NIGHTMARE LETHARGY

  While living in New York City in 1923, a woman named Eleanore Carey developed severe pain in the back of her head, which migrated to her shoulder. She later became feverish and fell into a “drugged lethargy, a semiconsciousness filled with the hodge-podge thoughts of a nightmare.” Years later, Carey, who started but did not complete medical school, wrote about her experiences for the American Mercury magazine.8 She wrote that her semiconscious state lasted for more than three months. She only dragged herself out of it because of her need to care for her young daughter. Her description of her daily existence sounds like Anna’s: “My entire day was clouded by one obsession—the wish to sleep. It was torture—this continual forcing oneself to keep conscious, and a great part of that time I was not entirely conscious—going about in a daze.” Friends viewed her with condescension or aversion, Carey wrote. She lost several jobs because her employers thought she was taking recreational drugs. A landlady accused her of being a “chronic inebriate” because of her confused appearance and behavior. A doctor who had cared for her during her months of delirium told her she should be grateful to be alive.

  In her article, Carey did not describe any cataplexy-like symptoms, so it was unlikely that she had the type 1 form of narcolepsy. Despite pleas to her doctor, she did not mention being given any medications; the stimulant ephedrine was first given for narcolepsy around 1930. She did recall symptoms consistent with hypnogogic hallucinations and also sleep inertia: “I find it difficult, particularly when I first rouse myself out of the lethargy, to remember directions.”

  Three years after the acute phase of her illness, Carey wrote that she could fall asleep in a warm bathtub and wake up hours later, the water having grown cold. She could slip into sleep while getting dressed or while waiting on a crowded subway platform. She thought of her life as divided like a soldier’s: before and after the war. Carey would fit in today at a hypersomnia support group meeting, although the term idiopathic would not apply, because encephalitis was the precipitating event.

  DEVASTATION WITHOUT A KNOWN CAUSE

  The pathogen responsible for encephalitis lethargica remains a mystery. To this day, nobody knows what caused it. Many in the 1920s proposed that encephalitis lethargica was related to the worldwide influenza pandemic that killed millions during and after World War I. Confusion came because encephalitis lethargica arrived when understanding of viruses was limited. It was before scientists had developed tools, such as filters and electron microscopes, for separating and visualizing viruses. In addition, because of press attention, encephalitis lethargica was overdiagnosed, and experts today believe that the label was applied to people with more than one underlying disorder. For her part, Eleanore Carey reported having the flu in 1917, years before her disabling encounter with encephalitis.

  Von Economo doubted that influenza was the cause of encephalitis lethargica, because he began seeing encephalitis cases before the flu arrived in Vienna, and he thought encephalitis lethargica was not as contagious as flu. He did believe encephalitis lethargica was infectious and tried to culture the pathogen responsible in monkeys. Several researchers unsuccessfully searched for a herpes-like virus as a potential culprit for encephalitis lethargica. Research on the origin of the disease had “run into sand” by 1930, according to the Australian medical historian Paul Foley.

  In the early 1980s, William Foege, then head of the U.S. Centers for Disease Control, reignited the debate. In the Lancet, Foege and his colleague Reimert Ravenholt argued that influenza infection almost certainly caused encephalitis lethargica. Their research was based on analyzing health records from Seattle and comparing the epidemic’s course in American and Western Samoa.9 They wrote that von Economo’s attention to extreme sleepiness “helped distinguish such cases, but distracted diagnostic and epidemiological attention from the much broader range of neurological disorders caused by influenza.”

  Modern molecular tools were used to look at autopsy samples from a few encephalitis lethargica cases, but no influenza virus was detectable.10 In autopsy samples, investigators in London have glimpsed viral particles and detected genetic sequences resembling those of enteroviruses, relatives of the virus that causes polio.11 However, this still hasn’t settled the matter, given the limited number of samples available and their condition after almost a century. Other researchers have proposed that encephalitis lethargica was the result of a slow burn, not driven by the pathogen directly: an autoimmune reaction perhaps brought about by bacterial infection.12

  NEUROANATOMICAL LEGACY

  In addition to human devastation, encephalitis lethargica established a scientific legacy. Von Economo observed that while most encephalitis patients developed lethargy and hypersomnolence, some developed insomnia. The first group had damage to a region of the brain near the junction of the brainstem and forebrain, close to the nerves that control eye movements (N. oculomot in figure 11.3). The second group had lesions in a more anterior region.

