Introduction. Overview

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1 Creutzfeldt-Jakob disease Raymond P Roos MD ( Dr. Roos of the University of Chicago Medical Center serves on the Scientific Advisory Board of Revalesio Corporation and a Data and Safety Monitoring Board for a clinical trial of a Mallinckrodt Pharmaceuticals product, has received consulting fees from M-T Pharmacy and Best Doctors and holds shares in Amgen, Merck, Ionis, and GE. ) John E Greenlee MD, editor. ( Dr. Greenlee of the University of Utah School of Medicine received an honorarium from Merck for authorship.) Originally released October 27, 1993; last updated June 22, 2018; expires June 22, 2021 Introduction This article includes discussion of Creutzfeldt-Jakob disease, Heidenhain syndrome, Jakob-Creutzfeldt disease, prion disease, and spastic pseudosclerosis. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations. Overview The author reviews Creutzfeldt-Jakob disease, a member of the group of diseases known as prion diseases or the subacute spongiform encephalopathies. Creutzfeldt-Jakob disease has a subacute clinical course and distinctive gray matter pathology. This disease is transmissible and is induced by an abnormal form of the prion protein that is extremely resistant to physical and chemical inactivation. The unusual nature of the transmissible agent and the emergence of variant Creutzfeldt-Jakob disease (as a result of ingestion of contaminated beef) have had a significant impact on public health in addition to science and medicine. The most recent epidemiological information suggests there will not be an epidemic of variant Creutzfeldt-Jakob disease. New diagnostic tests, protein misfolding cyclic amplification and real time quaking-induced conversion, and new ideas about treatment of Creutzfeldt-Jakob disease are discussed. Key points The transmissible subacute spongiform encephalopathies, or prion diseases, have a similar noninflammatory spongiform pathology and are caused by a similar transmissible agent -- an abnormal ( scrapie-like ) proteaseresistant conformation of the prion protein (PrP), which is designated PrPSc Creutzfeldt-Jakob disease is a subacute fatal disease with a clinical triad of dementia, myoclonus, and EEG abnormalities that is usually associated with other neurologic signs, along with neuropathological evidence of neuronal loss, spongiform changes, and astrocytosis. A new test that makes use of protein misfolding cyclic amplification (real time quaking-induced conversion) has high sensitivity and specificity and is extremely valuable in making the diagnosis. Iatrogenic cases of Creutzfeldt-Jakob disease have been described related to corneal transplantation, implantation of intracerebral electrodes (inadequately sterilized with formaldehyde), growth hormone injection (from pooled pituitary glands), and dura mater implantation (from pooled dura maters). A variant form of Creutzfeldt-Jakob disease caused by bovine spongiform encephalopathy (mad cow disease) is distinctive because of the relatively young age of the patients, frequent behavioral abnormalities early in the disease, few EEG abnormalities, an MRI finding of increased signal in the pulvinar, and abundant florid plaques in the brain (similar to those seen with kuru). Prion diseases are transmissible after a prolonged incubation period by inoculating the infected CNS into nonhuman primates and some other species via multiple routes of inoculation; however, transmission is most efficient with an intracerebral inoculation into a species identical to the source of the infected CNS tissue. Historical note and terminology Jakob deserves credit for being 1 of the first to draw attention to a clinical and pathologic syndrome that we now refer to as Creutzfeldt-Jakob disease. Although Jakob believed that a previously published case by Creutzfeldt reported on the same condition, this patient is now thought to have probably suffered from another disease process. In 1959 Klatzo and colleagues remarked on the similarity between the neuropathology of Creutzfeldt-Jakob disease and that seen in kuru, a noninflammatory ataxic spongiform encephalopathy found among the Fore tribesmen of the Eastern Highlands of Papua, New Guinea (Klatzo et al 1959). In 1966 kuru was transmitted to subhuman primates following intracerebral inoculation of CNS tissue (Gajdusek 1966); this prompted the inoculation of subhuman primates with Creutzfeldt-Jakob

2 disease-infected brain and its successful transmission (Gibbs et al 1968). Creutzfeldt-Jakob disease, kuru, Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia, sporadic fatal insomnia, and a number of animal diseases (including scrapie, bovine spongiform encephalopathy, and chronic wasting disease of deer and elk) are grouped as prion diseases, or transmissible subacute spongiform encephalopathies, because of their similar clinical and pathologic features and their transmissibility (Gajdusek 1966). Table 1. Human Prion Diseases Human prion diseases Description Etiology Kuru Creutzfeldt-Jakob disease Sporadic Familial Iatrogenic Variant Gerstmann-Sträussler-Scheinker disease Fatal insomnia (either sporadic or familial) Cerebellar disease of New Guinea, now eradicated Dementia, myoclonus, and other neurologic