RU2821017C1 - Method of differential diagnosis of epileptic and psychogenic non-epileptic seizures - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely neurology and psychiatry, and can be used for the differential diagnosis of epileptic seizures and psychogenic non-epileptic seizures with motor manifestations. The level of cortisol in the blood serum (COR) collected within an hour after the attack, the time of onset of the attack (TIME), the moment of onset of the attack during sleep (SLEEP) are determined. With a COR value equal to or more than 600 nmol / l, "5 points" are assigned, with a value from 500 to 599 nmol / l - "4 points", with a value from 400 to 499 nmol / l - "3 points", with a value from 300 to 399 nmol / l - "2 point", at a value of less than 300 nmol / l - "1 point". TIME is assigned "3 points" if the paroxysmal event occurred in the morning from 6:00 to 10:59, "1 point" - if the attack occurred in the daytime from 11:00 to 15:59, "-1 point" - if the attack occurred in the evening- night time in the period from 16:00 to 5:59. SLEEP is assigned "2 points" if the attack occurred during sleep, without first waking up. The points obtained are summarized and the integral indicator Sz is determined: Sz = COR + TIME + SLEEP. If the Sz value is "4 or more points", then an epileptic seizure is diagnosed, if the Sz value is "less than 4 points", then a psychogenic non-epileptic seizure with motor manifestations is diagnosed.

EFFECT: method makes it possible to determine the genesis of the paroxysmal condition with high accuracy without conducting instrumental diagnostic studies, which allows you to choose an adequate therapeutic approach in a timely manner, by determining the level of cortisol in the blood, the time of onset of an attack and taking into account the moment of onset of an attack in a dream.

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Description

The invention relates to the field of medicine, namely neurology and psychiatry, and can be used in a hospital as an auxiliary method for differential diagnosis of epileptic seizures (EP) and psychogenic nonepileptic seizures (PNES) with motor manifestations.

Epilepsy is one of the most common chronic diseases of the nervous system: according to WHO, there are at least 50 million people with epilepsy in the world, and the annual incidence is 5 million people. The prevalence of active epilepsy (the concept of active epilepsy means the patient has seizures and/or is taking antiepileptic therapy) in the general population in different countries ranges from 4 to 10 cases per 1000 (Guekht A., Hauser W.A., Milchakova L., Churillin Y., Shpak A., Gusev E. The epidemiology of epilepsy in the Russian Federation. Epilepsy Res. 2010;92(2-3):209-218. The burden of epilepsy includes not only the presence of epileptic seizures themselves. Among patients with epilepsy, there is a higher prevalence of somatic and psychiatric comorbid diseases (including depression and anxiety disorders) compared to the general population (Téllez-Zenteno J.F., Matijevic S., Wiebe S. Somatic comorbidity of epilepsy in the general population in Canada . Epilepsia. 2005;46(12):1955-1962; Tellez-Zenteno J.F., Patten S.B., Jetté N., Williams J.. Psychiatric comorbidity in epilepsy: a population-based analysis. (12):2336-2344; Zinchuk M., Kustov G., Pashnin E., et al. Validation of the Russian version of neurological disorders depression inventory for epilepsy (NDDI-E) 2020;113:107549; Zinchuk M., Kustov G., Pashnin E., et al. Validation of the Generalized Anxiety Disorder-7 (GAD-7) in Russian people with epilepsy. EpilepsyBehav 2021;123:108269), including increased risk of premature mortality. from suicide (Zinchuk M.S., Reader F.K., Kustov G.V., Pashnin E.V., Akzhigitov R.G., Gudkova A.A., Gekht A.B. Suicidality in epilepsy: epidemiological aspects and risk factors. Journal of Neurology and Psychiatry. S.S. Korsakov. Special issues. 2018;118(10-2):45-52). Patients with epilepsy suffer from external and internal stigmatization (Braga P. Exploring quality of life perception in people with epilepsy and people imagining life with epilepsy. Seizure. 2021;90:182-185; Parfenova E.V., Reader F.K., Gersamiya A.G. Stigmatization of patients with epilepsy. Neurology, neuropsychiatry, psychosomatics, 2017;9:78-83.). A timely diagnosis and correct treatment tactics with antiepileptic drugs (AEDs) significantly improves the patient’s quality of life and allows for drug-induced remission in 70% of cases.