  Some of the sleepiness in acute encephalitis lethargica probably came from temporary inflammation and cytokines. Still, the anatomical distribution of sleep disturbances drove von Economo to postulate the existence of a two-part “center for regulation of sleep” in the brain. He attained his insights based on pathology; he described in detail what the destruction in the brain looked like under a microscope. He was building on ideas from others, such as the Austrian neuroanatomist Ludwig Mauthner, who made a similar proposal in the nineteenth century. Von Economo gave a nod to Pieron’s hypnotoxins, suggesting that the sleep regulatory center was more sensitive to fatigue-related substances than other brain regions.

  FIGURE 11.3. Diagram from von Economo. Lesions in the posterior wake-promoting region, marked by slanted lines, resulted in hypersomnolence. Injury to the anterior sleep-promoting region, marked by horizontal lines, resulted in insomnia.

  Source: Lazaros C. Triarhou, “The Percipient Observations of Constantin von Economo on Encephalitis Lethargica and Sleep Disruption and Their Lasting Impact on Contemporary Sleep Research,” Brain Research Bulletin 69, no. 3 (2006). ©2006 with permission from Elsevier.

  Over the long term, von Economo’s ideas were influential, although they met with resistance at the time. Neuroscientists celebrate him today because his predictions approximated what is now known about the brain’s circuitry. Parts of von Economo’s sleep regulatory center may match up to regions of the hypothalamus.13

  Sandwiched between the thalamus and the pituitary, the hypothalamus is a fingernail-sized structure in the middle of the brain. The hypothalamus lies at the center of a network of brain circuits that filter sensory stimulation and pain and focus attention and alertness. In addition to regulating sleep and wake, the hypothalamus is home to several bundles of neurons that regulate body temperature, heart rate, blood pressure, and appetite. It’s as if a house’s light switches, plumbing shutoff valve, thermostat, and alarm clock were all together on one panel.14

  Von Economo sometimes gets credit for correctly guessing that the hypothalamus is ground zero for narcolepsy type 1. In a 1929 lecture, he predicted that narcolepsy “has its primary cause in a yet unknown disease of that region.” However, he wasn’t very precise. His diagram appears to include both the posterior hypothalamus and territory farther back, extending to a region known as the periaqueductal gray. Today, neuroscientists have established that several wake-promoting circuits run through that area.

  Putting this together, a venerable and still viable theory for idiopathic hypersomnia is that people with IH have experienced something similar to what happened to Eleanore Carey. This idea frames IH as a regional neuronal injury, somewhat like narcolepsy type 1. Many people with IH recall that they began to feel extra sleepy after a viral infection, whether it was influenza, Epstein-Barr, or some other virus. Widespread neuroinflammation, seen in postviral chronic illnesses, can leave individuals with a long list of symptoms, sometimes including excessive sleepiness and brain fog. For IH, a case can be made that a more selective strike is occurring against the regions of the brain that regulate sleep. The site of injury could be part of the hypothalamus or another region of the brain.

  Bedřich Roth considered this mechanism a possibility, since he had several patients with hypersomnia resulting from encephalitis. His French and Czech mentors had studied encephalitis lethargica, and Roth cited von Economo extensively in his books. Although Roth made a distinction between symptomatic hypersomnia, coming from encephalitis, and functional or idiopathic hypersomnia, he wrote in 1980: “It is therefore highly probable that the same structures are affected in the two conditions and that they have the same type of pathophysiological mechanisms—i.e. excessive facilitation of non-REM sleep.”15

