asking your doctor about clarithromycin - living with hypersomnia · asking your doctor about...

Asking Your Doctor About Clarithromycin

Have you been reading some of the articles on the web about the benefits of Clarithromycin for people with Idiopathic Hypersomnia? The results are yet to be published but a clinical trial has been completed by Emory University and anecdotally there were very promising results. Clarithromycin does not represent a cure to Idiopathic Hypersomnia, but it does represent another treatment option that has the potential for significant improvement.

The question that keeps being repeated is: “What do I say to my doctor if I want to get a prescription to see how it works for me?”

And that is what this article sets out to answer!

Before writing this article I talked to a doctor and asked for their opinion. This is, in essence, what they said:

Here’s what I would say to my doctor to try to get Clarithromycin. If I’d had a patient say this to me, I would have given it a try.

I’d first educate your doctor that researchers at Emory University have discovered a possible mechanism of most IH cases, the GABA-A receptor hyperactivity. Print the clarithromycin trials from clinicaltrials.gov along with the Wikipedia page on idiopathic hypersomnia and give them to your doctor (links further down this blog article). You might highlight the most pertinent parts to help your time poor doctor digest it quickly.

Tell your doctor that Emory University has done 2 clinical trials of medication that reduce GABA-A receptor hyperactivity. The Flumazenil trial is done, published, and positive, but there’s no easy access to flumazenil. The Clarithromycin trial is done, with results pending. The results are good enough that all the Emory sleep doctors are routinely prescribing clarithromycin off-label for their patients, and some have been on the med for more than 2 years without serious complications.

AND you are absolutely dying now from the awfulness of this disease worsening, and you are desperate to try anything that might help.

It might also help to make the point that Clarithromycin is doubtfully more dangerous than stimulants, Xyrem, etc… It is also likely to help if you request permission to do a trial for 2 months. Putting a time limit on the trial will make it seem like a better idea to many doctors.

The dosage that they used in the Clinical Trials was:

• Starting(Dosage:!1000mg!daily!(500mg!at!breakfast!and!500mg!at!lunch)!• Medium(Dosage:!1500mg!daily!(1000mg!at!breakfast!and!500mg!at!

lunch)!• Maximum(Dosage:!2000mg!daily!(1000mg!at!breakfast!and!1000mg!at!

lunch)!

Start on the Starting Dosage. If you tolerate the side effects and don’t feel amazing then a few weeks later you can increase to 1000 mg breakfast and 500 mg lunch. If you tolerate the side effects and don’t feel amazing, then a few weeks later, you might increase to 1000 mg breakfast and 1000 mg lunch (this is the max dose with safety data for treating infections).

Explain this to your doctor. Depending on how regularly you see your doctor you might ask that they prescribe the Medium or Maximum Dosage at first and allow you to handle your increase gradually. This means you won’t run out of tablets prior to your next doctors appointment if after a few weeks you increase from the Starting Dosage.

IMPORTANT! It is also super important that you take Probiotics as well. This will help prevent many of the potential side effects of using anti-biotics for an extended period of time. Generally it is recommended that you take a Probiotic twice a day – 2 hours after taking the anti-biotics. The information isn’t perfect when it comes to Probiotics but generally the ones kept in the fridge are likely to contain more helpful bacteria than the ones stored at room temperature.

In terms of monitoring it is primarily about tracking how you feel on the Clarithromycin. It might take a few days before you notice an effect so stay on the Starting Dosage for at least a week. In the medium term if this treatment works for you then you want to request your doctor checks your liver enzymes after 2 months of use, and then approximately every 6 months after that. This is because Clarithromycin can sometimes cause liver toxicity. The liver is one of the best organs at regenerating itself but it is important to track this level so you know if toxicity ever starts to occur.

Remember, it is about helping your doctor see the potential in this treatment for improving your quality of life. The better you can present this information to your doctor, the more likely they will feel comfortable supporting you in your request to trial Clarithromycin.

Relevant Links:

1. http://en.wikipedia.org/wiki/Idiopathic_hypersomnia – highlight the section on GABA treatments, especially Clarithromycin. Highlight the section on Causes too.

2. http://www.clinicaltrials.gov/ct2/show/NCT01146600 - Clarithromycin 3. http://stm.sciencemag.org/content/4/161/161ra151.short - Flumazenil

This study has been completed.

Sponsor:Lynn Marie Trotti

Information provided by (Responsible Party):Lynn Marie Trotti, Emory University

ClinicalTrials.gov Identifier:NCT01146600

First received: June 15, 2010Last updated: November 5, 2012Last verified: November 2012History of Changes

Full Text View Tabular View No Study Results Posted Disclaimer How to Read a Study Record

A service of the U.S. National Institutes of Health

Clarithromycin for the Treatment of Hypersomnia

Tracking Information

First Received Date ICMJE June 15, 2010

Last Updated Date November 5, 2012

Start Date ICMJE July 2010

Primary Completion Date September 2012 (final data collection date for primary outcome measure)

Current Primary OutcomeMeasures ICMJE

(submitted: June 16, 2010)

Psychomotor Vigilance Task (PVT) reaction time [ Time Frame: change from baseline to week 2 of eachintervention ] [ Designated as safety issue: No ]

Median reaction time on the PVT will be collected at baseline and 1 and 2 weeks on each intervention. Thedifference at each timepoint from baseline will be calculated, with the difference at week 2 the primary outcome

