Creutzfeldt-Jakob disease with unusually extensive neuropathology in a child treated with native human growth hormone
Clin Neuropathol. 2012 May-Jun;31(3):127-34.
Creutzfeldt-Jakob disease with unusually extensive neuropathology in a
child treated with native human growth hormone.
Mikol J, Deslys JP, Zou WQ, Xiao W, Brown P, Budka H, Goutieres F.
Source
Denis Diderot University. Jacqueline.mikol@wanadoo.fr
Abstract
We report a case of iatrogenic Creutzfeldt-Jakob disease(iCJD) in a child
with a neonatal growth hormone (GH) deficiency that was treated with native
human growth hormone (hGH) between the ages of 9 months and 7 years. Three years
after the end of treatment a progressive neurological syndrome consistent with
Creutzfeldt-Jakob disease (CJD) developed, leading to death within a year, at
age 11. Neuropathological examination showed an unusual widespread form of CJD,
notably characterized by (i) involvement of the cerebellar white matter, (ii)
cortico-spinal degeneration and (iii) ballooned neurons. A transitional form of
the disease between common iatrogenic and panencephalopathic CJD is suggested.
SHORT REPORT
Creutzfeldt-Jakob disease 38 years after diagnostic use of human growth
hormone
E A Croes, G Roks, G H Jansen, P C G Nijssen, C M van Duijn
...............................................................
J Neurol Neurosurg Psychiatry 2002;72:792-793
A 47 year old man is described who developed pathology proven
Creutzfeldt-Jakob disease (CJD) 38 years after receiving a low dose of human
derived growth hormone (hGH) as part of a diagnostic procedure. The patient
presented with a cerebellar syndrome, which is compatible with iatrogenic CJD.
This is the longest incubation period described so far for iatrogenic CJD.
Furthermore, this is the first report of CJD after diagnostic use of hGH. Since
the patient was one of the first in the world to receive hGH, other cases of
iatrogenic CJD can be expected in the coming years.
Prion diseases are potentially transmissible. Human to human transmission
was first reported in 1974, when a 55 year old woman was described who developed
symptoms of Creutzfeldt-Jakob disease (CJD) 18 months after a corneal
transplant.1 Since then, transmission has been reported after stereotactic
electroencephalographic (EEG) depth recording, human growth hormone (hGH) and
gonadotrophin treatment, and dura mater transplantation.2-5 More than 267
patients with iatrogenic CJD are known today and their number is growing.6 The
most important iatrogenic cause of CJD is still contaminated cadaveric hGH.
Exposure to contaminated hGH occurred before 1985, when recombinant growth
hormone became available. In a recent study, incubation periods in 139 patients
with hGH associated CJD were found to range from 5-30 years, with a median of 12
years.6 One of the factors influencing incubation time is genotype on
polymorphic codon 129 of the prion protein gene.7 The incubation time is
significantly shorter in people who are homozygous for either methionine or
valine on this polymorphism.7
We describe the second patient with hGH related CJD in the Netherlands. The
patient developed the disease 38 years after hGH injections. To our knowledge,
this is the longest incubation period described for any form of iatrogenic CJD.
Further-more, our patient was not treated with hGH but only received a low dose
as part of a diagnostic procedure.
CASE REPORT
This patient presented at the age of 47 years with paraesthesia in both
arms for six months, difficulty with walking for four weeks, and involuntary
movements of mainly the upper extremities of two weeks' duration. He did not
notice any change in cognitive function, although his twin sister had noticed
minor memory disturbances. There was no family history of neurological disease.
During childhood the patient had experienced a growth delay compared with his
twin sister and with the average in the Netherlands. When he was 9 years old, a
nitrogen retention test with 6 IU hGH over five days was performed to exclude
growth hormone deficiency. Since the result was not decisive, a quantitative
amino acid test was performed, which measures 30 amino acids during fasting and
one, two, and three hours after growth hormone injection. No abnormal amino acid
concentrations were found making the diagnosis of primordial dwarfism most
likely. Therefore, no treatment with hGH was given.
On neurological examination we found a slight dysarthria without aphasia.
Cranial nerve function was normal. Walking was unstable and wide based. During
movements of the upper extremities myoclonic jerks were present. Sensation,
muscle tone, and strength were normal. Co-ordination was impaired in all four
limbs with a disturbed balance. Tendon reflexes were brisk at the arms and
increased at the legs with a clonus in the ankle reflex. Plantar responses were
both normal. On the mini mental state examination, the patient scored 30/30.