  Supporting a hypothalamic lesion theory, people who undergo surgery for tumors or cysts close to the pituitary or hypothalamus often experience severe hypersomnolence, attributed to tissue injury inflicted by the tumor or by surgery. One 2002 study found that children who underwent such surgeries slept an average of more than thirteen hours per day.16 Another case review of children with brain tumors concluded: “Children who sustained damage to the hypothalamic/pituitary region developed EDS [excessive daytime sleepiness] regardless of whether the damage was the result of the tumor, surgery, hydrocephalus, or radiation to the whole brain.”17

  While the hypothalamus is a plausible place to look for problems in both narcolepsy type 2 and IH, we have to be careful about availability bias: the error of the drunk man looking for his keys under a bright street lamp. Also, perturbing the hypothalamus can affect several other aspects of physiology besides sleep. Injury to another area of the hypothalamus can lead to diabetes insipidus: daily generation of gallons of urine, which is generally not a symptom of IH!

  However, many people with IH do experience symptoms of autonomic nervous system dysfunction.18 Examples include feeling lightheaded or fainting upon standing up, as well as numbness in the extremities in response to cold (Raynaud’s syndrome), both of which are related to problems regulating blood pressure or blood flow. Others include problems regulating body temperature, including heavy sweating or feeling colder or warmer than others in the same room, and gastrointestinal difficulties.

  Whatever is happening in IH has to be restricted in scope. IH doesn’t leave someone with tremors or paralyzed limbs, and it is uncommon for people with IH to have recognizable abnormalities on a brain MRI scan.19 With IH, we should not focus on lesions in regions such as the parabrachial nuclei of the brainstem, the equivalent of the fuse box in the basement, where injuries can produce a coma. Instead, we are looking for what may be a subtler injury—a bruise, not a gaping wound.

  THE HOME BASE OF SLEEPINESS

  Learning about the hypothalamus also allows us to envision the sources of the symptoms experienced by people with IH. If sleepiness can be localized within any specific place in the brain, the hypothalamus could be considered its headquarters. Neurologists now think that the anterior part of the hypothalamus is the most probable location of the sleep-promoting region von Economo identified. He certainly knew about the hypothalamus; some of his teachers in Vienna were the first to do experiments testing its physiological function with electrical stimulation. However, in von Economo’s often-cited 1929 lecture, he only mentions the hypothalamus once, to say that the sleep-promoting region may extend into it.

  Decades of experimental work in animals, beginning in the 1940s with the Dutch neuroscientist Walle Nauta, have refined our understanding of the sleep-promoting region’s location and function.20 In mice and rats, one of the critical bundles of neurons within the hypothalamus is called the VLPO (VentroLateral PreOptic area). During sleep, neurons within the VLPO and allied regions act like a source of soothing music, helping keep the rest of the brain asleep with inhibitory GABA signals.21 The VLPO has connections to other parts of the hypothalamus and to several wake-promoting regions in the brainstem and forebrain. Along with the basal forebrain, the VLPO is thought to be a main target for both adenosine and for GABA-enhancing sedative and anesthetic drugs. Because of its role as a source of inhibition via GABA, the VLPO may be the site in the brain where flumazenil loosens the grip of sleepiness.

  In the 1990s, Cliff Saper’s group at Harvard defined the importance of the VLPO in regulating sleep in rats.22 VLPO neurons are responsible for sending messages of sleepiness to the rest of the brain when time awake has lasted too long. That is, they increase firing when an animal is kept awake during a time when it would normally be asleep, even for a few hours.23 VLPO neurons are active during both REM and non-REM sleep, and their activity ramps up as sleep deepens.24

  While most studies of the VLPO’s role in sleep were performed in animals, some evidence for its importance comes from looking at older humans. Loss of neurons in the VLPO’s counterpart in humans, the intermediate nucleus of the hypothalamus, has been associated with greater sleep fragmentation, or awakenings that interrupt nighttime sleep.25 Aging-related loss of sleep-promoting cells may partly explain why older people are less susceptible to sleep deprivation, in terms of sustained attention.26 It’s not that older people need less sleep; they are less sensitive to the molecules that prompt the transition into sleep.