Original Primary OutcomeMeasures ICMJE

Same as current

Change History Complete list of historical versions of study NCT01146600 on ClinicalTrials.gov Archive Site

Current SecondaryOutcome Measures ICMJE

(submitted: June 16, 2010)

PVT reaction time at week 1 [ Time Frame: week 1 compared to baseline ] [ Designated as safety issue: No ]

Difference in reaction time at week 1 of each intervention compared to baseline

PVT number of lapses [ Time Frame: baseline, week 1, week 2 ] [ Designated as safety issue: No ]

Number of lapses (no response for > 500 msec) will be computed for each PVT trial and difference frombaseline calculated for each timepoint

ESS [ Time Frame: baseline, week 1, week 2 ] [ Designated as safety issue: No ]

Changes in scores on the Epworth Sleepiness Scale (ESS) will be calculated at each time point relative tobaseline

FOSQ [ Time Frame: baseline, 1 week, 2 weeks ] [ Designated as safety issue: No ]

Changes in scores on the Functional Outcomes of Sleep Questionnaire (FOSQ) will be calculated at eachtime point relative to baseline

SF-36 [ Time Frame: baseline, week 1, week 2 ] [ Designated as safety issue: No ]

changes relative to baseline

PSQI [ Time Frame: baseline, 1 week, 2 weeks ] [ Designated as safety issue: No ]

changes in the Pittsburgh Sleep Quality Index (PSQI) at all time points compared to baseline

reported adverse events [ Time Frame: baseline, week 1, week 2 ] [ Designated as safety issue: Yes ]

Original SecondaryOutcome Measures ICMJE

Same as current

Current Other OutcomeMeasures ICMJE

Original Other OutcomeMeasures ICMJE

http://www.clinicaltrials.gov/ct2/show/record/NCT01146600

Descriptive Information

Brief Title ICMJE Clarithromycin for the Treatment of Hypersomnia

Official Title ICMJE Clarithromycin for the Treatment of Hypersomnia

Brief Summary The term 'hypersomnia' describes a group of symptoms that includes severe daytime sleepiness and sleeping longperiods of time (more than 10 hours per night). Sometimes, hypersomnia is caused by a problem with the qualityof sleep occurring at night, for instance when nighttime sleep is disrupted by frequent breathing pauses. In othercases, however, hypersomnia occurs even when nighttime sleep is of good quality. These cases of hypersomniaare presumed to be a symptom of brain dysfunction, and so are referred to as hypersomnias of central (i.e., brain)origin.

The causes of most of these central hypersomnias are not known. However, our group has recently identified aproblem with the major brain chemical responsible for sedation, known as GABA. In a subset of our hypersomniapatients, there is a naturally-occurring substance that causes the GABA receptor to be hyperactive. In essence, itis as though these patients are chronically medicated with Valium (or Xanax or alcohol, all substances that actthrough the GABA system), even though they do not take these medications.

Current treatment of central hypersomnias is limited. For the fraction of cases with narcolepsy, there areFDA-approved, available treatments. However, for the remainder of patients, there are no treatments approved bythe FDA. They are usually treated with medications approved for narcolepsy, but sleep experts agree that thesemedications are often not effective for this group of patients.

Based on our understanding of the GABA abnormality in these patients, we evaluated whether clarithromycin (anantibiotic approved by the FDA for the treatment of infections) would reverse the GABA abnormality. In a test tubemodel of this disease, clarithromycin does in fact return the function of the GABA system to normal. Theinvestigators have treated a few patients with clarithromycin and most have felt that their hypersomnia symptomsimproved with this treatment.

To determine whether clarithromycin is truly beneficial for central hypersomnia, this study will compareclarithromycin to an inactive pill (the placebo). All subjects will receive both clarithromycin and the placebo atdifferent times, and their reaction times and symptoms will be compared on these two treatments to determine ifone is superior. If this study shows that clarithromycin is more effective than placebo in the treatment ofhypersomnia, it will identify a potential new therapy for this difficult-to-treat disorder.

Detailed Description Central hypersomnias are characterized by severe excessive daytime sleepiness despite long sleep periods (>10hours/night) and the absence of nocturnal sleep pathology. They preferentially affect young adults, may result inloss of employment, and can lead to motor vehicle accidents (1). Despite these health, safety, and quality of lifeconsequences, there are no FDA-approved therapies for several forms of central hypersomnia, includingidiopathic hypersomnia (IH). Currently, IH is treated using therapies approved for narcolepsy, despite a lack ofclinical trial data and a consensus that treatment response is poor (2). Treatments include traditionalpsychostimulants (e.g., amphetamine derivatives) as well as wake-promoting agents with unknown mechanisms ofaction such as modafanil and sodium oxybate. In addition to side effects including high abuse potential,tachycardia, and altered mental status, treatments are often ineffective and substantial residual sleepinessfrequently persists despite poly-therapy.

