Compounds for diagnosing and treating epilepsy syndromes, methods and uses thereof

Abstract

The present disclosure relates to medical diagnostics and therapeutics, specifically methods and compositions for predicting and preventing Sudden Unexpected Death in Epilepsy (SUDEP) and / or; treating, preventing and / or ameliorating symptoms associated with epileptic seizure syndromes; particularly Dravet Syndrome. It involves the use of biomarkers, selected from cortisol, corticosterone, cortisone, aldosterone, adrenocorticotropic hormone (ACTH), or combinations thereof, to assess SUDEP risk. Additionally, the present subject-matter describes compositions containing cortisone, hydrocortisone, dexamethasone, fludrocortisone, prednisolone, ganaxolone, tetracosactide, adrenocorticotropic hormone (ACTH) or combinations thereof, in a therapeutically effective amount with a pharmaceutically acceptable carrier, adjuvant, or excipient for SUDEP prevention. The disclosure also includes the use of these compositions for treating, preventing, and / or ameliorating seizures in epilepsy patients, particularly those with Dravet Syndrome and / or preventing / predicting SUDEP.

Description

D E S C R I P T I O NCOM POUNDS FOR DIAGNOSING AND TREATING EPI LEPSY SYNDROM ES, M ETHODS AND USES TH EREOFTECH NICAL FIELD

[0001] The present disclosure relates to the fields of medical diagnostics and therapeutics, specifically to methods and compositions for the prediction and prevention of Sudden Unexpected Death in Epilepsy (SUDEP) and treatment of epilepsy syndromes, in particular Dravet syndrome.

[0002] The present disclosure relates to the use of a biomarkerfor determining the risk of SUDEP. This biomarker is selected from a list consisting of: cortisol, corticosterone, cortisone, aldosterone, adrenocorticotropic hormone (ACTH), or mixture thereof. Additionally, it describes a method for assessing whether a patient is at risk of SUDEP.

[0003] Furthermore, the present disclosure addresses the use of a composition comprising cortisone, hydrocortisone, dexamethasone, fludrocortisone, prednisolone, ACTH, ganaxolone, tetracosactide or combinations thereof in a therapeutically effective amount and a pharmaceutical acceptable carrier, adjuvant, excipient, or mixtures thereof for SUDEP prevention.

[0004] Additionally, the present disclosure relates to the use of cortisone, hydrocortisone, dexamethasone, fludrocortisone, ACTH, prednisolone, ganaxolone, tetracosactide or combinations thereof for use in treating, preventing and / or ameliorating seizures experienced by epilepsy patients or preventing SUDEP; namely for treating, preventing and / or ameliorating seizures experienced by sufferers of Dravet Syndrome.BACKGROU ND

[0005] Epilepsy is a heterogeneous clinical condition characterized by recurrent unprovoked seizures, their causes, and complications. There are numerous causes of epilepsy including, but not limited to birth trauma, perinatal infection, anoxia, infectious diseases, ingestion of toxins, tumors of the brain, inherited disorders or degenerative disease, head injury or trauma, metabolic disorders, cerebrovascular accident, and alcohol withdrawal1. Also, a person'sepilepsy diagnosis can be further specified by identifying their epilepsy syndrome. An epilepsy syndrome is defined by a unique set of clinical features, signs, and symptoms that accompany the seizures. Examples of epilepsy syndrome include but are not limited to juvenile myoclonic epilepsy, Lennox-Gastaut Syndrome, Landau-Kleffner syndrome, West syndrome, febrile seizures and Dravet Syndrome2.

[0006] Among deaths directly attributable to epilepsy or seizures, SUDEP is estimated to account for up to 50% of deaths in patients with chronic refractory epilepsy, and up to 17% of deaths in all epileptic patients3, being the leading cause of epilepsy-related death4. Risk population is difficult to define, since there is an apparent lack of agreement regarding features such as age of onset of epilepsy, polytherapy, genetic predispositions, alcohol abuse or intellectual disability5. Still, epidemiological data allows to identify chronic refractory epilepsy, in particular nocturnal generalized tonic-clonic seizures (GTCS) in prone position as the major risk factor for SUDEP6. The risk of SUDEP in Dravet Syndrome is up to 15 times higher than other childhood-onset epilepsies. It is the biggest cause of death in Dravet Syndrome, responsible for nearly half of all Dravet Syndrome deaths. SUDEP tends to occur at a younger age (73% before the age of 11) than in other epilepsies7’.

[0007] SUDEP is the sudden, unexpected, witnessed or unwitnessed, non-traumatic, and nondrowning death of patients with epilepsy with or without evidence of a seizure, excluding documented status epilepticus, and in which post-mortem examination does not reveal a structural or toxicological cause of death3. Despite of being well defined, SUDEP cannot be predicted nor prevented, thus being the leading cause of epilepsy-related death.

[0008] SUDEP underlying pathomechanisms, involves the cardiac, respiratory, and autonomic nervous systems. Possible respiratory disabilities contributing to SUDEP include central and obstructive apnea, pulmonary edema, ictal hypoxia, aspiration, and laryngospasm8. Simultaneously, seizures can induce cardiac arrhythmias, changes in blood pressure or asystole9. The chronological causality is controversial since apnea is rarely secondary to brain hypoperfusion due to cardiac dysfunction5. Likewise, a change in cardiac rhythm cannot be interpreted as the primary problem unless there is also respiratory monitoring because arrhythmias can be secondary to hypoxia and hypercapnia4. Postictal generalized electroencephalogram suppression is a fatal downstream event of cardiorespiratory arrest in SUDEP. In the MORTEM US study during SUDEP event, the initial GTCS triggered a short period of normal or increased heart and respiratory rates then severe bradycardia and central apnoea withPGES9. Electrocerebral shutdown, not being the primary cause of death, was fatal in one third of the cases4.

[0009] Given the frequency and severity of seizure-induced respiratory abnormalities, it is surprising that death does not occur more often5. It may be that ictal respiratory dysfunction is only dangerous when associated with impaired arousal. In MORTEMUS study, patients who died of SUDEP were frequently found prone positioned in bed with no observable corrective action to optimize their position, remaining in the same position from seizure until death. Prone position allows the mouth and nose to be wholly or partly occluded, and it may take more muscular effort to expand the chest, increasing the risk of rebreathing or asphyxia if the patient fails to achieve arousal5.Diencephalon and upper brainstem constitute ascending arousal system (AAS) and are responsible for arousal and consciousness. Impairment of the AAS leaves a patient with epilepsy at greater risk of SUDEP since in some individuals with postictal depression of consciousness, protective reflexes are suppressed during the postictal coma6. AAS serotonin neurons are triggered by hypoxia and hypercapnia, stimulating breathing, and causing arousal when they are activated. Dysfunction of serotonin neurons leads to reduced ability to respond appropriately to an external stressor during a state of generalized central nervous system depression (sleep vs postictal state)4. In sum, ictal and postictal arousal impairment demonstrated contribution to SUDEP, indicate arousal as a crucial process to endure and evade cardiorespiratory arrest in SUDEP being the SUDEP risk manager.

