Biomarkers and methods for detection of seizures and epilepsy

Abstract

Epileptic seizures are difficult to diagnose and are often difficult to distinguish from several conditions with similar presentations, and therefore, diagnosis of seizures is often a long, expensive, and unreliable process. This invention provides biomarkers for identifying seizures and epilepsy, assays for measuring and assessing biomarker concentration, predictive models based on biomarkers and computational systems for detecting, assessing and diagnosing phasic and tonic changes associated with seizures and epilepsy in all clinical and healthcare settings. Diagnostic and treatment methods, systems, kits, and predictive models provided herein, provide quantitative and/or qualitative assessment in order to allow patients to proceed immediately to diagnostic and/or treatment protocols, and assess therapeutic treatment effectiveness.

1 .- 59 . (canceled) 
     
     
         60 . A non-transitory computer readable storage medium for determining a likelihood that a human subject afflicted with one or more seizures will be responsive to a treatment regimen that comprises administering to the subject an epilepsy therapeutic agent, the non-transitory computer readable storage medium storing one or more programs for execution by one or more processors of a computer system, the one or more computer programs comprising instructions for:
 obtaining a concentration of interleukin-16 (IL-16) in a blood sample obtained from the subject by contacting the blood sample with one or more antibodies targeting IL-16;   comparing the concentration of IL-16 in the blood sample to a concentration of IL-16 in a control;   determining that the concentration of IL-16 in the blood sample is elevated relative to the concentration of IL-16 in the control; and   providing instructions for treating the subject for epilepsy to the subject or to a practitioner charged with caring for the subject.   
     
     
         61 . The non-transitory computer readable storage medium of  claim 60 , wherein the elevated concentration of IL-16 in the blood sample compared to the concentration of IL-16 in the control indicates a positive likelihood that the human subject afflicted with the one or more seizures will be responsive to the treatment regimen. 
     
     
         62 .- 71 . (canceled) 
     
     
         72 . The non-transitory computer readable storage medium of  claim 60 , wherein the treatment regimen comprises administering to the subject one or more therapeutic agents selected from the group consisting of phenytoin, fosphenytoin, midazolam, pregabalin, acetazolamide, methsuximide, ethotoin, piracetam, nitrazepam, paraldehyde, stiripentol, vigabatrin, brivaracetam, peramepanel, rufinamide, lurasidone HCl, carbamazepine, clobazam, clonazepam, diazepam, divalproex, eslicarbazepine acetate, ethosuxemide, ezogabine, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, lorazepam, oxcarbazepine, phenobarbital, primidone, tiagabine, topiramate, valproic acid, zonisamide, cannabis-based drugs, and pharmaceutically acceptable salts, prodrugs, and derivatives thereof. 
     
     
         73 .- 74 . (canceled) 
     
     
         75 . The non-transitory computer readable storage medium of  claim 60 , further comprising instructions for:
 obtaining a concentration of intercellular adhesion molecule (ICAM)-1 in the blood sample obtained from the subject by contacting the blood sample with one or more antibodies targeting ICAM-1;   comparing the concentration of ICAM-1 in the blood sample to a concentration of ICAM-1 in a control; and   determining that the concentration of ICAM-1 in the blood sample is elevated relative to the concentration of ICAM-1 in the control.   
     
     
         76 . The non-transitory computer readable storage medium of  claim 75 , wherein the elevated concentration of ICAM-1 in the blood sample compared to the concentration of ICAM-1 in the control indicates a positive likelihood that the human subject afflicted with the one or more seizures will be responsive to the treatment regimen. 
     
     
         77 . The non-transitory computer readable storage medium of  claim 75 , wherein the treatment regimen comprises administering to the subject one or more therapeutic agents selected from the group consisting of phenytoin, fosphenytoin, midazolam, pregabalin, acetazolamide, methsuximide, ethotoin, piracetam, nitrazepam, paraldehyde, stiripentol, vigabatrin, brivaracetam, peramepanel, rufinamide, lurasidone HCl, carbamazepine, clobazam, clonazepam, diazepam, divalproex, eslicarbazepine acetate, ethosuxemide, ezogabine, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, lorazepam, oxcarbazepine, phenobarbital, primidone, tiagabine, topiramate, valproic acid, zonisamide, cannabis-based drugs, and pharmaceutically acceptable salts, prodrugs, and derivatives thereof. 
     
     
         78 . The non-transitory computer readable storage medium of  claim 60 , further comprising instructions for:
 obtaining a concentration of thymus and activation-regulated chemokine (TARC) in the blood sample obtained from the subject by contacting the blood sample with one or more antibodies targeting TARC;   comparing the concentration of TARC in the blood sample to a concentration of TARC in a control; and   determining that the concentration of TARC in the blood sample is elevated relative to the concentration of TARC in the control.   
     