The investigators hypothesize that pathology in the GABA neurotransmitter system, the brain's major inhibitorysystem, underlies these central hypersomnias. Currently, there are no hypersomnia therapies that areGABA-antagonists. However, the macrolide antibiotic clarithromycin has been shown to have GABA-modulatingproperties, resulting in the development of insomnia or mania in a subset of patients. Clarithromycin is therefore apotentially viable, promising therapeutic agent for hypersomnia related to positive modulation of the GABAAreceptor. Open-label use of clarithromycin in six hypersomnia patients with known (n = 4) or suspected (n = 2)excess GABAA potentiation resulted in marked improvements in vigilance, as measured on the psychomotorvigiliance task (PVT) (unpublished data). The investigators therefore propose a pilot, crossover trial comparingclarithromycin to placebo for the treatment of hypersomnia in patients with excess GABAA potentiation. Theprimary endpoint will be a decrease in PVT reaction time. Secondary endpoints will include a decrease in PVTlapses and changes in Epworth, Stanford, and FOSQ sleep scales. Successful results from this trial would provideearly evidence for a more rational and efficacious treatment for hypersomnia that could avoid the potential abuse,toxicities, and treatment failures associated with traditional treatments.

This will be a pilot crossover trial of clarithromycin and placebo to treat central hypersomnia. Subjects who areuntreated for hypersomnia or who experience persistent symptoms despite traditional therapies will be eligible.Subjects who are on medication for hypersomnia at the beginning of the study will be asked to maintain stabledoses of these medications for one month before and throughout the study period. Twenty subjects will beassessed at baseline and one and two weeks after being on each study drug (clarithromycin 500 mg bid andmatched placebo bid). After two weeks on study drug, they will undergo a one week washout period, then changeto the other study drug for an additional two weeks. Patients will be randomized to order of presentation of studydrugs such that ten subjects will be randomized to each group. Random sequence generation will be performedour pharmacy. All study investigators and subjects will remain blinded to group assignment.

Study Type ICMJE Interventional

Study Phase Phase 2


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Lloyd Johnson

Lloyd Johnson

Study Design ICMJE Allocation: RandomizedEndpoint Classification: Efficacy StudyIntervention Model: Crossover AssignmentMasking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)Primary Purpose: Treatment

Condition ICMJEHypersomnia

Idiopathic Hypersomnia

Narcolepsy

Intervention ICMJEDrug: Clarithromycin followed by placeboClarithromycin 500 mg po bid for two weeks, then one week with no medication, then matched placebo pobid for two weeks.Other Name: Biaxin

Drug: Placebo then ClarithromycinMatched placebo po bid for two weeks, then one week with no intervention, then clarithromycin 500 mg pobid for two weeksOther Name: Biaxin

Study Arm (s) Experimental: Random Group ASubjects will be randomized to group A or group B. The order of presentation of placebo and clarithromycinwill be opposite in these two groups, but investigators and subjects will remain blinded to group allocationand order of treatment presentation within the groups.Intervention: Drug: Clarithromycin followed by placebo

Experimental: Random Group BSubjects will be randomized to group A or group B. The order of presentation of placebo and clarithromycinwill be opposite in these two groups, but investigators and subjects will remain blinded to group allocationand order of treatment presentation within the groups.Intervention: Drug: Placebo then Clarithromycin

Publications *

* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.

Recruitment Information

Recruitment Status ICMJE Completed

Estimated Enrollment ICMJE

20

Completion Date September 2012

Primary Completion Date September 2012 (final data collection date for primary outcome measure)

Eligibility Criteria ICMJE Inclusion Criteria:

Hypersomnia (meeting clinical criteria for Idiopathic hypersomnia with or without long sleep time, narcolepsylacking cataplexy, or symptomatic hypersomnia not meeting ICSD criteria)

evidence for GABA-related abnormality, as demonstrated by in-house, in vitro assay

age > 18

high performance liquid chromatography/liquid chromatography tandem mass spectrometry verification of theabsence of exogenous benzodiazepines

Exclusion Criteria:

Contraindications to use of clarithromycin (pregnancy, severe renal impairment, history of QT prolongation,hypomagnesemia, hypokalemia, bradycardia, history of myocardial infarction or cardiomyopathy, myastheniagravis, age > 70)

Current use of cisapride, pimozide, astemizole, terfenadine, colchicines, and ergotamine or dihydroergotamine

Current use of benzodiazepines or benzodiazepine-receptor agonists

moderate or severe sleep apnea (RDI > 15/hr), severe periodic limb movement disorder (PLMI > 30/hr)

diagnosis of narcolepsy with cataplexy, as determined by cerebrospinal hypocretin levels

metabolic disorders such as anemia, severe iron deficiency, B12 deficiency, or hypothyroidism that mayexplain symptoms of hypersomnia


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Lloyd Johnson

Lloyd Johnson

Gender Both

Ages 18 Years and older

Accepts HealthyVolunteers

No

Contacts ICMJE Contact information is only displayed when the study is recruiting subjects

Location Countries ICMJE United States

Administrative Information

NCT Number ICMJE NCT01146600

Other Study ID Numbers ICMJE

Emory44170

Has Data MonitoringCommittee

No

Responsible Party Lynn Marie Trotti, Emory University

Study Sponsor ICMJE Lynn Marie Trotti

Collaborators ICMJE

Investigators ICMJEPrincipal Investigator: Lynn Marie Trotti, MD Emory University

Information Provided By Emory University

Verification Date November 2012

ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP


Idiopathic HypersomniaClassification and external resources

An illustration of the brain mechanism thought tocause excessive daytime sleepiness in those with

idiopathic hypersomnia.

