December 4, 2017History of Medicine
Photo credit: Unknown - http://www.sammlungen.hu-berlin.de/dokumente/11727/, Public Domain, https://commons.wikimedia.org/w/index.php?curid=4008658
Hans Gerhard Creutzfeldt was born into a medical family in Harburg, which was incorporated into Hamburg in 1937. In 1903, at the age of 18, Creutzfeldt was drafted into the German army and spent his service stationed in Kiel. Afterwards, he attended the School of Medicine of the Universities of University of Jena and University of Rostock, receiving his doctorate at the latter in 1909. Part of his practical training was undertaken at St. Georg - Hospital in Hamburg. After qualification he sought adventure as a ship's surgeon, voyaging the Pacific Ocean, taking the opportunity to study local crafts, linguistics, and tropical plants. After returning to Germany, Creutzfeldt worked at the Neurological Institute in Frankfurt am Main, at the psychiatric-neurological clinics in Breslau, Kiel and Berlin, and at the Deutsche Forschungsanstalt fur Psychiatrie in Munich. Creutzfeldt was habilitated at Kiel in 1920, and in 1925 became Extraordinarius of psychiatry and neurology. In 1938 he was appointed professor and director of the university psychiatric and neurological division in Kiel. Later, Creutzfeldt helped to recognize a neurodegenerative disease, with Alfons Maria Jakob, now known as Creutzfeldt-Jakob disease, in which the brain tissue develops holes and takes on a sponge-like texture. It is now known that this disease is due to a type of infectious protein called a prion. Prions are misfolded proteins which replicate by converting their properly folded counterparts.
In the Third Reich, Creutzfeldt became a Patron Member of Heinrich Himmler's SS. However, when Creutzfeldt was 54 years old and WW2 broke out, he was unmoved by the Nazi regime and was able to save some people from death in concentration camps. He also managed to rescue almost all of his patients from being murdered under the Nazi Action T4 euthanasia program, an unusual event since most mental patients identified by T4 personnel were gassed or poisoned at separate euthanasia clinics such as Hadamar Euthanasia Centre. During the war, bombing raids destroyed his home and clinic. After the war he was director of the University of Kiel for six months, before being dismissed by the British occupation forces. His efforts to rebuild the university caused a series of conflicts with the British because he wanted to allow more former army officers to study there. In 1953 he moved on to Munich to work on scientific research commissioned by the Max Planck Society.
Creutzfeldt was married to Clara Sombart, a daughter of Werner Sombart. They had five children, among them Otto Detlev Creutzfeldt and Werner Creutzfeldt (1924-2006), a renowned German Internist. Hans Gerhard Creutzfeldt died in 1964 in Munich.
As mentioned above, Creutzfeldt-Jakob disease, is a subacute spongiform encephalopathy caused from prions involving the cerebral cortex, the basal ganglia and the spinal cord. Some of the clinical findings described in the Creutzfeldt and Jakob first papers do not match current criteria for Creutzfeldt-Jakob disease. It has been speculated that at least two of the patients in initial studies were suffering from a different ailment. A study published in 1997 counted more than 100 cases worldwide of transmissible CJD and new cases continued to appear at the time. The first report of suspected iatrogenic CJD was published in 1974. Animal experiments showed that corneas of infected animals could transmit CJD, and the causative agent spreads along visual pathways. A second case of CJD associated with a corneal transplant was reported without details. In 1977, CJD transmission caused by silver electrodes previously used in the brain of a person with CJD was first reported. Transmission occurred despite decontamination of the electrodes with ethanol and formaldehyde. Retrospective studies identified four other cases likely of similar cause. The rate of transmission from a single contaminated instrument is unknown, although it is not 100%. In some cases, the exposure occurred weeks after the instruments were used on a person with CJD.
A review article published in 1979 indicated that 25 dura mater cases had occurred by that date in Australia, Canada, Germany, Italy, Japan, New Zealand, Spain, the United Kingdom, and the United States.
By 1985, a series of case reports in the United States showed that when injected, cadaver-extracted pituitary human growth hormone could transmit CJD to humans. In 1992, it was recognized that human gonadotropin administered by injection could also transmit CJD from person to person. In 2004, a report published by Edinburgh doctors in the Lancet medical journal demonstrated that vCJD was transmitted by blood transfusion.