signs. Positive CSF RT-QuIC test. MRI DWI can show cortical ribboning. EEG can show positive sharp wave complexes. Autosomal dominant with clinical features similar to sporadic CJD Clinical features similar to sporadic CJD except frequent cerebellar signs Early age of onset with psychiatric/behavioral symptoms. Declining incidence. Autosomal dominant usually with cerebellar dysfunction and slower tempo than CJD. Insomnia, autonomic abnormalities Infection from endocannibalistic ritual Unknown Mutation in PrP gene, PRNP Infection from corneal transplants, intracerebral electrodes, dura mater grafts, growth hormone administration Infection from bovine spongiform encephalopathy tissue Mutation in PrP gene, PRNP Sporadic unknown Familial mutation in PrP gene, PRNP The transmission of these diseases is of special interest because of the noninflammatory nature of the clinicopathologic syndrome, the long incubation period (ie, a slow virus infection), and the unusual nature of the transmissible agent, the prion (Prusiner 1997; Prusiner et al 1998). The importance of these diseases was demonstrated by Gajdusek s and Prusiner s receipt of the Nobel Prize in 1976 and 1997, respectively. The prion diseases have become more visible in recent years because of an epidemic of bovine spongiform encephalopathy ( mad cow disease), found primarily in the United Kingdom, and the subsequent emergence of a new variant of Creutzfeldt-Jakob disease, which is thought to result from oral transmission of the bovine spongiform encephalopathy agent to humans. In addition, the recognition of chronic wasting disease as a prion disease of deer and elk in the United States has focused attention on the prion diseases. Clinical manifestations Presentation and course Creutzfeldt-Jakob disease generally occurs from 50 to 70 years of age (although cases in the teens and 80s have been described); a mean age of about 62 years has been reported (Brown et al 1986; Brown et al 2000; Brown 1988). The most common syndrome has a subacute course with a "clinical triad" of dementia, myoclonus, and a characteristic EEG (periodic or pseudoperiodic paroxysms of sharp waves or spikes against a slow background) (Roos et al 1973). Although this triad is not always seen in its entirety, the absence of all 3 features is distinctly unusual. Various other neurologic abnormalities are frequently seen, including behavioral abnormalities, sensory complaints, higher cortical dysfunction, and signs of cerebellar, pyramidal, extrapyramidal, and lower motor neuron dysfunction. At times, patients have sleep-wake disturbances (Landolt et al 2006). Patients usually decline virtually on a weekly basis, leading to a mute akinetic state and eventually to death within 6 months to 1 year. Less commonly, patients may have a slow progression with a late onset of dementia, myoclonus, or EEG abnormalities; more prolonged durations have been described in cases of familial disease (Jayadev et al 2011). Abnormalities in the spinal fluid and on MRI and published criteria for the diagnosis of sporadic Creutzfeldt-Jakob disease are detailed in the diagnostic workup section. A typical case is described below as well in a case record of the Massachusetts General Hospital (Johnson et al 2005).

3 About 10% of cases are familial with an autosomal dominant inheritance pattern (Takada et al 2017). Familial cases are classified on the basis of clinical and pathologic features and the particular mutation in the sequence of the prion protein gene as either familial Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome, or fatal familial insomnia (Masters et al 1981; Farlow et al 1989; Manetto et al 1992; Medori et al 1992; Reder et al 1995). Patients with Gerstmann-Straussler-Scheinker syndrome generally manifest a slower course than those with Creutzfeldt-Jakob disease with prominent cerebellar findings but less dementia and fewer EEG abnormalities; the pathology shows prominent amyloid plaques in the cerebellum. Patients with fatal familial insomnia manifest prominent insomnia, autonomic abnormalities, and fewer EEG abnormalities than do those with Creutzfeldt-Jakob disease. A noninherited disease with a similar clinical and pathological phenotype to fatal familial insomnia has also been described and referred to as sporadic fatal insomnia (Mastrianni et al 1999). A report of a large kindred with Gerstmann-Straussle- -Scheinker syndrome highlights the phenotypic heterogeneity in this disease (Webb et al 2009). Patients with familial cases that manifest a Creutzfeldt-Jakob disease clinicopathologic picture without features of Gerstmann-Straussle- -Scheinker syndrome or fatal familial insomnia are classified as having familial Creutzfeldt-Jakob disease. Some cases of Creutzfeldt-Jakob disease are iatrogenic with known sources of contamination occurring from corneal transplants, intracerebral recording electrode implants, growth hormone injections, and dura mater implants (Nozaki et al 2010; Brown et al 2012). Data strongly suggest that cases of a variant form of Creutzfeldt-Jakob disease result from transmission of bovine spongiform encephalopathy to humans. Over 225 cases of variant Creutzfeldt-Jakob disease have now been identified (Will et al 2000) ( primarily in the United Kingdom. Fortunately, the