Skip to main content

GABAB receptor encephalitis in a patient diagnosed with amyotrophic lateral sclerosis

Abstract

Background

In 2010 the spectrum of known antigens in autoimmune encephalitis has been expanded by GABAB receptors. Until now over 80 patients with GABAB receptor encephalitis have been described. We report the occurrence of GABAB receptor antibodies in a patient with clinically diagnosed amyotrophic lateral sclerosis (ALS). GABAB receptor antibodies have not been described previously in an ALS patient.

Case presentation

A 75-year-old female patient presented with cerebellar ataxia, bulbar palsy and cognitive impairment. In the later course of disease signs for affection of the second motor neuron evolved and she was diagnosed with ALS. A post-mortem analysis of cerebrospinal fluid revealed high titers of GABAB receptor antibodies.

Conclusions

This case provides an idea of the natural course of GABAB receptor encephalitis and demonstrates that antibody-mediated autoimmunity could be one of several pathways leading to the ALS phenotype. Furthermore this unique case stimulates the question whether neuronal antibodies might be more common in ALS than previously suspected.

Peer Review reports

Background

The spectrum of antibody-mediated encephalitis has recently been expanded to GABAB receptor (GABABR) autoantibodies [1]. Most patients present with cognitive impairment and seizures [2], but also cerebellar ataxia and brainstem dysfunction [1,2,3] often with small cell lung cancer [4]. We describe a patient diagnosed with amyotrophic lateral sclerosis (ALS), in whom post-mortem analysis revealed high titers of GABABR autoantibodies.

Case presentation

In 2007, an otherwise healthy 75-year-old woman was admitted with progressive dysexecutive and behavioral syndrome, drowsiness, dysarthria and cerebellar signs, starting eight months earlier after severe bronchitis (Additional file 1). Neurologic examination revealed a pseudobulbar syndrome resulting in dysarthria and mild dysphagia, gait instability, bradydiadochokinesia, dysmetric finger-to-nose-test and saccadic eye movements. No fasciculations or tongue fibrillations occurred, eutrophic muscles had normal tone, pyramidal signs were negative, masseter reflex and motor-evoked potentials (MEPs) normal, EEG without epileptiform discharges, the patient had no fever or epileptic seizures. Electromyography showed generalized acute denervation and chronic neurogenic changes, nerve conduction studies showed motor-dominant neuropathy. MRI showed global atrophy and multiple white matter lesions (Fig. 1). Body CT with contrast and immunofixation was unremarkable. Cerebrospinal fluid (CSF) had elevated protein (90.1 mg/dl), normal cell count (3/μl) and no antibodies against CV2, Hu, Yo, Ri, Amphiphysin or acetylcholine receptors.

Fig. 1
figure 1

Cerebral MRI six months after symptom onset showed cortical atrophy (a), multiple, mainly periventricular white matter lesions (b), bilateral mesiotemporal atrophy (c) and cerebellar atrophy (d). The findings are not characteristic for ALS, but occur regularly in patients with GABAB receptor encephalitis

Five months later, pseudobulbar symptoms and cerebellar ataxia worsened. Fasciculations appeared at the trunk and all extremities showing an asymmetric but generalized spreading pattern. Bulbar symptoms, paresis and atrophy of limbs, shoulder girdle and hand muscles evolved. There was an increased muscle tone without hyperreflexia. MEPs remained physiological. The diagnosis of ALS was made (probable ALS according to revised El Escorial criteria) [5] and treatment with riluzole started. The patient had no family history of ALS. After three months, the patient received percutaneous endoscopic gastrostomy and non-invasive ventilatory support. She died 18 months after symptom onset.

Given some early symptoms not characteristic for ALS such as cerebellar signs, archived CSF and serum were tested for neuronal surface autoantibodies and revealed high titers (1:3200 in serum, 1:320 in CSF; cell-based assay, Euroimmun, Lübeck, Germany) of GABABR IgG antibodies, while approximately 30 further antibodies (including LGI1, Caspr2, GABAA and AMPA receptor) were negative.

Discussion and conclusions

GABABR antibodies have not been described previously in an ALS patient. Due to post-mortem identification of high-level GABABR autoantibodies and the lack of immunotherapy, we cannot unambiguously determine whether the patient suffered from autoimmune encephalitis. Also no pathological test for the presence of TDP-43 could be performed. Given the similarity to published patients, we assume that our patient primarily developed GABABR encephalitis followed by a secondary manifestation of clinical ALS symptoms. Indeed, the initial presentation encompassed symptoms not typical for ALS (including drowsiness and cerebellar symptoms), while dysphagia, dysarthria, hypomimia and cognitive impairment belong to the known symptoms in GABABR encephalitis [1]. Elevated CSF protein and brain atrophy are also described [2, 4, 6]. A similar case of paraneoplastic GABABR encephalitis with dysarthria, dysphagia, ataxia and respiratory failure was stabilized with methylprednisolone and plasma exchange [3].

