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

Joyce Schenkein, PhD; Pasquale Montagna, MD

Disclosures
In This Article

Discussion

This article describes the various strategies that were attempted by an FFI patient to live with his symptoms. Because these approaches were arbitrarily selected, and often combined, altered unsystematically, and occasionally interrupted by medical emergencies, scientific rigor is obviously lacking. The study authors also are frustrated that DF's constant mobility made it difficult to monitor and document his vital signs.

FFI is a rare disorder and case management is not widely known, even among professionals. Each period of DF's hospitalization involved an abrupt and total disruption of treatment protocol, some of which might have compromised later responses to the same medications or even jeopardized his health. Furthermore, when unorthodox methods were tried, records were deliberately made unavailable. Therefore, interpretation of the results was speculative at best.

Finally, the progressive nature of the disorder complicates evaluation of the best approach. However, the fact that DF far outlived and functioned more efficiently than the typical Met-Met patient suggests that at least some of these strategies warrant further study.

The protective value of antioxidant supplements is already recognized in mainstream medicine. Their use may have slowed the progress of DF's disease, possibly by mopping up free radicals that are produced during apoptosis[5] and possibly by reducing tissue damage caused by frequent low-grade fever. VN-3 fatty acids, vitamin E, and coenzyme Q10 may be beneficial in reducing the risk for heart attack associated with emotional stress, physical exertion, and sleep deprivation (Singh, personal communication, 2001).

The use of vitamins does not reverse the disease. However, meganutrients (as provided by the Clymer institute) had the initial result of inducing sleep. Vitamins B6 and B12 and zinc participate in sleep biochemistry.[6] As additional support, DF's father, a lifelong nutritionist and vitamin advocate, did not develop FFI until he was in his mid-70s. No systematic trend has been determined to explain age of onset. In an Austrian family, different members were diagnosed at ages 20, 25, 37, 58, and 60 years.[7] Once the disease is established, the time course may be similar for all patients, that is, the age of onset does not predict the rate of progression.[8] In the absence of a better preventive treatment, a nutritional protocol might be tried for those identified as FFI carriers who have not yet shown signs of the disease.

Narcoleptics tend to be of limited value in FFI. However, ethchlorvynol became more helpful late in the course of the disease, suggesting that it is worthwhile to retry narcoleptic agents despite initial inefficacy. Only the GABA agonist diazepam had a reliable benefit. Physiologically, GABA contributes to the sleep-related reduction of activity in the basal forebrain,[9] to suprachiasmatic nucleus rhythms,[10] and to a drop in arterial pressure and heart rate, mediated through the mediodorsal nucleus of the thalamus.[11] Although DF believed that diazepam helped him sleep, supportive data were not available. Polysomnography performed on other FFI patients who had been medicated with benzodiazepines failed to demonstrate the same spindling activity that occurs in normals.[12,13,14]

Although the various stimulants improve vigilance during sleep deprivation, they differ in their pharmacologic actions and effects on sleep recovery. Comparative studies have shown modafinil to be relatively nondisruptive of subsequent sleep (in terms of reduced need for rebound sleep)[15,16] and subjective restfulness.[16,17] On the other hand, phentermine is associated with a decrease in REM sleep.[18] Amphetamines (eg, benzedrine) and amphetamine-like stimulants tend to reduce sleep efficiency in terms of increased sleep latency, intrasleep wakefulness, and reduction in total sleep time.[16,19] Methylphenidate is known to cause occasional problems with sleep induction, although these attenuate over time.[20] As mentioned, DF preferred the effects of phentermine compared with those of modafinil. This could be either idiosyncratic or reflect the FFI biochemistry.

The potential for an increase in blood pressure that is frequently associated with the use of sympathomimetics did not occur with DF's early use of stimulants. To the contrary, his blood pressure appeared to drop. However, during his illness he developed cardiac arrhythmias, and experienced a heart attack in the 25th month. As a medical precaution, his usual dose of stimulant was reduced. Use of stimulants represents a trade-off between physical and mental well-being.

Both internally (grand mal) and externally (ECT) induced seizures could offer some relief of symptoms through the action of forced sleep. The duration of SWS has been reported to increase significantly during the development of kindling in the hippocampus and amygdala, although later stages of kindling interrupt this process, presumably by interfering with SWS-inducing centers.[21]

The association between epilepsy and sleep deprivation is not normally regarded as therapeutic. In rats, 30 or more seizures results in permanent hippocampal damage.[22] Recent evidence suggested that seizures beget seizures and may be related to sudden premature death.[22] As reported by Cirelli and Tononi,[23] hundreds of genes change their expression in the dentate gyrus a few hours after seizures and electroconvulsive shock, in contrast to fewer than 100 genes of cortical cells, which respond during normal sleep states.[23] An electroencephalogram (EEG) taken of DF in his 24th month showed epileptiform activity, which, although characteristic of end-stage FFI, may reflect either sleep deprivation[24] or earlier ECT experience.

