428

Prion Disease
Kelly J. Baldwin, MD1 Cynthia M. Correll, MD1

1 Department of Neurology, Geisinger Commonwealth School of Address for correspondence Kelly J. Baldwin, MD, Department of
Medicine, Danville, Pennsylvania Neurology, Geisinger Commonwealth School of Medicine, MC 14-03,
100 North Academy Ave, Danville, PA 17822
Semin Neurol 2019;39:428–439. (e-mail: kjbaldwin@geisinger.edu).

Abstract Prion diseases are a phenotypically diverse set of disorders characterized by protease-
Keywords resistant abnormally shaped proteins known as prions. There are three main groups of
► transmissible prion diseases, termed sporadic (Creutzfeldt–Jakob disease [CJD], sporadic fatal
spongiform insomnia, and variably protease-sensitive prionopathy), genetic (genetic CJD, fatal
encephalopathies familial insomnia, and Gerstmann–Straussler–Scheinker syndrome), and acquired
► prion disease (kuru, variant CJD, and iatrogenic CJD). This article will review the pathophysiology,

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► Creutzfeldt–Jakob genetics, clinical presentations, and diagnostic challenges in patients with prion
disease disease. Case discussions, images, and tables will be used to highlight important
► fatal familial insomnia characteristics of prion disease and prion mimics.
► variant CJD
► Gerstmann–
Straussler–Scheinker
syndrome
► kuru
► Wernicke–Korsakoff
syndrome
► Bovine spongiform
encephalopathy

Human prion diseases, also termed transmissible spongiform The most prevalent human prion diseases are sporadic.
encephalopathies, are rare fatal neurological diseases with a These include sporadic Creutzfeldt–Jakob disease (sCJD) as
unique disease etiology. These diseases can be acquired, well as the rare entities of sporadic fatal insomnia and
sporadic, or genetic, and are characterized by the accumula- variably protease-sensitive prionopathy (VPSPr). Genetic
tion and aggregation of prions, or abnormally folded proteins. forms are the next most common and are caused by auto-
The abnormally folded proteins, termed PrPsc, have a high somal-dominant mutations in the PRNP gene that encodes
number of β-pleated sheets in their posttranslational confor- for the prion protein. Genetic CJD (gCJD), Gerstmann–
mation compared with the typical α-helices seen in the normal Straussler–Scheinker (GSS), and familial fatal insomnia
form of the protein (PrPc).1,2 The PrPsc conformation is partially (FFI) all fall into this category. Although the most notorious,
resistant to proteases and acts as a template for further the rarest forms of disease are acquired prion diseases and
misfolding of the normal PrPc to abnormal PrPsc.3 Each PrPsc include kuru, iatrogenic CJD (iaCJD), and variant CJD (vCJD).
converts a normal protein into an abnormal protein, leading to Human prion disease can be hard to diagnosis given the
exponential conversion over a rapid period. The conversion to variable phenotypic presentations, which we will outline in
abnormal protein and subsequent accumulation and aggrega- this article. Fortunately, newer testing techniques such as real-
tion of the PrPsc is associated with neuronal death and the time quaking-inducing conversion (RT-QuIC) and immunohis-
pathognomonic spongiform appearance (nerve cell loss, glio- tochemistry/western blot techniques for PrPsc deposition are
sis, and vacuolation) of the brain observed in prion disease.4,5 improving our diagnostic accuracy. When diagnosing human

Issue Theme Neuroinfectious Disease, Copyright © 2019 by Thieme Medical DOI https://doi.org/
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Arslanian, MD New York, NY 10001, USA. ISSN 0271-8235.
Tel: +1(212) 584-4662.
 Prion Disease Baldwin, Correll 429

Table 1 Common mimics of prion disease listed in order of level resulted as undetectable, securing a diagnosis of Wer-
most common to least common nicke syndrome.
Comments: this case is an example of rapidly progressive
Autoimmune/antibody mediated disorders dementia with myoclonus, oculomotor abnormalities, and
Alzheimer disease, frontal temporal dementia ataxia. The initial history, neurologic examination, and abnor-
Other dementia (Lewy body, vascular, unclassified) mal EEG were suspicious for a diagnosis of CJD. The presenta-
tion of progressive cognitive impairment, myoclonus, visual
Encephalitis, not specified
signs, and EEG findings met probable sCJD criteria based on the
Corticobasal degeneration, multiple systems atrophy World Health Organization (WHO) and University of Califor-
Infection (herpes virus, syphilis) nia, San Francisco (UCSF) diagnostic criteria (►Table 2). Wer-
Neoplastic nicke–Korsakoff syndrome is a well described CJD mimic, as
this case demonstrates. This patient was treated successfully
Metabolic/toxic
with intravenous (IV) thiamine replacement and had rapid and
sustained improvement in his mentation, gait, and movement
prion disease, it is important to be aware of the broad disorder. His neurologic examination returned to normal at
differential diagnoses that may fall into a rapidly progressive outpatient follow-up in 1 year. This case illustrates the impor-
dementia.5 Please refer to ►Table 1 for common CJD mimics. tance of neurologists to consider alternate reversible causes of

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This article will review the current information on sporadic, rapidly progressive dementia. General cerebrospinal fluid
genetic, and acquired human prion diseases and provide (CSF) findings in CJD are normal and clinicians should be clued
clinical vignettes highlighting the need for a thorough inves- into a CJD mimic with CSF pleocytosis, presence of oligoclonal
tigation to obtain an accurate and timely diagnosis. bands, or elevated immunoglobulin G synthetic rates.

