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Group Members- Bobin Lee z3328378- Josh Robb z3291503- Lamia Hossain z3330474- Daniel Vargha z3332998































Introduction
'Sleep Disorder FFI fatal familial insomnia' is from channel 9 news, which shows a snippet from a documentary called "Explorer: Fatal Insomnia", aired on National Geographic Channel. It was uploaded on__Youtube__ by__AmericanNeurolab__ on the 13th of September, 2010.

American Neuro Lab Inc is a research centre that is located in two places around the world, one of which specialises in sleep studies. They diagnose and offer cures that is 'designed to fit each patient', under their policy of 'Patient Comes First'. * Their latest update is that they have hired a physician who specialises in epilepsy.

The video gives a sensationalised picture of FFI - a disease that is very little researched upon, thus known about. It shows patients that exhibit FFI symptoms, 'professionals' giving opinions and some explanation of FFI in layman's terms. It specifically focuses on one woman who has lost nine family members due to FFI. She expresses that she does not want to find out whether she may be affected in the future.



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Neuroscientific Context

i) What is FFI ?



Fatal Familial Insomnia (FFI) is an autosomal dominant disease that affects the thalamus. It the third most frequent genetic prion disease in the world, however it is a very rare condition amongst the general population - only 28 families have been affected by FFI around the world. Patients usually are affected between 30 to 60 years of age and the disorder runs for 7 to 18 months.

There are two types of FFI - inherited and sporadic.

The first type of FFI, caused by genetic mutation, is more common amongst the patients. Prion diseases are caused by mutations in PrNP genes. These genes form the protein PrP, the cellular form of which is PrPc. The exact function of PrP is unknown, although, amongst the proposed theories are: cell signalling, cell protection and formation of synapses. The mutation produces PrPSc instead of PrPc, which promotes the transformation of more PrPc proteins into PrPSc. The process of this transformation is not yet completely understood. PrPSc accumulates in the brain and leads to severe loss of neurons, leading to gliosis in the thalamus.

There are two subtypes of genetically inherited FFI. Each involve a substitution of asparagine at the 178 codon and methionine at the 129 codon of the PrNP gene. One type has a valine on the non mutated allele at the 129 codon (refereed to as Met-Val or MV) and the other has another substituted methionine (Met-Met or MM) (Schenkein & Montagna, 2006). The Met-Met variation tends to run a shorter course (Montagna et.al. 1998).

Sporadic FFI occurs spontaneously.



Symptoms
Chief clinical symptoms are progressive insomnia, hallucinations, increased autonomic activity (suggestive of sympathetic overdrive), cognitive changes, and motor system deficits. As the disease progresses, cognitive changes include a “confusional state resembling dementia and, ultimately, death” (Schenkein & Montagna, 2006).

A study done evaluating clinical data from 41 German FFI patients showed that 96% of patients displayed organic sleep disturbances (including insomnia, hypersomnia, restless sleep, sleep attacks), 87% showed cognitive/memory deficits, and 87% showed psychiatric symptoms (61% hallucinations, 57% personality change, 22% depression, 17% anxiety, and others noted) (Krasnianski, et al., 2008).

Sleep disturbances appear as early and progressive symptoms in FFI, involving reductions in sleep spindles and K-complexes (characteristics of stage 2 NREM sleep (Gennaro & Ferrara, 2003), total sleep time, and disruption to normal sleep cycles. “SWS [slow wave sleep] is lost first, then REM disengages from its circadian cycle and intrudes into the waking state” (Schenkein & Montagna, 2006).




ii) History


In his book, “The Family That Couldn’t Sleep”, D.T. Max documents the history of Fatal Familial Insomnia in an Italian family living in Venice. These are the earliest recorded casualties of FFI, beginning in 1765. Passed down the generations, the disease claimed many lives, yet remained a mystery. In the 1980’s, a man by the name of Silvano fell ill with the disease, and having watched his two sisters pass away from the illness, he decided to seek answers. In the early 1990’s, Fatal Familial Insomnia was recognised as a rare genetic prion disease of the brain.





iii) Theories & Causes


The thalamus region of the brain is responsible for maintaining sleep and most of the sensory/motor systems. FFI is caused by the prions attacking & taking over this region of the thalamus by engulfing it then eating it away which malfunctions the sleeping routine of the individual.
This allows the indiviudal to be prevented from falling asleep keeping them conscious. Interestingly patients with FFI go through sleep deprivation but this state causes them to still have the ability to dream even though they are wide awake.

