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Methods of diagnosing and treating migraine

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Methods of diagnosing and treating migraine


The present invention provides methods of diagnosing migraine attacks and determining predisposition of an individual to the development of migraine based on sodium level in the cerebrospinal fluid (CSF) and/or brain extracellular fluid. The invention also provides methods of treating migraine, wherein the individual is selected for treatment based in the individual's sodium level in the CSF and/or brain extracellular fluid. The CSF sodium level may be based on the sodium concentration in the saliva.
Related Terms: Cerebrospinal Fluid Migraine

Inventors: Michael G. Harrington, Alfred N. Fonteh
USPTO Applicaton #: #20120270816 - Class: 514 26 (USPTO) - 10/25/12 - Class 514 
Drug, Bio-affecting And Body Treating Compositions > Designated Organic Active Ingredient Containing (doai) >O-glycoside >Cyclopentanohydrophenanthrene Ring System

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The Patent Description & Claims data below is from USPTO Patent Application 20120270816, Methods of diagnosing and treating migraine.

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CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the priority benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 60/794,965, filed Apr. 25, 2006, the content of which is herein incorporated by reference In its entirety.

TECHNICAL FIELD

This application pertains to methods of diagnosing and treating migraine. Specifically, the application pertains to methods of diagnosing and treating migraine based on sodium levels in the cerebrospinal fluid, the brain extracellular fluid, and/or the saliva.

BACKGROUND

Migraine is a chronic, episodic, and debilitating primary headache syndrome that affects about 15 to 20% of the world population. Arunagiri et al., Curr. Opin. Ophthalmol 14:344-352 (2003). Migraine has two main types. One type, migraine without aura (previously known as common migraine), affects about 15% of the population. In migraine without aura, the headache is unilateral, pulsating, and moderate to severe in intensity, and may last a few hours to 3 days. The headache may also be associated with nausea, vomiting, photophobia, phonophobia, and other symptoms. The second type, migraine with aura (previously known as classic migraine), affects about 8% of the population. In migraine with aura, one or more auras, such as visual, somatosensory, and motor symptoms, develop prior to the development of a migraine attack. Migraine without aura and migraine with aura co-occur in 13% of migraineurs.

The two prevailing views of migraine pathophysiology are the neuronal and trigeminovascular theories. In the neuronal hypothesis, cortical spreading depression (CSD), a slowing of electroencephalographic activity that propagates across the cortex at 3-5 mm/min, has been recorded during migraine aura. The trigeminovascular hypothesis asserts that an altered modulation of the perivascular nerves of the intracranial vessels sensitizes the nociceptive perivascular fibers\' projection to the trigeminal caudate nucleus, which propagates the headache. The current model of migraine is an integration of these two theories linking the intrinsic brain activity of CSD with trigeminal meningeal afferents. In addition, Moskowitz and colleagues present logic to explain the loss/gain of functions found in two different familial hemiplegic migraine genes with the migraine phenotype. However, the basis for hypersensitivity features of migraine,—pain, photophobia, phonophobia, osmophobia, nausea, vomiting, and confusion—remains unexplained.

Calcium channel, sodium transporter, and sodium channel gene mutations have been found in familial hemiplegic migraine. For example, mutations in the slow calcium channel gene (CACNA1A), the Na+, K+-ATPase transporter gene (ATP1A2), or the voltage-gated sodium channel gene (SCN1A) underlie cases of the rare familial hemiplegic migraine. Pharmaceuticals with calcium or sodium channel blocking activities have also been shown to be useful in migraine prophylaxis. Although these studies suggest that ion transport may be implicated in migraine pathogenesis, a link between sodium homeostasis and migraine has never been established.