ICD-10 G47.1

ICD-9 327.11, 327.12

MedlinePlus 000803

eMedicine med/3129

MeSH D006970

Idiopathic hypersomniaFrom Wikipedia, the free encyclopedia

Idiopathic hypersomnia is a disease, thought tobe a neurological disorder, which is characterizedprimarily by severe excessive daytime sleepiness(EDS).[1] It has historically been rarely diagnosedand is often very difficult to diagnose at an earlystage; it is a lifelong chronic disease, which isoften debilitating. There is a very low level ofpublic awareness of idiopathic hypersomnia,which often leads to stigma for those who sufferfrom it. Currently, there is no cure, there are noFDA-approved treatments, and research dollarsfor its study are scarce.

In the medical literature, idiopathic hypersomniamay also be referred to as IH, IHS, primaryhypersomnia, central hypersomnia, orhypersomnia of brain origin. The Diagnostic andStatistical Manual of Mental Disorders, FourthEdition (DSM-IV) defines idiopathic hypersomniaas EDS without narcolepsy or the associatedfeatures of other sleep disorders.[2] It occurs in theabsence of medical problems that can causesecondary hypersomnia, and it occurs "despitenormal quality and quantity of night time sleep(and sometimes despite exceptionally long periodsof night time sleep). Primary Hypersomnia is thought to arise from problems with the brain’s systemsthat regulate sleep and wake."[3]

Contents1 Classification2 Symptoms3 Causes4 Epidemiology5 Diagnosis6 Management

6.1 Common Off-Label Medications6.1.1 Stimulants6.1.2 Non-Stimulants6.1.3 Sodium Oxybate

6.2 Medications Being Researched6.2.1 Levothyroxine

http://en.wikipedia.org/wiki/Idiopathic_hypersomnia

6.2.2 Histamines6.2.3 GABA-directed Medications

6.2.3.1 Flumazenil6.2.3.2 Clarithromycin

6.3 Future Treatments7 Prognosis8 Support Groups9 Society and Culture10 See also11 External links12 References

1 ClassificationIn addition to differentiating between the primary and secondary hypersomnias, the 2001International Classification of Sleep Disorders (ICSD) further classifies the primary hypersomniasyndromes. These include idiopathic hypersomnia, narcolepsy, and the recurrent hypersomnias (likeKlein-Levin syndrome).[3]

The ICSD defines idiopathic hypersomnia as "a disorder of presumed central nervous system causethat is associated with a normal or prolonged major sleep episode and excessive sleepiness consistingof prolonged (1 to 2 hour) sleep episodes of N-REM"(non-rapid eye movement sleep).[1] The ICSDinitially described two clinical forms of idiopathic hypersomnia: "1) a polysymptomatic form withnocturnal sleep and naps of abnormally long duration with ‘sleep drunkenness’ on awakening, and 2)a monosymptomatic form manifested by isolated EDS." These forms were later described asidiopathic hypersomnia with long sleep time and idiopathic hypersomnia without long sleep time,respectively.[4]

Note: In the upcoming 5th edition of the Diagnostic and Statistical Manual of Mental Disorders, duefor publication in May 2013, idiopathic hypersomnia (with or without long sleep time) is reclassifiedas major somnolence disorder.[5]

2 SymptomsThose who suffer from idiopathic hypersomnia have recurring episodes of excessive daytimesleepiness (EDS). These occur in spite of “adequate, or more typically, extraordinary sleep amounts(e.g., greater than 10 hours per night).”[3] Sleep is usually quite deep, with significant difficultyarousing from sleep, even with use of several alarm clocks. In fact, patients with IH often have todevelop elaborate rituals to wake, as alarm clocks and even physical attempts by friends/family towake them may fail. Despite getting more hours of sleep than typically required by the human body,patients awake unrefreshed and may also suffer sleep inertia, known more descriptively in its severeform as sleep drunkenness (significant disorientation upon awakening).[6] Daytime naps aregenerally very long (up to several hours) and are also unrefreshing, as opposed to the short refreshingnaps associated with narcolepsy.[3]


Other symptoms may include anxiety, increased irritation, decreased energy, restlessness, slowthinking, slow speech, loss of appetite, hallucinations, memory difficulty and difficulty regulatingbody temperature.[7] Peripheral vascular symptoms, such as cold hands and feet (Raynaud’s-typephenomena) are quite common. In addition to difficulty with temperature regulation and Raynaud’stype symptoms, other symptoms associated with autonomic dysfunction are not uncommon inidiopathic hypersomnia. These may include: fainting episodes (syncope); dizziness upon arising(orthostatic hypotension); and headaches (possibly migrainous in quality).[7] Some patients also“exhibit hypersensitivity to sedating medications such as anesthetics, sleeping pills, or alcohol."[3]

Patients with idiopathic hypersomnia display these symptoms continually for months or years.[8]

Symptom intensity often varies between weeks, months, or years, and symptoms sometimes worsenjust prior to menses in women.[3] Many patients are chronically tardy to work, school or socialengagements[9] and, over time, may lose the ability to function in family, social, occupational orother settings altogether.[8] (See Prognosis section below).

3 CausesUntil recently, the cause of idiopathic hypersomnia has been largely unknown, hence its name.However, researchers have identified a few abnormalities associated with idiopathic hypersomnia,which with further study may help to clarify the etiology.

