Self-management of Fatal Familial Insomnia. Part 2: Case Report

Joyce Schenkein, PhD; Pasquale Montagna, MD

In This Article

Case Report

DF was a right-handed, 52-year-old, white, American man with a doctorate in naturopathy. DF's father, paternal uncle, and 2 male cousins were diagnosed with fatal familial insomnia (FFI). His father died at age 76; his uncle died at age 74; and each of DF's cousins died before the age of 50. Because disease onset beyond age 60 is rare, it is worth mentioning that DF's father was a prominent talk radio nutritionist who promoted the regular consumption of wheat germ and who richly supplemented his own diet with antioxidant vitamins. Because the trigger that begins FFI is unknown, the possibility that a specific diet might delay onset is worth considering.

Although DF had always been a short sleeper and nocturnally active, in March 2001, he experienced a marked reduction in the duration of his sleep and occasional nights of total insomnia. This symptom did not initially concern him. However, in subsequent months, the additional appearance of a hand tremor, fever spikes, profuse sweating, and problems with short-term memory led him to seek medical attention. The diagnosis of FFI (subtype Met-Met) was confirmed by DNA testing.

At this time, DF was 10 months into his illness (stage I). He resolved to make the most of his life before the onset of stage IV. DF purchased a motor home and embarked on a solo tour of the United States. He typically drove great distances, but only after a refreshing sleep; he would stay in rest stops for several days until again renewed by sleep. Before embarking, he required himself to recall many numbers, including his date of birth, social security number, etc, and drove only if he remembered all of these.

When he was stranded by prolonged insomnia, DF was frequently disoriented and confused. He reported sometimes finding himself in a parking lot without knowing how he got there, or discovering by the date on a newspaper that several days had elapsed. After 5 months of traveling in this fashion (18 months into his illness), he hired a professional driver and caretaker. During this period, DF was besieged by a number of medical illnesses that were either a consequence of his illness or his treatments, eg, fevers as high as 102°F, hypertension, cardiac arrhythmias, renal hypertension, diabetes, and a heart attack. Descriptions of DF's treatments were conveyed either by phone or emails from his caretakers. Unfortunately, corroborative physiologic measures were not always available.

Shortly after his diagnosis (at 10 months into the disease), DF received vitamin therapy at the Clymer Institute for Alternative Health in Quakertown, Pennsylvania. At 9:00 o'clock every evening, DF took a combination of niacin, antioxidant powder (comprising vitamins A, C, E, and D), blue-green algae, brewer's yeast, B complex, zinc (sublingually), magnesium, inositol, PABA, grape seed extract, CoQ-10, choline, Tiger's Milk nutrition bar, highly concentrated wheat germ oil, tryptophan, and 2 g of melatonin. He also injected a gelatinous form of B12 into his nasal cavity.

Within 30 minutes of this treatment, DF reported that he fell into a natural and restful sleep. On this regimen, he experienced 5 out of 6 consecutive nights of sleep, ranging from 5 to 6.5 hours per night. (Prior to these treatments, he had frequently endured 72-96 hours of total insomnia.)

Later in his illness, DF added what he referred to as massive, but unspecified, doses of octocosonal (a spinach derivative prepared with long-chain alcohols). Of all supplements, he found this to be most effective and quick-acting in masking symptoms of fatigue following long periods of sleeplessness.

By the 20th month, DF had added a commercially available combination of vitamin B12, B6, and folic acid formulated for sublingual absorption. Because this preparation was taken in conjunction with other medications, it cannot be evaluated independently.

By month 15 (early stage II), vitamins alone failed to induce sleep. Following 5 consecutive nights of insomnia, DF became intensely irritable and delusional. An evaluation at the Massachusetts General Hospital in Boston, Massachusetts, found that he had suffered a minor stroke; he was anesthetized until he fell asleep. While hospitalized, he slept for 3 consecutive days and was fully alert and refreshed afterward.

In later months, DF continued the strategy of anesthesia. Ketamine and nitrous oxide induced short (15-minute) periods of restful sleep, and were reapplied to offer more prolonged relief. Chloral hydrate in a light alcohol mix and/or chloroform also worked.

Approximately 15 months into his illness, DF began to take sleep medications on a rotating schedule. Ethclorvynol, zolpidem, and diazepam reliably relieved his insomnia for roughly 1 month. During subsequent months, only diazepam offered intermittent relief. DF took 90 mg daily before bedtime, plus 2 doses of 30 mg each during the day. In the 24th month of his illness, he retried the other narcoleptics and discovered that both zolpidem and ethclorvynol again helped him sleep. The ethclorvynol also functioned as a mood elevator.

At month 16, when the narcoleptics ceased to work, DF rarely slept. Indeed he lost awareness of whether he had slept or not and no longer felt refreshed. He likened his insomnia to the experience of approaching an open doorway, only to have it suddenly become inaccessible. He said that something of a "jolt" would overtake him and render him vitally awake. Subjectively, he found this experience to be exhilarating, similar to a drug-induced high. As his disease advanced and he was physically more debilitated, this phenomenon became less appealing. In addition, that doorway to sleep became progressively more remote, and was obliterated by any noise or distraction.