     
         79 . The non-transitory computer readable storage medium of  claim 78 , wherein the elevated concentration of TARC in the blood sample compared to the concentration of TARC in the control indicates a positive likelihood that the human subject afflicted with the one or more seizures will be responsive to the treatment regimen. 
     
     
         80 . The non-transitory computer readable storage medium of  claim 78 , wherein the treatment regimen comprises administering to the subject one or more therapeutic agents selected from the group consisting of phenytoin, fosphenytoin, midazolam, pregabalin, acetazolamide, methsuximide, ethotoin, piracetam, nitrazepam, paraldehyde, stiripentol, vigabatrin, brivaracetam, peramepanel, rufinamide, lurasidone HCl, carbamazepine, clobazam, clonazepam, diazepam, divalproex, eslicarbazepine acetate, ethosuxemide, ezogabine, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, lorazepam, oxcarbazepine, phenobarbital, primidone, tiagabine, topiramate, valproic acid, zonisamide, cannabis-based drugs, and pharmaceutically acceptable salts, prodrugs, and derivatives thereof. 
     
     
         81 . The non-transitory computer readable storage medium of  claim 60 , further comprising instructions for:
 obtaining a concentration of tumor necrosis factor (TNF)-α in the blood sample obtained from the subject by contacting the blood sample with one or more antibodies targeting TNF-α;   comparing the concentration of TNF-α in the blood sample to a concentration of TNF-α in a control; and   determining that the concentration of TNF-α in the blood sample is elevated relative to the concentration of TNF-α in the control.   
     
     
         82 . The non-transitory computer readable storage medium of  claim 81 , wherein the elevated concentration of TNF-α in the blood sample compared to the concentration of TNF-α in the control indicates a positive likelihood that the human subject afflicted with the one or more seizures will be responsive to the treatment regimen. 
     
     
         83 . The non-transitory computer readable storage medium of  claim 81 , wherein the treatment regimen comprises administering to the subject one or more therapeutic agents selected from the group consisting of phenytoin, fosphenytoin, midazolam, pregabalin, acetazolamide, methsuximide, ethotoin, piracetam, nitrazepam, paraldehyde, stiripentol, vigabatrin, brivaracetam, peramepanel, rufinamide, lurasidone HCl, carbamazepine, clobazam, clonazepam, diazepam, divalproex, eslicarbazepine acetate, ethosuxemide, ezogabine, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, lorazepam, oxcarbazepine, phenobarbital, primidone, tiagabine, topiramate, valproic acid, zonisamide, cannabis-based drugs, and pharmaceutically acceptable salts, prodrugs, and derivatives thereof. 
     
     
         84 . The non-transitory computer readable storage medium of  claim 60 , further comprising instructions for:
 obtaining a concentration of intercellular adhesion molecule (ICAM)-1 in the blood sample obtained from the subject by contacting the blood sample with one or more antibodies targeting ICAM-1;   obtaining a concentration of thymus and activation-regulated chemokine (TARC) in the blood sample obtained from the subject by contacting the blood sample with one or more antibodies targeting TARC;   comparing the concentration of ICAM-1 in the blood sample to a concentration of ICAM-1 in a control;   comparing the concentration of TARC in the blood sample to a concentration of TARC in a control;   determining that the concentration of ICAM-1 in the blood sample is elevated relative to the concentration of ICAM-1 in the control; and   determining that the concentration of TARC in the blood sample is elevated relative to the concentration of TARC in the control.   
     
     
         85 . The non-transitory computer readable storage medium of  claim 84 , wherein the treatment regimen comprises administering to the subject one or more therapeutic agents selected from the group consisting of phenytoin, fosphenytoin, midazolam, pregabalin, acetazolamide, methsuximide, ethotoin, piracetam, nitrazepam, paraldehyde, stiripentol, vigabatrin, brivaracetam, peramepanel, rufinamide, lurasidone HCl, carbamazepine, clobazam, clonazepam, diazepam, divalproex, eslicarbazepine acetate, ethosuxemide, ezogabine, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, lorazepam, oxcarbazepine, phenobarbital, primidone, tiagabine, topiramate, valproic acid, zonisamide, cannabis-based drugs, and pharmaceutically acceptable salts, prodrugs, and derivatives thereof. 
     
     
         86 . The non-transitory computer readable storage medium of  claim 60 , further comprising instructions for:
 obtaining a concentration of intercellular adhesion molecule (ICAM)-1 in the blood sample obtained from the subject by contacting the blood sample with one or more antibodies targeting ICAM-1;   obtaining a concentration of tumor necrosis factor (TNF)-α in the blood sample obtained from the subject by contacting the blood sample with one or more antibodies targeting TNF-α;   comparing the concentration of ICAM-1 in the blood sample to a concentration of ICAM-1 in a control;   comparing the concentration of TNF-α in the blood sample to a concentration of TNF-α in a control;   determining that the concentration of ICAM-1 in the blood sample is elevated relative to the concentration of ICAM-1 in the control; and   determining that the concentration of TNF-α in the blood sample is elevated relative to the concentration of TNF-α in the control.   
     