[0010] The major challenge to SUDEP prediction and prevention is the multiplicity of potential underlying pathomechanisms and the phenotypical heterogeneity among epileptic subjects affected by SUDEP. There is an unmet medical need to find a wide-range biomarker within the epilepsy population, aiming specifically the molecular pathomechanisms involved in SUDEP. Ideally this biomarker should be used as a clinical endpoint to drive SUDEP preventive treatments and predictive tests. To identify SUDEP biomarkers, several epidemiological studies led to the state-of-the-art tool / frontier that currently exists: a clinical rating scale named SUDEP-7 Inventory10. However, neither the SUDEP-7 Inventory score nor the cumulative presence of independent SUDEP risk factors reliably distinguish individuals dying of SUDEP from living epilepsy patient controlsn. Cutting edge functional electroencephalograms and structural magnetic resonance imaging techniques are being tested in the hospital environment for SUDEP detection. However, the unpredictability of seizures reduces the probability of having a terminalevent in the hospital, thus limiting the practical use of these approaches. Seizure-detection technologies such as mattress, watch, camera, and motion devices that alert the caregivers upon an epileptic seizure are being studied for their potential to avoid SUDEP. These devices are currently limited by the immediate availability and education of the caregiver on resuscitation maneuvers and by the unknown critical window for resuscitation. One case of SUDEP was reported in a patient wearing a wrist -worn seizure detection system and respiratory cessation happened within 5 minutes suggesting a very limited time to react3. Finally, none of the above- mentioned technologies can distinguish a life-threatening seizure nor provide data on the evolution of SUDEP risk in order to allow the patients to adapt their medication to prevent SUDEP.

[0011] In conclusion, up to now, there is no biomarker nor predictive test available to define or predict SUDEPn.

[0012] Glucocorticoids, cortisol in humans and corticosterone in rodents, are a major subclass of steroid hormones that regulate metabolic, cardiovascular, immune, and behavioral processes12. Cortisol is the primary endogenous adrenal steroid in most mammals, including humans, whereas corticosterone is the primary adrenal corticosteroid in laboratory rodents (2-6). Rats and mice do not produce appreciable cortisol, because they lack the adrenocortical zona fasciculata enzyme 17-a hydroxylase (CYP17)13. CORT is the rodent stress hormone analog of cortisol in humans and is the major output of the HPA axis. Chronic corticosterone administration induces negative valence and impairs positive valence behaviors in mice, often used as a functional equivalent to cortisol in humans in preclinical research and experimental models14.

[0013] Cortisol exerts its effects via hypothalamic-pituitary-adrenal (HPA) axis15. In a presence of a stimulus, the secreted corticotropin-releasing hormone (CRH) by the hypothalamus triggers cells in the neighbouring anterior pituitary to secrete ACTH into the vascular system which in turn stimulates cortisol release in the adrenal cortex16. Over the course of a typical day, levels of cortisol increase during the hour post-awakening, followed by a steep decline over the next three hours after awakening. This is then followed by a more gradual decline overthe remainder of the day, reaching the lowest point during the first half of the sleep period. During sleep, cortisol levels remain low and then rise again until morning awakening17. In turn, in an acute stressful event the rise in corticosteroids reaches its peak levels 20-30 min after de initiation of stress, influencing cellular processes throughout the body, including the brain. Negative feedback at the level of the hypothalamus and pituitary causes the system to return to baseline levels inapproximately 2 h after cessation of the stressor15. However, if the stress exposure occurs repeatedly and stress hormone levels stay elevated over a longer period of time, this chronic stress can cause more permanent changes in stress hormone regulation and brain processes being associated with an increased risk of chronic diseases development15.

[0014] Cortisol is a biomarker for arousal. In healthy subjects, the cortisol awakening response is needed for arousal regaining. Cortisol awakening response is superimposed on circadian rhythm of cortisol release (1.5-to-3-fold increase) and occurs in response to the transition from sleep to wakefulness. Serotonin signalling is associated with the ascending arousal system, cortisol awakening response and stress16. Under physiological stress, such as an epileptic seizure, the brainstem serotoninergic neurons afferents to the paraventricular nucleus of the hypothalamus are activated to promote cortisol release. In contrast, extreme conditions as burn-out, fatigue and brain damage are associated with marked attenuation or absence of cortisol awakening response16.

[0015] Cortisol is associated with sudden death. Sudden death has been attributed to adrenal crisis18-20(a life-threatening condition in which adrenal glands do not produce enough cortisol), which is now identified as the principal death cause in 15% of Addison patients21. Furthermore, a near sudden infant death, similar condition to SUDEP, was identified as a consequence of adrenal crisis22. Moreover, serum cortisol levels are significantly higher in surviving victims of cardiopulmonary arrest than non-survived patients, suggesting that serum cortisol levels may serve as a predictor of survival23.

[0016] Cortisol is associated with epilepsy, both by its circadian fluctuation24and through its role in stress response25. A systematic review performed by Campen and colleagues in 2015, revealed that circadian seizure distribution varied with localization of the epileptic focus in patients with focal seizures and between seizure types. Furthermore, in the particular case of GTCS there was an increase in the early morning. Similarity to the cortisol rhythm was however less striking because their occurrence was already high during the night and showed a downward trend during the day24.

[0017] People with epilepsy often report seizures precipitated by stress. This is believed to be due to effects of stress hormones, such as cortisol on neuronal excitability26. In this duality of stress, it is proposed that acute stress is protective against seizure events whereas chronic stress may be deleterious25. The major sources of chronic stress for the person with epilepsy are thefrequency of seizures, their unpredictability, the risk of injury and their bizarre behavior during seizures. Hence, in a devastating positive feedback loop, the chronic stress may lead to increased seizure frequency, which may exacerbate the state of chronic stress27. This is demonstrated by the increased basal levels of cortisol commonly found in epileptic patients28. However, mainly due to the seizure's heterogeneity and stress adaptive capacities, reports on hormone levels in patients with epilepsy at resting conditions have been contradictory15.

[0018] In opposition to the contradictory reports on cortisol hormone levels in patients with epilepsy at resting conditions, this consistency was surprisingly found in the postictal cortisol and ACTH values. Directly after an epileptic seizure, which is often considered an acute stressor itself, a consistent and sharp increase in cortisol and ACTH was shown. This is a specific physiological adaptation in response to seizure, named hereinafter in the present application as Cortisol Acute Epileptic Seizure Adaptive Response CAESAR is a consistent fast-sharp cortisol rise found specifically in the postictal phase of epileptic seizures29-34-36. Although changes in cortisol and ACTH concentrations are not specific of a particular stressful event, this particular dynamic increase is a distinctive pattern of epileptic seizures.

