- Email: [email protected]
Clinical and electrographic characteristics of seizures in LGI1-antibody encephalitis
Epilepsy & Behavior 88 (2018) 277–282
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Clinical and electrographic characteristics of seizures in LGI1-antibody encephalitis Li-hao Li, Cong-cong Ma, Hai-feng Zhang, Ya-jun Lian ⁎ Department of Neurology, First Affiliated Hospital of Zhengzhou University, China
a r t i c l e
i n f o
Article history: Received 27 June 2018 Revised 13 August 2018 Accepted 15 August 2018 Available online xxxx Keywords: Autoimmune encephalitis LGI1 FBDS Neuroimmunology Epilepsy
a b s t r a c t Purpose: The purpose of this study was to analyze the clinical and electrographic characteristics of seizures in LGI1-antibody encephalitis. Methods: The methods utilized in this study were prospective analysis of the clinical manifestations, types of seizures, electroencephalogram (EEG), adjuvant examination, treatment and prognosis of 19 cases of LGI1-antibody encephalitis diagnosed from January 2017 to February 2018 in First Affiliated Hospital of Zhengzhou University, and reviewed related literatures. Results: The 15/19 (79%) patients were male, and the average onset age was 58 years (23–82). The following cases were observed: 17 (89%) with epilepsy seizures, 14 (73%) with mental disorders, and 13 (68%) with cognitive impairment. Types of epilepsy were including focal aware seizures, focal-impaired awareness seizures, focal to bilateral tonic–clonic seizures, and status epilepticus. The motor events were most commonly clonus or automatisms, and the sensory events were frequently body shuddering. The 13 patients had faciobrachial dystonic seizures (FBDS); the median frequency was 48 per day (range 5–180). In some video-EEGs, multifocal ictal epileptiform discharges from frontal, temporal, and apical regions, and interictal slow wave activity were observed in patients. Normal EEG appeared in all patients during FBDS. Five patients had hyponatremia, and brain magnetic resonance imaging (MRI) results of 5 cases were abnormal. All patients were treated with antiepileptic drugs and immunotherapy, and their clinical symptoms were improved. During the follow-up period, 13 patients recovered basically, and 6 patients relapsed. One patient died of status epilepticus after relapse. Conclusions: Faciobrachial dystonic seizure and various types of epileptic seizures are characteristic manifestations of LGI1-antibody encephalitis, which can assist in early diagnosis. Once this has been diagnosed, antiepileptic drugs and immunotherapy should be given as soon as possible to the patient. © 2018 Elsevier Inc. All rights reserved.
1. Introduction
2. Materials and methods
LGI1-antibody encephalitis is a kind of autoimmune-related limbic encephalitis (LE), with the clinical features of subacute onset cognitive impairment, mental disorders, and seizures; imaging of the medial temporal lobe and hippocampus signal changes [1]. Epileptic seizures include typical temporal lobe epilepsy and the more distinctive faciobrachial dystonic seizures (FBDS), which characteristic clinical manifestation can make accurate diagnosis without auxiliary examination [2]. Previous descriptions of these types of seizures were reported in retrospective studies and some reports had video-electroencephalogram (EEG) [3–5]. In order to improve the clinical understanding of this disease, we analyzed the seizure characteristics of patients with LGI1-antibody encephalitis diagnosed in our hospital from January 2017 to February 2018.
This study comprised of 476 consecutive patients who were suspected of having autoimmune encephalitis between January 2017 and February 2018, at First Affiliated Hospital of Zhengzhou University. We used indirect immunofluorescence staining kit (German EU Division, FAIl2d-6), testing for cerebrospinal fluid, including N-methyl-Daspartic acid receptor (NMDAR) antibody, resistance γ-aminobutyric acid receptor (GABABR) antibody, contact protein associated protein-2 (CASPR2) antibody, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor 1, 2 (AMPAR1, 2) antibody, and LGI1 antibody. Among the 57 patients who showed positive results, NMDAR antibodies were identified in 23 patients; GABABR antibodies were present in 13 patients, and AMPA2 and CASPR2 antibodies were found in 1 patient each; LGI1 antibody were present in 19 patients. We only tested antibodies in the cerebrospinal fluid, and did not find other antibodies emerge from immunological testing in the 19 patients. The study was approved by the ethics committee of the First Affiliated Hospital of
⁎ Corresponding author. E-mail address: [email protected] (Y. Lian).
https://doi.org/10.1016/j.yebeh.2018.08.019 1525-5050/© 2018 Elsevier Inc. All rights reserved.
278
L. Li et al. / Epilepsy & Behavior 88 (2018) 277–282
Zhengzhou University and all patients consented to the use of their medical records for research purposes. Detailed information of 19 patients with LGI1-antibody encephalitis was collected, including clinical manifestation, laboratory examination (serum and cerebrospinal fluid), EEG, brain magnetic resonance imaging (MRI), chest computed tomography (CT), abdominal and urinary color Doppler ultrasound, treatment, and prognosis. Based on the patient's hospitalization data, the follow-up was conducted by telephone for 3–12 months.
