es Human Growth Hormone-Related Iatrogenic Creutzfeldt-Jakob Disease With Abnormal Imaging Aaron M. Lewis, MD; Melissa Yu, MD: Stephen J. DeArmond, MD, PhD; William P. Dillon, MD; Bruce L. Miller, MD; Michael D. Geschwind, MD, PhD sek ground: Although more than 160 cases of iatro~ genic Creutzfldt-Jakob disease (iCJD) from human growth hormone (hGH) treatment have been documented, to our knowledge abnormal cerebellar findings on magnetic reso- nance imaging (MRI) have not been reported, Objective: To report case of hGH-related iCJD with ab- normal cerebellar MRI findings on fluid-attentiated inver- sion recovery (FLAIR) and diffusion-weighted MRI (DWD. Design: Case report Setting: Outpatient neurology clinic ata university medi- cal center Patient: A 33-year old man who had subscute gait ataxia Results: Beginning 19 years prior, this patient had re- ceived cadaveric pituitary-derived hGH treatment for at least 5 years. Magnetic resonance imaging revealed FLAIR, and DWI abnormalities, particularly in the cerebellum, He died 7 months after disease onset of autopsy- confirmed \CJD. Pathological changes corresponded largely to MRI findings Conelustons: To our knowledge, this is the first case of hGHL-related iCJD with FLAIR and DWI abnormalities within the cerebellum. As symptoms referable to the ce bellum occur early in iCJD, it suggests that these MRL sequences may allow earlier diagnosis ofthis form of prion disease and blurred vision, Arch Neurol. 2006;63:288-290 Author Affiliations: Departments of Neurology (Drs Lewis, Miller, and Geschwind), Radiology (Des Yu and Dillon), and Pathology (Dr DeArmond), Univesity of Californi, San Francisco, Downloaded From: on 0307/2018. ROM THE LATE 19505 UNTIL 1985, approximately 30 000 luals, mostly chil- ere treated with hu- man growth hormone (hGH) derived from cadaveric human pituitary tis- sue. The occurrence of autopsy-conlirmed CCreutzleldt-Jakob disease (CJD) in3 young, adults in 1985,” all of whom had been treated with hGH, suggested iatrogenic transmission of CJD. Since then, more than 160 cases of iatrogenic CJD (CJD) from AGH treatment have been reported world- wide." We report the case of a former hGH recipient who was initially seen witha rap- idly progressive pancerebellar syndrome due to hGt-related iCJD in whom brain mag- netic resonance imaging (MRI) showed cer~ cbellar diusion abnormalities Enea} A 33-year-old man was initially seen in 2003, with a 6-week history ofa progressively un- steady galt. Balance was particularly poor when climbing stairs. Four weeks prior 1o presentation he noticed mild blurred vi- sion while watching television or reading, He had a history of a childhood “pituitary problem? for which he had received cadav- ceric human pituitary-derived hGH treat- ‘ment for at least 5 years starting in 1974. (Onneurologic examination, he had mild bi- lateral horizontal end-gaze nystagmus, symm- ‘metric past-pointing on confrontational test- ing, and dysmetria on finger-nose-finger and. hieel-knee-shin examinations. Gait was mildly wide-based, and he was unable 10 tandem walk. Findings from derof his neurologic examination were nor- ‘mal. Computed tomography of the head without enhanced contrast medium and re- sults of routine laboratory tests were nor- ‘mal, Lumbar puncture yielded clear, color less cerebrospinal luid with normal opening pressure; the following levels were noted in the cerebrospinal fluid: protein, 48 mg/dL; glucose, 64 mg/dL (3.6 mmol/.