Fatal Familial Insomnia

Earn CME/CE in your profession:

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. A detailed history and neurological examination are of paramount importance as fatal familial insomnia is primarily a clinical diagnosis. Treatment is centered mainly on symptomatic relief and palliative care, as there is no cure for FFI. This activity for healthcare professionals aims to enhance learners' competence in selecting appropriate diagnostic tests, managing fatal familial insomnia, and fostering effective interprofessional teamwork to improve outcomes.


  • Identify characteristic symptoms of fatal familial insomnia, distinguishing them from other sleep disorders.

  • Implement evidence-based interventions for fatal familial insomnia management, addressing both symptomatic relief and supportive care.

  • Apply appropriate palliative measures to alleviate suffering and enhance quality of life.

  • Implement interprofessional team strategies for enhancing care coordination to manage fatal familial insomnia and improve outcomes.


Fatal familial insomnia (FFI) is a very rare and 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, leading to atrophy in the thalamic nucleus.[1][2] Aggressively progressive insomnia, with subsequent autonomic (eg, tachycardia, hyperhidrosis, hypertension), cognitive (eg, short-term memory and attentional deficits), motor system (eg, balance problems), and endocrine dysfunction are hallmarks 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.[3][4] A detailed history and neurological examination are of paramount importance as fatal familial insomnia is primarily a clinical diagnosis. Treatment is centered mainly on symptomatic relief and palliative care, as there is no cure for FFI. 


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]


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]


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]


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]


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.

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]


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]


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]


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.

Deterrence and Patient Education

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

Enhancing Healthcare Team Outcomes

FFI is a rare, hereditary prion disease characterized by relentless insomnia leading to severe neurodegeneration. Clinicians must recognize its unique symptoms, including sleep disturbances and autonomic dysfunction. Early identification through genetic testing is crucial. Management involves symptomatic relief, palliative care, and an interprofessional approach. The prognosis is poor, with death typically occurring within a year. 

FFI is best managed by an interprofessional team, including sleep specialists, neurologists, psychiatrists and psychologists, social workers, palliative nurses, and hospice care. Hospice should be involved early in the care. Psychosocial counseling for family members is necessary as well. Effective communication is essential in supporting patients and families through the complex challenges of FFI, emphasizing compassionate end-of-life care and addressing psychological and social aspects alongside medical considerations.



Zalan Khan


2/25/2024 2:37:54 PM



Nafe R, Arendt CT, Hattingen E. Human prion diseases and the prion protein - what is the current state of knowledge? Translational neuroscience. 2023 Jan 1:14(1):20220315. doi: 10.1515/tnsci-2022-0315. Epub 2023 Oct 16     [PubMed PMID: 37854584]


Bagyinszky E, Giau VV, Youn YC, An SSA, Kim S. Characterization of mutations in PRNP (prion) gene and their possible roles in neurodegenerative diseases. Neuropsychiatric disease and treatment. 2018:14():2067-2085. doi: 10.2147/NDT.S165445. Epub 2018 Aug 14     [PubMed PMID: 30147320]


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 PMID: 1347910]


Schenkein J, Montagna P. Self management of fatal familial insomnia. Part 1: what is FFI? MedGenMed : Medscape general medicine. 2006 Sep 14:8(3):65     [PubMed PMID: 17406188]


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 pathology (Zurich, Switzerland). 1998 Jul:8(3):515-20     [PubMed PMID: 9669701]


Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, Zerr I, Schmitz M. Genetic Prion Disease. GeneReviews(®). 1993:():     [PubMed PMID: 20301407]


Chen C, Dong XP. Epidemiological characteristics of human prion diseases. Infectious diseases of poverty. 2016 Jun 2:5(1):47. doi: 10.1186/s40249-016-0143-8. Epub 2016 Jun 2     [PubMed PMID: 27251305]

Level 2 (mid-level) evidence


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. Journal of neurology, neurosurgery, and psychiatry. 2022 Mar:93(3):291-297. doi: 10.1136/jnnp-2021-327247. Epub 2021 Oct 19     [PubMed PMID: 34667102]


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. Electroencephalography and clinical neurophysiology. 1989 Aug:73(2):117-23     [PubMed PMID: 2473878]


Montagna P. Fatal familial insomnia and the role of the thalamus in sleep regulation. Handbook of clinical neurology. 2011:99():981-96. doi: 10.1016/B978-0-444-52007-4.00018-7. Epub     [PubMed PMID: 21056239]


