Acta Neurol Belg DOI 10.1007/s13760-014-0322-y


Infliximab-associated autoimmune limbic encephalitis: a case report Niels Fockaert • Karolien Goffin • Philippe Demaerel Wim Van Paesschen

Received: 1 February 2014 / Accepted: 7 June 2014 Ó Belgian Neurological Society 2014

Keywords Limbic encephalitis  Auto-immune epilepsies  VGKC-antibodies

We present a patient who developed seizures due to a VGKC-antibody-mediated LE after initiation of infliximab (IFX).

Introduction Case report In a significant number of patients developing epilepsy in adult life, the aetiology of their seizures remains unclear. Limbic encephalitis (LE) manifests as subacute memory impairment and temporal lobe epileptic seizures. LE can be associated with classical onconeural antibodies or antibodies against neuronal surface antigens. Tumor necrosis factor alpha (TNFa)-antagonists are widely used in the treatment of autoimmune diseases. Newonset seizures during these therapies have been reported but the pathogenesis remains uncertain.

N. Fockaert (&)  W. Van Paesschen Department of Neurology, University Hospital Leuven, Louvain, Belgium e-mail: [email protected] N. Fockaert AZ Sint-Jan Brugge, Ruddershove 10, 8000 Brugge, Belgium K. Goffin Department of Nuclear Medicine, University Hospital Leuven, Louvain, Belgium P. Demaerel Department of Radiology, University Hospital Leuven, Louvain, Belgium P. Demaerel Department of Imaging and Pathology, KU Leuven, Louvain, Belgium

A 52-year-old salesman presented in July 2008, 4 months after IFX was initiated for the treatment of rheumatoid arthritis. For 2 months, he had experienced partial temporal lobe seizures characterized by de´ja`-vu, olfactory and gustatory hallucinations, palpitations, non-fluent aphasia, goose bumps, retained awareness and automatisms in the left arm. These seizures were not controlled by valproate 300 mg BID and levetiracetam 1,500 mg BID. MRI was consistent with limbic encephalitis (Fig. 1a), the interictal and ictal EEG, SISCOM and ictal FDG-PET with an ictal onset zone in the left temporal lobe (Fig. 1b, c). Neuropsychological examination could not reveal any memory disturbances. In October 2008, serum anti-VGKC-antibodies were documented. CSF analysis and onco-PET/CT were normal. Antibodies were not measured in the CSF. We diagnosed a non-paraneoplastic autoimmune LE and treatment with high-dose oral corticosteroids and plasmapheresis was started at that time. IFX was discontinued 2 months later, in December 2008. After five sessions of plasmapheresis, he reported a seizure reduction of 90 %. He became seizure-free in April 2009, after association of lamotrigine 50 mg BID. Serum anti-VGKC-antibodies were still present in July 2009, but were absent in February 2010. Treatment with oral corticosteroids was stopped at that time. EEGs remained normal. Consecutive MRIs showed a reduction of the hyperintense signal in the left medial temporal lobe


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Fig. 1 Multimodal image with co-registration of MRI, subtracted ictal SPECT and FDG-PET. a MRI/FLAIR: hyperintense signal in both medial temporal lobes, more pronounced on the left side, with swelling of the left amygdala and hippocampus. b SISCOM: ictal

hyperperfusion in the left medial temporal lobe. c Ictal FDG-PET (patient had a habitual temporal lobe seizure during FDG-uptake): hypermetabolic focus in the left amygdala

with only a discrete signal alteration in February 2011. In May 2013, anti-epileptic drugs were discontinued without seizure recurrence.

