Hal A Droogleever Fortuyn

Severe fatigue in narcolepsy with cataplexy.

Excessive daytime sleepiness (EDS) is the core symptom of narcolepsy. However, there have been indications that fatigue – which should be separated from EDS – is also a frequent complaint. We determined the prevalence of severe fatigue in a group of narcolepsy patients and its relation with excessive daytime sleepiness, psychological distress, functional impairment and quality of life. We included 80 patients fulfilling the International Classification of Sleep Disorders (ICSD)‐2 diagnostic criteria of narcolepsy with cataplexy. Fatigue was measured using the Checklist Individual Strength (CIS). In addition psychological distress, including symptoms of depression, functional impairment and quality of life, were assessed. Comparisons were made between patients with (CIS‐fatigue score ≥ 35) and without severe experienced fatigue. Fifty patients (62.5%) reported severe fatigue. There were no sex or age differences between patients with and without severe fatigue. Both fatigued and non‐fatigued patients had the same amount of daytime sleepiness (Epworth Sleepiness Score 14.3 ± 4.2 versus 13.1 ± 4.4, P = 0.22), confirming the separation between sleepiness and fatigue. Interestingly, fatigued patients more often used stimulant medication (64% versus 40%, P = 0.02). Severe fatigue was associated with a significantly increased functional impairment, increased depressive symptoms and a lowered general quality of life. In conclusion, a majority of patients with narcolepsy suffer from severe fatigue, which can be distinguished from daytime sleepiness, and results in severe functional impairment.

Diurnal spectral EEG fluctuations in narcoleptic patients during rest and reaction time tasks.

Narcolepsy is associated with lowered vigilance. Diurnal variation in vigilance appears altered, but the exact nature of this change is unclear. It was hypothesized that the homeostatic sleep drive is increased in narcolepsy. Decreased levels of vigilance are reflected in low frequency band power in the electroencephalogram (EEG), so these frequencies were expected to be increased in the narcolepsy group. Furthermore, it was expected that low frequency power should increase over the day. Narcoleptic patients and healthy controls participated (36 participants in total); they were not allowed to take medication or naps on the experimental day. EEG was measured at 9:00, 11:00, 13:00, 15:00, and 17:00 hours, during rest and during reaction time tasks. In the narcolepsy group, alpha power was lower at rest at all times. Delta and theta power during rest and task performance increased steadily over the day in this group, from 11:00 hours onwards. Additionally, in the narcolepsy group beta1 and beta2 power during rest appeared increased at the end of the day. The effects in the lower frequency bands strongly suggest that vigilance is low at all times. The progressive increase in low frequency power indicates that the sleep drive is enhanced. It is not clear whether this pattern reflects an extreme state of low vigilance, or a pathological brain condition. The effects in the higher frequencies suggest that narcoleptic patients may make an effort to counteract their low vigilance level.

Is Fatigue a Disease-Specific or Generic Symptom in Chronic Medical Conditions?

Objective: Severe fatigue is highly prevalent in various chronic diseases. Disease-specific fatigue models have been developed, but it is possible that fatigue-related factors in these models are similar across diseases. The purpose of the current study was to determine the amount of variance in fatigue severity explained by: (a) the specific disease, (b) factors associated with fatigue across different chronic diseases (transdiagnostic factors), and (c) the interactions between these factors and specific diseases. Method: Data from 15 studies that included 1696 patients with common chronic diseases and disorders that cause long-term disabilities were analyzed. Linear regression analysis with the generalized least-squares technique was used to determine fatigue-related factors associated with fatigue severity, that is, demographic variables, health-related symptoms and psychosocial variables. Results: Type of chronic disease explained 11% of the variance noted in fatigue severity. The explained variance increased to 55% when the transdiagnostic factors were added to the model. These factors were female sex, age, motivational and concentration problems, pain, sleep disturbances, physical functioning, reduced activity and lower self-efficacy concerning fatigue. The predicted variance increased to 61% when interaction terms were added. Analysis of the interactions revealed that the relationship between fatigue severity and relevant predictors mainly differed in strength, not in direction. Conclusions: Fatigue severity can largely be explained by transdiagnostic factors; the associations vary between chronic diseases in strength and significance. This suggests that severely fatigued patients with different chronic diseases can probably benefit from a transdiagnostic fatigue-approach which focuses on individual patient needs rather than a specific disease.