Destruction of nonadrenergic neurons has produced hypersomnia in experimental animal studies, andinjury to adrenergic neurons has also been shown to lead to hypersomnia. Idiopathic hypersomniahas also been associated with a malfunction of the norepinephrine system and decreased CSFhistamine levels.[10]

Researchers have more recently found a problem with GABA (the major brain chemical responsiblefor sedation) in a large subset of their patients with IH and narcolepsy without cataplexy. They havefound a naturally-occurring substance in the cerebrospinal fluid (CSF) of afflicted patients thatcauses their GABAA receptors to be hyperactive. This discovery led the researchers to suggest that

IH and narcolepsy without cataplexy are potentially part of the same disease spectrum.[9] In essence,it is as though these patients are chronically sedated with a benzodiazepine such as Versed or Xanaxeven though they do not take these medications.[11][12]

4 EpidemiologyTypically, idiopathic hypersomnia is first recognized in adolescence or young adulthood, although itcan begin at a later age.[13] The disorder usually develops slowly over a period of months andyears.[14] It "is initially progressive but often is stable by the time of diagnosis. It appears to belifelong."[1] Spontaneous remission is only seen in 10-15% of patients.[3]

"There is no indication of gender predominance. Family cases are frequent, in a range from 25% to66% without any clear mode of inheritance."[4]

Idiopathic hypersomnia has long been considered a rare disease and was believed to be 10 times lessfrequent than narcolepsy.[4] The prevalence of narcolepsy is known to be about 1 in 2000.[15] "In


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Europe and in North America there is now a public health concern about helping patients andfamilies affected by these rare diseases. Due to the complexity of the disease, they often experiencedifficulties to be diagnosed and often face social and professional consequences."[16] (see Prognosis)

Because idiopathic hypersomnia has been considered a rare disease, it has not received enoughattention from authorities and researchers. "Patients are rare, researchers and scientists involved inthe field are few and research findings are therefore scarce."[16] Because of the absence of a goldstandard test for idiopathic hypersomnia and the diagnostic confusion (including the use of manydifferent labels and names), a true prevalence for idiopathic hypersomnia has not, in fact, beendetermined. Researchers have recently suggested that the prevalence is higher, at least 1 in 800,which translates to about 400,000 in the U.S. alone.[15]

5 DiagnosisIdiopathic hypersomnia has historically been "difficult to diagnose at an early stage," especiallybecause many other disorders can cause symptoms of excessive daytime sleepiness (EDS).Therefore, "at the time of presentation, most patients have had the disorder for many years."[1]

In 2001, the ICSD (International Classification of Sleep Disorders) updated their criteria for thediagnosis of idiopathic hypersomnia. Essentially, EDS must be present for at least 6 months, sleepstudies (polysomnography and multiple sleep latency test) must show certain characteristicabnormalities, and all other known causes for long sleep time and EDS must be ruled out (seehypersomnia).[1] For the patient, this diagnostic process is often tedious, expensive andtime-consuming, as other than the sleep studies, it is still basically a diagnosis of exclusion.

Further complicating the diagnostic process, idiopathic hypersomnia lacks a clearly-defining clinicalfeature. Whereas narcolepsy is associated with cataplexy and sleep-onset REM episodes, andKleine-Levin syndrome is associated with megaphagia (compulsive food cravings) andhypersexuality, idiopathic hypersomnia has no such dramatic associated features, except perhapssleep drunkenness. “Consequently there has been an unfortunate tendency to label all difficult toclassify cases of excessive daytime sleepiness as idiopathic hypersomnia.” For example, upperairway resistance syndrome and delayed sleep phase disorder were formerly confused with idiopathichypersomnia, but now that they have been more clearly defined, one can more carefully excludethese causes of EDS in order to more correctly diagnose idiopathic hypersomnia.[17]

It is important to note that although sleep latencies are typically short in idiopathic hypersomnia, theclinical severity may not correlate closely with the MSLT results, i.e., shorter sleep latencies do notindicate more severe symptoms. In fact, “latencies above 5 minutes are not uncommon in patientswith clinically severe hypersomnia."[1] When sleep latency is below 10 minutes, the presence ofsleep-onset rapid eye movement periods (SOREMPs) in two or more of the MSLT naps suggests adiagnosis of narcolepsy whereas sleep periods lacking rapid eye movement (NREM sleep epochs) inthe various naps suggests a diagnosis of idiopathic hypersomnia.[8]

Although the MSLT is currently the best available test to diagnose EDS in general, the MSLTprotocol lacks the ability to document the extended, unrefreshing daytime naps typical of thepolysymptomatic form of idiopathic hypersomnia. Complicating the matter, several groups ofresearchers have found normal MSLT results in patients who otherwise seem to have idiopathichypersomnia. When idiopathic hypersomnia is suspected, Billiard and other researchers suggest


appending a 24-hour continuous polysomnography to the standard overnight/MSLT study in order torecord total sleep time and the result thereof.[8] Alternatively, an assay of the patient's cerebrospinalfluid (CSF) can be performed in order to test for an adequate level of hypocretin (to excludenarcolepsy with cataplexy) and to determine whether the patient’s CSF abnormally boosts GABAAreceptor sensitivity (thought to underlie many cases of idiopathic hypersomnia and narcolepsywithout cataplexy).[3]

Note: Globally, the number of labs capable of performing the CSF assay referenced above can becounted on one hand.

