tebartz van Elst Ludger 1
1 https://ror.org/0245cg223 grid.5963.9 0000 0004 0491 7203 Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
2 https://ror.org/0245cg223 grid.5963.9 0000 0004 0491 7203 Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
3 https://ror.org/0245cg223 grid.5963.9 0000 0004 0491 7203 Laboratory of Clinical Biochemistry and Metabolism, Department of General Pediatrics, Adolescent Medicine and Neonatology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
4 https://ror.org/0245cg223 grid.5963.9 0000 0004 0491 7203 Department of Neurology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
5 Department for Neurology, Helios Clinic Pforzheim, Pforzheim, Germany
6 https://ror.org/0245cg223 grid.5963.9 0000 0004 0491 7203 Department of Diagnostic and Interventional Radiology, Faculty of Medicine, Medical Physics, Medical Center - University of Freiburg, University of Freiburg, Freiburg, Germany
7 https://ror.org/0245cg223 grid.5963.9 0000 0004 0491 7203 Department of Stereotactic and Functional Neurosurgery, Faculty of Medicine, Medical Center - University of Freiburg, University of Freiburg, Freiburg, Germany
8 https://ror.org/0245cg223 grid.5963.9 0000 0004 0491 7203 Department of Neuroradiology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
9 https://ror.org/001w7jn25 grid.6363.0 0000 0001 2218 4662 Department of Neurology and Experimental Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany
10 grid.424247.3 0000 0004 0438 0426 German Center for Neurodegenerative Diseases (DZNE) Berlin, Berlin, Germany
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© The Author(s) 2024
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Subject terms

Diagnostic markers
Biochemistry
The article processing charge was funded by the Baden-Wuerttemberg Ministry of Science, Research and Art and the University of Freiburg in the funding programme Open Access Publishing. The work-up of this case study was supported by the German Research Foundation (Project-Nr.: 419859038).issue-copyright-statement© Springer Nature Limited 2024
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pmcTo the Editor:

According to the biopsychosocial model, major depression usually has multimodal causes [1, 2]. The biological factors associated with the development of depression include stress, (epi-)genetics, monoamines, excitatory/inhibitory neurotransmission, inflammation, myelination, the gut-brain axis, neurotrophins/neurogenesis, mitochondrial processes, and the opioid system [1]. Autoimmune depression [3] as an oligosymptomatic manifestation of autoimmune encephalitis [4] may be associated with anti-central nervous system (CNS) antibodies in the cerebrospinal fluid (CSF) [5]. This article reports a complex case study of a patient with depression, anti-CNS antibodies, and further biological alterations.

A 55-year-old female patient presented with severe depressive syndrome for approximately three years, with core symptoms of depressed mood, reduced energy levels, loss of interest, and severe cognitive deficits (Beck-Depression-Inventory [BDI] score: 42 points). A neurological examination detected no focal neurological deficits. The patient reported a history of repeated alcohol abuse for approximately 20 years but was currently abstinent for several years. Four years earlier, she had developed multisegmental herpes zoster (treated with acyclovir) with persistent neuralgia in the left arm, and she had experienced a traumatic subarachnoid hemorrhage after a fall three years prior to presentation. In addition, she had suffered from restless legs syndrome, which was treated with dopaminergic medication. The patient’s mother had developed dementia in old age, and her father had symptoms of depression.

For approximately three years, the patient had also been experiencing physical symptoms, including joint pain, dyspnea, cough with sputum production, diffuse digestive problems, and skin changes with Raynaud’s syndrome with tricolor phenomenon. These physical complaints were initially assessed as “somatoform” by physicians in charge.

A recent systematic diagnostic work-up revealed a suspected mild polymyositis-scleroderma overlap syndrome with anti-PM-Scl (+++), anti-PM-Scl 100 (++), and anti-Mi2 beta (+) antibodies along with Raynaud’s syndrome (with a small reduction in perfusion in the fingers and toes and megacapillaries) as well as nonspecific, biopsy-proven inflammatory skin changes (interface dermatitis with mucin deposition).

