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Iatrogenic Creutzfeldt–Jakob disease
Handbook of Clinical Neurology, Vol. 153 (3rd series) Human Prion Diseases M. Pocchiari and J. Manson, Editors https://doi.org/10.1016/B978-0-444-63945-5.00012-X Copyright © 2018 Elsevier B.V. All rights reserved
Chapter 12
Iatrogenic Creutzfeldt–Jakob disease ATSUSHI KOBAYASHI1, TETSUYUKI KITAMOTO2, AND HIDEHIRO MIZUSAWA3* Laboratory of Comparative Pathology, Graduate School of Veterinary Medicine, Hokkaido University, Kita-ku, Sapporo, Japan
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Department of Neurological Science, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Japan 3
National Center of Neurology and Psychiatry, Kodaira, Japan
Abstract Iatrogenic transmission of Creutzfeldt–Jakob disease (CJD) has occurred through particular medical procedures. Among them, dura mater grafts and pituitary-derived growth hormone obtained from human cadavers undiagnosed as CJD are the most frequent sources of infection. Recent advances in our knowledge about dura mater graft- and human pituitary-derived growth hormone-associated CJD patients have revealed that the combination of the infected CJD strain and the PRNP genotype of the patient determines their clinical, neuropathologic, and biochemical features. In this chapter, we summarize the clinical, neuropathologic, biochemical, and diagnostic features of dura mater graft- and human pituitary-derived growth hormone-associated CJD patients for the appropriate diagnosis of iatrogenic CJD.
INTRODUCTION AND BRIEF HISTORY Iatrogenic Creutzfeldt–Jakob diseases (iCJD) represent a part of acquired prion diseases that have known sources of etiologic prions and include kuru and variant CJD as well. iCJD are defined as CJD transmitted by medical and surgical procedures. Neurosurgical transmission was first suggested by Nevin et al. in 1960, when 3 CJD cases developed 18–24 months after neurosurgical procedures in a hospital where a few CJD patients received brain biopsy and other invasive procedures (Nevin et al., 1960). The very first case associated with a cadaveric corneal graft was reported in 1974 when the patient developed CJD 18 months after transplantation from a donor with pathologically proven CJD (Duffy et al., 1974). The second case developed CJD 30 years after transplantation and was described in 1997 (Heckmann et al., 1997). Electroencepalogram (EEG) recordings with deep needle electrodes were also reported as a transmission procedure in 2 cases of iCJD in 1977 (Bernoulli et al., 1977). This was confirmed by experimental implantation of the suspected electrodes causing CJD in a chimpanzee
(Brown et al., 1992). Another case of neurosurgical transmission was reported in France in 1980 (Foncin et al., 1980). Dura mater graft-associated iCJD (dCJD) was first reported in 1987 in the United States (CDC, 1987) and more than 200 cases have since been documented in many countries (Brown et al., 2012). Among them, more than half were registered in Japan (Sato et al., 2005; Hamaguchi et al., 2013). The number of Japanese dCJD patients reached 152 by August 2017. In other countries, the numbers of patients ranged from 1 to 14 (Clavel and Clavel, 1996; Brooke et al., 2004; Heath et al., 2006; Toovey et al., 2006; Heinemann et al., 2007; Kim et al., 2011; Brandel et al., 2013; Hall et al., 2014). The source of cadaveric dura mater in most cases when identified was Lyodura produced by B. Broun Melsungen. Two other sources include 1 case of Tutoplast dura (Hannah et al., 2001) and another case of locally produced dura. In 1996 when the first case of variant CJD case was reported, the Japanese Government conducted a nationwide survey that unexpectedly revealed many CJD cases with cadaveric dura grafting. After two more nationwide
*Correspondence to: Hidehiro Mizusawa, National Center Hospital, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi-machi, Kodaira, 187–8511, Japan. Tel: +81-42-346-1780, E-mail: [email protected]
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surveys a prospective survey was carried out for all the cases of prion diseases including dCJD (Sato et al., 2005; Nozaki et al., 2010). Analysis of the 152 dCJD cases in Japan revealed etiologic diseases, including tumor, bleeding, unruptured aneurysms, hematoma, hemifacial spasm, trigeminal neuralgia, malformation, trauma, and ossification of the posterior longitudinal ligament, as reported previously (Nozaki et al., 2010; Hamaguchi et al., 2013). Grafting was performed very frequently from 1982 to 1987 when the first case of dCJD was reported in the United States and 1N NaOH treatment had been added to the sterilization process of cadaveric dura mater (Sato et al., 2005). In 1985, 2 CJD cases that had received human pituitary-derived growth hormone (hGH) in the United States and 1 such case in the United Kingdom were reported (Gibbs et al., 1985; Koch et al., 1985; PowelJackson et al., 1985). Since then, by 2012, 226 cases had accumulated from many countries, mostly in France (119 cases/1170 recipients, 10.2%), the United Kingdom (65 cases/1800 recipients, 3.6%), and the United States (29 cases/2700 recipients, 1.1%) (Brown et al., 2012). There were only one or a few cases in other countries, including New Zealand, Brazil, the Netherlands, Australia, Ireland, and Qatar. The circumstantial evidence of cadaveric hGH transmission to humans is a unique clinical feature of patients, which include unusually young age at onset with progressive cerebellar syndrome with only delayed dementia, if any, as compared with typical sporadic CJD (sCJD) which is characterized by old age at onset with rapidly progressive dementia (Will, 2003; Rudge et al., 2015). The evidence was supported by successful transmission of CJD in a squirrel monkey with a potentially contaminated batch of hGH (Gibbs et al., 1993).
CLINICAL FEATURES Dura mater graft-associated CJD (dCJD) The age at onset ranged from the second to ninth decade of life with mean age at onset of 56.0 14.9 years, which is more than 10 years younger than that of sCJD. The incubation time was 13.4 6.7 years (1–30 years and 11 months). Neuropathologic analyses of 23 dCJD cases showed there are two types: plaque and nonplaque types (Noguchi-Shinohara et al., 2007). Plaque-type dCJD has a plaque-type deposition of abnormal prion protein (PrPTSE) which sometimes resembles the florid plaques found in variant CJD (Shimizu et al., 1999). Nonplaque-type dCJD was pathologically characterized by spongiform encephalopathy similar to that of the sCJD MM/MV1 subtype. The relative frequency of plaque-type dCJD is estimated to be
about 30–40% and nonplaque-type about 60–70% in Japan. The clinical and laboratory features of plaque-type dCJD include onset with progressive gait disturbance, mainly ataxia, a relatively long clinical course, and no or late occurrence of periodic sharp-wave complexes (PSWCs) on EEG. In contrast, clinical and laboratory features of nonplaque-type dCJD are similar to those of sCJD MM/MV1 subtype. High signal intensity of diffusion-weighted imaging (DWI) on magnetic resonance imaging (MRI) and positive 14-3-3 protein of CSF are common features in both plaque and nonplaque types of dCJD. DWI high signal intensity in the thalamus may be a characteristic of plaque-type dCJD in addition to that in the striatum and cerebral cortices (Fig. 12.1). The clinical features of plaque-type dCJD are diagnostic challenge in cases with progressive ataxia in human cadaveric dura mater recipients which could be diagnosed as probable dCJD.
Human pituitary-derived growth hormoneassociated CJD (hGH CJD) The mean incubation period of all available cases was estimated to be 17 (5–42) years based on the midpoint date as the date of infection because, usually, the treatment periods ranged over many years. There are some differences among countries with many hGH CJD cases; the mean incubation period is 13 years in France, 20 years in the United Kingdom, and 22 years in the United States (Huillard d’Aignaux et al., 1999; Swerdlow et al., 2003). The shorter period in France may result from the narrower limit of infection date and is close to the 13.5 years of 4 CJD patients who received human gonadotropin in Australia. This is also similar to the 13.4 years of dCJD. A recent study on the incubation periods of UK cases related to the codon 129 polymorphism described 30.8 (26.9–32.6) years in 129 M/M homozygotes, 23.4 (9.0–36.7) years in 129 M/V heterozygotes, and 14.3 (7.7–20.2) years in 129 V/V homozygotes (Rudge et al., 2015). Clinically, ataxic gait is the most common initial symptom followed by tremor, leg pain, daytime somnolence, dizziness, headache, myoclonus, and cognitive impairment (Will, 2003; Rudge et al., 2015). Rarely, cognitive decline appears at an early stage (Cordery et al., 2003). The leg pain includes hypersensitivity to light touch and various dysesthesia, such as itchy sensation, patchy tingling, burning, and numbness. Neurologic findings include cerebellar ataxic gait, myoclonus, cerebellar dysarthria, pyramidal tract sign, cognitive impairment, urine and fecal incontinence, and finally akinetic mutism.
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Fig. 12.1. Magnetic resonance imaging (MRI)-diffusion-weighted imaging (DWI) of dura mater graft-associated iatrogenic Creutzfeldt–Jakob disease (dCJD) and human growth hormone (hGH) CJD. More thalamic hyperintensity on MRI-DWI may be a characteristic of plaque-type dCJD. (Courtesy of Dr. Yoshihisa Watanabe.) In addition to cerebral cortical involvement, hyperintensities of the basal ganglia and thalamus in hGH CJD resemble those in plaque-type dCJD. (Courtesy of Dr. Harpreet Hyare and Dr. Peter Rudge.)
