CN115575646A - Application of metabolic marker group in preparation of kit for predicting epileptic seizure - Google Patents
Application of metabolic marker group in preparation of kit for predicting epileptic seizure Download PDFInfo
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Abstract
The invention relates to the field of epilepsy, in particular to application of a metabolic marker group in preparation of a kit for predicting epileptic seizure. The invention provides a use of a metabolic marker panel in the preparation of a kit for assessing the risk of epileptic seizure in a subject, wherein the metabolic marker panel comprises L-threonine, homovanillic acid and glycine, the kit comprises a detection reagent for detecting the content of the metabolic marker panel in a urine sample of the subject, and the subject is diagnosed with epileptic seizure and has seizure tendency. The invention also provides the metabolic marker group.
Description
Technical Field
The invention relates to the field of epilepsy, in particular to application of a metabolic marker group in preparation of a kit for predicting epileptic seizure.
Background
Epilepsy is one of the most common chronic neurological diseases, with over 7000 million patients worldwide. Seizures are caused by abnormal, self-sustaining discharges that occur suddenly in the brain network, usually lasting less than a few minutes. The symptoms of a seizure may affect any part of the body, and the seizure is usually manifested by a sudden recurrence of sensory disturbances, loss of consciousness, or convulsions.
Because of the frequent sudden onset of epilepsy and the lack of predictability of epilepsy per se, about 12 million people worldwide are deprived of epilepsy every year. Accidental seizures are often accompanied by accidental death, such as drowning, car accidents, sudden epileptic death, and the like, and thus can lead to accidents, injuries, embarrassment, and expensive first aid costs. The inability to know when a seizure occurs can place enormous limitations on family, social, educational and occupational activities, and it follows that the social consequences of epilepsy are generally more influential than the seizure itself. In addition to the potential for serious injury from falls and other accidents during epileptic seizures, the social stigma associated with epilepsy and its unpredictability may lead to serious spontaneous abandonment, irritability and anxiety in epileptic patients. This anxiety may further lead to an increased incidence of seizures, and increased seizures may further increase chronic anxiety.
In view of the above, seizures are difficult to predict and dangerous. The epileptic seizure is predicted and early warned in advance, so that the life quality of the epileptic can be improved and the epileptic patient has enough time to take action in advance. The prior art typically utilizes electroencephalography (EEG) to analyze whether an epileptic patient is at a seizure or even to predict a seizure. However, such predictions are based on EEG data acquired from long-term monitoring of brain signals of epileptic patients to predict an immediately upcoming seizure (e.g. within 1 hour). Thus, such predictions require a long time to continuously acquire EEG data for an epileptic patient, and do not allow the epileptic patient sufficient time to take action to control the seizure (e.g., take preventative medication) and schedule an appropriate life plan in advance.
Disclosure of Invention
In one aspect, the present invention provides a use of a metabolic marker panel comprising L-threonine, homovanillic acid and glycine in the manufacture of a kit for assessing the risk of seizures in a subject diagnosed with seizures and having a predisposition to seizures, the kit comprising detection reagents for detecting the content of the metabolic marker panel in a urine sample of the subject.
In some embodiments, the subject is at least 18 years of age.
In some embodiments, the subject is assessed as having a risk of seizure within a predicted time frame when the amount is greater than its reference amount to which it is referenced.
In some embodiments, the prediction period is 1-3 days from the date the urine sample is collected.
In some embodiments, the L-threonine and the glycine are used to assess the risk of seizures in a female subject; said female subject is assessed as strongly positive for seizures when said levels of both said L-threonine and said glycine are above their reference levels; said female subject is assessed as seizure positive when said content of said L-threonine or said glycine is higher than said reference content to which it is referred; said female subject is assessed as seizure negative when neither said content of L-threonine nor said glycine is higher than said reference content to which it is referred.
In some embodiments, the L-threonine and the homovanillic acid are used to assess the risk of seizure in a male subject; said male subject is assessed as strongly positive for seizures when both said L-threonine and said homovanillic acid are present in an amount greater than their reference amounts; (ii) the male subject is assessed as seizure positive when the content of the L-threonine or homovanillic acid is higher than the reference content to which it is referred; said male subject is assessed as seizure negative when neither said content of L-threonine nor said homovanillic acid is higher than said reference content to which it is referred.