Campbell and colleagues reported in 1951 that blood sodium levels in migraine are increased, and were accompanied by a decrease in protein that they attributed to overhydration. Campbell et al., Br. Med. J. 1951, 4745:1424-1429. The reference used a gavimetric method based on pyroantimonate, which has now been abandoned as being indirect. The reference also did not address variations of sodium levels from circadian rhythm fluctuation, a phenomenon that had not been identified at the time of the study. Meanwhile, Jowett reported that sodium and potassium levels were within normal ranges when measured by flame photometry in cerebrospinal fluids from 20 patients during migraine attack. Jowett, Brain, 1967, 90(4):785-94. That study did not compare the levels of well with sick migraineurs, and its controls were ill-defined. Brainard reported salt loading as a trigger of migraine. Brainard J. B., Minn. Med. 1976, 59(4):232-233. He correlated this phenomenon with increased plasma angiotensin and aldosterone levels rather than sodium levels. None of these references provide a correlation between sodium level in the brain extracellular fluid/cerebrospinal fluid and migraine.

Use of sodium pump inhibitors to treat various diseases has been disclosed in U.S. Pat. No. 5,872,103, U.S. Pat. Pub. No. 2003/0229029, and WO05/102371.

The disclosures of all publications, patents, patent applications and published patent applications referred to herein are hereby incorporated herein by reference in their entirety.

BRIEF

SUMMARY

OF THE INVENTION

The present invention provides methods of diagnosing migraine in an individual or determining predisposition of an individual to the development of migraine, wherein the diagnosis or determination is based on the CSF or brain extracellular fluid sodium level of the individual. In some embodiments, the method is for diagnosing migraine attack in an individual exhibiting one or more symptoms of migraine. In some embodiments, the method is for determining predisposition of an individual to the development of migraine.

In one aspect, the invention provides methods of diagnosing and treating migraine attack. In some embodiments, the invention provides a method of diagnosing migraine attack in an individual exhibiting one or more symptoms of migraine (such as headache), comprising comparing the cerebrospinal fluid (CSF) sodium level in the individual with the CSF sodium level in the same individual at a symptom free stage, wherein an increase in CSF sodium level above the level at a symptom free stage is indicative of a migraine attack. In some embodiments, the invention provides a method of diagnosing migraine attack in an individual exhibiting one or more symptoms of migraine (such as headache), comprising: a) determining the CSF sodium level in the individual, and b) comparing the CSF sodium level in the individual with the CSF sodium level in the same individual at a symptom free stage, wherein an increase in CSF sodium level above the level at a symptom free stage is indicative of a migraine attack. In some embodiments, the invention provides a method of diagnosing migraine attack in an individual exhibiting one or more symptoms of migraine (such as headache), comprising: a) comparing the CSF sodium level in the individual with the CSF sodium level in the same individual at a symptom free stage, and b) determining whether the individual has a migraine attack based on an increase in CSF sodium level above the level at a symptom free stage. In some embodiments, there is provided a method of providing information for diagnosis of a migraine attack in an individual exhibiting one or more symptoms of migraine (such as headache), comprising: a) determining the CSF sodium level in the individual, and b) providing information about the CSF sodium level of the individual, wherein an increase in CSF sodium level above the level at a symptom free stage is indicative of a migraine attack.

In some embodiments, the CSF sodium level is based on the sodium concentration in the CSF of the individual. In some embodiments, an increase in sodium concentration in the CSF by at least about any of 1 mmol/L, 2 mmol/L, 3 mmol/L, 4 mmol/L, 5 mmol/L, 6 mmol/L, 7 mmol/L, 8 mmol/L, 9 mmol/L, 10 mmol/L, or more is indicative of a migraine attack. In some embodiments, an increase in sodium concentration by at least about any of 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, or more is indicative of a migraine attack. In some embodiments, the increase in CSF sodium level is based on the increase in molar ratio of sodium to another analyte (such as potassium ion) in the CSF of the individual.