3. Results 3.1. Clinical characteristics Among the 19 patients, 15 (79%) were male; 4 (21%) were female, and the median age was 58 years (23–82); 7 were acute onset; 12 were subacute onset. Seventeen (89%) patients had epilepsy seizures; 13 (68%) patients had FBDS; 8 cases involved the face and arm; 3 cases involved the face, arm, and leg; 2 cases involved the arm alone, and 1 case involved the arm and leg. It was observed that FBDS were associated with vocalization, swallowing, fear, or loss of consciousness. Faciobrachial dystonic seizures occurred during wakefulness and sleep period in 12 cases, and only occurred during sleep period in 1 case; the median frequency was 48 per day (range 5–180), and the seizure duration varied from 2 to 5 s. Some FBDS showed associated ictal features including dysphasia, fear, automatisms, vocalizations, or loss of awareness. They were provoked in some patients by change of position, an unexpected sound, emotion, or stress. In addition to FBDS, 12 cases showed other types of epileptic seizures, including 11 cases of focal to bilateral tonic–clonic seizures, 6 cases of focal aware seizures, 4 cases of focal-impaired awareness seizures, and 1 case of status epilepticus (Table 1). The sensory events were described as body shuddering, ascending epigastric, blockpnea, tingling, lip quivering, and goosebumps. The motor semiologies showed features including automatisms, clonus, vocalizations, and dystonic posturing. Among them, the only clinical symptom of 3 cases was a variety of epileptic seizures; they were diagnosed after two to eight months. The 14 (73%) patients had mental disorders, including visual hallucinations, auditory hallucinations, personality changes, and gibberish speech. Thirteen (68%) patients had cognitive impairment, mainly manifested as recent memory
deterioration, orientation disturbance, and understanding disorder. Four patients had diabetes; 1 had schizophrenia, and 1 had cerebral infarction. 3.2. Laboratory examination Lumbar puncture was performed in all patients before immunotherapy. Six cases had increased cerebrospinal fluid pressure (200–400 mmH2O above); all cases had normal white blood cell counts (2 − 4 × 106/L); 9 cases had increased protein levels (234-869 mg/L, the normal value was 150-450 mg/L), and sugar was slightly higher in 5 cases. There were 5 cases of hyponatremia and hypochloremia, one of which was refractory low sodium; 3 cases of serum thyroid peroxidase antibody (TPOAb) were elevated, and 5 cases of serum tumor markers were mildly abnormal. 3.3. EEG Video-electroencephalograms were performed in 17 patients with epileptic seizures. In 8 cases, FBDS were detected in the video-EEG, and the corresponding EEGs showed obvious electromyography pseudo difference, which lasted 0.3–1.8 s, and no abnormal waves were observed. In addition to FBDS, 5 cases were monitored, and the abnormal epilepsy wave originated from the temporal lobe, forehead, and parietal lobe. In interictal EEGs, there were 7 cases of unilateral or bilateral sharp and slow wave complexes and slow wave activity in temporal lobe, and 1 case of central sharp and slow wave complexes during sleep or drowsiness. No abnormalities in EEGs were found in 6 cases (Figs. 1, 2). 3.4. Brain MRI All 19 patients underwent brain MRI examination, of which 3 patients had bilateral hippocampal abnormal signal, 1 had abnormal signal of left basal ganglia, and 1 had bilateral basal ganglia abnormal signal (Fig. 3). 3.5. Auxiliary examinations All 19 patients underwent chest CT and abdominal and urinary color Doppler ultrasound, including double lung pneumonia in 8 cases and fatty liver in 3 cases; no tumors were found.
Table 1 Clinical and electrographic characteristics of patients with LGI1-antibodies. Age (years) LGI1-antibody level FBDS
67 57 66 66 65 48 69 54 61 47 51 82 51 58 23 66 58 48 66
1/3.2 1/3.2 1/3.2 1/3.2 1/3.2 1/3.2 1/3.2 1/3.2 1/3.2 1/32 1/32 1/32 1/3.2 1/3.2 1/32 1/3.2 1/3.2 1/32 1/32
Seizures types
Number per day
Arm, face, and/or leg involved
120 7 15 20 – 40 180 35 28 – – 8 – 96 – 10 – 72 5
AF AFL A AF – AF AFL AFL AL – – AF – AF, A – AF – AF AF
– – FAS (cold sensation, numbness) FTBTCS FTBTCS, FAS (body shuddering) – FTBTCS, FAS (fear) FTBTCS, SE, FIAS (unresponsive, vocalizations) FTBTCS – FTBTCS, FIAS (automatisms), FAS (body shuddering) FAS (pain left face) – FTBTCS, FAS (tingling) FTBTCS FTBTCS FTBTCS, FIAS (unresponsive), FAS (body shuddering, goosebumps) FTBTCS FIAS (lip smacking, automatisms)
Electroencephalogram Brain MRI Interictal
Ictal
– BL Temp – L FT BL Temp R Temp BL Temp – L Temp – – – – BL Temp – – L Temp – –
– – L CT – – – – – L FCP – – – – L Temp – R Temp – BL Temp –
– BL basal ganglia L basal ganglia BL Temp – – – – – BL hippocampus – – – – – – – – BL hippocampus
Abbreviations: A arm, F face, L leg involvement during FBDS; M male; F female; L left; R right; BL bilateral; FIAS focal-impaired awareness seizures; FTBTCS focal to bilateral tonic–clonic seizures; FAS focal aware seizures; SE status epilepticus; CT centrotemporal; T temporal; FT frontotemporal; FCP frontocentroparietal.
L. Li et al. / Epilepsy & Behavior 88 (2018) 277–282
279
Fig. 1. LGI1-antibody encephalitis video-EEG. (A) Monitoring the FBDS, corresponding EEG was not abnormal; (B) The EEG showed interictal bilateral temporal lobe sharp and slow wave complex.
3.6. Treatment and prognostic
4. Discussion
All 19 patients were treated with immunotherapy, including intravenous methylprednisolone 500 mg and/or intravenous immunoglobulin (IVIg) 0.4 g/kg daily for 3–5 days, and later changed to oral prednisone 60 mg/d, gradually decreased and then ceased. Among them, 10 cases were treated with corticosteroids alone; 7 cases were combined with IVIg, and 2 cases were treated with IVIg alone; each method was effective. The corticosteroids combined with IVIg worked faster, but each method had patient recurrence. The 13 patients with epileptic seizures were treated with antiepileptic drugs (AEDs), including oxcarbazepine, sodium valproate, levetiracetam, and topiramate; 7 patients were treated with AEDs before immunotherapy, and 3 had reduced seizures but not fully controlled. Because the side effects of oxcarbazepine may cause hyponatremia, we did not use it in the 5 patients with hyponatremia, other 3 patients who used it did not develop hyponatremia. At the follow-up, 13 patients had good prognoses, and their lives returned to normal; there was no epileptic seizure after 1 month of follow-up. However, 6 patients recovered from epilepsy and mental abnormalities after being discharged from the hospital for 2–3 months. Readmission to the hospital for immunotherapy can be improved again. One patient died of status epilepticus after relapse.