}; red blood cell count, 23 X 10°/L; white blood cell count, 2 X10". The IgG index and eyto- logic findings were normal. ‘ALthe 3-week follow-up visit, his bal- ance had worsened; he required handrail support while walking. Truncal and limb ataxia were more pronounced, affecting the lelt side slightly more than the right side. Speech was mildly slurred and he reported having double vision. He continued to re- port no cognitive symptoms. No myoclo- rus was observed. The Centers for Disease Controland Prevention, Atlanta, Ga, which hhasbeen trackingall US patientsat risk for hGH-related CD, confirmed he was a re- ipient of potentially contaminated hGH. Brain MRI (Figure) revealed increased signal involving the superior cerebellar ver~ (©2006 American Medical Association. AI rights reserved,Figure. Manat resorance nage of pat wth human growth hornonereltd (HGH) Cruel ~Jako sens (CJD) shoving an abaral certo. ‘Ail uate inversion ecovery (FLAIR) demonstrates increased signal win the suparorcerebalar ver, bst valued by nrasng image entas 8, Carespnding anal sin waght imaging (Ml) more lary snows ncresadceeblar sna C, ecreaeed signal within the caraelun onthe apparent fusion coetiient map cons atte DWI sna abnormality the raul of educed te watar maton rat 2 “shne through” D, Coronal FLA image shows possble mid typerinansiy inthe cng and insula and no cer abnormal inh basal ganglia, Cocesponding eral OW eves increased signal win the paramedian otal cartx biateraly, extending super oe the convo (rows) ad ily increased Signal thn tral aut ads (sod arrowheads) Notte suscep rift Hom skll base secondary te a-boe inate (pan arrowheads) Ccaspondng corona FLA (F and WI sequanee 6) show ieeased eign! wn the euprior ereblar vari (ons) sis on both fluid-attenuated inversion recovery (FLAIR) ce and diffusion-weighted MRI (DWD. Thecortex ofthe para- median frontal lobesdemonstratedamoresubtle increase ‘Thereare more than 310 known cases of JD worldwide {msignal bilaterally on DWLwith suggestion ofanincrease __Sourceshaveincluded contaminated neurosurgical equip- in FLAIR signal within the bilateral cingulate gyriand in- ment, depth electrodes for stereotactic electroencephalog. sila, Mildly increased DW/ signal wasalsoobservedinthe raphy, cadaveric dura mater and corneal grafts, human right greater than leltcaudatcheads, withoutdefinitecor- _pituilary-derived gonadotrophin, and hGH. “Human responding FLAIRabnormality. Theareasofinereased DWI gonadotrophin- and hGH-related ICJD differ from most sighal within the cerebellum and cortex showed reduced other forms of iCJD because they are due to peripheral in- signal ontheapparent diffusion coelficient map, confirm- _oculation, rather than direct inoculation of prions into the ing that theabnormal DW signal represents reduced free central nervoussystem.* Human gonadotrophin-and hGH water motion rather than the underlying T2signalabnor- related iCJDalso share the unique propensity to manifest mality,orT2shinethrough.”*Theelectroeneephalogram —_signsand symptomsearly in the disease courseasa largely \wasnormal;resultsofaparancoplasticantibody panelwere isolated cerebellar syndrome. Visual symptoms are also normal, variably present; however, dementiaand myoclonus pres About3 monthsalter onset, hewas severely dysarthric, ent, are usually mild and occurlate inthe disease course.” usinga wheelchairand having memory lapsesand occasional Starting in 1963, the National Hormone and Pitu- urinary incontinence. Hisalaxiaworsened;myoclonus,sei- itary Program, the main source of hGH in the United sures, and dementia developed later. He died 7 months al- sponsored the centralized collection of extracted terdisease onset. Aulopsy confirmed (CJD, with the most human pituitary issue for the production of hGH.’ This extensivedepositionof prionsinthe brainstem, cerebellum, program was discontiniied in 1985 alter cases of CJD were and thalamus, with significant involvement,although toa reported. All US eases of hGH-related CJD occurred in lesserextent,inthe insula, basal ganglia, anteriorcingulate, individuals who began hGH treatment prior to 1977, be and caudate. There was heavy vacuolation in the cerebel- fore a new purification step was added to the protocol.® lar molecular layer and cingulate, followed by the basal Most hGH-related CJD eases have occurred in France and ganglia, thalamus, brainstem, and insula. The frontal and these cases were traced (o a particularly high-risk treat- parietal cortices had mild pathologicleatues, but the tem- ment period [rom 1083 to mid-1985. The reason for the poral and occipital cortices were largely spared. hhigh incidence of iCJD in patients treated during this (©2006 American Medical Association. AI rights reserved, Downloaded From: on 0307/2018.critical period is unclear, but may stem from eross- contamination by one or several highly infectious batches of pituitary tissue during the manufacturing process." ‘An important factor influencing the incubation period and clinical manifestation in all forms of CJD is the poly- morphism at codon 129 of the prion protein (PrP) gene. In healthy white populations, genotype frequency at codon 129 is 50% heterozygous, 40% homozygous for methio- nine, and 10% homozygous for valine; homozygosity in- creases the risk for CJD." In hGH-related CJD, the fre- quency of homozygous valine is especially high, with a codon 129 distribution of 23% heterozygous valine, 48% homozygous lor methionine, and 20% homozygous for va- line.’ Our patient was homozygous for valine at codon 129. To our knowledge, this pattern of abnormal FLAIR and DWlsignal with significant cerebellar involvement has not yetbeen reported in CJD. Incase reports of FLAIRand DWI abnormalitiesin hGH-relatedsCJD,cerebellarsignal changes: are not mentioned despite abnormal findings inthe basal ganglia, thalami, or cortex.*"' Abnormal cerebellar signal by FLAIR and DWI was reported in a patient with the Brownell-Oppenhelmer variant of sporadic CJD"; patients with this form of sporadic CJD exhibit predominantly cer- ebellar features both clinically and pathologically.*** Specific FLAIRand DWlabnormalities, particularly cor- tical and basal ganglia hyperintensities, have been wel dem- onstrated insporadicand familial formsof CJD. Although cerebellar symptoms are common in these patients, cer- cbellar abnormalities on MRI, including FLAIR and DWI, rarely occur." This may be owing to the involvement by prions of cerebellar connections, rather than the cer- bellum itself Billette de Villemeur etal reported that of 33MRisin 34 hGH-related iCJD casesin France all were normal or unchanged from prior studies when performed atthe time of symptom onset. Fifteen patients’ MRIs re- ‘mained normal, while the others developed cerebellar oF diffuse cerebral atrophy following aperiod of 3 to8 months. Although Billewe de Villemeur etl did not specify MRI sequences, given the period itis unlikely that PLAIR and DWiwere used in most, nota, cases. This may explain the lack of MRI findings other than atrophy ‘In our patient, the neuropathology correlated very well with the MRI, particularly in the cerebellum, cingulate, and insula. The significant neuropathological changes in the basal ganglia, brainstem, and thalamus, with mini- smal, ifany, corresponding involvement on MRI in these areas, may be because of these analyses being per- formed 5 months apart. Why hGH-related iC] spreads {in this manner, with a predilection for the cerebellum and sparing certain cortical regions, isan interesting re- search question that requires further study. Neverthe- less, this case report suggests that in cases