  Saper has described the mutually inhibitory relationship between VLPO neurons and wake-promoting regions as resembling a “flip-flop” electrical circuit. He credited one of his graduate students, trained as an electrical engineer, with introducing him to the concept. In a flip-flop circuit, when signals from one side get strong enough, they squeeze out activity on the other side. Like a see-saw, the system is stable on either side but not in the middle. The circuit’s organization may explain why sleep typically dissolves quickly after someone wakes up. In people with IH who experience sleep inertia or sleep drunkenness, some of the flip-flop switches may have become stuck, so that VLPO activity continues after waking.

  David Rye’s proposal about IH and related sleep disorders was not mainly about where the problem in the nervous system occurs. It was about what makes people sleepy (the suspected somnogen) and how (GABA). However, his proposed mechanism shares something with Mahlon DeLong’s insight regarding Parkinson’s. Underactivity in one part of a brain circuit can result in overactivity in another. When Rye described giving stimulants to Anna as like driving a car with the parking brake on, he envisioned the sleep-promoting regions of the brain—namely, the VLPO and allied regions in the hypothalamus—as the overactive brake. On the other side, several regions of the brain activated by stimulants, both within the hypothalamus and beyond it, grind against the brake.

  The hypothalamus appears to be the site where many forces—temperature, sensory stimulation, attention, extended time awake, or recent food consumption—engage in a tug of war over sleepiness (figure 11.4). Recent research has revealed that the VLPO is not a uniform bundle, and some neurons in it can be wake-promoting. Nearby bundles of neurons in the hypothalamus are also active in promoting sleep, and their function is intertwined with temperature regulation.27 This may explain why sleepiness is so sensitive to skin temperature.28

  FIGURE 11.4. The VLPO (ventrolateral preoptic area) inhibits the activity of several wake-promoting regions, such as the tuberomammillary nucleus (TMN), the ventral periaqueductal gray (vPAG), the locus coeruleus (LC), and the dorsal raphe. Damage or impaired function of these regions in idiopathic hypersomnia has not been documented.

  Source: C. B. Saper et al., “Hypothalamic Regulation of Sleep and Circadian Rhythms,” Nature 437 (2005). Reprinted by permission from Nature ©2005.

  A LONG BIOLOGICAL NIGHT

  The second theory about IH hasn’t received as much fanfare as Rye’s GABA-enhancing somnogen theory, but it has caught on with others in the sleep research field. It is more concerned with the processes that are disrupted rather than with a particular region of the brain or an underlying cause. The second theory says that people with IH, especially those who require long sleep periods, may have a distortion of their circadian rhythms. Robert Thomas, a neurologist at Beth Israel Hospital in Boston, uses an evocative phrase to describe this imbalance, saying that people with IH have a “long biological night.” It may explain why IHers have such difficulty waking up in the morning—their bodies and brains tell them that it’s the middle of the night.

  In the early 1980s, the Swiss sleep researcher Alexander Borbely developed a “two-process” model for how the body regulates sleep. It’s a bit simplified, and the two-process model leaves out a lot, including the powerful effects of our conscious behavior. Still, it’s a helpful way to think about the forces that may be driving excessive sleepiness in someone with IH.

  The first major force is Process C: the circadian rhythm or body clock, which corrals our sleep into daily cycles of light and dark imposed by the sun. Circadian rhythm–promoted wakefulness is part of what keeps someone functioning during daylight hours, even if they have had little sleep or poor sleep the night before. Circadian rhythms drive inconvenient wakefulness in jet-lag, when someone quickly shifts to a different time zone. In addition to sleepiness, circadian rhythms modulate body temperature and processes such as metabolism, urination, and digestion.

  Circadian clocks can be found in every cell in the body. They consist of oscillations in the levels of a set of core clock proteins. When enough of the core clock components accumulate, they are able to block activity of the corresponding genes that encode the same proteins. This creates a delayed negative feedback loop, making the clock proteins’ abundance swing up and down, with a rhythm of about twenty-four hours. Many cellular enzymes modify the core clock proteins, offering opportunities for regulatory adjustment and entrainment—the influence of light.