Fatal Familial Insomnia

Etiology

FFI is part of a family of genetic human prion diseases, including familial Creutzfeldt-Jakob disease, prion protein amyloidosis, Gerstmann-Straussler-Scheinker syndrome, and Huntington disease-like 1.[2] 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 (20p13), responsible for making the prion protein PrPC. Approximately 10% to 15% of all cases diagnosed with prion disease are inherited due to autosomal dominant mutations in the PRPN gene. Specifically, FFI is genetically due to a mutation called D178N, associated with the M129 genotype in the pPrPC gene. Although it is unknown when the disease occurs, evidence suggests that the onset of the disease depends on the critical amount of prion protein conversion to the faulty prion protein.[4][5][6]

Epidemiology

Worldwide, hundreds of cases of FFI have been documented, predominantly in Europe and Asia, with a notable increase in recent years, particularly in China.[7] A total of 131 FFI patients were identified and reported, including 57 women and 72 men. The average disease onset age was 47.5 years, ranging from 17 to 76 years. In the same report, 106 patients passed away, and the disease duration averaged 13.2 months, with a range of 2 to 48 months.[8] The connection between the variations in characteristics across regions and genetic makeup is a subject of scientific interest. A small-scale study suggested that a particular genetic difference at codon 129 of PRNP might be linked to the features of FFI disease. Among Asians, there is an occurrence of symptoms like movements, sleep breathing difficulties, and laryngeal stridor. Additionally, another separate cluster displayed hypertension, excessive sweating, and weight loss. On the other hand, Asians have rates of diplopia (ie, double vision) and myoclonus compared to other ethnicities.[8] Overall, genetic prion diseases are very rare. Annually, 1 to 1.5 new cases of genetic and nongenetic prion diseases per 1 million people.[9] Hereditary forms of prion disease constitute approximately 10% of the total cases of prion diseases.[1]

Pathophysiology

FFI neuropathological changes include neuronal loss and gliosis, particularly in the thalamus, which is responsible for various sensory and motor functions and sleep regulation.[10] Hence, these neuropathological changes contribute to the clinical manifestations of FFI, including severe sleep disturbances and autonomic dysfunction. The spread of pathological changes to different brain regions explains the diverse clinical features observed in individuals with FFI.

Parietal, temporal, and frontal lobes have shown higher involvement degrees than the occipital lobe. Furthermore, the involvement of the brain cortex in almost all cases, with the degree of spongiosis and astrogliosis, is positively correlated to the duration of the disease. However, the prion protein’s deposition pattern favors the brainstem and thalamus earlier in the disease, with the thalamus being most affected by the degenerative changes. The reason for this involvement pattern is poorly understood but can explain the variety of symptoms seen in the disease.[4][6][9]

Histopathology

A Western blot and immunocytochemistry test on human brains showed a disconnection between the amount and location of prion protein deposits, the protease-resistant form, and the severity of the histopathological changes. In a study examining the patient's cerebellar cortex, prion protein deposits were heavily concentrated in the molecular layer and exhibited a unique patchy and strip-like pattern perpendicular to the surface.[11] In another patient from the same study, a single neuron in the inferior olivary nuclei contained abundant protease-resistant prion protein deposits within its vacuoles, which resembled the changes seen in brainstem neurons in bovine spongiform encephalopathy.

History and Physical

Patients with FFI most commonly become symptomatic between the ages of 20 and 61 years, with an average age of 50 years. FFI usually manifests with heterogeneous clinical phenotypes and pronounced neuronal loss and gliosis, particularly in the thalamus.[12] A detailed history and neurological examination are important as FFI is primarily a clinical diagnosis. When interviewing and examining a patient with possible FFI, the following features should be considered:

