Abstract
Background and Objectives Patients with anti–GABA-A receptor encephalitis characteristically experience therapy-refractory epileptic seizures. General anesthesia is often required to terminate refractory status epilepticus. The immunologic mechanisms leading to antibody formation remain to be elucidated. Described triggers of anti–GABA-A autoimmunity are tumors, mainly thymomas, and herpes simplex encephalitis.
Methods We present a young woman with prediagnosis of relapse remitting multiple sclerosis (MS), treated with interferons, natalizumab, and alemtuzumab. Six months after one and only cycle of alemtuzumab, speech arrest and behavioral changes with aggressive and anxious traits appeared. She showed increasing motor convulsions resulting in focal status epilepticus.
Results Anti–GABA-A receptor antibodies in CSF and serum were confirmed in different external laboratories, in a more extensive analysis after antibodies against NMDAR, CASPR2, LGI1, GABABR, and AMPAR were ruled out during in-house examination. Clinical condition improved temporarily with cortisone therapy, plasmapheresis, and IVIG but deteriorated rapidly after steroid discontinuation, resulting in brain biopsy. On histopathologic confirmation consistent with anti–GABA-A receptor antibody-associated CNS inflammation, completing the first rituximab cycle, continuing oral corticosteroids and supplementing immunosuppression with cyclosporine A led to quick recovery.
Discussion Our case describes a severe autoantibody-induced encephalitis in a young patient with MS, with alemtuzumab as a potential trigger for anti–GABA-A receptor encephalitis.
Several specific antibodies against neuronal surface antigens (ABNSAs) that have been identified over the past 2 decades are known to cause encephalitis and autoimmune-mediated seizures. The effects of γ-Aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the CNS, are mediated through GABA-A and GABA-B receptors. Anti–GABA-A receptor antibodies mediating receptor dysfunction are a much rarer cause of autoimmune encephalitis than, for example, antibodies against the NMDA receptor or against LGI1. A large-scale study showed that of almost 2,500 patients with proven autoimmune encephalitis, over 1,500 had antibodies against the NMDA receptor, while an antibody against the GABA-A receptor could only be detected in 70 cases. In anti–GABA-A receptor encephalitis, the average age at onset is 40 years, and the data already collected showed no differences in sex distribution.1 Therapy-refractory seizures are the most common manifestation in patients with antibodies against GABA-A receptors, but disorders of consciousness and behavioral abnormalities occur as well. The largest review of a total of 26 patients with proven anti–GABA-A receptor encephalitis showed abnormalities in CSF with an increase in cell count, protein content, or positive oligoclonal bands in more than half of the cases (58%). Nearly 90% of these patients showed abnormalities on T2 fluid-attenuated inversion recovery weighted MRI imaging. All but 2 patients had multilocular changes involving both cortex and subcortical region.2 Therapeutic strategies are in line with the recommendations for autoimmune encephalitis caused by other ABNSAs. Initially, high-dose methylprednisolone, plasma exchange, or IV immunoglobulins are administered. Maintenance therapy is usually performed with immunosuppressants such as azathioprine, cyclosporine, rituximab, or cyclophosphamide. In all cases presented, a monophasic course was found. Less than 30% of the patients achieved a complete recovery from seizures. The 2 documented deaths were related to sepsis and status epilepticus.2 Clinically, our patient also had primarily refractory epilepsy with evidence of antibodies against the GABA-A receptor. A tumor as a potential trigger could be excluded. However, the medical history revealed that a prediagnosed multiple sclerosis (MS) had been treated with alemtuzumab a few months earlier.
Case Report
We report on a 22-year-old woman with super-refractory status epilepticus. Relapsing MS was diagnosed 3 years earlier, clinically showing sensorimotor disturbance. Retrospectively, she reported an initial presentation at the age 15 years with paraparesis and disturbed bladder function. On the maternal side, the family history revealed the presence of diabetes mellitus type I, Hashimoto thyroiditis, chronic atrophic gastritis, lupus erythematosus, and unspecified autoimmune endocrinopathy and other predispositions are not found. Based on juxtacortical and spinal lesions, the McDonald criteria for dissemination in space were fulfilled. CSF analysis showed mild cell count increase but negative oligoclonal bands. The treatment was started with interferons and due to relapses escalated to natalizumab and ultimately to alemtuzumab. Six months after the first cycle of alemtuzumab, new-onset epilepsy was explained by an increase in cerebral lesions.
A MS relapse was suspected and treated with methylprednisolone, prompting reduction of seizure frequency for 2–3 weeks. However, pharmacologic control of seizures was only moderately successful, resulting only in reduction of frequency of convulsions, leading to referral to our hospital.