As opposed to ECT, which involves a random and massive impact on brain cells, another strategy may involve the implantation of an electrode into the anterior thalamus or basal forebrain with the hope of specifically activating hypometabolic neurons in the sleep circuit. (Of note, surgical instruments that are used in patients with FFI must receive special postoperative cleaning because prion contamination is not removed by routine sterilization).[25]

A device not tried by DF but which deserves mention is the so-called "sleep machine," which was used in the Soviet Union and Europe during the 1970s.[26] These devices delivered a weak rhythmic DC current to the brain. The subject wore a sleep mask with electrodes buried in it and experienced a pulsing square wave of 1 msecond duration over the eyes and occipital region. Treatments lasted about 30 minutes and were given once daily for several weeks. Subjective reports were of a pleasant and deeply relaxing experience. Insomniacs who were given this treatment experienced a shorter sleep latency than a placebo group (approximately 10 minutes vs 59 minutes).[27]

Exercise, such as long walks, helped DF to maintain overall fitness and permitted sunshine to externally entrain whatever was left of his circadian rhythms. Of interest, studies of prolonged sleep deprivation suggested that vigorous exercise is an effective tool against the excessive sleepiness accompanying sleep deprivation.[28]

At the most superficial level, immersion in the deprivation tank can be equated to a warm bath, which has been shown to induce a 25% to 33% increase in SWS.[28] An additional explanation is that sleep and arousal are governed by opposing systems originating in the pontine (PRF) and mesencephalic (MRF) regions, respectively. In normal sleep, the PRF mechanism predominates and shuts off the MRF waking mechanism. However, in FFI the PRF mechanism is flawed and cannot establish sleep. Therefore, the MRF mechanism always prevails. The only remaining strategy is to externally shut the MRF by dramatically reducing its input.

Classic studies showed that the destruction of the MRF region results in sleep, whereas cutting all of the sensory pathways in the brainstem does not.[29] The MRF region acts as a second type of sensory system in parallel with those of the specific sensory systems, receiving its afferents from various specific tracts passing alongside it.[30] The inputs are multisensory and respond to electrical stimulation of the auditory, visual, and somatosensory systems.[30] Maruzzi and Magoun[29] suggested that the MRF region acts on the nonspecific thalamic nuclei to interfere with their pacemaker activity. Recruiting waves from the thalamus, including the spindling of SWS, could be blocked by stimulation of the MRF region.[29,31] Because most of the input to the MRF region is sensory, then the total absence of sensory input should shift the balance in favor of the PRF region. This model does not explain why barbiturates, which are inhibitory of the MRF region,[30] are of limited usefulness in the treatment of FFI.[4,14]

Limited information is available on another FFI patient, a man in his 60s, who made 3 unsuccessful attempts to sleep in the deprivation chamber. Upsetting hallucinations prevented him from remaining in the tank long enough for sleep to result. However, information was not made available about the pretrial preparation — whether anesthesia or other premedication was used to "start the man off," as had been the case with DF. Those who try this method might consider the finding that, in rats, ketamine administration 4-5 hours before sleep onset is associated with an increase in SWS and delta EEG in subsequent sleep.[21]

Daily exposure to bright lights, which theoretically entrain the melatonin cycle, appears to have been important in establishing sleep for DF. Light exposure is typically not sought by a bedridden FFI patient, but may be of some help in clock setting. In normal subjects kept awake for 36 hours, melatonin release remained robust even during the nighttime of forced wakefulness.[32] GH secretion, however, was absent in this condition. The potential therapeutic value of melatonin and drugs that promote the production of GH in treating sleep disorders is under consideration for treatment of insomnia in the elderly.[33] Naturally cycling melatonin induces SWS and is associated with enhanced immunity, a nocturnal disinhibition of the pituitary-adrenal axis with an associated drop in corticoid levels.[6] Drugs that target ML-1 melatonin receptors (eg, TAK- 375) reduce sleep latency by approximately 15 minutes (and hence, increase the total time asleep by 15 minutes), but without increasing the subjective impression of restfulness compared with placebo.[34]

The effects of meditation are difficult to evaluate for DF, because he was relatively inexperienced with the technique. In addition, he did not begin meditating until his disease was already far advanced and substantial systemic damage had occurred. However, the approach is conceptually sound. Studies of meditating subjects showed a 20% reduction in metabolism (as measured by both O2 consumption and CO2 production), a decrease in skin conductance (or the galvanic skin response) (suggesting anxiety reduction), decreases in blood pressure, and a reduction in heart rate by 3 beats per minute.[35]

The concentration of lactic acid (an indicator of anaerobic metabolism) falls precipitously during transcendental meditation (TM), at a rate 4 times faster than in resting controls. Excesses of lactic acid are normally associated with anxiety, whereas lower levels of lactic acid are associated with a reduction in arterial pressure. EEG shows an increase in alpha waves in the frontal and central brain areas as well as theta in the frontal area. Wallace and Benson[35] postulated that TM results in a hypometabolic state (associated with a reduction in norepinephrine) that is directly opposite the fight-or-flight system of Cannon. To the extent that insomnia is a disorder of stress regulatory mechanisms,[33] TM may protect against the ravages of sympathetic overdrive.

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