Among 21 patients, 6 showed normal EEG initially and the other 15 showed generalized slow activity. Only one of the 15 revealed short runs of PSWCs (Rudge et al., 2015). On MRI DWI, high signal intensity was observed in the thalamus, caudate nucleus, and putamen in most cases (Fig. 12.1). In the cerebral cortex, the cingulate gyrus, frontal gyrus, and cerebellum were also frequently affected and the paracentral lobule, parietal lobe, and hippocampus were less frequently involved (Lewis et al., 2006; Appleby et al., 2013; Rudge et al., 2015).
NEUROPATHOLOGIC FEATURES dCJD The neuropathologic features of dCJD patients are not uniform, as mentioned above. In Japan, 68% of dCJD patients show the synaptic-type deposition of PrPTSE in the brain similar to that of patients with the sCJD MM/MV1 subtype, and are designated as nonplaquetype dCJD, while 32% of dCJD patients show PrPTSE amyloid plaques similar to those of patients with the sCJD MV2 subtype and are designated as plaque-type dCJD (Fig. 12.2) (Takashima et al., 1997; Shimizu et al., 1999; Hoshi et al., 2000; Kimura et al., 2001; Mochizuki
et al., 2003; Satoh et al., 2003; Noguchi-Shinohara et al., 2007; Yamada et al., 2009). The neuropathologic features of the nonplaque-type dCJD patients resemble those of the sCJD MM/MV1 subtype, including severe brain atrophy, spongiform changes, neuronal loss, astrocytic gliosis, and diffuse synaptic-type PrPTSE deposition in the cerebral and cerebellar gray matter (Satoh et al., 2003; Yamada et al., 2009). In contrast, the neuropathologic features of plaque-type dCJD patients are characterized by mild brain atrophy, perineuronal PrPTSE deposition, and PrPTSE amyloid plaques, in addition to spongiform changes, neuronal loss, and gliosis (Satoh et al., 2003; Yamada et al., 2009). The PrPTSE amyloid plaques are widely distributed over the cerebral gray matter, the cerebellar gray matter, and the cerebellar white matter. Some PrPTSE amyloid plaques are surrounded by vacuoles, resembling the florid plaques of variant CJD (Shimizu et al., 1999; Mochizuki et al., 2003; Yamada et al., 2009). The two subgroups of dCJD have also been recognized in European countries and the United States (Lane et al., 1994; Kopp et al., 1996; Radbauer et al., 1998; Kretzschmar et al., 2003). The reason for the existence of the two neuropathologically distinct subgroups of dCJD has remained elusive for years. However, recent advances in our knowledge of
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Fig. 12.2. Neuropathologic features of nonplaque-type dura mater graft-associated iatrogenic Creutzfeldt–Jakob disease (dCJD) and plaque-type dCJD. (A–F) Nonplaque-type dCJD patients show fine granular to diffuse synaptic-type deposition of PrPTSE in the cerebral gray matter (A, B), hippocampus (C, D), and cerebellar gray matter (E, F). (G-O) Plaque-type dCJD patients show large PrPTSE amyloid plaques (H, I, K, N: open arrowheads) and perineuronal PrPTSE deposition (L: arrow) besides the synaptictype PrPTSE deposition (Lane et al., 1994; Kopp et al., 1996; Takashima et al., 1997; Radbauer et al., 1998; Shimizu et al., 1999; Hoshi et al., 2000; Kimura et al., 2001; Kretzschmar et al., 2003; Mochizuki et al., 2003; Satoh et al., 2003; Noguchi-Shinohara et al., 2007; Yamada et al., 2009). In the cerebellum, the formation of PrPTSE amyloid plaques is most prominent in the granular cell layer (M, N). In addition, perivascular PrPTSE deposition is remarkable in the cerebellar white matter (M, O: filled arrowheads). Immunohistochemical analysis of PrP (A–H, J–O); hematoxylin and eosin stain (I). Scale bars, 100 mm (A, C, E, F, G, J, M, O); 10 mm (B, D, H, I, K, L, N).
dCJD patients and those gained from experimental animal models of iCJD have raised the possibility that the distinct neuropathologic features might be caused by different sCJD strains (Kobayashi et al., 2007, 2009, 2014). To date, five sCJD strains have been proposed according to the disease phenotypes in patients and their transmission properties in transgenic mice expressing human prion protein (PrP), namely M1 (MM1/MV1 subtype, which corresponds to 40% of total sCJD cases), V1 (VV1 subtype, 1%), M2C (MM2C subtype, 1%), M2T (MM2T subtype, 1%), and V2 (VV2 and MV2 subtypes, 23%) (Parchi et al., 1999, 2011; Bishop et al., 2010; Moda et al., 2012). In addition, the co-occurrence of distinct prion strains in the same patient such as M1 +M2C (MM/MV1 + 2C subtype, which corresponds to 28% of total sCJD cases) has been recognized (Parchi et al., 2011). In experimental animal models of iCJD, infection with the M1 strain or the co-occurring M1 + M2C strains caused synaptic-type PrPTSE deposition in the brain similar to that of
nonplaque-type dCJD patients, while infection with the V2 strain caused plaque-type PrPTSE deposition similar to that of plaque-type dCJD patients (Fig. 12.3) (Kobayashi et al., 2007, 2013, 2016). Interestingly, mice inoculated with the M1 strain or the co-occurring M1 +M2C strains showed the synaptic-type PrPTSE deposition regardless of their genotype at polymorphic (methionine, M or valine, V) codon 129 of the PRNP gene, whereas the V2 strain-inoculated mice showed various amounts of PrPTSE plaques depending on their PRNP codon 129 genotype, i.e., mice carrying the 129 M/M genotype showed numerous PrPTSE plaques but mice carrying the 129 V/V or M/V genotype showed only a small number of PrPTSE plaques (Kobayashi et al., 2013, 2015a). Indeed, all plaque-type dCJD cases reported to date were 129 M/M homozygotes not only in Japan, where the vast majority of the general population are 129 M/M homozygotes, but also in European countries (Kopp et al., 1996; Kretzschmar et al., 2003; Yamada et al., 2009; Nozaki et al., 2010). Further
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Fig. 12.3. Experimental animal models of iatrogenic Creutzfeldt–Jakob disease (CJD). To model the iatrogenic transmission of sporadic CJD (sCJD) prions, knockin mice expressing human prion protein (PrP) with the 129 M/M, M/V, or V/V genotype were intracerebrally challenged with the representative sCJD strains. Mice inoculated with the M1 sCJD strain or co-occurring M1 + M2C strains showed synaptic-type PrPTSE deposition and type 1 PrPTSE accumulation in the brain regardless of their PRNP codon 129 genotype. Meanwhile, mice inoculated with the V2 sCJD strain showed diverse neuropathologic and biochemical features depending on the codon 129 genotype (Kobayashi et al., 2007, 2013, 2016). *Intermediate-type PrPTSE. †The number and distribution of PrPTSE plaques were relatively limited. ‡A mixture of the intermediate-type and type 2 PrPTSE.
neuropathologic analysis of dCJD patients with the 129 V/Vor M/V genotype will be needed in the future to clarify whether they show the two distinct neuropathologic features similar to those of the 129 M/M patients. Meanwhile, similarities in transmissibility to experimental animals (Kobayashi et al., 2007, 2010, 2013, 2015a) or in seeding activity in protein misfolding cyclic amplification (Takeuchi et al., 2016a) among the M1 sCJD strain, the co-occurring M1 +M2C sCJD strains, and brain materials from nonplaque-type dCJD patients, or between the V2 sCJD strain and brain materials from plaque-type dCJD patients, also support the possibility that the two distinct subgroups of dCJD might be caused by infection with different sCJD strains. The similar transmissibility between the M1 sCJD strain and the co-occurring M1 +M2C strains has been considered to be due to the reduced infectivity of the M2C sCJD strain (Kobayashi et al., 2013, 2016). Furthermore, it is noteworthy that the ratio of the nonplaque-type dCJD among total dCJD cases in Japan is quite similar to the combined ratio of the sCJD MM/ MV1 subtype (M1 strain) and the sCJD MM/MV1 + 2C subtype (co-occurring M1 +M2C strains) among total sCJD cases in Europe where the causative dura mater grafts were prepared. Meanwhile, the ratio of the plaque-type dCJD among total dCJD cases is similar to the combined ratio of the sCJD VV2 and MV2 subtypes
(V2 strain) among total sCJD cases (Yamada et al., 2009; Parchi et al., 2011; Kobayashi et al., 2016). During 1983–1987, when 80% of dCJD patients underwent dura mater transplantation, as many as 100,000 patches were used in Japan (Nakamura et al., 1999; Hamaguchi et al., 2013). Thus, a portion of these grafts might have been contaminated with more than one sCJD strain, reflecting the existing ratio of the sCJD subtypes in donors. Taken together, accumulating evidence suggests that infection with the M1 sCJD strain or the co-occurring M1 + M2C sCJD strains might be responsible for the dCJD subgroup that shows the synaptic-type PrPTSE deposition, whereas infection with the V2 sCJD strain might be responsible for the dCJD subgroup that shows the plaque-type PrPTSE deposition.