The diagnostic work-up for possible autoimmune CNS involvement included magnetic resonance imaging (MRI) that revealed some mild periventricular signal increase. In the automated MRI morphometry, a globally reduced brain volume was identified with accentuation in the orbitofrontal, parietal, occipital, frontal, central, and cerebellar regions (https://www.veobrain.com/?page=veomorph). Tissue-based assays on unfixed mouse brain sections using serum and CSF [6] have repeatedly shown strong immunoglobulin (Ig) G binding (+++) against myelin in the cerebellum (Fig. 1). The testing for anti-ganglioside antibodies in serum/CSF showed borderline positive IgM GM1 antibodies (IgG GM1 antibodies were negative) only in serum. A wide range of previously characterized anti-myelin and the established well-characterized neuronal antibodies in serum and CSF were all negative [5]. Negative results were also returned for anti-nuclear antibodies (and for tests for extractable nuclear antigens) in the CSF. The routine CSF parameters were normal, including degeneration markers. Research analysis on neurotransmitters in the CSF has revealed reduced serotonin levels [7, 8], reduced glutamate concentrations, and slightly increased GABA [8, 9]. An examination of the gastrointestinal tract revealed bacterial miscolonisation of the small intestine (treated with rifaximin; Supplemental Table 1).Fig. 1 Diagnostic findings: Magnetic resonance imaging (MRI; A/B) findings, antibody patterns from cerebrospinal fluid (CSF; C), and neuropsychological test results (D).

A The automated MRI morphometry (https://www.veobrain.com/?page=veomorph) revealed a relatively global reduction of gray matter (the mean percentage of voxel with z-score < −2 of affected brain regions are shown in blue). B The MRI shows some mild periventricular signal increase (red arrows). These findings were suggestive on an incomplete rather than a disturbed myelination. In addition, hemosiderin deposits in the right intraparietal sulcus (open white arrow) as residual of a traumatic subarachnoid hemorrhage were identified. C Tissue-based assays on unfixed mouse brain sections using CSF (and serum, not presented here) showed strong immunoglobulin G binding against myelin fibers in the cerebellum [6]. In addition, quantitative profiling of serum/CSF metabolites by liquid chromatography and mass spectrometry was added. Metabolite extraction, quantification, and quality controlling were performed as described in earlier papers [7]. Analysis of neurotransmitters and precursor metabolites in CSF revealed reduced citrate (63 µM; ref. range 176 ± 50 µM), succinate (1.1 µM; ref. range: 29 ± 5 µM), glutamate (4.6 µM; ref. range: 33 ± 7 µM), serine (15 µM; ref. range: 42 ± 15 µM), glutamine (156 µM; ref. range: 440 ± 80 µM), and serotonin (0.018 µM; ref. range 0.82 ± 0.48 µM), as well as slightly elevated GABA (0.213 µM; ref. range 0.1270 ± 0.0052 µM). Dopamine (0.160 nM, ref. range: 0.04–4.5 nM) and 5-hydroxyinolacetic acid (5-HIAA) concentrations (0.127 µM; ref. range: 0.055–0.163 µM) were normal. Analysis of a plasma sample withdrawn on the same day revealed normal concentrations of the above metabolites with the exception of reduced citrate (11 µM; ref. range: 100–150 µM), and elevated concentrations of aromatic amino acids tryptophan (157 µM; ref. range 43–89 µM), and phenylalanine (115 µM; ref. range 28–85 µM; 8,9). D The neuropsychological testing for attentional performances showed mainly below-average values (ref. from −1 to +1 z-values).

After a multidisciplinary case conference, the patient was given detailed therapeutic options. The patient first preferred classical psychopharmacotherapy, but her BDI showed no change (again 42 points) under venlafaxine and mirtazapine for approximately five weeks. Sertraline had already been tried without effect (each showed good serum levels). Therefore, the patient agreed to try immunotherapeutic treatment, and a low-dose trial with corticosteroids was given starting with 25 mg per day of prednisolone, slowly tapering to 15 mg after six weeks. The BDI showed only slight improvement (36 points) and neuropsychological findings were unchanged, so the steroids were again tapered off. Trimipramine was not well tolerated and did not lead to relevant changes in the BDI (37 points). Pregabalin, which the patient had taken long term, was slowly stopped. With the addition of lithium (and continuation of venlafaxine), the patient showed slight improvement (BDI: 34 points). Under this medication and after intensive psychotherapy, the patient decided she wanted to be discharged (after she was informed about further treatment options).