LGI1-antibody encephalitis, which is relatively rare in clinic, is a disease caused by the combination of autoantibodies and neuronal surface proteins. LGI1 antibody encephalitis has an estimated annual incidence of 0.5 per million people in the China population. The incidence may be rising, owing to improved recognition. Human LGI1 gene deficiency can lead to autosomal dominant temporal lobe epilepsy [6]. Mice in the weeks after birth that knock out the LGI1 gene die of fatal epilepsy [7]; it proves that LGI1 is closely related to epileptic seizures. In this study, 19 patients were mainly elderly men, no children, no significant tumor correlation, suggesting that potential contributions from later life environmental triggers and genetic predispositions, such as the described HLA-DRB1*07:01 association [8]. There were 17 patients with seizures, including FBDS, focal aware seizures, focal-impaired awareness seizures, focal to bilateral tonic–clonic seizures, and status epilepticus. In addition to FBDS, focal to bilateral tonic–clonic seizures were the most common. The motor events were most commonly clonus or automatisms, and the sensory events were frequently body shuddering. Accompanying EEG changes were present in half events and seen in frontal, temporal, and parietal lobes. It was indicating that the pathological changes caused by LGI1 antibody were not limited to the medial hippocampus and temporal lobe. In a report, the epileptic seizures in
280
L. Li et al. / Epilepsy & Behavior 88 (2018) 277–282
Fig. 2. LGI1-antibody encephalitis video-EEG. (A) The EEG showed Left anterior and middle temporal spike wave; (B) The EEG showed left temporal lobe slow waves.
patients with LGI1-antibody encephalitis were usually induced by excessive ventilation, with few interictal epileptiform discharges [5]. On the contrary, we observed 8 cases of focal sharp and slow wave complexes and slow wave activity in the interictal EEGs. The discharges were usually multifocal and most prominent over the temporal regions. There was 1 patient who developed a lot of repetitive sharp waves over the whole left hemisphere, but without acceleration or deceleration suggestive of seizure activity. We thought that the motor cortex and hippocampus may be two main cortical targets. The encephalitis may initially affect either of these two regions independently, as previously reported [3]. Usually only the patients with cognitive impairment and mental disorders that were improved can be examined by video-EEGs, so most of the video-EEGs were not carried out before treatment; our study may underestimate the maximum frequency of epileptic seizures. We found that 9 of 11 patients with abnormal EEG had cognitive impairment, while only 1 of 6 patients with normal EEG had cognitive impairment, suggesting that cognitive impairment is associated with abnormal EEG, similar to previous reports [9]. Faciobrachial dystonic seizure is a special clinical symptom in patients with positive LGI1 antibody. It is characterized by frequent, transient, and ipsilateral spasms of upper limb, face, and leg, usually lasting less than 3 s, with a frequency of about 50 episodes per day [10]; FBDS
may involve motor cortex and striatum [3]. In this study, 13 cases of FBDS were observed of which only 3 had clinical symptoms. Most of the seizures involved unilateral face and upper limb, and there were only facial, upper, and lower extremities, or two different manifestations of FBDS, which varied from several to more than 100 times a day, similar to literature reports [11]. We observed 8 cases with FBDS in video-EEGs, but did not see an obvious abnormal EEG. Although the onset may be accompanied by loss of consciousness, vocalization, and fear, whether FBDS is a type of seizure or dystonia still remains a controversy. Sidra et al. recorded 86 episodes of FBDS with video-EEGs in 16 patients, of which 81 were not abnormal. Rhythmic δ wave activities were observed in frontal temporal lobe and anterior central area before onset in the remaining 5 [4]. Because of the absence of ictal EEG abnormalities, the inconsistent response to AEDs and the extrapyramidal manifestation that cannot be ruled out, FBDS cannot be classified into any type of seizure. In previous studies, most of the brain MRI findings were hyperintense on T2 and Flair images of the medial temporal lobe and hippocampus, and involved the basal ganglia [12]. There were 5 cases of abnormal MRI in the 19 cases, which involved bilateral hippocampus and unilateral or bilateral basal ganglia, but no abnormal MRI was found in most patients with epileptic seizures. Positron emission computed
L. Li et al. / Epilepsy & Behavior 88 (2018) 277–282
281
Fig. 3. LGI1-antibody encephalitis brain MRI. (A) T2 Flair image visible right basal ganglia high signal; (B) T2 Flair image visible bilateral temporal lobe medial high signal.
tomography (PET) was examined in 14 patients; the abnormal rate of brain was 60% [13]. It can be seen that PET is more sensitive than MRI and is helpful in the early diagnosis of the disease. Hyponatremia is also a common symptom of this disease. Because of abnormal antidiuretic hormone (ADH) secretion, hyponatremia can occur in 60% of the patients at the early stage of onset. Some studies have suggested that LGI1 antibody can bound to hypothalamic paraventricular nucleus neurons that produce ADH, which mediates water retention. This suggests that LGI1 antibody binding may increase ADH secretion to generate the hyponatremia [14]. In this study, there were 5 cases of hyponatremia and hypochloremia, of which 1 case was obstinate hyponatremia, which still appeared many times after the supplement of concentrated sodium, but did not appear after immunotherapy. Although there is no clear medical evidence, immunotherapy is thought to be effective against LGI1 antibody encephalitis and to alleviate clinical symptoms [15]. Treatment with AEDs alone is not as effective as immunotherapy, and they are often used in combination. Seven patients were treated with AEDs before immunotherapy, and 3 had reduced seizures but not fully controlled. It has been reported that rituximab is effective but lacks clinical trial support [16]. In this study, 19 patients were treated with immunotherapy and AEDs; the clinical symptoms were controlled, especially if FBDS disappeared quickly, but the recovery of cognitive impairment was slow. We found that immunotherapy was more effective than AEDs, and the earlier the immunotherapy was performed, the better the prognosis was. There were 3 cases with multiple types of epilepsy as the only clinical symptoms, and no imaging abnormalities. From 2 to 8 months after the onset of symptoms to diagnosis, the treatment of patients was greatly delayed, although immunotherapy was given after diagnosis. There are still 2 cases of recurrence. So for patients over the age of 50 years who have their first epileptic seizures and have various types, we suggest that they should actively perform lumbar puncture examination to exclude autoimmune encephalitis. Thompson et al.'s study of 103 patients with FBDS showed that immunotherapy is time sensitive and complete cessation of seizures can prevent the development of cognitive impairment, which also supports our view [9]. In this study, 12 patients had no epileptic seizure after one month of follow-up, and their life was basically normal. The 6 patients recurred after 2–3 months of discharge, and one of them died of persistent epileptic status during the third
relapse. Shin et al. Pointed out that high-dose hormone combined with immunoglobulin therapy may protect the structure and function of hippocampus and temporal lobe and thus avoid refractory epilepsy [16]. The recurrence rate of patients with previously reported LGI1-antibody encephalitis ranged from 0 to 20%, and it was possible to recur within a few years after the first onset. The recurrence rate of patients without cognitive impairment was low [17]. Among the 17 patients with epilepsy, 10 patients continued to take corticosteroids and AEDs for 2–4 months after symptom remission, and 3 patients relapsed. In addition, 7 cases were not treated after symptom relief, and 3 patients relapsed. The longest follow-up was 1 year for a patient, who continued to use drugs for 3 months after discharge and did not relapse. Therefore, we think that the hormone and antiepileptic drugs should be maintained for at least half a year after discharge from hospital. If there is abnormality in the brain MRI, antiepileptic drugs should be used for a long time, as reported in the literature [18]. 5. Conclusions To sum up, LGI1-antibody encephalitis is rare in clinic, and it is easy to miss diagnosis and misdiagnosis without antibody detection. Our study found that this disease is more common in elderly men, often with acute or subacute onset, mainly characterized by seizures, mental disorders, cognitive impairment, hyponatremia, and brain MRI abnormalities, such as the occurrence of FBDS and multiple motor and sensory seizures should be highly considered in this disease. Once diagnosed, AEDs and immunotherapy should be applied as soon as possible. This study still has a lot of shortcomings, such as the total number of cases is too small, and the follow-up time is relatively short, but we will continue to improve these deficiencies in the future. Acknowledgments The study was supported by the National Natural Science Foundation of China (grant number 81771397). Disclosure of conflict of interest None of the authors has any conflict of interest to disclose.