hGH CJD hGH CJD patients can also be divided into two subgroups based on their neuropathologic features, presumably reflecting the neuropathologic properties of the infected sCJD strains (Cali et al., 2015), as suggested in dCJD. One subgroup showed neuropathologic features resembling those of the nonplaque-type dCJD or sCJD MM/MV1 subtype, whereas the other subgroup showed characteristic features resembling those of the plaque-type dCJD (Delisle et al., 1993;
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Billette de Villemeur et al., 1994; Croes et al., 2002; Cali et al., 2015). In contrast to dCJD, however, the majority of hGH CJD cases showed the plaque-type pathology and appeared to have been caused by infection with the V2 sCJD strain (Rudge et al., 2015; Head et al., 2016; Peckeu et al., 2016; Ritchie et al., 2016). In pathologically examined French hGH CJD cases, all 129 M/M patients and half of the 129 M/V patients showed PrPTSE amyloid plaques in the brain (Billette de Villemeur et al., 1994; Peckeu et al., 2016). In the UK cases, 3 out of 4 129 M/M patients and all 129 M/V patients had PrPTSE amyloid plaques (Rudge et al., 2015; Moore et al., 2016; Ritchie et al., 2016). Thus, a large number of hGH CJD patients showed PrPTSE amyloid plaques that were indicative of infection with the V2 sCJD strain. In addition, although hGH CJD patients with the 129 V/V genotype lacked PrPTSE amyloid plaques and showed only perineuronal and plaque-like PrPTSE deposits (Peckeu et al., 2016; Ritchie et al., 2016), the scarcity of PrPTSE amyloid plaques in the 129 V/V patients cannot exclude the possibility of infection with the V2 sCJD strain because the V2 sCJD strain-infected 129 V/V mice showed only a small number of PrPTSE plaques compared with the 129 M/M mice in experimental transmission studies, as described above (Fig. 12.3) (Kobayashi et al., 2007, 2013, 2015a), and sCJD VV2 patients show only perineuronal and plaque-like PrPTSE deposits (Parchi et al., 1999, 2011). In fact, the biochemical features of the 129 V/V hGH CJD patients (Collinge et al., 1996; Head et al., 2016; Ritchie et al., 2016) also support the possibility of infection with the V2 sCJD strain, as described below. Furthermore, similarities in the seeding activity in protein misfolding cyclic amplification between the V2 sCJD strain and brain materials from hGH CJD patients with PrPTSE amyloid plaques or plaque-like PrPTSE deposits also suggested that these hGH CJD cases might have been infected with the V2 sCJD strain (Ritchie et al., 2016; Takeuchi et al., 2016b). On the other hand, the number of patients infected with the M1 sCJD strain or the co-occurring M1 + M2C sCJD strains and showing only synaptic-type PrPTSE deposition appeared to be limited in hGH CJD compared with dCJD (Rudge et al., 2015; Head et al., 2016; Peckeu et al., 2016; Ritchie et al., 2016). It has been estimated that 400,000 pituitary glands were used to treat 1848 patients from 1959 to 1985 in the United Kingdom (Swerdlow et al., 2003). UK mortality data indicate that 1 in 7000 deaths could have been due to sCJD in the 1970s (Rudge et al., 2015). Therefore, a portion of these pituitary glands are considered to have been contaminated with more than one sCJD strain, reflecting the existing ratio of the sCJD subtypes in donors, as were cadaveric dura mater grafts that caused
dCJD. Nevertheless, in hGH CJD, the V2 sCJD strainoriginated subgroup has been overrepresented, whereas the M1 sCJD strain-originated subgroup has been underrepresented. Since the routes of prion infection were different between hGH CJD cases and dCJD cases, i.e., intramusucular or subcutaneous administration vs. intracerebral administration, these data raise the possibility that the M1 sCJD strain might infect less efficiently than the V2 sCJD strain through peripheral routes. Taken together, infection with the M1 sCJD strain or the co-occurring M1+M2C sCJD strains might be responsible for the hGH CJD subgroup showing the synaptictype PrPTSE deposition, whereas infection with the V2 sCJD strain might be responsible for the hGH CJD subgroup showing the plaque-type PrPTSE deposition, similar to the two subgroups of dCJD. However, the proportion of the subgroup originating from the V2 sCJD strain compared to that originating from the M1 sCJD strain seems to be higher in hGH CJD than in dCJD.
BIOCHEMICAL FEATURES dCJD The biochemical features of dCJD patients are also variable, probably reflecting the heterogeneity of the infected sCJD strains. In Japanese dCJD patients, who were almost entirely 129 M/M homozygotes, the nonplaque-type dCJD cases had type 1 (21 kDa) PrPTSE (according to Parchi’s classification of PrPTSE: Parchi et al., 1999), whereas the plaque-type dCJD cases had the unusual type (20 kDa) of PrPTSE that were intermediate between type 1 and type 2 (19 kDa) PrPTSE and were therefore designated as the intermediate type (type i PrPTSE) (Fig. 12.4) (Kobayashi et al., 2007). The i PrPTSE type has also been reported in a German plaque-type dCJD patient carrying the 129 M/M genotype (Kretzschmar et al., 2003). Thus, not only the neuropathologic features but also the biochemical features of dCJD patients might be determined by the infected sCJD strain. In fact, in experimental animal models of iCJD, infection with the M1 sCJD strain or the co-occurring M1 + M2C sCJD strains caused type 1 PrPTSE accumulation in the brain regardless of the host PRNP codon 129 genotype, whereas infection with the V2 sCJD strain caused type i PrPTSE accumulation in the 129 M/M mice, type 2 PrPTSE accumulation in the 129 V/V mice, and a mixture of type i and type 2 PrPTSE accumulation in the 129 M/V mice (Fig. 12.3) (Kobayashi et al., 2007, 2013, 2016). Thus, these experimental data indicate that the dCJD subgroup originating from the M1 sCJD strain might show type 1 PrPTSE accumulation regardless of the host PRNP codon 129 genotype, whereas that originating from the V2 sCJD strain might show type i and/or type 2 PrPTSE accumulation depending on the host PRNP
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Fig. 12.4. Biochemical features of non-plaque-type dura mater graft-associated iatrogenic Creutzfeldt–Jakob disease (dCJD) and plaque-type dCJD. Western blot analysis of protease-resistant PrPTSE reveals type 1 (21 kDa) PrPTSE accumulation in the brain of nonplaque-type dCJD patients with the 129 M/M genotype. Meanwhile, plaque-type dCJD patients with the 129 M/M genotype show the intermediate type (type i, 20 kDa) PrPTSE located between type 1 and type 2 (19 kDa) PrPTSE (Kobayashi et al., 2007). sCJD, sporadic CJD.
codon 129 genotype. To confirm this possibility, further biochemical analysis of dCJD patients with the 129 V/V or M/V genotype will be required. At present, analysis of a limited number of nonplaque-type dCJD patients, i.e., the dCJD subgroup originating from the M1 sCJD strain, carrying the 129 V/Vor M/V genotype, has shown type 1 PrPTSE accumulation in the brain (Jansen et al., 2012).
hGH CJD The biochemical features of hGH CJD patients were not investigated so much until recently compared with those of dCJD patients. It has been reported that hGH CJD patients with the 129 M/M genotype showed type 1 PrPTSE accumulation, while patients with the 129 V/V or M/V genotype showed type 2 PrPTSE accumulation (Collinge et al., 1996; Jansen et al., 2012; Cali et al., 2015; Rudge et al., 2015; Peckeu et al., 2016). A recent sophisticated analysis of hGH CJD patients in the United Kingdom has shown that the biochemical
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features of hGH CJD patients are as variable as those of dCJD patients, reflecting the diversity of the infected sCJD strains (Ritchie et al., 2016). In the 21 UK hGH CJD cases examined, 1 129 M/M patient had type 1 PrPTSE, 1 129 M/M patient had type i PrPTSE, 12 129 M/V patients had a mixture of type i and type 2 PrPTSE, and 7 129 V/V patients had type 2 PrPTSE in the brain. The accumulation of type 1 PrPTSE is indicative of infection with the M1 sCJD strain, whereas that of type i and/or type 2 PrPTSE is indicative of infection with the V2 sCJD strain, as described above. Thus, the biochemical properties of the hGH CJD patients also suggest that the proportion of the subgroup originating from the V2 sCJD strain compared to that originating from the M1 sCJD strain is higher in hGH CJD than in dCJD. Of note, the 129 M/M hGH CJD patients reported to date to have had type 1 PrPTSE were neuropathologically divided into two subgroups, showing the synaptic-type PrPTSE deposition or PrPTSE amyloid plaques (Cali et al., 2015; Rudge et al., 2015). Further studies will be required to determine whether these 129 M/M hGH patients with PrPTSE amyloid plaques might have actually had type i PrPTSE. It is noteworthy that type i PrPTSE in plaque-type dCJD patients had long been confused with type 1 until stringent protease conditions and long gel electrophoresis were introduced for the PrPTSE typing (Notari et al., 2004, 2007). In addition, analysis of the carboxyl-terminal PrPTSE fragments may help to distinguish type i PrPTSE from type 1 PrPTSE (Kobayashi et al., 2015a).
