Fatal Familial Insomnia: What Happens When You Can't Sleep

NhiVan Tran -

Introduction

Memory loss, paranoia, double vision, disorientation, confusion, and an abnormal sleep pattern: these were the irregular symptoms of a 57-year-old man in the Netherlands. During the day, he would fall asleep while carrying out his regular activities, and his sleep was riddled with vivid dreams and frequent muscle jerks. He soon began experiencing painful, itching sensations in both arms and lost concerning amounts of weight despite eating more food. Four months after his symptoms began, he was disoriented, struggled to pay attention, and his limbs twitched spontaneously. Trying to pinpoint the problem, his doctors ordered an array of tests, and the sleep study in particular turned up the most interesting results: the patient’s brain waves were irregular compared to those typically associated with sleep. One of the only other clues in this perplexing mystery was the fact that his sisters and father had been affected by similar symptoms. However, the doctors could not decode the identity of the bewildering illness before his health began to rapidly decline. Soon after, he passed away at the age of 58—only seven months following the onset of his symptoms. Following his death, the hospital performed an autopsy; sequencing of the patient’s genome, in combination with his symptoms, pointed to Fatal Familial Insomnia (FFI) as the culprit [1].  

FFI is a rare genetic disease of the central nervous system that causes all patients to gradually lose the ability to sleep over the span of a mere few months, ultimately leading to death. FFI is extremely rare and has a rate of diagnosis of about one in a million annually [2]. As of 2018, only around 200 members of 70 different family lines and 18 people with no familial history of the disease have been diagnosed [3]. Although the average age onset of FFI is around 50 years of age, the disease has appeared as early as 20 and as late as 61. The illness can last anywhere between 7 to 36 months, with an average duration of 18 months [4, 5]. This disease severely impacts the brain, altering our sleep and a host of other bodily functions, making it crucial that we understand its causes and how it functions. 

Causes Of FFI:

FFI is a neurodegenerative prion disease. Healthy human prion proteins (PRNP) are located on the surface of every cell and have been suggested to bring together different proteins to create a stable structure that can perform a variety of functions [6]. Prion diseases arise due to abnormal, disease-causing prions that can be introduced genetically or through medical treatment. This causes the misfolding of the shape of the healthy prion protein, creating an infectious agent that continues to build up, replicate, and spread throughout the nervous system [6]. These misfolded prion proteins damage and destroy neurons, leading to neuropathological and psychological behavioral changes like dementia, paranoia, mood change, and eventually death.

DNA is composed of four building blocks called nucleotides which are named adenine (A), thymine (T), guanine (G), and cytosine (C) respectively. These nucleotides are arranged in different sequences and act as an instruction manual to construct proteins out of amino acids. These amino acids are then used to build all the different proteins that make up our cells. It only takes one change in our DNA for FFI to occur. To cause FFI, the mutation of PRNP changes a codon, a sequence of three nucleotides, on chromosome 20 from GAC to AAC. This change causes the incorrect sequence of amino acids to be built into the protein and causes the prion protein to misfold and change shape, leading to the symptoms associated with FFI such as dementia and the altered sleep patterns in FFI [2].

There is an additional variation of the PRNP gene which affects single amino acids in the protein and can increase the risk and severity of FFI. At one point in the gene, the amino acid can either be a methionine or a valine. Because each person receives a PRNP gene copy from each parent, they can inherit two methionines (met/met), a methionine and a valine (met/val), or two valines (val/val) in this position. Most of the time, FFI patients with the met/met amino acid combination present symptoms at an earlier age than the average onset age, survive for a shorter time period, and have more severe disruptions in sleep rhythms when compared with patients who have the met/val variant [7, 8, 9, 5]. It is currently unknown exactly why the met/met combination results in a different level of risk, but some researchers speculate having met/met could facilitate greater structural changes in the PRNP [8].

Contrasting patterns in disease onset for individuals with met/met and met/val combinations is illustrated in one case study where a 23-year-old woman presented with double vision whenever she looked down, to the left, or to the right. After being examined, she was diagnosed with bilateral trochlear nerve palsy, a condition that causes double vision and was quite unusual for a person her age [10]. She also had a family history of prion disease through her maternal grandfather and his brother. Genetic analysis determined she had the mutation for FFI along with the met/met combination. Three months later, she began presenting with symptoms characteristic of FFI, including a disrupted sleep cycle, cognitive decline, nervous system disorders, and movement dysfunction. Given that FFI usually affects people around 50 years of age and lasts an average of 18 months, her early symptoms and rapid neurodegeneration at such a young age are considered to be associated with the met/met combination. Only five months later, she died due to respiratory failure related to FFI [9].