In some embodiments, the CSF sodium level is based on the sodium concentration in saliva of the individual. For example, in some embodiments, the invention provides a method of diagnosing migraine attack in an individual exhibiting one or more symptoms of migraine (such as headache), comprising comparing the saliva sodium concentration in said individual with the saliva sodium concentration in the same individual at a symptom free stage, wherein an increase in saliva sodium concentration above the level at the symptom free stage is indicative of a migraine attack. In some embodiments, an increase in sodium concentration in saliva by at least about any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, or 30 mmol/L is indicative of a migraine attack. In some embodiments, an increase in saliva sodium concentration by at least about any of 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, or more is indicative of a migraine attack. In some embodiments, the increase in CSF sodium level is based on the increase in molar ratio of sodium to another analyte (such as potassium ion) in the saliva of the individual.

In some embodiments, the CSF sodium level is intracranial CSF sodium level. For example, in some embodiments, the invention provides a method of diagnosing migraine attack in an individual exhibiting one or more symptoms of migraine (such as headache), comprising comparing the intracranial CSF sodium level in the individual with the intracranial CSF sodium level in the same individual at a symptom free stage, wherein an increase in intracranial CSF sodium level above the level at a symptom free stage is indicative of a migraine attack. In some embodiments, the intracranial CSF sodium level is based on intracranial sodium concentration determined by brain magnetic resonance spectrometry.

In some embodiments, there is provided a method of diagnosing migraine attack in an individual exhibiting one or more symptoms of migraine (such as headache) comprising comparing the brain extracellular fluid sodium level in said individual with the brain extracellular fluid sodium level in the same individual at a symptom free stage, wherein an increase in brain extracellular fluid sodium level above the level at a symptom free stage is indicative of a migraine attack. In some embodiments, the invention provides a method of diagnosing migraine attack in an individual exhibiting one or more symptoms of migraine (such as headache), comprising: a) determining the brain extracellular fluid sodium level in the individual, and b) comparing the brain extracellular fluid sodium level in the individual with the brain extracellular fluid sodium level in the same individual at a symptom free stage, wherein an increase in brain extracellular fluid sodium level above the level at a symptom free stage is indicative of a migraine attack. In some embodiments, the invention provides a method of diagnosing migraine attack in an individual exhibiting one or more symptoms of migraine (such as headache), comprising: a) comparing the brain extracellular fluid sodium level in the individual with the brain extracellular fluid sodium level in the same individual at a symptom free stage, and b) determining whether the individual has a migraine attack based on an increase in brain extracellular fluid sodium level above the level at a symptom free stage. In some embodiments, there is provided a method of providing information for diagnosis of a migraine attack in an individual exhibiting one or more symptoms of migraine (such as headache), comprising: a) determining the brain extracellular fluid sodium level in the individual, and b) providing information about the brain extracellular fluid sodium level of the individual, wherein an increase in brain extracellular fluid sodium level above the level at a symptom free stage is indicative of a migraine attack.

In some embodiments, the brain extracellular fluid sodium level is based on regional brain tissue sodium concentration. For example, in some embodiments, the invention provides a method of diagnosing migraine attack in an individual exhibiting one or more symptoms of migraine (such as headache), comprising comparing the regional brain tissue sodium concentration in the individual with the regional brain tissue sodium concentration in the same individual at a symptom free stage, wherein an increase in regional brain tissue sodium concentration above the level at a symptom free stage is indicative of a migraine attack. In some embodiments, the regional brain tissue sodium concentration is determined by brain magnetic resonance spectrometry.

