|Year : 2021 | Volume
| Issue : 1 | Page : 37-44
Different attitudes in the management of different types of status epilepticus: A survey study among neurologists demonstrating evidence gap
Yasemin Bicer Gomceli1, Ebru Aykutlu Altındağ2, Betül Baykan3
1 Department of Neurology, Antalya Education and Research Hospital, Antalya, Turkey
2 Department of Neurology, Istanbul Florence Nightingale Hospital, Istanbul, Turkey
3 Department of Neurology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey
|Date of Submission||21-May-2020|
|Date of Decision||18-Jun-2020|
|Date of Acceptance||22-Jun-2020|
|Date of Web Publication||26-Mar-2021|
Yasemin Bicer Gomceli
Antalya Education and Research Hospital, Muratpasa, Antalya
Source of Support: None, Conflict of Interest: None
Purpose: The aim is to identify current diagnostic and therapeutic approach to different types of status epilepticus (SE) including convulsive SE (CSE), non-CSE (NCSE), and epilepsia partialis continua (EPC) to detect unmet needs and problems encountered during the management of these neurological emergencies in our country, Turkey. Methods: The specifically designed SE survey included 31 questions that were related to the incidence, the distribution of etiological causes, the diagnostic process, and the treatment approaches of the neurologists and individual electroencephalography (EEG) facilities of the institutions. Results: The total number of respondents was 152 with a median years of experience in professional practice of 10.8 years (1–39 years). The great majority of the neurologists preferred diazepam plus phenytoin as the first choice drug in the treatment of CSE. Of the respondents, only 55% accepted the SE as refractory after applying the second drug and they monitored these patients in the intensive care unit (ICU). Most of the participants (67.7%) did not provide any treatment except the standard medical approaches, while only 39 (30.7%) had used immunotherapy in the treatment of super-refractory SE. Forty-seven respondents (37%) indicated that they had difficulty identifying NCSE on EEG. While 37% of the participants treated EPC patients with preserved consciousness in ICU by general anesthesia, only 15% were previously applied immunotherapy. Strikingly, 41% of the participants stated that they did not feel themselves as sufficiently competent in terms of practical and theoretical knowledge about the management of SE. Conclusion: We demonstrated that there are no standardized attitudes for the management of different types of SE among neurologists. It is worth to emphasize that the neurologists did not feel themselves sufficiently competent in terms of practical and theoretical knowledge, especially with regard to the subtypes of SE.
Keywords: Antiepileptic drugs, epilepsia partialis continua, nonconvulsive status epilepticus, status epilepticus, survey
|How to cite this article:|
Gomceli YB, Altındağ EA, Baykan B. Different attitudes in the management of different types of status epilepticus: A survey study among neurologists demonstrating evidence gap. Neurol Sci Neurophysiol 2021;38:37-44
|How to cite this URL:|
Gomceli YB, Altındağ EA, Baykan B. Different attitudes in the management of different types of status epilepticus: A survey study among neurologists demonstrating evidence gap. Neurol Sci Neurophysiol [serial online] 2021 [cited 2023 Mar 22];38:37-44. Available from: http://www.nsnjournal.org/text.asp?2021/38/1/37/311969
| Introduction|| |
Status epilepticus (SE) is a life-threatening medical emergency that requires prompt recognition and treatment. According to the new classification system, SE is dichotomized to convulsive SE (CSE) and non-CSE (NCSE) based on semiological findings at first glance. The most recent definition of CSE is a convulsive seizure lasting more than 5 min or consecutive seizures without recovery of consciousness. On the other hand, NCSE is characterized as a change in behavior or cognition in the absence of obvious motor manifestations with prolonged seizure activity, evidenced by epileptiform discharges on EEG. Moreover, a focal motor type of SE, epilepsia partialis continua (EPC) is defined as spontaneous regular or irregular clonic muscular twitching affecting a limited part of the body, sometimes aggravated by action or sensory stimuli, occurring for a minimum of 1 h and recurring at intervals of no more than 10 s.
Despite the well-known need for urgent and efficient treatment of SE, data on the appropriate choices of pharmacotherapy in patients with SE are most often observational, having a high degree of heterogeneity. In addition, a handful of high-class randomized, controlled trials are available only for the early stages of SE. Evidence is also insufficient about the management of super-refractory EPC and NCSE with coma. Therefore, diagnostic and treatment protocols are often developed by individual institutions and are largely based on the expert opinion. The behavior of neurologists facing these different forms of SE in clinical practice is largely not known.