While patients like the 23-year-old woman can die of respiratory failure, there is no clear uniform cause of death in patients with FFI. For many patients though, one symptom seems to consistently appear: disruption in the sleep cycle and a reduced overall sleep time [5]. The University of Chicago performed a study showing that complete sleep deprivation in rats lead to weight loss, debilitation, poor resistance to infection, a lowered body temperature, and eventually death [5]. Considering humans and rats have a similar genetic profile, sharing about 95% of the same genes, as well as a similar brain structure, this study’s results suggest that sleep deprivation may be enough to cause many FFI symptoms [11]. In human studies performed by the Cerrahpasa Medical School, a lack of sleep was found to lower immune response, worsen short-term memory, cause a loss of sensory acuity and motor speed, induce visual hallucinations, and cause behavioral changes [5]. Sleep deprivation, as a result, is thought to be the main cause of death in patients with FFI given how crucial sleep is for both humans and animals.

FFI and Sleep 

Extreme sleep disturbances in FFI can be explained by looking at a region in the brain called the thalamus. Located near the center of the brain, the thalamus is a hub which coordinates the proper execution of cognitive processes happening across the brain, including sleep. A hallmark of FFI pathology is thalamic degeneration with neuronal loss ranging anywhere from between 50% to 80% of neurons lost at time of autopsy. This neurodegeneration is due to infection from the misfolded prion proteins [7, 4].  Though not as severe as in the thalamus, there is also neuronal loss observed in other regions of the brain. Alterations to the regulation of molecular processes, such as protein folding, are also observed in FFI though molecular changes correlated to the disease are not well understood [7]. The degeneration in the thalamus results in the disrupted sleep cycles we see in patients with FFI [2].

When we sleep, different populations of neurons exhibit different firing patterns than when we are engaging in a relaxing activity such as sitting. The thalamus’ nuclei play an important, though not completely clear, role in synchronization. They receive extensive input from the brainstem, which regulates sleep and projects these electrical signals to other parts of the brain. Thus, The thalamus’ position allows it to help activate different parts of the brain that work together to produce sleep and its brain waves [12, 13].  

Scientists can measure brain waves using electroencephalogram (EEG) tests that track the electrical activity in the brain using electrodes attached to the scalp. These electrodes pick up electrical charges from the brain and present them on a graph with waves representing the electrical activity. In EEG tests, non-rapid eye movement (NREM) stages of sleep show synchronized activity in the thalamocortical areas. These electrical waves between nuclei clusters result in brain wave oscillations of different frequencies during different times during sleep [12]. 

Normally, humans experience sleep in four different stages regulated by our circadian rhythm. The first three stages—Stage 1 (N1), Stage 2 (N2), Stage 3 (N3)—make up non-rapid eye movement (NREM) sleep. When we first start falling asleep, both alpha and beta waves are present, which indicate a high level of brain activity, similar to when we are awake [14]. When presented on a graph, these waves are densely packed together. During N1, low-amplitude mixed-frequency brain activity replaces half of the alpha waves present. N2 and N3 occur in our deepest stages of sleep, with about half the time of sleep spent in N2. It is during this time that sleep spindles and k-complexes, two different wave types typically measured by EEG during sleep, are produced. N2 is when we first see sleep spindles, characterized by high-frequency bursts of brain activity. They are caused by interactions between neurons in the thalamus and the cerebral cortex; on the graph, the waves look like wool spindles unraveling. The waves here are even more densely packed than the alpha and beta waves but only occur sporadically. K-complexes also emerge during N2, with long slow waves lasting for a second, showing the transition into a deeper state of sleep. Their measured waves are higher in amplitude than alpha and beta waves. In N3, the K-complexes completely replace the sleep spindles seen in N2. Lastly, REM sleep is when dreaming occurs, and the brain waves present are very similar to when we are awake. These stages will usually cycle throughout the night. FFI changes patients’ sleep schedules completely [14].

For patients with FFI, changes to the thalamus lead to atypical brain waves and disruptions in sleep. They do not, however, suddenly stop sleeping all at once. In fact, in a study from 1993 to 1997, a group of nine German patients with FFI were asked to report their symptoms and wear an EEG headset while sleeping. The group consisted of FFI patients with ages of onset ranging from 44 to 70, with the duration of the disease lasting between 8 to 16 months. EEGs conducted during the study revealed periodic sharp waves or k-complexes, suggesting disturbed sleep. Despite the EEG results, observable sleep disturbances were only recognized with the help of family reports and viewing old hospital records, meaning the patients themselves could not tell they were awake. In FFI patients, sleep EEGs show a state of sub-wakefulness; rhythms and patterns during the sleep cycle do not resemble those normally associated with sleeping or waking. Even if patients think they are sleeping, their sleep patterns can still show a lack of necessary sleep rhythms needed to reap the benefits [15]. 