BIOMARKERS Several biomarkers for CSF tests are available for the clinical diagnosis of iCJD as well as sCJD. These markers include 14-3-3 protein, tau protein, and disease-associated PrP (Sanchez-Juan et al., 2006; Atarashi et al., 2011). The sensitivity of 14-3-3 tests for the detection of dCJD is similar to that of sCJD. In Japan, the positive rates for 14-3-3 tests were 83% in dCJD and 87% in sCJD (Nozaki et al., 2010). It is noteworthy that the positive rate of the plaque-type dCJD patients (50%) was lower than that of the nonplaque-type dCJD patients (88%) (Yamada et al., 2009). The lower sensitivity of the 14-3-3 tests in Japanese plaque-type dCJD cases might be related to its lowest sensitivity in the sCJD MV2 subtype (30–76%) among the sCJD subtypes (Zerr et al., 2000; Castellani et al., 2004; Sanchez-Juan et al., 2006; Heinemann et al., 2007). Indeed, the plaque-type dCJD and sCJD MV2 subtype share common features such as slow progression of the disease, the lack or late occurrence of PSWCs on EEG, mild brain atrophy, PrPTSE amyloid plaques, and type i PrPTSE
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accumulation in the brain (Parchi et al., 1999; Notari et al., 2004; Kobayashi et al., 2007, 2013; NoguchiShinohara et al., 2007; Yamada et al., 2009). Similarly, the sensitivity of the 14-3-3 tests in the hGH CJD cases in European countries appeared to be lower than that in sCJD cases. The positive rate of the 14-3-3 tests was 85% in European sCJD cases (Sanchez-Juan et al., 2006), whereas in hGH CJD cases it dropped to 43–70% (Brandel et al., 2001; Rudge et al., 2015). Since plaque-type dCJD and the majority of hGH CJD cases can be considered to have been caused by infection with the V2 sCJD strain, these data indicate that the sensitivity of 14-3-3 tests for the detection of the iCJD subgroup originating from the V2 sCJD strain might be relatively low compared with that originating from the M1 sCJD strain. To test this possibility, further studies with a larger number of iCJD patients will be needed. Meanwhile, the sensitivity of tau tests for the detection of iCJD was also lower than that for sCJD in European countries, though it was not specified whether the iCJD cases were hGH CJD or dCJD. The positive rates of tau tests were 53% in iCJD and 86% in sCJD (Sanchez-Juan et al., 2006). Of note, the sensitivity of tau tests was also the lowest in the sCJD MV2 subtype (53%) among the sCJD subtypes (Sanchez-Juan et al., 2006). Therefore, these data may indicate that the sensitivity of the tau tests for detection of the iCJD subgroup originating from the V2 sCJD strain might also be relatively low compared with that originating from the M1 sCJD strain. Detection of the disease-associated PrP in CSF by real-time quaking-induced conversion (RT-QuIC) has also been reported in iCJD as well as sCJD (Atarashi et al., 2011; Ritchie et al., 2016). The sensitivity of the RT-QuIC assay was not significantly different between the iCJD subgroup originating from the M1 sCJD strain and that originating from the V2 sCJD strain. This finding is compatible with reports that the sensitivity of RT-QuIC assay was not significantly different between the M1 sCJD strain and the V2 sCJD strain (Atarashi et al., 2011; McGuire et al., 2012; Peden et al., 2012). Since only a limited number of iCJD patients have so far been examined using the RT-QuIC assay, further studies will be needed to confirm the usefulness of this assay for the diagnosis of iCJD.
GENOTYPE dCJD There are two nonpathogenic polymorphisms in the PRNP gene: methionine (M) or valine (V) at codon 129, and glutamic acid (E) or lysine (K) at codon 219. In Japan, almost all dCJD patients were 129 M/M homozygotes, reflecting the predominance of this genotype in
Fig. 12.5. Distribution of the genotypes at polymorphic codon 129 of the PRNP gene. In European sporadic Creutzfeldt– Jakob disease (sCJD) cases, 129 M/M homozygotes and 129 V/V homozygotes have been overrepresented compared with the general population (Alperovitch et al., 1999; Brandel et al., 2003). Meanwhile, 129 M/V heterozygotes have been underrepresented in European sCJD cases, suggesting protective effects of this genotype against CJD (Palmer et al., 1991; Laplanche et al., 1994; Salvatore et al., 1994; Windl et al., 1996; Kobayashi et al., 2015b). A similar genotypic distribution has been recognized in dura mater graft-associated iatrogenic CJD (dCJD) cases in countries other than Japan and human growth hormone (hGH) CJD cases in France (Brown et al., 2012). In contrast, in hGH CJD cases in the United Kingdom, 129 V/V homozygotes have been overrepresented, whereas 129 M/M homozygotes have been underrepresented (Brandel et al., 2003; Rudge et al., 2015).
the general population (Doh-ura et al., 1991; Nozaki et al., 2010; Kobayashi et al., 2015b). In dCJD patients in countries other than Japan, 129 M/M homozygotes and 129 V/V homozygotes have been overrepresented, whereas 129 M/V heterozygotes have been underrepresented (Fig. 12.5) (Brown et al., 2012). This pattern of genotypic distribution is quite similar to that of sCJD patients (Palmer et al., 1991; Laplanche et al., 1994; Salvatore et al., 1994; Windl et al., 1996). Therefore, the 129M/V heterozygosity might confer partial resistance against dCJD as well as against sCJD (Kobayashi et al, 2015b). It has not been examined so far whether the dCJD subgroup originating from the M1 sCJD strain and that originating from the V2 sCJD strain show the distinct predispositions of the PRNP codon 129 genotypes. It is noteworthy that 219 E/K heterozygosity is not protective against dCJD originating from the M1 sCJD strain (Kobayashi et al., 2015b), though this genotype confers resistance against the development of sCJD (Shibuya et al., 1998).
hGH CJD In hGH CJD patients in France and the United States, 129 M/M homozygotes and 129 V/V homozygotes have
IATROGENIC CREUTZFELDT–JAKOB DISEASE been overrepresented, whereas 129 M/V heterozygotes have been underrepresented (Fig. 12.5) (Brandel et al., 2003; Brown et al., 2012). In addition, these 129M/V heterozygous patients showed significantly longer incubation periods than the homozygous patients (d’Aignaux et al., 1999). Thus, the 129M/V heterozygosity might confer partial resistance against hGH CJD, as well. On the other hand, hGH CJD patients in the United Kingdom showed a distinct pattern in the PRNP genotypic distribution. In the United Kingdom, 129 V/V homozygotes have been overrepresented, whereas 129 M/M homozygotes have been underrepresented (Fig. 12.5). The reason for the different PRNP genotypic distribution in the United Kingdom has remained elusive. It may be explained by contamination with a high titer of the V2 sCJD strain in hGH used in the United Kingdom or by successful screening of donors particularly showing the typical CJD features, i.e., the M1 sCJD strainassociated features (Rudge et al., 2015). Of note, both in France and the United Kingdom, hGH cases with the 129 V/V genotype occurred earlier than 129 M/M or M/V cases (Brandel et al., 2003; Brown et al., 2012; Rudge et al., 2015). In the initial study of French and UK patients, 22 or 52% were 129 V/V homozygotes (Brandel et al., 2003). However, the number of 129 V/V cases did not increase thereafter, except for one UK case, whereas the number of 129 M/M and M/V cases increased in subsequent studies (Brown et al., 2012; Rudge et al., 2015). These epidemiologic data are compatible with the experimental finding that the V2 sCJD strain-inoculated 129 V/V mice showed shorter incubation periods than the 129 M/M or M/V mice (Kobayashi et al., 2013). The effects of the PRNP codon 219 genotypes on the susceptibility to hGH CJD have remained unknown because the polymorphism at codon 219 is found only in Asian and Pacific populations.
CONCLUDING REMARKS Recent progress in the study of dCJD and hGH CJD has revealed that the combination of the infected sCJD strain and the PRNP genotype of the patient determines the clinical, neuropathologic, and biochemical features. As the characteristic features of the V2 sCJD strainoriginated subgroup could help to identify iCJD cases among presumed sporadic cases (Kobayashi et al., 2015a), the possibility of iatrogenic infection should be carefully considered in CJD patients showing atypical clinicopathologic and biochemical features.
ACKNOWLEDGMENTS We thank Brent Bell for critical review of the manuscript. The surveillance on CJD has been supported by Grants-
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in-Aid from the Ministry of Health, Labor and Welfare of Japan (TK and HM), and the experimental transmission study of iCJD was supported by Grants-in-Aid from the Ministry of Health, Labor and Welfare of Japan (AK and TK), Grants-in-Aid for Scientific Research from JSPS (AK and TK), a grant from MEXT for the Joint Research Program of the Research Center for Zoonosis Control, Hokkaido University (TK), and a Grant-in-Aid for Scientific Research on Innovative Areas (Brain Protein Aging and Dementia Control) from MEXT (TK).