[0019] Abbott and colleagues found elevated postictal cortisol levels in three patients in the first hour (between 21.5 pg / dl and 46.0 pg / dl), with a decline tendency afterwards. In one patient, cortisol was not assessed and interestingly the last patient whose cortisol values remained stably low within the first hour (10.6 pg / dl and 11.8 pg / dl), had an unusual, prolonged seizure lasting for 30 minutes and received diazepam. In the stimulated seizure group, they found a consistent rise of cortisol levels posticta I ly from tOmin (~11 pg / dl) to tl5min (~17 pg / dl) with a decline to the basal levels at t45min. Additionally, in a third group of postictal patients, cortisol levels were found increased (30.5 pg / dl) when compared with control group (17.7 pg / dl). They concluded that the change in cortisol level may reflect a non-specific stress response and these findings may have a clinical value in the diagnosis of epilepsy29. Four years later, 24 single GTCS were studied in 20 patients. The results obtained in 30 minutes intervals showed a significant consistent postictal elevation in plasma cortisol preceded by a marked increase in plasma ACTH30. In line with these results, this seizure cortisol response was compared between 6 epileptic and 6 pseudoepileptic seizures. In all epileptic seizures they found a consistent rise of cortisol levels within the first 15 minutes with a further increase until the 30 minutes posticta lly and a decay in the 45 and 60 minutes after seizure. In the particular case of the only tonic-clonic seizure analyzed, the cortisol levels duplicated within the first 30 minutes after seizure (tOmin 21.6 pg / dl;tl5min 32.4 pg / dl; t30min 40.6 pg / dl). Conversely, the values obtained for pseudo epileptic seizures followed a tendency of decay for all time points within the first hour33. Reinforcing homogeneity of previous results, Rao demonstrated in 1989 that cortisol is increased postictally, followed by a decrease after grand mal or complex partial seizure but not after psychogenic seizure in comparison to baseline levels obtained during the same time on a seizure-free day31. The most recent study dedicated to cortisol seizure response is of particular interest for SUDEP research since it was studied on nocturnal GTCS. The change of serum ACTH and cortisol (Table 1) showed a course declining from wake status (33.8 pg / dl, 10.5 pg / dl) to sleep status (16.1 pg / dl, 4.7 pg / dl), slightly falling just before a seizure (11.5 pg / dl, 4.6 pg / dl). During the seizure, there is a sharp raise of both ACTH and cortisol levels (39.3 pg / dl, 11.3 pg / dl), even more pronounced postictally (97.2 pg / dl, 15.3 pg / dl)32.

[0020] Table 1. Cortisol variation during seizures: Case epileptic seizures vs control psychogenic seizures; Spontaneous vs Induced seizure (Adapted from32).

[0021] Corticosteroids have been used for the treatment of patients with epilepsy for over 60 years. In 1958, Sorel and Dusaucy-Bauloye first reported a marked improvement in 21 patients with epileptic spasms treated with ACTH. Since then, corticosteroids have evolved into an essential component of the standard therapy of epileptic spasms backed up by evidence of randomized controlled trials35.

[0022] At present, although some retrospective studies show good response rates of various steroid treatment regimens in various epilepsy syndromes, there is a lack of results fromrandomized controlled trials providing clear evidence for the use of specific steroid regimens in epilepsies other than epileptic spasms35.

[0023] There is accordingly a need to provide a therapeutic and diagnostic method for predicting and preventing SUDEP, as well as an improved method for treating Dravet Syndrome and / or for treating, preventing and / or ameliorating seizures experienced by sufferers of Dravet Syndrome.

[0024] These facts are disclosed in order to illustrate the technical problem addressed by the present disclosure.GENERAL DESCRIPTION

[0025] The present disclosure relates to novel methods for diagnosing the risk of SUDEP in patients with epilepsy using specific biomarkers. It also covers therapeutic compositions and methods for preventing SUDEP and / or treating, preventing and / or ameliorating symptoms associated with epileptic seizure syndromes, such as Dravet Syndrome, and / or reducing the incidence of SUDEP. The present disclosure aims to provide improved outcomes for epilepsy patients by facilitating early SUDEP risk detection and prevention and an effective disease management.

[0026] It is therefore an object of the present disclosure to provide a biomarker for SUDEP and a method for determining whether a patient has or is at risk of developing Sudden Unexpected Death in Epilepsy (SUDEP).

[0027] The present disclosure relates to the use of a biomarkerfor determining the risk of SUDEP wherein said biomarker is selected from a list consisting of: cortisol, corticosterone, cortisone, aldosterone, ACTH, or mixture thereof; as well as to a method of determining whether a patient is at risk of SUDEP. The present disclosure also relates to a composition comprising cortisone, hydrocortisone, dexamethasone, fludrocortisone, ACTH, prednisolone, ganaxolone, or combinations thereof in a therapeutically effective amount and a pharmaceutical acceptable carrier, adjuvant, excipient or mixtures thereof; as well as for preventing and / or reducing the incidence of SUDEP; and / or treating or ameliorating symptoms associated with epileptic seizure syndromes, in particular Dravet Syndrome.

[0028] In the present disclosure it was surprisingly found that cortisol, cortisone, corticosterone, aldosterone, ACTH, or mixture thereof can be used as a biomarker for SUDEP.

[0029] In an embodiment, it was observed a fast sharp rise in cortisol levels, similar to cortisol awakening response (doubling of cortisol levels within 30 to 45 minutes), as a postictal effect of epileptic seizures and is named in the present disclosure as Cortisol Acute Epileptic Seizure Adaptive Response - CAESAR b) (Figure 1). As for cortisol awakening response, CAESAR was surprisingly found, by the inventors of the present disclosure, to enable epilepsy patients to achieve arousal after a seizure (Figure l.A). In contrast, CAESAR was observed to be impaired (Figure l.B) in life-threatening seizures since this cortisol burst is absent in both near SUDEP and impaired arousal.

[0030] An aspect of the present disclosure relates to a biomarker for use in the diagnostic of the risk of SUDEP in a sample, wherein said biomarker is selected from a list consisting of: cortisol, cortisone, corticosterone, aldosterone, ACTH, or mixtures thereof.

[0031] In an embodiment, said biomarker may be cortisol; cortisol and corticosterone; cortisol and cortisone, cortisol and aldosterone; cortisol and adrenocorticotropic hormone; corticosterone and cortisone, corticosterone and aldosterone; corticosterone adrenocorticotropic hormone; aldosterone and cortisone, aldosterone and adrenocorticotropic hormone; adrenocorticotropic hormone and cortisone, preferably cortisol.

[0032] In an embodiment, the sample is a biological sample collected from a patient.

[0033] In an embodiment, the content of biomarker is determined in a (ex vivo) biological sample collected from a patient to be tested.

[0034] In an embodiment, the level of biomarker in the biological sample collected from the patient during an epileptic seizure is below to a threshold value indicative of a lower limit from the historical data of the level of biomarker in the same patient during epileptic seizures, then the patient is at risk of SUDEP.