Patients with FFI display a wide array of symptoms, many of which are unique to each individual case [7]. The most notable are prominent sleep impairment and neuropsychiatric disorders, such as dementia [2, 7]. In one study of five FFI patients, all patients were affected by sleep-related symptoms of insomnia, involuntary movements, difficulty breathing, and laryngeal stridor—noisy or high-pitched sounds when breathing. The patients also had rapidly progressive dementia, and a few presented with other symptoms such as motor abnormalities. There are also involuntary response symptoms that include hypertension, sweating, rapid heart rate, and irregular breathing [2]. With such a diversity of symptoms, in addition to its low prevalence, a clear set of diagnostic criteria is needed for diagnosis. 

Diagnosis:

Diagnosis of FFI can be difficult, especially in cases without a family history of prion diseases, and due to the small sample size of FFI patients to study. Generally, a diagnosis is based on symptoms, clinical exam, imaging tests, labs, and sleep studies [16]. Unlike some other prion diseases, lab testing is not as insightful. For example, MRIs and EEGs can be normal at the onset of the disease, providing no clues for diagnosis. The new diagnostic criteria, suggested by a team at Georg-August University, takes this into account. It consists of three categories with specific requirements for each [17]: 

A) Organic sleep disturbances (A sleep study can be performed if this criteria is not initially apparent.) 

  • These include insomnia, hypersomnia, restless sleep, and sleep attacks

B) Two or more of the following “CJD-like symptoms/signs”

  • Psychiatric symptoms, impaired coordination, muscle jerks, visual or cognitive defects

C) At least one of the following “relatively disease-specific symptoms/signs”

  • Loss of weight with a cut off of >10 kg during the last six months, vegetative state, husky voice

By applying the new diagnostic criteria to a group of patients with FFI, the team found they could make an accurate diagnosis for 9 out of 10 patients. That statistic lowered slightly to 8 out of 10, when the criterion was also applied to Creutzfeldt-Jakob disease (CJD). The study establishing this diagnostic criteria also showed 100% correct diagnosis in patients with the met/val polymorphism and 88% in the patients with the met/met polymorphism. In addition, the median time of diagnosis was 4.4 months after onset of symptoms, allowing patients more time to get treatment [17]. 

Treatment:

Because there is no cure for FFI, treatment centers around managing symptoms. This could include discontinuing medications that worsen confusion, memory, and insomnia. Trying to induce sleep with current sedatives is not effective, but there are ongoing studies being conducted to find alternatives to sedatives [18]. 

In one Italian study, a 10-year trial tried using Doxycycline, a protein production inhibitor, to prevent FFI in high-risk patients is underway. Additionally, one patient experienced increased slow-wave sleep after the administration of the depressant gamma-hydroxybutyrate, a controlled substance in the United States [18]. Generally, though, treatment is specific to the individual and their symptoms and requires the specialized care of a team of healthcare personnel. Psychosocial support for the patients and their families is crucial as well. 

Treating FFI as if it was another closely-related illness has been shown to have temporary positive effects. A 46-year-old man came to the Emergency Department after four months of symptoms including amnesia, attention impairment, a tremor, gait instability, progressive insomnia, severe weight loss, involuntary muscle jerks, and excessive sweating. A number of antibody and genetic tests were conducted, but due to the rapid deterioration of the patient’s symptoms, a flurry of medical treatments consisting of steroids, antibodies, and anticonvulsants was given before a clear diagnosis. His medical team initially prescribed him medications for another debilitating neurological disorder, autoimmune encephalitis, which also presents with insomnia and autonomic failure. After this course of medication, the patient showed improved symptoms. His tremor and involuntary muscle jerks resolved themselves, his cognition, mood, and insomnia improved, and he regained control of his gait [19]. However, despite the initial improvements, his symptoms began to worsen; this included a general loss of movement, inability to communicate, disorientation, worsened insomnia, and restlessness. He died seven months after the initial onset of the disease. A genetic study revealing a mutation in the PRNP gene confirmed he had FFI [19].

Another possible treatment could be the use of a type of drug called corticosteroids, which are used to decrease inflammation. It has been suggested inflammation plays a role in neurodegenerative disorders, especially in prion diseases. There is an inflammatory response to neurodegeneration, and in cases like these, immunotherapy can help to lessen the symptoms caused by inflammation. While promising, there have been no human studies conducted, so further research is needed to better understand this route of treatment [19]. 

Conclusion:

Fatal Familial Insomnia is an extremely rare inherited prion disease. Despite its low frequency in the population, its effects are fatal. While the basic concept of not being able to sleep that defines FFI seems simple enough, the experiences and symptoms of patients are wide-ranging, complicated, and affect their lives severely. This disease still remains unknown to many, and different aspects of it still require further research. 

By studying FFI, its causes, and symptoms, we can better understand prion diseases, sleep, and other dementia-related diseases, such as CJD and even Alzheimer’s and Parkinson’s—studies that revolve around neurodegeneration. Thus, while FFI may not directly impact every individual, further research into it can help not only those that are diagnosed with it but also those with other neurodegenerative diseases. 

References:

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