In some embodiments, the subject is a drug refractory epilepsy patient.
In some embodiments, the seizure type of the subject is of focal origin.
In some embodiments, the subject has at least one seizure per month.
In some embodiments, the means of detection is selected from one or more of chromatography, mass spectrometry, a combination of chromatography and mass spectrometry, an immunochemical method, a fluorescence assay, and a radiochemical assay.
In another aspect, the present invention also provides a metabolic marker panel for assessing the risk of epileptic seizures in a subject, wherein the metabolic marker panel comprises L-threonine, homovanillic acid and glycine, and the subject is diagnosed with epilepsy and has a seizure propensity.
Compared with the prior art, the invention has the beneficial effects that:
prior art prediction of epileptic seizures typically relies on EEG data acquired by long-term monitoring of brain signals in epileptic patients. In some cases, the continuous EEG data that needs to be analyzed may be up to 24 hours long, and may also be interpreted as different results due to different analytical means (e.g., manual analysis and machine learning model analysis based on EEG). Not only does this take a significant amount of time for an epileptic patient, the interpretation results are subjective, but it does not allow the epileptic patient sufficient time to take preventive action to control the epileptic seizure and to schedule an appropriate plan.
The method is based on a noninvasive, convenient and massively available urine sample, and can predict the risk of epileptic seizure of an epileptic in 1-3 days (from the date of urine sample collection) by detecting the content change of a specific metabolic marker group (L-threonine, homovanillic acid and glycine) only by collecting urine of the epileptic.
Compared with the prior art, the metabolic marker set of the invention provides relatively longer response and preparation time for epileptic patients to take preventive measures or intervention measures in advance, for example, increasing the dosage in advance, preventing epileptic seizure by means of vagus nerve stimulation or transcranial magnetic stimulation, avoiding inducement of epileptic seizure (such as staying up night, drinking alcohol) and other suitable measures. Therefore, the metabolic marker set provided by the invention can avoid other risks accompanied by sudden onset of epilepsy without early warning to a certain extent.
In addition, because the technical scheme of the invention is based on the collection and detection of the urine sample, the standardization of detection is relatively easy to realize, and the early warning function can still be realized while the detection cost is saved to a certain extent. Of course, the metabolic marker panel of the present invention is also suitable for being used in combination with other detection methods to further predict the status of epileptic seizure.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below. It is obvious that the drawings in the following description are some embodiments of the invention, and that for a person skilled in the art, other drawings can be derived from them without inventive exercise.
FIG. 1 is a graph showing the results of cluster analysis (Fuzzy C-Means) of male patients according to a third embodiment of the present invention;
FIG. 2 is a graph showing the results of cluster analysis (analysis by FCM) of male patients according to a third embodiment of the present invention;
FIG. 3 is a graph showing the results of L-threonine levels in male patients according to the third embodiment of the present invention;
FIG. 4 is a graph showing the results of high vanilloid levels in a male patient in accordance with example three of the present invention;
FIG. 5 is a graph showing the results of cluster analysis (by FCM) of female patients according to the third embodiment of the present invention;
FIG. 6 is a graph showing the results of cluster analysis (by FCM) of female patients according to the third embodiment of the present invention;
FIG. 7 is a graph showing the results of L-threonine levels in female patients according to the third embodiment of the present invention;
FIG. 8 is a graph showing the results of glycine levels in a female patient according to example three of the present invention;
FIG. 9 is a summary chart of baseline information for an incorporated drug refractory epilepsy patient, in accordance with an embodiment of the present invention;
FIG. 10 is a summary plot of elevated metabolites 1-3 days prior to seizure in male and female patients according to example three of the present invention;
FIG. 11 is a graph summarizing the levels of L-threonine and homovanillic acid before seizure in male patients in example four of the present invention;
FIG. 12 is a graph summarizing the levels of L-threonine and glycine before a seizure in a female patient according to example four of the invention;
fig. 13 is a schematic diagram of the seizure risk assessment according to the fourth embodiment of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention. It is to be understood that the embodiments described are only a few embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Herein "and/or" includes any and all combinations of one or more of the associated listed items.