Clinical Vignette 1 Clinical Vignette 2

A 59-year-old Caucasian male presented to the emergency A 79-year-old Caucasian male presented for evaluation of
department with 3 months of progressive cognitive decline 3 weeks of progressive cognitive decline, dysarthria, and
and gait instability. History was gathered from his wife who difficulty walking. Prior to presentation, the patient was
reported that over the past 3 months the patient’s person- independent in all activities of daily living without neuro-
ality drastically changed from jovial to irritable, impatient, logic deficits. Over the course of his hospitalization the
and angry. He also began to make up stories about where he patient’s mental status rapidly deteriorated and he also
had been and what he was going to do, such as stating he was developed abnormal movements in the right upper and
in another state the day prior. More recently, the wife lower extremity. Neurologic examination was significant
reported him having vivid hallucinations of people breaking for poor attention and concentration, severe deficits in
into the house, for which the patient responded by getting registration and recall, severe dysarthria and dysphagia,
out a gun to shoot them. The personality changes were and involuntary myoclonus of the right-upper and left-lower
accompanied by a change in sleep pattern, in which his extremities.
typical 6 hours of sleep per night was replaced with over MRI brain with and without contrast demonstrated gyri-
12 hours per night. During the 3 weeks prior to presentation, form increased T2 fluid-attenuated inversion recovery (FLAIR)
the patient had progressive worsening of his gait with signal and restricted diffusion in the gray matter of the left
repeated falls. Per his wife, his gait was unsteady and more than the right frontoparietal cortex with involvement of
wobbling as seen with intoxication. His neurologic examina- the left insular cortex (►Fig. 1). EEG demonstrated left hemi-
tion was significant for drowsiness, poor recall, decreased spheric intermittent epileptiform discharges. Laboratory and
attention and concentration, slow speech, and slow reaction CSF analysis was negative for metabolic, nutritional, toxic,
time. Cranial nerve examination was significant for discon- inflammatory, paraneoplastic, or neoplastic causes for his
jugate primary gaze with left eye abduction and decreased symptoms. CSF analysis was significant for positive 14–3-3
bilateral upgaze. There was nonfatiguing direction changing protein and elevated neuron specific enolase (NSE) and tau
nystagmus. There was severe bilateral appendicular ataxia proteins. The patient’s neurologic status continued to rapidly
with a wide-based gait and severe truncal ataxia. Intermit- decline, leading to death 3 weeks later.
tent large-amplitude negative myoclonic jerks were present Comment: this case illustrates a classic presentation of
in the extremities, most evident in outstretched arms. sCJD presenting with rapidly progressive dementia. The
The patient was admitted to the hospital for neurologic diagnosis in this case was supported by the MRI findings
evaluation. Initial magnetic resonance imaging (MRI) brain of cortical ribboning and the CSF findings of elevated 14–3-
with and without contrast was normal; however, his elec- 3, NSE, and tau proteins. Both the WHO and UCSF probable
troencephalogram (EEG) was significant for periodic multi- CJD criteria were met including rapid cognitive decline,
focal left-sided sharp waves. Initial laboratory results for HIV, myoclonus, pyramidal symptoms, and cerebellar findings
syphilis, Lyme disease, metabolic disorders, toxins, and with an abnormal EEG and MRI. Extensive workup to
heavy metals were negative. Lumbar puncture for infectious evaluate for other causes was negative, leading to a final
or neoplastic etiologies was also unremarkable. Vitamin B1 diagnosis of sCJD.

Seminars in Neurology Vol. 39 No. 4/2019

430 Prion Disease Baldwin, Correll

Table 2 Diagnostic criteria

World Health Organization (WHO) criteria (1998)a

Progressive dementia
Two of the following four signs/symptoms:
• Myoclonus
• Pyramidal/extrapyramidal symptoms
• Visual/cerebellar dysfunction
• Akinetic mutism
Typical EEG or elevated CSF protein 14–3-3 with total disease duration <2 years
Routine investigations should not suggest an alternative diagnosis
University of California, San Francisco (UCSF) criteria (2007)a
Rapid cognitive decline
Two of the following six signs/symptoms:
• Myoclonus
• Pyramidal/extrapyramidal dysfunction
• Visual dysfunction

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• Cerebellar dysfunction
• Akinetic mutism
• Focal cortical signs (e.g., neglect, aphasia, acalculia, apraxia)
Typical EEG and/or MRI
Other investigations should not suggest an alternative diagnosis
Amended diagnostic criteria for sporadic CJDb
Clinical symptoms
I. Progressive cognitive impairment
II. A. Myoclonus
B. Visual or cerebellar signs
C. Pyramidal or cerebellar signs
D. Akinetic mutism
Probable sCJD
I þ two of II and typical EEG
OR I þ two of II and typical MRI brain scan
OR I þ two of II and positive CSF 14–3-3
OR I þ one of II and positive CSF RT-QuiC
Possible sCJD
I þ two of II þ duration <2 years
And exclusion of other causes in complete diagnostic workup
Diagnostic algorithm for fatal familial insomniac
Obligatory organic sleep disturbances. If not yet clinically apparent, a polysomnograph has to be performed.
At least two of the following “CJD-like symptoms/signs”:
• Psychiatric (visual hallucinations, personality change, depression, aggressiveness, disinhibition, listlessness)
• Ataxia
• Visual
• Myoclonus
• Cognitive
At least one with the following “relatively disease-specific symptoms/signs”:
• Loss of weight with a cutoff point of >10 kg during the last 6 months
• Vegetative (hyperhidrosis, newly diagnosed arterial hypertension, tachycardia, obstipation, hyperthermia)
• Husky voice
Diagnostic criteria for variant CJDd
Definite: IA and neuropathological confirmation of vCJD.
Probable: I and four of the five criteria of II and IIIA and IIIB; or I and IVA.
Possible: I and four of the five criteria of II and IIIA.

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 Prion Disease Baldwin, Correll 431

Table 2 (Continued)

I A Progressive neuropsychiatric disorder

B Duration of illness >6 mo
C Routine investigations do not suggest alternative diagnosis
D No history of potential iatrogenic exposure
E No evidence of a familial form of TSE
II A Early psychiatric features
B Persistent painful sensory symptoms
C Ataxia
D Myoclonus or chorea or dystonia
E Dementia
III A EEG does not show the typical appearance of sporadic CJD in the early stages of illness
B Bilateral pulvinar high signal on MRI scan
IV A Positive tonsil biopsy

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Abbreviations: CJD, Creutzfeldt–Jakob disease; CSF, cerebrospinal fluid; EEG, electroencephalogram; MRI, magnetic resonance imaging; RT-QuIC,
real-time quaking-inducing conversion; sCJD, sporadic Creutzfeldt–Jakob disease; TSE, transmissible spongiform encephalopathy; vCJD, variant
Creutzfeldt–Jakob disease.
a
Revised from Geschwind MD. Rapidly progressive dementia. Continuum 2016;22:510–37.
b
Revised from Hermann P, Laux M, Glatzel M, et al. Validation and utilization of amended diagnostic criteria in Creutzfeldt–Jakob disease surveillance.
Neurology 2018;91:e331–e338.
c
Revised from Krasnianski A, Vartl M, Sanchez Juan PJ, et al. Fatal familial insomnia: clinical features and early identification. Ann Neurol 2008;63:658–661.
d
Revised from Heath CA, Cooper SA, Murray K, et al. Diagnosing variant Creutzfeldt–Jakob disease: a retrospective analysis of the first 150 cases in the
UK. J Neurol Neurosurg Psychiatry 2011;82:646–651.

Fig. 1 Case 2: axial MRI brain without contrast. Diffusion-weighted imaging (DWI) demonstrates restricted diffusion within the cortical ribbon
of bilateral temporal, parietal, and occipital lobes (A, B). FLAIR imaging demonstrates cortical hyperintensities in the left temporal lobe
corresponding with the areas of restricted diffusion (C). FLAIR, fluid-attenuated inversion recovery; MRI, magnetic resonance imaging.

