key: cord-1001165-x2jldffr
authors: Yavuz, Ebru Nur Vanli; Altındağ, Ebru; Tüzün, Erdem; Baykan, Betül
title: Do the neurologists recognize autoimmune epilepsy well enough? What is the effect of the pandemic on this matter?
date: 2022-04-05
journal: Neurol Sci
DOI: 10.1007/s10072-022-06044-5
sha: 1252a34478525954d14871d1068e297c1bcd05da
doc_id: 1001165
cord_uid: x2jldffr

INTRODUCTION: The concept of “autoimmune epilepsy” (AE) has been emphasized more frequently through the recent increase in recognition of various autoantibodies specific to neuronal proteins. AIMS: To evaluate the attitudes of neurologists in regard to AE, to review the differential diagnosis, treatment options, and to reveal the effect of COVID-19 on this matter. METHODS: A detailed questionnaire prepared for AE was sent to neurologists via social media and WhatsApp after the approval of the Ethics Committee. The responses of 245 respondents working in different settings were analyzed, and the group with 15 years or less experience in neurology was statistically compared to the group with more than 15 years of experience. RESULTS: Awareness and knowledge levels on AE seemed high in all groups, while 11% had never thought about AE during the differential diagnosis in real life. Before starting treatment, 20% thought that the autoantibody result should definitely support it, and 77.6% reported that they did not recognize AE well. Participants stated that satisfactory guidelines for diagnosis and treatment (88.2%) and widespread laboratory support (83.7%) were lacking. Neurologists with less experience and those working outside of training hospitals get more often consultation from an experienced clinician while diagnosing and conduct more detailed investigations at the diagnosis stage (p = 0.0025, p = 0.0001). CONCLUSION: This first survey study conducted in a large group of neurologists on the attitudes for the concept of AE suggested that postgraduate education, and diagnostic and treatment guidelines should be organized and antibody screening tests need to be better disseminated. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10072-022-06044-5.

Although epilepsies are caused by many different etiologies such as structural, metabolic, genetic, and infective causes, the etiology is not yet elucidated in a large patient group [1] .

In recent years, the concept of "autoimmune epilepsy (AE)" has become increasingly recognized in etiology, along with the presence of anti-neuronal antibodies in many patients presenting with encephalopathy and/or seizures. In addition, the decrease in the frequency and severity of seizures with immunosuppressive treatments in some patients increased the interest in this concept of "AE" [2] . For this reason, AE is now included as a separate entity in the last classification of the International League Against Epilepsy (ILAE) [1] . The definition of AE mostly depends on the presence of various types of associated neuronal autoantibodies, and the current knowledge of the associated clinical phenotypes gradually developed over the years. The clinical spectrum is regarded as being only epilepsy or accompanied by typical limbic encephalitis (LE) features like encephalopathy, behavioral, cognitive impairments, and also movement disorders. Accurate diagnosis and treatment of AE can significantly improve clinical outcomes, as affected patients often have treatment-resistant seizures that improve only with immunotherapy. Although the triggering event of autoimmunity is generally unknown, underlying cancer that causes a paraneoplastic immune response can be detected in some patients. In addition, the concept of immune-mediated epileptogenesis may lead to other treatment trials targeting the main cause of seizure formation, and new treatment options can be offered to these patients [2, 3] .

The described different autoantibodies detected in the sera of the patients with AE arise mainly against neuronal membrane proteins such as ion channel or receptor proteins, which also have the potential to be pathogenic [4, 5] . Neuronal surface antibodies have also been reported in other cases with complaints such as psychosis, nystagmus, and palatal tremor in addition to epilepsy [6, 7] . Diagnosis is confirmed by demonstration of antibodies in serum and/or cerebrospinal fluid (CSF). Besides neuronal autoantibodies targeting extracellular synaptic and cell membrane proteins, those targeting intracellular antigens like GAD have also been associated with AEs. Neuronal surface antibodies are apparently not specific to a particular neurological syndrome; low titers should be evaluated carefully and together with clinical findings [8] . Anti-N-methyl-d-aspartate (NMDA) receptor antibody, one of these antibodies, was first described in 2007 in young female patients with ovarian teratoma-associated encephalitis. Thus, malignancy screening of patients with these antibodies is of crucial importance [9] .