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Chapter 12
Iatrogenic Creutzfeldt–Jakob disease ATSUSHI KOBAYASHI1, TETSUYUKI KITAMOTO2, AND HIDEHIRO MIZUSAWA3* Laboratory of Comparative Pathology, Graduate School of Veterinary Medicine, Hokkaido University, Kita-ku, Sapporo, Japan
1
2
Department of Neurological Science, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Japan 3
National Center of Neurology and Psychiatry, Kodaira, Japan
Abstract Iatrogenic transmission of Creutzfeldt–Jakob disease (CJD) has occurred through particular medical procedures. Among them, dura mater grafts and pituitary-derived growth hormone obtained from human cadavers undiagnosed as CJD are the most frequent sources of infection. Recent advances in our knowledge about dura mater graft- and human pituitary-derived growth hormone-associated CJD patients have revealed that the combination of the infected CJD strain and the PRNP genotype of the patient determines their clinical, neuropathologic, and biochemical features. In this chapter, we summarize the clinical, neuropathologic, biochemical, and diagnostic features of dura mater graft- and human pituitary-derived growth hormone-associated CJD patients for the appropriate diagnosis of iatrogenic CJD.
INTRODUCTION AND BRIEF HISTORY Iatrogenic Creutzfeldt–Jakob diseases (iCJD) represent a part of acquired prion diseases that have known sources of etiologic prions and include kuru and variant CJD as well. iCJD are defined as CJD transmitted by medical and surgical procedures. Neurosurgical transmission was first suggested by Nevin et al. in 1960, when 3 CJD cases developed 18–24 months after neurosurgical procedures in a hospital where a few CJD patients received brain biopsy and other invasive procedures (Nevin et al., 1960). The very first case associated with a cadaveric corneal graft was reported in 1974 when the patient developed CJD 18 months after transplantation from a donor with pathologically proven CJD (Duffy et al., 1974). The second case developed CJD 30 years after transplantation and was described in 1997 (Heckmann et al., 1997). Electroencepalogram (EEG) recordings with deep needle electrodes were also reported as a transmission procedure in 2 cases of iCJD in 1977 (Bernoulli et al., 1977). This was confirmed by experimental implantation of the suspected electrodes causing CJD in a chimpanzee
(Brown et al., 1992). Another case of neurosurgical transmission was reported in France in 1980 (Foncin et al., 1980). Dura mater graft-associated iCJD (dCJD) was first reported in 1987 in the United States (CDC, 1987) and more than 200 cases have since been documented in many countries (Brown et al., 2012). Among them, more than half were registered in Japan (Sato et al., 2005; Hamaguchi et al., 2013). The number of Japanese dCJD patients reached 152 by August 2017. In other countries, the numbers of patients ranged from 1 to 14 (Clavel and Clavel, 1996; Brooke et al., 2004; Heath et al., 2006; Toovey et al., 2006; Heinemann et al., 2007; Kim et al., 2011; Brandel et al., 2013; Hall et al., 2014). The source of cadaveric dura mater in most cases when identified was Lyodura produced by B. Broun Melsungen. Two other sources include 1 case of Tutoplast dura (Hannah et al., 2001) and another case of locally produced dura. In 1996 when the first case of variant CJD case was reported, the Japanese Government conducted a nationwide survey that unexpectedly revealed many CJD cases with cadaveric dura grafting. After two more nationwide
*Correspondence to: Hidehiro Mizusawa, National Center Hospital, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi-machi, Kodaira, 187–8511, Japan. Tel: +81-42-346-1780, E-mail: [email protected]
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surveys a prospective survey was carried out for all the cases of prion diseases including dCJD (Sato et al., 2005; Nozaki et al., 2010). Analysis of the 152 dCJD cases in Japan revealed etiologic diseases, including tumor, bleeding, unruptured aneurysms, hematoma, hemifacial spasm, trigeminal neuralgia, malformation, trauma, and ossification of the posterior longitudinal ligament, as reported previously (Nozaki et al., 2010; Hamaguchi et al., 2013). Grafting was performed very frequently from 1982 to 1987 when the first case of dCJD was reported in the United States and 1N NaOH treatment had been added to the sterilization process of cadaveric dura mater (Sato et al., 2005). In 1985, 2 CJD cases that had received human pituitary-derived growth hormone (hGH) in the United States and 1 such case in the United Kingdom were reported (Gibbs et al., 1985; Koch et al., 1985; PowelJackson et al., 1985). Since then, by 2012, 226 cases had accumulated from many countries, mostly in France (119 cases/1170 recipients, 10.2%), the United Kingdom (65 cases/1800 recipients, 3.6%), and the United States (29 cases/2700 recipients, 1.1%) (Brown et al., 2012). There were only one or a few cases in other countries, including New Zealand, Brazil, the Netherlands, Australia, Ireland, and Qatar. The circumstantial evidence of cadaveric hGH transmission to humans is a unique clinical feature of patients, which include unusually young age at onset with progressive cerebellar syndrome with only delayed dementia, if any, as compared with typical sporadic CJD (sCJD) which is characterized by old age at onset with rapidly progressive dementia (Will, 2003; Rudge et al., 2015). The evidence was supported by successful transmission of CJD in a squirrel monkey with a potentially contaminated batch of hGH (Gibbs et al., 1993).
CLINICAL FEATURES Dura mater graft-associated CJD (dCJD) The age at onset ranged from the second to ninth decade of life with mean age at onset of 56.0 14.9 years, which is more than 10 years younger than that of sCJD. The incubation time was 13.4 6.7 years (1–30 years and 11 months). Neuropathologic analyses of 23 dCJD cases showed there are two types: plaque and nonplaque types (Noguchi-Shinohara et al., 2007). Plaque-type dCJD has a plaque-type deposition of abnormal prion protein (PrPTSE) which sometimes resembles the florid plaques found in variant CJD (Shimizu et al., 1999). Nonplaque-type dCJD was pathologically characterized by spongiform encephalopathy similar to that of the sCJD MM/MV1 subtype. The relative frequency of plaque-type dCJD is estimated to be
about 30–40% and nonplaque-type about 60–70% in Japan. The clinical and laboratory features of plaque-type dCJD include onset with progressive gait disturbance, mainly ataxia, a relatively long clinical course, and no or late occurrence of periodic sharp-wave complexes (PSWCs) on EEG. In contrast, clinical and laboratory features of nonplaque-type dCJD are similar to those of sCJD MM/MV1 subtype. High signal intensity of diffusion-weighted imaging (DWI) on magnetic resonance imaging (MRI) and positive 14-3-3 protein of CSF are common features in both plaque and nonplaque types of dCJD. DWI high signal intensity in the thalamus may be a characteristic of plaque-type dCJD in addition to that in the striatum and cerebral cortices (Fig. 12.1). The clinical features of plaque-type dCJD are diagnostic challenge in cases with progressive ataxia in human cadaveric dura mater recipients which could be diagnosed as probable dCJD.
Human pituitary-derived growth hormoneassociated CJD (hGH CJD) The mean incubation period of all available cases was estimated to be 17 (5–42) years based on the midpoint date as the date of infection because, usually, the treatment periods ranged over many years. There are some differences among countries with many hGH CJD cases; the mean incubation period is 13 years in France, 20 years in the United Kingdom, and 22 years in the United States (Huillard d’Aignaux et al., 1999; Swerdlow et al., 2003). The shorter period in France may result from the narrower limit of infection date and is close to the 13.5 years of 4 CJD patients who received human gonadotropin in Australia. This is also similar to the 13.4 years of dCJD. A recent study on the incubation periods of UK cases related to the codon 129 polymorphism described 30.8 (26.9–32.6) years in 129 M/M homozygotes, 23.4 (9.0–36.7) years in 129 M/V heterozygotes, and 14.3 (7.7–20.2) years in 129 V/V homozygotes (Rudge et al., 2015). Clinically, ataxic gait is the most common initial symptom followed by tremor, leg pain, daytime somnolence, dizziness, headache, myoclonus, and cognitive impairment (Will, 2003; Rudge et al., 2015). Rarely, cognitive decline appears at an early stage (Cordery et al., 2003). The leg pain includes hypersensitivity to light touch and various dysesthesia, such as itchy sensation, patchy tingling, burning, and numbness. Neurologic findings include cerebellar ataxic gait, myoclonus, cerebellar dysarthria, pyramidal tract sign, cognitive impairment, urine and fecal incontinence, and finally akinetic mutism.
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Fig. 12.1. Magnetic resonance imaging (MRI)-diffusion-weighted imaging (DWI) of dura mater graft-associated iatrogenic Creutzfeldt–Jakob disease (dCJD) and human growth hormone (hGH) CJD. More thalamic hyperintensity on MRI-DWI may be a characteristic of plaque-type dCJD. (Courtesy of Dr. Yoshihisa Watanabe.) In addition to cerebral cortical involvement, hyperintensities of the basal ganglia and thalamus in hGH CJD resemble those in plaque-type dCJD. (Courtesy of Dr. Harpreet Hyare and Dr. Peter Rudge.)