282
L. Li et al. / Epilepsy & Behavior 88 (2018) 277–282
References [1] Irani SR, Alexander S, Waters P, Kleopa KA, Pettingill P, Zuliani L, et al. Antibodies to K potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan's syndrome and acquired neuromyotonia. Brain 2010;133:2734–48. https://doi.org/10.1093/brain/ awq213. [2] Irani SR, Buckley C, Vincent A, Cockerell CO, Rudge P, Johnson MR, et al. Immunotherapy-responsive seizure-like episodes with potassium channel antibodies. Neurology 2008;71:1647–8. https://doi.org/10.1212/01.wnl.0000326572.93762.51. [3] Navarro V, Kas A, Apartis E, Chami L, Rogemond V, Levy P, et al. Motor cortex and hippocampus are the two main cortical targets in LGI1-antibody encephalitis. Brain 2016;139:1079–93. https://doi.org/10.1093/brain/aww012. [4] Aurangzeb S, Symmonds M, Knight RK, Kennett Robin, Wehner Tim, Irani Sarosh R. LGI1-antibody encephalitis is characterised by frequent, multifocal clinical and subclinical seizures. Seizure 2017;50:14–7. https://doi.org/10.1016/j.seizure.2017.05. 017. [5] Steriade C, Mirsattari SM, Murray BJ, Wennberg R. Subclinical temporal EEG seizure pattern in LGI1-antibody-mediated encephalitis. Epilepsia 2016;57:e155–60. https://doi.org/10.1111/epi.13436. [6] Morante-Redolat JM, Gorostidi-Pagola A, Piquer-Sirerol S, Sáenz A, Poza JJ, Galán J, et al. Mutations in the LGH/Epitempin gene on 10q24 cause autosomal dominant lateral temporal epilepsy. Hum Mol Genet 2002;11(9):1119–28. https://doi.org/10. 1093/hmg/11.9.1119. [7] Fukata Y, Lovero KL, Iwanaga T, Watanabe A, Yokoi N, Tabuchi K, et al. Disruption of LGI1-linked synaptic complex causes abnormal synaptic transmission and epilepsy. Proc Natl Acad Sci U S A 2010;107:3799–804. https://doi.org/10.1073/pnas. 0914537107. [8] Binks Sophie, Varley James, Lee Wanseon, Makuch Mateusz, Elliott Katherine, Gelfand Jeffrey M, et al. Distinct HLA associations of LGI1 and CASPR2-antibody diseases. Brain August 1 2018;141(8):2263–71. https://doi.org/10.1093/brain/ awy109.
[9] Thompson J, Bi M, Murchison AG, Makuch Mateusz, Bien Christian G, Chu Kon, et al. The importance of early immunotherapy in patients with faciobrachial dystonic seizures. Brain 2018;141(2):348–56. [10] Andrade DM, Tai P, Dalmau J, Wennberg R. Tonic seizures: a diagnostic clue of antiLGI1 encephalitis? Neurology 2011;76:1355–7. https://doi.org/10.1212/wnl. 0b013e3182152808. [11] Gastaldi M, Thouin A, Vincent A. Antibody-mediated autoimmune encephalopathies and immunotherapies. Neurotherapeutics 2016;13(1):147–62. https://doi.org/10. 1007/s13311-015-0410-6. [12] van Sonderen A, Schreurs MW, Wirtz PW, Sillevis Smitt PA, Titulaer MJ. From VGKC to LGI1 and Caspr2 encephalitis: the evolution of a disease entity over time. Autoimmun Rev 2016;15(10):970–4. https://doi.org/10.1016/j.autrev.2016.07.018. [13] Shin YW, Lee ST, Shin JW, Moon Jangsup, Lim Jung-Ah, Byun Jung-Ick, et al. VGKCcomplex/LGI1-antibody encephalitis: clinical manifestations and response to immunotherapy. J Neuroimmunol 2013;265(1-2):75–81. https://doi.org/10.1016/j. jneuroim.2013.10.005. [14] Irani SR, Pettingill P, Kleopa KA, Schiza N, Waters P, Mazia C, et al. Morvan syndrome: clinical and serological observations in 29 cases. Ann Neurol 2012 Aug;72 (2). https://doi.org/10.1002/ana.23577. [15] van Sonderen A, Petit-Pedrol M, Dalmau J, Titulaer MJ. The value of LGI1, Caspr2 and voltage-gated potassium channel antibodies in encephalitis. Nat Rev Neurol 2017 May;13(5). https://doi.org/10.1038/nrneurol.2017.43. [16] Ariño H, Armangué T, Petit-Pedrol M, Sabater L, Martinez-Hernandez E, Hara M, et al. Anti-LGI1-associated cognitive impairment: presentation and long-term outcome. Neurology 2016;87:759–65. https://doi.org/10.1212/wnl.0000000000003009. [17] Bien CG, Elger CE. Limbic encephalitis: a cause of temporal lobe epilepsy with onset in adult life. Epilepsy Behav 2007;10(4):529–38. https://doi.org/10.1016/j.yebeh. 2007.03.011. [18] Malter MP, Frisch C, Schoene-Bake JC, Helmstaedter C, Wandinger KP, Stoecker W, et al. Outcome of limbic encephalitis with VGKC-complex antibodies: relation to antigenic specificity. J Neurol 2014;261(9):1695–705. https://doi.org/10.1007/s00415014-7408-6.