When autoantibody screening tests are not available or antibody tests yield negative results, clinicians may seek for different predictive findings in patients' EEG, CSF, cranial MRI, or PET examinations, as listed elsewhere [10] . These particular findings suggest that AE can be a reasonable diagnostic option. Furthermore, in these high-risk individuals, positive response to a trial of immunotherapy further supports the AE diagnosis [10] . A clinically significant response to immunotherapy may favor the administration of long-term immunosuppressive therapy, as well. Treatment recommendations are largely based on observational reports and the clinical experience of major neuroimmunology centers, as there are no randomized controlled studies. As a result of all these developments, in epilepsy cases that are thought to associate with autoimmune mechanisms, defining the clinical phenotypes will be very beneficial in the diagnosis and treatment of subgroups with seizures that may respond to immunosuppression [2, 3] .

In addition, it is highlighted that the diagnosis of AE and many other neurological diseases can be delayed or even ignored due to the increased popularity and awareness of COVID-19 encephalopathy in the last 2 years of the pandemic [11] [12] [13] .

The aim of this study was to evaluate the current diagnosis and treatment approaches of the neurologists in Turkey for AE, which requires early diagnosis of malignancies and correct and prompt initiation of immunosuppression in addition to administration of antiepileptic drugs. We also aimed to reveal the effect of COVID-19 on diagnosing AE.

In June 2021, a detailed questionnaire (Supplementary  Table) aimed at investigating the views and orientations of the neurologists in the determined areas regarding AE was designed by the authors. First, a pilot study was conducted with a small group of neurologists and questions considered necessary for revision were corrected. The last form of the questionnaire included a total of 28 questions. The questionnaire consisted of six sections: profiles of the participants, diagnosis, examination, treatment, follow-up of AE, and further suggestions for AE. Except for a total of 5 yes/no questions and a total of 2 demographic numeric data (age and experience time as a year), all questions were designed as multiple choice. The invitation to participate in the survey was sent to all neurologists, from residents to expert neurologists at every level, working in Turkey between May 25 and July 11, 2021, via social media. They were asked to participate in this questionnaire about AE after giving informed consent via the internet. Each participant could complete the questionnaire only once. Participation in the survey was without any charge.

Given that the aim was to evaluate the level of knowledge of neurologists about AE, the neurologists were asked to choose the answer most appropriate for them. There was no time limit when completing the questionnaire. Participants were given the right to choose to answer or not answer some questions, except for compulsory ones, like age, clinical duty, and professional experience. As the literature on AE is growing in the last 15 years, participants with 0-15 years of professional experience were named group I, and those with 16 or more years of professional experience were considered group II.

The responses of the groups with different experience durations and working in different settings were compared statistically to evaluate the differences of the approach to AE. The SPSS version 26 package program was used for data analysis. Descriptive analyses were performed and percentage values were given for categorical variables. The chi-square test was used for comparisons between two independent categorical variables. Statistical significance was accepted as p < 0.05.

A total of 245 neurologists participated in the survey. The average age of the participants was 41.74 ± 10.24 (minimum-maximum 25-71) years. The average duration of professional experience of the participants was 16.01 ± 10.01 (minimum-maximum 0-42) years. As for the distribution of duties in the clinic, specialists constituted the largest group with 119 (48.5%) people. Of the remaining participants, 79 (32.2%) were lecturers, 40 (16.3%) were residents, and 7 (3%) were retired physicians. Training and research hospitals (37.1%) and university hospitals (37.1) were the main institutions.