cases of variant Creutzfeldt-Jakob have become less frequent and are declining; for example, there was only 1 case in 2013 in the United Kingdom. These patients had a number of distinctive features compared to classical Creutzfeldt-Jakob disease. The average age of onset was less than 30 years, and there was a longer disease duration. Anxiety and depression were common early symptoms; other early signs were ataxia and sensory disturbances. Characteristic EEG abnormalities were absent. A number of the cases had an abnormal MRI with increased signal in the posterior thalamus on T2-weighted images (the pulvinar sign ). Postmortem examination of the brain revealed a much higher than usual occurrence of widespread amyloid plaques. These plaques, known as "florid" plaques, are prion protein-immunoreactive with an eosinophilic core and a pale periphery surrounded by spongiform change. Diagnostic criteria for variant Creutzfeldt-Jakob disease have been published and validated (Heath et al 2010). Prognosis and complications Creutzfeldt-Jakob disease patients usually become mute and bedridden with little movement except myoclonus, with death ensuing usually from respiratory complications occurring within 6 to 12 months of disease onset. Survival is rarely prolonged over a year or 2, except in atypical and some familial prion disease cases. Clinical vignette This 75-year-old man was in excellent health until 3 months prior to admission when, shortly after returning from a trip to Asia, he noticed difficulty in walking and in balance. The patient s difficulties were initially subtle, confined to his lower extremities, and made worse when attempting to turn. Over the ensuing weeks, however, his balance became increasingly worse, and the patient began to notice incoordination of both legs, such that he needed to use a cane and then a walker. This was followed by difficulties with coordination in his upper extremities, complaints of muscle twitching in both arms, and difficulty in writing. Initial evaluation by the patient s physician 2 months after onset of symptoms revealed only incoordination: MRI studies of both brain and spine were unremarkable, and EMG was normal, as were all laboratory studies including vitamin B12 level and serologies for dengue virus, West Nile virus, and enteroviruses. The patient was suspected of having a paraneoplastic disorder and was admitted to hospital for lumbar puncture and further evaluation. On admission the patient was alert, oriented, and afebrile. General physical examination was unremarkable. Neurologic examination revealed normal cranial nerves, normal strength and tone, and normal sensation. Deep tendon reflexes were brisk, but without Babinski sign or other pathological reflexes. Cerebellar examination, however, showed slowing of rapid alternating movements and a bilateral perpendicular tremor most prominent in the lower extremities but also present in the arms. Balance was severely impaired: the patient walked on a widened base with significant unsteadiness and inability to perform tandem gait. Routine blood studies were normal, as were angiotensin converting enzyme in both serum and CSF. Repeat viral serologies were unremarkable. CSF analysis showed 1 white blood cell/mm3, protein of 43 mg/dl, glucose of 56 mg/dl, absent oligoclonal bands, and negative CSF VDRL. CSF cultures for bacteria, Mycobacterium tuberculosis, and fungi were negative. Repeat MRI studies of brain and thoracic spine

4 were unremarkable. Studies of serum and CSF for paraneoplastic and anti-gad65 antibodies were negative. The patient s coordination and balance did not appear to change, but, late in his hospital course, he was noted to have become forgetful. On outpatient follow-up 3 weeks after discharge the patient was found to have become completely unable to stand without assistance and to have become significantly cognitively impaired. MRI at that time showed increased cortical signal on diffusion-weighted magnetic resonance imaging, suggesting Creutzfeldt-Jakob disease. CSF was positive for both and tau proteins, consistent with the diagnosis. Over the ensuing weeks, the patient became increasingly more ataxic, declined rapidly in terms of memory and cognition, and eventually became anarthric. By 4 months after admission he had become bedridden and rigid, with prominent startle myoclonus. The patient died 5 months after onset of his initial symptoms. Autopsy revealed extensive vacuolar change and astrogliosis, confirming the diagnosis of Creutzfeldt-Jakob disease. (Vignette contributed by John Greenlee MD.) Biological basis Etiology and pathogenesis Creutzfeldt-Jakob disease, like the other spongiform encephalopathies, is transmissible via multiple routes of inoculation, although the intracerebral route is the most efficient. The transmissible agent is an isoform of the prion protein that is proteinase-resistant, which is thought to be a result of a change in conformation from the normal cellular form of prion protein (Prusiner 1997; Prusiner et al 1998). The abnormal prion protein isoform (PrPSc) is generally considered to be all or part of a proteinaceous infectious agent, the prion, which apparently lacks nucleic acid (Legname et al 2004). Interactions of the abnormal prion protein with the normal cellular