By "plurality" herein is meant two or more, i.e. it includes two, three, four, five, etc.
It should be noted that, in this document, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus. Without further limitation, an element defined by the phrase "comprising a … …" does not exclude the presence of another identical element in a process, method, article, or apparatus that comprises the element.
As used in this specification, the term "about" typically means +/-5% of the stated value, more typically +/-4% of the stated value, more typically +/-3% of the stated value, more typically +/-2% of the stated value, even more typically +/-1% of the stated value, and even more typically +/-0.5% of the stated value.
In this specification, certain embodiments may be disclosed in a range of formats. It should be understood that this description of "within a certain range" is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range. For example, the description of range 1-6 should be viewed as having specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., as well as individual numbers within this range, e.g., 1,2,3,4,5 and 6. The above rules apply regardless of the breadth of the range.
As used herein, the term "sample" or "biological sample" or "specimen" refers to a biological material isolated from a subject. The sample may comprise any biological material suitable for detecting a desired biomarker, and may comprise cellular and/or non-cellular material from a subject. The sample may be isolated from any suitable biological tissue or fluid, for example, a blood, plasma, serum, skin, epidermal tissue, adipose tissue, liver tissue, urine, or cell sample. In some preferred embodiments, the sample is urine. The sample may be pretreated prior to actual detection, the pretreatment methods including filtration, distillation, extraction, concentration, inactivation of interfering components, addition of reagents, and the like.
As used herein, the term "epilepsy" refers to a clinical phenomenon in which an individual has more than two non-evoked seizures. Exemplary seizures include very brief loss of consciousness or muscle reflexes and severe and persistent convulsions. The frequency of seizures varies from epileptic patient to epileptic patient, e.g., some patients have a lower frequency, with fewer seizures per year; however, some patients have a high frequency and have multiple attacks per day. Herein, exemplary seizure types for epilepsy include seizures of global and focal origin, and exemplary categories of epilepsy include temporal lobe epilepsy, frontal lobe epilepsy, parietal lobe epilepsy, occipital lobe epilepsy, epileptic encephalopathy, and the like. Herein, the terms "seizure" and "epilepsy" are used interchangeably, unless otherwise indicated.
As used herein, the terms "subject," "individual," and "patient" are used interchangeably and refer to the mammal from which a sample is taken, unless otherwise indicated. A subject, individual, or patient may have, be at risk for, or be suspected of having a predisposition to a seizure or a condition that is symptomatic of a seizure. In some embodiments, a typical subject includes a human susceptible to, suffering from, or having suffered one or more epileptic seizures. In some preferred embodiments, the subject is an adult (i.e., the subject is 18 years of age and older).
As used herein, the term "predisposition," e.g., "predisposition to have seizures," refers to a reasonable medical probability of an event (e.g., seizure occurrence or recurrence). The term "predisposition" also includes the frequency with which such events may occur before, after or during the duration of treatment.
The "content" or "level" of one or more biomarkers (simply "marker") refers to the absolute (quantitative) or relative (qualitative) amount or concentration of the biomarker in the sample.
As used herein, the term "metabolite" refers to any chemical or biochemical product of a metabolic process, which is typically present in the form of a small molecule. Exemplary small molecules include sugars, fatty acids, amino acids, nucleotides, intermediates formed during cellular processes, and other small molecules present inside the cell.
Biological samples suitable for detecting markers include biological material isolated from a subject. In some embodiments, the sample may be a blood, plasma, serum, skin, epidermal tissue, adipose tissue, liver tissue, urine, or cell sample. In some preferred embodiments, the sample is urine.
Any suitable method may be used to analyze a biological sample to determine the amount of one or more markers in the sample. Exemplary suitable methods include chromatography (e.g., liquid Chromatography (LC), high Performance Liquid Chromatography (HPLC), gas Chromatography (GC)), mass spectrometry (e.g., mass Spectrometry (MS), tandem mass spectrometry (MS/MS 2)), combinatorial methods (gas chromatography/mass spectrometry (GC-MS), liquid chromatography/mass spectrometry (LC-MS), ultra-high performance liquid chromatography/tandem mass spectrometry (UHLC/MS 2), and gas chromatography/tandem mass spectrometry (GC/MS 2)), immunochemical techniques such as enzyme-linked immunosorbent assay (ELISA), and combinations thereof, refractive index spectrometry (RI), ultraviolet spectrometry (UV), fluorescence analysis, radiochemical analysis, near-infrared spectrometry (near-IR), nuclear magnetic resonance spectrometry (NMR), light scattering analysis (LS). In addition, in some embodiments, the amount of one or more markers can also be measured by indirect measurement, such as measuring the amount of a compound (or compounds) that correlates with the amount of marker desired to be measured.