of suspected {CJD, invariably seen with early cerebellar signs, the find- ing of associated cerebellar FLAIR and DWI abnormali- lies may ald in eatlir diagnosis, prompt initiation of sup- portive care, and possibly even treatment. Accepted for Publication: October 17, 2005. Correspondence: Michael D. Geschwind, MD, PhD, Uni- versity of California, San Francisco, Memory and Aging Cen- ter, Departmentof Neurology, 350 Parnassus Ave, Suite 706, San Francisco, CA 04117 (michael geschwind@uesf edu). Author Contributions: Study conceptand design: Lewisand Geschwind. Acquisition of data: Lewis, DeArmond, Dillon, and Geschwind, Analysis and interpretation of data: Yu DeArmond, Dillon, Miller, and Geschwind. Drafting ofthe ‘manuscript: Lewis, Yu, Dillon, and Geschwind. Critical e~ vision of the manuscript for important intellectual content: Lewis, DeArmond, Dillon, and Geschwind. Statistical analy sis: DeArmond. Obtained funding: Miller and Geschwind. Administrative, technical, and material support: Yu, Dillon, and Miller. Study supervision: Dillon, Miller, and Geschwind, Funding/Support: Dr Geschwind was supported by The John Douglas French Alzheimer's Foundation (Los An- eles, Cali) the Peter McBean Fellowship from The McBean, Foundation (San Mateo, Calif) and grant K23 AGO21989- 01 from the National Institutes of Health/National Insti tute on Aging (NIH/NIA) (Bethesda, Md). Dr Miller was, supported by grant P50 AG-03-006-01 from the NIH/NIA; {grant 03-75271 from the State of California Department of Health Services, Alzheimer's Disease Program, Alzhei- mers Disease Research Centers of California Sacramento) {grant AGO19724-02 [rom the NIH: grant 2002/2F from The Larry Hllblom Foundation (Petaluma, Calif);and grant 199.0102 from The Koret Foundation (San Francisco, Cali). Acknowledgments: We thankkLawrence B.Schonberger, MD, MPH, Centers for Disease Controland Prevention, Atlanta, Ga, forassistance in tracking hGH recipients at risk foriC]D, and the National Prion Disease Pathology Surveillance Cen- ter, Cleveland, Ohio, for prion gene analysis. Es 1. Koch TK Bey BO, DeArmond Si, ran AF. retain Yeung a th dps ypoptatarompasublrestan ote admit omot xcs aman gant homone ng ed. TBS 312 31-133. (Sts Cle Joy A Metar ta Ca. ‘ator conan of reel (ead human grow armor. N Engl ea 1085318 734738 8. Pomal-Jcson, ela RO. Kena, Press MA Whiconbs El, anon ‘aCe ese sta nme ume roathorone inet es 240 246, Wal Acqua pon boos e268, ude HEAD, Res PE. Aes cabrio: gunn ts ‘ety snd T2 stn tough hanomara on disor ged MR nag ado 19021233038, Bron Prose, Brandl Pt a avoganc Creuset desea ‘helm Nesey. 2000,5:107-1et, Fred Je Schorr 8M 3 Ceol dese in puiny (owt torone pens inthe nied Ses AMA 09 25 800288, perovah kar Pocehan Metal Cason 29 pron rot pina and Sorat Crist disease (ubishedcoacton appears in Lancet 70038872) Lane 1005517 1674 Banc Pesce Broun ea Ditton of ofon 120 gneypein ie anager, vara U0, a. Br Med Bt "an ru nomone rested CAD patents inane andthe Uk. Lancet 2005 eos 10, Oppeein uber, Gaara, tl Specoseop and stil ison MR fringe nn Cueterkoe eae. Jr Nera Paci 2008 TE 168 abot 0, Huang Lops GA. avogenc Curl ao dese fo ‘oun human row hamene thr: asap. A Heros 202 saber Poo A, Say S, Store HR eieoe of eter and pocampal event Graveh hee deeee,Nerraagy 20016746109, oun Operbemar DR ster ube prseie poe. pay (eu hb eae Jur Mewes Psy 18S 2 ry euro 20454450, "Young 6S. Gescvnd MD, Fach 1 at a Dtutn-weghed a i teu nesin oer) maingin raul ase: gh eat lyardspecteny dagen AUN Ar Jewel 205.26 155 182 16, lee de Vilemeu Dey Pac eta eta das ron lms growth emaeexacin anes Newly, one 50.28, 18 (©2006 American Medical Association. AI rights reserved, Downloaded From: on 0307/2018.