form of prion protein (PrPC) are critical for disease pathogenesis (Scott et al 1993). The abnormal prion protein aggregates to produce amyloid. The amino acid sequence of PrP varies in the normal population, with either a methionine or valine at codon position 129 of PrP (ie, a polymorphism that is found in the normal population) and affects the infectivity and phenotype of prion disease. Interestingly, variant Creutzfeldt-Jakob disease seems to be almost exclusively confined to patients that are homozygous for methionine at codon 129. Different PrPSc strains can be identified or typed on the basis of Western blots of affected tissues that show varying glycosylation patterns and electrophoretic mobility of PrP after proteinase K digestion, presumably because of their different conformation. The Creutzfeldt-Jakob disease agent can be classified into 6 subtypes (MM1 or 2, VV 1 or 2, and MV or 2) on the basis of the PrP gene haplotype (methionine [M], or valine [V], homozygosity or heterozygosity [MV] at codon 129) and the electrophoretic mobility and degree of glycosylation of proteinase K-digested fragments (Parchi et al 2012; Puoti et al 2012). Clinical phenotypes of prion diseases are thought to correlate with these molecular subtypes. For example, most patients with MM1 or MV1 subtype have a rapid disease with progressive dementia along with myoclonus and visual disturbance, whereas patients with MV2 or VV2 have an atypical disease with a longer duration and late dementia (Polymenidou et al 2005). Variant Creutzfeldt-Jakob disease manifests a distinctive electrophoretic subtype that is also seen in bovine spongiform encephalopathy. In some forms of human prion disease resembling Creutzfeldt-Jakob disease, PrP accumulates and is not sensitive to protease treatment (Gambetti et al 2008). These cases of variably protease-resistant prionopathies can have very atypical disease courses that lack the usual EEG and MRI findings. The pathogenesis of Creutzfeldt-Jakob disease is not completely understood. It is known that this disease is transmissible to nonhuman primates and other animals following filtration of the inoculum, indicating that the agent is small and "replicating" (Gibbs et al 1968). The intracerebral route of inoculation is more efficient than the peripheral route, with a mean incubation period of 24 months in squirrel monkeys. The transmissible agent is unusually resistant to chemical and physical agents (eg, heat inactivation, UV irradiation, X-irradiation), which led to suggestions that it does not contain nucleic acid. A distinctive protein that corresponds to an abnormal scrapie-like isoform of prion protein, PrPSc (Prusiner 1991), is present in Creutzfeldt-Jakob disease CNS tissue. As noted above, this protein differs from its normal cellular prion protein counterpart, PrPC, because it is protease-resistant, presumably owing to a change in conformation of the protein (although it has an identical amino acid sequence). It is believed that PrPSc deposits in the CNS of Creutzfeldt-

5 Jakob patients causing dysfunction, and that in the presence of PrPSc, PrPC is converted to PrPSc. In the case of experimentally transmitted Creutzfeldt-Jakob disease, the inoculated PrPSc is believed to enter the CNS and thereby start the conversion of PrPC to more PrPSc and the induction of disease. In the case of familial Creutzfeldt-Jakob disease (as well as Gerstmann-Straussler-Scheinker syndrome and fatal familial insomnia), a mutated form of the prion protein gene appears to lead to prion protein deposition. In a landmark experiment, the presence of a mutated prion protein gene (from a patient with Gerstmann-Straussler-Scheinker syndrome) as a transgene in mice was found to induce a spongiform neuropathology (Hsiao et al 1990). This latter result suggested that the mutant PrPSc is sufficient to produce disease (ie, a mutant form of prion protein replicates and induces disease). The importance of interactions between PrPSc and PrPC in disease was further supported by prion protein knock-out mice (Bueler et al 1993). These knock-out mice do not develop prion disease following inoculation of (mouse-adapted) PrPSc; reintroduction of PrPC as a transgene into the knock-out mouse leads to a return in susceptibility of these mice. Transgenic mice with PrPC expressed have an enhanced susceptibility to human prion disease, such as Creutzfeldt- Jakob disease, further supporting the importance of interactions of PrPC and PrPSc for disease development. Several observations demonstrate the potential of a broad spectrum of abnormalities that can be caused by PrP. One study found that overexpression of PrPC in muscle leads to a primary myopathy in transgenic mice (Huang et al 2007). In addition, cardiac disease can be induced by overexpression of PrPSc in the heart (Trifilo et al 2006). The pathogenesis of sporadic Creutzfeldt-Jakob disease remains unclear. It has been hypothesized that a spontaneous somatic change in conformation of prion protein in the CNS initiates the disease. Of note, transgenic mice that overproduce wild type rodent PrPC, or part of PrPC, develop neurodegeneration (Westaway et al 1994; Supattapone et al 2001; Flechsig 2003). This suggests that prion disease can be induced by excessive amounts of PrPC or