After determining the amount of one or more markers in a biological sample obtained from a subject, the amount is compared to a reference amount thereof (e.g., derived from the subject and/or selected reference amounts (e.g., selected for age, sex, type of epilepsy, etc.)). If the levels of all of the markers in the subject's metabolic marker panel (in a female subject, "all" refers to L-threonine and glycine; in a male subject, "all" refers to L-threonine and homovanillic acid) are not significantly increased (i.e., are not higher) as compared to a reference level for the subject (e.g., are the same as the reference level, are substantially the same as the reference level, are not statistically different from the reference level, are within an established range of the reference level, etc.), then the subject is assessed as negative for seizures, i.e., the subject has a lower probability of seizures (which can be considered as having no seizures) within 1-3 days of the day the biological sample is taken. If the level of one or more markers in the set of metabolic markers is increased compared to a reference level to which it is referred, then the subject is assessed as seizure positive, i.e., the subject has a higher probability of seizures within 1-3 days of the date the biological sample is taken. In particular, if the levels of all the markers of the metabolic marker panel are increased compared to the reference level to which they are referred, then the subject is assessed as strongly positive for seizures, i.e. the subject has a very high probability of seizures within 1-3 days of the day the biological sample is taken.
A "reference amount" of a marker can be an absolute or relative amount or concentration of the marker, the presence or absence of the marker, an amount or range of concentrations of the marker, a minimum and/or maximum amount or concentration of the marker, an average amount or concentration of the marker, and/or a median amount or concentration of the marker. An appropriate reference level of a marker can be determined by measuring the desired level of the marker in the same subject multiple times; can also be determined by measuring the levels of marker required in a plurality of particular subjects (e.g., subjects of the same sex and age) to serve as a reference level for a particular population. The reference content and marker content of the subject may vary depending on the particular technique (e.g., LC-MS, GC-MS) used to measure the marker in the biological sample.
The subject's marker content can be compared to its reference content in a variety of ways, such as simple comparison, statistical analysis (e.g., t-test, wilcoxon rank sum test). In some embodiments, the comparison may be accomplished by a manual and/or automated system. In some embodiments, a subject having a level of one or more markers that is 5%, 10%, 15%, 20% or more above its reference level can be considered to have an increased level of one or more markers in the subject.
In some embodiments, the reference amount can be determined by regular collection (e.g., 1 collection per day) over a period of time (e.g., 2 weeks) for subjects with an average seizure frequency of at least 1 time per month. If the subject has seizures during the acquisition, the level 1 week before its seizures can be considered as its reference level for reference.
Example one
Subjects studied by the present invention: the invention relates to an epileptic patient who is treated at the epileptic center of the western hospital of Sichuan university from 2021 to 2022 at 8 months (the epileptic patient is independently diagnosed as epilepsia by two doctors). Inclusion criteria for epileptic patients were: (1) The epileptic seizure frequency in the last 6 months is 1 or more per month on average; (2) the age is 18-50 years. Exclusion criteria were: (1) Patients with kidney disease, taking drugs that clearly affect changes in urine protein or kidney function; (2) Patients with abnormal urine routine and liver and kidney function detection results; (3) Patients suffering from other nervous system diseases such as stroke, brain tumor, alzheimer disease, parkinson and the like; (4) patients with other chronic diseases; (5) patients in gestation or lactation; (6) Patients who were unable to coordinate the study of the present invention for other reasons.