Routine laboratory investigation, thyroid function, vitamin concentrations (B-1,
B-6, B-12, and E), and copper metabolism were normal. Admission EEG examination
showed generalised arrhythmic slow activity with diffuse spikes and spike waves.
EEG examination two months later showed a further slowing of the rhythm with
bilateral diphasic sharp waves but was not typical for CJD. Cerebral magnetic
resonance imaging was normal. Cerebrospinal fluid examination showed 1 cell/3
µl, normal glucose and protein concentrations, and a strongly positive 14-3-3
protein test. The patient was homozygous for methionine on the PRNP codon 129
polymorphism. On clinical grounds, CJD was diagnosed. Within one month the
patient's condition deteriorated rapidly and because of severe disturbances in
coordination and progressive myoclonus he became bedridden. An eye movement
disorder developed with slow saccadic and dysmetric eye movements. Temperature
became unstable with peaks of 39°C without an infectious focus, for which a
disorder of autoregulation was presumed. Until a very advanced stage, cognitive
function was intact. The patient died five months after admission. The diagnosis
of CJD was confirmed at necropsy. The brain weighed 990 g and showed clear
cortical and cerebellar atrophy. Spongiosis, neuronal loss, and gliosis were
found predominantly in the putamen, caudate nucleus, and basotemporal and
cerebellar cortex; the cerebellum was the most severely affected of these.
Vacuoles ranged from 2-12 µm. No amyloid or Kuru plaques were found.
Immunohistochemical staining (3F4 antibody 1:1000, Senetek, USA) was clearly
positive for prion protein accumulation in a "synaptic" distribution. Most
deposition was found in the stratum moleculare of the cerebellum.
DISCUSSION
We describe a 47 year old patient who developed pathology proven CJD 38
years after hGH injections. The patient was never treated with hGH but received
a small dose as part of a diagnostic procedure. The onset of CJD was signalled
by prodromal symptoms of paraesthesia followed by a rapidly progressive ataxia.
The disease presentation and course with predominantly cerebellar and eye
movement disorders are compatible with iatrogenic CJD caused by hGH treatment.6
8
Growth hormone treatment was first described in 1958 but hGH was not
produced on a larger scale from human pituitary glands until the beginning of
the 1960s. In the Netherlands growth hormone extraction started in 1963 and was
soon centrally coordinated. Until 1979 growth hormone was extracted
non-commercially from pituitaries by a pharmaceutical company. In 1971
commercial products also became available. Our patient was one of the first to
receive hGH in the Netherlands but the origin of this product was not recorded.
A causal relation can therefore not be established with full certainty, but
coincidentally receiving growth hormone and developing this very rare disease is
unlikely. Since the clinical course in this relatively young patient is in
accordance with an iatrogenic cause, we think the probability is high that the
hGH injections explain the development of CJD in this patient.
The first Dutch patient with hGH related CJD died in 1990. 9 During several
periods from 1963 to 1969 she received intramuscular injections of hGH. During
an unknown period the hGH was derived from South America. At age 39, 27 years
after starting the treatment, she developed an ataxic gait, slurred speech,
sensory disorders, and myoclonus, but her cognitive function remained normal.
Postmortem examination of the brain confirmed the diagnosis of CJD.9 Following
the identification of this patient, a retrospective study was started to trace
all 564 registered hGH recipients who were treated before May 1985. Until
January 1995, none of these was suspected of having CJD.10 Since 1993
prospective surveillance for all forms of human prion disease has been carried
out in the Netherlands and, apart from the patient described above, a further
two patients with iatrogenic CJD have been identified, who developed the disease
after dura mater transplantation.11
An incubation period as long as 38 years had never been reported for
iatrogenic CJD. Huillard d'Aignaux et al7 studied the incubation period in 55
patients with hGH related CJD in a cohort of 1361 French hGH recipients. The
median incubation period was between 9 and 10 years. Under the most pessimistic
model, the upper limit of the 95% confidence interval varied between 17 and 20
years. Although the infecting dose cannot be quantified, it can be speculated
that the long incubation period in our patient is partly explained by the
administration of a limited amount of hGH. This hypothesis is supported by
experimental models, in which higher infecting doses usually produce shorter
incubation periods.6 Since our patient was one of the first in the world to
receive hGH, this case indicates that still more patients with iatrogenic CJD
can be expected in the coming years. Another implication of our study is that
CJD can develop even after a low dose of hGH. This case once more testifies that
worldwide close monitoring of any form of iatrogenic CJD is mandatory.