Sporadic Human Prion Disease behavioral changes, visual impairment, spasticity, weakness,
and akinetic mutism.10 One notable sporadic variant has been
Sporadic Creutzfeldt–Jakob Disease referred to as the “Heidenhain variant” described in the 1950s.
sCJD is the most common human prion disease with an age of This variant of CJD may manifest as disturbed color perception,
onset between 50 and 80 years and has a mean survival of hallucinations, cortical blindness, or Anton syndrome. With this
6 months.6,7 The typical clinical features are rapidly progressive variant, dementia and other findings of typical CJD do not
dementia, ataxia, and myoclonus, but beyond this there is manifest until late in the disease course.11
significant phenotypic heterogeneity (►Table 3).8,9 Other clin- Attempts to better classify the phenotypes focus on
ical symptoms include language disturbances, neuropsychiatric molecular prion types 1 and 2 and the methionine (M) and

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 432

Table 3 Sporadic prion subtypes, clinical presentation, imaging findings, and diagnostic testing

Pathophysiology Clinical presentation Imaging EEG characteristics Diagnostic testing Special notes
characteristics
Sporadic CJD: MM1/MVI: diffuse Early rapid dementia, Diffusion-weighted 1–2 Hz periodic Mild elevation in CSF Affects ages 55–75 years;
Prion Disease

Seminars in Neurology
polymorphism in cortical, including myoclonus, ataxia, 25% images (DWIs) and sharp-wave (often protein. one-third of patients may
the prion gene, occipital, and visual disturbance apparent diffusion biphasic or triphasic) CSF biomarkers, including have constitutional
PRNP, at codon 129, thalamic coefficient with complexes—these NSE, t-tau, and S100β, CSF symptoms of fatigue,

Vol. 39
which can be either involvement restricted diffusion in appear late in disease 14–3-3 protein headache, vertigo, altered
methionine (M) the cortex, caudate, Real-time quaking-indu- sleep or eating patterns.
MM2: thalamic Insomnia, psychomotor
or valine (V) and/or putamen. cing conversion (RT-QuIC) 15% have cortical features
agitation, ataxia, and
Abnormal FLAIR amplification of CSF prion of apraxia, neglect.

No. 4/2019
cognitive changes
Baldwin, Correll

hyperintensities in the protein

MM2 cortical: Progressive dementia cortex (cortical Histopathology: nerve cell
all cortical layers ribboning) loss, gliosis, vacuolation
(formerly called
MV2 Early ataxia or cognitive
spongiform change), and
decline—slowly
PrPsc deposition, protease-
progressive
resistant PrPsc with immu-
VV1 Progressive dementia nohistochemistry or
VV2: cerebellar Rapidly progressive western blot
ataxia, with later
dementia
Variably VV Neuropsychiatric MRI with generalized Paucity of protease- Affects ages 50–70 years
protease-sensitive polymorphisms features and later atrophy resistant PrPsc when run with a longer disease
prionopathy cognitive decline and on western blot. duration (12–78 mo).
motor symptoms Neuropathologically: 50% with ataxia
spongiform changes and EEG, CSF, and MRI are not
MM Prominent parkinson-
gliosis. helpful for diagnosis
polymorphism ism and myoclonus
without psychiatric and
cognitive changes
MV Neuropsychiatric
polymorphism features and later
cognitive decline and
motor symptoms

Abbreviations: CJD, Creutzfeldt–Jakob disease; CSF, cerebrospinal fluid; EEG, electroencephalogram; FLAIR, fluid-attenuated inversion recovery; MRI, magnetic resonance imaging; NSE, neuron-specific enolase.

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 Prion Disease Baldwin, Correll 433

valine (V) 129 codon polymorphism.9,12,13 Researchers have tures pathological changes throughout all cortical layers,
described six subtypes of sCJD: MM1/MV1, MM2 cortical, while VV1 features changes in both the cortex and striatum.
MM2 thalamic, MV2, VV1, and VV2.14,15 MM1/MVI is con- While these subtypes are useful, it is important to note that
sidered the more classical form with diffuse cortical involve- they do not fully characterize the broad spectrum of this
ment, including occipital and thalamic. Clinical features disease, as up to 35% of subjects can show a mixed pheno-
include early dementia and myoclonus, typical periodic typic presentation with two or more PrPsc subtypes coloca-
sharp-wave complexes on EEG, and frequent visual distur- lized in these individuals.16,17
bances. VV2 has significant involvement of the subcortical Diagnostic testing including EEG, MRI, and CSF para-
structures, including the brainstem nuclei, with earlier clin- meters are useful to help secure a diagnosis of sCJD. As
ical signs of ataxia and later dementia. MV2 presents simi- described above, EEG may show typical 1 to 2 Hz periodic
larly to VV2 with early ataxia progressing to dementia often sharp-wave complexes but are often absent until late in the
with a longer disease duration. There is prominent cerebellar disease process.18,19 A helpful diagnostic feature commonly
involvement in this form. MM2 thalamic has spongiform seen in sCJD is the MRI finding of abnormal restricted
changes mostly isolated to the thalamus and inferior olives. It diffusion in the cortex, caudate, and/or putamen and abnor-
is associated with insomnia, psychomotor agitation, ataxia, mal FLAIR hyperintensities in the cortical ribbon.20–22 MRI
and cognitive changes. MM2 cortical and VV1 are both has variable sensitivity (92–96%) and specificity (93–94%) for
characterized by progressive dementia. MM2 cortical fea- the diagnosis of sCJD (►Fig. 2).5 CSF biomarkers including

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Fig. 2 Axial MRI brain without contrast. Diffusion-weighted imaging (DWI) demonstrates restricted diffusion within the cortical ribbon of bilateral frontal,
parietal, and occipital lobes (A, B). FLAIR imaging demonstrates cortical hyperintensities in the right frontal lobe and left parietal lobe which correspond with
the areas of restricted diffusion (C, D). FLAIR, fluid-attenuated inversion recovery; MRI, magnetic resonance imaging.