particular peptides of PrPC, presumably because the chance of misfolding of the overexpressed PrPC into an abnormal PrPSc conformation is more likely than if there is a normal amount of PrPC expressed. It is likely that some of the presumed sporadic cases of Creutzfeldt-Jakob disease may actually represent an unrecognized transmission from infectious material, either as result of iatrogenic exposure or an environmental focus. Interestingly, a number of reports have been published that demonstrate the presence of prion-like elements in yeast. Experiments show that these elements lead to aggregation and amyloid formation of a protein. The transmission of these abnormal properties is related to the presence of the altered protein, rather than nucleic acid (Lindquist 1997). These studies suggest that prions (ie, abnormally folded proteins) as a cause of abnormal phenotypes are more widespread than realized. Misfolded proteins have been hypothesized to underlie a number of neurodegenerative diseases (Prusiner 2012; Stopschinski and Diamond 2017). Although these diseases may not be transmissible in the same way that the subacute spongiform encephalopathies are, the pathogenic protein specific for these diseases is misfolded and thought to spread throughout the CNS by means of a prion-like mechanism, in which the misfolded protein leads to misfolding of the wild type protein. Epidemiology" Creutzfeldt-Jakob disease occurs worldwide, with an annual incidence of about 0.5 per million population (Masters et al 1979). About 5% to 10% of Creutzfeldt-Jakob disease cases are familial and are caused by particular mutations of the prion protein gene (Hsiao et al 1989; Goldfarb et al 1992). Clusters of Creutzfeldt-Jakob disease cases have been reported, at times in a particular geographic region. In some of these cases, the geographic focus has been found to actually represent a cluster of familial cases, as in a focus among Libyan Jews (Hsiao et al 1991). In other cases, the cluster can represent horizontal transmission from a common source (eg, contaminated beef, as is the case of transmission of variant Creutzfeldt-Jakob disease). Iatrogenic Creutzfeldt-Jakob disease has been reported as a result of a number of different procedures. Transmission has occurred as a result of contamination of the following from prions of an affected individual: intracerebral electrodes that were incompletely sterilized and implanted, cornea or dura mater that was transplanted, and pools of human growth hormone that were inoculated (Brown et al 2012). For unclear reasons, cases related to contaminated preparations of growth hormone, in contrast to sporadic cases, have a far more frequent occurrence of cerebellar and basal ganglia signs with relatively little mental deterioration, myoclonus, or typical EEG abnormalities (Brown 1988; Brown et al 2012). In the UK, patients with iatrogenic Creutzfeldt-Jakob disease due to pituitary-derived growth hormone had incubation periods of up to 40 years (Rudge et al 2015). Interestingly, patients were initially predominantly valine homozygous at codon 129, but later patients had a mixed picture over time, with methionine homozygous and methionine-valine heterozygous (fewer patients with methionine homozygous). These data suggest

6 that the infecting prion contaminating the pituitary pool was from an individual with valine-valine homozygosity and an individual with methionine-valine heterozygosity. Disease among members of the medical profession has been reported only rarely. Of concern has been the occurrence of an outbreak of bovine spongiform encephalopathy ("mad-cow disease") in Britain with the subsequent emergence of variant Creutzfeldt-Jakob disease. Compelling evidence indicates that variant Creutzfeldt-Jakob disease resulted from oral ingestion of beef contaminated with the bovine spongiform encephalopathy agent (Will et al 2000). Fortunately, there has been a steadily decreasing number of variant Creutzfeldt-Jakob cases, with a total of only 1 case occurring in 2013 in the United Kingdom, presumably because of the decline in cases of bovine spongiform encephalopathy. A new atypical sporadic strain of bovine spongiform encephalopathy in a number of countries is under observation ( Also, of significant concern is a 2013 report from the United Kingdom that found that 16 of 32,441 ( Prevention The identification of particular mutations of the prion protein gene among cases of familial Creutzfeldt-Jakob disease signifies that in utero identification of this disease and an informed decision regarding elective therapeutic abortion are possible. Prevention of disease among individuals who are known to carry the mutation, but are not yet affected, is unfortunately not possible at present. The transmissible agent of Creutzfeldt-Jakob disease is highly resistant to chemical and physical agents, prompting the publication of guidelines concerning inactivation of the agent's infectivity and safety precautions at the time of autopsy, which can be found on the Centers for Disease Control and Prevention website. Patients should generally be kept on "stool and needle" precautions in the hospital, and body fluids should be labeled as potentially dangerous. Invasive procedures should be carried out using precautions similar