• Sleep disturbance: Patients can initially present with insomnia (ie, delayed sleep onset latency and decreased total sleep time), which increases in severity as the disease progresses. However, vivid dreaming is common during the limited amount of sleep time. In addition, disruption of normal sleep architecture, increased frequency of periodic leg movements, and central sleep apnea were reported in 40% to 60% of patients.[12] As the FFI disease progresses, it can disrupt the circadian sleep-wake cycle, leading to a confused state during wakefulness (ie, dreamlike status).[13][14]
• Autonomic dysfunction: The patient may present with varying degrees of autonomic dysfunction, including high blood pressure, episodes of tachypnea, increased lacrimation and sweating, constipation, sexual dysfunction, and variabilities in body temperature.[15][14]
• Neurological impairments: Due to the joint involvement of the brainstem, multiple cranial nerves can be affected. Patients can present with double vision early in the disease, swallowing difficulties, and gaze abnormalities. In addition, the onset of extrapyramidal signs and hallucinations occur after a median duration of 12 weeks, after which loss of temporal and spatial orientation becomes evident. Subsequently, dysarthria, ataxia, myoclonus, movement disorders, gait difficulty, and pyramidal signs emerge later in the disease course.[16] Gait dysfunction in FFI can be affected by the disease's duration, which is also determined by the genotype. The progression of gait dysfunction during the disease may reflect the spread of neuronal degeneration from the thalamus to other brain regions involved in gait control.[17] The bulbar and vegetative symptoms and signs become more apparent much later in the disease course, whereas hallucinations were not observed in patients until the advanced stages of the disease. The cortical involvement can manifest as slowing thought processing, attentional disturbances, and short-term memory loss. As the disease progresses, a delirium- condition develops.[16]
• Mental health disease: Behavioral and intellectual capacity remains largely intact even in the late stages. Mood changes are common as patients may become depressed or apathetic as insomnia worsens. Behavioral and intellectual capacity tends to remain largely intact even in the late stages of the disease.[18]
• Systemic and endocrine changes: Progressive frailty and weight loss are seen in most patients.[11] In addition, endocrine dysfunction has been reported as decreased corticotropin (ACTH) secretion and increased cortisol secretion. Additionally, FFI can cause a loss of the normal diurnal variations in growth hormone levels, melatonin, and prolactin.[19]

Diagnostic Clinical Features

In 2022, an international group established diagnostic clinical criteria to help differentiate FFI from other differential diagnoses with similar presenting symptoms and identify the disease at earlier stages. The duration of the following core symptoms is typically <2 years:

• Organic sleep disturbances, including intractable insomnia, agrypnia excitata with or without laryngeal stridor, sleep apnea, or involuntary movements (eg, hypnic jerks, restless sleep with frequent body position changes)
• Neurologic and mental health impairment, including rapidly progressive dementia, ataxia, myoclonus, hallucination, delusion, or personality changes (eg, depression, anxiety, apathy, and confusion)
• Progressive autonomic and systemic abnormalities, including hypertension, tachycardia, irregular breathing, hyperthermia, sweating, or weight loss >10 kg during the last 6 months [20]

In addition to the core clinical features, the following features support a FFI diagnosis:

• Family history of organic insomnia symptoms
• Probable organic insomnia (eg, loss of circadian rhythm, sleep fragmentation, reduction of total sleep time, or sleep–wake cycle disruption) with or without involuntary movements on video polysomnography [20]

Evaluation

FFI is diagnosed clinically; however, various diagnostic studies are typically performed to support the diagnosis and exclude other conditions.[20]

Diagnostic Studies 

• 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) can show a reduction in total sleep time and a dysfunctional transition between sleep stages. Specifically, PSG shows reduced REM sleep, reduced sleep efficiency, and slow wave sleep.[12] 
• 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.[12]
• Cerebrospinal Fluid (CSF) studies for biomarkers (eg, 14-3-3 protein) are non-specific and may be seen in various diseases, causing neuronal death. 

Imaging Studies

• 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) examinations can potentially aid in diagnosing FFI. PET imaging can reveal hypometabolism in the thalamic and cingulate regions with a tendency to spare the occipital lobe.[21]

Molecular Genetic Testing: Suspected patients should undergo genetic testing for targeted analysis of the pathogenic variant of PRNP or full gene sequencing.

Histopathological Testing: Brain biopsies, although nondiagnostic for FFI, may be considered to rule out other neurological diseases.

