Fatal Familial Insomnia: Understanding this Rare Prion Disease

Introduction

Fatal Familial insomnia (FFI) stands as an exceptionally rare and devastating inherited neurodegenerative condition, classified as a prion disease. This relentlessly progressive disorder is intrinsically linked to a mutation within the prion protein (PRNP) gene, following an autosomal dominant inheritance pattern. The defining characteristics of FFI encompass a cascade of debilitating symptoms, starting with intractable insomnia that rapidly escalates. This is soon accompanied by profound autonomic dysregulation, manifesting as tachycardia, hyperhidrosis, and hypertension. Cognitive functions are significantly impaired, notably affecting short-term memory and attention. Patients also experience balance disturbances and endocrine abnormalities, painting a grim clinical picture. Currently, there is no cure for FFI, and the disease typically runs a rapid course, averaging just 18 months from onset to death.

Diagnosis of fatal familial insomnia hinges primarily on a meticulous clinical evaluation, underscored by a detailed patient history and thorough neurological examination. While there is no curative treatment, management strategies focus on alleviating symptoms and providing comprehensive palliative care to improve patient comfort and quality of life during the disease progression. This article serves as a resource for healthcare professionals, aiming to enhance their knowledge in diagnosing and managing fatal familial insomnia, selecting appropriate diagnostic modalities, and fostering effective interdisciplinary teamwork to optimize patient outcomes in this challenging condition.

Etiology of Fatal Familial Insomnia

Fatal familial insomnia is categorized within the spectrum of genetic human prion diseases. This group also includes conditions like familial Creutzfeldt-Jakob disease, prion protein amyloidosis, Gerstmann-Straussler-Scheinker syndrome, and Huntington disease-like 1. The root cause of FFI is a specific autosomal dominant mutation located at codon 178 of the PRNP gene. This gene resides on the short (p) arm of chromosome 20 at position p13 (20p13) and is responsible for producing the normal prion protein, PrPC. Inherited mutations in the PRPN gene account for approximately 10% to 15% of all diagnosed prion disease cases. Specifically, FFI arises from the D178N mutation, which is typically associated with the M129 genotype in the pPrPC gene. The precise timing of disease onset remains unclear; however, current evidence suggests that the development of FFI is contingent upon the accumulation of a critical mass of prion protein that has converted into its misfolded, pathogenic form.

Epidemiology of Fatal Familial Insomnia

Globally, fatal familial insomnia remains exceedingly rare, with only hundreds of documented cases. The majority of these cases have been reported in Europe and Asia. Notably, there has been an observed increase in reported cases in recent years, particularly in China. A comprehensive review identified 131 patients with FFI, comprising 57 women and 72 men. The mean age of disease onset was 47.5 years, with a wide range from 17 to 76 years. Among these patients, 106 had died, with an average disease duration of 13.2 months, varying from 2 to 48 months. The variability in FFI characteristics across different geographical regions and ethnic backgrounds is an area of ongoing scientific investigation. A smaller study has indicated a potential link between a specific genetic variation at codon 129 of the PRNP gene and the clinical features of FFI. In Asian patients, symptoms such as abnormal movements, sleep-related breathing difficulties, and laryngeal stridor appear to be more prevalent. Another distinct cluster of symptoms observed in Asian populations included hypertension, excessive sweating, and significant weight loss. Conversely, diplopia (double vision) and myoclonus seem to be less common in Asians compared to other ethnic groups. Overall, genetic prion diseases are exceptionally uncommon. The annual incidence of both genetic and non-genetic prion diseases is estimated to be 1 to 1.5 new cases per million people. Hereditary forms, such as fatal familial insomnia, constitute approximately 10% of all prion disease cases.

Pathophysiology of Fatal Familial Insomnia

The neuropathological hallmark of fatal familial insomnia is characterized by neuronal loss and gliosis, particularly concentrated in the thalamus. The thalamus is a critical brain structure involved in a multitude of sensory and motor functions, most notably sleep regulation. These pathological changes in the thalamus directly contribute to the cardinal clinical features of FFI, including severe sleep disturbances and autonomic dysfunction. The progressive spread of these pathological changes to other brain regions accounts for the diverse range of clinical symptoms observed in individuals affected by FFI.