We conducted a survey study among neurologists to identify in our country the current diagnostic and therapeutic approach to different types of SE, including NCSE and EPC, with the aim of detecting the problems encountered during the management of these patients with different types of SE in a comparative style.
| Methods|| |
A national survey dedicated for SE was developed and optimized in three runs by the SE Commission including 14 members with expertise in epileptology and SE. The final form containing 31 questions was electronically distributed to 2340 members of the Turkish Neurology Society. The mailing process (by using SurveyMonkey) was repeated five times between November 2017 and January 2018 and responses were collected. The survey questions contained responders' demographics as to their institutions (public hospital, private hospital, training, and research hospital or university hospital), academic positions (specialist, academician) and years of experience in professional practice.
Questions about SE were divided into three comparative categories: CSE, NCSE, and EPC. The survey included questions that were related to the incidence of these three different conditions, the distribution of the etiological causes, the diagnostic process, and the treatment approaches. Treatment practices of neurologists were evaluated using questions to elicit the timing of antiepileptic drug (AED), the intensive care unit (ICU) process, the initiation of immunomodulatory treatments, mortality rates, and the causes. The correct approach for the definition of refractory SE was accepted as the continuation of seizures despite the appropriate use of two AEDs.
Individual EEG facilities of the institutions (continuous/portable EEG monitoring, immediate implementation) and problems in the recognition of NCSE in the EEG during the diagnostic process were carefully questioned.
Finally, there were questions about whether the participants regarded themselves as sufficiently competent in the diagnosis and treatment of SE types, whether they benefited from the guidelines or not and whether they had problems with drug supply during the treatment process.
Statistical analysis was performed using the Statistical Package for the Social Sciences v22.0 (IBM SPSS, Turkey) software package program. In the normality test, when the number of samples in the group was smaller than 50, Shapiro–Wilk and Kolmogorov–Smirnov test were used. Mann–Whitney U-test was used in the analysis of the difference between the measured values of the two groups in the absence of normal distribution. P < 0.05 was considered statistically significant.
| Results|| |
The total number of respondents was 152, but 25 participants who were not able to record their full data were excluded from the evaluation. Seventy percent of the 127 participants (85 of whom were female) reported that they practice in academic settings (89/127) [Figure 1]a. The median number of years of experience in professional practice was 10.8 years (1–39 years) [Figure 1]b.
|Figure 1: Demographic features of participants. (a) Institutions. (b) Years in practice|
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Convulsive status epilepticus
The majority of the participants (93%) reported that they managed 1–5 CSE per month and that the most common causes in the diagnosed epileptic patients were related to triggering factors such as drug noncompliance, abrupt withdrawal followed by other causes, such as stroke and metabolic disturbances [Figure 2].
|Figure 2: Comparative etiology of status epilepticus types. *Previously diagnosed epileptic patients, with triggering factors such as drug compliance problems. Note: Participants were able to mark more than one option|
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It was recorded that the initial evaluation and treatment of the patients with CSE had been performed by emergency service residents or specialists, and the first choice of drug treatment was the benzodiazepines, diazepam (78%), or midazolam (18%) in the institutions to which most of the participants were attached. Remarkably, about one-fourth of the participants claimed that SE patients were not treated properly in the emergency department. Incorrect drugs and doses (15%) or low intravenous (IV) drug administration rates (4%), early and unnecessary anesthesia and intubation (8%) were noted as frequent causes of inappropriate treatment.
Approximately, 90% of the participants preferred diazepam plus phenytoin as the first choice drug in the treatment of CSE, while only 4.7% preferred midazolam [Figure 3]a.
|Figure 3: Treatment choices of status epilepticus types. (a) Convulsive status epilepticus. (b) Nonconvulsive status epilepticus|
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Forty-four percent of the participants preferred levetiracetam as the second drug in the treatment. As the third drug, midazolam (26%) and general anesthetics (27.6%) were preferred in similar ratios. Other choices in the third-line therapy were repeating some secondary-line agents such as valproic acid (19.7%) and levetiracetam (20.5%).
Of the respondents, 23% answered that they accepted the SE as refractory after the first stage and monitored these patients in the ICU, while 55% did so after applying the second drug and 15% only after the third drug. Only 3 respondents had waited for 24 h for the diagnosis of refractory CSE. While 4 respondents indicated that each refractory SE, the patient was referred to other centers due to the lack of ICU. There was no statistically significant relationship between the correct approach selected for the diagnosis of refractory SE and the participants' years of expertise (P = 0.598).