ACKNOWLEDGEMENTS
We are grateful to M Jansen PhD MD for his search for the origin of the
growth hormone and P P Taminiau MD. CJD surveillance in the Netherlands is
carried out as part of the EU Concerted Action on the Epidemiology of CJD and
the the EU Concerted Action on Neuropathology of CJD, both funded through the
BIOMED II programme, and is supported by the Dutch Ministry of Health. This
surveillance would not have been possible without the cooperation of all Dutch
neurologists and geriatricians. ........................................
Authors' affiliations
E A Croes, G Roks*, C M van Duijn, Genetic Epidemiology Unit, Department of
Epidemiology and Biostatistics, Erasmus University Medical Centre Rotterdam, PO
Box 1738, 3000 DR Rotterdam, Netherlands
P C G Nijssen, Department of Neurology, St Elisabeth Hospital, PO Box
90151, 5000 LC Tilburg, Netherlands
G H Jansen, Department of Pathology, University Medical Centre Utrecht,
Heidelberglaan 100, 3584 CX Utrecht, Netherlands
*Also the Department of Neurology, St Elisabeth Hospital
Correspondence to: Professor C M van Duijn, Genetic Epidemiology Unit,
Department of Epidemiology and Biostatistics, Erasmus University Medical Centre
Rotterdam, PO Box 1738, 3000 DR Rotterdam, Netherlands;
vanduijn@epib.fgg.eur.nl
Received 27 December 2001 In revised form 1 March 2002 Accepted 12 March
2002
Competing interests: none declared
REFERENCES
1 Duffy P, Wolf J, Collins G, et al. Possible person-to-person transmission
of Creutzfeldt-Jakob disease. N Engl J Med 1974;290:692-3.
2 Bernoulli C, Siegfried J, Baumgartner G, et al. Danger of accidental
person-to-person transmission of Creutzfeldt-Jakob disease by surgery. Lancet
1977;i:478-9.
3 Koch TK, Berg BO, De Armond SJ, et al. Creutzfeldt-Jakob disease in a
young adult with idiopathic hypopituitarism: possible relation to the
administration of cadaveric human growth hormone. N Engl J Med
1985;313:731-3.
4 Cochius JI, Burns RJ, Blumbergs PC, et al. Creutzfeldt-Jakob disease in a
recipient of human pituitary-derived gonadotrophin. Aust NZ J Med
1990;20:592-3.
5 Thadani V, Penar PL, Partington J, et al. Creutzfeldt-Jakob disease
probably acquired from a cadaveric dura mater graft: case report. J Neurosurg
1988;69:766-9.
6 Brown P, Preece M, Brandel JP, et al. Iatrogenic Creutzfeldt-Jakob
disease at the millennium. Neurology 2000;55:1075-81.
7 Huillard d'Aignaux J, Costagliola D, Maccario J, et al. Incubation period
of Creutzfeldt-Jakob disease in human growth hormone recipients in France.
Neurology 1999;53:1197-201.
8 Billette de Villemeur T, Deslys JP, Pradel A, et al. Creutzfeldt-Jakob
disease from contaminated growth hormone extracts in France. Neurology
1996;47:690-5.
9 Roos RA, Wintzen AR, Will RG, et al. Een patiënt met de ziekte van
Creutzfeldt-Jakob na behandeling met humaan groeihormoon. Ned Tijdschr Geneeskd
1996;140:1190-3.
10 Wientjens DP, Rikken B, Wit JM, et al. A nationwide cohort study on
Creutzfeldt-Jakob disease among human growth hormone recipients.
Neuroepidemiology 2000;19:201-5.
11 Croes EA, Jansen GH, Lemstra AF, et al. The first two patients with dura
mater associated Creutzfeldt-Jakob disease in the Netherlands. J Neurol
2001;248:877-81.
P.4.4
Possible iatrogenic Creutzfeldt-Jakob Disease in an adult male 50 years
after treatment with human chorionic gonadotrophin
Brian Appleby1, Paul Brown2 1Johns Hopkins University School of Medicine,
USA; 2CEA/DSV/iMETI/SEPIA, France
Background: Known causes of iatrogenic Creutzfeldt-Jakob disease (iCJD)
include cadaverous corneal transplants, dural mater grafts, human growth hormone
(hGH), neurosurgical depth electrodes, and neurosurgical instrument
contamination. Four cases of iCJD from human gonadotrophin have been described
to date, all of whom have been women.