Studies have shown that the parietal, temporal, and frontal lobes exhibit more significant involvement compared to the occipital lobe in FFI. Furthermore, the cerebral cortex is affected in almost all cases, with the degree of spongiosis and astrogliosis correlating positively with the duration of the disease. However, the deposition pattern of the prion protein tends to favor the brainstem and thalamus in the earlier stages of the disease, with the thalamus consistently exhibiting the most pronounced degenerative changes. The precise reasons for this specific pattern of involvement remain poorly understood, but it offers a plausible explanation for the heterogeneity of symptoms seen in fatal familial insomnia.

Histopathology of Fatal Familial Insomnia

Histopathological examination of brain tissue in fatal familial insomnia reveals unique characteristics. Western blot and immunocytochemistry analyses have demonstrated a notable disconnect between the quantity and distribution of prion protein deposits, specifically the protease-resistant form, and the severity of the observed histopathological changes. In one study focusing on the cerebellar cortex of FFI patients, prion protein deposits were found to be highly concentrated in the molecular layer, exhibiting a distinctive patchy and strip-like pattern oriented perpendicularly to the surface. In another patient examined in the same study, a single neuron within the inferior olivary nuclei contained abundant protease-resistant prion protein deposits within its vacuoles. These vacuolar changes were reminiscent of those observed in brainstem neurons in bovine spongiform encephalopathy, highlighting the prion protein’s role in the disease process.

History and Physical Examination in Fatal Familial Insomnia

The typical age of symptom onset for fatal familial insomnia ranges from 20 to 61 years, with a mean age of approximately 50 years. FFI often presents with varied clinical phenotypes, but a consistent neuropathological finding is pronounced neuronal loss and gliosis, especially within the thalamus. A detailed patient history and a thorough neurological examination are paramount, as FFI diagnosis is primarily based on clinical assessment. When evaluating a patient suspected of having FFI, specific clinical features should be carefully considered.

Diagnostic Clinical Features of Fatal Familial Insomnia

In 2022, an international consensus group established diagnostic clinical criteria to aid in differentiating FFI from other conditions that may present with similar symptoms and to facilitate earlier disease identification. The duration of the following core symptoms is typically crucial for diagnosis:

Organic sleep disturbances: These are hallmark symptoms and include intractable insomnia, agrypnia excitata (a state of wakefulness with motor and autonomic hyperactivity, sometimes with laryngeal stridor), sleep apnea, or abnormal involuntary movements during sleep (e.g., hypnic jerks, restless sleep with frequent changes in body position).
Neurologic and mental health impairment: This category encompasses rapidly progressive dementia, ataxia, myoclonus, hallucinations, delusions, or personality changes (such as depression, anxiety, apathy, and confusion).
Progressive autonomic and systemic abnormalities: These include hypertension, tachycardia, irregular breathing patterns, hyperthermia, excessive sweating (hyperhidrosis), or significant weight loss (greater than 10 kg or approximately 22 lbs) within the preceding 6 months.

In addition to these core clinical features, certain supporting features can strengthen the suspicion of FFI:

Family history of organic insomnia symptoms, suggesting a genetic predisposition.
Probable organic insomnia, characterized by disruptions in circadian rhythm, fragmented sleep, reduced total sleep time, or overall sleep-wake cycle disturbance, potentially accompanied by involuntary movements observed on video polysomnography.

Image: Brain MRI scan in FLAIR sequence showing hyperintensity in the basal ganglia and cortex, which can be indicative of prion disease, though thalamic atrophy is more specific to FFI.

Evaluation and Diagnosis of Fatal Familial Insomnia

While fatal familial insomnia is primarily a clinical diagnosis, several diagnostic studies play a critical role in supporting the clinical suspicion and excluding other potential conditions.

