Agrypnia Excitata: Current Concepts and Future Prospects in Management

Fatal familial insomnia is characterized by behavioral disturbances, ataxia, pyramidal signs, autonomic problems, and widespread neurological compromise. 3 After the initial onset of symptoms, FFI evolves rapidly, and death occurs months after the first symptom sets in. 3, 4 The symptoms of FFI are directly related to the area of neurological involvement in the disorder. Since the thalamus and associated thalamic structures are the most affected in FFI, it stands to reason that bodily functions controlled by the thalamus are commensurately affected in patients with FFI. The thalamus is a prominent mass of gray matter located above the brainstem that controls bodily functions including motor control and somatosensory and visual sensory signals. It also relays sensory signals to and from the cerebral cortex and vital anatomical structures throughout the body. Typically, patients complain of persistent insomnia, frequent nocturnal awakenings, and persistent daytime fatigue. 1, 5, 6 Autonomic activation in the form of excessive salivation and perspiration along with elevated blood pressure, tachycardia, pyrexia, and appetite disturbances are also common. 1, 6, 7 Bizarre dreams often occur and tend to be superseded by a stupor-like state that eventually leads to coma and death. 1

During sleep, the ability of the thalamus to effectively relay such signals becomes compromised, allowing the body to succumb to the sleep state. Therefore, the thalamic dysfunction that ensues in FFI yields a myriad of problems associated with the aforementioned thalamic functions, namely those related to or affected by sleep. The disease runs a uniformly fatal course that manifests in four stages ( Table 1 ). Ultimately, patients expire 18 months after the onset of symptoms. 2 Common clinical features of FFI include hallucinations, phobias, dementia, decreased reflexes, and an inability to lacrimate or appreciate pain. 1, 2 Later stages of the disease lead to autonomic dysfunction, which manifests as dementia, coma, and loss of sphincter control. 1 The wide array of symptoms in FFI has led experts to classify it as a pleiotropic disease, or a disease with one mutant gene that yields one mutant protein but results in many phenotypic abnormalities. The pleiotropic basis of the disorder may account for the significant variation in disease presentation from individual to individual, even in patients from the same family.

Fatal familial insomnia is transmitted via autosomal dominant inheritance, meaning it affects both genders with equal frequency. 8, 9 On average, individuals with the mutant gene most often develop symptoms between the ages of 40 to 60 years, with an average of onset at 51 years old. 10 Death ensues by 32–72 weeks after first onset of symptoms. 5 – 7, 10

Fatal familial insomnia results from a genetic mutation in the prion protein gene, or PRNP gene, that results in the replacement of asparagine with aspartic acid at codon 178, along with substitution of asparagine for methionine at codon 129. 1, 3, 11 Although the exact function of the PRNP gene remains uncertain, it is likely involved in the cell signaling in the CNS. The inborn genetic error in FFI results in a dramatic accumulation of protease resistant prion protein, which is responsible for the cognitive dysfunction that characterizes the disorder. 1 The mutation yields significant thalamolimbic impairment, which is believed to cause the striking phenotypic and clinical features of FFI. 1, 3 Pathology and imaging studies corroborate this finding by demonstrating widespread hypometabolism throughout the thalami of patients with FFI. 3 Furthermore, the presence of atrophy, gliosis, and neuronal loss in the thalami along with spongiosis in the cerebellum is a common finding in patients with FFI. 1, 3, 9 The atrophic changes within the thalamus that characterize FFI are believed to underlie the sleep, autonomic, and circadian disturbances that appear in FFI. 1, 4

A number of tests are used to diagnosis FFI. Since FFI is familial in origin, a thorough family history may help in arriving at an accurate diagnosis. A thorough physical examination and detailed history are recommended to rule out systemic or exogenous conditions as a cause of clinical presentation. The physical exam of FFI patients often demonstrates bilateral hyperreflexia and reflex myoclonia. 3 Laryngeal examination may also demonstrate paralysis of the laryngeal cords. 3 Although exact cause of death in FFI remains unclear, experts have pointed to the paralysis of laryngeal cords in FFI as a possible cause of laryngospasm-induced death in such patients. 3, 4 Given the many neuropsychological sequelae of FFI, comprehensive neuropsychological testing is warranted. Depending on the stage of disease development, the patient may demonstrate any of a wide array of symptoms from hallucinations, behavioral disturbances, autonomic disturbances, alteration in attention and immediate memory, or a propensity to confabulate. 3 The patient’s history will reveal significant sleep disturbances in the form of insomnia and repeated nocturnal awakenings. As with other patients with deterioration of sleep function, a polysomnogram is considered necessary for the diagnosis of FFI and typically reveals the complete absence of spindles and slow-wave sleep along with extended REM periods without muscle atonia. 1, 3, 4, 12 Stridor, nocturnal groaning, loud snoring, and persistent talking and moving may also be present during polysomnogram testing in FFI patients. 3 Finally, given the genetic nature of the disease, genetic testing for mutations in the D178N gene in codon 129 can help confirm the diagnosis. 3, 8, 11

Although FFI runs a fatal course, recent data suggest that the use of vitamins, sedative-hypnotics (e.g., ethchlorvynol, zolpidem, or diazepam), stimulants, sensory deprivation, exercise, light entrainment, and growth hormone may offer promising methods of managing FFI patients. 13 – 17 Electroconvulsive therapy may improve symptoms in such patients through forced sleep and the use of vitamins, sedative-hypnotics, and stimulants may yield improved quality of life by minimizing stupor-like states that often accompany periods of prolonged sleeplessness. 13, 14, 17 Despite improving a patient’s ability to sleep, ECT should be used with caution due to the myriad of side effects such therapy courts, including memory loss and cognitive damage. 13, 18, 19 Despite advances in therapeutic strategies and the resultant improvement in symptoms of FFI, a cure for FFI continues to elude clinicians. The need for broader research on the topic is warranted considering the fact that all patients expire within 32–72 weeks after first onset of symptoms. 5, 7