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Department of Anesthesiology

Post-anesthetic inertia in IH

A recent paper from neurologists Lynn Marie Trotti and Donald Bliwise, with anesthesiologist Paul Garcia, substantiates a phenomenon discussed anecdotally in the idiopathic hypersomnia (IH) community. Let’s call it “post-anesthetic inertia.” People with IH say that undergoing general anesthesia made their sleepiness or disrupted sleep-wake cycles worse, sometimes for days or weeks. This finding is intriguing because it points toward a trigger mechanism for IH. And it pushes anesthesiologists to take IH diagnoses into account when planning patient care, just as is already done for myotonic dystrophy.

Lab Land obtained some confirmation from a couple IHers. One woman had surgery a couple of months ago and felt like the anesthetic was still in her system for weeks and she still didn’t feel right. Another reported “severe insomnia for months and it felt like every body system was completely scrambled.”

Where does this all come from? People with IH getting together and telling their stories. Journalist Virginia Hughes described a moment at the 2014 patient-organized IH meeting in Atlanta in her article “Wake No More”:

Andy Jenkins, the neuroscientist who developed the spinal fluid test, gave an impressively entertaining lecture on GABA receptors. “Why do we have more GABA activity?” somebody asked. Nobody knows, said Jenkins. One idea is that it’s triggered by anesthesia. Lloyd [Johnson, a meeting organizer from Australia] asked the audience how many of them believed their hypersomnia was the result of anesthesia. About one-quarter of the hands went up. “Whoa, whoa, whoa, whoa, whoa,” Jenkins said as he watched the sleepyheads* come alive.

The new paper, in Frontiers in Human Neuroscience, is more quantitative than that informal show of hands. In a way, it begins to question the basis for the term idiopathic hypersomnia, since idiopathic means “arising spontaneously or having no cause”. For some people surveyed in the paper, anesthesia was an exacerbating factor, if not the only factor.

Confusion or agitation post-anesthesia can happen in people who don’t have sleep disorders. What’s peculiar to the hypersomnolent group is how long sleepiness or disrupted sleep-wake cycles last — long after the anesthetic has left the body. The hypersomnolent group was mostly people with IH or narcolepsy type 2 (30 plus 15 out of 57). In the paper, people with restless legs syndrome were used as controls:

While patients in both groups were equally likely to report surgical complications and difficulty awakening from anesthesia, hypersomnolent patients were more likely to report worsened sleepiness (40% of the hypersomnolent group vs. 11% of the RLS group, p = 0.001) and worsening of their sleep disorder symptoms (40% of the hypersomnolent group vs. 9% of the RLS group, p = 0.0001).

Hypersomnolent patients who perceived their symptoms to worsen reported that symptoms had never returned to baseline in 66.7%, took months or years to return to baseline in 9.5%, and resolved in days to weeks in 23.8%.

Note: first author Vincent LaBarbera is now a neurology resident at Brown.

Mechanistic speculation

Several years ago, Emory researchers found that some IH patients appear to have a substance in their cerebrospinal fluid that acts similarly (but not quite the same) as a benzodiazepine drug. This still-mysterious substance enhances signaling by GABA, the major inhibitory neurotransmitter.

Inhaled anesthetics such as sevoflurane, as well as the injected anesthetic propofol, act by enhancing GABA too. So when someone undergoes general anesthesia, their GABA receptors are being pushed hard for an extended period of time. GABA signaling has a kind of global “dimmer switch” function as well as working through specific circuits in the brain to bring on anesthesia.

GABA receptors are complex, but they usually adjust to pressure. It explains development of tolerance to benzodiazepine drugs. GABA receptors also modulate in response to alcohol or women’s menstrual cycles (certain derivatives of progesterone, so-called “neurosteroids,” act on them). What may be happening after anesthesia is that GABA receptors of people with IH have trouble adjusting back, or may overshoot, perhaps because their internal clocks are less resilient.

The Emory authors conclude:

Because the half-life of anesthetic agents is generally short, any prolonged worsening of sleepiness post-procedure cannot easily be attributed to immediate GABA-mediated effects. Whether the putative long-term changes in hypersomnolence that we are detecting in our patients’ reports may be related to changes in GABA-related neural circuitry caused by anesthetic neurotoxicity or other mechanisms remains to be determined.

A similar interaction, with reversed polarity, may be occurring in post-partum depression.

*Lab Land has been told that sleepyhead is not a fully accepted term in the IH community.

Posted on by Quinn Eastman in Neuro Leave a comment

Calming an electrical storm in the heart

AT = anterior tubercle of C6, C = carotid artery, LC = longus colli muscle, T = thyroid gland, IJ = internal jugular vein, compressed

The most recent issue of Emory Medicine features a story that first came to Lab Land’s attention when it was presented as an abstract at the 2017 American College of Cardiology Scientific Sessions meeting.

Emory doctors were challenged by a patient who repeatedly developed cardiac arrhythmias, called “refractory electrical storm.” They used a local anesthesia procedure called stellate ganglion block — normally used for complex pain — to calm the storm. Cardiac electrophysiologist Michael Lloyd, who likes solving puzzles, was the one who decided to try it.

Emory anesthesiologist Boris Spektor provided this ultrasound picture of the procedure. Stellate ganglion block is also being tested for conditions such as PTSD. Please read the whole story!

Posted on by Quinn Eastman in Heart Leave a comment

The journey of a marathon sleeper

A marathon sleeper who got away left some clues for Emory and University of Florida scientists to follow. What they found could provide benefits for patients with the genetic disease myotonic dystrophy (DM) and possibly the sleep disorder idiopathic hypersomnia (IH).