to those used with AIDS patients. Attempts to decrease the incidence of iatrogenic disease have been implemented. Intracerebral electrodes are no longer sterilized by paraformaldehyde vapor, and guidelines regarding transplantation of tissues and transfusion of blood are in continuing discussion. Genetically engineered material, rather than purified human extracts, is used in growth hormone treatments. Changes in the way that cattle are fed and slaughtered have been implemented in order to eradicate bovine spongiform encephalopathy and subsequent transmission as variant Creutzfeldt-Jakob disease to humans. Because secondary transmission of variant Creutzfeldt-Jakob disease can occur through transfusion of blood from a patient with variant Creutzfeldt-Jakob disease and because white cells are known to carry the transmissible agent, leuko-depleted blood is used for transfusions in the United Kingdom. One direction for prevention of prion diseases involves the plan to interfere with oral transmission of prion diseases through mucosal vaccination. This plan is based on experiments showing that oral vaccination of mice with PrP expressed in an attenuated Salmonella vector led to the formation of mucosal antibodies that slowed or perhaps prevented disease caused by oral infection with PrPSc (Goni et al 2008). Another direction for prevention of prion disease involves targeting the amino acid sequence variation at codon position 129 of PrP, which normally has either a methionine or valine residue. This amino acid affects the susceptibility and phenotype of prion diseases, including both scrapie and variant Creutzfeldt-Jakob disease. Also, studies of Kuru have demonstrated that a valine at codon 127 leads to an inhibition of wild-type prion propagation (Asante et al 2015). These findings may have an impact on preventing prion disease in animals and even perhaps in humans. Differential diagnosis The usual manifestations of Creutzfeldt-Jakob disease are fairly distinctive, and other diseases rarely produce a similar picture; however, Creutzfeldt-Jakob disease can, at times, have atypical clinical features. In addition, early in the disease course, Creutzfeldt-Jakob disease may be confused with other disorders. The availability of a new laboratory CSF test, RT-QuIC, and the identification of MRI abnormalities in Creutzfeldt-Jakob disease are important tools in helping to clarify the diagnosis. Many of the diseases in the differential diagnosis of Creutzfeldt-Jakob disease fall into a group of rapidly progressive

7 dementia (Geschwind 2016). A study from the US National Prion Disease Pathology Surveillance Center (Chitravas et al 2011) noted that 352 (32%) of 1106 brain autopsies from cases that were suspicious for prion disease had another diagnosis, most frequently Alzheimer s disease (154 cases) or vascular dementia (36 cases). Other diagnoses of incurable neurologic disease included: unspecified degenerative brain disease (10), frontotemporal lobar dementia (9), mesial temporal lobe sclerosis (5), diffuse Lewy body disease (4), tauopathy (4), hereditary diffuse leukoencephalopathy with spheroids (3), progressive supranuclear palsy (3), corticobasal ganglionic degeneration (1), adult polyglucosan body disease (1), Huntington disease (1), Marchiafava-Bignami disease (1), and superficial siderosis (1). Of special concern was the finding that 71 individuals (23%) had a potentially treatable neurologic disease that included: immune mediated disorders (26) (primary CNS angiitis, acute disseminated encephalomyelitis, limbic encephalitis, neurosarcoidosis, paraneoplastic cerebellar degeneration, and Wegener granulomatosis), neoplasms, infections (fungal, viral, and parasitic), and toxic encephalopathies (6). As noted above, the most common disease that can masquerade as Creutzfeldt-Jakob disease is Alzheimer disease, especially familial Alzheimer disease (Roos et al 1973). The pathologic features of these 2 diseases may sometimes also be confused; in these cases, the use of antisera directed against beta peptide or prion protein may be critical for differentiating Alzheimer disease amyloid plaques from those of Creutzfeldt-Jakob disease (or Gerstmann-Straussle- -Scheinker syndrome). Infectious or granulomatous processes (eg, neurosyphilis, CNS fungal disease, sarcoid, HIV-- -related diseases, Lyme disease), tumors, and vasculitis may present a clinical picture similar to that seen with Creutzfeldt-Jakob disease; however, imaging studies and blood and CSF investigations usually identify neoplastic or inflammatory processes. More confusing may be disease processes related to toxins (especially inorganic mercury), a primary central nervous system vasculitis with little or no laboratory evidence of systemic inflammation, Hashimoto thyroiditis, paraneoplastic syndromes (eg, cerebellar degeneration or limbic encephalitis), "mixed" neurodegenerative processes (eg, Lewy body dementia, frontotemporal dementia, Parkinson disease with dementia, amyotrophic lateral sclerosis with dementia), and autoimmune encephalitis, such as that directed against anti-nmda receptor. Diagnostic workup In order to rule out other causes of rapidly progressive disease, the following studies should be performed: complete blood count, comprehensive metabolic