It was stated that approximately 50% of the ICU follow-up of CSE patients were performed only by the neurologist (40% in neurological ICU and 11% in medical ICU). It was indicated that 42% of CSE patients were followed in the medical ICU with the cooperation of the relevant physician and the neurologist, while 6% of the CSE patients in medical ICU were followed only by the anesthesiologists. About half of the respondents (48.5%) reported that they were unable to record the EEG due to the lack of portable or continuous EEG monitoring (cEEGm) device in the ICU, while only 8% of them stated that they could make cEEGm recording.
Eighty-six of the participants (67.7%) did not provide any treatment, except the standard medical approaches for the treatment of super-refractory CSE. While 39 (30.7%) of the participants used immunotherapy in the treatment of super-refractory SE, only one participant applied additional surgical treatment and one applied ketogenic diet. There was no statistically significant relationship between the years of expertise of the participants using immunotherapy and the preference for only standard treatment approaches in super-refractory SE (P = 0.386).
Nonconvulsive status epilepticus
Only 72 respondents (56%) indicated that they did not have any difficulty in recognizing NCSE either clinically or electrographically. Forty-seven respondents (37%) indicated that they were able to identify NCSE clinically but had difficulty identifying it on EEG. There were two participants who indicated that they had difficulty in recognizing NCSE both clinically and electrographically. It was observed that clinical and electrographic diagnosis of NCSE was easier among participants with longer years of expertise (P < 0.001). Six participants indicated that they had not followed any NCSE patients up to that time. Four of these 6 participants had a practice of neurology about 1 year only, while the others had 15 and 8 years of experience, respectively. Approximately 90% of the participants reported that they evaluated 1–5 NCSE patients per month and that the most common causes of NCSE were stroke and metabolic causes.
Three quarters of the participants indicated that they could perform emergent EEG for the diagnosis of NCSE only during the work hours. Seventeen respondents indicated that EEG could be performed any time, while 7 others indicated that they could not perform emergent EEG. One of the respondents, on the other hand, indicated that there was no EEG device in his/her institution. Diazepam was the first choice drug for 102 (80.7%) of the participants, while the rest of the participants preferred midazolam, phenytoin, and levetiracetam with similar proportions [Figure 3]b. Phenytoin was the second choice drug for 50 (39.4%) of the participants in the treatment of NCSE. Thirty-six (28.3%) of them choose levetiracetam and 25 (19.7%) of them choose valproic acid. Levetiracetam was the third preferred drug for the treatment of NCSE in 39 (30.7%) of the participants. Valproic acid and midazolam were preferred in similar ratios (20.5% and 23.6%, respectively), and 12 (9.4%) of the participants preferred general anesthetics at this stage.
Epilepsia partialis continua
Seven participants indicated that they had not followed any EPC patients before. Five of these 7 participants had a practice of neurology for <5 years, while the other two had a professional experience of 17 and 7 years, respectively. Eighty respondents (63%) indicated that they did not have any difficulty in recognizing EPC clinically and electrographically. Thirty-two respondents (25.2%) indicated that they were clinically able to identify EPC but had difficulty identifying them electrographically. There were 5 participants who indicated that they had difficulty recognizing EPC both clinically and electrographically. It was observed that as the participants' span of years of professional expertise increased, there was no problem in the diagnosis of EPC (clinical and electrographic) (P < 0.001). The major causes of EPC were reported as stroke and other acute etiologies by the participants.
About half of the participants (47%) stated that they used only AED in the treatment of EPC. While 47 of the participants (37%) reported having treated EPC patients with preserved consciousness in ICU by general anesthesia, only 19 of them (15%) stated that they were able to apply immunotherapy when it was necessary. Only one participant stated that he/she referred to the surgical options. There was no statistically significant relationship between the years of expertise of the participants and their approaches to the correct treatment in EPC (P = 0.280).
Almost all of the participants (97%) indicated that they benefited from the guidelines prepared by the National Society of Neurology for the treatment of SE. Thirty-two percent of the participants stated that they did not feel themselves sufficiently competent in the management of SE in terms of practical and theoretical knowledge.
Although it was indicated that there was no difficulty in supplying emergency drugs for the treatment of SE, this does not seem to have been the case for IV valproic acid (17 respondents).
| Discussion|| |
The study has demonstrated that there is no standardized approach even among the neurologists in the diagnoses of NCSE and EPC in the treatment of different types of SE There are still limited randomized controlled clinical trials even for CSE, and therefore the treatment algorithms are largely based on expert opinion. In addition, there is a clear need for education on every diagnostic and management aspect for this life-threatening emergency.