Among 21 patients, 6 showed normal EEG initially and the other 15 showed generalized slow activity. Only one of the 15 revealed short runs of PSWCs (Rudge et al., 2015). On MRI DWI, high signal intensity was observed in the thalamus, caudate nucleus, and putamen in most cases (Fig. 12.1). In the cerebral cortex, the cingulate gyrus, frontal gyrus, and cerebellum were also frequently affected and the paracentral lobule, parietal lobe, and hippocampus were less frequently involved (Lewis et al., 2006; Appleby et al., 2013; Rudge et al., 2015).
NEUROPATHOLOGIC FEATURES dCJD The neuropathologic features of dCJD patients are not uniform, as mentioned above. In Japan, 68% of dCJD patients show the synaptic-type deposition of PrPTSE in the brain similar to that of patients with the sCJD MM/MV1 subtype, and are designated as nonplaquetype dCJD, while 32% of dCJD patients show PrPTSE amyloid plaques similar to those of patients with the sCJD MV2 subtype and are designated as plaque-type dCJD (Fig. 12.2) (Takashima et al., 1997; Shimizu et al., 1999; Hoshi et al., 2000; Kimura et al., 2001; Mochizuki
et al., 2003; Satoh et al., 2003; Noguchi-Shinohara et al., 2007; Yamada et al., 2009). The neuropathologic features of the nonplaque-type dCJD patients resemble those of the sCJD MM/MV1 subtype, including severe brain atrophy, spongiform changes, neuronal loss, astrocytic gliosis, and diffuse synaptic-type PrPTSE deposition in the cerebral and cerebellar gray matter (Satoh et al., 2003; Yamada et al., 2009). In contrast, the neuropathologic features of plaque-type dCJD patients are characterized by mild brain atrophy, perineuronal PrPTSE deposition, and PrPTSE amyloid plaques, in addition to spongiform changes, neuronal loss, and gliosis (Satoh et al., 2003; Yamada et al., 2009). The PrPTSE amyloid plaques are widely distributed over the cerebral gray matter, the cerebellar gray matter, and the cerebellar white matter. Some PrPTSE amyloid plaques are surrounded by vacuoles, resembling the florid plaques of variant CJD (Shimizu et al., 1999; Mochizuki et al., 2003; Yamada et al., 2009). The two subgroups of dCJD have also been recognized in European countries and the United States (Lane et al., 1994; Kopp et al., 1996; Radbauer et al., 1998; Kretzschmar et al., 2003). The reason for the existence of the two neuropathologically distinct subgroups of dCJD has remained elusive for years. However, recent advances in our knowledge of
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Fig. 12.2. Neuropathologic features of nonplaque-type dura mater graft-associated iatrogenic Creutzfeldt–Jakob disease (dCJD) and plaque-type dCJD. (A–F) Nonplaque-type dCJD patients show fine granular to diffuse synaptic-type deposition of PrPTSE in the cerebral gray matter (A, B), hippocampus (C, D), and cerebellar gray matter (E, F). (G-O) Plaque-type dCJD patients show large PrPTSE amyloid plaques (H, I, K, N: open arrowheads) and perineuronal PrPTSE deposition (L: arrow) besides the synaptictype PrPTSE deposition (Lane et al., 1994; Kopp et al., 1996; Takashima et al., 1997; Radbauer et al., 1998; Shimizu et al., 1999; Hoshi et al., 2000; Kimura et al., 2001; Kretzschmar et al., 2003; Mochizuki et al., 2003; Satoh et al., 2003; Noguchi-Shinohara et al., 2007; Yamada et al., 2009). In the cerebellum, the formation of PrPTSE amyloid plaques is most prominent in the granular cell layer (M, N). In addition, perivascular PrPTSE deposition is remarkable in the cerebellar white matter (M, O: filled arrowheads). Immunohistochemical analysis of PrP (A–H, J–O); hematoxylin and eosin stain (I). Scale bars, 100 mm (A, C, E, F, G, J, M, O); 10 mm (B, D, H, I, K, L, N).
dCJD patients and those gained from experimental animal models of iCJD have raised the possibility that the distinct neuropathologic features might be caused by different sCJD strains (Kobayashi et al., 2007, 2009, 2014). To date, five sCJD strains have been proposed according to the disease phenotypes in patients and their transmission properties in transgenic mice expressing human prion protein (PrP), namely M1 (MM1/MV1 subtype, which corresponds to 40% of total sCJD cases), V1 (VV1 subtype, 1%), M2C (MM2C subtype, 1%), M2T (MM2T subtype, 1%), and V2 (VV2 and MV2 subtypes, 23%) (Parchi et al., 1999, 2011; Bishop et al., 2010; Moda et al., 2012). In addition, the co-occurrence of distinct prion strains in the same patient such as M1 +M2C (MM/MV1 + 2C subtype, which corresponds to 28% of total sCJD cases) has been recognized (Parchi et al., 2011). In experimental animal models of iCJD, infection with the M1 strain or the co-occurring M1 + M2C strains caused synaptic-type PrPTSE deposition in the brain similar to that of
nonplaque-type dCJD patients, while infection with the V2 strain caused plaque-type PrPTSE deposition similar to that of plaque-type dCJD patients (Fig. 12.3) (Kobayashi et al., 2007, 2013, 2016). Interestingly, mice inoculated with the M1 strain or the co-occurring M1 +M2C strains showed the synaptic-type PrPTSE deposition regardless of their genotype at polymorphic (methionine, M or valine, V) codon 129 of the PRNP gene, whereas the V2 strain-inoculated mice showed various amounts of PrPTSE plaques depending on their PRNP codon 129 genotype, i.e., mice carrying the 129 M/M genotype showed numerous PrPTSE plaques but mice carrying the 129 V/V or M/V genotype showed only a small number of PrPTSE plaques (Kobayashi et al., 2013, 2015a). Indeed, all plaque-type dCJD cases reported to date were 129 M/M homozygotes not only in Japan, where the vast majority of the general population are 129 M/M homozygotes, but also in European countries (Kopp et al., 1996; Kretzschmar et al., 2003; Yamada et al., 2009; Nozaki et al., 2010). Further
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Fig. 12.3. Experimental animal models of iatrogenic Creutzfeldt–Jakob disease (CJD). To model the iatrogenic transmission of sporadic CJD (sCJD) prions, knockin mice expressing human prion protein (PrP) with the 129 M/M, M/V, or V/V genotype were intracerebrally challenged with the representative sCJD strains. Mice inoculated with the M1 sCJD strain or co-occurring M1 + M2C strains showed synaptic-type PrPTSE deposition and type 1 PrPTSE accumulation in the brain regardless of their PRNP codon 129 genotype. Meanwhile, mice inoculated with the V2 sCJD strain showed diverse neuropathologic and biochemical features depending on the codon 129 genotype (Kobayashi et al., 2007, 2013, 2016). *Intermediate-type PrPTSE. †The number and distribution of PrPTSE plaques were relatively limited. ‡A mixture of the intermediate-type and type 2 PrPTSE.
neuropathologic analysis of dCJD patients with the 129 V/Vor M/V genotype will be needed in the future to clarify whether they show the two distinct neuropathologic features similar to those of the 129 M/M patients. Meanwhile, similarities in transmissibility to experimental animals (Kobayashi et al., 2007, 2010, 2013, 2015a) or in seeding activity in protein misfolding cyclic amplification (Takeuchi et al., 2016a) among the M1 sCJD strain, the co-occurring M1 +M2C sCJD strains, and brain materials from nonplaque-type dCJD patients, or between the V2 sCJD strain and brain materials from plaque-type dCJD patients, also support the possibility that the two distinct subgroups of dCJD might be caused by infection with different sCJD strains. The similar transmissibility between the M1 sCJD strain and the co-occurring M1 +M2C strains has been considered to be due to the reduced infectivity of the M2C sCJD strain (Kobayashi et al., 2013, 2016). Furthermore, it is noteworthy that the ratio of the nonplaque-type dCJD among total dCJD cases in Japan is quite similar to the combined ratio of the sCJD MM/ MV1 subtype (M1 strain) and the sCJD MM/MV1 + 2C subtype (co-occurring M1 +M2C strains) among total sCJD cases in Europe where the causative dura mater grafts were prepared. Meanwhile, the ratio of the plaque-type dCJD among total dCJD cases is similar to the combined ratio of the sCJD VV2 and MV2 subtypes
(V2 strain) among total sCJD cases (Yamada et al., 2009; Parchi et al., 2011; Kobayashi et al., 2016). During 1983–1987, when 80% of dCJD patients underwent dura mater transplantation, as many as 100,000 patches were used in Japan (Nakamura et al., 1999; Hamaguchi et al., 2013). Thus, a portion of these grafts might have been contaminated with more than one sCJD strain, reflecting the existing ratio of the sCJD subtypes in donors. Taken together, accumulating evidence suggests that infection with the M1 sCJD strain or the co-occurring M1 + M2C sCJD strains might be responsible for the dCJD subgroup that shows the synaptic-type PrPTSE deposition, whereas infection with the V2 sCJD strain might be responsible for the dCJD subgroup that shows the plaque-type PrPTSE deposition.