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Clinical and electrographic characteristics of seizures in LGI1-antibody encephalitis Li-hao Li, Cong-cong Ma, Hai-feng Zhang, Ya-jun Lian ⁎ Department of Neurology, First Affiliated Hospital of Zhengzhou University, China
a r t i c l e
i n f o
Article history: Received 27 June 2018 Revised 13 August 2018 Accepted 15 August 2018 Available online xxxx Keywords: Autoimmune encephalitis LGI1 FBDS Neuroimmunology Epilepsy
a b s t r a c t Purpose: The purpose of this study was to analyze the clinical and electrographic characteristics of seizures in LGI1-antibody encephalitis. Methods: The methods utilized in this study were prospective analysis of the clinical manifestations, types of seizures, electroencephalogram (EEG), adjuvant examination, treatment and prognosis of 19 cases of LGI1-antibody encephalitis diagnosed from January 2017 to February 2018 in First Affiliated Hospital of Zhengzhou University, and reviewed related literatures. Results: The 15/19 (79%) patients were male, and the average onset age was 58 years (23–82). The following cases were observed: 17 (89%) with epilepsy seizures, 14 (73%) with mental disorders, and 13 (68%) with cognitive impairment. Types of epilepsy were including focal aware seizures, focal-impaired awareness seizures, focal to bilateral tonic–clonic seizures, and status epilepticus. The motor events were most commonly clonus or automatisms, and the sensory events were frequently body shuddering. The 13 patients had faciobrachial dystonic seizures (FBDS); the median frequency was 48 per day (range 5–180). In some video-EEGs, multifocal ictal epileptiform discharges from frontal, temporal, and apical regions, and interictal slow wave activity were observed in patients. Normal EEG appeared in all patients during FBDS. Five patients had hyponatremia, and brain magnetic resonance imaging (MRI) results of 5 cases were abnormal. All patients were treated with antiepileptic drugs and immunotherapy, and their clinical symptoms were improved. During the follow-up period, 13 patients recovered basically, and 6 patients relapsed. One patient died of status epilepticus after relapse. Conclusions: Faciobrachial dystonic seizure and various types of epileptic seizures are characteristic manifestations of LGI1-antibody encephalitis, which can assist in early diagnosis. Once this has been diagnosed, antiepileptic drugs and immunotherapy should be given as soon as possible to the patient. © 2018 Elsevier Inc. All rights reserved.
1. Introduction
2. Materials and methods
LGI1-antibody encephalitis is a kind of autoimmune-related limbic encephalitis (LE), with the clinical features of subacute onset cognitive impairment, mental disorders, and seizures; imaging of the medial temporal lobe and hippocampus signal changes [1]. Epileptic seizures include typical temporal lobe epilepsy and the more distinctive faciobrachial dystonic seizures (FBDS), which characteristic clinical manifestation can make accurate diagnosis without auxiliary examination [2]. Previous descriptions of these types of seizures were reported in retrospective studies and some reports had video-electroencephalogram (EEG) [3–5]. In order to improve the clinical understanding of this disease, we analyzed the seizure characteristics of patients with LGI1-antibody encephalitis diagnosed in our hospital from January 2017 to February 2018.
This study comprised of 476 consecutive patients who were suspected of having autoimmune encephalitis between January 2017 and February 2018, at First Affiliated Hospital of Zhengzhou University. We used indirect immunofluorescence staining kit (German EU Division, FAIl2d-6), testing for cerebrospinal fluid, including N-methyl-Daspartic acid receptor (NMDAR) antibody, resistance γ-aminobutyric acid receptor (GABABR) antibody, contact protein associated protein-2 (CASPR2) antibody, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor 1, 2 (AMPAR1, 2) antibody, and LGI1 antibody. Among the 57 patients who showed positive results, NMDAR antibodies were identified in 23 patients; GABABR antibodies were present in 13 patients, and AMPA2 and CASPR2 antibodies were found in 1 patient each; LGI1 antibody were present in 19 patients. We only tested antibodies in the cerebrospinal fluid, and did not find other antibodies emerge from immunological testing in the 19 patients. The study was approved by the ethics committee of the First Affiliated Hospital of
⁎ Corresponding author. E-mail address: [email protected] (Y. Lian).
https://doi.org/10.1016/j.yebeh.2018.08.019 1525-5050/© 2018 Elsevier Inc. All rights reserved.
278
L. Li et al. / Epilepsy & Behavior 88 (2018) 277–282
Zhengzhou University and all patients consented to the use of their medical records for research purposes. Detailed information of 19 patients with LGI1-antibody encephalitis was collected, including clinical manifestation, laboratory examination (serum and cerebrospinal fluid), EEG, brain magnetic resonance imaging (MRI), chest computed tomography (CT), abdominal and urinary color Doppler ultrasound, treatment, and prognosis. Based on the patient's hospitalization data, the follow-up was conducted by telephone for 3–12 months.