The patient presented to our clinic with psychomotor slowing and mild dysarthria as well as continuous focal motor convulsions of the left upper limb and of the left side of her face. In addition, the parents described that the patient gradually developed a change of character, accompanied by aggressive outbursts and self-harming behavior over the past few weeks.
Follow-up brain MRI after admission showed new-onset cortical and subcortical T2 hyperintensity without contrast agent enhancement with subtle cortical swelling. Taking into account the absence of oligoclonal bands in radiologically proven demyelinating disease, anti-MOG antibodies were determined yet could not be detected. In addition, further laboratory tests such as ANA, ANCA, or anti-DNA antibodies were not indicative of collagenosis or vasculitis.
Owing to refractory focal status epilepticus, with EEG progression and generalization, despite anticonvulsant medication with lamotrigine, valproate, brivaracetam, lacosamide, perampanel, and lorazepam, we escalated the therapy by general anesthesia on the intensive care unit 9 days after admission.
Re-examination of CSF in our in-house CSF laboratory was performed after another lumbar puncture and revealed a mild pleocytosis (7 cells/μL), a normal protein level (0.327 g/L), and negative oligoclonal bands. Rarer infections such as JC virus, West Nile virus, or Japanese encephalitis, which had not been considered before, could be excluded. FDG PET scan did not show any malignancies but multifocal increase glucose uptake with a punctum maximum in the right temporoparietal lobe. The diagnosis of autoimmune encephalitis was made based on the application of the Graus criteria with available clinical and imaging findings3 and was confirmed by the detection of antibodies against GABA-A receptors in both serum and CSF in an extended autoantibody assay in 2 different laboratory results (USKH, Kiel Lübeck; Euroimmun, Germany). The results reached us after induction of anesthesia.
The patient initially received high-dose methylprednisolone treatment for 5 days, together with 5 cycles of plasmapheresis. Owing to persistent focal seizures, IVIGs were also administered; the patient received 150 g distributed over 5 days (30 g/d) in a weight-adapted manner. The patient showed a decrease in seizure intensity and frequency approximately 10 days after admission to the ICU. A cranial MRI showed a decrease in lesion size. We started the first cycle of rituximab and also gave the patient oral prednisolone through feeding tube (30 mg/d). In parallel, the sedation was reduced, which was accompanied by increasing wakefulness. In the following 2 weeks, there was a renewed increase in seizure frequency as well as vegetative derangements, such as spontaneous recurrent tachycardia or elevation of blood pressure. The cranial MRI scan 3 weeks after admission to the ICU showed a marked increase in the previously regressing lesion (Figure 1C), prompting open biopsy of the right frontal lobe to exclude vasculitis, collagenosis, neoplastic, or infectious genesis of the lesions and therefore gather further evidence for the presence of autoimmune-mediated encephalitis. Microscopic investigation revealed cerebral tissue (cortex and white matter) with moderate inflammatory changes, blood vessel activation, diffuse neuronal loss, and reactive astrogliosis and microgliosis, consistent with anti–GABA-A receptor encephalitis (Figure 2). After another methylprednisolone pulse therapy over 3 days, we observed a clinical improvement with decreasing of focal discharges and an increase in vigilance. Owing to pronounced steroid responsiveness, we continued oral prednisolone (60 mg/d) in addition to maintenance therapy with rituximab and further augmented immunosuppression with cyclosporine A to enhance of the T-cell suppression. Before rituximab therapy, the B-cell and T-cell fractions of the total lymphocytes were determined. Here, we saw an increased relative (20%) and absolute (210/µL) B-cell fraction, whereas the relative T-cell fraction of 61% was in the normal range at the lower limit, but the absolute number of 640/µL was below the normal range. The patient was transferred to the intermediate care ward after 44 days of intensive care treatment. EEG follow-up could not detect any signs of increased cerebral excitability. After the end of intensive medical treatment, the anticonvulsant medication was gradually reduced. Initially, we stopped the treatment with valproate and, due to sustained absence of seizures and stable EEG findings, also the administration of lacosamide. At the time of discharge, anticonvulsant therapy consisted of brivaracetam, perampanel, lamotrigine, and lorazepam. We were able to transfer her to the neurologic rehabilitation facility after 57 days of hospitalization. At the time of discharge, 60 mg of prednisolone were taken per day. According to our recommendations in rehabilitation, the daily dose of prednisolone was reduced to 50 mg orally. This was followed by a tapering of 10 mg per week, down to 10 mg per day. Subsequently, the dose was decreased in smaller steps by 2.5 mg per week until a daily dose of 2.5 mg was reached, which was taken for 1 week, followed by a further dose reduction to 1 mg, and then after 1 week with 1 mg prednisolone per day, and treatment with steroids was terminated.