6 ManagementCurrently, there is no cure for idiopathic hypersomnia. Also, because the underlying diseasemechanism is not yet fully understood (see Causes), treatment efforts have only been able to focus onsymptom management. Although there are several FDA-approved medications for use in narcolepsy,there are no FDA-approved medicines for idiopathic hypersomnia. Therefore, the wake-promotingmedications used in narcolepsy are also commonly used off-label to help manage the excessivedaytime sleepiness of idiopathic hypersomnia. “These treatments have not been studied to nearly thesame extent in patients with idiopathic hypersomnia, and some patients with idiopathic hypersomniado not achieve adequate control of symptoms with these medications."[18]

However, current research is raising the possibility of several other potential medication options foridiopathic hypersomnia. "As the brain systems regulating sleepiness and wakefulness are betterunderstood, scientists will be in a better position to design treatments that target key portions of thissystem."[18]

In addition to medications, “behavioral approaches and sleep hygiene techniques are recommended,although they have little overall positive impact on this disease.”[19] That said, the goal, as in CBT(cognitive behavioral therapy), is often to help patients learn to reduce their negative emotionalresponses (e.g. frustration, anger, depression) to their disease symptoms. Furthermore, becauseidiopathic hypersomnia "may lead to marriage breakdown, extensive counseling for the patient'spartners, educating them about the symptomatology and treatment options, must be part of acomprehensive management plan... Education of relatives, friends, and colleagues helps the patientto function much better with this incurable disease.”[20]

6.1 Common Off-Label Medications

Overall, the medications currently used for idiopathic hypersomnia (all off-label) are far fromsatisfactory. CNS stimulants tend to be less effective for idiopathic hypersomnia than they are fornarcolepsy and may be less well tolerated.[8]

6.1.1 Stimulants

There are several stimulants approved by the FDA for treatment of excessive sleepiness due tonarcolepsy. These include methylphenidate (e.g., Ritalin) and dextroamphetamine. Althoughstimulants can effectively reduce sleepiness in the short to medium term, they are rarely effectivelong-term, as patients frequently become resistant to their effects. In addition, there are many


common, unpleasant side effects, which include heart problems, aggressive behavior, anddependence.[18]

6.1.2 Non-Stimulants

The non-stimulant wake-promoting medications approved for use in narcolepsy include modafiniland armodafinil. Their pharmacology is not completely understood, but these medications “appear toinfluence brain chemistry that increases wakefulness.”[18] They are known to bind to the dopaminetransporter, thereby inhibiting dopamine reuptake. Unfortunately, these medications can causeseveral unpleasant side effects, including nausea, headache, and a life-threatening rash.[21] They mayalso reduce effectiveness of hormonal birth control.[18]

6.1.3 Sodium Oxybate

Sodium oxybate is an orphan drug which was designed specifically for the treatment of narcolepsy. Ithas been shown to promote deep sleep and improve daytime sleepiness (as well as cataplexy) inpatients with narcolepsy; however, “its effects in those with idiopathic hypersomnia are not wellcharacterized."[18] Common side effects include nausea, dizziness, and hallucinations.[22]

6.2 Medications Being Researched

6.2.1 Levothyroxine

There have been some studies suggesting levothyroxine as a possible treatment for idiopathichypersomnia, especially for patients with subclinical hypothyroidism.[23][24] This treatment doescarry potential risks (especially for patients without hypothyroidism or subclinical hypothroidism)which include cardiac arrhythmia.[25]

6.2.2 Histamines

"Based on the role of histamine in keeping people awake (and hence the common side effect ofanti-histamines such as diphenhydramine causing sleepiness), medications that act on histamine areunder development for the treatment of excessive sleepiness."[18]

6.2.3 GABA-directed Medications

Given the possible role of hyper-active GABA-A receptors in idiopathic hypersomnia, medicationsthat could counteract this activity are being studied to test their potential to improve sleepiness.These currently include clarithromycin and flumazenil.[11][12]

6.2.3.1 Flumazenil

Flumazenil is the only GABA-A receptor antagonist on the market as of Jan 2013, and it is currentlymanufactured only as an intravenous formulation. It is also currently restricted by the FDA for useonly in anesthesia reversal and benzodiazepine overdose, so it cannot be prescribed off-label.However, given its pharmacology, researchers consider it to be a promising medication in the


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treatment of idiopathic hypersomnia. Results of a small, double-blind, randomized, controlledclinical trial were published in November 2012. This research showed that flumazenil provides relieffor most patients whose CSF contains the unknown "somnogen" that enhances the function ofGABA-A receptors, making them more susceptible to the sleep-inducing effect of GABA. For onepatient, daily administration of flumazenil by sublingual lozenge and topical cream has proveneffective for several years.[9][11] Unfortunately, since flumazenil went off patent in 2008, "theamount of the generic version produced annually for all of North America—enough to counteract10,000 sedative overdoses—would supply only a handful of patients" with idiopathic hypersomnia,even if the FDA restriction were removed.[26]

6.2.3.2 Clarithromycin

In a test tube model, clarithromycin (an antibiotic approved by the FDA for the treatment ofinfections) was found to return the function of the GABA system to normal in patients withidiopathic hypersomnia. Investigators therefore treated a few patients with off-label clarithromycin,and most felt their symptoms improved with this treatment. In order to help further determinewhether clarithromycin is truly beneficial for the treatment of idiopathic hypersomnia, a small,double-blind, randomized, controlled clinical trial was completed in 2012. Results have not yet beenpublished.[12]

6.3 Future Treatments

More research dollars are needed to further define the true etiology of idiopathic hypersomnia and tofurther treatment efforts. Unfortunately, research dollars are scarce, given the historically rarediagnosis of this disease. Interested parties can consider donating to the Hypersomnia Foundation,though their donation page is currently listed as "Coming Soon".[27]