hGH CJD hGH CJD patients can also be divided into two subgroups based on their neuropathologic features, presumably reflecting the neuropathologic properties of the infected sCJD strains (Cali et al., 2015), as suggested in dCJD. One subgroup showed neuropathologic features resembling those of the nonplaque-type dCJD or sCJD MM/MV1 subtype, whereas the other subgroup showed characteristic features resembling those of the plaque-type dCJD (Delisle et al., 1993;
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Billette de Villemeur et al., 1994; Croes et al., 2002; Cali et al., 2015). In contrast to dCJD, however, the majority of hGH CJD cases showed the plaque-type pathology and appeared to have been caused by infection with the V2 sCJD strain (Rudge et al., 2015; Head et al., 2016; Peckeu et al., 2016; Ritchie et al., 2016). In pathologically examined French hGH CJD cases, all 129 M/M patients and half of the 129 M/V patients showed PrPTSE amyloid plaques in the brain (Billette de Villemeur et al., 1994; Peckeu et al., 2016). In the UK cases, 3 out of 4 129 M/M patients and all 129 M/V patients had PrPTSE amyloid plaques (Rudge et al., 2015; Moore et al., 2016; Ritchie et al., 2016). Thus, a large number of hGH CJD patients showed PrPTSE amyloid plaques that were indicative of infection with the V2 sCJD strain. In addition, although hGH CJD patients with the 129 V/V genotype lacked PrPTSE amyloid plaques and showed only perineuronal and plaque-like PrPTSE deposits (Peckeu et al., 2016; Ritchie et al., 2016), the scarcity of PrPTSE amyloid plaques in the 129 V/V patients cannot exclude the possibility of infection with the V2 sCJD strain because the V2 sCJD strain-infected 129 V/V mice showed only a small number of PrPTSE plaques compared with the 129 M/M mice in experimental transmission studies, as described above (Fig. 12.3) (Kobayashi et al., 2007, 2013, 2015a), and sCJD VV2 patients show only perineuronal and plaque-like PrPTSE deposits (Parchi et al., 1999, 2011). In fact, the biochemical features of the 129 V/V hGH CJD patients (Collinge et al., 1996; Head et al., 2016; Ritchie et al., 2016) also support the possibility of infection with the V2 sCJD strain, as described below. Furthermore, similarities in the seeding activity in protein misfolding cyclic amplification between the V2 sCJD strain and brain materials from hGH CJD patients with PrPTSE amyloid plaques or plaque-like PrPTSE deposits also suggested that these hGH CJD cases might have been infected with the V2 sCJD strain (Ritchie et al., 2016; Takeuchi et al., 2016b). On the other hand, the number of patients infected with the M1 sCJD strain or the co-occurring M1 + M2C sCJD strains and showing only synaptic-type PrPTSE deposition appeared to be limited in hGH CJD compared with dCJD (Rudge et al., 2015; Head et al., 2016; Peckeu et al., 2016; Ritchie et al., 2016). It has been estimated that 400,000 pituitary glands were used to treat 1848 patients from 1959 to 1985 in the United Kingdom (Swerdlow et al., 2003). UK mortality data indicate that 1 in 7000 deaths could have been due to sCJD in the 1970s (Rudge et al., 2015). Therefore, a portion of these pituitary glands are considered to have been contaminated with more than one sCJD strain, reflecting the existing ratio of the sCJD subtypes in donors, as were cadaveric dura mater grafts that caused
dCJD. Nevertheless, in hGH CJD, the V2 sCJD strainoriginated subgroup has been overrepresented, whereas the M1 sCJD strain-originated subgroup has been underrepresented. Since the routes of prion infection were different between hGH CJD cases and dCJD cases, i.e., intramusucular or subcutaneous administration vs. intracerebral administration, these data raise the possibility that the M1 sCJD strain might infect less efficiently than the V2 sCJD strain through peripheral routes. Taken together, infection with the M1 sCJD strain or the co-occurring M1+M2C sCJD strains might be responsible for the hGH CJD subgroup showing the synaptictype PrPTSE deposition, whereas infection with the V2 sCJD strain might be responsible for the hGH CJD subgroup showing the plaque-type PrPTSE deposition, similar to the two subgroups of dCJD. However, the proportion of the subgroup originating from the V2 sCJD strain compared to that originating from the M1 sCJD strain seems to be higher in hGH CJD than in dCJD.
BIOCHEMICAL FEATURES dCJD The biochemical features of dCJD patients are also variable, probably reflecting the heterogeneity of the infected sCJD strains. In Japanese dCJD patients, who were almost entirely 129 M/M homozygotes, the nonplaque-type dCJD cases had type 1 (21 kDa) PrPTSE (according to Parchi’s classification of PrPTSE: Parchi et al., 1999), whereas the plaque-type dCJD cases had the unusual type (20 kDa) of PrPTSE that were intermediate between type 1 and type 2 (19 kDa) PrPTSE and were therefore designated as the intermediate type (type i PrPTSE) (Fig. 12.4) (Kobayashi et al., 2007). The i PrPTSE type has also been reported in a German plaque-type dCJD patient carrying the 129 M/M genotype (Kretzschmar et al., 2003). Thus, not only the neuropathologic features but also the biochemical features of dCJD patients might be determined by the infected sCJD strain. In fact, in experimental animal models of iCJD, infection with the M1 sCJD strain or the co-occurring M1 + M2C sCJD strains caused type 1 PrPTSE accumulation in the brain regardless of the host PRNP codon 129 genotype, whereas infection with the V2 sCJD strain caused type i PrPTSE accumulation in the 129 M/M mice, type 2 PrPTSE accumulation in the 129 V/V mice, and a mixture of type i and type 2 PrPTSE accumulation in the 129 M/V mice (Fig. 12.3) (Kobayashi et al., 2007, 2013, 2016). Thus, these experimental data indicate that the dCJD subgroup originating from the M1 sCJD strain might show type 1 PrPTSE accumulation regardless of the host PRNP codon 129 genotype, whereas that originating from the V2 sCJD strain might show type i and/or type 2 PrPTSE accumulation depending on the host PRNP
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Fig. 12.4. Biochemical features of non-plaque-type dura mater graft-associated iatrogenic Creutzfeldt–Jakob disease (dCJD) and plaque-type dCJD. Western blot analysis of protease-resistant PrPTSE reveals type 1 (21 kDa) PrPTSE accumulation in the brain of nonplaque-type dCJD patients with the 129 M/M genotype. Meanwhile, plaque-type dCJD patients with the 129 M/M genotype show the intermediate type (type i, 20 kDa) PrPTSE located between type 1 and type 2 (19 kDa) PrPTSE (Kobayashi et al., 2007). sCJD, sporadic CJD.
codon 129 genotype. To confirm this possibility, further biochemical analysis of dCJD patients with the 129 V/V or M/V genotype will be required. At present, analysis of a limited number of nonplaque-type dCJD patients, i.e., the dCJD subgroup originating from the M1 sCJD strain, carrying the 129 V/Vor M/V genotype, has shown type 1 PrPTSE accumulation in the brain (Jansen et al., 2012).
hGH CJD The biochemical features of hGH CJD patients were not investigated so much until recently compared with those of dCJD patients. It has been reported that hGH CJD patients with the 129 M/M genotype showed type 1 PrPTSE accumulation, while patients with the 129 V/V or M/V genotype showed type 2 PrPTSE accumulation (Collinge et al., 1996; Jansen et al., 2012; Cali et al., 2015; Rudge et al., 2015; Peckeu et al., 2016). A recent sophisticated analysis of hGH CJD patients in the United Kingdom has shown that the biochemical
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features of hGH CJD patients are as variable as those of dCJD patients, reflecting the diversity of the infected sCJD strains (Ritchie et al., 2016). In the 21 UK hGH CJD cases examined, 1 129 M/M patient had type 1 PrPTSE, 1 129 M/M patient had type i PrPTSE, 12 129 M/V patients had a mixture of type i and type 2 PrPTSE, and 7 129 V/V patients had type 2 PrPTSE in the brain. The accumulation of type 1 PrPTSE is indicative of infection with the M1 sCJD strain, whereas that of type i and/or type 2 PrPTSE is indicative of infection with the V2 sCJD strain, as described above. Thus, the biochemical properties of the hGH CJD patients also suggest that the proportion of the subgroup originating from the V2 sCJD strain compared to that originating from the M1 sCJD strain is higher in hGH CJD than in dCJD. Of note, the 129 M/M hGH CJD patients reported to date to have had type 1 PrPTSE were neuropathologically divided into two subgroups, showing the synaptic-type PrPTSE deposition or PrPTSE amyloid plaques (Cali et al., 2015; Rudge et al., 2015). Further studies will be required to determine whether these 129 M/M hGH patients with PrPTSE amyloid plaques might have actually had type i PrPTSE. It is noteworthy that type i PrPTSE in plaque-type dCJD patients had long been confused with type 1 until stringent protease conditions and long gel electrophoresis were introduced for the PrPTSE typing (Notari et al., 2004, 2007). In addition, analysis of the carboxyl-terminal PrPTSE fragments may help to distinguish type i PrPTSE from type 1 PrPTSE (Kobayashi et al., 2015a).