Psychogenic nonepileptic seizures are paroxysmal changes in behavior, consciousness, motor activity, similar to epileptic seizures, but not accompanied by epileptiform phenomena on the EEG (Brigo F., Igwe S.C., Ausserer H., etal. Terminology of psychogenic nonepileptic seizures. Epilepsia. 2015;56 (3):e21-e25).Despite the similarity of clinical manifestations, epileptic and psychogenic non-epileptic seizures have different genesis, pathophysiological basis, and, accordingly, require completely different approaches to treatment.

Differential diagnosis of EP and PNEP is a difficult task. Currently, it takes about 7 years on average to establish a diagnosis of PNEP, which indicates, on the one hand, the low awareness of doctors about this condition, and on the other hand, the insufficient effectiveness of existing diagnostic approaches (Reuber M., House A.O. Treating patients with psychogenic non-epileptic seizures. CurrOpin Neurol. 2002;15(2):207-211 Jafari A., Rezaei Tavirani M., ParvareshiHamrah M., Ahmadi Karvigh S., Bashi Zadeh Fakhar H. Psychogenic Non-Epileptic Seizures; Review Arch Acad Emerg Med 2020;8(1):e10). Particularly difficult are cases in which one patient has a combination of epileptic and non-epileptic seizures.

Over the past decades, the efforts of the scientific community have been aimed at developing a sensitive and specific method that makes it possible to differentiate true epileptic seizures from non-epileptic ones with a high degree of reliability, but to date such a method has not been found. A variety of biochemical, instrumental, and psychometric tools have been proposed, each of which has its own advantages and disadvantages. Currently, video-electroencephalographic monitoring (VEEGM) with recording of a paroxysmal event is recognized as the gold standard for the diagnosis of psychogenic nonepileptic seizures (LaFrance W.C., Baker G.A., Duncan R., Goldstein L.H., Reuber M. Minimum requirements for the diagnosis of psychogenic nonepileptic seizures: a staged approach: a report from the International League Against Epilepsy Nonpileptic Seizures Task Force. 2013;54(11):2005-2018). However, the use of this method is associated with a number of limitations: the study is expensive and time-consuming (Gasparini S, Beghi E, Ferlazzo E, etal. Management of psychogenic non-epileptic seizures: a multidisciplinary approach. Eur J Neurol. 2019;26(2):205 -e15) the probability of fixing PNEP in the first two days of VEEGM is 50-70%), requires special equipment and trained personnel, and also guarantees optimal diagnostic value only in the case of registration of a paroxysmal event.

It should be remembered that the EEG records the bioelectrical activity of the brain only from the superficial areas of the convexital cerebral cortex, and if the focus of epileptiform activity is located in the deep areas of the gray matter or on the mediobasal surface of the hemispheres, epileptiform phenomena may not be recorded on the EEG with scalp placement of the electrodes.

Patients with epilepsy and, to an even greater extent, with PNEP are characterized by a high prevalence of mental comorbid diseases, primarily depression and anxiety disorders. It is known that chronic stress contributes to epileptogenesis and the development of epileptic seizures. Stress hormones - glucocorticoids (cortisol in humans and corticosterone in laboratory animals), circulating in biological fluids, resulting from the functioning of the hypothalamic-pituitary-adrenal axis (HPA) and largely reflecting its condition, bind to receptors in various brain structures, firstly turn in the hippocampus, which is sensitive to stress and easily develops epileptogenesis. At the same time, epileptic seizures themselves are stress factors for humans (Novakova B., Harris P.R., Ponnusamy A., Reuber M. The role of stress as a trigger for epileptic seizures: a narrative review of evidence from human and animal studies . Epilepsia. 2013;54(11):1866-1876; Gulyaeva N.V. Stress-associated molecular-cellular mechanisms common to epilepsy and comorbid depressive disorders. In this regard, it is not surprising that the literature data and the results of our own studies indicate an increase in the level of cortisol in the blood in patients with epilepsy, as well as epilepsy and depression (Druzhkova T.A., Yakovlev A.A., Rider F.K., Zinchuk M.S., Guekht A.B., Gulyaeva N.V. Elevated serum cortisol levels in patients with focal epilepsy, depression, and comorbid epilepsy and depression. Int J Mol Sci 2022;23(18):10414). Stressful situations (both in history and as a direct cause of the development of paroxysmal states) are a typical trigger for PNEP, however, according to a number of authors, PNEP to some extent develop as a response to stress, allowing one to cope with it (Kustov G.V. ., Zinchuk M.S., Reader F.K., Pashnin E.V., Voinova N.I., Avedisova A.S., Gekht A.B. Comorbidity of psychogenic non-epileptic seizures with mental disorders. Journal of neurology and psychiatry. S.S. Korsakova 2022;122(2):28-35).

