2012 Meeting Minutes

Public Health Service

Meeting of the Interagency Coordinating Committee on Human Growth Hormone and Creutzfeldt-Jakob Disease

December 5, 2012

National Institutes of Health - Bethesda, Maryland

Committee Members Attending Also Attending
Dr. Judith Fradkin, NIDDK
Dr. Ellen Leschek, NIDDK
Dr. Eugene Major, NINDS (by speakerphone)
Dr. Griffin Rodgers, NIDDK, Chairman
Dr. Lawrence Schonberger, CDC (by speakerphone)
Dr. Diane Wysowski, FDA (by speakerphone)
Dr. Greg Germino, NIDDK
Mary Harris, NIDDK
Ryan Maddox, CDC (by speakerphone)
Jody Nurik, NIDDK
Amy Reiter, NIDDK
Dr. B. Tibor Roberts, NIDDK
Dr. May Wong, NINDS (by speakerphone)

Th meeting began at 2:30 p.m.

1. Welcome

Dr. Rodgers welcomed the group, and those attending introduced themselves.

2. National Hormone & Pituitary Program (NHPP) cohort update

Dr. Leschek updated the committee on the status of the Westat contract, which is set to expire in June 2013. NIDDK is planning to renew the contract for another 5 years.

According to Committee practice, she then updated the Committee on confirmed and possible U.S. cases of CJD in the following categories:

  1. Neuropathologically confirmed CJD (confirmed based on the assessment of brain tissue)
  2. Clinically confirmed CJD (confirmed based on clinical findings alone because brain tissue was not available to allow neuropathological confirmation)
  3. Clinically suspicious (neurologic findings of uncertain etiology with insufficient information to confirm or exclude CJD)
  4. Deaths under investigation (clinically suspicious and still under investigation)

Case Categories I, II, and III:

Dr. Leschek reviewed a case that had been introduced to the committee at the 2011 meeting. The cohort member, who had received NHPP growth hormone from 1965 to 1970, died in May of 2009. The National Prion Disease Pathology Surveillance Center contacted Dr. Schonberger to inform him of a death, reporting that autopsy confirmed CJD. This was considered to be a new case of CJD, pending the release of a death certificate and/or medical records. Since the 2011 meeting, Dr. Leschek was able to obtain the patient’s death certificate, confirming the case and bringing the total number of neuropathologically confirmed (category I) cases to 14. The patient’s neurologist has not yet released the detailed medical records, as he is planning to incorporate them into a publication. Based on the verbal account of date of onset of symptoms provided by the neurologist, and growth hormone treatment records, the incubation period for this case is between 39.3 and 44.8 years (from start and end of treatment respectively), with a midpoint of 42.1 years. Because the previous longest possible incubation time was about 33 years (from midpoint of treatment), this new case extends the maximum incubation period for the cohort by more than 11 years.

Dr. Leschek will obtain the patient’s medical records to determine the date of symptom onset and report an incubation period for the fact sheet from initial treatment to onset of symptoms. Because the increase in potential incubation time is so significant, Dr. Wysowski also recommended checking all of the information we had on treatment dates for this individual, to ensure that source documents are in agreement. This was the only case confirmed over the past year.

There were no new cases in category II (clinically confirmed CJD), so the number of cases that fall into this category remains at 15. Therefore, the total number of CJD cases in the cohort is increased from 28 to 29. All 29 received at least some of their hGH treatment prior to 1977, when Dr. Parlow’s laboratory began producing hGH for the National Hormone and Pituitary Program.

The number of cases regarded as “clinically suspicious—insufficient information to confirm” (category III) remains four. Cases are placed in category III when there is clinical suspicion for CJD but confirmation cannot be attained because available clinical information is insufficient, no further clinical information is likely to become available, and brain tissue is not and never will be obtainable for neuropathological assessment.