BIOMARKERS Several biomarkers for CSF tests are available for the clinical diagnosis of iCJD as well as sCJD. These markers include 14-3-3 protein, tau protein, and disease-associated PrP (Sanchez-Juan et al., 2006; Atarashi et al., 2011). The sensitivity of 14-3-3 tests for the detection of dCJD is similar to that of sCJD. In Japan, the positive rates for 14-3-3 tests were 83% in dCJD and 87% in sCJD (Nozaki et al., 2010). It is noteworthy that the positive rate of the plaque-type dCJD patients (50%) was lower than that of the nonplaque-type dCJD patients (88%) (Yamada et al., 2009). The lower sensitivity of the 14-3-3 tests in Japanese plaque-type dCJD cases might be related to its lowest sensitivity in the sCJD MV2 subtype (30–76%) among the sCJD subtypes (Zerr et al., 2000; Castellani et al., 2004; Sanchez-Juan et al., 2006; Heinemann et al., 2007). Indeed, the plaque-type dCJD and sCJD MV2 subtype share common features such as slow progression of the disease, the lack or late occurrence of PSWCs on EEG, mild brain atrophy, PrPTSE amyloid plaques, and type i PrPTSE
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accumulation in the brain (Parchi et al., 1999; Notari et al., 2004; Kobayashi et al., 2007, 2013; NoguchiShinohara et al., 2007; Yamada et al., 2009). Similarly, the sensitivity of the 14-3-3 tests in the hGH CJD cases in European countries appeared to be lower than that in sCJD cases. The positive rate of the 14-3-3 tests was 85% in European sCJD cases (Sanchez-Juan et al., 2006), whereas in hGH CJD cases it dropped to 43–70% (Brandel et al., 2001; Rudge et al., 2015). Since plaque-type dCJD and the majority of hGH CJD cases can be considered to have been caused by infection with the V2 sCJD strain, these data indicate that the sensitivity of 14-3-3 tests for the detection of the iCJD subgroup originating from the V2 sCJD strain might be relatively low compared with that originating from the M1 sCJD strain. To test this possibility, further studies with a larger number of iCJD patients will be needed. Meanwhile, the sensitivity of tau tests for the detection of iCJD was also lower than that for sCJD in European countries, though it was not specified whether the iCJD cases were hGH CJD or dCJD. The positive rates of tau tests were 53% in iCJD and 86% in sCJD (Sanchez-Juan et al., 2006). Of note, the sensitivity of tau tests was also the lowest in the sCJD MV2 subtype (53%) among the sCJD subtypes (Sanchez-Juan et al., 2006). Therefore, these data may indicate that the sensitivity of the tau tests for detection of the iCJD subgroup originating from the V2 sCJD strain might also be relatively low compared with that originating from the M1 sCJD strain. Detection of the disease-associated PrP in CSF by real-time quaking-induced conversion (RT-QuIC) has also been reported in iCJD as well as sCJD (Atarashi et al., 2011; Ritchie et al., 2016). The sensitivity of the RT-QuIC assay was not significantly different between the iCJD subgroup originating from the M1 sCJD strain and that originating from the V2 sCJD strain. This finding is compatible with reports that the sensitivity of RT-QuIC assay was not significantly different between the M1 sCJD strain and the V2 sCJD strain (Atarashi et al., 2011; McGuire et al., 2012; Peden et al., 2012). Since only a limited number of iCJD patients have so far been examined using the RT-QuIC assay, further studies will be needed to confirm the usefulness of this assay for the diagnosis of iCJD.
GENOTYPE dCJD There are two nonpathogenic polymorphisms in the PRNP gene: methionine (M) or valine (V) at codon 129, and glutamic acid (E) or lysine (K) at codon 219. In Japan, almost all dCJD patients were 129 M/M homozygotes, reflecting the predominance of this genotype in
Fig. 12.5. Distribution of the genotypes at polymorphic codon 129 of the PRNP gene. In European sporadic Creutzfeldt– Jakob disease (sCJD) cases, 129 M/M homozygotes and 129 V/V homozygotes have been overrepresented compared with the general population (Alperovitch et al., 1999; Brandel et al., 2003). Meanwhile, 129 M/V heterozygotes have been underrepresented in European sCJD cases, suggesting protective effects of this genotype against CJD (Palmer et al., 1991; Laplanche et al., 1994; Salvatore et al., 1994; Windl et al., 1996; Kobayashi et al., 2015b). A similar genotypic distribution has been recognized in dura mater graft-associated iatrogenic CJD (dCJD) cases in countries other than Japan and human growth hormone (hGH) CJD cases in France (Brown et al., 2012). In contrast, in hGH CJD cases in the United Kingdom, 129 V/V homozygotes have been overrepresented, whereas 129 M/M homozygotes have been underrepresented (Brandel et al., 2003; Rudge et al., 2015).
the general population (Doh-ura et al., 1991; Nozaki et al., 2010; Kobayashi et al., 2015b). In dCJD patients in countries other than Japan, 129 M/M homozygotes and 129 V/V homozygotes have been overrepresented, whereas 129 M/V heterozygotes have been underrepresented (Fig. 12.5) (Brown et al., 2012). This pattern of genotypic distribution is quite similar to that of sCJD patients (Palmer et al., 1991; Laplanche et al., 1994; Salvatore et al., 1994; Windl et al., 1996). Therefore, the 129M/V heterozygosity might confer partial resistance against dCJD as well as against sCJD (Kobayashi et al, 2015b). It has not been examined so far whether the dCJD subgroup originating from the M1 sCJD strain and that originating from the V2 sCJD strain show the distinct predispositions of the PRNP codon 129 genotypes. It is noteworthy that 219 E/K heterozygosity is not protective against dCJD originating from the M1 sCJD strain (Kobayashi et al., 2015b), though this genotype confers resistance against the development of sCJD (Shibuya et al., 1998).
hGH CJD In hGH CJD patients in France and the United States, 129 M/M homozygotes and 129 V/V homozygotes have
IATROGENIC CREUTZFELDT–JAKOB DISEASE been overrepresented, whereas 129 M/V heterozygotes have been underrepresented (Fig. 12.5) (Brandel et al., 2003; Brown et al., 2012). In addition, these 129M/V heterozygous patients showed significantly longer incubation periods than the homozygous patients (d’Aignaux et al., 1999). Thus, the 129M/V heterozygosity might confer partial resistance against hGH CJD, as well. On the other hand, hGH CJD patients in the United Kingdom showed a distinct pattern in the PRNP genotypic distribution. In the United Kingdom, 129 V/V homozygotes have been overrepresented, whereas 129 M/M homozygotes have been underrepresented (Fig. 12.5). The reason for the different PRNP genotypic distribution in the United Kingdom has remained elusive. It may be explained by contamination with a high titer of the V2 sCJD strain in hGH used in the United Kingdom or by successful screening of donors particularly showing the typical CJD features, i.e., the M1 sCJD strainassociated features (Rudge et al., 2015). Of note, both in France and the United Kingdom, hGH cases with the 129 V/V genotype occurred earlier than 129 M/M or M/V cases (Brandel et al., 2003; Brown et al., 2012; Rudge et al., 2015). In the initial study of French and UK patients, 22 or 52% were 129 V/V homozygotes (Brandel et al., 2003). However, the number of 129 V/V cases did not increase thereafter, except for one UK case, whereas the number of 129 M/M and M/V cases increased in subsequent studies (Brown et al., 2012; Rudge et al., 2015). These epidemiologic data are compatible with the experimental finding that the V2 sCJD strain-inoculated 129 V/V mice showed shorter incubation periods than the 129 M/M or M/V mice (Kobayashi et al., 2013). The effects of the PRNP codon 219 genotypes on the susceptibility to hGH CJD have remained unknown because the polymorphism at codon 219 is found only in Asian and Pacific populations.
CONCLUDING REMARKS Recent progress in the study of dCJD and hGH CJD has revealed that the combination of the infected sCJD strain and the PRNP genotype of the patient determines the clinical, neuropathologic, and biochemical features. As the characteristic features of the V2 sCJD strainoriginated subgroup could help to identify iCJD cases among presumed sporadic cases (Kobayashi et al., 2015a), the possibility of iatrogenic infection should be carefully considered in CJD patients showing atypical clinicopathologic and biochemical features.
ACKNOWLEDGMENTS We thank Brent Bell for critical review of the manuscript. The surveillance on CJD has been supported by Grants-
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in-Aid from the Ministry of Health, Labor and Welfare of Japan (TK and HM), and the experimental transmission study of iCJD was supported by Grants-in-Aid from the Ministry of Health, Labor and Welfare of Japan (AK and TK), Grants-in-Aid for Scientific Research from JSPS (AK and TK), a grant from MEXT for the Joint Research Program of the Research Center for Zoonosis Control, Hokkaido University (TK), and a Grant-in-Aid for Scientific Research on Innovative Areas (Brain Protein Aging and Dementia Control) from MEXT (TK).
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