profile, sedimentation rate, collagen vascular screen, CSF analysis with culture, HIV-1 antibody, paraneoplastic antibodies, anti-nmda receptor antibody, a toxic screen, and antithyroid antibody. A brain MRI study with gadolinium infusion should be performed to look for hyperintensities in the striatum, thalamus, or cortex and to rule out the possibility of a mass lesion or inflammatory focus. If vasculitis is strongly suspected, an arteriogram should be considered. An EEG is important to identify the typical pattern seen in Creutzfeldt-Jakob disease and to rule out seizures. The most important studies in making the diagnosis of Creutzfeldt-Jakob disease are: (1) a relatively new protein misfolding cyclic amplification test called the real-time quaking-induced conversion (RT-QuIC) and (2) MRI (Gaudino et al 2017). The results of RT-QuIC on CSF from 126 patients who were suspected to have Creutzfeldt-Jakob disease (111 sporadic disease and 15 genetic) and had prion disease confirmed at autopsy and from 67 patients who had other diseases at autopsy had a specificity of 98.5% and sensitivity of 92.1% (Foutz et al 2016). A subsequently published review notes that the sensitivity of RT-QuIC for CSF in Creutzfeldt-Jakob disease CSF is 96% and the specificity is 100% (Zanusso et al 2016). The diagnostic value of RT-QuIC far exceeded that of other CSF biomarkers that have been used in the past, viz, and Tau. Interestingly, the patterns generated in the RT-QuIC along with PRNP sequencing allowed differentiation of subtypes of sporadic Creutzfeldt-Jakob; for example, RTQuIC provided a 95% probability that the more aggressive MM1 pattern could be differentiated from the more slowly progressive MM2. Modifications of the amplification test have been used to detect variant Creutzfeldt-Jakob prions in blood (Concha-Marambio et al 2016) and urine (Moda et al 2014). MRI is helpful in making the diagnosis of Creutzfeldt-Jakob disease. A consensus review of 48 cases of Creutzfeldt- Jakob disease by 2 neuroradiologists blinded to the diagnosis found that MRI had a sensitivity of 96% and 93%, respectively, and that the pattern of FLAIR/DWI can effectively differentiate Creutzfeldt-Jakob disease from other rapidly progressive dementias (Vitali et al 2011). There are gray matter hyperintensities in DWI sequences of the MRI in all the 48 cases, with certain regions preferentially involved, as found in this study and others, especially the cortex ( cortical ribboning ), basal ganglia, and thalamus and to a lesser degree the left occipital lobe. The hyperintensity was always greater on DWI than FLAIR, and the ADC in these regions was hypointense, indicating restricted diffusion.

8 Patients with variant Creutzfeldt-Jakob disease have a distinctive finding with increased signal in the posterior thalamus on T2-weighted images (the pulvinar sign ). Interestingly, MRI abnormalities were found preclinically in atrisk patients who carry a mutation that is highly penetrant for familial Creutzfeldt-Jakob disease; diffusion was significantly reduced in thalamic-striatal structures, including the putamen and mediodorsal, ventrolateral, and pulvinar thalamic nuclei (Lee et al 2009). The EEG characteristically shows positive sharp wave complexes. In a large, well-controlled study, 58% of sporadic Creutzfeldt-Jakob disease patients (1261 of 2083 cases) showed this typical EEG, although the chances of finding it were more likely with a patient over 50 years of age and a disease duration under 6 months (Collins et al 2006); in addition, the typical EEG was more likely seen with patients with the MM1 subtype and less likely with the MV1, MV2, and VV2 subtypes. If the characteristic EEG findings are not initially seen, serial EEGs should be performed because these abnormalities frequently appear as the clinical syndrome evolves. The European criteria for the diagnosis of sporadic Creutzfeldt-Jakob disease is as follows ( Definite: progressive neurologic syndrome and neuropathologically or immunohistochemically or biochemically confirmed Probable: I plus two of II and typical EEG (III) OR I plus two of II and typical MRI (IV) OR I plus two of II and positive cerebrospinal fluid OR progressive neurologic syndrome and positive RT-QuIC in CSF or other tissue Possible: I plus two of II plus duration of <2 years (1) Rapidly progressive cognitive impairment (2) (3) (a) Myoclonus (b) Visual or cerebellar disturbance (c) Pyramidal or extrapyramidal signs (d) Akinetic mutism (a) Periodic EEG discharges (4) Hyperintensity on DWI or FLAIR sequences of the MRI in the caudate/putamen or in at least 2 cortical areas (temporal, parietal, or occipital) Criteria are also available for the diagnosis of iatrogenic and genetic transmissible spongiform encephalopathy as well as variant Creutzfeldt-Jakob disease ( It is likely that the availability of RT-QuIC will play a major role in the future diagnostic criteria. If the patient is suspected of having a family history of a similar disease process, prion protein gene sequencing should be performed on white blood cell DNA to look for evidence of a pathogenic mutation. As a result of difficulties in obtaining a reliable family history, obtaining prion protein gene genotyping on all clinically suspect Creutzfeldt-Jakob disease