[0035] In an embodiment, if the basal level of a biomarker in a patient exceeds a threshold value, indicating a higher limit based on historical data of the same biomarker in the patient, then the patient is at risk of developing Sudden Unexpected Death in Epilepsy (SUDEP). Conversely, if the biomarker level falls below this historical basal level, the patient requires treatment to preventSUDEP. Therefore, it is necessary to define the normal basal level of the biomarkerforthe patient in some cases and determine the difference.

[0036] In an embodiment, if the basal level of biomarker in the patient is below a threshold value indicative of a lower limit from the historical data of the basal level of one of said biomarker in the same patient, then the patient is at risk of SUDEP.

[0037] The basal level of a biomarker refers to the normal, baseline concentration or activity of that biomarker in a patient's body when they are in a stable, healthy state. This level is determined based on measurements taken under consistent conditions, usually when the patient is at rest and not experiencing any external factors that could influence the biomarker. The basal level serves as a reference point against which deviations can be compared to assess the risk of SUDEP occur.

[0038] In an embodiment, the biological sample is interstitial fluid (ISF), saliva, blood, plasma, urine or serum; preferably ISF.

[0039] Another aspect of the present disclosure relates to a method for determining whether a patient with epilepsy has, or is at risk of SUDEP, comprising the steps of: i) providing a test sample from said patient. ii) assaying the basal level or amount at least one of the following biomarkers selected from a list consisting of: cortisol, cortisone, aldosterone, corticosterone, ACTH or mixtures thereof; iii) comparing the level or amount determined in step ii) to a reference historical value reflecting the basal level or amount of biomarker in a healthy person, wherein a higher level or amount relative to the reference value is indicative for risk of SUDEP.

[0040] Another aspect of the present disclosure relates to a method of determining whether a patient with epilepsy has, or is at risk of SUDEP, comprising the steps of: i) measuring a content of a biomarker in a (ex vivo) biological sample collected from the patient during an epileptic seizure, wherein said biomarker is selected from a list consisting of: cortisol, corticosterone, cortisone, aldosterone, ACTH, or mixtures thereof; ii) comparing the level of the biomarker in the biological sample with a threshold value indicative of a lower limit of the historical data of the level of the biomarker in the same patient during epileptic seizures;iii) wherein if the level of at least one of the said biomarkers in the biological sample is below the threshold value then the patient is diagnosed with having SUDEP.

[0041] Another aspect of the present disclosure relates to a method for determining whether a patient with epilepsy is at risk of SUDEP, comprising the steps of: i) providing a test sample from said subject, wherein said test sample is collected during an epileptic seizure; ii) assaying the level or amount of at least one of said biomarkers, wherein said biomarker is selected from a list consisting of: cortisol, cortisone, corticosterone, ACTH, aldosterone or mixtures thereof; iii) comparing the level or amount determined in step ii) to a reference value reflecting the historical data of the level or amount of at least one of said biomarkers in the same subject during an epileptic seizure, iv) wherein a decrease in the level or amount relative to the reference value is indicative for risk of SUDEP.

[0042] In an embodiment, concentration of at least one of said biomarkers is inputted into a statistical methodology to produce an output value that indicates whether the patient has or is at risk of SUDEP.

[0043] In an embodiment, the statistical methodology used is selected from the list consisting of: logistic regression, decision trees, support vector machines, neural networks, random forest or another machine learning algorithm.

[0044] The present disclosed subject matter also relates to a composition comprising cortisone, hydrocortisone, dexamethasone, fludrocortisone, prednisolone, ganaxolone, tetracosactide, ACTH, or combinations thereof and also to composition includes these substances in a therapeutically effective amount along with a pharmaceutically acceptable carrier, adjuvant, excipient, or mixtures thereof for use in the treatment, prevention or ameliorating epileptic seizure syndrome; in particular seizures experienced of Dravet Syndrome; or predict and / or prevent Sudden Unexpected Death in Epilepsy .

[0045] In an embodiment for better results, the epilepsy syndrome is Dravet Syndrome, preferably a Dravet Syndrome associated with a mutation in one, some or all of the genes selected from the group consisting of SCN1A, SCN1B, SCN2A, SCN3A, SCN9A, GABRG2, GABRD and PCDH19.

[0046] In an embodiment for better results, the composition is in a solid form or liquid form.

[0047] In an embodiment for better results, the composition is administrable orally, nasally, transdermally, rectally, vaginally, by inhalation or by intravenous injection or intramuscular injection.

[0048] In an embodiment for better results, the composition may further comprise a sodium salt, preferably sodium chloride. Such a combination improves the results by further reducing the risk of SUDEP and diminishing the frequency and severity of seizures in Dravet Syndrome. The inclusion of sodium chloride enhances the therapeutic efficacy of the composition, providing additional benefits in managing these severe epilepsy-related conditions.

[0049] In an embodiment for better results, the composition may further comprise a pharmaceutically acceptable salt thereof; and a nonaqueous liquid carrier, wherein the nonaqueous carrier comprises propylene glycol, glycerin, polyethylene glycol (PEG), alcohol, or a combination thereof; wherein the liquid pharmaceutical composition is an oral solution, and wherein the liquid pharmaceutical composition contains less than 5% weight by weight (% wt) of water.

[0050] In some embodiments, hydrocortisone or a pharmaceutically acceptable salt thereof may be present in the liquid pharmaceutical composition in an amount of about 1 mg / mL.

[0051] In an embodiment for better results, the compound / composition of the present disclosure may be administered as a daily dosage to the patient is at least 0.5 mg per day; preferably at least 1 mg per day; more preferably at least 20 mg per day, even more preferably from 20 to 240 mg per day.

[0052] In an embodiment for better results, the dosage can be formulated for once-a-day administration, or for multiple daily administrations (e.g. 2, 3 or 4 times a day administration).

[0053] In an embodiment for better results, the compound / composition of the present disclosure may be formulated in any pharmaceutically acceptable dosage form including oral dosage forms such as tablets including orally disintegrating tablets, capsules, lozenges, oral solutions or syrups, oral emulsions, oral gels, oral films, buccal liquids, powder e.g. for suspension, and the like; injectable dosage forms; transdermal dosage forms such as transdermal patches, ointments, creams; inhaled dosage forms; and / or nasally, rectally, vaginallyadministered dosage forms. Liquid dosage forms, such as solutions, emulsions and syrups, e.g. for oral administration.

[0054] In an embodiment for better results, the compound / composition of the present disclosure may be prepared by combining the compound / composition of the present disclosure with one or more pharmaceutically acceptable diluents, carriers, adjuvants, and the like in a manner known to those skilled in the art of pharmaceutical formulation.

[0055] In an embodiment for better results, the compound / composition of the present disclosure may be employed as a monotherapy, i.e. it is employed as the sole therapeutic agent in those treatments.

[0056] Alternatively, the compound / composition of the present disclosure may be coadministered simultaneously, sequentially, or separately with one or more co-therapeutic agents, such as anticonvulsants. Preferred co-therapeutic agents can be selected from the group consisting of carbamazepine, ethosuximide, fosphenytoin, lamotrigine, levetiracetam, phenobarbitol, progabide, topiramate, stiripentol, valproic acid, valproate, verapamil, and benzodiazepines such as clobazam, clonazepam, diazepam, ethyl loflazepate, lorazepam, midazolam. Use of a pharmaceutically acceptable salt of a co-therapeutic agent is also disclosed.