Objectives: To present a case of possible iCJD from human chorionic
gonadotrophin (hCG) and review data from four other cases Methods: Case report
and descriptive analysis
Results: A 62-year-old Caucasian man developed ataxia that resulted in
frequent falls and an initial diagnosis of benign positional vertigo. Further
workup including brain magnetic resonance imaging (MRI), electroencephalogram
(EEG), and a lumbar puncture were unrevealing. A cerebrospinal 14-3-3 protein
analysis was indeterminate. At the end of the third month of his illness, he
developed short-term amnesia, disorientation, and confabulation. A repeat EEG
showed generalized slowing without evidence of periodic sharp wave complexes and
a repeat 14-3-3 analysis was positive. A second brain MRI showed hyperintensity
in the basal ganglia on diffusion- weighted images. He died following a
four-month illness. Severe vacuolization was noted on microscopic examination
and Western blot analyses detected type II prion proteins. Genomic analyses
detected a silent polymorphism at codon 117 and valine homozygousity at codon
129 of the prion protein gene. Further review of his medical records revealed a
history of cryptorchidism and treatment with hCG as a child in the
1940’s-1950’s.
Discussion: This case report describes a possible case of iCJD from hCG
injections and is unique in that the patient was male and the incubation period
approached 50 years. His clinical presentation, EEG findings, and codon 129
homozygousity are similar to previously described cases.
Tuesday, November 23, 2010
Prosecutors call for prison terms for CJD growth hormone doctors France -
Tuesday, May 04, 2010
Review of the Human Pituitary Trust Account and CJD
Monday, February 01, 2010
Import Alert 57-20 and 84-03 Human Dura Mater and risk factors there from
due to Creutzfeldt Jakob Disease (CJD)
Saturday, January 26, 2008
CJD HGH BODY SNATCHERS Saturday, January 26, 2008 CJD HGH BODY SNATCHERS
HORMONE DRUGS LED TO CJD DEATH
Friday, March 25, 2011
Detection of Prion Protein in Urine-Derived Injectable Fertility Products
by a Targeted Proteomic Approach
Tuesday, January 10, 2012
ESHRE position statement concerning prion detection in urinary gonadotropin
formulations
16 YEAR OLD SPORADIC FFI ?
Monday, January 14, 2013
Gambetti et al USA Prion Unit change another highly suspect USA mad cow
victim to another fake name i.e. sporadic FFI at age 16 CJD Foundation goes
along with this BSe
Sunday, February 10, 2013
Creutzfeldt-Jakob disease (CJD) biannual update (February 2013) Infection
report/CJD
the great baby food debate about BSE and CJD
Vickey Rimmer, 16, DID NOT DIE FROM nvCJD, she died from a form of sporadic
CJD, whatever the hell that is. and there have been 16 year old die from
sporadic CJD in the USA as well.
RESTRICTED - POLICY
CJD IN ADOLESCENTS
snip...
3. The first case is that of CJD in a 19 year old boy. This is already
publicly known and was the subject of a ''World In Action'' programme over the
summer. The second case is in a 17 year old girl, and is the one I reported to
the Minister in my minute of 22 September. This patient is still alive, but CJD
has been confirmed by brain biopsy. This will be the first time in which this
case had been made public.
95/10.25/6.1
T E D EDDY
SEAC HAS STILL FAILED TO EXPLAIN THIS ;