7 PrognosisIdiopathic hypersomnia is a lifelong disorder (with only rare spontaneous remissions) that follows achronic, stable course after its onset around the ages of 15-30. Its main consequences areprofessional and social.[28]

Idiopathic hypersomnia profoundly affects work, education, and quality of life. Patients are often toosleepy to work or attend school regularly, and they are predisposed "to develop serious performancedecrements in multiple areas of function as well as to potentially life-threatening domestic,work-related and driving accidents."[16] Furthermore, these risks are higher for idiopathichypersomnia patients than for those with sleep apnea or severe insomnia. In fact, "the most severecases of daytime somnolence are found in patients affected by narcolepsy or idiopathichypersomnia."[16] And idiopathic hypersomnia is often as, if not more, disabling than narcolepsy;[1]

surprisingly, excessive daytime sleepiness is even more handicapping than the cataplectic attacks ofnarcolepsy.[16]

Due to the consequences of their profound EDS, both idiopathic hypersomnia and narcolepsy canoften result in unemployment. Several studies have shown a high rate of unemployment innarcoleptics (from 30-59%), which was felt to be related to the severe symptoms of their illness.[29][30]


Lloyd Johnson

8 Support GroupsHistorically, there have been no large, well-known support groups dedicated specifically to idiopathichypersomnia, perhaps because of the rarity and difficulty of its diagnosis. Therefore, patients aretypically referred to narcolepsy support groups, in spite of the significant differences between thesetwo diseases. An increased grass-roots effort of idiopathic hypersomnia patients to create theseresources for themselves began around 2012.

Living With Hypersomnia - A website created to raise awareness about idiopathichypersomnia by volunteers who suffer from idiopathic hypersomnia themselves

1.

"Major Somnolence Disorder" – Closed Facebook group for major somnolence disorder(formerly idiopathic hypersomnia) patients around the world

2.

"Idiopathic Hypersomnia - Australia" – Closed Facebook group for Australian idiopathichypersomnia patients

3.

"Petition for Flumazenil to be available to Idiopathic Hypersomnia Sufferers" - PublicFacebook Group dedicated to increasing awareness of idiopathic hypersomnia and to helpingconvince a pharmaceutical company to produce flumazenil lozenges and cream

4.

9 Society and CultureIdiopathic hypersomnia is rarely in the public eye and has a very low level of public awareness.

Because of this low awareness, patients with idiopathic hypersomnia “often need significant supportbecause they are at risk of being misunderstood as being incompetent or slothful. Therefore,education of relatives, friends, and colleagues helps the patient to function much better with thisincurable disease.”[20]

Several books and movies feature narcolepsy (examples include: Deuce Bigalow: Male Gigolo, MyOwn Private Idaho, and The Little Sleep, a detective novel by Paul Tremblay). However, based on aJanuary 2013 search of both Amazon.com[31] and IMDB.com,[32] there are no such pop culturereferences for idiopathic hypersomnia.

Additionally, idiopathic hypersomnia does not have a celebrity spokesperson, nor are there anycurrently known celebrities with idiopathic hypersomnia. Since there are many famous narcoleptics,one assumes some famous folks with idiopathic hypersomnia will eventually be identified. Please seethe List of people with narcolepsy.

10 See alsoHypersomniaInsomniaReticular Formation (includes info about Hypersomnia)

11 External linksHypersomnia FoundationLiving With HypersomniaLiving With Hypersomnia YouTube Channel


National Sleep FoundationTalk About Sleep - Idiopathic HypersomniaHelp: I can't stay awake! - Public Radio Interview with Dr. David Ryemed/3129 at eMedicine - "Primary Hypersomnia"06-081c. at Merck Manual of Diagnosis and Therapy Home Edition - "Circadian RhythmSleep Disorders"-483065848 at GPnotebook

12 References

^ a b c d e f g "International classification of sleep disorders, revised: Diagnostic and coding manual".American Academy of Sleep Medicine. 2001. http://www.esst.org/adds/ICSD.pdf. Retrieved 25 January2013.

1.

^ Diagnostic and statistical manual of mental disorders : DSM-IV-. Washington, DC: AmericanPsychiatric Association. 2000. ISBN 0-89042-025-4.

2.

^ a b c d e f g h "About Hypersomnia". Hypersomnia Foundation. http://hypersomniafoundation.org/about-hypersomnia. Retrieved 2013-01-25.

3.

^ a b c Dauvilliers, Yves et al (2006-04-01). "Differential Diagnosis in Hypersomnia". Current Neurologyand Neuroscience Reports (Current Medicine Group) 6 (2): 156–162. doi:10.1007/s11910-996-0039-2.

4.

^ "DSM-5: The Future of Psychiatric Diagnosis". DSM-5 Development. American PsychiatricAssociation. http://www.dsm5.org/Pages/Default.aspx.

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^ Bendrich Roth, MD; Sonia Nevsimalova, MD; Allan Rechtschaffen, PhD (May 1972). "HypersomniaWith "Sleep Drunkenness"". Arch Gen Psychiatry 26 (5): 456–462.doi:10.1001/archpsyc.1972.01750230066013.

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^ a b Vernet, C., Leu-Semenescu, S., Buzare, M.-A. and Arnulf, I. (2010). "Subjective symptoms inidiopathic hypersomnia: beyond excessive sleepiness". Journal of Sleep Research 19 (4): 525–534.doi:10.1111/j.1365-2869.2010.00824.x.