Strong hypothetical provided by Perani, D., et al. (1993) that FFI is inititaed in the thalamus in the brain where this is the first region to be affected, this is where the disease is spread fastest. FFI can affect the brain in two different ways which could be just the thalamus being affected or the affect on a larger proportion of the brain. But mainly the thalamus is the region worst affected in FFI patients.

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Prions (purple dots) clustered in the thalamic region eating away the thalamus



iv) Case Studies




The Silvano Case

The Silvano Case may be considered as a milestone of both the history of FFI and the overall prion disease research field due to its significant contribution in initial discovery and classification of FFI as well as providing evidence to the linkage between prions and Creutzfeldt-Jakob Disease.

In 1984, Silvano, a dancer descendant from a Venetian aristocratic family, started showing numerous signs of sleep deprivation at the age of 53 as noted by relatives (Max, 2001). With only a mere knowledge of the existence of a mysterious sleeplessness in the family, Silvano was presented to a sleep expert at University of Bologna under the suspicion of yet unproven genetic disease which later was classified as a novel terminal disease FFI (Max, 2001). The Silvano Case, hence is noted as the first documented case of FFI.
The significance of the current case indeed is marked as its major contribution to the discovery of the hereditary nature of the disease, observation of symptoms and the post-mortem research. Given the fact that the case of FFI as a clinical disorder was unprecedented before Silvano, novel pathological information such as the symptoms and the ineffectiveness of conventional insomnia treatments could be observed and recorded in a professional setting. Additionally, by initiating an intensive tracing of family lines, the first suspected case of FFI was identified that is “Patient Zero” of Venice in 1700’s (Max, 2001), enabling the estimation of epidemiology of FFI. Post-mortem study of Silvano revealed the growth of mutated proteins on the thalamus which shortly contributed to the identification of prion disease and its link to the likes of diseases with unknown causes such as Creutzfeldt-Jakob Disease by Purisner in 1996 (Schenkein & Montagna, Self Management. Part 1, 2006).



Silvano - a member of the first FFI family to be discovered (from the media item)
Silvano - a member of the first FFI family to be discovered (from the media item)


The Patient DF Case

Patient 'DF' Case is a more recently documented case of FFI in which the patient self-implemented various strategies and possible beneficial treatments in order to increase his survival period as well as to preserve his quality of life post-onset of the disease. DF was an American white male of 52 years of age by the time of diagnosis (Schenkein & Montagna, Self-management. Part 2, 2006). Once the feared diagnosis of such terminal nature was delivered in 2001, with progression estimation of 10 months in (Stage 1), DF committed himself to make the most of the remainder of his life and took leave on a road trip in which he would self-implement various methods that he deemed beneficial to his condition (Schenkein & Montagna, Self-management. Part 2, 2006). Such strategies included vitamin therapy, anaesthesia, narcoleptics, stimulants, ECT and circadian rhythms therapy to name a few. The following outcome was that DF could partially manage his symptoms so that his survival time was nearly doubled compared to that of typical estimation from the time of onset. Additionally, he could stay conscious at the stage of progression where most patients were completely incapacitated (Schenkein & Montagna, Self-management. Part 2, 2006).


Though none of the implemented treatments could reverse the symptoms of FFI, some presented a degree of improvement and hence providing a possible outlook of a set of strategies that may enhance the quality of life of FFI patients. For instance, vitamin treatment may be speculated to have delayed the progression of FFI due to the involvement of anti-oxidants in sleep regulation. Similarly, exposure to light in order to stimulate natural circadian rhythms may also have produced such delay (Schenkein & Montagna, Self-management. Part 2, 2006). However, more extreme measures such as stimulant therapy for mere fatigue management and ECT for instant sleep induction are doubtable in their beneficial factors and practicality.


