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 computer systems for detecting, assessing and diagnosing phasic and tonic changes associated with seizures and epilepsy in all clinical and healthcare settings. Diagnostic methods, 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.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional Application No. 62 / 274,551, filed Jan. 4, 2016, and U.S. Provisional Application No. 62 / 274,578, filed Jan. 4, 2016, the entireties of which are incorporated herein by reference.GOVERNMENT SUPPORT[0002]This invention was made with Government support under Grant No. 1R43NS079029-01A1, awarded by the National Institutes of Health. The Government may have certain rights in the invention.FIELD OF THE INVENTION[0003]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. Predictive Models (EvoScore™) give clinicians the ability to quickly triage patients by ruling out epilepsy. Predictive Models will allow patients to proceed immediately to diagnostic protocols that are most likely to result in effective treatment, saving ...

AI Technical Summary

Benefits of technology

The invention is a blood-based diagnostic test called EvoScore that can identify measurable changes in proteins in patients who have seizures. This test can predict if a patient has had a seizure or not, and can also track changes in protein levels over time as patients are treated. EvoScore can be used in clinical and healthcare settings.

Problems solved by technology

Seizures and epilepsy are very common neurological disorders that are associated with significant morbidity, health care cost, and even mortality.

Epilepsy is a common neurological affliction affecting over 2.3 million patients in the US and 65 million patients worldwide, with significant financial burden.

The financial burden of epilepsy care is substantial with a major expense contributed by tests required for appropriate diagnosis.

A major limitation in providing care for patients with seizures is the lack of a diagnostic blood test to identify clinical events as seizures as opposed to other disorder such as transient ischemic attacks, fainting, sleep disorders, and psychogenic events.

Epilepsy, defined by spontaneous and recurrent seizures, is a highly prevalent public health problem.

One-third of people with epilepsy live with uncontrolled seizures because no available treatment works for them.

While much research has been devoted to developing new anti-epileptic drugs (AEDs), the “gold standard” diagnostic protocol—which often hinges on EEGs—has remained constant and inadequate.

When patients present with a suspected seizure, the process to diagnose whether the event was caused by epilepsy or another disorder is most often long and expensive.

In addition to the high cost associated with a long engagement with the health system, the current state of epilepsy diagnosis presents another critical issue: in the absence of a good triage tool for early diagnosis, patients who experience suspected seizures because of other underlying conditions may be either over- or under-treated erroneously with AEDs, during which time their underlying conditions actually remain untreated while they experience undesirable medication side-effects.

Thus, timely diagnosis of the patient's condition (whether epilepsy or not) remains a significant unmet medical need.

Accurately diagnosing epilepsy is very challenging and time consuming because clinicians rarely observe the actual seizure, plus there are many different types of seizures and epilepsy syndromes with differing presentations.

Furthermore, other neurological disorders can be mimics for seizures leading to erroneous diagnosis, inappropriate treatments with significant potential adverse events, incorrect prognosis, and significant waste of health care resources.

Currently, obtaining a definitive diagnosis of seizures or epilepsy is expensive and inconvenient for patients as it may require inpatient evaluation and a battery of costly tests.

The challenge with EEG is that it is typically performed as a post hoc assay, that is, after the clinical event is finished, and may in fact be normal.

This requires a costly inpatient hospital stay, and there is no way to know for certain that a clinical event will occur during the stay.

Obviously, this provides a significant logistical challenge to caregivers in the outpatient and emergency department (ED) settings since most patients come to the ED after the event has ended and only historical information is gathered; definitive diagnosis of a single seizure is essentially impossible and empiric at best.

Often the patients or caregivers cannot give the level of detail needed for accurate diagnosis.

Measurement of prolactin levels is unreliable.

The diagnostic process can take several months before clinical events are pinpointed as epileptic seizures, and often clinical care is largely empiric, based on supporting but not definitive evidence—often resulting in either under- or over-diagnosis and treatment.

Thus, timely and accurate seizure diagnosis remains an unmet medical need.

Not only is the diagnostic process long, there is a significant burden on the healthcare system with annual figures for epilepsy diagnostic methodologies totaling greater than $15 billion in the US alone.

Accurately diagnosing epilepsy is very challenging and time consuming because clinicians rarely observe seizures and there are many different types of seizures and epilepsy syndromes with differing presentations.

A major challenge in the diagnosis of epilepsy using the gold standard EEG is the fact that EEG has a low sensitivity for epilepsy, ranging between 25-56%.

Especially when considering the side-effect-laden and in some cases teratogenic consequences of AEDs, this unnecessary medication cost is huge and when combined with the long diagnostic process, there is a significant burden on the health care system with annual figures for epilepsy diagnostic methodologies totaling greater than $15 billion in the US alone.

Accordingly, the short window of viability (minutes after), coupled with inadequate diagnostic sensitivity, specificity, and accuracy, preclude prolactin from being a practical seizure biomarker, and is rarely, if ever used today in clinical settings.

However, little is known about changes in plasma TARC expression as a consequence of seizures.

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