Continuing Education Activity

Fatal familial insomnia is a very rare and invariably fatal autosomal dominant neurodegenerative prion disease caused by a mutation of the prion protein (PRNP) gene. Hallmarks of the disease include aggressively progressive insomnia, subsequent autonomic disturbances, including tachycardia, hyperhidrosis, and hypertension, cognitive disturbances including deficits in short-term memory and attention, balance problems, and endocrine dysfunction. The disease is currently incurable and has an average duration of 18 months, ultimately leading to death. This activity describes the pathophysiology, presentation, and management of fatal familial insomnia and highlights the role of the interprofessional team in the care of affected patients and families.

Objectives:

• Describe the pathophysiology of fatal familial insomnia.
• Review the presentation of fatal familial insomnia.
• Summarize the treatment options for fatal familial insomnia.
• Explain interprofessional team strategies for enhancing care coordination and communication to enhance the management of fatal familial insomnia and improve outcomes.

Introduction

Fatal familial insomnia (FFI) is a remarkably rare and invariably fatal inherited neurodegenerative prion disease. The mode of inheritance of this disease is autosomal dominant and involves a mutation of the prion protein (PRNP) gene. Aggressively progressive insomnia, with subsequent autonomic (tachycardia, hyperhidrosis, hypertension), cognitive (short-term memory and attentional deficits), motor system (balance problems), and endocrine dysfunction are a hallmark of the disease. The disease is currently incurable and has a mean course of 18 months, ultimately leading to death. The earliest description of the disease dates back to 1765 with a report of an Italian man with symptoms suggestive of FFI. The disease was formally identified and clinically described in 1986 by Lugaresi E. et al., followed by subsequent studies, further describing its pathophysiology, etiology, and clinical course.[1][2]

Etiology

The cause of FFI has been identified as an autosomal dominant mutation at the codon 178 of the PRNP gene, located on the short (p) arm of chromosome 20 at position p13 responsible for making the prion protein PrPC.

The disease-causing mutation consists of substitution from the normal aspartic acid (Asp) to asparagine (Asn). The presence of methionine at codon 129 is distinct for FFI compared to valine at the same position in familial Creutzfeldt-Jakob disease (fCJD). Furthermore, an aggressive form of the disease has been linked to the configuration of the nonmutated allele (Met) at codon 129 of the disease-causing mutated gene. The more aggressive variant has methionine (Met-Met) on the nonmutated allele compared to when it has valine (Met-Val).

Evidence suggests that the onset of the disease depends on the critical amount of PrP conversion to the faulty prion protein.[2][3][4]

Epidemiology

Genetic prion diseases are very rare. Annually, there are 1 to 1.5 new cases of genetic and non-genetic prion diseases per one million people.[5] Genetic forms of prion disease constitute approximately 10% of the total cases of prion diseases. FFI is exceptionally rare with the disease-causing mutation found in around 50 families worldwide.[4] Patients with fatal familial insomnia (FFI) most commonly present between the ages of 20 and 61 years with a mean of 50 years and it affects males and females equally.[6]

Pathophysiology

Fatal familial insomnia (FFI) remains neuropathologically ambiguous but is seen to manifest as a focal neuronal loss in the thalamus, inferior olivary nucleus, cerebellum, and varying degrees of spongiform changes in the cerebral cortex.

FFI is described to mainly affect the thalamus with a propensity for anterior ventral and mediodorsal thalamic nuclei. Other parts of the brain, including the inferior olives of the medulla oblongata and the cerebral cortex, have also been shown to be involved.

Parietal, temporal, and frontal lobes have shown higher degrees of involvement compared to the occipital lobe. Furthermore, the entorhinal cortex shows involvement in almost all cases, and the degree of spongiosis and astrogliosis is positively correlated to the duration of the disease. The prion protein’s deposition pattern favors the brainstem and thalamus earlier in the disease, but the thalamus is understood to be more vulnerable to subsequent degenerative changes. The reason for this involvement pattern is poorly understood but can explain the variety of symptoms seen in the disease.[2][4][5]

History and Physical

Patients with fatal familial insomnia (FFI) most commonly present between the ages of 20 and 61 years with a mean of 50 years. The disease leads to death eventually, and the course can range from 7 to 36 months, with a mean of 18 months. Patients with the homozygous Met-Met variant exhibit a shorter mean survival time in comparison to heterozygous Met-Val.[4][6]