Despite the fact that the array of strategies were randomly selected in trial and error fashion and the methods do not indicate an effective solution, the unprecedented length of survival time and enhanced quality of life previous to death indicate that the methods are worth reviewing for potential implication of benefits.




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Perani, D., et al. (1993) PET scans in their case study on normal healthy subjects compared with patients with different severity types of FFI. Decrease in brain cortex & thalamus regions (shown in Case 4,3 & 1). Severity of FFI worsens from right to left of subjects




v) Possible Treatment?



There are so far no treatment found to cure FFI. But there are treatments which are able to help reduce the symptoms of FFI which can improve the quality of life for those diagnosed with the disease. Polysomnography (PSG) a sleep study performed in (Krasnianski, A., et al. 2008) found to be a useful tool diagnostic tool in sleep medicine & genetic testing are all beneficial in to patients for clinical care of treating FFI. PET scans which run a nuclear medicine imaging procedure can reliably monitor pathological near areas of the thalamic region of FFI during the life of the FFI patient (Harder, A., et al. 2004).

There aren't many treatments available in curing FFI because many studies have been based on insomnia related behaviours resulted in unsuccessful outcomes. Gene therapy was believed to be the strongest cure for FFI but evidence later found it was useless & unsuccessful. Many sleep problems are misdiagnosed due to lack of interest in this type of research area. Traditionary inhibitory drugs have little or no effect at all on FFI. Diagnostic tests success rate for treating FFI is low (Krasnianski, A., et al. 2008). Also a study found in Harder, A., et al (2004) that early onset of FFI factors are unknown meaning young individuals develop FFI have no explainable reason to why it occurs so early when normally FFI occurs at later ages.





Analysis of Quality of Media Item


Target Audience:


The target audience seem to encompass a broad range of population, most likely to be targeting mass public with some or little scientific knowledge & for those with a history of the disease in the family. As popular science media, and given the fact that the excerpt was used as news material, the item is channeled towards general informative and entertainment purposes.

Pitched Aim:


The media item is well adapted to the target population by providing information on prions as the key cause of FFI in a simplified and organised manner in order to appeal to a broad array of audience. In achieving this, the item also tends to avoid more specific scientific explanations to aid the adaptation of the field-specific topic into a popular science item. Additionally, the use of cases of ordinary individuals as sufferers has a dramatic effect which raises awareness of the audience regarding such a rare, relatively unexplored field of neural disease.

Assessment of Quality:

While limited in scope, due in part to the segments duration and also its target audience, the information provided is accurate, although belies the complexity of the cause and symptoms. The simplification also gives the impression of certainties which don't exist due to the lack of clinical data about the disease purely because of its rarity and only recent identification.
The item provides some information on the famous case of the Italian man 'Silvano', coupled with an interview with D.T. Max, a journalist and author of the book "The Family That Couldn't Sleep", who is knowledgeable in the case study of Silvano, and also helps effectively bridge the gap between the audience and the scientific content.

The information is limited in several key features, specifically the genetic variants of the disease, and the many other symptoms, in particular psychological (Krasnianski, et al., 2008). As is often the case in transcribing scientific data into popular science, unsubstantiated conclusions are drawn, such as noting that in regard to 'Silvano', "his case proving that never sleeping will eventually kill". While progressive sleep disturbance is a characteristic of FFI, a direct causal relationship has not been established, and its plausibility in contention (Billiard, 2005). This is a particularly naive conclusion, given the previous statement from the interview with D.T. Max, "We know very little about how we sleep, but we know even less about why we sleep".
The second case provides more dramatisation than information, however it is noted that the disease is genetic, with a 50% chance of inheritance. It is not said that the disease is autosomal dominant, although this is implied - with sufficient knowledge to extrapolate.