Epidemiologic implications of Creutzfeldt-Jakob disease in a 19 year-old
girl
Journal European Journal of Epidemiology Publisher Springer Netherlands
ISSN 0393-2990 (Print) 1573-7284 (Online) Issue Volume 1, Number 1 / March,
1985
P. Brown1, F. Cathala2, R. Labauge3, M. Pages3, J. C. Alary3 and H.
Baron
(1) Laboratory of CNS Studies, NINCDS, National Institutes of Health, 20205
Bethesda, Maryland, USA (2) Laboratoire de Neurovirologie, Hôpital de la
Salpêtrière, Paris, France (3) Départment de Neurologie, Centre Hospitalier
Universitaire, Montpellier, France
Abstract A histopathologically-verified, clinically typical case of
Creutzfeldt-Jakob disease (CJD) is described in a 19 year-old girl. Only 3
previous cases of CJD have been reported in adolescents, and one of these was
iatrogenically transmitted, while another was familial. Epidemiologic
investigation of the present case excluded a familial component, and provided no
evidence for iatrogenic or natural case-to-case transmission, or of other
environmental sources of viral contamination. Young patients such as this one
serve to emphasize the obscurity that still sourrounds the epidemiology of CJD,
and invite serious reconsideration of the possibilities of transmission by
undetected virus carriers, or of the agent as a natural resident of human cells,
replication of which might be triggered by non-infective (e.g., traumatic or
mutational) environmental events. Key words Creutzfeldt-Jakob disease -
Epidemiology
P. Brown1, F. Cathala2, R. Labauge3, M. Pages3, J. C. Alary3 and H.
Baron
(1) Laboratory of CNS Studies, NINCDS, National Institutes of Health, 20205
Bethesda, Maryland, USA (2) Laboratoire de Neurovirologie, Hôpital de la
Salpêtrière, Paris, France (3) Départment de Neurologie, Centre Hospitalier
Universitaire, Montpellier, France
Abstract A histopathologically-verified, clinically typical case of
Creutzfeldt-Jakob disease (CJD) is described in a 19 year-old girl. Only 3
previous cases of CJD have been reported in adolescents, and one of these was
iatrogenically transmitted, while another was familial. Epidemiologic
investigation of the present case excluded a familial component, and provided no
evidence for iatrogenic or natural case-to-case transmission, or of other
environmental sources of viral contamination. Young patients such as this one
serve to emphasize the obscurity that still sourrounds the epidemiology of CJD,
and invite serious reconsideration of the possibilities of transmission by
undetected virus carriers, or of the agent as a natural resident of human cells,
replication of which might be triggered by non-infective (e.g., traumatic or
mutational) environmental events. Key words Creutzfeldt-Jakob disease -
Epidemiology
2. Sporadic CJD normally occurs in people in their 50s and 60s although it
can occur more rarely in younger age groups. Until this year the youngest case
of sporadic CJD in the UK had been in a 34 year old. Other countries, howver,
have reported sporadic CJD in teenagers. Those we know about are;
* in the USA, a 16 year old in 1978;
* in France, a 19 year old in 1982;
* in Canada, a 14 year old of UK origin in 1988;
* in Poland cases in people aged 19, 23, and 27 were identified in a
retrospective study (published 1991), having been originally misdiagnosed with a
viral encephalitis;
* Creutzfeldt's first patient in 1920 was aged 23.
full text ;
snip...
J Neurol Neurosurg Psychiatry. Published Online First: 23 May 2007.
doi:10.1136/jnnp.2006.104570 © 2007 by BMJ Publishing Group Ltd
Original articles
Sporadic creutzfeldt-jakob disease in two adolescents
K Murray 1, D L Ritchie 1, M Bruce 2, C A Young 3, M Doran 3, J W Ironside
4 and R G Will 4* 1 NationalCJD Surveillance Unit, United Kingdom 2
Neuropathogenesis Unit, United Kingdom 3 Walton Centre for Neurology and
Neurosurgery, United Kingdom 4 National CJD Surveillance Unit, United
Kingdom
* To whom correspondence should be addressed. E-mail: r.g.will@ed.ac.uk.
Accepted 15 April 2007
Abstract
Background: Sporadic Creutzfeldt-Jakob disease (CJD) is a condition
predominantly affecting older age groups, with cases aged less than 45 years
rare and an age at onset or death of less than 20 years exceptional.
Methods: Data from the systematic study of sporadic CJD in the UK are
available from 1970 onwards. Clinical and pathological data are reviewed in
order to identify atypical cases, including those at the extremes of the age
range of sporadic CJD. Detailed analysis of atypical cases is undertaken and in
selected cases laboratory transmission studies are carried out in order to
provide information on the characteristics of the infectious agent.
Results: In the UK two cases of sporadic CJD in adolescents have been
identified, dying aged 16 and 20 years. The first case predated the epidemic of
bovine spongiform encephalopathy and the characteristics of the second case,
including laboratory transmission studies, are consistent with a diagnosis of
sporadic rather than variant CJD.
Conclusion: The cases in this report indicate that sporadic CJD can develop
at a very young age, that variant CJD is not the only form of CJD occurring in
this age group and that neuropathological examination is essential to accurate
diagnosis of human prion disease.
see full text ;
TSS
posted by Terry S. Singeltary Sr. at
9:43 PM
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