Case Category IV:

Dr. Leschek presented cases under investigation. The first, who has been discussed in the past, was that of a cohort member who received hormone therapy between 1982 and 1984, and who died in 2004. Although no autopsy was performed, the death is considered “suspicious” because the patient died at the age of 35, and “encephalopathy” was listed as the cause. Dr. Schonberger obtained limited medical records, including multiple EEGs, from the hospital where the patient died. These EEGs were reviewed by a neurologist in the Prion and Public Health Office at the CDC, who saw no evidence for CJD. The staff at the nursing home where the patient was staying reported that the patient was alert, self-feeding, oriented most of the time, and primarily in a wheelchair, but was able to propel herself with her feet and was walking occasionally with some assistance. A CT scan at that time showed some central and cerebellar atrophy, prominent ventricles, and dystrophic calcification of the cerebellum, brain stem, and basal ganglia. The medical records were sent to the NRG. The first neurologist who reviewed the records concluded that CJD was unlikely, but noted that the information provided was very limited. The second neurologist felt the information to be completely insufficient to eliminate the possibility of CJD. The records have now been sent to a third neurologist. Once the opinion of the third neurologist is received, the committee will need to make a decision on how to proceed with this case.

The second is a previously undiscussed case of a cohort member who was treated with NHPP hormone between 1981 and 1985 for panhypopituitarism due to craniopharyngioma resection and irradiation. The patient died in 2008. The death certificate listed the cause of death as “unknown,” along with “multiple stable health problems.” This case is still under investigation due to the need for more information on the cause of death. Attempts to locate next of kin have been unsuccessful. Dr. Leschek noted that it is getting increasingly more difficult to locate next of kin because as the patients age, many of their parents are more likely to be deceased. Notes from the Westat interviews with the patient’s family in 1988 and 1989 indicate that the patient was living in a chronic care facility and was on Tegretol for seizures, Coumadin for blood clots, and the neuroleptic Mellaril for behavior issues. An autopsy was performed, and Westat is attempting to obtain the amended death certificate and permission from next of kin to release the medical records, including slides from the autopsy. The Committee agreed that determining whether brain sections were examined as part of the autopsy will help to determine how much effort should be applied to obtaining the autopsy report.

Dr. Leschek discussed a case that was presented at the 2011 meeting: a man who died at age 33 in 2008 from anoxic encephalopathy and respiratory failure. No autopsy was performed. This case is under investigation because of the listed cause of death. There are no known living next of kin. The patient’s spouse is still living, but IRB rules prohibit contact with her unless she initiates communication. Dr. Maddox was able to obtain the discharge summary from the hospital where the patient stayed for 5 days shortly before his death, and the consulting neurologist at the hospital believed the patient suffered from repeated hypoglycemic episodes that resulted in profound brain injury and death. The discharge summary also listed several possible secondary causes of death, including hypoglycemia, elevated liver function, rhabdomyolysis, type 1 diabetes, a congenital unilateral kidney, and alcoholism. The discharge summary did not mention subacute neurological symptoms that would suggest CJD. There are no more options available to obtain more information. Dr. Fradkin suggested that the information be forwarded to the NRG for review. Dr. Leschek concurred, and will report when she hears back from the NRG.

Case Summary by Category (resulting from adjudication during this meeting):
Category # cases Net change since 2011
I 14 +1
II 15 0
III 4 0
IV 3 +1

Dr. Leschek and Dr. Schonberger provided an update to the Committee on the collaboration with Drs. Trojanowski and Irwin of the University of Pennsylvania to determine whether the cohort could shed light on the potential infectivity of other neurological diseases, such as Parkinson’s disease, Amyotrophic lateral sclerosis (ALS), frontal temporal lobular dystrophy (FTLD), and Alzheimer’s disease. Recently published papers suggest that prions or prion-like particles may have a role in transmission of these diseases. Drs. Leschek and Schonberger searched the cohort and found two cases of ALS, both in people who were about 30 years old at the time of death. A literature search uncovered the existence of another recipient of hGH—not in the cohort—who also died of ALS, bringing the total to three. No confirmed cases of the other neurological diseases were found in patients who received growth hormone from the NHPP.