Appendix


Fatal Familial Insomnia was chosen as the topic of interest due to the rarity and the terminal nature of the disease with no current functional treatment, which sparked curiosity and interest from all of the members of the group. The media item was then chosen by browsing a video sharing website, Youtube, based on the clip's capability of interpretation and mediatisation of the disease with the purpose of conveying scientific information to the mass public.
While the video is in fact a news item from Channel 9, the excerpt is from a program aired on National Geographic, an acclaimed documentary channel. Within the clip, some degree of scientific information is presented with interviews of two renowned scientists in the field of sleep research and of an author of "The Family that Couldn't Sleep", a non-fiction book which explores the origins and the sufferers of FFI. Additionally, combined with real-life cases of victims of FFI and the interviews with their relatives, the clip also contains dramatised portrayal of the disease and its impact, which contributes to the dynamic atmosphere of the media item.
Hence, this documentary excerpt was chosen as an appropriate media item for further analysis.






References


Almer, G., Hainfellner, J.A., Brucke, T., Jellinger, K., Kleinert, R., Bayer, G., Windl, O., Kretzschmar, H.A., Hill, A., Sidle, K., Collinge, J. & Budka, H. (1998). Fatal familial insomnia: a new Austrian family. Brain, vol. 122, no. 1, 5-16

Billiard, M. (2005), Fatal Familial Insomnia, Sleep Medicine Reviews, 9, 337-338

Gennaro, L.D. & Ferrara, M. (2003), Sleep Spindles: an overview, Sleep Medicine Reviews, 7(5), 423-440.

Harder, A., Gregor, A., Wirth, T., Kreuz, F., Schulz-Schaeffer, W.J., Windl, O., Plotkin, M., Amthauer, H., Neukirch, K. & Kretzschmar, H.A., et al. (2004). Early age of onset in fatal familial insomnia. Two novel cases and review of the literature. Journal of Neurology, vol. 251, no.6, 715-724

Krasnianski, A., Bartl, M., Sanchez Juan, P. J., Heinemann, U., Meissner, B., Varges, D., Schulze-Sturm, U., Kretzschmar, H.A., Schulz-Schaeffer, W.J. & Zerr, I. (2008). Fatal Familial Insomnia: Clinical Features and Early Identification. Annals of Neurology, 63 (5), 658-661.

Max, D. T. (2001, May 6). To Sleep No More . New York Times Magazine, pp. 74-78.
Montagna P, Cortelli P, Avoni P, Tinuper P, Plazzi G, Gallassi R, Portaluppi F, Julien J, Vital C, Delisle MB, Gambetti P, Lugaresi E (1998), Clinical features of fatal familial insomnia: phenotypic variability in relation to a polymorphism at codon 129 of the prion protein gene. Brain Pathology. 8(3). 115-120.

Perani, D., Cortelli, P., Lucignani, G., Montagna, P., Tinuper, P., Gallassi, R., Gambetti, P., Lenzi, G.L., Lugaresi, E. & Fazio, F. (1993). [18F]FDG PET in fatal familial insomnia:The functional effects of thalamic lesions. Neurology, vol. 43, no. 12, 2565 - 2569

Schenkein, J. & Montagna, P. (2006), Self Management of Fatal Familial Insomnia. Part 1: What Is FFI?. MedGenMed, 8(3), 65

Schenkein, J., & Montagna, P. (2006). Self-management of Fatal Familial Insomnia. Part 2: Case Report. MedGenMed, 8 (3), 66.

Tabernero, C., Polo, J.M., Sevillano, M.D., Muñoz, R., Berciano, J., Cabello, A., Báez, B., Ricoy, J.R., Carpizo, R., Figols, J., Cuadrado, N. & Claveria, L.E. (2000). Fatal familial insomnia: clinical, neuropathological, and genetic description of a Spanish family. Journal of Neurology, Neurosurgery & Psychiatry, vol. 68, no. 6, 774-777