To date, a number of biochemical differential diagnostic biomarkers of EP and PNEP have also been identified, including: prolactin (sensitivity 69%, specificity 93% (Wang Y.Q., Wen Y., Wang M.M., Zhang Y.W., Fang Z.X. Prolactin levels as a criterion to differentiate between psychogenic non-epileptic seizures and epileptic seizures: A systematic review. Epilepsy Res. 2021;169:106508)), glial fibrillary acidic protein (sensitivity 72%, specificity 59%, area under the ROC curve 0.68 (Simani L ., Elmi M., Asadollahi M. Serum GFAP level: A novel adjunctive diagnostic test in differentiating epileptic seizures from psychogenic attacks. Seizure 2018;61:41-44)), creatine kinase (sensitivity 75%, specificity 85.5% ( Brigo F., Igwe S.C., Erro R., etal. Postictal serum creatine kinase for the differential diagnosis of epileptic seizures and psychogenic non-epileptic seizures: a systematic review. , ubiquitin C-terminal hydrolase (sensitivity 93.75%, specificity 66%, area under the ROC curve 0.801 (Yasak I.H., Yilmaz M., GÖnen M., etal. Evaluation of ubiquitin C-terminal hydrolase-L1 enzyme levels in patients with epilepsy. Arq Neuropsiquiatr. 2020;78(7):424-429)), other biochemical parameters (IL-6, IL-1b, IL-8, interferon gamma and lambda, neutrophil/lymphocyte ratio (Li H, Yang Y, Hu M, et al The correlation of temporal changes in neutrophil-lymphocyte ratio with seizure severity and the following seizure tendency in patients with epilepsy. FrontNeurol 2022;13:964923). PNEP is practically not carried out, primarily due to methodological difficulties associated with the need to document PNEP and a multidisciplinary approach.

The closest to the claimed technical solution is a method for differential diagnosis of EP and PNEP based on the level of prolactin in the blood serum taken after an attack (Wang Y.Q., Wen Y., Wang M.M., Zhang Y.W., Fang Z.X. Prolactin levels as a criterion to differentiate between psychogenic non -epileptic seizures and epileptic seizures: A systematic review. Epilepsy Res. 2021;169:106508). The disadvantage of this method is the high variability of prolactin levels in the blood serum depending on age, gender, time of day and medications taken, as well as the short half-life of prolactin and the ability to clearly distinguish only generalized tonic-clonic EP from PNEP. At the same time, thanks to the use of a complex of clinical and paraclinical indicators, the described limitations can be partially overcome.

The technical problem solved in the developed method is to obtain a minimally invasive, accessible for use and easily performed in a hospital, method for the differential diagnosis of EP and PNEP with motor manifestations based on the assessment of the level of cortisol in the blood serum within an hour after the attack, as well as the time of onset of the attack and onset attack during sleep.

The achieved technical result is the determination of the genesis of the paroxysmal state with high accuracy without conducting instrumental diagnostic studies, which allows timely selection of an adequate therapeutic approach.