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 : a journal of neurology. 1999 Jan:122 ( Pt 1)():5-16     [PubMed PMID: 10050890]


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. Annals of neurology. 2008 May:63(5):658-61. doi: 10.1002/ana.21358. Epub     [PubMed PMID: 18360821]


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 PMID: 9406326]


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. The New England journal of medicine. 1986 Oct 16:315(16):997-1003     [PubMed PMID: 3762620]


Baldelli L, Provini F. Fatal familial insomnia and Agrypnia Excitata: Autonomic dysfunctions and pathophysiological implications. Autonomic neuroscience : basic & clinical. 2019 May:218():68-86. doi: 10.1016/j.autneu.2019.02.007. Epub 2019 Feb 26     [PubMed PMID: 30890351]


Gallassi R, Morreale A, Montagna P, Gambetti P, Lugaresi E. "Fatal familial insomnia": neuropsychological study of a disease with thalamic degeneration. Cortex; a journal devoted to the study of the nervous system and behavior. 1992 Jun:28(2):175-87     [PubMed PMID: 1499304]


Cortelli P, Fabbri M, Calandra-Buonaura G, Capellari S, Tinuper P, Parchi P, Lugaresi E. Gait disorders in fatal familial insomnia. Movement disorders : official journal of the Movement Disorder Society. 2014 Mar:29(3):420-4. doi: 10.1002/mds.25786. Epub 2013 Dec 27     [PubMed PMID: 24375448]


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 PMID: 8780067]


Montagna P, Cortelli P, Gambetti P, Lugaresi E. Fatal familial insomnia: sleep, neuroendocrine and vegetative alterations. Advances in neuroimmunology. 1995:5(1):13-21     [PubMed PMID: 7795890]

Level 3 (low-level) evidence


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. Journal of neurology. 2022 Sep:269(9):4909-4919. doi: 10.1007/s00415-022-11135-6. Epub 2022 May 3     [PubMed PMID: 35501502]


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 : a journal of neurology. 2006 Mar:129(Pt 3):668-75     [PubMed PMID: 16399807]


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 PMID: 7783865]


Zerr I. Therapeutic trials in human transmissible spongiform encephalo-pathies: recent advances and problems to address. Infectious disorders drug targets. 2009 Feb:9(1):92-9     [PubMed PMID: 19200019]

Level 3 (low-level) evidence


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. doi: 10.1080/19336896.2015.1027857. Epub     [PubMed PMID: 25996399]


Burchell JT, Panegyres PK. Prion diseases: immunotargets and therapy. ImmunoTargets and therapy. 2016:5():57-68. doi: 10.2147/ITT.S64795. Epub 2016 Jun 16     [PubMed PMID: 27529062]


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. The New England journal of medicine. 1992 Feb 13:326(7):444-9     [PubMed PMID: 1346338]


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 : a journal of neurology. 2009 Oct:132(Pt 10):2659-68. doi: 10.1093/brain/awp191. Epub 2009 Sep 22     [PubMed PMID: 19773352]


Cracco L, Appleby BS, Gambetti P. Fatal familial insomnia and sporadic fatal insomnia. Handbook of clinical neurology. 2018:153():271-299. doi: 10.1016/B978-0-444-63945-5.00015-5. Epub     [PubMed PMID: 29887141]


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 pathology (Zurich, Switzerland). 1995 Jul:5(3):201-11     [PubMed PMID: 8520719]


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. 2018 May:97(18):e0646. doi: 10.1097/MD.0000000000010646. Epub     [PubMed PMID: 29718878]

Level 3 (low-level) evidence


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. La Radiologia medica. 2017 May:122(5):369-385. doi: 10.1007/s11547-017-0725-y. Epub 2017 Jan 21     [PubMed PMID: 28110369]


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. Neurosurgical focus. 2015 Nov:39(5):E2. doi: 10.3171/2015.8.FOCUS15328. Epub     [PubMed PMID: 26646926]


Lindsley CW. Genetic and Rare Disease of the CNS. Part I: Fatal Familial Insomnia (FFI). ACS chemical neuroscience. 2017 Dec 20:8(12):2570-2572. doi: 10.1021/acschemneuro.7b00463. Epub     [PubMed PMID: 29258312]


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 pathology (Zurich, Switzerland). 1998 Jul:8(3):539-48     [PubMed PMID: 9669705]


Montagna P, Gambetti P, Cortelli P, Lugaresi E. Familial and sporadic fatal insomnia. The Lancet. Neurology. 2003 Mar:2(3):167-76     [PubMed PMID: 12849238]