3. Results 3.1. Clinical characteristics Among the 19 patients, 15 (79%) were male; 4 (21%) were female, and the median age was 58 years (23–82); 7 were acute onset; 12 were subacute onset. Seventeen (89%) patients had epilepsy seizures; 13 (68%) patients had FBDS; 8 cases involved the face and arm; 3 cases involved the face, arm, and leg; 2 cases involved the arm alone, and 1 case involved the arm and leg. It was observed that FBDS were associated with vocalization, swallowing, fear, or loss of consciousness. Faciobrachial dystonic seizures occurred during wakefulness and sleep period in 12 cases, and only occurred during sleep period in 1 case; the median frequency was 48 per day (range 5–180), and the seizure duration varied from 2 to 5 s. Some FBDS showed associated ictal features including dysphasia, fear, automatisms, vocalizations, or loss of awareness. They were provoked in some patients by change of position, an unexpected sound, emotion, or stress. In addition to FBDS, 12 cases showed other types of epileptic seizures, including 11 cases of focal to bilateral tonic–clonic seizures, 6 cases of focal aware seizures, 4 cases of focal-impaired awareness seizures, and 1 case of status epilepticus (Table 1). The sensory events were described as body shuddering, ascending epigastric, blockpnea, tingling, lip quivering, and goosebumps. The motor semiologies showed features including automatisms, clonus, vocalizations, and dystonic posturing. Among them, the only clinical symptom of 3 cases was a variety of epileptic seizures; they were diagnosed after two to eight months. The 14 (73%) patients had mental disorders, including visual hallucinations, auditory hallucinations, personality changes, and gibberish speech. Thirteen (68%) patients had cognitive impairment, mainly manifested as recent memory
deterioration, orientation disturbance, and understanding disorder. Four patients had diabetes; 1 had schizophrenia, and 1 had cerebral infarction. 3.2. Laboratory examination Lumbar puncture was performed in all patients before immunotherapy. Six cases had increased cerebrospinal fluid pressure (200–400 mmH2O above); all cases had normal white blood cell counts (2 − 4 × 106/L); 9 cases had increased protein levels (234-869 mg/L, the normal value was 150-450 mg/L), and sugar was slightly higher in 5 cases. There were 5 cases of hyponatremia and hypochloremia, one of which was refractory low sodium; 3 cases of serum thyroid peroxidase antibody (TPOAb) were elevated, and 5 cases of serum tumor markers were mildly abnormal. 3.3. EEG Video-electroencephalograms were performed in 17 patients with epileptic seizures. In 8 cases, FBDS were detected in the video-EEG, and the corresponding EEGs showed obvious electromyography pseudo difference, which lasted 0.3–1.8 s, and no abnormal waves were observed. In addition to FBDS, 5 cases were monitored, and the abnormal epilepsy wave originated from the temporal lobe, forehead, and parietal lobe. In interictal EEGs, there were 7 cases of unilateral or bilateral sharp and slow wave complexes and slow wave activity in temporal lobe, and 1 case of central sharp and slow wave complexes during sleep or drowsiness. No abnormalities in EEGs were found in 6 cases (Figs. 1, 2). 3.4. Brain MRI All 19 patients underwent brain MRI examination, of which 3 patients had bilateral hippocampal abnormal signal, 1 had abnormal signal of left basal ganglia, and 1 had bilateral basal ganglia abnormal signal (Fig. 3). 3.5. Auxiliary examinations All 19 patients underwent chest CT and abdominal and urinary color Doppler ultrasound, including double lung pneumonia in 8 cases and fatty liver in 3 cases; no tumors were found.
Table 1 Clinical and electrographic characteristics of patients with LGI1-antibodies. Age (years) LGI1-antibody level FBDS
67 57 66 66 65 48 69 54 61 47 51 82 51 58 23 66 58 48 66
1/3.2 1/3.2 1/3.2 1/3.2 1/3.2 1/3.2 1/3.2 1/3.2 1/3.2 1/32 1/32 1/32 1/3.2 1/3.2 1/32 1/3.2 1/3.2 1/32 1/32
Seizures types
Number per day
Arm, face, and/or leg involved
120 7 15 20 – 40 180 35 28 – – 8 – 96 – 10 – 72 5
AF AFL A AF – AF AFL AFL AL – – AF – AF, A – AF – AF AF
– – FAS (cold sensation, numbness) FTBTCS FTBTCS, FAS (body shuddering) – FTBTCS, FAS (fear) FTBTCS, SE, FIAS (unresponsive, vocalizations) FTBTCS – FTBTCS, FIAS (automatisms), FAS (body shuddering) FAS (pain left face) – FTBTCS, FAS (tingling) FTBTCS FTBTCS FTBTCS, FIAS (unresponsive), FAS (body shuddering, goosebumps) FTBTCS FIAS (lip smacking, automatisms)
Electroencephalogram Brain MRI Interictal
Ictal
– BL Temp – L FT BL Temp R Temp BL Temp – L Temp – – – – BL Temp – – L Temp – –
– – L CT – – – – – L FCP – – – – L Temp – R Temp – BL Temp –
– BL basal ganglia L basal ganglia BL Temp – – – – – BL hippocampus – – – – – – – – BL hippocampus
Abbreviations: A arm, F face, L leg involvement during FBDS; M male; F female; L left; R right; BL bilateral; FIAS focal-impaired awareness seizures; FTBTCS focal to bilateral tonic–clonic seizures; FAS focal aware seizures; SE status epilepticus; CT centrotemporal; T temporal; FT frontotemporal; FCP frontocentroparietal.
L. Li et al. / Epilepsy & Behavior 88 (2018) 277–282
279
Fig. 1. LGI1-antibody encephalitis video-EEG. (A) Monitoring the FBDS, corresponding EEG was not abnormal; (B) The EEG showed interictal bilateral temporal lobe sharp and slow wave complex.
3.6. Treatment and prognostic
4. Discussion
All 19 patients were treated with immunotherapy, including intravenous methylprednisolone 500 mg and/or intravenous immunoglobulin (IVIg) 0.4 g/kg daily for 3–5 days, and later changed to oral prednisone 60 mg/d, gradually decreased and then ceased. Among them, 10 cases were treated with corticosteroids alone; 7 cases were combined with IVIg, and 2 cases were treated with IVIg alone; each method was effective. The corticosteroids combined with IVIg worked faster, but each method had patient recurrence. The 13 patients with epileptic seizures were treated with antiepileptic drugs (AEDs), including oxcarbazepine, sodium valproate, levetiracetam, and topiramate; 7 patients were treated with AEDs before immunotherapy, and 3 had reduced seizures but not fully controlled. Because the side effects of oxcarbazepine may cause hyponatremia, we did not use it in the 5 patients with hyponatremia, other 3 patients who used it did not develop hyponatremia. At the follow-up, 13 patients had good prognoses, and their lives returned to normal; there was no epileptic seizure after 1 month of follow-up. However, 6 patients recovered from epilepsy and mental abnormalities after being discharged from the hospital for 2–3 months. Readmission to the hospital for immunotherapy can be improved again. One patient died of status epilepticus after relapse.