Diagnostic Studies for Fatal Familial Insomnia

Initial Laboratory Workup: A comprehensive initial evaluation should include a complete blood count (CBC), erythrocyte sedimentation rate (ESR), serum chemistry panel, liver function tests (LFTs), ammonia levels, and blood cultures, particularly if bacterial infections are suspected as part of the differential diagnosis.
Assessment for Reversible Causes of Cognitive Decline: To rule out treatable conditions mimicking FFI, thyroid function tests (TFTs), vitamin B-12 and folate levels should be assessed. Testing for neurosyphilis and human immunodeficiency virus (HIV) is also recommended.
Polysomnography (PSG): This sleep study is highly informative in FFI, often revealing a significant reduction in total sleep time and disruptions in the normal transitions between sleep stages. Specifically, PSG in FFI typically shows reduced REM sleep, decreased sleep efficiency, and a reduction or absence of slow-wave sleep.
Electroencephalogram (EEG): While periodic sharp-wave complexes (PSWC) on EEG are suggestive of sporadic Creutzfeldt-Jakob disease and other prion diseases, they are not commonly seen in genetic forms like FFI. Patients with FFI typically exhibit generalized slowing on EEG, but without the characteristic periodic sharp-wave complexes.
Cerebrospinal Fluid (CSF) Analysis: CSF biomarkers, such as the 14-3-3 protein, are not specific for FFI and can be elevated in various conditions causing neuronal death. Therefore, CSF analysis has limited diagnostic utility in FFI specifically.

Imaging Studies in Fatal Familial Insomnia

Computed Tomography (CT) and Magnetic Resonance Imaging (MRI): Routine CT and MRI scans are often not particularly helpful in diagnosing FFI directly, as findings can be subtle or nonspecific in early stages. However, these imaging modalities are crucial for excluding other neurological pathologies that could mimic FFI symptoms.
Diffusion-Weighted MRI (DWI): Diffusion MRI may reveal reduced thalamic diffusion in some FFI cases, potentially due to gliosis. Atrophic changes in the thalamus may become more evident on MRI as the disease progresses.
Fluorodeoxyglucose Positron Emission Tomography (FDG-PET): FDG-PET imaging can be a valuable tool in diagnosing FFI. PET scans may demonstrate hypometabolism (reduced glucose uptake) in the thalamic and cingulate regions of the brain, often with relative sparing of the occipital lobe. This pattern of hypometabolism can be suggestive of FFI.

Molecular Genetic Testing for Fatal Familial Insomnia

Genetic testing is a definitive diagnostic step for FFI. Individuals suspected of having FFI should undergo genetic testing, which typically involves targeted analysis for the pathogenic D178N variant in the PRNP gene or full gene sequencing of PRNP.

Histopathological Testing in Fatal Familial Insomnia

Brain biopsies are generally not diagnostically conclusive for FFI and are rarely performed. However, in some atypical presentations or to definitively rule out other treatable neurological diseases, brain biopsy might be considered.

Diagnostic Approach to Fatal Familial Insomnia

A comprehensive diagnostic approach to FFI involves integrating clinical findings, polysomnography results, and genetic testing. Genetic counseling should precede genetic testing to ensure informed consent and understanding of the implications of test results. Targeted screening for the D178N mutation of the PRNP gene is particularly useful for early diagnosis in suspected cases. While clinical evaluation and ancillary tests provide valuable information, genetic testing and counseling are essential for confirming the diagnosis and assessing potential risks for family members. Early and accurate diagnosis, often facilitated by targeted genetic screening, is crucial for appropriate patient management and family counseling, even though curative treatments are currently lacking.

Utilizing the 2022 international group diagnostic criteria allows for a structured approach to determining the likelihood of FFI. This approach incorporates core clinical features, supportive features, diagnostic study findings, and exclusionary factors:

Exclusionary Features:
- Periodic sharp wave complexes (PSWC) on EEG.
- Hyperintense signal in the caudate nucleus and putamen or in two or more cortical regions on MRI.
- The pattern of neurological deficits can be better explained by an alternative diagnosis.
Diagnostic Studies (Confirmatory): Positive molecular genetic testing for a pathogenic PRNP mutation (specifically D178N for FFI).
Probability of FFI Diagnosis Based on Criteria:
- Possible FFI: Presence of 2 out of 3 core clinical features without any exclusionary features.
- Probable FFI: Presence of 2 out of 3 core clinical features, plus at least one supportive feature, and no exclusionary features.
- Definite FFI: Presence of 2 out of 3 core clinical features and positive confirmatory diagnostic studies (genetic testing).