A detailed history and neurological examination are of paramount importance as FFI is largely a clinical diagnosis. When interviewing and examining a patient with possible FFI, the following points need to be considered:

• Patients can initially present with insomnia (total sleep time decreased), which increases in severity as the disease progresses. However, vivid dreaming is common during the limited amount of sleep time. Daytime sleepiness is not uncommon. History should be formulated to rule out different causes of insomnia.
• The patient may present with varying degrees of autonomic dysfunction in the form of high blood pressure, episodes of tachypnea, increased lacrimation and/or sweating, constipation, sexual dysfunction, and/or variabilities in body temperature. 
• Common involvement of the brainstem warrants a detailed examination of cranial nerves. Patients can present with double vision (early disease), dysarthria (late disease), swallowing difficulties, and/or gaze abnormalities. 
• Cortical involvement can manifest as slowing of thought processing, attentional disturbances, and short-term memory loss. As the disease progresses, a delirium-like state will eventually prevail. Behavioral and intellectual capacity tends to remain largely intact even in the late stages of the disease.
• An examination of gait can reveal ataxia, which worsens as the disease progresses.
• Weight loss is seen in most patients.
• Mood changes are common as patients may become depressed and/or apathetic as insomnia worsens.
• Changes in muscle tone coupled with weakness and abnormal movements may be seen, which tend to worsen with the duration of the disease.
• Detailed family history is important due to the heritable nature of the disease.

A diagnostic criterion following the analysis of the frequency of presenting symptoms has been proposed.[7]

• Obligatory organic sleep disturbances: If not yet clinically apparent, polysomnography (PSG) must be performed.

At least two of the following “CJD-like" symptoms/signs:

1. Psychiatric symptoms including visual hallucinations, personality changes, depression, anxiety, aggressiveness, disinhibition, listlessness
2. Ataxia
3. Visual
4. Myoclonus
5. Cognitive deficits

At least one of the following “relatively disease-specific" symptoms/signs:

1. Loss of weight with a cutoff point of greater than 10 kg during the last six months
2. Vegetative symptoms including hyperhidrosis, tachycardia, obstipation, hyperthermia

Evaluation

Labs

• The initial workup should include a complete blood count (CBC), erythrocyte sedimentation rate (ESR), serum chemistry, liver function tests (LFT), ammonia levels, and blood cultures for suspected bacterial infections.
• Investigating reversible causes of cognitive decline should include thyroid function tests (TFT), vitamin B-12, and folate levels, along with testing for neurosyphilis and human immunodeficiency virus (HIV) testing.

Polysomnography (PSG)

• PSG can show a reduction in total sleep time and a dysfunctional transition between sleep stages. 

Electroencephalogram (EEG)

• Periodic sharp-wave complexes (PSWC) can suggest prion disease but are seen in only a small percentage of patients with genetic forms of prion disease. Pathogenic variants with pronounced spongiform degeneration and CJD-like clinical presentation are more likely to have an abnormal EEG.
• Although non-specific, patients with FFI show generalized slowing without periodic sharp-wave complexes.

Cerebrospinal Fluid (CSF) Studies

• CSF studies for biomarkers such as 14-3-3 protein are non-specific and may be seen in a variety of diseases, causing neuronal death. 

Imaging

• Computed tomography (CT) and magnetic resonance imaging (MRI) have limited value in diagnosing FFI but may help rule out other neurological pathologies.
• Reduced thalamic diffusion may be present on diffusion MRI due to gliosis. Atrophic changes may become evident as the disease progresses.
• Fluorodeoxyglucose positron emission tomography (FDG-PET) imaging can reveal hypometabolism in the thalamic and cingulate regions with a tendency to spare the occipital lobe.

Molecular Genetic Testing

• Suspected patients should undergo genetic testing for targeted analysis of the pathogenic variant of PRNP or full gene sequencing.

Brain Biopsy

• Brain biopsies, although non-diagnostic for FFI, may be considered to rule out other neurological diseases.