Diagnostic Approach

Polysomnography and genetic testing are recommended following comprehensive genetic counseling. Specifically, conducting a targeted screening for the D178N mutation of the PRNP gene can aid in diagnosing FFI at an early stage.[2]While clinical diagnostics can provide valuable information, genetic testing, and counseling can help confirm a diagnosis and identify potential risks for family members. Additionally, targeted screening for specific genetic mutations, such as the D178N mutation of PRNP, can be instrumental in establishing an early diagnosis and developing effective treatment plans.[12]

Using the 2022 international group diagnostic criteria, the likelihood of FFI can be determined. This diagnostic approach consists of the core clinical and supportive features and the following diagnostic study findings, and exclusionary factors:[20]

• Exclusionary features
  • Periodic sharp wave complex on EEG
  • Hyperintense signal in the caudate nucleus and putamen or ≥2 cortical regions on imaging or MRI sequencing
  • Pattern of deficits explained by differential diagnoses
• Diagnostic studies: positive molecular genetic testing for PRNP mutation
• Probability of FFI diagnosis based on diagnostic criteria
  • Possible FFI: 2 out of 3 core clinical features without any exclusion features present
  • Probable FFI: 2 out of 3 core clinical features, ≥ 1 supportive feature without any exclusion features present
  • Definite FFI: 2 out of 3 core clinical features and positive diagnostic studies

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.

• Discontinuation of medications that may exacerbate confusion, memory, and insomnia is essential.
• 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.[9]
• Problems with swallowing may warrant the placement of a feeding tube.
• A case report investigated gamma-hydroxybutyrate (GHB) and found its administration to induce slow-wave sleep (SWS) in a patient with FFI.[22]
• Several treatments using compounds such as pentosane polysulfate, quinacrine, and amphotericin B have been studied with inconclusive results.[23]
• A clinical trial is currently being conducted in Italy to prevent the onset of prion disease in individuals who are carriers of the PRNP D178N/M129 mutation. The study involves administering the antibiotic doxycycline 100 mg orally daily for 10 years to 10 carriers and comparing the results with a control group of 15 noncarriers from the same family. The trial is ongoing, and the outcomes are yet to be determined.[24]
• Immunotherapy has reported promising results in vitro and in vivo in animal studies and clinical trials. The 3 main types of immunotherapy research focus on antibody vaccines, dendritic cell vaccines, and adoptive transfer of physiological prion protein-specific CD4(+) T-lymphocytes. Antibody vaccines aim to target unique epitopes only displayed on the misfolded form of prion protein (PrP(Sc)).[25]
• Psychosocial therapy is essential for both the patient and the family. Hospice care can also be beneficial.
(B3)

Differential Diagnosis

When evaluating patients with FFI, consideration of other prion diseases due to overlap in symptomatology is essential,[6][26] including the following:[6][26]

• Sporadic Creutzfeldt-Jakob disease (sCJD) and familial Creutzfeldt-Jakob disease (fCJD) are clinically and pathologically similar, with sCJD being more aggressive with a later onset. Both primarily present with memory problems and confusion, followed by myoclonus and ataxia. Spongiform degeneration and astrogliosis are more profuse and widespread compared to FFI.[27]
• Sporadic familial insomnia (sFI) is well-defined genetic, clinical, and histopathological features that mimic FFI but without the presence of a genetic mutation. Like other neurodegenerative diseases, sFI lacks a precise animal model and effective therapeutic intervention. Developing a precise disease model is crucial to understanding the pathogenic mechanism.[28]
• Gerstmann-Straussler-Scheinker syndrome (GSS) typically manifests with impairments in cerebellar functioning, with little to no disturbance in sleep. Cognitive dysfunction is generally minimal and, if present, is more likely to be observed in the later stages of the disorder. The mode of inheritance for this condition is autosomal dominant, and it displays high penetrance, which can be attributed to a range of point mutations and insertion mutations involving octapeptide repeats.[29]
• 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)[30]

Furthermore, ruling out other causes of dementia, which may be reversible, is necessary. Some of these include, but are not limited to, herpes encephalitis, paraneoplastic syndromes including limbic encephalitis, Hashimoto encephalitis, lithium poisoning, chronic meningitis, HIV encephalopathy, and hydrocephalus.[30][31] 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.[32]

Staging

FFI has been described as having 4 stages:

• Stage 1: The first stage of the disease is identified by the subacute onset of insomnia, which worsens over a 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 3 months is typically dominated by total insomnia and complete sleep-wake cycle disruptions.
• Stage 4: The final stage of the disease can last for 6 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.[33]

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 than heterozygous (Met-Val) patients.[34][35]

Complications

FFI is universally fatal. Various autonomic, cognitive, motor, and endocrine complications. Refer to the History and Physical section for more information on complications of FFI.