The biological factors in the case patient with depression included anti-myelin antibodies in the CSF, MRI changes with volume loss and altered myelination, reduced CSF serotonin levels, hyper-inhibitory neurotransmitter changes, bacterial gut miscolonisation, genetic vulnerability, and a systemic autoimmune process.

Initially, autoimmune depression was suspected [3]. Similar anti-myelin antibodies have not previously been detected in patients with depression [5]. The previously characterized IgG antibodies against specific myelin targets—such as MOG, MBP, and MAG—and against anti-ganglioside GM1 all showed negative in the case patient. Interestingly, borderline anti-ganglioside GM1 IgM antibodies were identified in the serum but not in the CSF [10], so a novel myelin-targeting antigen was assumed. The periventricular signal increase in the MRI was suggestive on an incomplete myelination. Impaired myelination is increasingly considered an important factor in the pathophysiology of depression [1]. The specific antibody-binding against cerebellar structures would be compatible with a “cerebellar cognitive affective syndrome” [11]. However, there was no relevant clinical improvement in response to immunotherapy. Therefore, the antibodies could also be irrelevant in the context of an unknown immunological process, representing natural autoantibodies in a susceptible individual or even “reactive” ones due to enormous “brain stress” (after the subarachnoid hemorrhage and alcohol abuse).

At the neurotransmitter level, the CSF finding of reduced serotonin levels were compatible with depressive symptoms [1, 2]. Some studies have found an association between myelin pathologies and serotonin [12], although the exact effects of anti-myelin antibodies on serotonin metabolism remain to be investigated. Therefore, several classical serotonergic antidepressants were started in the patient, which finally yielded a slight improvement. In addition, her marginally elevated GABA concentrations and reduced glutamate levels could reflect a hyper-inhibitory electrophysiological state [13]. Therefore, pregabalin was tapered off in parallel.

A limitation is that the underlying antigen and functionality of the antibodies is unclear, and the examinations did not provide further evidence of neuroinflammation beyond the novel antibodies.

In summary, a multimodal diagnostic work-up may contribute to the understanding of the underlying biological processes in individual patients with depression [1] and thus open the way for precision medicine.

Supplementary information

Supplemental Table 1

Supplementary information

The online version contains supplementary material available at 10.1038/s41380-024-02436-5.

Acknowledgements

We would like to thank the patient for the opportunity to publish this case study. DE and LTvE are members of the Immuno-NeuroPsychiatry Network of the ECNP. KR was funded by the Berta-Ottenstein-Programme for Clinician Scientists, Faculty of Medicine, University of Freiburg. LTvE and KR were supported by the KKS Foundation.

Author contributions

All authors were critically involved in diagnosis and treatment of the patient, and/or in the theoretical discussion and composition of the manuscript. All authors read and approved the final version of the manuscript.

Funding

The work-up of this case study was supported by the German Research Foundation (Project-Nr.: 419859038). Open Access funding enabled and organized by Projekt DEAL.

Data availability

All necessary data can be found in the paper.

Competing interests

KD: Formerly: Steering Committee Neurosciences and speaker honoraria, Janssen-Cilag, within the last three years. LTvE: Advisory boards, lectures, or travel grants within the last three years: Roche, Eli Lilly, Janssen-Cilag, Novartis, Shire, UCB, GSK, Servier, Janssen and Cyberonics. All other authors declare no potential conflicts of interest.

Consent for publication

The patient gave her signed written informed consent for this case report to be published.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

These authors contributed equally: Dominique Endres, Lea Berninger.

These authors jointly supervised this work: Harald Prüss, Ludger Tebartz van Elst.
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