     
         87 . The non-transitory computer readable storage medium of  claim 86 , wherein the treatment regimen comprises administering to the subject one or more therapeutic agents selected from the group consisting of phenytoin, fosphenytoin, midazolam, pregabalin, acetazolamide, methsuximide, ethotoin, piracetam, nitrazepam, paraldehyde, stiripentol, vigabatrin, brivaracetam, peramepanel, rufinamide, lurasidone HCl, carbamazepine, clobazam, clonazepam, diazepam, divalproex, eslicarbazepine acetate, ethosuxemide, ezogabine, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, lorazepam, oxcarbazepine, phenobarbital, primidone, tiagabine, topiramate, valproic acid, zonisamide, cannabis-based drugs, and pharmaceutically acceptable salts, prodrugs, and derivatives thereof. 
     
     
         88 . The non-transitory computer readable storage medium of  claim 60 , further comprising instructions for:
 obtaining a concentration of thymus and activation-regulated chemokine (TARC) in the blood sample obtained from the subject by contacting the blood sample with one or more antibodies targeting TARC;   obtaining a concentration of tumor necrosis factor (TNF)-α in the blood sample obtained from the subject by contacting the blood sample with one or more antibodies targeting TNF-α;   comparing the concentration of TARC in the blood sample to a concentration of TARC in a control;   comparing the concentration of TNF-α in the blood sample to a concentration of TNF-α in a control;   determining that the concentration of TARC in the blood sample is elevated relative to the concentration of TARC in the control; and   determining that the concentration of TNF-α in the blood sample is elevated relative to the concentration of TNF-α in the control.   
     
     
         89 . The non-transitory computer readable storage medium of  claim 88 , wherein the treatment regimen comprises administering to the subject one or more therapeutic agents selected from the group consisting of phenytoin, fosphenytoin, midazolam, pregabalin, acetazolamide, methsuximide, ethotoin, piracetam, nitrazepam, paraldehyde, stiripentol, vigabatrin, brivaracetam, peramepanel, rufinamide, lurasidone HCl, carbamazepine, clobazam, clonazepam, diazepam, divalproex, eslicarbazepine acetate, ethosuxemide, ezogabine, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, lorazepam, oxcarbazepine, phenobarbital, primidone, tiagabine, topiramate, valproic acid, zonisamide, cannabis-based drugs, and pharmaceutically acceptable salts, prodrugs, and derivatives thereof. 
     
     
         90 . The non-transitory computer readable storage medium of  claim 60 , further comprising instructions for:
 obtaining a concentration of intercellular adhesion molecule (ICAM)-1 in the blood sample obtained from the subject by contacting the blood sample with one or more antibodies targeting ICAM-1;   obtaining a concentration of thymus and activation-regulated chemokine (TARC) in the blood sample obtained from the subject by contacting the blood sample with one or more antibodies targeting TARC;   obtaining a concentration of tumor necrosis factor (TNF)-α in the blood sample obtained from the subject by contacting the blood sample with one or more antibodies targeting TNF-α;   comparing the concentration of ICAM-1 in the blood sample to a concentration of ICAM-1 in a control;   comparing the concentration of TARC in the blood sample to a concentration of TARC in a control;   comparing the concentration of TNF-α in the blood sample to a concentration of TNF-α in a control;   determining that the concentration of ICAM-1 in the blood sample is elevated relative to the concentration of ICAM-1 in the control;   determining that the concentration of TARC in the blood sample is elevated relative to the concentration of TARC in the control; and   determining that the concentration of TNF-α in the blood sample is elevated relative to the concentration of TNF-α in the control.   
     
     
         91 . The non-transitory computer readable storage medium of  claim 90 , wherein the treatment regimen comprises administering to the subject one or more therapeutic agents selected from the group consisting of phenytoin, fosphenytoin, midazolam, pregabalin, acetazolamide, methsuximide, ethotoin, piracetam, nitrazepam, paraldehyde, stiripentol, vigabatrin, brivaracetam, peramepanel, rufinamide, lurasidone HCl, carbamazepine, clobazam, clonazepam, diazepam, divalproex, eslicarbazepine acetate, ethosuxemide, ezogabine, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, lorazepam, oxcarbazepine, phenobarbital, primidone, tiagabine, topiramate, valproic acid, zonisamide, cannabis-based drugs, and pharmaceutically acceptable salts, prodrugs, and derivatives thereof.