Treatment and Management of Fatal Familial Insomnia

The management of fatal familial insomnia is primarily focused on symptomatic relief and providing palliative care. Currently, there is no cure for FFI, and treatments are aimed at improving patient comfort and quality of life. Various treatment modalities have been explored and reported in medical literature:

Medication Review: It is crucial to discontinue any medications that could potentially exacerbate confusion, memory impairment, or insomnia. A thorough review of the patient’s medication list is essential.
Limited Response to Sedatives: Patients with FFI typically exhibit a poor response to conventional sedatives, including barbiturates and benzodiazepines. Studies have shown that these medications often lack efficacy in improving sleep or altering EEG patterns in FFI patients.
Nutritional Support: As the disease progresses, swallowing difficulties may arise, necessitating the consideration of feeding tube placement to ensure adequate nutritional intake and prevent aspiration.
Gamma-Hydroxybutyrate (GHB): One case report explored the use of gamma-hydroxybutyrate (GHB). The administration of GHB was found to induce slow-wave sleep (SWS) in a patient with FFI. However, this is not a standard or widely used treatment.
Investigational Compounds: Several compounds, including pentosane polysulfate, quinacrine, and amphotericin B, have been investigated as potential treatments for prion diseases, including FFI. However, clinical trials and studies using these agents have yielded inconclusive or negative results, and they are not currently recommended treatments.
Doxycycline Prevention Trial: A clinical trial is ongoing in Italy, focusing on preventative strategies for prion disease in individuals who are known carriers of the PRNP D178N/M129 mutation. This study involves administering the antibiotic doxycycline (100 mg orally daily for 10 years) to mutation carriers and comparing outcomes to a control group of non-carrier family members. The trial is still in progress, and results are pending.
Immunotherapy Research: Immunotherapy approaches are being actively investigated for prion diseases and have shown some promising results in in vitro studies, animal models, and early clinical trials. The main types of immunotherapy research in this area focus on antibody vaccines, dendritic cell vaccines, and adoptive transfer of physiological prion protein-specific CD4(+) T-lymphocytes. Antibody vaccines are designed to target unique epitopes specifically found on the misfolded prion protein form (PrP(Sc)).
Psychosocial Support and Hospice Care: Psychosocial therapy is a vital component of care for both the patient and their family. Given the devastating and progressive nature of FFI, hospice care should be considered early in the disease course to provide comprehensive support, pain management, and end-of-life care.

Differential Diagnosis of Fatal Familial Insomnia

When evaluating patients suspected of having fatal familial insomnia, it is essential to consider other prion diseases in the differential diagnosis due to overlapping symptomatology. Conditions to differentiate from FFI include:

Sporadic Creutzfeldt-Jakob disease (sCJD) and familial Creutzfeldt-Jakob disease (fCJD): These conditions share clinical and pathological similarities with FFI. However, sCJD tends to be more aggressive with a later age of onset. Both sCJD and fCJD typically present with memory problems and confusion, followed by myoclonus and ataxia. Pathologically, spongiform degeneration and astrogliosis are generally more widespread and profuse in CJD compared to FFI.
Sporadic Fatal Insomnia (sFI): Sporadic fatal insomnia presents with clinical and histopathological features that closely mimic FFI but occurs without any identifiable genetic mutation in the PRNP gene. Like other neurodegenerative diseases, sFI lacks a precise animal model and effective therapeutic interventions, making research challenging.
Gerstmann-Straussler-Scheinker syndrome (GSS): GSS typically manifests with prominent cerebellar dysfunction, while sleep disturbances are less pronounced or absent. Cognitive dysfunction in GSS is generally milder and tends to appear later in the disease course if present. GSS is also inherited in an autosomal dominant pattern and exhibits high penetrance, often linked to various point mutations and insertion mutations in the PRNP gene involving octapeptide repeats.
Variably Protease-Sensitive Prionopathy (VPSPr): VPSPr can present with a range of symptoms, including aphasia and behavioral changes. Definitive diagnosis usually requires histopathological examination of brain tissue.
Lithium Toxicity: Lithium overdose or toxicity can cause neurological symptoms including confusion and cognitive impairment, mimicking some aspects of FFI.
Familial Myoclonic Dementia: This group of disorders can present with dementia and myoclonus, requiring differentiation from prion diseases.
Diffuse Lewy Body Disease (DLB): DLB is another neurodegenerative dementia that can sometimes be confused with prion diseases, particularly in early stages.
Chronic Meningitis: Chronic infections of the meninges can cause progressive neurological decline and need to be considered.
Dementia as a Paraneoplastic Syndrome: Certain cancers can trigger paraneoplastic syndromes that affect the brain and cause dementia.
Dementia in Motor Neuron Disease: Some forms of motor neuron disease can have a dementia component.
Nonherpes Viral Encephalitis: Viral infections of the brain, other than herpes encephalitis, can cause acute or subacute neurological syndromes.
Hashimoto Encephalopathy (Steroid-Responsive Encephalopathy Associated with Autoimmune Thyroiditis – SREAT): This autoimmune condition is associated with thyroiditis and can cause encephalopathy and cognitive dysfunction, often responsive to steroid treatment.
Limbic Encephalitis and Other Paraneoplastic Syndromes: Limbic encephalitis, whether paraneoplastic or autoimmune, can cause rapid cognitive decline and psychiatric symptoms.

Furthermore, it is critical to rule out other potentially reversible causes of dementia. These include conditions such as herpes encephalitis, other paraneoplastic syndromes (including limbic encephalitis), Hashimoto encephalitis, lithium poisoning, chronic meningitis, HIV encephalopathy, and hydrocephalus. Neurodegenerative diseases with slower progression, such as Alzheimer’s disease, Pick disease, corticobasal degeneration, multiple system atrophy, frontotemporal dementia, and familial myoclonic dementia, should also be considered in the differential diagnosis, even though their typical progression rate differs from FFI.

Staging of Fatal Familial Insomnia

Fatal familial insomnia is often described as progressing through four distinct stages:

Stage 1: This initial stage is characterized by the subacute onset of insomnia, which gradually worsens over several months. Psychiatric symptoms, such as phobias, paranoia, and panic attacks, may emerge. Patients may also report experiencing vivid or lucid dreams during this stage.
Stage 2: Over the subsequent five months, psychiatric symptoms intensify, insomnia becomes more severe, and patients may begin to experience hallucinations. Autonomic dysfunction becomes evident, often manifesting as sympathetic hyperactivity (e.g., increased heart rate, sweating).
Stage 3: This stage is relatively short, typically lasting around three months. It is marked by near-total or total insomnia and severe disruption of the sleep-wake cycle.
Stage 4: The final stage can last for approximately six months or even longer. It is defined by rapid cognitive decline and the development of dementia. Patients lose the ability to voluntarily move or speak, eventually progressing to coma and ultimately death.

Prognosis of Fatal Familial Insomnia

Fatal familial insomnia carries a uniformly poor prognosis. The disease course is typically rapid and progressive, with a duration ranging from 7 to 36 months. The average disease duration is approximately 18 months from symptom onset to death. Genetic factors can influence disease progression; for instance, patients with a homozygous (Met-Met) mutation at codon 129 of the PRNP gene may have a shorter mean survival time compared to heterozygous (Met-Val) patients.

Complications of Fatal Familial Insomnia

Fatal familial insomnia is invariably fatal. Patients experience a wide array of complications spanning autonomic, cognitive, motor, and endocrine systems. Detailed information on these complications can be found in the “History and Physical” section.

Deterrence and Patient Education for Fatal Familial Insomnia

Given the devastating and fatal nature of fatal familial insomnia, thorough patient and family education is paramount. Healthcare providers should ensure that patients and their families are fully informed about the disease’s prognosis and relentless progression. It is important to convey that current treatment options are limited to symptom management and palliative care, while also communicating that ongoing research efforts are exploring potential therapeutic avenues. Genetic counseling should be offered to family members, as FFI is an inherited condition with autosomal dominant inheritance, allowing for informed decisions regarding genetic testing and family planning.