[0057] In an embodiment for better results, the daily form consists of a tablet, suppository, ampoule, or other device, comprising a definitive amount of the composition disclosed in the present disclosure, the whole of which is intended to be administered as a single dose.

[0058] The compounds and compositions of the present disclosure can be used in high doses during the acute phase to prevent SUDEP, or in lower doses as a prophylactic measure to treat epilepsy syndrome.BRI EF DESCRIPTION OF TH E DRAWINGS

[0059] The following figures provide preferred embodiments for illustrating the disclosure and should not be seen as limiting the scope of invention.

[0060] Figure 1: Cortisol variation during seizures: A: GTCS; B: Complex Partial Seizures; C: Minor seizures (Adapted from Takeshita, Kawahara, Nagabuchi34).

[0061] Figure 2: Change in free corticosterone concentration (nanograms per milliliter) overtime in the interstitial fluid using dual-probe microdialysis in the same freely behaving Scnla+ / - mouse, beginning with the baseline, following by seizure induction, and ending after seizure. (A -first seizure; B- last seizure followed by SUDEP). Free corticosterone levels show a clear increase after the non-life-threatening epileptic seizure (Figure 2A) and a reduction after SUDEP (Figure 2B). Free corticosterone basal levels are higher before the first seizure in comparison with the values before the terminal seizure (5 / 5).

[0062] Figure 3: Change in free corticosterone concentration (nanograms per milliliter) overtime in the interstitial fluid using dual-probe microdialysis in the same freely behaving Scnla+ / - mouse, beginning with the baseline, following by fluorethyl induction, and ending after seizure. (A - first seizure; B- last seizure followed by SUDEP). Free corticosterone levels show a clear increase after the non-life-threatening epileptic seizure (Figure 3A) and a reduction after SUDEP (Figure 3B). Free corticosterone basal levels are higher before the first seizure in comparison with the values before the terminal seizure (7 / 7).

[0063] Figure 4: Change in free corticosterone concentration (nanograms per milliliter) overtime in the interstitial fluid using dual-probe microdialysis in the same freely behaving Scnla+ / - mouse, beginning with the baseline, following by fluorethyl induction, and ending after seizure. (A - first seizure; B- last seizure followed by SUDEP). Free corticosterone levels show a clear increase after the non-life-threatening epileptic seizure (Figure 4A) and a reduction after SUDEP (Figure 4B). Free corticosterone basal levels are higher before the first seizure in comparison with the values before the terminal seizure (5 / 5).

[0064] Figure 5: Change in free corticosterone concentration (nanograms per milliliter) overtime in the interstitial fluid using dual-probe microdialysis in the same freely behaving Scnla+ / - mouse, beginning with the baseline, following by fluorethyl induction, and ending after seizure. (A - first seizure; B- last seizure followed by SUDEP). Free corticosterone levels show a clear increase after the non-life-threatening epileptic seizure (Figure 5A) and a reduction after SUDEP (Figure 5B). Free corticosterone basal levels are higher before the first seizure in comparison with the values before the terminal seizure (9 / 9).DETAILED DESCRIPTION

[0065] The present disclosure relates to medical diagnostics and therapeutics, specifically methods and compositions for predicting and preventing Sudden Unexpected Death in Epilepsy (SUDEP) and / or; treating, preventing and / or ameliorating symptoms associated with epileptic seizure syndromes; particularly Dravet Syndrome. It involves the use of biomarkers, selected from cortisol, corticosterone, cortisone, aldosterone, adrenocorticotropic hormone (ACTH), or combinations thereof, to assess SUDEP risk. Additionally, it describes compositions containing cortisone, hydrocortisone, dexamethasone, fludrocortisone, prednisolone, ACTH, ganaxolone, tetracosactide, or combinations thereof, in a therapeutically effective amount with a pharmaceutically acceptable carrier, adjuvant, or excipient for SUDEP prevention. The disclosure also includes the use of these compositions for treating, preventing, and / or ameliorating seizures in epilepsy patients, particularly those with Dravet Syndrome and / or preventing / predicting SUDEP.

[0066] It involves the use of biomarkers, selected from cortisol, corticosterone, cortisone, aldosterone, adrenocorticotropic hormone (ACTH), or combinations thereof, to assess SUDEP risk. Additionally, it describes compositions containing cortisone, hydrocortisone, dexamethasone, fludrocortisone, prednisolone, ACTH, ganaxolone, tetracosactide, or combinations thereof, in a therapeutically effective amount with a pharmaceutically acceptable carrier, adjuvant, or excipient for SUDEP prevention. The disclosure also includes the use of these compositions for treating, preventing, and / or ameliorating seizures in epilepsy patients, particularly in patients with Dravet Syndrome and / or; prediction and / or prevention of SUDEP.

[0067] The present disclosure relates to the use of a biomarker for determining the risk of developing SUDEP wherein said biomarker is selected from a list consisting of cortisol, corticosterone, cortisone, aldosterone, ACTH, or mixture thereof; preferably cortisol; as well as to a method of determining whether a patient is at risk of developing SUDEP.

[0068] In an embodiment, the content of cortisol, corticosterone, cortisone, aldosterone, ACTH, or mixture thereof; is determined in a biological sample collected from a subject to be tested. Furthermore, the present disclosure relates to a method of determining whether a patient died from or is at risk of SUDEP.Example 1 describes a situation wherein cortisol is used as a biomarker for determining whether a patient died from or is at risk of developing SUDEP:

[0069] Example 1 - Level of cortisol collected from the patient during an epileptic seizure is below a threshold value indicative of a lower limit of the historical data of the level of cortisol in the same patient during epileptic seizures.

[0070] Scenario 1 - Immediately before an epileptic seizure, a baseline for cortisol levels is established. The seizure dysregulates the brainstem serotoninergic neurons afferents to the paraventricular nucleus of the hypothalamus (PVN). Immediately after the onset of the epileptic seizure (post-ictal phase), the brainstem serotoninergic neurons afferents to the paraventricular nucleus of the hypothalamus (PVN) are compromised and therefore not activated. In the PVN, parvocellular neurons fail to release the corticotropin-releasing hormone (CRH) to the portal vein, not promoting the release of adrenocorticotropic hormone (ACTH) from the pituitary to blood stream failing to activate the release of cortisol from the adrenal cortex from baseline. This prevents arousal and the re-establishment of the cardiopulmonary function leading to sudden death.