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434 Prion Disease Baldwin, Correll

14–3-3 protein, NSE, and total tau protein can be helpful cause familial CJD, most subjects have either octapeptide
when taken into clinical context to support the diagnosis of insertional mutations or point mutations at codons 102, 178,
sCJD; however, it is important to note that these are not 200, and 210.38,39 Compared with sCJD, gCJD subjects pre-
specific for disease and can be negative in many disease sent earlier and have a younger age of mortality, though
subtypes (►Tables 3 and 4).23–25 The more recently available disease duration is not significantly different.7,14,39 Interest-
test of RT-QuIC amplification of CSF prion protein has shown ingly, most patients with genetic prion disease have no
a sensitivity ranging from 77 to 92% and specificity of 99 to family history. Common presenting symptoms include
100% for sCJD, and is a promising test for many CJD dementia, ataxia, myoclonus, parkinsonism, and neuropsy-
subtypes.26–29 ►Table 2 shows the amended diagnostic chiatric symptoms.40,41 While periodic complexes on EEG,
criteria for CJD with the use of RT-QuIC amplification.29–31 diffusion-weighted abnormalities on MRI, and elevated 14–
3-3 can be helpful in diagnosing gCJD, they are less sensitive
Sporadic Fatal Insomnia than in the diagnosis of sCJD.15,39 Definitive diagnosis of gCJD
An extremely rare form of fatal insomnia has been described requires a clinical diagnosis of CJD with definitive or prob-
with no mutation identified and no family history to suggest able diagnosis of CJD in a first degree relative or neuropsy-
a genetic disorder.32,33 The clinical symptoms and thalamic chiatric disorder with a disease-specific PRNP gene mutation
pathology are identical to FFI (described below). Clinical (►Table 2).31
presentations include abnormalities in sleep, neuropsychia-

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tric changes, gait abnormalities, and movement disorders. Gerstmann–Straussler–Scheinker Syndrome
Neuropathological changes are most significant in the tha- GSS is the second most commonly inherited prion disorder. It
lamus and inferior olives.34 High levels of type 2 PrPsc were is caused by a variety of missense, nonsense, and octapeptide
found and all patients identified had MM homozygosity. repeat insertional mutations in the PRNP gene, with the most
frequently reported being a Pro102Leu mutation.42,43 The
Variably Protease-Sensitive Prionopathy disease has nearly 100% penetrance with clinical signs of
VPSPr, first described in 2008, is the most recent human prion cerebellar ataxia, tremor, speech and swallowing abnormal-
disease to be discovered.34,35 The initial cohort of patients all ities, pyramidal signs, parkinsonism, sensory dysesthesias,
contained VV polymorphisms at codon 129 of the PRNP gene and cognitive changes.44
and were significantly protease-sensitive. The later discovery Disease onset and duration are quite broad with onset
of patient with MM and MV codon 129 polymorphisms as well ranging from 20s to 80s and duration lasting as short as a few
as variability in protease sensitivity leads to the current term of months to >10 years.45 The specific mutation can help
variably protease-sensitive prionopathy. The western blot of narrow onset, duration, and clinical symptoms. Codon 129
this prion differs from CJD in size and structure. As the name polymorphisms can also play a role in the phenotype of this
implies, it is also relatively more sensitive to protease digestion disease. In the Pro102Leu mutation, MM homozygosity is
than other prion diseases. Symptom onset is typically in the associated with earlier onset compared with MV patients,
50s to 70s with a longer disease duration of 12 to 78 months.36 whereas apolipoprotein E carriers have later onset of symp-
The initial clinical description included only MM codon 129 toms.46 Neuropathologically, GSS is characterized by prion
polymorphism patients with predominant neuropsychiatric protein-immunopositive amyloid plaques and tau-immuno-
features and later cognitive decline and motor symptoms.35 positive neurofibrillary tangles with or without spongiform
The same authors later described a cohort of 15 patients with changes.47 This unique pathology has led to the term “dom-
other codon 129 polymorphisms, suggesting polymorphic- inantly inherited prion protein cerebral amyloidosis” rather
specific phenotypes in this disease as well.37 Patients with than the historical name of Gerstmann–Straussler–Scheinker
homozygous MM polymorphism were more likely to have disease.46 Diagnosis requires obtaining a thorough clinical
prominent parkinsonism and myoclonus without psychiatric and family history. MRI is not typically helpful· While EEG
and cognitive changes. On the other hand, the MV and VV and 14–3-3 can be helpful, they are neither sensitive nor
patients displayed much more prominent psychiatric and specific in this disease.43 RT-QuIC has shown a positive result
dementia symptoms with less parkinsonism and myoclonus. in 90% of patients when testing in the Pro102Leu mutation
At least half of the reported patients in all three polymorphism population.39,48 Western blot and genetic testing are the
groups also displayed ataxia. EEG, CSF 14–3-3, and MRI testing most definitive testing available.46
are less helpful for diagnosis compared with sCJD.34 Neuro-
pathologically, spongiform changes and gliosis are seen Familial Fatal Insomnia
throughout the cerebral cortex, basal ganglia, and thalamus, FFI is the third most common inherited prion disorder.
with smaller changes noted in the cerebellum (►Table 3).35,36 Despite this fact, it is still extremely rare with a risk of one
in 30 million people in the general population. It is associated
with a missense D178N mutation at codon 178 of the PRNP
Genetic Human Prion Diseases
gene.15,32,49 Interestingly, this same mutation in seen in
Genetic Creutzfeldt–Jakob Disease sCJD. Once again, codon 129 polymorphism plays a role,
Genetic, or familial, CJD is the most common form of inher- with the methionine polymorphism leading to an FFI phe-
ited prion disease and is largely indistinguishable from sCJD. notype and valine polymorphism leading to a CJD pheno-
While dozens of different mutations in the PRNP gene can type.50–52 Onset of FFI is between the 30s and 60s with a

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 Table 4 Genetic and acquired subtypes, clinical presentation, imaging findings, and diagnostic testing