In our survey, the most common etiologic factor for CSE was the drug noncompliance problems in the epilepsy patients, while stroke and metabolic causes were other common factors. About 15% of the epilepsy patients experience SE episodes at least once in their lives. Similarly, in many previous studies, the most common etiologic factors for SE have been reported to be drug compliance problems in the epilepsy patients, stroke, acute, and distant symptomatic causes.,, When asked about the causes of NCSE, the most common response was metabolic disturbances, while others were reported as existing epilepsy history and stroke, respectively. Our questionnaire did not include questions which focused on specific details, such as focal-generalized, with or without coma. Many different etiological causes have been reported for different types of NCSE: history of epilepsy, diffuse primary or secondary brain disturbances (anoxic, toxic, metabolic, infectious, and degenerative), focal brain lesions and stroke. The most common response to the etiology-related question for EPC was stroke. In accordance with this, the most commonly reported EPC etiologies were stroke, inflammatory causes, neoplasms, and metabolic disorders.,
In our survey, it was carefully questioned whether there were problems in identifying “refractory” SE and clinical or electrographic recognition of NCSE and EPC. Still persisting seizures after second-line treatments should be accepted as refractory CSE and these patients should be preferably transferred to the ICU., However, of the respondents, 23% stated that they accepted the SE as refractory after the first drug only, while 55% did so after the second and 15% after the third drug. It was interesting to note that about half of the participants behaved outside the recommended refractory SE definition, and there was no relationship between the years of expertise of the participants and their preference for a specific approach for the treatment. This finding revealed the need for focus on the definition gap of the refractory SE, both with clinical and experimental studies.
NCSE is a well-known diagnostic problem due to nonspecific clinical findings and especially EEG findings, which are difficult to interpret., Various EEG criteria have been proposed for the diagnosis of NCSE. The most current approach is the modified Salzburg criteria, which is considered to have high diagnostic accuracy., Similarly in EPC, clinical presentation may not always be obvious; limited, unimpressive motor findings may not be recognized, and somatosensory EPC is even more difficult to recognize and may often be missed. Focal specific and nonspecific abnormalities and periodic lateralized epileptiform discharges were delineated in the EEG of EPC patients, and one-fifth of the patients with EPC had strikingly normal EEG. Accordingly, 37% of the participants stated that they had difficulties in identifying EEG in patients with NCSE and 25% in patients with EPC. Clinical and electrographic recognition of both NCSE and EPC was found to be easier among participants with longer years of expertise. This finding clearly reveals the current need for educational programs to improve diagnostic reliability among neurologists.
Benzodiazepines are well-known and recognized as first-line treatment for CSE because of Class I evidence. Midazolam was identified as the best option for non-IV drug treatment, out-of-hospital CSE. Although IV lorazepam is the most recommended benzodiazepine in the international guidelines, in Turkey, the most preferred one is diazepam, since lorazepam does not have IV formulation. This shows the importance of national guidelines and the lack of uniformity in the treatment of SE worldwide.
It was also striking to note that about one-fourth of the participants already realized that SE patients were not treated properly in the emergency department. It was stated that there were a number of inappropriate approaches to the management of treatment that could be harmful, such as insufficient doses or early intubation of cases with EPC or NCSE. Although BZPs have been reported to fail in 10%–55% of the patients with SE, there are many studies suggesting that this is associated with inappropriate dosing and timing.,, In a very recent study, it was reported that in the initial treatment of SE, benzodiazepines was administered in multiple, small, and inadequate doses rather than in a single full dose, in approximately 70% of the patients, as recommended in the guidelines.
In our survey, while the first choice of 90% of the neurologists was IV diazepam followed by phenytoin, 18% of the first-line treatments in the emergency department were reported as IV midazolam. Despite the fact that IV midazolam is recommended for the treatment of the “refractory” stage of SE incurrent treatment guidelines, there are a few studies conducted in the pediatric patient populations in the initial treatment stage.,,,, In a very recent retrospective study of pediatric patients in Turkey (mean age: 2.7 years), it was also noted that IV midazolam (0.1–0.2 mg/kg, bolus) was the first choice in their SE hospital protocols in children. Similar to these recent studies, IV midazolam treatment is applied by the emergency service specialists and residents (18%) as well as by some neurologists (4.7%) as the first-line treatment. This, however, is not a generally accepted practice in adults.
In the latest evidence-based guidelines, fosphenytoin, valproic acid, and levetiracetam are offered as options in second-line therapy, without obvious superiority of one over the other. In our survey, 44% of the participants preferred levetiracetam as the second drug in the treatment. There is no clear evidence to guide treatment in the third-line therapy phase, as evidenced in the disperse distribution of choices in our survey [Figure 3].