The diagnosis methods described herein provide basis for treatment of migraine. Accordingly, in some embodiments, there is provided a method of treating or continuing to treat migraine attack in an individual exhibiting one or more symptoms of migraine (such as headache), comprising administering to the individual an effective amount of a migraine rescue drug (such as a sodium pump inhibitor), wherein determination of migraine attack is based on the comparison between the CSF sodium level (or brain extracellular fluid sodium level) in the individual with the CSF sodium level (or brain extracellular fluid sodium level) in the same individual at a symptom free stage, wherein an increase in CSF sodium level (or brain extracellular fluid level) above the level at a symptom free stage is indicative of a migraine attack. In some embodiments, the invention provides a method of treating or continuing to treat migraine attack in an individual exhibiting one or more symptoms of migraine (such as headache), comprising: a) comparing the CSF sodium level (or brain extracellular fluid level) in the individual with the CSF sodium level (or brain extracellular fluid level) in the individual with the CSF sodium level (or brain extracellular fluid level) in the same individual at a symptom free stage, wherein an increase in the CSF sodium level (or brain extracellular fluid level) above the level at a symptom free stage is indicative of a migraine attack, and b) administering to the individual an effective amount of a migraine rescue drug (such as a sodium pump inhibitor).

In some embodiments, the migraine rescue drug increases the flow of sodium into cells in the brain. In some embodiments, the migraine rescue drug decreases movement of intracellular sodium to the outside of the cell. In some embodiments, the migraine rescue drug is a sodium pump inhibitor. In some embodiments, the sodium pump inhibitor is steroid glycoside. In some embodiments, the steroid glycoside is any of (and in some embodiments selected from the group consisting of) ouabain, dihydroouabain, digoxin, proscillaridin, digitoxin, lanatoside, acetyldigitoxin, digitoxigenin, and digoxigenin. In some embodiments, the steroid glycoside is ouabain. In some embodiments, the steroid glycoside is digoxin. In some embodiments, a single dose of the migraine rescue drug (such as sodium pump inhibitor) is administered.

In another aspect, there is provided a method of determining predisposition of an individual to the development of migraine by monitoring the sodium level in an individual who has been exposed to a challenging condition (such as administration of a challenging agent). For example, in some embodiments, there is provided a method of determining predisposition of an individual to the development of migraine, comprising: a) subjecting the individual to a challenging condition sufficient to trigger migraine at a symptom free stage; b) monitoring the CSF sodium level in said individual for a certain period of time, wherein a characteristic change in the CSF sodium level in the individual is indicative that the individual is predisposed to the development of migraine. In some embodiments, there is provided a method of determining predisposition of an individual to the development of migraine, comprising: a) administering a sufficient amount of a challenging agent to the individual at a symptom free stage; b) monitoring the CSF sodium level in said individual for a certain period of time, wherein a characteristic change in the CSF sodium level in the individual is indicative that the individual is predisposed to the development of migraine. In some embodiments, the method further comprises the step of determining a baseline CSF sodium level in the individual prior to, during, or immediately after subjecting the individual to a challenging condition (such as administering a challenging agent to the individual).

In some embodiments, there is provided a method of determining predisposition of an individual to the development of migraine, comprising monitoring the CSF sodium level in said individual for a certain period of time, wherein said individual has been subject to a challenging condition sufficient to trigger migraine at a symptom free stage, and wherein a characteristic change in the CSF sodium level in the individual is indicative that the individual is predisposed to the development of migraine. In some embodiments, there is provided a method of determining predisposition of an individual to the development of migraine, comprising monitoring the CSF sodium level in said individual for a certain period of time, wherein the individual has been administered with a sufficient amount of a challenging agent at a symptom free stage, and wherein a characteristic change in the CSF sodium level in the individual is indicative that the individual is predisposed to the development of migraine.

In some embodiments, the CSF sodium level is based on the sodium concentration in the CSF of the individual. In some embodiments, the change (such as increase) of CSF sodium level is based on the change (such as increase) of the molar ratio of sodium to another analyte (such as potassium ion) in the CSF of the individual.