Pathophysiology Clinical presentation Imaging characteris- EEG characteristics Diagnostic testing Special notes
tics
Genetic CJD Autosomal dominant Dementia, ataxia, High signal on the Periodic sharp-wave PRNP gene mutation Young age of presentation.
mutations in the PRNP myoclonus, parkinson- diffusion-weighted complexes (late disease 14–3-3, NSE, and t-tau Most common PRNP
gene ism, and neuropsychia- images (DWIs) localized finding) often are elevated; mutation worldwide,
tric symptoms to the cortex, caudate, RT-QuIC on CSF E200K.
and/or putamen
Gerstmann– Autosomal-dominant Progressive ataxia, Generalized slowing PRNP gene mutation Biomarkers not helpful.
Straussler– mutations in the PRNP dysarthria, dysphagia, Heterozygosity at the PRNP
Scheinker gene: over a dozen tremor, and motor codon 129 appears to be
syndrome mutations dysfunction protective.
Less cognitive symptoms
than other subtypes
Fatal Autosomal-dominant Abnormalities in sleep, FDG-PET hypometabo- Generalized slowing PRNP gene mutation; Dysautonomia common.
familial mutations in the PRNP neuropsychiatric lism in thalamic and sleep studies with Biomarkers and MRI are not
insomnia gene: a single PRNP changes, gait abnorm- cingulate regions reduction in total sleep helpful.
point mutation, D178N alities, and movement times, dream enactment,
with the cis codon disorders and disorganization of
129M typical sleep cycles
Kuru Acquired form from Progressive ataxia, PRNP polymorphism at
cannibalism in Papua dysarthria, dysphagia, codon 127 seems to be
New Guinea tremor, and motor protective.
dysfunction Less cognitive complaints
Iatrogenic Medical devices and Cerebellum with pro- Codon 129 polymorphisms
CJD transplanted human minent ataxia and later seem to effect susceptibil-
substances (growth cognitive impairment ity to and incubation time-
hormone, dura matter lines of iaCJD (5–42 years)
grafts) that have been
contaminated by PrPsc
Variant CJD Codon 129 polymorph- Initial neuropsychiatric MRI diffusion-weighted Brain biopsy, tonsil biopsy Bovine spongiform
ism, methionine symptoms that pro- imaging signal intensity encephalopathy
homozygous genotype. gress to ataxia, abnor- in the pulvinar region of prion present in lymphore-
Transmission directly mal movements, and the thalamus (pulvinar ticular system.
from animals to cognitive decline sign), which is seen in EEG, CSF, and RT-QuIC are
humans over 90% of subjects not helpful for diagnosis
Prion Disease

Abbreviations: CJD, Creutzfeldt–Jakob disease; CSF, cerebrospinal fluid; EEG, electroencephalogram; iaCJD, iatrogenic CJD; MRI, magnetic resonance imaging; NSE, neuron-specific enolase; RT-QuIC, real-time

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436 Prion Disease Baldwin, Correll

typical duration of 1 to 2 years.53 FFI is characterized by rapidly progressive dementia, ataxia, and myoclonus. Pre-
abnormal vigilance and sleep patterns. Subjects can initially sentations related to peripheral growth hormone injection
appear hypersomnolent with psychiatric and mood changes, tend to more strongly affect the cerebellum with prominent
which are associated with abnormal nocturnal sleep pat- ataxia and later cognitive impairment.73 iaCJD is more likely
terns that may not be recognized in the initial stage of the to occur in the younger population.74 Like the other prion
disease.54–57 As the disease progresses, polysomnography diseases, codon 129 polymorphisms seem to effect suscept-
shows reduction in typical sleep transients on EEG, reduction ibility to and incubation timelines of iaCJD.6,73,75 Fortu-
in total sleep times, dream enactment, and disorganization nately, the incidence of iaCJD has significantly decreased in
of typical sleep cycles.58–60 Eventually, subjects experience the last decade with only rare new diagnoses likely due to
prolonged periods of abnormal stupor. Autonomic abnorm- long incubation periods.70 This improvement can be linked to
alities with hypertension, pyrexia, and tachycardia as well as changes in medical practice with better infectivity preven-
movement disorders and gait changes can also be present.61 tion and use of recombinant growth hormone and autolo-
Overall metabolic demand is heightened with resultant gous or synthetic dura mater grafts (►Table 4).
cachexia. While MRI findings are nonspecific showing dif-
fuse atrophy, positron-emission tomography (PET) scans Variant Creutzfeldt–Jakob Disease
show prominent thalamic hypometabolism and milder The first cases of vCJD were described in 1996.76 They were
decreases in corpus callosum metabolism.62,63 CSF 14–3-3 eventually found to be transmitted through ingestion of

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has low sensitivity in FFI. Neuronal loss and gliosis are severe cattle found to have bovine spongiform encephalopathy. To
in the anterior ventral and mediodorsal nuclei of the thala- date, over 225 cases have been reported worldwide with the
mus as well as the inferior olives, with spongiform changes largest number reported in the United Kingdom.77,78 With
noted very late in the disease course.54,64,65 While genetic regard to codon 129 polymorphism, only the methionine
testing is needed for the diagnosis of this disorder, various homozygous genotype has been identified in vCJD subjects,
schema have been proposed to help with the diagnosis and suggesting this genotype is susceptible to this disease.79 vCJD
establish which patients should undergo definitive genetic typically presents with initial neuropsychiatric symptoms
testing. These algorithms, such as the one proposed by that progress to ataxia, abnormal movements, and cognitive
Krasnianski et al66 (►Table 2), focus on clinical signs and decline with typical duration of over a year.70–82 EEG
polysomnography. abnormalities and CSF 14–3-3 are not very sensitive.83,84
CSF RT-QuIC testing has been negative.10 The most sensitive
finding is MRI diffusion-weighted imaging signal intensity in
Acquired Human Prion Diseases
the pulvinar region of the thalamus (pulvinar sign), which is
Kuru seen in over 90% of subjects.85,86 While definite diagnosis of
Kuru, first described in the 1950s, was an epidemic disease of vCJD requires brain biopsy, the abnormal prion in vCJD can be
the Fore tribe of Papua New Guinea. This spongiform ence- found in lymphoreticular tissue, leading to tonsillar biopsy
phalopathy had a typical duration of 1 year characterized by being the location of choice for tissue diagnosis.87 Diagnostic
progressive ataxia, dysarthria, dysphagia, tremor, and motor criteria for definite and probable vCJD using clinical presen-
dysfunction with less cognitive dementia symptoms than tation, lack of EEG periodic complexes, and pulvinar high-
other human prion diseases. The disease was determined to signal MRI (►Table 2) have been shown to have high sensi-
be caused by ritualistic endocannibalism, with women and tivity and specificity.82,88,89 With better food production
children more highly affected as they typically prepared and methods, the initial epidemic of this disease has declined,
consumed the brains.67 Spongiform changes were often with only two reported deaths from this disease in the
severe in the cerebellum, but also seen throughout the United Kingdom since 2012 (►Table 4).90
cerebral cortex, basal ganglia, and thalamus. Heterozygosity
at the PRNP codon 129 appears to be protective as it was
Conclusions
associated with significantly longer incubation periods.68
Fortunately, kuru is now extinct following the decline of Human prion diseases, while rare, are devastating and fatal
the Fore endocannibalism ritual in the 1960s.10 neurological diseases with no current treatment options.
Despite this fact, they are still important to diagnose given
Iatrogenic Creutzfeldt–Jakob Disease the potential genetic ramifications and risk of acquired
iaCJD is caused by the use of medical devices and trans- transmission. sCJD is by far the most likely to be observed
planted human substances that have been contaminated by in clinical practice, and recent improvements in diagnostic
PrPsc. The initial reports occurred in the 1970s in the setting testing with EEG, MRI, and RT-QuIC have dramatically
of transplantation of contaminated corneas. Later larger increased sensitivity and specificity for the diagnosis of
sources of outbreaks occurred due to contaminated growth this disease. Fortunately, the acquired prion diseases (kuru,
hormone and dura mater grafts.69,70 There have even been iaCJD, and vCJD), which are the rarest yet in many ways the
rare cases of vCJD passed through contaminated blood most concerning forms of human prion disease, have become
transfusion.71,72 With contamination that occurs near the nearly nonexistent thanks to better preventative measures.
brain due to dura mater grafts and intracranial surgical Nonetheless, it is still important to be vigilant for cases with
devices, the clinical presentation is similar to sCJD with prolonged incubation periods or new variants of prion