The third case of ALS was discovered during the early phase of CJD surveillance of pituitary hGH recipients. FDA received about 10 reports of hGH recipients who had developed neurological disorders besides CJD, including one patient who had developed ALS (Rappaport EB, Graham DJ. Pituitary growth hormone from human cadavers: Neurologic disease in 10 recipients. Neurol, 1987; 37:1211-1213). Dr. Wysowski and others at FDA attempted to locate the case report in the FDA’s Adverse Event Reporting System but they were unable to do so. This third case of ALS was in a patient who received NHPP-distributed hormone, but was not part of the study cohort, which serves as a useful reminder that an estimated 1,400 NHPP hGH recipients were not included in the 6,272 person cohort because their records were not available in 1985, and 5 of the 29 known cases of CJD are from that non-cohort group. The rate of CJD in that group is similar to the incidence of CJD in the cohort group. Dr. Schonberger noted that given the prevalence of ALS in the U.S., the most likely number of deaths from ALS expected in the cohort would be zero, but the prevalence of ALS in the cohort is not statistically significant when the analysis includes the prevalence of other neurological diseases such as Parkinson’s, FTLD, and Alzheimer’s, and correction for multiple comparisons. Dr. Wysowski also mentioned that Alzheimer’s, Parkinson’s, and FTLD would not necessarily be attributed as causes of death, and so they may not be on the death certificate, which would result in under-reporting of these diseases. Dr. Schonberger agreed that this presents a weakness in existing data, although the control group (i.e., cases outside of the cohort) used the same methods to establish cause of death. Dr. Leschek added that although Westat always obtains death certificates for deceased cohort members, these documents are very operator-dependent, and there is variability from state to state. Many states also list secondary factors that may have contributed to the cause of death, and sometimes other information that may not have been related to the death but still may raise a “red flag,” such as a younger patient living in a nursing home.

Dr. Schonberger discussed a proposal to search clinical and autopsy records of cohort members who die in the future not only for CJD but for other neurodegenerative diseases as well. Dr. Leschek noted that such an analysis would add minimal cost because she always reviews the medical records and the autopsy reports, and if anything questionable comes up, she will see it.

The timeframe for the follow-up studies was then discussed. It had been previously agreed upon that if there were no new cases of confirmed CJD within a 5-year period, surveillance would be discontinued. Because the last confirmed case was originally presented to the Committee at the 2011 meeting, the Committee will continue to perform the follow-up studies through at least 2016. Dr. Germino inquired as to the type of information that will be garnered from continuation of the study. Dr. Fradkin answered that it would be valuable to know whether anyone who only received hormone after 1977 (i.e., after Dr. Parlow received the NHPP contract) is at risk for developing CJD. This could be complicated because many patients received hormone both before and after this transition. At present, no one who started NHPP hormone treatments after 1977 (64 percent of the cohort) has developed CJD. This question is of particular interest since CJD has now developed in patients receiving commercial (non-NHPP) pituitary growth hormone that may have been prepared using a similar approach to the one used by Dr. Parlow. Dr. Fradkin noted that we currently have no data to compare the quality of the commercial preparations to those of Dr. Parlow. Dr. Roberts added that if we follow the patients who received hormone between 1977 and 1985 for the maximum known incubation time of 44 years, this Committee would potentially be active through 2029.

Dr. Schonberger reported that since the 2011 meeting he was able to obtain the medical records, including an MRI, on the second patient who developed CJD after treatment with commercial (non-NHPP) hGH. He sent these to the National Prion Disease Pathology Surveillance Center, which confirmed a CJD diagnosis. Because no autopsy was performed, this is a “probable” case of CJD. The patient received hGH from two sources, Serono and Kabivitrum. The other known case involving commercial hGH (an Austrian discussed in the 2008 Committee Meeting minutes) also received Crescormon manufactured by Kabivitrum. The new U.S. case report has been compiled as a manuscript that is currently under review.

3. Report on CJD in foreign GH recipients

Dr. Schonberger summarized the number of foreign CJD cases. There were a total of four new cases in the U.K., including two patients who are still living. Thus, the number of cases in the U.K. is increased from 64 to 68. The total number of iatrogenic CJD cases attributed to hGH treatment outside the United States increased to 200.