At 16 months, his symptoms included consistently elevated body temperature (as high as 102°F), profuse sweating, serious impairment of short-term memory (for which he compensated by keeping lists), difficulty maintaining attention (he often did not know that the phone was ringing), difficulty distinguishing reality from fantasy (he didn't remember whether he had called a friend or had only imagined doing so), persistent headaches, hallucinations while driving (believed he saw people on the road when it was, in fact, empty), panic attacks (which were treated with meprobate), and a complete loss of sense of time. His blood pressure was 160/90 mm Hg, from a premorbid 120/80 mm Hg.

Much of the time DF was confused, and sat entranced for hours. On occasion, he would get up for water, forget why he had gotten up, and return to the couch empty-handed. He might repeat this behavior for hours, never actually obtaining the water and not guided by the fact that he was thirsty. He could not decipher notes that he had written to himself on previous days. His speech was dysarthric.

By the 16th month of his illness, DF spent much of the day as an akinetic mute with terrible headaches, confusion, mood swings, and myoclonus of the left arm (treated with levodopa). Despite his outward "dementia," he inwardly pondered approaches to his condition, and, when again able to speak, he requested a regimen of stimulants.

He was prescribed phentermine HCl 37.5 mg (time-release), which he took twice daily and eventually 3 times daily (before meals and no later than 6:00 pm). The drug had immediate and dramatic effects, promoting not only alertness during the day, but apparently a sleep-inducing rebound when it wore off. He described the sleep experience as "natural"; he felt well upon arising, despite a slight headache that faded as the day wore on. For 4 consecutive nights, DF slept 5 hours each night, was able to drive, and returned to his daily routines, which included writing a novel. It was at this time when he began taking walks to physically tire himself. He no longer felt confused and reported that, aside from problems with his short-term memory and sense of time, he felt as well as before the onset of FFI. His blood pressure fell from 160/90 mm Hg to 140/80 mm Hg. His body temperature had returned to normal (98.2°F), and he did not experience any feverish surges in temperature while taking the medication.

Unfortunately, he was accidentally overmedicated by his caretakers and received 2 pills (75 mg) of phentermine in close succession. This overdose resulted in cardiac arrhythmias and another hospital stay. Medical examination revealed protein in his urine and tiny retinal hemorrhages, and stimulants were discontinued. He spent subsequent weeks sleeplessly and in the characteristic stupor of stage III. When the phentermine was resumed, DF regained his ability to function and drive, but after a week, believed that he had developed a tolerance to the drug. It was no longer alerting him, nor was he sleeping.

At that point, methylphenidate offered some relief. After a few days, however, DF had a grand mal seizure and was again hospitalized. Although his thinking was clear and oriented, his speech was labored, dysarthric, and perseverative, and his fever had returned.

During his last months, DF received a new stimulant protocol, and he took these on a daily rotating basis: diethylpropion + propoxyphene-acetaminophen (for headaches), methylphenidate, phentermine, modafinil, and a benzedrine inhaler (which is illegal in the United States, but which he was nevertheless able to obtain). Benzedrine enabled him to successfully drive 500 miles alone (on several occasions) during the 24th month of his illness. DF believed that the diethylpropion + propoxyphene-acetaminophen combination restored his function to that of a far earlier stage of the disease. However, phentermine was his preferred stimulant because he was always able to sleep well when it wore off. Of interest, DF said that if taken when he was exhausted, phentermine interfered with his sleep, whereas when rested, it improved both the quality of his day and his sleep. He believed that the benefit of phentermine was dose-related and that the exhausted person should take a much lower dosage to enable the sleep rebound.

While using these various stimulants, DF slept about 16-18 hours/week, or roughly half of his preillness baseline. Thus, many symptoms of FFI abated with the stimulants; however, the long-term effects of these medications in conjunction with his ongoing disease resulted in extensive kidney damage and may have contributed to the cardiac problems that appeared in the 25th month of his illness. In the 26th month, DF began taking time-released benzphetamine (90 mg) and a small amount of methylphenidate to reduce the stress on cardiovascular and renal systems.

Because the exhausted FFI patient tends to be inactive, DF implemented regular walks to increase natural fatigue and enhance the likelihood of sleep. An exhausted insomniac seems to be a poor candidate for physical rigor. Furthermore, if elevated temperature is toxic for patients with FFI (McGinty, personal communication, 2002), then heat loads and stress should be avoided. Ironically, regular exercise is considered critical for overall health, fitness, and quality sleep for most of these patients. In particular, because the homeostatic imbalance of the FFI patient is biased to sympathetic overdrive, some form of "fight-or-flight" activity may be appropriate. Because DF's response to rigorous exercise was rapid overheating with slow recovery to baseline temperature, he maintained moderate but persistent activity and believed that he derived benefit from the workout.