The technical result is achieved by assessing the following indicators:

serum cortisol levels (COR) collected within an hour of the attack,

time of attack (TIME),

moment of onset of seizure during sleep (SLEEP),

with a COR value equal to or more than 600 nmol/l, “5 points” are assigned, with a value from 500 to 599 nmol/l - “4 points”, with a value from 400 to 499 nmol/l - “3 points”, with a value from 300 to 399 nmol/l - “2 points”, with a value less than 300 nmol/l - “1 point”;

TIME is assigned “3 points” if the paroxysmal event occurred in the morning from 6:00 to 10:59, “1 point” - if the attack occurred in the daytime from 11:00 to 15:59, “-1” point - if the attack occurred in the evening-night time from 16:00 to 5:59;

SLEEP is assigned “2 points” if the attack occurred during sleep, without prior awakening;

The obtained points are summed up and the integral indicator Sz is determined:

Sz = COR + TIME + SLEEP,

if the Sz value is “4 or more” points, then an epileptic seizure is diagnosed; if the Sz value is “less than 4 points,” then a psychogenic non-epileptic seizure with motor manifestations is diagnosed.

Implementation of the invention .

It is known that EP is often associated with the sleep-wake cycle and most often occurs at night (during sleep) and shortly after awakening (Karoly P.J., Rao V.R., Gregg N.M., et al. Cycles in epilepsy. Nat Rev Neurol. 2021;17(5):267-284; Rao V.R., Leguia M.G., Tcheng T.K., Baud M.O. Cues for seizure timing. With regard to PNEP, a slightly different pattern has been described: they more often occur in the evening and shortly after midnight, but only in rare cases during sleep; accordingly, the occurrence of an attack during night sleep is a significant predictor of an epileptic attack (Seneviratne U., Minato E., Paul E. Seizures by the clock: Temporal patterns of psychogenic nonpileptic seizures. EpilepsyBehav 2017;76:71-75). In our cohort of patients, PNEP occurred more often in the evening (58%), and epileptic seizures more often in the morning (40%). This makes it possible to use the time of occurrence of an attack and the onset of an attack during sleep as additional differential diagnostic signs.

The method for differential diagnosis of EP and PNEP with motor manifestations based on the time of onset of the attack, the onset of the attack during sleep and assessment of the level of cortisol in the blood serum within an hour after the attack is carried out as follows. Within an hour after a paroxysmal event with motor manifestations, blood is drawn from the patient's antecubital vein. After centrifugation for 10 minutes at a speed of 2000 g at 4°C, the blood serum is separated from the clot and placed in the analyzer cups. The cortisol level (nmol/l) is determined. The time of onset of the attack is also taken into account: morning (6.00 - 10.59), afternoon (11.00 - 15.59), evening/night (16.00 - 05.59) - and whether the attack occurred during sleep. Depending on the result obtained for each indicator, points are awarded, which are then summed up. If the result obtained is 4 or more points, then with a sensitivity of 100% and specificity of 72%, the paroxysmal event can be interpreted as an epileptic seizure.

Experimental substantiation was carried out on a sample of patients over 18 years of age with epilepsy and without an established diagnosis of epilepsy, who had EP and PNEP with motor manifestations. Exclusion criteria were: pregnancy, the presence of systemic diseases and diseases of the respiratory and cardiovascular systems in the acute phase, neurodegenerative diseases, taking drugs with an immunosuppressive effect within a month before admission to the hospital.

The sample included 54 people: 17 men and 37 women, 13 of whom had a combination of PNEP and EP.