Reported cases by country as of December 2012:
Country Reported Cases
France 119
United Kingdom 68 1, 2
New Zealand 6
Brazil 2
Holland 2
Australia 1
Austria 1
Qatar 1
Non-U.S. Total 200

1 does not include four known cases of iatrogenic CJD from Australian pituitary gonadotropin (one in the U.K., three in Australia).

2 includes two individuals still surviving as of December 5, 2012.

In addition to those noted in the table, a possible (albeit unlikely) case was reported in Australia.

Dr. Major discussed a study performed in the U.K. in which the presence of CJD prion was found in approximately 1 appendix out of 2000. This number seems high compared to the incidence of the disease; therefore, it is possible that there are significant numbers of patients who are harboring the disease but are not displaying symptoms.

4. Update on Fact Sheet and Public Inquiries

Ms. Nurik reported that the updates from the 2011 meeting have been incorporated into the fact sheets, and she will work with Drs. Fradkin, Leschek, and Schonberger on incorporating new updates following this meeting.

Ms. Nurik suggested that the resource lists on the comprehensive report and the summary report be incorporated into the separate Resource List that was updated in 2011, with links to the online publications. Some of the resources in the comprehensive report are older than the resources in the Resource List, so she will work with Drs. Fradkin, Leschek, Roberts, and Schonberger on identifying the set of resources that should be preserved.

Ms. Harris reported that 19 people had contacted the NHPP inquiry line since the 2011 meeting, 13 of whom were cohort members. Eight of the 13 contacted the NIDDK only to report a change of address, and three were requesting an information update. Two of the cohort members reported health problems. One had dizziness and difficulty walking and thinking, which the patient’s doctor attributed to diabetes. The other cohort member had dizziness and balance problems; this patient had been diagnosed with Chiari malformation type I but was still symptomatic despite two operations. The six people who were not in the cohort were experiencing health problems and were seeking medical care. Dr. Fradkin suggested that we converse with these people to determine whether they received hGH and, if so, where they got it. Westat can assist with this, as long as they are provided with identifiers. Dr. Leschek also noted that the parents of the patient are the only next-of-kin who can be contacted, and it is important to update changes in the parents’ addresses because many of the patients live with their parents.

5. Brief Highlights of Progress in CJD Research

Dr. Schonberger selected the following papers and reports:

A paper by Luk et al. (Science, 2012. 338:949-953) describing how a single injection of a-synuclein into wild-type mice leads to cell-to-cell transmission of a-synuclein, Lewy body formation, and a Parkinson’s-like pathology in anatomically interconnected regions;

A summary in Health Protection Report (Vol. 6, August 2012) (PDF, 766 KB) reporting a national (U.K.) survey of vCJD prion prevalence in appendix specimens;

A Position Statement (July 2012) (PDF, 134 KB) from the Advisory Committee on Dangerous Pathogens (ACDP) TSE Risk Assessment Group commenting on the above Health Protection Report and the occurrence and prevalence of vCJD infections in the U.K. population;

Papers by McGuire et al (PDF, 391 KB) . (Ann Neurol., 2012. 72:278-85) and Orru et al (PDF, 2.4 MB) . (MBio, 2011. 2:e00078-11) describing a new method (“real-time quaking-induced conversion”) to detect minute amounts (attograms per milliliter) of abnormal prion protein in clinical samples;

A paper by Brown et al. (Emerg Infect Dis., 2012. 18:901-7) providing a current global assessment of iCJD cases, including sources of infection and prevalence by country.

Dr. Major selected the following additional papers and reports:

A paper by Freundt et al (PDF, 401 KB) . (Ann Neurol., 2012. 72:517-24) describing the transmission of a-synuclein between neurons independent of synaptic contact;

A paper by Atarashi et al. (Nat Med., 2011. 17:175-78) that initially described the “quaking-induced conversion” method of detecting abnormal prion protein in cerebral spinal fluid (CSF);

A paper by Parchi and Capellari on the practicality of using 14-3-3 protein in CSF as a biomarker for CJD.

The meeting was adjourned at 3:50 p.m.

Griffin P. Rodgers, M.D.
Director, NIDDK