LGI1-antibody encephalitis, which is relatively rare in clinic, is a disease caused by the combination of autoantibodies and neuronal surface proteins. LGI1 antibody encephalitis has an estimated annual incidence of 0.5 per million people in the China population. The incidence may be rising, owing to improved recognition. Human LGI1 gene deficiency can lead to autosomal dominant temporal lobe epilepsy [6]. Mice in the weeks after birth that knock out the LGI1 gene die of fatal epilepsy [7]; it proves that LGI1 is closely related to epileptic seizures. In this study, 19 patients were mainly elderly men, no children, no significant tumor correlation, suggesting that potential contributions from later life environmental triggers and genetic predispositions, such as the described HLA-DRB1*07:01 association [8]. There were 17 patients with seizures, including FBDS, focal aware seizures, focal-impaired awareness seizures, focal to bilateral tonic–clonic seizures, and status epilepticus. In addition to FBDS, focal to bilateral tonic–clonic seizures were the most common. The motor events were most commonly clonus or automatisms, and the sensory events were frequently body shuddering. Accompanying EEG changes were present in half events and seen in frontal, temporal, and parietal lobes. It was indicating that the pathological changes caused by LGI1 antibody were not limited to the medial hippocampus and temporal lobe. In a report, the epileptic seizures in
280
L. Li et al. / Epilepsy & Behavior 88 (2018) 277–282
Fig. 2. LGI1-antibody encephalitis video-EEG. (A) The EEG showed Left anterior and middle temporal spike wave; (B) The EEG showed left temporal lobe slow waves.
patients with LGI1-antibody encephalitis were usually induced by excessive ventilation, with few interictal epileptiform discharges [5]. On the contrary, we observed 8 cases of focal sharp and slow wave complexes and slow wave activity in the interictal EEGs. The discharges were usually multifocal and most prominent over the temporal regions. There was 1 patient who developed a lot of repetitive sharp waves over the whole left hemisphere, but without acceleration or deceleration suggestive of seizure activity. We thought that the motor cortex and hippocampus may be two main cortical targets. The encephalitis may initially affect either of these two regions independently, as previously reported [3]. Usually only the patients with cognitive impairment and mental disorders that were improved can be examined by video-EEGs, so most of the video-EEGs were not carried out before treatment; our study may underestimate the maximum frequency of epileptic seizures. We found that 9 of 11 patients with abnormal EEG had cognitive impairment, while only 1 of 6 patients with normal EEG had cognitive impairment, suggesting that cognitive impairment is associated with abnormal EEG, similar to previous reports [9]. Faciobrachial dystonic seizure is a special clinical symptom in patients with positive LGI1 antibody. It is characterized by frequent, transient, and ipsilateral spasms of upper limb, face, and leg, usually lasting less than 3 s, with a frequency of about 50 episodes per day [10]; FBDS
may involve motor cortex and striatum [3]. In this study, 13 cases of FBDS were observed of which only 3 had clinical symptoms. Most of the seizures involved unilateral face and upper limb, and there were only facial, upper, and lower extremities, or two different manifestations of FBDS, which varied from several to more than 100 times a day, similar to literature reports [11]. We observed 8 cases with FBDS in video-EEGs, but did not see an obvious abnormal EEG. Although the onset may be accompanied by loss of consciousness, vocalization, and fear, whether FBDS is a type of seizure or dystonia still remains a controversy. Sidra et al. recorded 86 episodes of FBDS with video-EEGs in 16 patients, of which 81 were not abnormal. Rhythmic δ wave activities were observed in frontal temporal lobe and anterior central area before onset in the remaining 5 [4]. Because of the absence of ictal EEG abnormalities, the inconsistent response to AEDs and the extrapyramidal manifestation that cannot be ruled out, FBDS cannot be classified into any type of seizure. In previous studies, most of the brain MRI findings were hyperintense on T2 and Flair images of the medial temporal lobe and hippocampus, and involved the basal ganglia [12]. There were 5 cases of abnormal MRI in the 19 cases, which involved bilateral hippocampus and unilateral or bilateral basal ganglia, but no abnormal MRI was found in most patients with epileptic seizures. Positron emission computed
L. Li et al. / Epilepsy & Behavior 88 (2018) 277–282
281
Fig. 3. LGI1-antibody encephalitis brain MRI. (A) T2 Flair image visible right basal ganglia high signal; (B) T2 Flair image visible bilateral temporal lobe medial high signal.
tomography (PET) was examined in 14 patients; the abnormal rate of brain was 60% [13]. It can be seen that PET is more sensitive than MRI and is helpful in the early diagnosis of the disease. Hyponatremia is also a common symptom of this disease. Because of abnormal antidiuretic hormone (ADH) secretion, hyponatremia can occur in 60% of the patients at the early stage of onset. Some studies have suggested that LGI1 antibody can bound to hypothalamic paraventricular nucleus neurons that produce ADH, which mediates water retention. This suggests that LGI1 antibody binding may increase ADH secretion to generate the hyponatremia [14]. In this study, there were 5 cases of hyponatremia and hypochloremia, of which 1 case was obstinate hyponatremia, which still appeared many times after the supplement of concentrated sodium, but did not appear after immunotherapy. Although there is no clear medical evidence, immunotherapy is thought to be effective against LGI1 antibody encephalitis and to alleviate clinical symptoms [15]. Treatment with AEDs alone is not as effective as immunotherapy, and they are often used in combination. Seven patients were treated with AEDs before immunotherapy, and 3 had reduced seizures but not fully controlled. It has been reported that rituximab is effective but lacks clinical trial support [16]. In this study, 19 patients were treated with immunotherapy and AEDs; the clinical symptoms were controlled, especially if FBDS disappeared quickly, but the recovery of cognitive impairment was slow. We found that immunotherapy was more effective than AEDs, and the earlier the immunotherapy was performed, the better the prognosis was. There were 3 cases with multiple types of epilepsy as the only clinical symptoms, and no imaging abnormalities. From 2 to 8 months after the onset of symptoms to diagnosis, the treatment of patients was greatly delayed, although immunotherapy was given after diagnosis. There are still 2 cases of recurrence. So for patients over the age of 50 years who have their first epileptic seizures and have various types, we suggest that they should actively perform lumbar puncture examination to exclude autoimmune encephalitis. Thompson et al.'s study of 103 patients with FBDS showed that immunotherapy is time sensitive and complete cessation of seizures can prevent the development of cognitive impairment, which also supports our view [9]. In this study, 12 patients had no epileptic seizure after one month of follow-up, and their life was basically normal. The 6 patients recurred after 2–3 months of discharge, and one of them died of persistent epileptic status during the third
relapse. Shin et al. Pointed out that high-dose hormone combined with immunoglobulin therapy may protect the structure and function of hippocampus and temporal lobe and thus avoid refractory epilepsy [16]. The recurrence rate of patients with previously reported LGI1-antibody encephalitis ranged from 0 to 20%, and it was possible to recur within a few years after the first onset. The recurrence rate of patients without cognitive impairment was low [17]. Among the 17 patients with epilepsy, 10 patients continued to take corticosteroids and AEDs for 2–4 months after symptom remission, and 3 patients relapsed. In addition, 7 cases were not treated after symptom relief, and 3 patients relapsed. The longest follow-up was 1 year for a patient, who continued to use drugs for 3 months after discharge and did not relapse. Therefore, we think that the hormone and antiepileptic drugs should be maintained for at least half a year after discharge from hospital. If there is abnormality in the brain MRI, antiepileptic drugs should be used for a long time, as reported in the literature [18]. 5. Conclusions To sum up, LGI1-antibody encephalitis is rare in clinic, and it is easy to miss diagnosis and misdiagnosis without antibody detection. Our study found that this disease is more common in elderly men, often with acute or subacute onset, mainly characterized by seizures, mental disorders, cognitive impairment, hyponatremia, and brain MRI abnormalities, such as the occurrence of FBDS and multiple motor and sensory seizures should be highly considered in this disease. Once diagnosed, AEDs and immunotherapy should be applied as soon as possible. This study still has a lot of shortcomings, such as the total number of cases is too small, and the follow-up time is relatively short, but we will continue to improve these deficiencies in the future. Acknowledgments The study was supported by the National Natural Science Foundation of China (grant number 81771397). Disclosure of conflict of interest None of the authors has any conflict of interest to disclose.