seronegative LE. She became seizure-free 18 months after IvIg therapy initiation. The pathophysiology of neurological diseases in antiTNFa-therapy remains uncertain. Several theories have been postulated and one of these proposes an autoimmune process [6]. Auto-antibody induction may be a consequence of anti-TNFa-therapy by inhibiting the induction of the cytotoxic T-lymphocyte response that normally suppresses autoreactive B cells. The presence of anti-VGKC-antibodies in our patient supports this autoimmune theory. Several factors suggest an aetiological role for IFX in our patient. First, disease onset was temporally associated with initiation of IFX. Second, there was improvement of clinical symptoms, antibody detection and cerebral imaging after discontinuation of IFX. Third, an auto-immune hypothesis has been provided for neurological complications in anti-TNFa-therapy [6]. Last, a similar case of LE after initiation of IFX-therapy has been reported [5]. We admit that the postulated causal link of IFX with LE can raise some questions. IFX is widely used but new-onset seizures have only been reported in 0.01 % of these patients, less than in the general population [2]. Further, the clinical improvement and disappearance of VGKC-antibodies upon cessation of IFX is a compelling argument, but can be due to immunosuppressive therapy. Another shortcoming is the lack of antibody specification, which makes the clinical relevance of the VGKC-antibodies in this patient unclear. Antibodies against the LGI1 and CASPR2subunit of the VGKC-complex are well known but an undefined antigenic target with unknown clinical relevance remains in a significant cohort of patients [7]. We postulate that seizures during treatment with IFX could be induced by a VGKC-antibody-mediated LE. However, since a rechallenge with IFX is unethical, the

Discussion To date, more than 500 cases of neurological disease have been reported as treatment emergent adverse events in antiTNFa-therapy [1]. These cases included multiple sclerosis, optic neuritis, polycranial neuritis, myelitis, Miller–Fisher syndrome, Guillain–Barre´ syndrome, chronic demyelinating, axonal or small fiber polyneuropathy, mononeuritis multiplex and myasthenia gravis. New-onset epileptic seizures have been described but the pathogenesis remains unclear [2]. In our case, anti-TNFa-therapy was associated with epilepsy due to LE. LE classically manifests as subacute memory impairment and temporal lobe seizures. However, as in this case, temporal lobe seizures are the major symptom in some patients, with memory and behavioural problems being less prominent [3]. The normal CSF analysis in our patient does not exclude a diagnosis of LE. CSF findings may be a useful marker in the diagnostic evaluation of people in whom autoimmune-mediated epilepsy is suspected but in patients with anti-VGKC-mediated LE, the sensitivity of elevated white blood cell count and oligoclonal bands is only 22 and 7 %, respectively [4]. One other patient, developing LE 1 week after IFXinfusion, has been reported [5]. This patient presented with an acute motor neuropathy and encephalopathy with partial right facial motor seizures. Cerebral imaging showed bilateral hypersignals in the hippocampal region, suggesting limbic encephalitis. Paraneoplastic and anti-VGKCantibodies, however, were absent, consistent with a


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ultimate proof of our hypothesis must come from similar observations in other patients.

Conflict of interest to disclose.

None of the authors has any conflict of interest

Ethical standard We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

References 1. Solomon J, Spain R, Kruer MC, Bourdette D (2011) Inflammatory neurological disease in patients treated with tumor necrosis factor alpha inhibitors. Mult Scler J 17(12):1472–1487

2. Khanna D, McMahon M, Furst DE (2004) Safety of tumour necrosis factor alpha antagonists. Drug Saf 27(5):307–324 3. Lancaster E, Martinez-Hernandez E, Dalmau J (2011) Encephalitis and antibodies to synaptic and neuronal cell surface proteins. Neurology 77(2):179–189 4. Malter MP, Elger CE, Surges R (2013) Diagnostic value of CSF findings in antibody-associated limbic and anti-NMDAR-encephalitis. Seizure 22:136–140 5. Faivre A, Franques J, De Paula AM et al (2010) Acute motor and sensory axonal neuropathy and concomitant encephalopathy during tumor necrosis factor-alpha antagonist therapy. J Neurol Sci 291:103–106 6. Atzeni F, Turiel M, Capsoni F, Doria A, Meroni P, Sarzi-Puttini P (2005) Autoantibody production in patients treated with anti-TNFalpha agents. Ann NY Acad Sci 1051:559–569 7. Paterson RW, Zandi MS, Armstrong R et al (2014) Clinical relevance of positive voltage-gated potassium channel (VGKC)complex antibodies: experience from a tertiary referral centre. J Neurol Neurosurg Psychiatry 85(6):625–630


Infliximab-associated autoimmune limbic encephalitis: a case report.

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