In some embodiments, the CSF sodium level is based on the sodium concentration in the saliva of the individual. In some embodiments, the change (such as increase) of CSF sodium level is based on the change (such as increase) of the molar ratio of sodium to another analyte (such as potassium ion) in the saliva of the individual. For example, in some embodiments, there is provided a method of determining predisposition of an individual to the development of migraine, comprising: a) subjecting the individual to a challenging condition sufficient to trigger migraine at a symptom free stage; b) monitoring the saliva sodium concentration in said individual for a certain period of time, wherein a characteristic change in the saliva sodium concentration in the individual is indicative that the individual is predisposed to the development of migraine. In some embodiments, there is provided a method of determining predisposition of an individual to the development of migraine, comprising: a) administering a sufficient amount of a challenging agent to the individual at a symptom free stage; b) monitoring the saliva sodium concentration in said individual for a certain period of time, wherein a characteristic change in the saliva sodium concentration in the individual is indicative that the individual is predisposed to the development of migraine.

In some embodiments, the CSF sodium level is intracranial sodium level, for example the intracranial sodium level determined by brain magnetic resonance spectrometry. For example, in some embodiments, there is provided a method of determining predisposition of an individual to the development of migraine, comprising: a) subjecting the individual to a challenging condition sufficient to trigger migraine at a symptom free stage; b) monitoring the intracranial CSF sodium level in said individual for a certain period of time, wherein a characteristic change in the intracranial CSF sodium level in the individual is indicative that the individual is predisposed to the development of migraine. In some embodiments, there is provided a method of determining predisposition of an individual to the development of migraine, comprising: a) administering a sufficient amount of a challenging agent to the individual at a symptom free stage; b) monitoring the intracranial CSF sodium level in said individual for a certain period of time, wherein a characteristic change in the intracranial CSF sodium level in the individual is indicative that the individual is predisposed to the development of migraine.

In some embodiments, there is provided a method for determining predisposition of an individual to the development of migraine, comprising: a) subjecting the individual to a challenging condition sufficient to trigger migraine at a symptom free stage; b) monitoring the brain extracellular fluid sodium level in said individual for a certain period of time, wherein a characteristic change in the brain extracellular fluid sodium level in the individual is indicative that the individual is predisposed to the development of migraine. In some embodiments, there is provided a method for determining predisposition of an individual to the development of migraine, comprising: a) administering a sufficient amount of a challenging agent to the individual at a symptom free stage; b) monitoring the brain extracellular fluid sodium level in said individual for a certain period of time, wherein a characteristic change in the brain extracellular fluid sodium level in the individual is indicative that the individual is predisposed to the development of migraine.

In some embodiments, there is provided a method of determining predisposition of an individual to the development of migraine, comprising monitoring the brain extracellular fluid sodium level in said individual for a certain period of time, wherein said individual has been subject to a challenging condition sufficient to trigger migraine at a symptom free stage, and wherein a characteristic change in the brain extracellular fluid sodium level in the individual is indicative that the individual is predisposed to the development of migraine. In some embodiments, there is provided a method of determining predisposition of an individual to the development of migraine, comprising monitoring the brain extracellular fluid sodium level in said individual for a certain period of time, wherein the individual has been administered with a sufficient amount of a challenging agent at a symptom free stage, and wherein a characteristic change in the brain extracellular fluid sodium level in the individual is indicative that the individual is predisposed to the development of migraine.

In some embodiments, the brain extracellular fluid sodium level is based on regional brain tissue sodium concentration for example the regional brain tissue sodium concentration as determined by brain magnetic resonance spectrometry. For example, in some embodiments, there is provided a method of determining predisposition of an individual to the development of migraine, comprising: a) subjecting the individual to a challenging condition sufficient to trigger migraine at a symptom free stage; b) monitoring the regional brain tissue sodium concentration in said individual for a certain period of time, wherein a characteristic change in the regional brain tissue sodium concentration in the individual is indicative that the individual is predisposed to the development of migraine. In some embodiments, there is provided a method of determining predisposition of an individual to the development of migraine, comprising: a) administering a sufficient amount of a challenging agent to the individual, at a symptom free stage; b) monitoring the regional brain tissue sodium concentration in said individual for a certain period of time, wherein a characteristic change in the regional brain tissue sodium concentration in the individual is indicative that the individual is predisposed to the development of migraine.