[0071] Scenario 2 - Immediately before an epileptic seizure, a baseline for cortisol levels is established. Brainstem serotoninergic neurons afferents to the paraventricular nucleus of the hypothalamus (PVN) are compromised due to physical damage or lesions in the neural pathways connecting brainstem serotoninergic neurons to the PVN due to recurrent epileptic seizures. Immediately after the onset of the epileptic seizure (post-ictal phase), the brainstem serotoninergic neurons afferents to the paraventricular nucleus of the hypothalamus (PVN) are not activated. In the PVN, parvocellular neurons fail to release the corticotropin-releasing hormone (CRH) to the portal vein, not promoting the release of adrenocorticotropic hormone (ACTH) from the pituitary to blood stream failing to activate the release of cortisol from the adrenal cortex from baseline. This prevents arousal and the re-establishment of the cardiopulmonary function leading to sudden death.

[0072] Scenario 3 - Due to the recurrent seizures, cortisol is chronically elevated. Immediately before an epileptic seizure, a baseline for cortisol levels is established. Immediately after the onset of the epileptic seizure (post-ictal phase), the brainstem serotoninergic neurons afferents to the paraventricular nucleus of the hypothalamus (PVN) are activated. In the PVN, parvocellular neurons release the corticotropin-releasing hormone (CRH) to the portal vein, promoting the release of adrenocorticotropic hormone (ACTH) from the pituitary to blood stream. As the adrenal function is already saturated no further release of cortisol from the adrenal cortex above10% from baseline is possible. This prevents arousal and the re-establishment of the cardiopulmonary function leading to sudden death.

[0073] Scenario 4 - Immediately before an epileptic seizure, a baseline for cortisol levels is established. Immediately afterthe onset of the epileptic seizure (post-ictal phase), the brainstem serotoninergic neurons afferents to the paraventricular nucleus of the hypothalamus (PVN) are activated. In the PVN, parvocellular neurons release the corticotropin-releasing hormone (CRH) to the portal vein, promoting the release of adrenocorticotropic hormone (ACTH) from the pituitary to blood stream. Due to an adrenal dysfunction due to (adrenal insufficiency, adrenal hyperfunction, adrenal tumors, infection and inflammation, medications or treatments that affect adrenal glands), no further release of cortisol from the adrenal cortex above 10% from baseline is possible. This prevents arousal and the re-establishment of the cardiopulmonary function leading to sudden death.

[0074] In an embodiment, near-to-baseline cortisol levels are found in SUDEP victims during all epileptic seizure stages, being translated in a flat cortisol curve. This impairment blunts the optimal sharp cortisol burst needed to achieve the threshold for the postictal arousal (Figure 1). This CAESAR impairment is a reflex of the incapacity to raise postictal cortisol levels in SUDEP victims. Cortisol Acute Epileptic Seizure Adaptive Response (CAESAR) b) is a consistent fast-sharp cortisol rise found specifically in the postictal phase of epileptic seizures20-21-22-23-24-25. Impaired CAESAR, translated in a postictal blunted cortisol rise, is observed only in life-threatening seizures, since this cortisol burst is absent in both near SUDEP and impaired arousal (upstream event of SUDEP). The main novelty of CAESAR concept of the present disclosure is therefore the ability to differentiate for the first time ever life-threatening seizures.

[0075] As shown in Figures 2-5 corticosterone levels increase after a seizure, as illustrated in CAESAR, and this response is blunted after SUDEP. Thus, increasing the level of corticosterone / cortisol during a seizure improves the CAESAR thus improving post-ictal arousal and consecutively preventing SUDEP.

[0086] It was also demonstrated that corticosterone baseline values are higher before the first seizure and decrease before a life-threatening seizure. Thus, increasing the baseline level of corticosterone / cortisol improves the CAESAR thus improving post-ictal arousal and consecutively preventing SUDEP.Study for seizure-synchronous ISF collection in SUDEP animal modelAll the experiments were performed with a Senia mutant mouse model (leading to a decrease level of Navl.l voltage-dependent sodium channel), or control littermate. This model is a relevant model of a developmental and epileptic encephalopathy in which patients are at high risk of SUDEP. A setup enabling interstitial fluid (ISF) collection on freely moving mice using the microdialysis technique (CMA probes and equipment, Kista, Sweden) was developed. The procedure enables collecting ISF with a minimum of stress to the animal. The samples were kept at -80°C and then corticosterone, murine equivalent of cortisol, was quantified using LC / MS-MS (Liquid chromatography / Mass spectrometry) with adequate sensitivity and specificity. It was induced acute seizure (using the inhalation of the convulsant fluorethyl in homemade recording boxes) during microdialysis collection, repeating the procedure once a day for 2 weeks. Surprisingly it was not observed acute variations of corticosterone during each seizure but rather a progressive diminution of baseline corticosterone levels seizure after seizure in mutant mice. This progressive loss of corticosterone leads to an increase susceptibility to SUDEP. To study this susceptibility, we implanted osmotic pumps that deliver corticosterone continuously to keep it in a normal physiological range or delivered an inhibitor of the HPA (Hypothalamic-pituitary- adrenal) axis to lower down corticosterone level. It was observed that a diminution of SUDEP in the first group and an increase in the second. These results showed the importance of cortisol / corticosterone as a biomarker and the interest of a device able to measure and i nfuse cortisol / corticosterone to avoid a low level.

[0076] The term "comprising" whenever used in this document is intended to indicate the presence of stated features, integers, steps, components, but not to preclude the presence or addition of one or more other features, integers, steps, components or groups thereof.

[0077] The disclosure should not be seen in any way restricted to the embodiments described and a person with ordinary skill in the art will foresee many possibilities to modifications thereof. The above-described embodiments are combinable.

[0078] Where ranges are provided, the range limits are included. Furthermore, it should be understood that unless otherwise indicated or otherwise evident from the context and / or understanding of a technical expert, the values which are expressed as ranges may assume any specific value within the ranges indicated in different achievements of the invention, at one tenth of the lower limit of the interval, unless the context clearly indicates the contrary. It should alsobe understood that, unless otherwise indicated or otherwise evident from the context and / or understanding of a technical expert, values expressed as range may assume any sub-range within the given range, where the limits of the sub-range are expressed with the same degree of precision as the tenth of the unit of the lower limit of the range.

[0079] In an embodiment, the epilepsy syndrome may be the Dravet Syndrome, preferably a Dravet Syndrome associated with a mutation in one, some or all of the genes selected from the group consisting of SCN1A, SCN1B, SCN2A, SCN3A, SCN9A, GABRG2, GABRD and PCDH19. In the following table the mutation are defined

[0080] The following dependent claims further set out particular embodiments of the disclosure.