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 Prion Disease Baldwin, Correll 437

disease transmitted from animals. With regard to the less type and co-occurrence of PrPSc types: an updated classification.
frequent sporadic and genetic human prior diseases (gCJD, Acta Neuropathol 2009;118(05):659–671
GSS, FFI, VPSPr, etc.), diagnostic testing has variable sensi- 18 Steinhoff BJ, Zerr I, Glatting M, Schulz-Schaeffer W, Poser S,
Kretzschmar HA. Diagnostic value of periodic complexes in
tivity, and RT-QuIC is not validated in these diseases. Hence,
Creutzfeldt-Jakob disease. Ann Neurol 2004;56(05):702–708
it is important to be aware of the typical clinical presenta- 19 Collins SJ, Sanchez-Juan P, Masters CL, et al. Determinants of diag-
tions and maintain a high clinical suspicion. When the more nostic investigation sensitivities across the clinical spectrum of
infrequent sporadic and genetic prion diseases are sus- sporadic Creutzfeldt-Jakob disease. Brain 2006;129(Pt 9):2278–2287
pected, and mimics have been excluded, either genetic 20 Meissner B, Kallenberg K, Sanchez-Juan P, et al. MRI lesion profiles
in sporadic Creutzfeldt-Jakob disease. Neurology 2009;72(23):
testing or autopsy neuropathological findings will be needed
1994–2001
for diagnosis.
21 Vitali P, Maccagnano E, Caverzasi E, et al. Diffusion-weighted MRI
hyperintensity patterns differentiate CJD from other rapid
Conflict of Interest dementias. Neurology 2011;76(20):1711–1719
None. 22 Gaudino S, Gangemi E, Colantonio R, et al. Neuroradiology of
human prion diseases, diagnosis and differential diagnosis. Radiol
Med (Torino) 2017;122(05):369–385
23 Zerr I, Pocchiari M, Collins S, et al. Analysis of EEG and CSF 14-3-3
References proteins as aids to the diagnosis of Creutzfeldt-Jakob disease.
1 Prusiner SB. Novel proteinaceous infectious particles cause scra- Neurology 2000;55(06):811–815

Downloaded by: Georgetown University Medical Center. Copyrighted material.

pie. Science 1982;216(4542):136–144 24 Green A, Sanchez-Juan P, Ladogana A, et al. CSF analysis in patients
2 Pan KM, Baldwin M, Nguyen J, et al. Conversion of alpha-helices with sporadic CJD and other transmissible spongiform encepha-
into beta-sheets features in the formation of the scrapie prion lopathies. Eur J Neurol 2007;14(02):121–124
proteins. Proc Natl Acad Sci U S A 1993;90(23):10962–10966 25 Hamlin C, Puoti G, Berri S, et al. A comparison of tau and 14-3-3
3 Prusiner SB. Prions. Proc Natl Acad Sci U S A 1998;95(23): protein in the diagnosis of Creutzfeldt-Jakob disease. Neurology
13363–13383 2012;79(06):547–552
4 Glatzel M, Stoeck K, Seeger H, Lührs T, Aguzzi A. Human prion 26 McGuire LI, Peden AH, Orrú CD, et al. Real time quaking-induced
diseases: molecular and clinical aspects. Arch Neurol 2005;62(04): conversion analysis of cerebrospinal fluid in sporadic Creutzfeldt-
545–552 Jakob disease. Ann Neurol 2012;72(02):278–285
5 Geschwind MD. Rapidly progressive dementia. Continuum (Minneap 27 Zanusso G, Monaco S, Pocchiari M, Caughey B. Advanced tests for
Minn) 2016;22( 2 Dementia):510–537 early and accurate diagnosis of Creutzfeldt-Jakob disease. Nat Rev
6 Ladogana A, Puopolo M, Croes EA, et al. Mortality from Creutz- Neurol 2016;12(06):325–333
feldt-Jakob disease and related disorders in Europe, Australia, and 28 Foutz A, Appleby BS, Hamlin C, et al. Diagnostic and prognostic
Canada. Neurology 2005;64(09):1586–1591 value of human prion detection in cerebrospinal fluid. Ann Neurol
7 Takada LT, Kim MO, Metcalf S, Gala II, Geschwind MD. Prion 2017;81(01):79–92
disease. In: Geschwin DH, Paulson HL, Klein C, eds. Handbook of 29 Hermann P, Laux M, Glatzel M, et al. Validation and utilization of
Clinical Neurology, 148. Amsterdam, Elsevier; 2018: 441–464 amended diagnostic criteria in Creutzfeldt-Jakob disease surveil-
8 Will RG. Clinical features of human prion diseases. In: Asbury AK, lance. Neurology 2018;91(04):e331–e338
McKhann GM, McDonald WI, et al. eds. Diseases of the Nervous 30 Bizzi A, Peoc’h K. Amended diagnostic protocol increases the early
System: Clinical Neuroscience and Therapeutic Principles. 3rd ed. diagnosis of sporadic Creutzfeldt-Jakob disease. Neurology 2018;
Cambridge: Cambridge University Press; 2002:1716–1727 91(04):155–156
9 Puoti G, Bizzi A, Forloni G, Safar JG, Tagliavini F, Gambetti P. 31 Center for Disease Control and Prevention. CDC’s diagnostic
Sporadic human prion diseases: molecular insights and diagnosis. criteria for Creutzfeldt–Jakob Disease (CJD), 2018. Available at:
Lancet Neurol 2012;11(07):618–628 https://www.cdc.gov/prions/cjd/diagnostic-criteria.html.
10 Will RG, Ironside JW. Sporadic and infectious human prion diseases. Updated September 17, 2018. Accessed October 29, 2018
In: Prusiner SB. ed. Prion Biology and Diseases, 2nd ed. Cold Spring 32 Mastrianni JA, Nixon R, Layzer R, et al. Prion protein conformation
Harbor, NY: Cold Spring Harbor Laboratory Press; 2004:73–93 in a patient with sporadic fatal insomnia. N Engl J Med 1999;340
11 Kropp S, Schulz-Schaeffer WJ, Finkenstaedt M, et al. The Heiden- (21):1630–1638
hain variant of Creutzfeldt-Jakob disease. Arch Neurol 1999;56 33 Montagna P, Gambetti P, Cortelli P, Lugaresi E. Familial and
(01):55–61 sporadic fatal insomnia. Lancet Neurol 2003;2(03):167–176
12 Parchi P, Castellani R, Capellari S, et al. Molecular basis of 34 Scaravilli F, Cordery RJ, Kretzschmar H, et al. Sporadic fatal
phenotypic variability in sporadic Creutzfeldt-Jakob disease. insomnia: a case study. Ann Neurol 2000;48(04):665–668
Ann Neurol 1996;39(06):767–778 35 Gambetti P, Dong Z, Yuan J, et al. A novel human disease with
13 Parchi P, Capellari S, Chen SG, et al. Typing prion isoforms. Nature abnormal prion protein sensitive to protease. Ann Neurol 2008;63
1997;386(6622)232–234 (06):697–708
14 Parchi P, Giese A, Capellari S, et al. Classification of sporadic 36 Head MW, Yull HM, Ritchie DL, et al. Variably protease-sensitive
Creutzfeldt-Jakob disease based on molecular and phenotypic prionopathy in the UK: a retrospective review 1991-2008. Brain
analysis of 300 subjects. Ann Neurol 1999;46(02):224–233 2013;136(Pt 4):1102–1115
15 Gambetti P, Kong Q, Zou W, Parchi P, Chen SG. Sporadic and 37 Zou WQ, Puoti G, Xiao X, et al. Variably protease-sensitive
familial CJD: classification and characterisation. Br Med Bull prionopathy: a new sporadic disease of the prion protein. Ann
2003;66(01):213–239 Neurol 2010;68(02):162–172
16 Parchi P, Capellari S, Roncaroli F, et al. Co-occurrence of type 1 and 38 Capellari S, Cardone F, Notari S, et al. Creutzfeldt-Jakob disease
type 2 PrPres in sporadic Creutzfeldt-Jakob disease: prevalence, associated with the R208H mutation in the prion protein gene.
intracerebral variability and phenotypic correlations. Neurol Sci Neurology 2005;64(05):905–907
2001;22:S116 39 Kovács GG, Puopolo M, Ladogana A, et al; EUROCJD Genetic prion
17 Parchi P, Strammiello R, Notari S, et al. Incidence and spectrum of disease: the EUROCJD experience. Hum Genet 2005;118(02):
sporadic Creutzfeldt-Jakob disease variants with mixed pheno- 166–174