All patients underwent VEEGM as the gold standard for the differential diagnosis of epileptic and non-epileptic seizures, and patient-typical seizures were recorded in all cases. Also, from all patients, blood was drawn from the ulnar vein at four time points: the next day after admission to the hospital in the morning on an empty stomach (baseline test, control), within an hour after the paroxysmal event, 6, 12 and 24 hours after the attack. The level of cortisol in the blood serum was determined using an ACCESS 2 immunochemical analyzer (BeckmanCoulter, USA). According to the results of a simultaneous analysis of clinical events (paroxysmal states) during VEEGM, 18 epileptic (6 men, 12 women, average age 38.4 ± 12.8 years) and 36 psychogenic non-epileptic attacks (11 men, 25 women, average age 35.2 ± 14.6 years). The cortisol content in the baseline sample in patients with EP was at the level of 428.9 ± 154.6 nmol/l, in patients with PNEP - 416 ± 140 nmol/l. There were no statistically significant differences in age, level of education, and cortisol and prolactin levels upon admission, as well as at points 6-12-24 hours after the attack between the groups. In patients with EP, the serum cortisol level within an hour after the attack was 536.1 ± 250.9 nmol/l, and in patients with PNEP - 243.9 ± 150.4 nmol/l (p < 0.001). In patients with PNEP, attacks occurred more often in the evening (p = 0.029). Considering the diurnal pattern of changes in serum cortisol levels, one could assume a relationship between the increase in cortisol levels after epileptic seizures and the time of their onset. However, when dividing patients into groups according to the time of onset of the paroxysmal event (morning from 6:00 to 10:59, day from 11:00 to 15:59; evening/night from 16:00 to 5:59), it was shown that the dynamics of the level cortisol levels persisted for an hour after the attack regardless of the time of day.

To create a predictive model, a ROC analysis was performed on the results of cortisol and prolactin levels within an hour after the attack. The area under curve (AUC) was 0.851 for cortisol. Using the values of sensitivity, specificity and their sum, a graph was constructed to determine the cut-off point. In terms of specificity, points >300 nmol/L (specificity 70%), >400 nmol/L (specificity 80%), >500 nmol/L (specificity 90%) and >600 nmol/L (specificity 100%) were identified. for cortisol. The odds ratio per 1 nmol/L of serum cortisol is 1.008 (95% CI 1.004-1.013), therefore, with an increase in cortisol levels of 100 nmol/L, the probability of an epileptic etiology of a paroxysmal event increases by 2.2 times.

The integral indicator we developed had the following form:

Sz = COR + TIME + SLEEP, where

COR is the serum cortisol level within an hour after an attack.
TIME - time of attack.
SLEEP - whether the attack occurred during sleep.

Cortisol level within an hour after an attack (nmol/L) point Time of attack point Seizure in a dream point <300 1 Evening/night (16:00-5:59) -1 No 0 300-399 2 Day (11:00-15:59) 1 Yes 2 400-499 3 Morning (6:00-10:59) 3 500-599 4 > 600 5

Table 1. Combined scale for the differential diagnosis of EP and PNEP. Three indicators are assessed: serum cortisol level within an hour after the attack, the time of onset of the attack, and the onset of the attack during sleep. For each indicator a certain number of points are awarded, depending on the result.

The patient data were analyzed in accordance with our integral indicator, and the ROC curve was again constructed based on the results of the analysis. The area under the curve was 0.918, the accuracy was 0.83, which indicates good predictive characteristics of the model. The best ratio of sensitivity and specificity is achieved when choosing a result of 4 points or higher as the cut-off point (sensitivity 100%, specificity 72%, Youden Index 0.72, positive predictive value 64%, negative predictive value 100%). Accordingly, if a result of 4 or more points is obtained, with a sensitivity of 100% and a specificity of 72%, the epileptic nature of the paroxysmal event can be stated.

Examples of using the method we have developed for the differential diagnosis of epileptic and psychogenic non-epileptic seizures:

Example 1.

Patient Zh., 20 years old. She complained of episodes of “freezing” (lasting up to a minute) with a frequency of up to several per day, which are accompanied by loss of consciousness, shuffling of the legs, oroalimentary and manual automatisms, and repetition of one simple phrase. Within a few minutes after the attack he regains consciousness. The patient herself has amnesia for these episodes; the description is given from the words of relatives.

On the third day of her stay in the department, after waking up, at 9:00, during the morning round by the attending physician, the patient had an attack with cessation of activity and oroalimentary automatisms, did not answer questions, and was unavailable for contact. The duration of the attack was 1 minute 32 seconds. 10 minutes after the attack, the patient’s consciousness was completely restored, her orientation in time, place and personality was correct, and she answered questions to the point. The fact of a paroxysmal event is amnesic. Within an hour after the attack, blood was drawn from the patient's antecubital vein for analysis of cortisol levels. The cortisol level was 592 nmol/l.