[0081] The following references should be considered herewith incorporated in their entirety:1. Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Eiger CE, et al. ILAE official report: a practical clinical definition of epilepsy Epilepsia. 2014 Apr;55:475-482.2. Ono T, Galanopoulou AS. Epilepsy and epileptic syndrome Adv Exp Med Biol. 2012;724:99-113.3. Nashef L. Sudden unexpected death in epilepsy: terminology and definitions Epilepsia. 1997 Nov;38:S6-8.4. Richerson GB, Buchanan GF. The serotonin axis: Shared mechanisms in seizures, depression, and SUDEP Epilepsia. 2011 Jan;52 Suppl 1:28-38.5. Dlouhy BJ, Gehlbach BK, Richerson GB. Sudden unexpected death in epilepsy: basic mechanisms and clinical implications for prevention J Neurol Neurosurg Psychiatry. 2016 Apr;87:402-413.6. Massey CA, Sowers LP, Dlouhy BJ, Richerson GB. Mechanisms of sudden unexpected death in epilepsy: the pathway to prevention Nat Rev Neurol. 2014 May;10:271-282.7. Kearney J. Sudden unexpected death in dravet syndrome Epilepsy Curr. 2013 Nov;13:264-265.8. Hirsch U, Donner EJ, So EL, Jacobs M, Nashef L, NoebelsJL, et al. Abbreviated report of the NIH / NINDS workshop on sudden unexpected death in epilepsy Neurology. 2011 May 31;76:1932-1938.9. Smithson WH, Colwell B, Hanna J. Sudden unexpected death in epilepsy: addressing the challenges Curr Neurol Neurosci Rep. 2014 Dec;14:502.10. Odom N, Bateman LM. Sudden unexpected death in epilepsy, periictal physiology, and the SUDEP-7 Inventory Epilepsia. 2018 Oct;59:el57-el60.11. Ryvlin P, Rheims S, Lhatoo SD. Risks and predictive biomarkers of sudden unexpected death in epilepsy patient Curr Opin Neurol. 2019 Apr;32:205-212.12. Smith SM, Vale WW. The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress Dialogues Clin Neurosci. 2006;8:383-395.13. Raff H. CORT, Cort, B, Corticosterone, and now Cortistatin: Enough Already! Endocrinology. 2016 Sep;157:3307-3308.14. Nandam LS, Brazel M, Zhou M, Jhaveri DJ. Cortisol and Major Depressive Disorder-Translating Findings From Humans to Animal Models and Back Frontiers in psychiatry. 2019;10:974.15. van Campen JS, Jansen FE, de Graan PN, Braun KP, Joels M. Early life stress in epilepsy: a seizure precipitant and risk factor for epileptogenesis Epilepsy Behav. 2014 Sep;38:160-171.16. Lanfumey L, Mongeau R, Cohen-Salmon C, Hamon M. Corticosteroid-serotonin interactions in the neurobiological mechanisms of stress-related disorders Neurosci Biobehav Rev. 2008 Aug;32:1174-1184.17. Elder GJ, Wetherell MA, Barclay NL, Ellis JG. The cortisol awakening response-applications and implications for sleep medicine Sleep Med Rev. 2014 Jun;18:215-224.18. Gitto L, Stoppacher R, Serinelli S. Death Due to Adrenal Crisis: Case Report and a Review of the Forensic Literature Am J Forensic Med Pathol. 2021 Dec l;42:392-396.19. Palmiere C. Sudden death due to acute adrenal crisis Forensic Sci Med Pathol. 2015 Dec;ll:629.20. Govi A, Fersini F, Tsokos M. Sudden death due to acute adrenal crisis Forensic Sci Med Pathol. 2015 Sep;ll:445-447.21. Erichsen MM, Lpvas K, Fougner KJ, Svartberg J, Hauge ER, Bollerslev J, et al. Normal overall mortality rate in Addison's disease, but young patients are at risk of premature death Eur J Endocrinol. 2009 Feb;160:233-237.22. Gassner HL, Toppari J, Quinteiro Gonzalez S, Miller WL. Near-miss apparent SIDS from adrenal crisis J Pediatr. 2004 Aug;145:178-183.23. Tavakoli N, Bidari A, Shams Vahdati S. Serum Cortisol Levels as a Predictor of Neurologic Survival inSuccessfully Resuscitated Victims of Cardiopulmonary Arrest Journal of cardiovascular and thoracic research. 2012;4:107-111.24. van Campen JS, Valentijn FA, Jansen FE, Joels M, Braun KP. Seizure occurrence and the circadian rhythm of cortisol: a systematic review Epilepsy Behav. 2015 Jun;47:132-137.25. Maguire J, Salpekar JA. Stress, seizures, and hypothalamic-pituitary-adrenal axis targets for the treatment of epilepsy Epilepsy Behav. 2013 Mar;26:352-362.26. van Campen JS, Hompe EL, Jansen FE, Velis DN, Otte WM, van de Berg F, et al. Cortisol fluctuations relate to interictal epileptiform discharges in stress sensitive epilepsy Brain. 2016 Jun;139:1673-1679.27. Yuen AW, Thompson PJ, Flugel D, Bell GS, Sander JW. Mortality and morbidity rates are increased in people with epilepsy: is stress part of the equation? Epilepsy Behav. 2007 Feb;10:l-7.28. Galimberti CA, Magri F, Copello F, Arbasino C, Cravello L, Casu M, et al. Seizure frequency and cortisol and dehydroepiandrosterone sulfate (DHEAS) levels in women with epilepsy receiving antiepileptic drug treatment Epilepsia. 2005 Apr;46:517-523.29. Abbott RJ, Browning MC, Davidson DL. Serum prolactin and cortisol concentrations after grand mal seizures J Neurol Neurosurg Psychiatry. 1980 Feb;43:163-167.30. Aminoff MJ, Simon RP, Wiedemann E. The hormonal responses to generalized tonic-clonic seizures Brain. 1984 Jun;107 ( Pt 2):569-578.31. Rao ML, Stefan H, Bauer J. Epileptic but not psychogenic seizures are accompanied by simultaneous elevation of serum pituitary hormones and cortisol levels Neuroendocrinology. 1989 Jan;49:33-39.32. Zhang SW, Liu YX. Changes of serum adrenocorticotropic hormone and cortisol levels during sleep seizures Neurosci Bull. 2008 Apr;24:84-88.33. Pritchard PB, 3rd, Wannamaker BB, Sagel J, Daniel CM. Serum prolactin and cortisol levels in evaluation of pseudoepileptic seizures Ann Neurol. 1985 Jul;18:87-89.34. Takeshita H, Kawahara R, Nagabuchi T, Mizukawa R, Hazama H. Serum prolactin, cortisol and growth hormone concentrations after various epileptic seizures Jpn J Psychiatry Neurol. 1986 Dec;40:617-623.35. Becker LL, Kaindl AM. Corticosteroids in childhood epilepsies: A systematic review Front Neurol. 2023;14:1142253.36. Clow A, Hucklebridge F, Stalder T, Evans P, Thorn L. The cortisol awakening response: more than a measure of HPA axis function Neurosci Biobehav Rev. 2010 Sep;35:97-103.

Claims

C L A I M S1. Biomarker for use in the diagnostic of the risk of developing Sudden Unexpected Death in Epilepsy (SUDEP) in a sample, wherein said biomarker is selected from a list consisting of: cortisol, cortisone, corticosterone, aldosterone, adrenocorticotropic hormone (ACTH), or mixtures thereof.