In some embodiments, an increase in the CSF sodium level (or brain extracellular fluid sodium level) above a baseline level after a certain time period is indicative that the individual is predisposed to the development of migraine. In some embodiments, an initial drop of the CSF sodium level (or brain extracellular fluid level) below a baseline level followed by a subsequent increase in the CSF sodium level (or brain extracellular fluid level) above the baseline level is indicative that the individual is predisposed to the development of migraine.

In another aspect, there is provided a method of determining predisposition of an individual to the development of migraine, comprising determining the CSF sodium level in said individual, wherein an increase in CSF sodium level above a threshold level is indicative that the individual is predisposed to the development of migraine. In some embodiments, there is provided a method of determining predisposition of an individual to the development of migraine, comprising: a) determining the CSF sodium level in said individual, and b) comparing the CSF sodium level of the individual with a threshold level, wherein an increase in CSF sodium level above a threshold level is indicative that the individual is predisposed to the development of migraine. In some embodiments, there is provided a method of determining predisposition of an individual to the development of migraine, comprising: a) comparing the CSF sodium level of the individual with a threshold level, and b) determining whether the individual is predisposed to the development of migraine based on an increase in CSF sodium level above the threshold level. In some embodiments, there is provided a method of providing information for determining predisposition of an individual to the development of migraine, comprising: a) determining the CSF sodium level in said individual, and b) providing information about CSF sodium level of the individual, wherein an increase in CSF sodium level above a threshold level is indicative that the individual is predisposed to the development of migraine.

In some embodiments, the CSF sodium level is based on the sodium concentration in the CSF of the individual. In some embodiments, the increase in CSF sodium level is based on the increase in molar ratio of sodium to another analyte (such as potassium ion) in the CSF of the individual.

In some embodiments, the CSF sodium level is based on the sodium concentration in saliva of the individual. For example, in some embodiments, there is provided a method of determining predisposition of an individual to the development of migraine, comprising determining saliva sodium concentration in said individual, wherein a saliva sodium concentration above a threshold concentration is indicative that the individual is predisposed to the development of migraine. In some embodiments, the increase in CSF sodium level is based on the increase in molar ratio of sodium to another analyte (such as potassium ion) in the saliva of the individual.

In some embodiments, the CSF sodium level is intracranial CSF sodium concentration. For example, in some embodiments, there is provided a method of determining predisposition of an individual to the development of migraine, comprising determining intracranial CSF sodium concentration in said individual, wherein an intracranial CSF sodium concentration above a threshold concentration is indicative that the individual is predisposed to the development of migraine. In some embodiments, the CSF sodium concentration is determined by brain magnetic spectrometry.

In some embodiments, there is provided a method of determining predisposition of an individual to the development of migraine, comprising determining brain extracellular fluid sodium level in said individual, wherein a brain extracellular fluid sodium level above a threshold level is indicative that the individual is predisposed to the development of migraine. In some embodiments, there is provided a method of determining predisposition of an individual to the development of migraine, comprising: a) determining the brain extracellular fluid sodium level in said individual, and b) comparing the brain extracellular fluid sodium level of the individual with a threshold level, wherein an increase in the brain extracellular fluid sodium level above a threshold level is indicative that the individual is predisposed to the development of migraine. In some embodiments, there is provided a method of determining predisposition of an individual to the development of migraine, comprising: a) comparing the brain extracellular fluid sodium level of the individual with a threshold level, and b) determining whether the individual is predisposed to the development of migraine based on an increase in the brain extracellular fluid sodium level above the threshold level. In some embodiments, there is provided a method of providing information for determining predisposition of an individual to the development of migraine, comprising: a) determining the brain extracellular fluid sodium level in said individual, and b) providing information about the brain extracellular fluid sodium level of the individual, wherein an increase in the brain extracellular fluid sodium level above a threshold level is indicative that the individual is predisposed to the development of migraine.