Seminars in Neurology Vol. 39 No. 4/2019

438 Prion Disease Baldwin, Correll

40 Meiner Z, Gabizon R, Prusiner SB. Familial Creutzfeldt-Jakob 61 Cortelli P, Parchi P, Contin M, et al. Cardiovascular dysautonomia
disease. Codon 200 prion disease in Libyan Jews. Medicine in fatal familial insomnia. Clin Auton Res 1991;1(01):15–21
(Baltimore) 1997;76(04):227–237 62 Perani D, Cortelli P, Lucignani G, et al. [18F]FDG PET in fatal
41 Kovács GG, Trabattoni G, Hainfellner JA, Ironside JW, Knight RS, familial insomnia: the functional effects of thalamic lesions.
Budka H. Mutations of the prion protein gene phenotypic spec- Neurology 1993;43(12):2565–2569
trum. J Neurol 2002;249(11):1567–1582 63 Cortelli P, Perani D, Montagna P, et al. Pre-symptomatic diagnosis
42 Arata H, Takashima H, Hirano R, et al. Early clinical signs and in fatal familial insomnia: serial neurophysiological and 18FDG-
imaging findings in Gerstmann-Sträussler-Scheinker syndrome PET studies. Brain 2006;129(Pt 3):668–675
(Pro102Leu). Neurology 2006;66(11):1672–1678 64 Manetto V, Medori R, Cortelli P, et al. Fatal familial insomnia:
43 Webb TE, Poulter M, Beck J, et al. Phenotypic heterogeneity and clinical and pathologic study of five new cases. Neurology 1992;
genetic modification of P102L inherited prion disease in an 42(02):312–319
international series. Brain 2008;131(Pt 10):2632–2646 65 Schmitz M, Dittmar K, Llorens F, et al. Hereditary human prior
44 Kong Q, Surewicz WK, Petersen RB, et al. Inherited prion diseases. diseases: an update. Mol Neurobiol 2017;54(06):4138–4149
In: Prusiner SB. ed. Prion Biology and Diseases, 2nd ed. Cold Spring 66 Krasnianski A, Sanchez Juan P, Ponto C, et al. A proposal of new
Harbor, NY: Cold Spring Harbor Laboratory Press; 2004:673–775 diagnostic pathway for fatal familial insomnia. J Neurol Neuro-
45 Piccardo P, Dlouhy SR, Lievens PM, et al. Phenotypic variability of surg Psychiatry 2014;85(06):654–659
Gerstmann-Sträussler-Scheinker disease is associated with prion 67 Liberski PP, Sikorska B, Lindenbaum S, et al. Kuru: genes, cannibals
protein heterogeneity. J Neuropathol Exp Neurol 1998;57(10): and neuropathology. J Neuropathol Exp Neurol 2012;71(02):
979–988 92–103
46 Ghetti B, Piccardo P, Zanusso G. Dominantly inherited prion 68 Collinge J, Whitfield J, McKintosh E, et al. Kuru in the 21st

Downloaded by: Georgetown University Medical Center. Copyrighted material.