Enhancing Healthcare Team Outcomes in Fatal Familial Insomnia Management

Fatal familial insomnia, a rare hereditary prion disease, is characterized by progressive and intractable insomnia leading to severe neurodegeneration. Effective management requires a multidisciplinary, interprofessional team approach. Clinicians must be adept at recognizing the unique symptom profile of FFI, particularly the sleep disturbances and autonomic dysfunction that are hallmark features. Early diagnosis, often facilitated by genetic testing, is crucial for appropriate management and family counseling. Treatment strategies are primarily focused on symptomatic relief and palliative care. Due to the uniformly poor prognosis, with death typically occurring within a year or two of symptom onset, hospice care should be integrated early into the care plan. An interprofessional team optimally manages FFI; this team includes sleep specialists, neurologists, psychiatrists, psychologists, social workers, palliative care nurses, and hospice care professionals. Psychosocial counseling is essential for family members to cope with the profound emotional and practical challenges posed by this disease. Effective communication and coordinated care are vital in supporting patients and families through the complex journey of FFI, with a strong emphasis on compassionate end-of-life care and addressing the psychological, social, and medical needs of all involved.

References

1.Nafe R, Arendt CT, Hattingen E. Human prion diseases and the prion protein – what is the current state of knowledge? Transl Neurosci. 2023 Jan 01;14(1):20220315. [PMC free article: PMC10579786] [PubMed: 37854584]
2.Bagyinszky E, Giau VV, Youn YC, An SSA, Kim S. Characterization of mutations in PRNP (prion) gene and their possible roles in neurodegenerative diseases. Neuropsychiatr Dis Treat. 2018;14:2067-2085. [PMC free article: PMC6097508] [PubMed: 30147320]
3.Medori R, Montagna P, Tritschler HJ, LeBlanc A, Cortelli P, Tinuper P, Lugaresi E, Gambetti P. Fatal familial insomnia: a second kindred with mutation of prion protein gene at codon 178. Neurology. 1992 Mar;42(3 Pt 1):669-70. [PubMed: 1347910]
4.Schenkein J, Montagna P. Self management of fatal familial insomnia. Part 1: what is FFI? MedGenMed. 2006 Sep 14;8(3):65. [PMC free article: PMC1781306] [PubMed: 17406188]
5.Montagna P, Cortelli P, Avoni P, Tinuper P, Plazzi G, Gallassi R, Portaluppi F, Julien J, Vital C, Delisle MB, Gambetti P, Lugaresi E. Clinical features of fatal familial insomnia: phenotypic variability in relation to a polymorphism at codon 129 of the prion protein gene. Brain Pathol. 1998 Jul;8(3):515-20. [PMC free article: PMC8098256] [PubMed: 9669701]
6.Zerr I, Schmitz M. Genetic Prion Disease. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. University of Washington, Seattle; Seattle (WA): Mar 27, 2003. [PubMed: 20301407]
7.Chen C, Dong XP. Epidemiological characteristics of human prion diseases. Infect Dis Poverty. 2016 Jun 02;5(1):47. [PMC free article: PMC4890484] [PubMed: 27251305]
8.Zhang J, Chu M, Tian Z, Xie K, Cui Y, Liu L, Meng J, Yan H, Ji YM, Jiang Z, Xia TX, Wang D, Wang X, Zhao Y, Ye H, Li J, Wang L, Wu L. Clinical profile of fatal familial insomnia: phenotypic variation in 129 polymorphisms and geographical regions. J Neurol Neurosurg Psychiatry. 2022 Mar;93(3):291-297. [PMC free article: PMC8862016] [PubMed: 34667102]