In some embodiments, the brain extracellular fluid sodium level is based on regional brain tissue sodium concentration as determined by brain magnetic resonance spectrometry. For example, in some embodiments, there is provided a method of determining predisposition of an individual to the development of migraine, comprising determining regional brain tissue sodium concentration in said individual, wherein a regional brain tissue sodium concentration above a threshold concentration is indicative that the individual is predisposed to the development of migraine.

Also provided herein are kits and devices for carrying out one or more methods described herein. Also provided herein are uses of CSF sodium level or brain extracellular extract fluid sodium level for diagnosis of a migraine attack or determination of predisposition of an individual to the development of migraine. It is to be understood that one, some, or all of the properties of the various embodiments described herein may be combined to form other embodiments of the present invention.

DETAILED DESCRIPTION

OF THE INVENTION

The present invention is based on an observation that the CSF sodium levels were increased in migraineurs in sick (MH+) state as compared to well (MH−) state. The increase in sodium level was independent from other clinical or pharmacological fluctuations, CSF concentrations of calcium, magnesium, and potassium, as well as blood plasma sodium levels in the individual. We also observed that the saliva sodium concentration increased in a migraineur in sick (MH+) state as compared to well (MH−) state. This correlates well with changes in CSF sodium concentration. In addition, we observed that the CSF sodium levels of migraineurs are statistically higher than those of nonmigraineurs.

We believe that all migraineurs have a common biochemistry distinct from non-migraineurs. This common biochemistry decompensates after different types of migraine triggers (including stress, dietary changes, hormonal changes), and has the following attributes: a) broad distribution and dissemination throughout the brain; b) capacity for immediate response that can be sustained for hours; c) influence by many different triggers; and d) association with many apparently disparate biochemical changes that have been implicated in migraine.

The observed increase in CSF sodium levels in migraineurs in sick state suggests that disturbance of sodium homeostasis is one of the common biochemical mechanisms underlying migraine attacks. CSF sodium equilibrates rapidly with sodium in the brain extracellular fluid, especially in mobile subjects. Thus we can confidently assume that the observed change in CSF sodium level reflects a similar change in sodium level in brain extracellular fluid. Sodium ion and sodium regulatory mechanisms are present throughout the brain, subject to tight physiologic regulation, and influenced by many different factors. Any deviation in Na+ is expected to have a wide and considerable impact on brain functions. For example, an increased extracellular sodium will slightly reduce the threshold for repetitive neuronal firing by increasing Na conductance, increase pH-induced nociceptor discharge, and alter coincidence detection in medial superior olivary neurons. These effects would contribute to a substantial neural disturbance that is consistent with the main clinical features of migraine: pain, photophobia, phonophobia, osmophobia, nausea, vomiting, and confusion.

Without wishing to be bound by the theory, it is hypothesized that sodium pumps in the brain are responsible for the increase in the CSF or brain extracellular fluid sodium level, and that all migraineurs have a sodium pump axis that is more sensitive to that of nonmigraineurs. It is further hypothesized that, during migraine, an initial sodium pump competitive inhibition, for example by an endogenous or exogenous substance, results in a low extracelluar sodium level. This low sodium level may lead to symptoms of aura in some individuals. In response to the low extracellular fluid sodium level (and thus an excess of intracellular sodium), more sodium pumps are made, for example by increased transcription, translation, and/or localization. The increase in sodium pump production overcompensates and leads to an increased brain extracellular fluid sodium level and neuronal hyperpolarization that manifests as the migraine attack. The high sodium level is reflected in the CSF, which is in direct communication with the brain extracellular fluid.