Noting that his grand mal seizure was followed by restful sleep, DF sought to duplicate the experience with electroconvulsive therapy (ECT). Beginning in the 19th month of his illness, he subjected himself to 30 sessions during several weeks. The ECT attendant placed the electrodes over the temporal lobes. The frontal area might have been a wiser choice because reduced function of the basal forebrain is common in FFI and previous research has shown that electrical stimulation to the basal forebrain can induce slow-wave sleep (SWS) in cats.[1]

Some form of sleep accompanied each of DF's experiences. Unfortunately, in his posttreated state, he experienced severe anomia, profound retrograde amnesia (extending back several years), and a disagreeable and paranoid overtone to his personality. Although these effects attenuated over the following weeks and long-term memory did return, DF was reluctant to repeat the experience. In retrospect, DF would have used a lower than conventional ECT voltage level and electrode placement over the frontal area.

Over time, the efficacy of DF's medications and strategies decreased. Despite occasional sleep lasting 5 hours in 1 night, periods of insomnia increased to as long as 3+ days. In tandem with insomnia, his cognitive functioning diminished.

At 22 months into his illness, DF purchased a sensory deprivation tank; a man-sized, egg-shaped chamber designed to eliminate all sensory input. DF became interested in this chamber because his sleep was constantly disturbed by any small sound, light, or motion.

In the sensory deprivation tank, the individual floats in concentrated Epson salt water at body temperature (experiencing no pain, gravity, temperature, touch, or kinesthetic information). Eyes and ears are shielded from light and sound, and the lid is shut. This device promotes total muscular relaxation. In the initial Hebb-Lilly experiments in the 1950s, subjects fell asleep shortly after entering one of these devices.[2] Upon awakening, most demanded immediate release. Those who remained experienced hallucinations, and had difficulty performing simple math calculations and tests of motor coordination (eg, walking and writing). The more time spent in the chamber, the more disoriented the later behavior.

Upon being immersed, DF was immediately anesthetized with nitrous oxide until he fell asleep. (Sleep was determined by a reduction in his heart and breathing rate). At his first attempt, he remained asleep for 4.5 hours. Subsequent use always resulted in the rapid onset of an unpredictable amount of sleep, ranging from 10 minutes to 8 hours. Similar to Hebb's subjects, upon awakening DF experienced disturbing hallucinations, - with the subjective uncertainty as to whether he was awake or dead. As always, long periods of sleep restored DF's mental clarity, suggesting, again, that at least some of the "confusion and dementia" of the FFI patient may be a consequence of insomnia.

For about 2 months, DF routinely used the deprivation chamber (unless hospitalized or traveling). Of note, while DF was away from his sleep tank, he was still able to sleep for 1-2 hours per night (see "Meditation"). Unfortunately, during one of his times away, winter temperatures froze the water in his outdoor tank and cracked its shell, rendering the device useless. DF chose not to replace it, noting that it limited his driving mobility and made him feel like the comic book freak Aquaman, who nightly slept in a fish tank.

To a person who lacks a circadian rhythm, "bedtime" is arbitrary. Early in the course of his illness, DF tried to maintain an artificial 24-hour diurnal rhythm. As his disease progressed, however, he took stimulants whenever he woke up, independent of chronologic hour, preferring to function at his best possible level, even if the hour corresponded to the normal local bedtime for others. Until roughly the 23rd month, DF's sleep patterns showed a definite cycle, which may have reflected his rotating schedule of the various medications. The first night, he slept well; the second night, less well; and the third, still less, followed by 1-2 sleepless nights. Then the cycle repeated.

Because of inconsistent results in the sleep tank, DF explored ways to externally bias his biorhythms to favor sleep at specific times. These involved daily exercise; exposure to sufficient sunlight; and timed use of melatonin, diazepam, and tryptophan. Early, but not later, in the course of his disease, this combination was effective. In the 24th month of his illness, DF began taking growth hormone (GH) prior to and after sleep. The immediate effect of GH was a dramatic reduction of his previously high blood sugar level. GH alsolowered his temperature from 102°F to normal. Because DF's experiments were interrupted by several, long, solo driving expeditions (away from his sleep tank), data collection was not complete.

Gamma-hydroxybutyrate (GHB) was administered during the last month of DF's life. To reduce the possibility of negative interaction with diazepam, he tapered his dosage for several days before trying GHB. According to his caretaker, GHB resulted in sleep within 30 minutes of administration, but did not last long enough for DF to feel rested. Similar to Reder's patient, described in Part 1, DF felt achy and irritable most of the time. He was unable to resume his stimulants because of potential heart and kidney failure.

During his last month, he was hospitalized for heart problems. Use of GHB was discontinued at this time and this was shortly followed by cardiac arrest. A causal association between stopping GHB and cardiac arrest cannot be made in view of the preexisting cardiac pathology and long-standing FFI. However, this reaction is also reminiscent of Reder's patient at the termination of the medication, and of the reports of others that abrupt cessation of GHB can lead to withdrawal symptoms, including tachycardia and hypertension.[3] At the minimum, it can be said that DF did not receive the expected benefit of GHB. Others have reported a nonresponse to GHB in patients with FFI.[4]

Whenever he traveled or was hospitalized and away from his sleep tank, DF practiced meditation. This technique enabled him to achieve what he described as "sleep," or a restful, restorative state.


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