The classic symptom for DM is: someone has trouble releasing their grip on a doorknob. However, the disease does not only affect the muscles. Clinicians have recognized for years that DM can result in disabling daytime sleepiness and sometimes cognitive impairments. At the Myotonic Dystrophy Foundation meeting in September, a session was held gathering patient input on central nervous system (CNS) symptoms, so that future clinical trials could track those symptoms more rigorously.

Emory scientists are investigating this aspect of DM. Cell biology chair Gary Bassell was interested in the disease, because it’s a triplet repeat disorder, similar to fragile X syndrome, yet the CNS mechanisms and symptoms are very different. In DM, an expanded triplet or quadruplet repeat produces toxic RNA, which disrupts the process of RNA splicing, affecting multiple cell types and tissues.

Rye at San Francisco myotonic dystrophy meeting. Photo courtesy of Hypersomnia Foundation.

Neurologist and sleep specialist David Rye also has become involved. Recall Rye’s 2012 paper in Science Translational Medicine, which described a still-mysterious GABA-enhancing substance present in the spinal fluid of some super-sleepy patients. (GABA is a neurotransmitter important for regulating sleep.)

In seven of those patients, his team tested the “wake up” effects of flumazenil, conventionally used as an antidote to benzodiazepines. One of those patients was an Atlanta lawyer, whose recovery was later featured in the Wall Street Journal and on the Today Show. It turns out that another one of the seven, whose alertness increased in response to flumazenil, has DM.

In an overnight sleep exam, this man slept for 12 hours straight – the longest of the seven. But an IH diagnosis didn’t fit, because in the standard “take a nap five times” test, he didn’t doze off very quickly. He became frustrated with the stimulants he was given and sought treatment elsewhere, Rye says. Lab Land doesn’t have all the details of this patient’s history, but eventually he was diagnosed with DM, which clarified his situation. Read more

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Gabbing about GABA — implications for hypersomnia treatments

Anesthesiologist Paul Garcia and his colleagues are presenting two posters at the Society of Neuroscience meeting this week, whose findings may raise concerns about two non-stimulant drugs Emory sleep specialists have studied for the treatment of hypersomnia: flumazenil and clarithromycin.

For both, the data is in vitro only, so caution is in order and more investigation may be needed.

With flumazenil, Garcia and colleagues found that when neurons are exposed to a low dose for 24 hours, the cells increase expression of some GABA receptor forms.

This could be part of a mechanism for tolerance. I heard some anecdotes describing how flumazenil’s wake-promoting effects wear off over time at the Hypersomnia Foundation conference in July, but it’s not clear how common the phenomenon is.

Flumazenil’s utility in hypersomnia became known after the pioneering experience of Anna Sumner, who has reported being able to use the medicine for years. See this 2013 story in Emory Medicine. Read more

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PTH for stroke: stem cells lite

I’d like to highlight a paper in PLOS One from anesthesiologists Shan Ping Yu and Ling Wei’s group that was published earlier this year. [Sorry for missing it then!] They are investigating potential therapies for stroke, long a frustrating area of clinical research. The “clot-busting” drug tPA remains the only FDA-approved therapy, despite decades of work on potential neuroprotective agents.

Yu’s team takes a different tactic. They seek to bolster the brain’s recovery powers after stroke by mobilizing endogenous progenitor cells. I will call this approach “stem cells lite.”

journal.pone.0087284.g006

PTH appears to encourage new neurons in recovery in a mouse model of ischemic stroke. Green = recent cell division, red = neuronal marker

It is similar to that taken by cardiologist Arshed Quyyumi and colleagues with peripheral artery disease: use a growth factor (GM-CSF), which is usually employed for another purpose, to get the body’s own regenerative agents to emerge from the bone marrow.

In this case, Yu’s team was using parathyroid hormone (PTH), which is an FDA-approved treatment for osteoporosis. They administered it, beginning one hour after loss of blood flow, in a mouse model of ischemic stroke. They found that daily treatment with PTH spurs production of endogenous regenerative factors in the stroke-affected area of the brain. They observed both increased new neuron formation and sensorimotor functional recovery. However, PTH does not pass through the blood-brain barrier and does not change the size of the stroke-affected area, the researchers found.

The conclusion of the paper hints at their next steps:

As this is the first report on this PTH therapy for ischemic stroke for the demonstration of the efficacy and feasibility, PTH treatment was initiated at 1 hr after stroke followed by repeated administrations for 6 days. We expect that even more delayed treatment of PTH, e.g. several hrs after stroke, can be beneficial in promoting chronic angiogenesis and other tissue repair processes. This possibility, however, remains to be further evaluated in a more translational investigation.

Posted on by Quinn Eastman in Neuro 1 Comment

Hypersomnia update: beyond subject one

It’s not sleep apnea. It’s not narcolepsy. Hypersomnia is a different kind of sleep disorder. There’s even an “apples and oranges” T-shirt (see below) that makes that point.

This weekend, your correspondent attended a patient-organized Living with Hypersomnia conference. One of the main purposes of the conference was to update sufferers and supporters on the state of research at Emory and elsewhere, but there was also a lot of community building — hence the T-shirts.

The story of how sleep took over one young lawyer’s life, and how her life was then transformed by flumazenil, a scarce antidote to sleeping pills she was not taking, has received plenty of attention.

Now an increasing number of people are emerging who have a condition similar to Anna Sumner’s, and several questions need answers. Read more

Posted on by Quinn Eastman in Neuro 6 Comments