9.Tinuper P, Montagna P, Medori R, Cortelli P, Zucconi M, Baruzzi A, Lugaresi E. The thalamus participates in the regulation of the sleep-waking cycle. A clinico-pathological study in fatal familial thalamic degeneration. Electroencephalogr Clin Neurophysiol. 1989 Aug;73(2):117-23. [PubMed: 2473878]
10.Montagna P. Fatal familial insomnia and the role of the thalamus in sleep regulation. Handb Clin Neurol. 2011;99:981-96. [PubMed: 21056239]
11.Almer G, Hainfellner JA, Brücke T, Jellinger K, Kleinert R, Bayer G, Windl O, Kretzschmar HA, Hill A, Sidle K, Collinge J, Budka H. Fatal familial insomnia: a new Austrian family. Brain. 1999 Jan;122 ( Pt 1):5-16. [PubMed: 10050890]
12.Krasnianski A, Bartl M, Sanchez Juan PJ, Heinemann U, Meissner B, Varges D, Schulze-Sturm U, Kretzschmar HA, Schulz-Schaeffer WJ, Zerr I. Fatal familial insomnia: Clinical features and early identification. Ann Neurol. 2008 May;63(5):658-61. [PubMed: 18360821]
13.Plazzi G, Schutz Y, Cortelli P, Provini F, Avoni P, Heikkila E, Tinuper P, Solieri L, Lugaresi E, Montagna P. Motor overactivity and loss of motor circadian rhythm in fatal familial insomnia: an actigraphic study. Sleep. 1997 Sep;20(9):739-42. [PubMed: 9406326]
14.Lugaresi E, Medori R, Montagna P, Baruzzi A, Cortelli P, Lugaresi A, Tinuper P, Zucconi M, Gambetti P. Fatal familial insomnia and dysautonomia with selective degeneration of thalamic nuclei. N Engl J Med. 1986 Oct 16;315(16):997-1003. [PubMed: 3762620]
15.Baldelli L, Provini F. Fatal familial insomnia and Agrypnia Excitata: Autonomic dysfunctions and pathophysiological implications. Auton Neurosci. 2019 May;218:68-86. [PubMed: 30890351]
16.Gallassi R, Morreale A, Montagna P, Gambetti P, Lugaresi E. “Fatal familial insomnia”: neuropsychological study of a disease with thalamic degeneration. Cortex. 1992 Jun;28(2):175-87. [PubMed: 1499304]
17.Cortelli P, Fabbri M, Calandra-Buonaura G, Capellari S, Tinuper P, Parchi P, Lugaresi E. Gait disorders in fatal familial insomnia. Mov Disord. 2014 Mar;29(3):420-4. [PubMed: 24375448]
18.Gallassi R, Morreale A, Montagna P, Cortelli P, Avoni P, Castellani R, Gambetti P, Lugaresi E. Fatal familial insomnia: behavioral and cognitive features. Neurology. 1996 Apr;46(4):935-9. [PubMed: 8780067]
19.Montagna P, Cortelli P, Gambetti P, Lugaresi E. Fatal familial insomnia: sleep, neuroendocrine and vegetative alterations. Adv Neuroimmunol. 1995;5(1):13-21. [PubMed: 7795890]
20.Chu M, Xie K, Zhang J, Chen Z, Ghorayeb I, Rupprecht S, Reder AT, Garay A, Honda H, Nagayama M, Shi Q, Zhan S, Nan H, Zhang J, Guan H, Cui L, Guo Y, Rosa-Neto P, Gauthier S, Wang J, Dong X, Wu L. Proposal of new diagnostic criteria for fatal familial insomnia. J Neurol. 2022 Sep;269(9):4909-4919. [PMC free article: PMC9363306] [PubMed: 35501502]
21.Cortelli P, Perani D, Montagna P, Gallassi R, Tinuper P, Provini F, Avoni P, Ferrillo F, Anchisi D, Moresco RM, Fazio F, Parchi P, Baruzzi A, Lugaresi E, Gambetti P. Pre-symptomatic diagnosis in fatal familial insomnia: serial neurophysiological and 18FDG-PET studies. Brain. 2006 Mar;129(Pt 3):668-75. [PubMed: 16399807]
22.Reder AT, Mednick AS, Brown P, Spire JP, Van Cauter E, Wollmann RL, Cervenàkovà L, Goldfarb LG, Garay A, Ovsiew F. Clinical and genetic studies of fatal familial insomnia. Neurology. 1995 Jun;45(6):1068-75. [PubMed: 7783865]