282
L. Li et al. / Epilepsy & Behavior 88 (2018) 277–282
References [1] Irani SR, Alexander S, Waters P, Kleopa KA, Pettingill P, Zuliani L, et al. Antibodies to K potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan's syndrome and acquired neuromyotonia. Brain 2010;133:2734–48. https://doi.org/10.1093/brain/ awq213. [2] Irani SR, Buckley C, Vincent A, Cockerell CO, Rudge P, Johnson MR, et al. Immunotherapy-responsive seizure-like episodes with potassium channel antibodies. Neurology 2008;71:1647–8. https://doi.org/10.1212/01.wnl.0000326572.93762.51. [3] Navarro V, Kas A, Apartis E, Chami L, Rogemond V, Levy P, et al. Motor cortex and hippocampus are the two main cortical targets in LGI1-antibody encephalitis. Brain 2016;139:1079–93. https://doi.org/10.1093/brain/aww012. [4] Aurangzeb S, Symmonds M, Knight RK, Kennett Robin, Wehner Tim, Irani Sarosh R. LGI1-antibody encephalitis is characterised by frequent, multifocal clinical and subclinical seizures. Seizure 2017;50:14–7. https://doi.org/10.1016/j.seizure.2017.05. 017. [5] Steriade C, Mirsattari SM, Murray BJ, Wennberg R. Subclinical temporal EEG seizure pattern in LGI1-antibody-mediated encephalitis. Epilepsia 2016;57:e155–60. https://doi.org/10.1111/epi.13436. [6] Morante-Redolat JM, Gorostidi-Pagola A, Piquer-Sirerol S, Sáenz A, Poza JJ, Galán J, et al. Mutations in the LGH/Epitempin gene on 10q24 cause autosomal dominant lateral temporal epilepsy. Hum Mol Genet 2002;11(9):1119–28. https://doi.org/10. 1093/hmg/11.9.1119. [7] Fukata Y, Lovero KL, Iwanaga T, Watanabe A, Yokoi N, Tabuchi K, et al. Disruption of LGI1-linked synaptic complex causes abnormal synaptic transmission and epilepsy. Proc Natl Acad Sci U S A 2010;107:3799–804. https://doi.org/10.1073/pnas. 0914537107. [8] Binks Sophie, Varley James, Lee Wanseon, Makuch Mateusz, Elliott Katherine, Gelfand Jeffrey M, et al. Distinct HLA associations of LGI1 and CASPR2-antibody diseases. Brain August 1 2018;141(8):2263–71. https://doi.org/10.1093/brain/ awy109.
[9] Thompson J, Bi M, Murchison AG, Makuch Mateusz, Bien Christian G, Chu Kon, et al. The importance of early immunotherapy in patients with faciobrachial dystonic seizures. Brain 2018;141(2):348–56. [10] Andrade DM, Tai P, Dalmau J, Wennberg R. Tonic seizures: a diagnostic clue of antiLGI1 encephalitis? Neurology 2011;76:1355–7. https://doi.org/10.1212/wnl. 0b013e3182152808. [11] Gastaldi M, Thouin A, Vincent A. Antibody-mediated autoimmune encephalopathies and immunotherapies. Neurotherapeutics 2016;13(1):147–62. https://doi.org/10. 1007/s13311-015-0410-6. [12] van Sonderen A, Schreurs MW, Wirtz PW, Sillevis Smitt PA, Titulaer MJ. From VGKC to LGI1 and Caspr2 encephalitis: the evolution of a disease entity over time. Autoimmun Rev 2016;15(10):970–4. https://doi.org/10.1016/j.autrev.2016.07.018. [13] Shin YW, Lee ST, Shin JW, Moon Jangsup, Lim Jung-Ah, Byun Jung-Ick, et al. VGKCcomplex/LGI1-antibody encephalitis: clinical manifestations and response to immunotherapy. J Neuroimmunol 2013;265(1-2):75–81. https://doi.org/10.1016/j. jneuroim.2013.10.005. [14] Irani SR, Pettingill P, Kleopa KA, Schiza N, Waters P, Mazia C, et al. Morvan syndrome: clinical and serological observations in 29 cases. Ann Neurol 2012 Aug;72 (2). https://doi.org/10.1002/ana.23577. [15] van Sonderen A, Petit-Pedrol M, Dalmau J, Titulaer MJ. The value of LGI1, Caspr2 and voltage-gated potassium channel antibodies in encephalitis. Nat Rev Neurol 2017 May;13(5). https://doi.org/10.1038/nrneurol.2017.43. [16] Ariño H, Armangué T, Petit-Pedrol M, Sabater L, Martinez-Hernandez E, Hara M, et al. Anti-LGI1-associated cognitive impairment: presentation and long-term outcome. Neurology 2016;87:759–65. https://doi.org/10.1212/wnl.0000000000003009. [17] Bien CG, Elger CE. Limbic encephalitis: a cause of temporal lobe epilepsy with onset in adult life. Epilepsy Behav 2007;10(4):529–38. https://doi.org/10.1016/j.yebeh. 2007.03.011. [18] Malter MP, Frisch C, Schoene-Bake JC, Helmstaedter C, Wandinger KP, Stoecker W, et al. Outcome of limbic encephalitis with VGKC-complex antibodies: relation to antigenic specificity. J Neurol 2014;261(9):1695–705. https://doi.org/10.1007/s00415014-7408-6.