2. Biomarker for use according to the previous claim 1, wherein said biomarker is cortisol; cortisol and corticosterone; cortisol and cortisone, cortisol and aldosterone; cortisol and adrenocorticotropic hormone; corticosterone and cortisone, corticosterone and aldosterone; corticosterone adrenocorticotropic hormone; aldosterone and cortisone, aldosterone and adrenocorticotropic hormone; adrenocorticotropic hormone and cortisone, preferably cortisol.

3. Biomarkerfor use according to any of the previous claims, wherein the sample is a biological sample collected from a patient.

4. Biomarkerfor use according to any of the previous claims, wherein the content of biomarker is determined in a (ex vivo) biological sample collected from a patient to be tested.

5. Biomarkerfor use as a biomarker according to any of the previous claims, wherein if the level of biomarker in the biological sample collected from the patient during an epileptic seizure is below to a threshold value indicative of a lower limit of the historical data of the level of biomarker in the same patient during epileptic seizures, then the patient is at risk of developing Sudden Unexpected Death in Epilepsy .

6. Biomarker for use as a biomarker according to any of the previous claims 1-3, wherein if the basal level of biomarker in the patient is below a threshold value indicative of a lower limit of the basal level of at least one of said biomarker of a healthy individual then the patient is at risk of developing Sudden Unexpected Death in Epilepsy .

7. Biomarker for use according to any of the previous claims wherein the biological sample is interstitial fluid , saliva, blood, plasma, urine or serum; preferably interstitial fluid .

8. Method for determining whether a patient with epilepsy has, or is at risk of developing Sudden Unexpected Death in Epilepsy, comprising the steps of: providing a test sample from said patient; assaying the basal level or amount at least one of the following biomarkers selected from a list consisting of: cortisol, corticosterone, cortisone, aldosterone, adrenocorticotropic hormone, or mixtures thereof; comparing the level or amount determined in the previous step to a reference value reflecting the basal level or amount of biomarker in a healthy person, wherein a higher level or amount relative to the reference value is indicative for risk of developing Sudden Unexpected Death in Epilepsy.

9. Method of determining whether a patient with epilepsy has, or is at risk of developing Sudden Unexpected Death in Epilepsy, comprising the steps of: measuring a content of a biomarker in a (ex vivo) biological sample collected from the patient during an epileptic seizure, wherein said biomarker is selected from a list consisting of: cortisol, corticosterone, cortisone, aldosterone, adrenocorticotropic hormone, or mixtures thereof; comparing the level of the biomarker in the biological sample with a threshold value indicative of a lower limit from the historical data of the level of the biomarker in the same patient during epileptic seizures; wherein if the level of at least on of the said biomarkers in the biological sample is below the threshold value then the patient is diagnosed with having Sudden Unexpected Death in Epilepsy.

10. Method for determining whether a patient with epilepsy has, or is at risk of developing Sudden Unexpected Death in Epilepsy, comprising the steps of: providing a test sample from said subject, wherein said test sample is collected during an epileptic seizure;assaying the level or amount of at least one of said biomarkers, wherein said biomarker is selected from a list consisting of: cortisol, corticosterone, cortisone, aldosterone, adrenocorticotropic hormone , or mixtures thereof; comparing the level or amount determined in the previous step to a reference value reflecting the historical data of the level or amount of at least one of said biomarkers in the same subject during an epileptic seizure, wherein a decrease in the level or amount relative to the reference value is indicative for risk of developing Sudden Unexpected Death in Epilepsy.

11. Method according to any of the previous claims 8-10 wherein the biological sample is interstitial fluid, saliva, blood, plasma, urine or serum; preferably interstitial fluid.

12. Method according to any of the previous claims 8-11 wherein concentration value of at least one of said biomarkers is inputted into a statistical methodology to produce an output value that indicates whether the patient has or is at risk of developing Sudden Unexpected Death in Epilepsy.

13. Cortisone, hydrocortisone, dexamethasone, fludrocortisone, prednisolone, ganaxolone, tetracosactide, adrenocorticotropic hormone or combinations thereof for use in the treatment, prevention or ameliorating epileptic seizure syndrome; in particular Dravet Syndrome; or for use in the prevention of Sudden Unexpected Death in Epilepsy.

14. The compounds for use according to the previous claim wherein the epilepsy syndrome is juvenile myoclonic epilepsy, Lennox-Gastaut Syndrome, Dravet Syndrome, preferably Dravet Syndrome.

15. The compounds for use according to any of the previous claims 13-14 wherein the epilepsy syndrome is Dravet Syndrome, preferably a Dravet Syndrome associated with a mutation in one, some or all of the genes selected from the group consisting of SCN1A, SCN1B, SCN2A, SCN3A, SCN9A, GABRG2, GABRD and PCDH19.

16. Pharmaceutical composition comprising cortisone, hydrocortisone, dexamethasone, fludrocortisone, prednisolone, ganaxolone, tetracosactide, adrenocorticotropic hormone orcombinations thereof in a therapeutically effective amount and a pharmaceutical acceptable carrier, adjuvant, excipient, or mixtures thereof for use in the treatment, prevention or ameliorating epileptic seizure syndrome; in particular Dravet Syndrome; or for use in the prevention of Sudden Unexpected Death in Epilepsy.

17. Composition for use according to the previous claim wherein the epilepsy syndrome is juvenile myoclonic epilepsy, Lennox-Gastaut Syndrome, Dravet Syndrome, preferably Dravet Syndrome.

18. Composition for use according to any of the previous claims 16-17 wherein the epilepsy syndrome is Dravet Syndrome, preferably a Dravet Syndrome associated with a mutation in one, some or all of the genes selected from the group consisting of SCN1A, SCN1B, SCN2A, SCN3A, SCN9A, GABRG2, GABRD and PCDH19.

19. Composition for use according to any of the previous claims 16-18 wherein the composition is in a solid form or liquid form.

20. Composition for use according to any of the previous claims 16-19 wherein the composition is administrable orally, nasally, rectally, vaginally, transdermally, by inhalation by intravenous injection or intramuscular injection, administered dosage forms.

21. Composition for use according to any of the previous claims 16-20 wherein the composition wherein the daily dose of the composition active substance is at least 0.5 mg per day, preferably at least 1 mg per day.

22. Composition for use according to any of the previous claims 16-21 wherein the composition wherein the daily dose of the composition active substance is at least 20 mg, preferably ranges from 20 to 240 mg / kg.

23. Composition according for use to any of the previous claims 16-22 further comprising a sodium salt, preferably sodium chloride.

24. Composition according for use to any of the previous claims 16-23 further comprising a co- therapeutic agent, in particular an anticonvulsant.

25. The use of a composition comprising cortisone, hydrocortisone, dexamethasone, fludrocortisone, prednisolone, ganaxolone, tetracosactide, adrenocorticotropic hormone or combinations thereof for the manufacture of a medicament for the treatment or prevention of an epilepsy syndrome.

26. A method for treating or preventing an epilepsy syndrome in a subject, the method comprising administering a composition comprising cortisone, hydrocortisone, dexamethasone, fludrocortisone, prednisolone, ganaxolone, tetracosactide, adrenocorticotropic hormone or combinations thereof to the subject.

Images