After admission (T0), 3 T (A); after clinical improvement (T0+18d), 1.5 T (B); after clinical deterioration, 3 T (C) (T0+37d); and after remission, 1.5 T (T0+126d) (D). Statistical parametric mapping (SPM) analysis of F-18-FDG PET-CT showed compared with the background FDG multifocal, multistorage lesions with punctum maximum in the right temporoparietal lobe and single small-spotted enhancement exemplarily in the right frontal lobe as well as in the left parietal lobe (E).
White matter (A) and cortical CNS tissue (B) showing massive astrocytosis and endothelial activation in blood vessels, without evidence for prominent lymphocytic infiltrates, perivascular “cuffs,” or active demyelinization (LFB/HE). Immunohistochemistry confirmed massive activation of microglia (C, CD68, cortex), even at the sites of maximal density only mild lymphocytic infiltrate (D, CD3, cortex), massive reactive gliosis (E, GFAP, cortex), and diffuse loss of neurons and axonal integrity with dystrophic neuritic structures (F, NF, cortex). Method for picture acquisition: Olympus BX46 microscope (×200), no further modifications.
On follow-up, 3 months after hospital discharge, we saw an alert, oriented, and cooperative patient with no evidence of psychotic experience and no involuntary motor activity. Cyclosporine A treatment was terminated after this follow-up, and anticonvulsive treatment reduced to lamotrigine monotherapy.
Discussion
Alemtuzumab is an anti-CD52 monoclonal antibody for high active relapsing-remitting MS that significantly reduces disease activity. Nevertheless, repeated cases have been documented in which the use of alemtuzumab has led to severe, in rare cases, even lethal autoimmune diseases. These included autoreactive diseases of the thyroid, hematopoietic system, or liver.4 Recently, a case report with the development of anti–GABA-A receptor antibodies after application of alemtuzumab has been published.5 Similar to this case, our patient developed encephalitis only months after the last dose of alemtuzumab which had been given for relapse-remitting MS. Remarkably in our case is the family history with an accumulation of autoimmune disorders in the maternal line. Autoimmune disorders, mainly thyroid autoimmunity reported in the past most likely due to the treatment with alemtuzumab, also developed after a latency period of several months and were most frequent within the first 3 years of treatment. A possible explanation is seen in the different rapid repopulation of T and B cells after depletion by alemtuzumab. The lack of regulatory T cells with a concomitant increase in B cell presence raises the possibility of the development of autoreactive plasma cells.6 Cell status evaluation in our case showed an increased absolute and relative number of B cells and a decrease in absolute number of T cells before rituximab treatment. In the previously published case, a disproportion of B and T cells was also present.5 Interestingly, in both cases, brain biopsy showed gliosis with only low lymphocytic infiltration. In our case, the brain biopsy was performed after the first dose of rituximab, which could explain the only slightly pronounced lymphocytic infiltration. The time of therapy at which the brain biopsy was performed in the other case is not described. Whether the treatment with alemtuzumab alone leads to the formation of antibodies or whether the demyelinating disease at hand makes an additional contribution to the formation of antibodies cannot be clarified within the scope of this work. The case workup was complex and interdisciplinary; various comprehensive examinations were performed, and the results of which provided a comprehensible diagnosis.
In the context of the individual patient's history, we placed this diagnosis in a potential correlation with the alemtuzumab treatment previously performed. Nevertheless, no general conclusions or recommendations can be drawn from a single report on a single patient. This case report joins several case reports of secondary developed autoimmune disease after treatment with alemtuzumab.7 In particular, one further case of autoimmune encephalitis without identification of any well-characterized neuronal antibody has been described so far.5,8 With respect to the other published case, this case suggests that anti–GABA-A receptor encephalitis might be an extremely rare adverse event after alemtuzumab administration. The diagnosis of autoimmune encephalitis based on the application of the Graus criteria should prompt specialized laboratory analyses if screening for autoantibodies that are more common yield negative results.
Study Funding
The authors report no targeted funding.
Disclosure
The authors report no relevant disclosures. Go to Neurology.org/NN for full disclosures.
Acknowledgment
The authors thank Karin Fricke, Kathrin Scheiwe, Sabine Lang, Katharina Dorsch, Ilona Cierpka-Leja, Linda Schneider, Sabine Stilo, Patricia Gerstenberger, Mandy Wenzel, and Claudia Wilmsmann for excellent technical assistance.
Appendix Authors
Footnotes
Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.
The Article Processing Charge was funded by Hannover Medical School, Department of Neurology.
Submitted and externally peer reviewed. The handling editor was Editor Josep O. Dalmau, MD, PhD, FAAN.
- Received October 18, 2022.
- Accepted in final form March 20, 2023.
- Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
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