protein cerebral amyloidosis – a modern view of Gerstmann- century–an acquired human prion disease with very long incuba-
Straussler-Scheinker. In: Pocchiari M, Manson J, eds. Handbook of tion periods. Lancet 2006;367(9528):2068–2074
Clinical Neurology. Amsterdam: Elsevier; 2018:243–269 69 Brown P, Preece M, Brandel JP, et al. Iatrogenic Creutzfeldt-Jakob
47 Masters CL, Gajdusek DC, Gibbs CJ Jr. Creutzfeldt-Jakob disease disease at the millennium. Neurology 2000;55(08):1075–1081
virus isolations from the Gerstmann-Sträussler syndrome with an 70 Brown P, Brandel JP, Sato T, et al. Iatrogenic Creutzfeldt-Jakob
analysis of the various forms of amyloid plaque deposition in the disease, final assessment. Emerg Infect Dis 2012;18(06):
virus-induced spongiform encephalopathies. Brain 1981;104 901–907
(03):559–588 71 Hewitt PE, Llewelyn CA, Mackenzie J, Will RG. Creutzfeldt-Jakob
48 Sano K, Satoh K, Atarashi R, et al. Early detection of abnormal disease and blood transfusion: results of the UK Transfusion
prion protein in genetic human prion diseases now possible using Medicine Epidemiological Review study. Vox Sang 2006;91(03):
real-time QUIC assay. PLoS One 2013;8(01):e54915 221–230
49 Medori R, Tritschler HJ, LeBlanc A, et al. Fatal familial insomnia, a 72 Seed CR, Hewitt PE, Dodd RY, Houston F, Cervenakova L. Creutz-
prion disease with a mutation at codon 178 of the prion protein feldt-Jakob disease and blood transfusion safety. Vox Sang 2018;
gene. N Engl J Med 1992;326(07):444–449 113(03):220–231
50 Goldfarb LG, Petersen RB, Tabaton M, et al. Fatal familial insomnia 73 Rudge P, Jaunmuktane Z, Adlard P, et al. Iatrogenic CJD due to
and familial Creutzfeldt-Jakob disease: disease phenotype deter- pituitary-derived growth hormone with genetically determined
mined by a DNA polymorphism. Science 1992;258(5083):806–808 incubation times of up to 40 years. Brain 2015;138(Pt 11):3386–3399
51 Monari L, Chen SG, Brown P, et al. Fatal familial insomnia and 74 Holman RC, Belay ED, Christensen KY, et al. Human prion diseases
familial Creutzfeldt-Jakob disease: different prion proteins deter- in the United States. PLoS One 2010;5(01):e8521
mined by a DNA polymorphism. Proc Natl Acad Sci U S A 1994;91 75 Brandel JP, Preece M, Brown P, et al. Distribution of codon 129
(07):2839–2842 genotype in human growth hormone-treated CJD patients in
52 Johnson RT. Prion diseases. Lancet Neurol 2005;4(10):635–642 France and the UK. Lancet 2003;362(9378):128–130
53 Harder A, Gregor A, Wirth T, et al. Early age of onset in fatal 76 Will RG, Ironside JW, Zeidler M, et al. A new variant of Creutzfeldt-
familial insomnia. Two novel cases and review of the literature. Jakob disease in the UK. Lancet 1996;347(9006):921–925
J Neurol 2004;251(06):715–724 77 Diack AB, Head MW, McCutcheon S, et al. Variant CJD. 18 years of
54 Lugaresi E, Medori R, Montagna P, et al. Fatal familial insomnia and research and surveillance. Prion 2014;8(04):286–295
dysautonomia with selective degeneration of thalamic nuclei. N 78 National CJD Research & Surveillance Unit Data and Reports.
Engl J Med 1986;315(16):997–1003 Latest NCJDSRU CJD Monthly Statistics. Available at: https://
55 Gallassi R, Morreale A, Montagna P, Gambetti P, Lugaresi E. “Fatal www.cjd.ed.ac.uk/sites/default/files/figs.pdf. Accessed October
familial insomnia”: neuropsychological study of a disease with 15, 2018
thalamic degeneration. Cortex 1992;28(02):175–187 79 Pocchiari M, Puopolo M, Croes EA, et al. Predictors of survival in
56 Gallassi R, Morreale A, Montagna P, et al. Fatal familial insomnia: sporadic Creutzfeldt-Jakob disease and other human transmissible
behavioral and cognitive features. Neurology 1996;46(04):935–939 spongiform encephalopathies. Brain 2004;127(10):2348–2359
57 Krasnianski A, Bartl M, Sanchez Juan PJ, et al. Fatal familial 80 Zeidler M, Johnstone EC, Bamber RW, et al. New variant Creutz-
insomnia: clinical features and early identification. Ann Neurol feldt-Jakob disease: psychiatric features. Lancet 1997;350
2008;63(05):658–661 (9082):908–910
58 Tinuper P, Montagna P, Medori R, et al. The thalamus participates 81 Zeidler M, Stewart GE, Barraclough CR, et al. New variant Creutz-
in the regulation of the sleep-waking cycle. A clinico-pathological feldt-Jakob disease: neurological features and diagnostic tests.
study in fatal familial thalamic degeneration. Electroencephalogr Lancet 1997;350(9082):903–907
Clin Neurophysiol 1989;73(02):117–123 82 Heath CA, Cooper SA, Murray K, et al. Diagnosing variant
59 Portaluppi F, Cortelli P, Avoni P, et al. Progressive disruption of the Creutzfeldt-Jakob disease: a retrospective analysis of the first
circadian rhythm of melatonin in fatal familial insomnia. J Clin 150 cases in the UK. J Neurol Neurosurg Psychiatry 2011;82(06):
Endocrinol Metab 1994;78(05):1075–1078 646–651
60 Sforza E, Montagna P, Tinuper P, et al. Sleep-wake cycle abnorm- 83 Green AJ, Thompson EJ, Stewart GE, et al. Use of 14-3-3 and other
alities in fatal familial insomnia. Evidence of the role of the brain-specific proteins in CSF in the diagnosis of variant Creutz-
thalamus in sleep regulation. Electroencephalogr Clin Neurophy- feldt-Jakob disease. J Neurol Neurosurg Psychiatry 2001;70(06):
siol 1995;94(06):398–405 744–748

Seminars in Neurology Vol. 39 No. 4/2019

 Prion Disease Baldwin, Correll 439

84 Binelli S, Agazzi P, Giaccone G, et al. Periodic electroencephalo- 87 Hill AF, Butterworth RJ, Joiner S, et al. Investigation of variant
gram complexes in a patient with variant Creutzfeldt-Jakob Creutzfeldt-Jakob disease and other human prion diseases with
disease. Ann Neurol 2006;59(02):423–427 tonsil biopsy samples. 1999;353(9148):183–189
85 Zeidler M, Sellar RJ, Collie DA, et al. The pulvinar sign on magnetic 88 Will RG, Zeidler M, Stewart GE, et al. Diagnosis of new variant
resonance imaging in variant Creutzfeldt-Jakob disease. Lancet Creutzfeldt-Jakob disease. Ann Neurol 2000;47(05):575–582
2000;355(9213):1412–1418 89 Heath CA, Cooper SA, Murray K, et al. Validation of diagnostic
86 Collie DA, Summers DM, Sellar RJ, et al. Diagnosing variant criteria for variant Creutzfeldt-Jakob disease. Ann Neurol 2010;67
Creutzfeldt-Jakob disease with the pulvinar sign: MR imaging (06):761–770
findings in 86 neuropathologically confirmed cases. AJNR Am J 90 Will B. Variant CJD: where has it gone, or has it? Pract Neurol
Neuroradiol 2003;24(08):1560–1569 2010;10(05):250–251

Downloaded by: Georgetown University Medical Center. Copyrighted material.

Seminars in Neurology Vol. 39 No. 4/2019