patients is not inappropriate although not standard practice. The analysis of CNS tissue remains the gold standard with respect to making a definite diagnosis; the performance of a brain biopsy, however, is generally difficult to carry out because of biohazard concerns. The CNS tissue usually shows the typical spongiform changes as well as evidence of protease-resistant PrPSc when subjected to electrophoresis. Affected tissue generally transmits disease in experimental animals. Management The fear of an epidemic of variant Creutzfeldt-Jakob disease has challenged the scientific community to identify potential treatments. A number of drugs have been tested in mice that carry PrPSc; however, there remains no confirmed effective treatment for any prion disease (Brown 2002). The finding that turning off expression of PrPC in prion infected mice rescues them from disease (Mallucci et al 2003) and leads to recovery from cognitive and behavioral symptoms (Mallucci et al 2007) is encouraging and suggests that the disease process is not inexorably fatal after it starts. Experiments showed that knockdown of PrPC following lentiviral delivery of RNAi into the hippocampus of scrapie-infected mice led to a prolongation in survival, with a decrease in behavioral defects and neuropathology (White et al 2008). Another promising avenue for treatment is osmotic pump delivery of antisense oligonucleotides into the ventricle (Nazor Friberg et al 2012). There have also been attempts to knockdown PrP by means of immunotherapy, primarily with antibodies directed to all

9 or part of PrP (Roettger et al 2013). These antibodies have been shown to increase lifespan, and in some cases prolong the incubation period of scrapie mice. Unfortunately, and surprisingly, some of the antiprion antibodies are neurotoxic in animals, a finding that is presently under investigation, and one that may clarify a mechanism by which prions cause disease (Sonati et al 2013). Of interest is a publication showing that treatment of a scrapie-infected mouse with a drug that inhibits a key kinase in the unfolded protein response abrogates the development of clinical disease and decreases the neuropathological abnormalities (Moreno et al 2013). A second study used a different drug to target this pathway again finding an amelioration of scrapie (Halliday et al 2015). Unfortunately, as of this date, there is still no treatment recommended to slow the course of Creutzfeldt-Jakob disease, and there is no way to prevent disease from developing in a clinically asymptomatic individual who carries a mutant PrP gene associated with familial Creutzfeldt-Jakob disease. Furthermore, it is clear that there is significant damage to the brain when most Creutzfeldt-Jakob disease patients are diagnosed, so that treatments may sadly have little benefit in the majority of patients. Special considerations Pregnancy No information is available regarding the effect of pregnancy on the course of Creutzfeldt-Jakob disease. To date, there is no evidence that children born to pregnant women with Creutzfeldt-Jakob disease develop the disease (Xiao et al 2009). An investigation of a child born from a pregnant woman with Creutzfeldt-Jakob disease found no evidence of proteinase K-resistant protein in gestational tissues, including the placenta and amniotic fluid (Xiao et al 2009); however, transmission studies or amplification-based detection assays were not performed. References cited Asante EA, Smidak M, Grimshaw A, et al. A naturally occurring variant of the human prion protein completely prevents prion disease. Nature 2015;522(7557): PMID Béringue V, Herzog L, Jaumain E, et al. Facilitated cross-species transmission of prions in extraneural tissue. Science 2012;335(6067): PMID Bosque PJ, Tyler KL. Prions travels feces and transmission of prion diseases. J Inf Dis 2008;198:81-9. PMID Brown P. The clinical neurology and epidemiology of Creutzfeldt-Jakob disease, with special reference to iatrogenic cases. In: Bock G, Marsh J, editors. Novel infectious agents and the central nervous system. Wiley, 1988:3-23. Brown P. Drug therapy in human and experimental transmissible spongiform encephalopathy. Neurology 2002;58: PMID Brown P, Brandel JP, Sato T, et al. Iatrogenic Creutzfeldt-Jakob disease, final assessment. Emerg Infect Dis 2012;18(6): PMID Brown P, Cathala F, Castaigne P, Gajdusek DC. Creutzfeldt-Jakob disease: clinical analysis of a consecutive series of 230 neuropathologically verified cases. Ann Neurol 1986;20: PMID Bueler H, Aguzzi A, Sailer A, et al. Mice devoid of PrP are resistant to scrapie. Cell 1993;73: PMID Chitravas N, Jung RS, Kofskey DM, et al. Treatable neurological disorders misdiagnosed as Creutzfeldt-Jakob disease. Ann Neurol 2011;70(3): PMID Collins SJ, Sanchez-Juan P, Masters CL, et al. Determinants of diagnostic investigation sensitivities across the clinical spectrum of sporadic Creutzfeldt-Jakob disease. Brain 2006;129(Pt 9): PMID Concha-Marambio L, Pritzkow S, Moda F, et al. Detection of prions in blood from patients with variant Creutzfeldt-Jakob disease. Sci Trans Med 2016;8:370ra183. PMID Dorsey K, Zou S, Schonberger LB, et al. Lack of evidence of transfusion transmission of Creutzfeldt-Jakob disease in a

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