Baseline information for subjects studied in the present invention: the baseline information acquisition is completed by the doctor and the patient face to face, and comprises demographic information, epilepsy-related medical history information, examination results, medication history and past history. Demographic information includes: gender, age, cultural degree, BMI. Epilepsy-related history information includes: the onset age, course, seizure type, seizure duration, seizure severity score, whether it is drug refractory epilepsy, etc. The inspection results include: skull MRI, skull PET-MRI, skull CT, general scalp electroencephalogram, video electroencephalogram, etc. The history of medication includes: the amount, type, dose, etc. of the drug to be administered. The past history includes: history of birth hypoxia, history of preterm birth (gestational age <37 weeks), history of febrile convulsion, history of meningitis before onset of disease, history of cranium trauma before onset of disease, and family history of epilepsy.
Considering that most epileptic seizures can be controlled after drug treatment, the present inventors selected drug refractory epileptic patients for the focus of the study, and the main baseline information is shown in fig. 9.
Urine sample collection and diary recordings: urine collection is done autonomously by the subject at home. Each subject was collected for 2 months continuously, with the first urine in the morning on empty stomach and within 1h after each seizure. During collection, the midstream urine is collected by a disposable urine cup, poured into a 15mL centrifuge tube and filled to 12-13mL, and 2 tubes are collected each time. After collection, the label printed with the serial number is attached to the centrifuge tube, and the date of the day and the time for collecting urine are written on the tube cover. If the urine is attacked for multiple times within one day, the urine after attack is collected for 2 times at most and is separated by more than 1 h. Subjects recorded diaries in the electronic diary card every day, starting on the first day urine was collected. The recording content includes: (1) date urine collection began; (2) date and time of collection of daily morning urine; (3) The daily seizure status and the date and time of collection of urine after seizure; (4) Diet, exercise, sleep condition and menstrual volume of women every day.
Urine transportation and storage: after each collection, the subject immediately placed the tube containing urine and labeled with the label in a-20 ℃ refrigerator. Subjects sent urine to the western hospital of Sichuan university with dry ice every 2 weeks. Urine of the subject is received by a specially-assigned person, is sorted and registered, and is finally stored in a refrigerator at-80 ℃ of a biological sample warehouse of western Sichuan university hospital.
Example two
Urine pretreatment: first, a urine sample was incubated with urease at a concentration of 100U to break down excess urea (considering that high abundance of urea is the major chromatographic disturbance). 50 μ L of incubated sample was transferred to a centrifuge tube (the sample was run all the way on ice), and after adding 250 μ L of spiked methanol, the sample was vortexed at 1550rpm for 3min at 4 ℃. Next, the vortexed sample was stored in a refrigerator at-20 ℃ for 20min, then sonicated in an ice bath for 15min, and finally centrifuged at 13300rpm for 15min at 4 ℃. 150 μ L of the supernatant was taken to a new EP tube and concentrated in vacuo at 30 ℃ for 2 hours. The dried extract was oximated using methoxylamine hydrochloride (2 hours at 60 ℃). Then, derivatization was performed (30 min at 60 ℃) using mstafa (N-methyl-N- (trimethylsilyl) trifluoroacetamide). The derivatized sample was centrifuged (at 13300rpm, room temperature for 10 min) and then transferred to a sample vial (sample injection over 24 hours). Finally, GC/MS detection analysis was performed on the treated samples.
And (3) GC-MS detection: GC-MS detection was performed on a gas chromatography system coupled to a mass spectrometer (Agilent 7890/MSD 5977B, CA, USA). The trimethylsilylated samples were isolated using a DB-5MS capillary column (30 m. Times.250 μm,0.25 μm film thickness; agilent J & W Scientific, folsom, calif., USA). Helium was used as the carrier gas at a flow rate of 0.5ml/min. The injection port temperature was 250 ℃. The temperature of the GC column box was set at 60 ℃ for the first 1 minute, then ramped up to 325 ℃ at a rate of 10 ℃/min, and finally held at 325 ℃ for 10 minutes. The temperatures of the transmission line and the ion source were 300 ℃ and 230 ℃, respectively. Mass spectral raw data were acquired in full scan mode (m/z 50-600) using electron impact ionization (70 eV). The dwell time for each scan was set to 1562u/s and the solvent delay was set to 5.9min. All samples were injected in random order with a volume of 0.5. Mu.L.
Data preprocessing and analysis: statistical analysis of mass spectral data was performed using the commercial software Agilent MassHunter and R software (version 3.4.0). Screening differentially expressed metabolites by univariate analysis and multivariate analysis (screening conditions are (1) t test, p value is less than 0.1, (2) OPLS-DA (orthogonal partial least squares discriminant analysis), VIP score is more than 1).