The biochemical hypothesis described herein, called “sodium pump hypothesis,” fits into: 1) the time course of aura and the sodium biochemistry of CSD; 2) the time course of migraine attack and our observation in CSF sodium levels; and 3) the fact that all known actions of drugs for treatment of migraine directly or close to directly act on sodium pump. This sodium pump hypothesis forms the basis of some aspects/embodiments of the present invention.

Accordingly, the present invention provides methods of diagnosing migraine in an individual or determining predisposition of an individual to the development of migraine, wherein the diagnosis or determination is based on the CSF or brain extracellular fluid sodium level of the individual. In some embodiments, the method is for diagnosing migraine attack in an individual exhibiting one or more symptoms of migraine. In some embodiments, the method is for determining predisposition of an individual to the development of migraine.

In one aspect, there is provided a method of diagnosing migraine attack in an individual exhibiting one or more symptoms of migraine (such as headache), comprising comparing the CSF sodium level (or brain extracellular fluid sodium level) in said individual with the CSF sodium level (or brain extracellular fluid sodium level) in the same individual at a symptom free stage, wherein an increase in CSF sodium level (or brain extracellular fluid sodium level) above the level at a symptom free stage is indicative of a migraine attack. In some embodiments, the CSF sodium level is based on sodium concentration in the saliva of the individual.

Also provided is a method of treating or continuing to treat migraine attack in an individual exhibiting one or more symptoms of migraine (such as headache), comprising administering to the individual an effective amount of a migraine rescue drug (such as sodium pump inhibitor), wherein determination of migraine attack is based on the comparison between the CSF sodium level (or brain extracellular fluid sodium level) in the individual with the CSF sodium level (or brain extracellular fluid sodium level) in the same individual at a symptom free stage, wherein an increase in CSF sodium level (or brain extracellular fluid sodium level) above the level at a symptom free stage is indicative of a migraine attack. In some embodiments, the CSF sodium level is based on sodium concentration in the saliva of the individual.

In another aspect, there is provided a method of determining predisposition of an individual to the development of migraine, comprising: a) subjecting the individual to a challenging condition sufficient to trigger migraine at a symptom free stage; b) monitoring the CSF sodium level (or brain extracellular fluid sodium level) in said individual for a certain period of time, wherein a characteristic change in the CSF sodium level (or brain extracellular fluid sodium level) in the individual is indicative that the individual is predisposed to the development of migraine. In some embodiments, the CSF sodium level is based on sodium concentration in the saliva of the individual.

In another aspect, there is provided a method of determining predisposition of an individual to the development of migraine, comprising determining CSF sodium level (or brain extracellular fluid sodium level) in said individual, wherein an increase in CSF sodium level (or brain extracellular fluid sodium level) above a threshold level is indicative that the individual is predisposed to the development of migraine. In some embodiments, the CSF sodium level is based on sodium concentration in the saliva of the individual.

It is understood that aspects and embodiments of the invention described herein include “consisting” and/or “consisting essentially of” aspects and embodiments.

Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X.”

As used herein and in the appended claims, the singular forms “a,” “or,” and “the” include plural referents unless the context clearly indicates otherwise.

Methods of Diagnosis and Treating Migraine Attack Diagnosis of Migraine Attack

The invention in one aspect provides a method of diagnosing migraine attack in an individual. Following the establishment of a baseline CSF sodium level in an individual at a symptom free stage, variation of CSF sodium level in conjunction with one or more symptoms of migraine can serve as an indication of a migraine attack. The diagnosis methods described herein provide sufficient warning for the individual to take suitable steps to minimize the effect or at least moderate the severity of a migraine attack, for example, by administering a migraine rescue drug, such as sodium pump inhibitors described below.



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stats Patent Info
Application #
US 20120270816 A1
Publish Date
10/25/2012
Document #
13413571
File Date
03/06/2012
USPTO Class
514 26
Other USPTO Classes
International Class
/
Drawings
0


Cerebrospinal Fluid
Migraine


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