Cheaper, Faster, Development of More Effective New Treatments

An historical review of the ‘strategic’ development or accidental discovery of new therapeutic interventions demonstrates that ‘evidence’ is needed to confirm progress. As early as 1940 Carl Popper provides a prescription for ‘Logic of Discovery’. A study will only provide new scientific information if it has a ‘falsifiable’ null-hypothesis. If the null-hypothesis is proven to be ‘false’, another falsifiable hypothesis needs to be formulated and tested. The first time a null hypothesis is confirmed is not enough to accept the null-hypothesis. Each positive confirmation of the null hypothesis increases the chance the investigators move in the right direction. The use of double blind randomized trials as recommended by FDA and EMA have no falsifiable null hypothesis. If the study collects enough patients’ one arm will always be better than the other arm at a probability of < 0.05, but a repeat study -almost never donecould show the other arm of the study is the best one with same low p-value. Radiolabeled Immunoglobulin Therapy (RIT) in patients with poor prognosis solid tumors, allows for the introduction of a falsifiable ‘null-hypothesis’ and the determination of radiation dose effect curves for normal tissues surrounding the tumor as well as tumor dose effect curves, without exposing the patient to unpredictable risks and increasing the chance for a beneficial tumor response. Vriesendorp, H.M., et al. page no: 47 Short title: The Null Hypothesis Vriesendorp, H.M., et al. Table 1: The Spoils of War War Military escalation Social/Health care improvements C r i m e a n War, 18531856 Better explosives. (Nobel sr.), use of railways and telegraph for more efficient warfare. Nursing, triage of wounded soldiers, (Florence Nightingale). Better anesthetics, plaster casts, enhanced amputation methods, (N.I. Pirgov) First War Correspondent, (Leo Tolstoy) Franco-Prussian War, 1870-1871 Improved command structures, guns, and cannons. Prisoners of war should receive the same treatment as the soldiers of the invading Army. World War I 1914-1918 First use of tear gas & nerve gas. Citizens/hostages are used to extract money and to decrease violence against the invading Army. Gasmasks; Accident with transportation of nitrogen mustard lead to the discovery of the first human chemotherapeutic agent: Nitrogen mustard. World War II 1939-1945 Bombarding civic centers, Atomic Warfare Extermination of Jews in gas-chambers, euthanasia of children with genetic ‘undesirable’ genetic disorders. Nuclear energy (‘Atoms for Peace’), International Atomic Energy Commission, Bone marrow transplantation. The Nuremberg Code for experimentation with human beings. Tsar Nicolas II responds by organizes 2 Peace Conferences in The Hague, the Netherlands in 1899 and 1907. US, Theodor Roosevelt, is a co-sponsor in 1907. An international arbitration court is proposed to adjudicate conflicts before they escalate into wars. Its deliberations are ignored, The Austrian Baroness Bertha von Suttner-Kinsky, a dedicated pacifist, writes a best seller in 1899, entitled ‘Die Waffen nieder’ (Lay down your arms). She is a revered celebrity at both Peace Conferences. Origins of the Nobel Prize Alfred Nobel Jr. is a chemist, engineer and inventor. He owns laboratories in twenty different countries and holds more than 350 patents, most of them on the use of different forms of explosives. All European countries are stocking his expensive explosives and have made Alfred and his brothers very wealthy. Alfred’s main interest is in making, nitroglycerin based explosives more powerful and less dangerous to handle by preventing premature, unscheduled explosions. An explosion in Nobel’s own laboratory kills several people, including his youngest brother. Nobel has other interests, such as blood transfusions, which he starts to study in dogs in a laboratory in France. When he hears his brother Ludvig is dying from cardiac failure in Cannes, France, Alfred hurries to Cannes to resolve old business conflicts with his brother before he dies. The day after Ludvig’s death, a French newspaper publishes a necrology entitled ‘Le Marchand de la mort est mort’ (The merchant of death is dead) assuming in error it is Alfred, who has died, not Ludvig. Alfred does not like to be labeled a ‘merchant of death’. Alfred corresponds for years with Baroness Bertha Von Suttner-Kinsky. In 1981 Alfred writes to Bertha: ‘Perhaps my factories will put an end to war sooner than your congresses: on the day that two army corpses can mutually annihilate each other in a second, all civilized nations will surely recoil with horror and disband their troops. Good wishes alone will not ensure peace.’ Albert continues to work hard, is lonely, and suffers from depressions. In Paris, his doctors try to convince him to take nitroglycerine for his heart trouble! October 25, 1896 Alfred writes to his friend, Ragnar Sohliman: ‘My heart trouble will keep me here in Paris for another few days at least, until my doctors are in complete agreement about my immediate treatment. Isn’t it the irony of fate that I have been prescribed N/G/I (Nitroglycerine) to be taken internally!’ Alfred Nobel refuses to be treated with nitroglycerine and dies December 10, 1896 at the age of 63, in San Remo, Italy. Alfred modified his will a year before his death. He informs Bertha, he did so. Bertha answers: ‘Whether I am around then or not does not matter, what we have given, you and I, is going to live on’ The whole world is surprised when Nobel’s modified will is made public. The French Government is disappointed by not being able to collect substantial inheritance taxes. Alfred has donated 96% of his financial assets to be used for a series of prizes for those who confer the ‘greatest benefit to mankind’ in 5 different categories. ‘I hereby appoint as Executors of my testamentary dispositions, Mr. Ragnar Sohlman, resident in Bofors, Väland (Sweden) and Mr. Rudolf Lilljequist, Oslo. (Norway).’ In 1893 Sohlman had become Nobel’s assistant. The execution of Nobel’s will makes Sohlman and Lilljequist very wealthy men. Sweden and Norway In 1900 Swedish King Oscar II promulgates the Nobel Foundation statutes. Each year the Nobel Assembly at The Karolinska Institute Institutet, (a Medical University) selects the Nobel Prize winners. The Assembly consists of fifty professors from various medical disciplines at the University. The Norwegian Nobel Committee, consisting of 5 members appointed by the Norwegian Parliament awards the yearly Peace Prize in a ceremony in Oslo. All Nobel prizes are awarded on December 10, the day Nobel died, in the presence of Norwegian or Swedish Royalty. Baroness Von Suttner is the first woman to receive a Nobel Prize, the Nobel Prize for Peace in 1905. Nobel upgrades his name from being ‘the merchant of death’, to being the provider of yearly, prestigious Prizes in 5, later 6 different disciplines,’ which are still being awarded more than 100 years later. Negative aspects of the Nobel Prize tradition are the competition and jealousy it can generates among scientists. With all his wealth and patents Alfred Nobel probably provides the wrong role model for those academicians, who want to cash in on their inventions, before sharing them for an affordable price with people who might benefit from their inventions. The first Nobel Peace Prize is awarded in 1901 to Henri Dunant, the founder of the Red Cross and Frédéric Passy, the founder of the French Peace Society. Nobel Prizes are only given to living people and to not more than three recipients per category per year. There are 5 categories: Physics, Chemistry, Physiology or Medicine, Literature and Peace. In 1969 Economics is added as a sixth category.