As GABABR are expressed in peripheral nerves [7] and throughout the CNS, particularly in the cerebellum [8], antibody-mediated interference with GABAergic transmission might have caused ataxia and axonal neuropathy [6]. As GABABR antibodies were in the reported case not revealed before death and consequently no immunotherapy had been started, we cannot prove their contribution to disease. However, considering the high antibody titers and symptoms compatible with GABABR encephalitis, they likely contributed to the severity of clinically diagnosed ALS, also given their pathogenic potential in vitro [9]. The findings give fresh impetus to the interpretation of autoimmunity as one of several etiologies of ALS, supported by findings of lymphocytic CNS infiltration [10] and IgG deposits [11].

The present case is remarkable for several reasons. First, the lack of immunotherapy potentially allows estimation of the natural course of GABABR encephalitis which could develop into an ALS phenocopy. Second, screening for GABABR antibodies seems useful in suspected ALS patients with cognitive impairment and ataxia. Third, it stimulates the question whether a systematic search for neuronal antibodies in ALS cohorts will reveal higher frequencies than hitherto suspected. It seems well possible that antibodies influence the ALS course. Potentially, antibody-mediated autoimmunity is one of several pathways leading to the ALS phenotype, comparable to HIV- or lymphoma-related ALS [12, 13].

Abbreviations

ALS:

Amyotrophic Lateral Sclerosis

CNS:

Central Nervous System

CSF:

Cerebrospinal Fluid

GABABR:

GABAB receptor

MEP:

motor-evoked potentials

References

  1. Lancaster E, Lai M, Peng X, et al. Antibodies to the GABA(B) receptor in limbic encephalitis with seizures: case series and characterisation of the antigen. The Lancet Neurology. 2010;9(1):67–76.

    Article  CAS  Google Scholar 

  2. Jarius S, Steinmeyer F, Knobel A, et al. GABAB receptor antibodies in paraneoplastic cerebellar ataxia. J Neuroimmunol. 2013;256(1):94–6.

    Article  CAS  Google Scholar 

  3. Mundiyanapurath S, Jarius S, Probst C, Stocker W, Wildemann B, Bosel J. GABA-B-receptor antibodies in paraneoplastic brainstem encephalitis. J Neuroimmunol. 2013;259(1–2):88–91.

    Article  CAS  Google Scholar 

  4. Hoftberger R, Titulaer MJ, Sabater L, et al. Encephalitis and GABAB receptor antibodies: novel findings in a new case series of 20 patients. Neurology. 2013;81(17):1500–6.

    Article  Google Scholar 

  5. Brooks BR, Miller RG, Swash M, Munsat TL. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the world Federation of Neurology. Research Group on Motor Neuron Diseases. 2000;1(5):293–9.

    CAS  Google Scholar 

  6. Jeffery OJ, Lennon VA, Pittock SJ, Gregory JK, Britton JW, McKeon A. GABAB receptor autoantibody frequency in service serologic evaluation. Neurology. 2013;81(10):882–7.

    Article  CAS  Google Scholar 

  7. Magnaghi V, Ballabio M, Cavarretta IT, et al. GABAB receptors in Schwann cells influence proliferation and myelin protein expression. Eur J Neurosci. 2004;19(10):2641–9.

    Article  Google Scholar 

  8. Benarroch EE. GABAB receptors: structure, functions, and clinical implications. Neurology. 2012;78(8):578–84.

    Article  CAS  Google Scholar 

  9. Nibber A, Mann EO, Pettingill P, et al. Pathogenic potential of antibodies to the GABAB receptor. Epilepsia Open. 2017;2(3):355–59.

  10. Troost D, van den Oord JJ, de Jong JM, Swaab DF. Lymphocytic infiltration in the spinal cord of patients with amyotrophic lateral sclerosis. Clin Neuropathol. 1989;8(6):289–94.

    CAS  PubMed  Google Scholar 

  11. Engelhardt JI, Appel SH. IgG reactivity in the spinal cord and motor cortex in amyotrophic lateral sclerosis. Arch Neurol. 1990;47(11):1210–6.

    Article  CAS  Google Scholar 

  12. Moulignier A, Moulonguet A, Pialoux G, Rozenbaum W. Reversible ALS-like disorder in HIV infection. Neurology. 2001;57(6):995–1001.

    Article  CAS  Google Scholar 

  13. Gordon PH, Rowland LP, Younger DS, et al. Lymphoproliferative disorders and motor neuron disease: an update. Neurology. 1997;48(6):1671–8.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

Not applicable.

Availability of data and materials

The data used for the current study are available from the corresponding author on reasonable request.

Author information

Authors and Affiliations

Authors

Contributions

HS and HP wrote the manuscript. TM and HP provided the patients’ data. HS and HP analyzed and interpreted the data. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Harald Prüss.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

The patient gave written, informed consent for data analysis and publication.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

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

Additional file

Additional file 1:

Timeline. The timeline gives an overview over the course of the disease of the patient and highlights diagnostic findings and therapeutic interventions. (PDF 25 kb)

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Schumacher, H., Meyer, T. & Prüss, H. GABAB receptor encephalitis in a patient diagnosed with amyotrophic lateral sclerosis. BMC Neurol 19, 41 (2019). https://doi.org/10.1186/s12883-019-1269-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12883-019-1269-7

Keywords