7.

^ a b c d e Michel Billiard, MD. "Idiopathic Hypersomnia". Sleep Disorders I. Gui-de-Chauliac Hospital,Neurology B Department, 34295 Montpellier, Cedex 05, France. pp. 573–582.http://www.beatcfsandfms.org/references/IdiopathicHypersomnia.html.

8.

^ a b c D.B. Rye, D.L. Bliwise, K. Parker, L.M. Trotti, P. Saini, J. Fairley, A. Freeman, P.S. Garcia, M.J.Owens, J.C. Ritchie and A. Jenkins (2012). "Modulation of Vigilance in the Primary Hypersomnias byEndogenous Enhancement of GABAA Receptors". Sci. Transl. Med. 4: 161ra151.doi:10.1126/scitranslmed.3004685.

9.

^ Preda, Adrian. "Primary Hypersomnia: Etiology". Medscape. http://emedicine.medscape.com/article/291699-overview#aw2aab6b2b2aa. Retrieved 25 January 2013.

10.

^ a b c Lynn Marie Trotti, MD (August 9, 2010). "Flumazenil for the Treatment of PrimaryHypersomnia". Emory University - Georgia Research Alliance. ClinicalTrials.gov. http://clinicaltrials.gov/show/NCT01183312. Retrieved 2013-01-25.

11.

^ a b c Lynn Marie Trotti, MD (June 15, 2010). "Clarithromycin for the Treatment of PrimaryHypersomnia". Emory University - Georgia Research Alliance. ClinicalTrials.gov. http://clinicaltrials.gov/show/NCT01146600. Retrieved 2013-01-25.

12.

^ National Institutes of Health (June 2008). "NINDS Hypersomnia Information Page".http://www.ninds.nih.gov/disorders/hypersomnia/hypersomnia.htm. Retrieved 2009-01-23.

13.

^ Sharon L. Schutte-Rodin, MD (January 12, 2006). "Idiopathic Hypersomnia with Long Sleep Time".American Academy of Sleep Medicine. http://yoursleep.aasmnet.org/disorder.aspx?id=48.

14.

^ a b "Hypersomnia Foundation Interview with David Rye". http://hypersomniafoundation.org/research/interview-with-david-rye. Retrieved 2013-01-25.

15.

^ a b c d e Bayon et al. (2009). "Socio-professional handicap and accidental risk in patients withhypersomnias of central origin". Sleep Med Rev 13: 421–426.

16.

^ Billiard, M.; Dauvilliers, Y. (Oct 2001). "Idiopathic Hypersomnia.". Sleep Med Rev 5 (5): 349–358.doi:10.1053/smrv.2001.0168. PMID 12530998.

17.

^ a b c d e f g "Hypersomnia Foundation - Treatment". http://hypersomniafoundation.org/treatment.Retrieved 2013-01-25.

18.


^ "Medscape - Treatment". http://emedicine.medscape.com/article/291699-treatment. Retrieved2013-01-25.

19.

^ a b "Medscape Overview#aw2aab6b2b5". http://emedicine.medscape.com/article/291699-overview#aw2aab6b2b5. Retrieved 2013-01-25.

20.

^ "Epocrates - Provigil". https://online.epocrates.com/u/10a2276/Provigil. Retrieved 2013-01-29.21.^ "Epocrates - Xyrem". https://online.epocrates.com/noFrame/showPage.do?method=drugs&MonographId=1663. Retrieved 2013-01-29.

22.

^ "Successful treatment with levothyroxine for idiopathic hypersomnia patients with subclinicalhypothyroidism". General Hospital Psychiatry - Elsevier Inc. http://www.ghpjournal.com/article/S0163-8343(08)00130-8/abstract. Retrieved 2010-08-05.

23.

^ H. Shinno et al. (June 2011). "Effect of levothyroxine on prolonged nocturnal sleep time and excessivedaytime somnolence in patients with idiopathic hypersomnia." Sleep Medicine Vol. 12 6: 578–583

24.

^ "Epocrates - levothyroxine". https://online.epocrates.com/noFrame/showPage.do?method=drugs&MonographId=42. Retrieved 2013-01-29.

25.

^ http://online.wsj.com/article/SB10001424127887324478304578171221462816296.html26.^ "Donate to the Hypersomnia Foundation". http://hypersomniafoundation.org/donate. Retrieved2013-01-25.

27.

^ "Primary Hypersomnia". http://emedicine.medscape.com/article/291699-overview. Retrieved2013-01-29.

28.

^ Gosmany M. "The influence of clinical symptoms on quality of life in patients with narcolepsy."Neurology 1998;50:S31–6

29.

^ Dodel R, Peter H, Walbert T, Spottke A, Noelker C, Berger K, et al. "The socio-economic impact ofnarcolepsy." Sleep 2004;27:1123–8

30.

^ "Search Results for "Idiopathic Hypersomnia" on Amazon.com". http://www.amazon.com/s/ref=nb_sb_noss?url=search-alias%3Daps&field-keywords=%22Idiopathic+Hypersomnia%22.Retrieved 2013-01-25.

31.

^ "Search Results for "Idiopathic Hypersomnia" on IMDB.com". http://www.imdb.com/find?q=Idiopathic+Hypersomnia&s=all. Retrieved 2013-01-25.

32.

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