Treatment / Management

Treatment is largely centered on symptomatic relief and palliative care as there is no cure for FFI. Different treatment modalities mentioned in the literature are as follows.[8][9][10]

• Discontinuation of medications that may exacerbate confusion, memory, and/or insomnia is important.
• FFI patients show an inadequate response to sedatives. Tinuper P et al. described a lack of effect of barbiturates or benzodiazepines on EEG in FFI patients.
• Problems with swallowing may warrant the placement of a feeding tube.
• Reder AT et al. investigated gamma-hydroxybutyrate (GHB) and found its administration to induce slow-wave sleep (SWS) in a patient with FFI.
• Several treatment options using compounds such as pentosane polysulfate, quinacrine, amphotericin B have been studied with inconclusive results.
• An Italian study using doxycycline, as a treatment option, over a period of 10 years is ongoing.
• Psychosocial therapy is important for both the patient and the family. Hospice care can also be beneficial.

Differential Diagnosis

When evaluating patients with FFI, it is important to consider other prion diseases due to overlap in symptomology.[4][11]

• Sporadic Creutzfeldt-Jakob disease (sCJD) and familial Creutzfeldt-Jakob disease (fCJD) are clinically and pathologically similar, with sCJD being more aggressive (6 months or less) with a later onset. Both primarily present with memory problems coupled with confusion followed by myoclonus and ataxia. Spongiform degeneration and astrogliosis are more profuse and widespread compared to FFI. 
• Gerstmann-Straussler-Scheinker syndrome (GSS) presents mainly with cerebellar dysfunction with limited to no problems with sleep. Cognitive dysfunction is minimal at most and can be seen in the later stages of the disease. 
• Variably protease-sensitive prionopathy can present with varying degrees of aphasia and behavioral symptoms and is best diagnosed with histopathological examination.
• Lithium toxicity
• Familial myoclonic dementia
• Diffuse Lewy body disease
• Chronic meningitis
• Dementia as a paraneoplastic syndrome
• Dementia in motor neuron disease
• Nonherpes viral encephalitis
• Hashimoto encephalopathy (or steroid-responsive encephalopathy associated with autoimmune thyroiditis [SREAT])
• Limbic encephalitis (and other paraneoplastic syndromes)[12]

Furthermore, ruling out other causes of dementia, which may be reversible, is necessary. Some of which include but are not limited to, herpes encephalitis, paraneoplastic syndromes (including limbic encephalitis), Hashimoto encephalitis, lithium poisoning, chronic meningitis, HIV encephalopathy, and hydrocephalus.[12][13]

Neurodegenerative diseases, including Alzheimer's disease, Pick disease, corticobasal degeneration, multiple system atrophy, frontotemporal dementia, and familial myoclonic dementia, irrespective of their slow progression, should be considered during evaluation.[14]

Staging

FFI has been described to have four stages:[15]

• Stage 1: The first stage of the disease is identified by the subacute onset of insomnia, which worsens over a period of few months and causes psychiatric symptoms such as phobia, paranoia, and panic attacks. During this time, patients may report lucid dreaming.
• Stage 2: In the next 5-month period, psychiatric symptoms worsen along with worsening insomnia, and patients experience hallucinations. Autonomic dysfunction in the form of sympathetic hyperactivity is seen.
• Stage 3: This short stage of around three months is typically dominated by total insomnia and complete disruptions of the sleep-wake cycle.
• Stage 4: The final stage of the disease can last for six months or more and is defined by rapid cognitive decline and dementia. Patients experience an inability to voluntarily move or speak, which is followed by coma and eventual death.

Prognosis

The disease course can last from 7 to 36 months, with an average duration of 18 months leading to eventual death. Patients with homozygous (Met-Met) mutation have a shorter mean survival time compared to heterozygous (Met-Val) patients.[16][17]

Complications

FFI is universally fatal. Various autonomic, cognitive, motor and endocrine complications can be present as described above.

Deterrence and Patient Education

Patients and families should be thoroughly educated about the fatal course of FFI. They should also be made aware that there are limited treatment options currently, but that studies are ongoing. Genetic counseling should be offered to family members as well.

Enhancing Healthcare Team Outcomes

Fatal familial insomnia is best managed by an interprofessional team, including sleep specialists, neurologists, psychiatrists and psychologists, social workers, palliative nurses, and hospice care. This disorder has no cure and is managed by first making the patient comfortable and improving the quality of life. Hospice should be involved early in the care. Psychosocial counseling for family members is necessary as well.