A total of 218 (88.9%) neurologists had considered AE at least once during daily practice. The distribution of the number of patients considered by neurologists to have AE when diagnosing during real life is shown in Fig. 1 . It was observed that those who did not make this diagnosis before were not only the new beginners to professional life but also participants with 1-38 years of professional experience working in different institutions. Among the suggestive clinical findings for autoimmune epilepsy, the most reminded ones are presentation with memory impairment, seizures with confusion (175/265), and coexistence of psychosis and seizure (164/265). The antibody screening tests were not available in the institutions of 198/245 (80.81%) neurologists. These neurologists referred the patient or shipped the patient's samples to another center. When autoimmune epilepsy was strongly suspected, only 49/245 neurologists chose to wait for the autoantibody results to support the diagnosis before commencing the treatment. Most of the participants (64.5%) reported difficulty in reaching the antibody screening tests. Ninety percent of the neurologists stated that CSF examination should be performed in every patient for AE diagnosis and 49% were aware that CSF examination may yield normal findings in autoimmune epilepsy cases. During the pandemic, 45.7% of neurologists stated that they might have ignored the diagnosis of AE and have wrongfully attributed AE symptoms to COVID-19 encephalopathy.

In cases that immunotherapy was considered, pulse methylprednisolone (89.8%) was used most frequently in the first-line treatment; IVIG (87.3%) was used in non-steroid-responsive patients, and seizure control was used as the main response parameter. 27.3% of the participants reported that they were unaware of the prognosis of the patients with chronic epilepsy and autoantibodies. Only 55 out of the 245 participants were confident that they could recognize AE well enough.

When group I (n = 121) and group II (n = 124) were compared, no statistical difference was observed in terms of referral to another center and waiting for the support of positive antibody results before treatment. When suggestive clinical findings for autoimmune epilepsy in groups compared seizure with pre-infection, febrile illness-and viral illness-like pictures were statistically significant in group 2 (p = 0.034). Due to the increased awareness and newly recognized antibodies, the concept of autoimmune epilepsy has become more known in the last 15 years; therefore, 15 years of experience was chosen as a cutoff. The comparison of the approaches of the neurologists regarding the diagnostic findings and treatment options of AE is shown in Table 1 . Furthermore, Table 2 shows comparison between neurologists working in institutions providing specialty education and other institutions. Comparisons of attitudes towards clinical findings and EEG, MRI, PET, and CSF findings of AE according to the answers of group I and group II are shown in Fig. 2 .

On the other hand, 217/245 neurologists stated that there should be guidelines for diagnosis and treatment, and 205/245 neurologists stated that laboratory support should be provided in all institutions and should allow widespread autoantibody screening.

We evaluated the approach of the Turkish neurologists to the diagnosis, examination, treatment, and follow-up processes of AE and compared the responses of neurologist groups with longer (16 or more years) and shorter (1-15 years) experience levels. The results suggest that less experienced neurologists had a higher rate of screening for LGI1 and mGluR5 antibodies, a higher screening rate even for nonspecific findings on MRI and normal findings on PET, more frequent counseling rate when diagnosing AE, and a higher rate of the use of thorax and abdomen CT, whereas the experienced group had a higher rate of screening for AE 27 Fortunately, we observed that awareness and knowledge levels of AE were high in both groups. The reason for the high level of knowledge is that many studies have been carried out from different groups in our country about AE [14] [15] [16] [17] [18] [19] . In addition, it is noteworthy that the AE subject was given a separate place in congresses and webinars before and during the pandemic, and the subject attracted a lot of attention from the participants. However, it was clearly stated that Neurologists mostly stated that guidelines for diagnosis and treatment of AE (88.2%) and widespread laboratory support (83.7%) were lacking. For this reason, neurologists with less experience get more consultation from an experienced clinician while diagnosing AE and conduct more detailed investigations at the diagnosis stage. When the literature was reviewed, no survey study could be found on the recognition of the concept of AE by neurologists. Considering the development of the subject in the last 15 years, there may be a difference between new neurologists and experienced ones, and in our study, no significant difference was observed in their main approaches. A recent case-based survey study was conducted with a large number of participants from all over the world and the diagnosis and treatment approaches for only 2 case examples with neuropsychiatric disease suggestive of AE and temporal-type seizures along with cognitive impairment were presented to the participants. It came out that neuroimmunologists applied immunotherapy more effectively [20] . In another survey study in which adult neurologists, pediatric neurologists, and pediatric rheumatologists had participated, firstline therapy, the transition time to second-line therapy, and second-line therapy preferences were reviewed for NMDA receptor encephalitis. Although the treatment approaches were similar, slight differences were observed according to participants' specialties [21] . We assessed a more detailed approach to AE in terms of diagnosis, differential diagnosis, treatment, and suggestions for better recognition of the matter with multiple-choice questions.