According to the formula Sz=СOR+TIME+SLEEP, the result for this patient was 7 points (COR=4 points (cortisol level in the blood serum 592 nmol/l), TIME=3 points (attack onset in the morning from 6:00 to 10: 59), SLEEP=0 points), which made it possible to assume with a high degree of probability the epileptic nature of the attack.

Two days later, the patient underwent video-EEG monitoring, on which at 8:30 a typical episode for this patient was recorded (clinically - a focal attack with impaired consciousness), which was accompanied by registration of a diffuse electrodecrement on the EEG with the further appearance of rhythmic regional theta and delta activity in the right hemisphere with subsequent restoration of cortical rhythm. Thus, the recorded clinical event was accompanied by the appearance of epileptiform activity, and the epileptic genesis of the episodes was confirmed.

Example 2.

Patient O., 64 years old. She complained of attacks with loss of consciousness and falls, which are accompanied by trembling in the body and twitching of the limbs, with a frequency of 1-2 attacks per month. The patient reports that she anticipates the onset of attacks (more often this occurs during prolonged standing or hot weather). At a young age, repeated traumatic brain injuries with loss of consciousness were noted; she was treated on an outpatient basis. A diagnosis of epilepsy has been established; for 10 years he has been taking antiepileptic drugs (carbamazepine, levetiracetam), while taking them the frequency of attacks has not changed. Directed for further examination and treatment correction.

The next day after admission, the patient had a typical attack in the evening (10:30 p.m.) while awake: during hyperventilation, the patient falls on her back, irregular tremors in the upper extremities with pedaling movements in the legs are noted, the duration of the episode is 3 minutes. There is no post-attack confusion, consciousness is clear within 5 minutes after the attack, answers questions, follows instructions. Medical staff took blood for analysis within an hour after the attack. The cortisol level was 367 nmol/l.

According to the formula Sz=СOR+TIME+SLEEP, the result for this patient was 1 point, (COR=2 points (cortisol level in blood serum 367 nmol/l), TIME=-1 point (onset of attack in the evening-night time from 16:00 to 5:59, SLEEP=0 points), which allowed us to assume the non-epileptic nature of the episodes.

The patient was subsequently prescribed and carried out video-EEG monitoring, during which, during a hyperventilation test, the patient again developed a typical attack: falling onto the bed, sweeping, irregular movements in the arms and legs, lasting about 2 minutes with a rapid restoration of the level of consciousness after the episode. After deciphering the VEEGM results, it was possible to state that no epileptiform activity was noted on the EEG during the recorded episode. Thus, the non-epileptic nature of the seizures in this patient was confirmed.

The method we have developed provides additional opportunities for the differential diagnosis of EP and PNEP with motor manifestations if it is impossible to conduct VEEGM, and also as an additional test.

Claims (10)

A method for the differential diagnosis of epileptic seizures and psychogenic non-epileptic seizures with motor manifestations, including the definition serum cortisol levels (COR) collected within an hour of the attack, time of attack (TIME), moment of onset of seizure during sleep (SLEEP), with a COR value equal to or more than 600 nmol/l, “5 points” are assigned, with a value from 500 to 599 nmol/l - “4 points”, with a value from 400 to 499 nmol/l - “3 points”, with a value of from 300 to 399 nmol/l - “2 points”, with a value less than 300 nmol/l - “1 point”; TIME is assigned “3 points” if the paroxysmal event occurred in the morning from 6:00 to 10:59, “1 point” - if the attack occurred in the daytime from 11:00 to 15:59, “-1 point” - if the attack occurred in the evening-night time from 16:00 to 5:59; SLEEP is assigned “2 points” if the attack occurred during sleep, without prior awakening; The obtained points are summed up and the integral indicator Sz is determined: Sz = COR + TIME + SLEEP, if the Sz value is “4 or more points,” then an epileptic seizure is diagnosed; if the Sz value is “less than 4 points,” then a psychogenic non-epileptic seizure with motor manifestations is diagnosed.