Stanley B. Prusiner of the University of California, San Francisco (UCSF) was awarded the Nobel Prize in physiology or medicine in 1997 for his discovery of Prions - a new biological principle of infection. However, Yale University neuropathologist Laura Manuelidis has challenged the prion protein (PrP) explanation for the disease. In January 2007, she and her colleagues reported that they had found a virus-like particle in naturally and experimentally infected animals. The high infectivity of comparable, isolated virus-like particles that show no intrinsic PrP by antibody labeling, combined with their loss of infectivity when nucleic acid-protein complexes are disrupted, make it likely that these 25-nm particles are the causal TSE virions. Four Australians had been reported with CJD following transfusion as of 1997. There have been ten cases of healthcare-acquired CJD in Australia. They consist of five deaths following treatment with pituitary extract hormone for either infertility or short stature, with no further cases since 1991. The five other deaths were caused by dura grafting during brain surgery, where the covering of the brain was repaired. There have been no other known healthcare-acquired CJD deaths in Australia. A case was reported in 1989 in a 25-year-old man from New Zealand, who also received dura mater transplant. Five New Zealanders have been confirmed to have died of the sporadic form of Creutzfeldt-Jakob disease (CJD) in 2012.
Researchers believe one in 2,000 people in the UK is a carrier of the disease linked to eating contaminated beef (vCJD). The survey provides the most robust prevalence measure to date - and identifies abnormal prion protein across a wider age group than found previously and in all genotypes, indicating infection may be relatively common. This new study examined over 32,000 anonymous appendix samples. Of these, 16 samples were positive for abnormal prion protein, indicating an overall prevalence of 493 per million population, or one in 2,000 people are likely to be carriers. No difference was seen in different birth cohorts (1941-60 and 1961-85), in both genders, and there was no apparent difference in abnormal prion prevalence in three broad geographical areas. Genetic testing of the 16 positive samples revealed a higher proportion of valine homozygous (VV) genotype on the codon 129 of the gene encoding the prion protein (PRNP) compared with the general UK population. This also differs from the 177 patients with vCJD, all of whom to date have been methionine homozygous (MM) genotype. The concern is that individuals with this VV genotype may be susceptible to developing the condition over longer incubation periods.
In 1988, there was a confirmed death from CJD of a person from Manchester, New Hampshire in the United States. Massachusetts General Hospital believed the patient acquired the disease from a surgical instrument at a podiatrist's office. In September 2013, another patient in Manchester, New Hampshire was posthumously determined to have died of the disease. The patient had undergone brain surgery at Catholic Medical Center three months before his death, and a surgical probe used in the procedure was subsequently reused in other operations. Public health officials identified thirteen patients at three hospitals who may have been exposed to the disease through the contaminated probe, but said the risk of anyone's contracting CJD is extremely low. In January 2015, the former speaker of the Utah House of Representatives, Rebecca D. Lockhart, died of the disease within a few weeks of diagnosis. John Carroll, former editor of The Baltimore Sun and Los Angeles Times, died of CJD in Kentucky in June 2015, after having been diagnosed in January. American actress Barbara Tarbuck (General Hospital, American Horror Story) died of the disease on December 26, 2016.
An experimental treatment was given to a Northern Irish teenager, Jonathan Simms, beginning in January 2003. The medication, called pentosan polysulphate (PPS) and used to treat interstitial cystitis, is infused into the patient's lateral ventricle within the brain. PPS does not seem to stop the disease from progressing, and both brain function and tissue continue to be lost. However, the treatment is alleged to slow the progression of the otherwise untreatable disease, and may have contributed to the longer than expected survival of the seven patients studied. Simms died in 2011. The CJD Therapy Advisory Group to the UK Health Departments advises that data are not sufficient to support claims that pentosan polysulphate is an effective treatment and suggests that further research in animal models is appropriate. A 2007 review of the treatment of 26 patients with PPS finds no proof of efficacy because of the lack of accepted objective criteria. Scientists have investigated using RNA interference to slow the progression of scrapie in mice. The RNA blocks production of the protein that the CJD process transforms into prions. This research is unlikely to lead to a human therapy for many years. Both amphotericin B and doxorubicin have been investigated as potentially effective against CJD, but as yet there is no strong evidence that either drug is effective in stopping the disease. Further study has been taken with other medical drugs, but none are effective. However, anticonvulsants and anxiolytic agents, such as valproate or a benzodiazepine, may be administered to relieve associated symptoms.
Scientists from the University of California, San Francisco are currently running a treatment trial for sporadic CJD using quinacrine, a medicine originally created for malaria. Pilot studies showed quinacrine permanently cleared abnormal prion proteins from cell cultures, but results have not yet been published on their clinical study. The efficacy of quinacrine was also assessed in a rigorous clinical trial in the UK and the results were published in Lancet Neurology, and concluded that quinacrine had no measurable effect on the clinical course of CJD. In a 2013 paper published in the Proceedings of the National Academy of Sciences, scientists from The Scripps Research Institute reported that Astemizole, a medication approved for human use, has been found to have anti-prion activity and may lead to a treatment for Creutzfeldt-Jakob disease.