Experienced neurologists are better acquainted with conditions like febrile infection-related epilepsy syndrome (FIRES), and their experience has led them to consider autoimmune therapy more often and rapidly. It was underlined that fever in FIRES started 24 h before the onset of symptoms in children. It is known that if untreated, it turns into new-onset refractory status epilepticus (NORSE) and progresses with a worse prognosis [22] . Neuronal autoantibodies are detected in 32% of patients who present with status epilepticus and a suspected autoimmune etiology. Clinical symptoms like headache and memory problems before the onset can be considered a precursor for antibody-positive patients [23] . It is also important to note that FIRES could also be seen in adults and may be misdiagnosed as "limbic encephalitis" without any evidence of paraneoplastic etiology [24] . It is necessary to raise awareness on this issue and to carry out further studies. Differential diagnosis of status epilepticus triggered by COVID-19 or autoimmune processes in a patient who applied with status epilepticus during the pandemic period is important because the treatment approaches are different [25] . It was widely appreciated that AE might be ignored during the pandemic in our study, and there was no statistical difference between the more and less experienced groups. LGI1 was the leading antibody screened in both groups (78.5% and 60.5%, respectively). The voltage-gated potassium channel (VGKC) complex consists of leucine-rich gliomainactivated 1 (LGI1), contactin-associated protein-like-2 (CASPR2), and contactin-2. LGI1 constitutes 70% of the complex [26] . Some patients with high titers of LGI1 antibodies may develop dystonic seizures of the face and arms (faciobrachial dystonic seizures) before temporal lobe seizures or other typical LE symptoms. These seizures, which are numerous during the day, are in the form of very short-term attacks in the form of simultaneous wrinkling of the face and dystonia in the ipsilateral arm. During follow-up, LE develops accompanied by amnesia, typical mesial TLE, and sometimes generalized tonic-clonic seizures [27] . In a previous study with a large cohort, the total ratio of various neuronal autoantibodies was 22.5%. However, LGI1 antibody was not detected in any patient, whereas CASPR2 was frequently observed [14] . The mGluR5 antibody, cited as one of the rarely screened antibodies, was better known to young neurologist participants. It can be seen clinically in a wide range of neuroimmunological diseases including patients with ataxia and Ophelia syndrome, and it accompanies Hodgkin lymphoma [10] .

Regarding neuroimaging correlates of AE, it is clearly known that a high rate of signal increase can be observed characteristically in the mesial temporal lobes on cranial MRI in limbic encephalitis and seizures in which autoantibodies are detected [28] . In addition to these regions, it has been reported that there may be abnormal signals in the cortex, cerebellum, brainstem, and basal ganglia [27, 29] . In addition, Ekizoğlu et al. showed that patients with autoantibodies may have nonspecific MRI findings such as white matter lesions on MRI [15] . In our study, neurologists with less experience are aware of these nonspecific cranial MRI findings, which were defined in recent years.

It is known that PET may have important clinical and prognostic findings in terms of LE in which neuronal autoantibodies are detected, especially showing hippocampal dysfunction [30] . In a previous study, we showed that there was a significant difference between the seropositive and seronegative groups in terms of coexistence of temporal lobe and extra-temporal lobe hypometabolism [14] , suggesting more widespread involvement in the presence of neuronal autoantibodies. In many related publications, it has also been stated that PET findings are not limited to the mesial temporal lobes, and that PET findings are more important than EEG findings [31, 32] . These findings are important in terms of the possible different involvement patterns of different autoantibodies and should be investigated with larger cohorts. It was remarkable that young neurologists follow the topic and had better knowledge of newly defined antibodies and MRI and PET findings in diagnosis. Also, considering that this group had little experience in diagnosing autoimmune epilepsy, they needed taking consultation/opinion from experienced colleagues while diagnosing AE at a higher level. Both the development of the AE as a remarkable clinical topic in the last 15 years and the lack of algorithms on this subject may have increased the need for counseling, taking consultation/opinion from experienced colleagues while diagnosing AE of young neurologists.