Data preprocessing: and (3) introducing the original data of the mass spectrum off-machine into commercial software Analyst (version 1.6.3) and Multiquant (version 3.0.2) for peak extraction, and obtaining the information such as the mass-to-charge ratio, retention time, peak area and the like related to the metabolite. Then, R software is used to preprocess the mass spectrum data extracted by Progenesis QI software, including correcting sample mass deviation, removing low-mass ions (more than 50% missing in QC samples, or more than 50% missing in actual samples), removing unstable ions (ion filtration with relative deviation (RSD) >20% in all QC samples), missing value filling (KNN algorithm), eignems normalization (median), PCA display Quality Control (QC) sample distribution. The change trend of the metabolites before and after the epileptic seizure is analyzed by adopting an unsupervised machine learning method FCM (fuzzy C-means), the metabolites are clustered (clustering) and the overall change trend of each cluster is obtained.
EXAMPLE III
In the present invention, a total of 93 urine samples were analyzed. Samples were divided into three groups by time of collection: n (normal state, i.e. the time taken for the urine sample to be taken 1 week before the seizure), B (pre-seizure, i.e. the time taken for the urine sample to be taken 1 to 3 days before the seizure), and a (post-seizure, i.e. the time taken for the urine sample to be taken within 1 hour after the seizure). The 77 metabolites in the above urine sample were analyzed by FCM, which finally yielded:
(1) There were 19 (as shown in the "male patients" column of fig. 10) metabolite levels that were significantly elevated 1-3 days before and significantly reduced after the seizure in the male patients (fig. 1, fig. 2, male cohort 2). Specifically, fig. 1 shows that FCM analysis forms metabolites into three clusters (i.e., male clusters 1,2, and 3). And fig. 2 further shows (referring to the auxiliary schematic line of the overall tendency of the colony), the metabolites in the male colony 1 gradually decrease from N to B to a, while the metabolites in the male colony 3 have no obvious tendency from N to B, and gradually increase from B to a, and only the metabolites in the male colony 2 significantly increase from N to B, and significantly decrease from B to a.
(2) There were 16 (as shown in the "female patients" column of fig. 10) metabolite levels that rose significantly overall 1-3 days before and then decreased significantly after the seizure in female patients (fig. 5, fig. 6, female cohort 1). Specifically, fig. 5 shows that FCM analysis formed metabolites into three clusters (i.e., female clusters 1,2, and 3). And fig. 6 further shows (referring to the auxiliary schematic line of the overall tendency of the clusters), that the metabolites in the female cluster2 gradually decrease from N to B to a, while the metabolites in the female cluster 3 have no overall obvious tendency from N to B, and gradually increase from B to a, and only the metabolites in the female cluster1 significantly increase from N to B, and significantly decrease from B to a.
Example four
Further studies on the metabolite change trends in the seizure cases of specific patients (8 actual seizure cases in each of the male and female groups) revealed that the levels of L-threonine (fig. 3) and homovanillic acid (fig. 4) were significantly elevated before seizures in male patients. Moreover, even if there are individual cases of male onset in which one of the above metabolites is not elevated, another metabolite is elevated (for example, L-threonine in onset number 7 is not elevated before onset (B) but elevated in homovanillic acid is significant; and L-threonine in onset number 5 is not elevated before onset (B) but elevated in particular).
In addition, the levels of L-threonine (fig. 7) and glycine (fig. 8) were significantly elevated in female patients prior to seizure. Also, even though there was a case where one of the above metabolites was not elevated in the case of individual female episodes, another metabolite was elevated (for example, L-threonine of female case episode Nos. 5, 6 was only slightly elevated before onset (B), but their glycine elevation was particularly pronounced).
On the whole, the two groups of metabolites are respectively adopted as detection markers for patients of different genders, so that the epilepsy attack risk can be predicted more specifically and more effectively. Moreover, since the two groups of metabolites contain L-threonine (which is obviously increased in most male patients and female patients) as a universal biomarker for predicting epileptic seizure, the number of detection markers can be reduced, and the cost of the detection scheme of the invention is reduced.
