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Human Growth Hormone-Related Iatrogenic
Creutzfeldt-Jakob Disease—Being Aware of
Diagnostic Features 25 Years Later
Kashinath Dixit, Ilonka Kreitschmann-Andermahr, Ambar Basu, Jeremy P. R. Dick,
Prakash Manoharan, Stephen Shalet, and Georg Brabant
Department of Endocrinology (K.D., I.K.-A., A.B., S.S., G.B.), The Christie, Manchester M20 4BX, United
Kingdom; Department of Neurosurgery (I.K.-A.), Rheinisch-Westfälische Technische Hochschule Aachen
University Hospital, 52074 Aachen, Germany; Greater Manchester Neuroscience Centre (J.P.R.D.), Hope Hospital,
Salford M6 8HD, United Kingdom; and Department of Radiology (P.M.), The Christie, Manchester M20 4BX,
United Kingdom
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n 2008, a 40-yr-old man, who had been treated for craniopharyngioma as a child and subsequently received cadaveric native human GH (hGH) from 1973 to 1985, developed
forgetfulness and behavioral changes. Prominent features
on neurological examination included ataxic gait, impaired
postural reflexes, intentional tremor, nystagmus, saccadic eye
movements, and early dementia. All blood and cerebrospinal
fluid tests were normal, including undetectable 14-3-31 and
S100B2 proteins in the cerebrospinal fluid. Electroencephalogram showed generalized slow wave activity.3 Magnetic resonance imaging (MRI) scanning revealed mostly right-sided
high signal in fluid-attenuated inversion recovery and diffusion-weighted imaging (DWI) in the caudate nucleus as
the only abnormality (Fig. 1). The predominantly cerebellar
symptomatology in combination with this MRI finding finally led to the diagnosis of iatrogenic Creutzfeldt-Jakob disease, confirmed by the central British Creutzfeldt-Jakob Disease unit.
World Health Organization criteria for diagnosis of iatrogenic Creutzfeldt-Jakob disease list progressive cerebellar syndrome in a recipient of human cadaveric pituitary hormone as a
main diagnostic criterion for clinical diagnosis (1). Unilateral or
bilateral abnormalities of the basal ganglia, often involving
the caudate nucleus, have been reported as early diagnostic
MRI features of sporadic Creutzfeldt-Jakob disease and are
thought to represent vacuolization of the neuropil4 (2). DWI
probably represents the most sensitive imaging technique in
the diagnosis of Creutzfeldt-Jakob disease (3). Between 1985,
when the first case of GH-dependent iatrogenic CreutzfeldtJakob disease was reported, and 2003, 162 cases were reported, mainly in France, the United Kingdom, and the United
States (1). Because the incubation period of Creutzfeldt-Jakob
disease may amount to several decades, with the longest one
described in hGH-related iatrogenic Creutzfeldt-Jakob disease being 38 yr (4), endocrinologists may expect further cases
in the years to come.
ISSN Print 0021-972X ISSN Online 1945-7197
Printed in U.S.A.
Copyright © 2009 by The Endocrine Society
doi: 10.1210/jc.2009-0167 Received January 29, 2009. Accepted May 21, 2009.
Abbreviations: DWI, Diffusion-weighted imaging; hGH, human GH; MRI, magnetic resonance
imaging.
Acknowledgments
Address all correspondence and requests for reprints to: Kashinath
Dixit, MRCP, Department of Endocrinology, The Christie, Manchester M20 4BX, United Kingdom. E-mail: kashinath.dixit@
yahoo.com.
Disclosure Summary: The authors have nothing to disclose.
4
Neuropil is a fibrous network of glial processes, synaptic terminals, axons, and dendrites.
1
14-3-3 is a neuronal protein that may be released into the cerebrospinal fluid in conditions
affecting neuronal integrity; it is positive in a high proportion of Creutzfeldt-Jakob disease
patients.
2
S100B is a cerebrospinal fluid protein marker for neuronal injury; it may be positive in
Creutzfeldt-Jakob disease.
3
The characteristic periodic sharp wave discharge of sporadic Creutzfeldt-Jakob disease
has only rarely been described in hGH-related iatrogenic disease (1).
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FIG. 1. Note right-sided high signal intensity on coronal FLAIR (A) and bilateral (right ⬎ left) hyperintensity on axial DWI (B) images of the caudate nucleus,
whereas DWI (C) shows hyperintensity of the caudate tail. Axial T2-weighted image (D) is normal. A recent assessment of a larger patient group (157 cases of
sporadic CJD) has reported that basal ganglia hyperintensity is 67% sensitive and 93% specific for the diagnosis of sporadic CJD (1). Data in the literature
suggest that MRI appearances in iatrogenic CJD are similar to those found in sporadic CJD. This may help to differentiate it from the variant bovine spongiform
encephalitis-driven form of CJD where a high signal in the pulvinar thalami, which is brighter than the basal ganglia changes, is considered pathognomonic (5).
It is not uncommon for these subtle MRI changes to be overlooked at primary reporting.
References
1. 2003 WHO manual for surveillance of human transmissible spongiform encephalopathies including variant Creutzfeldt-Jakob disease. ISBN 92 4 154588.
Geneva: World Health Organization
2. Ukisu R, Kushihashi T, Kitanosono T, Fujisawa H, Takenaka H, Ohgiya Y,
Gokan T, Munechika H 2005 Serial diffusion-weighted MRI of CreutzfeldtJakob disease. AJR Am J Roentgenol 184:560 –566
3. Kallenberg K, Schulz-Schaeffer WJ, Jastrow U, Poser S, Meissner B, Tschampa
HJ, Zerr I, Knauth M 2006 Creutzfeldt-Jakob disease: comparative analysis of
MR imaging sequences. AJNR Am J Neuroradiol 27:1459 –1462
4. Croes EA, Roks G, Jansen GH, Nijssen PC, van Duijn CM 2002 CreutzfeldtJakob disease 38 years after diagnostic use of human growth hormone. J Neurol
Neurosurg Psychiatry 72:792–793
5. Tschampa HJ, Zerr I, Urbach H 2007 Radiological assessment of CreutzfeldtJakob disease. Eur Radiol 17:1200 –1211