Great majority of the Turkish participants reported that refractory CSE patients were followed up either by neurologists or in cooperation with the neurologists in the neurological or general ICUs. However, nearly half of the respondents (48.5%) stated that they were unable to record EEG in ICU conditions, while only 8% said they have the facility for cEEGm recording.
Although currently, there are no randomized trials or any compelling evidence, immune therapies consisting of corticosteroids, IV immunoglobulins (IVIG), and plasma exchange are increasingly being used in super-refractory SE, even though there might be no definite immunological disease. Super-refractory SE is most commonly described after severe brain injuries, but it can be observed also in patients without a history of epilepsy-new-onset refractory SE (NORSE)., Although the etiology cannot be detected in about half of the NORSE patients (similar to presumed encephalitis with refractory SE), autoimmune/paraneoplastic encephalitis has been reported as the most common etiologic cause. Even when an inflammatory etiology cannot be identified, immunotherapy is thought to be effective in NORSE and its subtypes. Cabrera Kang et al. conducted an important survey among Neurocritical Care Society members to evaluate NORSE diagnostic and therapeutic approaches. Although most of the participants stated that they would initiate immunotherapies either immediately (46%) or if there was no improvement (45%) within 1 week, the general tendency of the participants was to delay initiating an immunotherapy until an abnormal antibody was identified. In line with this, in our SE survey, approximately two-thirds of the respondents stated that they did not provide any treatment other than standard medical approaches for the treatment of super-refractory CSE. While only one third of the participants used immunotherapy in the treatment of super-refractory SE, additional surgical treatment and ketogenic diet practice were reported to have been used only by two participants despite the fact that all participants were clearly aware of all these options., Moreover, there was no statistically significant relationship between the years of expertise of the participants opting for immunotherapy and their preference for following only the standard treatment approaches in super-refractory SE, which showed that the reluctance of the group did not relate to fewer years of professional experience. This data denoted that there is a tremendous need for future studies and objective guidelines to change the behavior of the neurologists and to help the SE patients who may benefit from immunological therapies.
The treatment of NCSE is suggested to be similar to CSE, but there is no consensus on how aggressively NCSE should be treated in order not to harm the patient. In clinical practice, the treatment approach is often based on the patient's status and clinical course. Absence SE is commonly terminated by low-dose of benzodiazepines. In the current survey, diazepam was the first choice drug for 102 (80.7%) of the participants in the treatment of NCSE. This was followed by phenytoin (39.4%) and levetiracetam as the second and third choice drugs, respectively. Given that the morbidity rate was lower in NCSE patients, it was noteworthy that the participants preferred midazolam and other anesthetic applications in these patients.
The overall prognosis of EPC is related to the underlying etiologic cause. However, it is often highly resistant to anti-epileptic treatment. A European non-Rasmussen nonstroke EPC survey reported relatively good results obtained with topiramate and levetiracetam. In addition to the recommended immunotherapies and hemispherectomy procedures in Rasmussen encephalitis, few successful individual treatments are reported with corticosteroids, IVIG, PE, vagus nerve stimulation, transcranial magnetic stimulation, and neocortical stimulation.,,, One of the most striking results of this survey is to observe that 37% of the participants ordered general anesthesia by monitoring EPC patients at ICU. This high rate is surprising, that aggressive management of this condition remains controversial. This fact underlines the gap that neither the old nor the current treatment guidelines establish protocols for the treatment of EPC., Since the clinical picture is a continuous seizure, it may cause uneasiness in clinicians and cause unnecessary general anesthesia and ICU stay in patients with preserved consciousness.
| Conclusion|| |
In accordance with the published trials and general guidelines, neurologists most often use diazepam followed by phenytoin as first-line therapies for CSE, since the IV formulation of lorazepam is not available in Turkey. In the most severe (refractory SE) or different (NKSE and EPC) forms of SE, there is clearly no consensus about the method (s) of treatment and decisions are based on anecdotal case series and expert opinions. It is interesting to note that some clinicians did not consider immunotherapy and other options, even though currently, there is increased awareness of these treatment options for refractory SE. It is worth to emphasize that neurologists did not feel themselves sufficiently competent in terms of practical and theoretical knowledge on subtypes of SE, such as NCSE and EPC. Therefore, in the absence of a consensus, there is a need for management guidelines. On the other hand, as seen in EPC patients, unnecessary anesthetics use and ICU-stays are of concern. Our survey results have provided evidence for the urgent need for evidence-based clear protocols for the management and treatment of different types of SE.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]