This example further demonstrates the reliability of seizure prediction with metabolites that are significantly elevated prior to seizures for both male and female patients. As shown in fig. 11 and 12, it was found that elevated levels of either threonine alone or homovanillic acid or glycine alone did not necessarily allow a better assessment of seizure risk, as both risks were "false negatives" (i.e., no elevation occurred prior to seizures). However, the risk of epileptic seizure was better evaluated by combining L-threonine and homovanillic acid (male patients) or L-threonine and glycine (female patients) (hereinafter, referred to as marker sets) because neither of the two metabolites in the marker sets was elevated (see FIG. 11-0% for both L-threonine and homovanillic acid before epileptic seizure in male patients; and 0% for both L-threonine and glycine before epileptic seizure in female patients), and the probability of elevated both metabolites in the marker sets was the highest (see FIG. 11-60% for both L-threonine and homovanillic acid before epileptic seizure in male patients; and 43.75% for both L-threonine and glycine before epileptic seizure in female patients).
Based on the above two sets of markers for predicting the effect of seizures, in some embodiments of the present invention, a subject is assessed as negative for seizures when the level of all markers in the subject's marker set is not increased (compared to a reference level, the same applies below), i.e., the subject has a low probability of seizures (which can be considered as no seizures, without taking precautionary or interventional measures in advance) within 1-3 days of the biological sample being collected. When the content of one or two markers in the marker group of the subject is increased, the subject is evaluated as positive for the epileptic seizure, i.e., the probability of the epileptic seizure is higher in the subject within 1-3 days of the collected biological sample, and the epileptic should be advised to take preventive measures or intervention measures in advance. When the content of all the markers in the marker group of the subject is increased, the subject is evaluated as a strong positive for the epileptic seizure, and the epileptic should be explicitly advised to take preventive measures or intervention measures in advance to reduce the possible harm caused by the epileptic seizure (as shown in fig. 13).
While the present invention has been described with reference to the embodiments shown in the drawings, the present invention is not limited to the embodiments, which are illustrative and not restrictive, and it will be apparent to those skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope of the invention as defined in the appended claims.
Claims (10)
1. Use of a metabolic marker panel comprising L-threonine, homovanillic acid and glycine for the manufacture of a kit for assessing the risk of epileptic seizures in a subject, the kit comprising detection reagents for detecting the content of the metabolic marker panel in a urine sample of the subject diagnosed with epilepsia and having a predisposition to seizures.
2. The use of claim 1, wherein the subject is at least 18 years of age.
3. The use according to claim 1, wherein the subject is assessed as having a risk of seizure within a predicted time frame when the content is above its reference content for reference.
4. The use of claim 3, wherein said prediction period is 1-3 days from the date of collection of said urine sample.
5. The use of claim 1, wherein said L-threonine and said glycine are used to assess the risk of seizures in a female subject; said female subject is assessed as strongly positive for seizures when said levels of both said L-threonine and said glycine are above their reference levels; said female subject is assessed as seizure positive when said content of said L-threonine or said glycine is higher than said reference content to which it refers; said female subject is assessed as seizure negative when neither said content of L-threonine nor said glycine is higher than said reference content to which it is referred.
6. The use of claim 1, wherein said L-threonine and said homovanillic acid are used to assess the risk of seizure in a male subject; said male subject is assessed as strongly positive for seizures when both said L-threonine and said homovanillic acid are present in an amount greater than their reference amounts; (ii) the male subject is assessed as seizure positive when the content of the L-threonine or homovanillic acid is higher than the reference content to which it is referred; said male subject is assessed as seizure negative when neither said content of L-threonine nor said homovanillic acid is higher than said reference content to which it is referred.
7. The use of claim 1, wherein the subject is a drug refractory epilepsy patient.
8. The use of claim 1, wherein the subject has at least one seizure per month.
9. Use according to claim 1, wherein the means of detection is selected from one or more of chromatography, mass spectrometry, a combination of chromatography and mass spectrometry, immunochemical, fluorescence analysis and radiochemical analysis.
10. A metabolic marker panel for assessing the risk of seizures in a subject diagnosed with seizures and having a predisposition to seizures, wherein the metabolic marker panel comprises L-threonine, homovanillic acid and glycine.
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