23.Zerr I. Therapeutic trials in human transmissible spongiform encephalo-pathies: recent advances and problems to address. Infect Disord Drug Targets. 2009 Feb;9(1):92-9. [PubMed: 19200019]
24.Forloni G, Tettamanti M, Lucca U, Albanese Y, Quaglio E, Chiesa R, Erbetta A, Villani F, Redaelli V, Tagliavini F, Artuso V, Roiter I. Preventive study in subjects at risk of fatal familial insomnia: Innovative approach to rare diseases. Prion. 2015;9(2):75-9. [PMC free article: PMC4601344] [PubMed: 25996399]
25.Burchell JT, Panegyres PK. Prion diseases: immunotargets and therapy. Immunotargets Ther. 2016;5:57-68. [PMC free article: PMC4970640] [PubMed: 27529062]
26.Medori R, Tritschler HJ, LeBlanc A, Villare F, Manetto V, Chen HY, Xue R, Leal S, Montagna P, Cortelli P. Fatal familial insomnia, a prion disease with a mutation at codon 178 of the prion protein gene. N Engl J Med. 1992 Feb 13;326(7):444-9. [PMC free article: PMC6151859] [PubMed: 1346338]
27.Zerr I, Kallenberg K, Summers DM, Romero C, Taratuto A, Heinemann U, Breithaupt M, Varges D, Meissner B, Ladogana A, Schuur M, Haik S, Collins SJ, Jansen GH, Stokin GB, Pimentel J, Hewer E, Collie D, Smith P, Roberts H, Brandel JP, van Duijn C, Pocchiari M, Begue C, Cras P, Will RG, Sanchez-Juan P. Updated clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease. Brain. 2009 Oct;132(Pt 10):2659-68. [PMC free article: PMC2759336] [PubMed: 19773352]
28.Cracco L, Appleby BS, Gambetti P. Fatal familial insomnia and sporadic fatal insomnia. Handb Clin Neurol. 2018;153:271-299. [PubMed: 29887141]
29.Hainfellner JA, Brantner-Inthaler S, Cervenáková L, Brown P, Kitamoto T, Tateishi J, Diringer H, Liberski PP, Regele H, Feucht M. The original Gerstmann-Sträussler-Scheinker family of Austria: divergent clinicopathological phenotypes but constant PrP genotype. Brain Pathol. 1995 Jul;5(3):201-11. [PubMed: 8520719]
30.Yang TW, Park B, Kim KT, Jun JS, Kim YS, Lee ST, Jung KH, Chu K, Lee SK, Jung KY. Fatal familial insomnia presenting with agrypnia excitata and very low atonia index level: A case report and literature review. Medicine (Baltimore). 2018 May;97(18):e0646. [PMC free article: PMC6392909] [PubMed: 29718878]
31.Gaudino S, Gangemi E, Colantonio R, Botto A, Ruberto E, Calandrelli R, Martucci M, Vita MG, Masullo C, Cerase A, Colosimo C. Neuroradiology of human prion diseases, diagnosis and differential diagnosis. Radiol Med. 2017 May;122(5):369-385. [PubMed: 28110369]
32.Manix M, Kalakoti P, Henry M, Thakur J, Menger R, Guthikonda B, Nanda A. Creutzfeldt-Jakob disease: updated diagnostic criteria, treatment algorithm, and the utility of brain biopsy. Neurosurg Focus. 2015 Nov;39(5):E2. [PubMed: 26646926]
33.Lindsley CW. Genetic and Rare Disease of the CNS. Part I: Fatal Familial Insomnia (FFI). ACS Chem Neurosci. 2017 Dec 20;8(12):2570-2572. [PubMed: 29258312]
34.Parchi P, Petersen RB, Chen SG, Autilio-Gambetti L, Capellari S, Monari L, Cortelli P, Montagna P, Lugaresi E, Gambetti P. Molecular pathology of fatal familial insomnia. Brain Pathol. 1998 Jul;8(3):539-48. [PMC free article: PMC8098344] [PubMed: 9669705]
35.Montagna P, Gambetti P, Cortelli P, Lugaresi E. Familial and sporadic fatal insomnia. Lancet Neurol. 2003 Mar;2(3):167-76. [PubMed: 12849238]