Although malignancy screening tools in encephalopathy or seizures suggestive of autoimmune etiology were performed at a similar rate in both groups, it was noteworthy that thorax and abdominal CT were performed more frequently in the younger group. When antibodies with high cancer relevance are detected, the cancer assessment should be very comprehensive and repeated after some time. If the initial computed tomography is negative, the body's computed tomography-positron emission tomography (CT-PET) will increase the diagnosis rate of cancer by an additional 18% [33] .

During the pandemic period, while the etiology is investigated, especially in patients presenting with fever, confusion, and seizure, PCR and thorax CT are primarily performed for diagnosis. Considering the MRI, CSF, and EEG findings, it was noteworthy that COVID-related encephalitis did not present with specific findings and was similar to autoimmune encephalitis in terms of clinical presentation. Immunosuppressive treatments are used in both disease groups because of immune mechanisms in the etiology [34, 35] . In addition, autoimmune epilepsies, which are rarely seen after severe SARS-CoV-2, show clinical diversity [11] . Although there was no statistical difference between group I and group II, the fact that AE was neglected at the rate of 45.7% in the whole group suggests that more attention should be drawn to the issue during the pandemic.

Thus, the awareness level of general neurologists should be increased with appropriate educations and guidelines.

IV methylprednisolone (IVMP) or intravenous immunoglobulin (IVIg) selected according to the comorbidities of the patients can be used as first-line therapy. In unresponsive patients, if autoimmune epilepsy is still suspected, another first-line agent may be tried; these patients are then reassessed after 4 to 6 weeks of treatment [3] . Patients who present with seizures then rapidly progress to status epilepticus, or have signs of autoimmune encephalitis syndrome should receive rapid plasma exchange and even second-line treatments such as rituximab or cyclophosphamide [36] . It has recently been suggested that rituximab treatment in the early period may be an effective treatment option in NMDA receptor, LGI1, and CASPR2-related autoimmune encephalitis [37] . This data indicate clearly that proper management styles of AE are rapidly evolving underlining the need for further attention in the correct diagnosis and management.

As a relatively newer anti-neuronal antibody, data on glycine receptor antibodies are scant. Seven of the 13 patients with long-term follow-up with glycine receptor antibodies were resistant to antiepileptic drugs. Only 2 of them used immunotherapy options and showed benefit. Among the heterogeneous group, one patient diagnosed with epileptic encephalopathy showed spontaneous remission, while 3 patients with mesial TLE-HS also benefit from epilepsy surgery [19] . This information indicates that it is possible to perform epilepsy surgery in some patients with autoantibodies if preoperative examinations like MRI and ictal records and PET findings are compatible with each other. In patients with a benign course, anti-seizure drugs alone are sufficient to achieve seizure freedom [14, 19] . In recent years, it has been underlined that patients with seropositivity for extracellular antibodies have a good prognosis and can even withdraw their antiepileptic drugs after immune therapy [38, 39] .

Our study is a survey study distributed via social media during the pandemic period and has the known limitations of surveys. Since the participants could not ask questions face to face, we tried to optimize the survey as clearly as possible and there were positive feedbacks. Attempts were made to reach out to all general neurologists who were also "not interested in epilepsy" but the participant number remained limited. As the literature on AE is growing in the last 15 years, the participants are divided into 2 groups. The number of participants in both groups was similar to make the comparisons.

In our country, the general awareness level of neurologists on AE is high and this seems true despite the pandemic. The fact that the younger neurologists and those working outside institutions giving neurology training take consultation/ opinion from experienced colleagues while diagnosing AE more frequently may indicate that awareness has increased in recent years in parallel with accumulating research. Our findings suggest that postgraduate education, guidelines, and antibody screening tests need to be better disseminated.

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