REVIEW

CJD mimics and chameleons

Simon Mead, Peter Rudge

NHS National Prion Clinic, ABSTRACT pinpoint. Nevertheless, the concept of

National Hospital for Neurology Rapidly progressive dementia mimicking RPD is sensible, as it differentiates a set
and Neurosurgery, University
College London Hospitals NHS
Creutzfeldt–Jakob disease (CJD) is a relatively of syndromes and diagnoses that are, to a
Foundation Trust, London, UK rare presentation but a rewarding one to significant degree, distinct from those
become familiar with, as the potential diagnoses seen in the differential diagnosis of
Correspondence to range from the universally fatal to the completely common neurodegenerative disorders.
Professor Simon Mead, NHS
reversible. Patients require urgent decisions about CJD is associated with progression from
National Prion Clinic, National
Hospital for Neurology and assessment and investigation and have quickly normal function to death in under a year
evolving needs for treatments and support,
Neurosurgery, University College in approximately 90% of patients.5
London Hospitals NHS through symptom management and end-of-life
Foundation Trust, Queen Square,
Those reporting the history of patient
care in most cases. We have based this
London WC1N 3BG, UK; s. with CJD witness a cognitive and neuro-
pragmatic review on the experiences of a
[email protected] logical disorder leading to obvious
specialist prion referral centre in the UK, which,
unsurprisingly, is strongly biased towards seeing
progressive changes in everyday functions
Accepted 21 December 2016
Published Online First patients with CJD. Cases eventually proven not over periods of weeks or a month’s dura-
2 February 2017 to have prion disease might be described as tion, rather than noticing change over 6
‘CJD-mimics’; being referred from UK months to a year, which would be more
neurologists, these are the most challenging typical of a common dementia.
cases. CJD in its classical presentation is very There are no population studies of
rarely mimicked; however, it is highly RPD, and the experience in prion disease
heterogeneous, and atypical forms can mimic referral centres is likely to be substantially
virtually all common neurodegenerative different from the reality in primary and
syndromes. Warning features of a mimic include secondary care centres. Referral patterns
generalised seizures, hyponatraemia, fever, a vary considerably between countries,
facial movement disorder, a normal neurological based on historical factors and the serv-
examination and a modestly rapid presentation. ices provided by a specialist clinic. The
Contrast-enhancing lesions or MRI signal proportion of RPD patients eventually
hyperintensity outside the striatum, thalamus or diagnosed as prion disease varies in
cortex and a cerebrospinal fluid pleocytosis are
reports from 20% to the large majority
key investigation pointers to a CJD mimic.
(>80% in our case).1 6 This variation
relates to the considerable amount of
INTRODUCTION filtering done by local physicians before
Rapidly progressive dementia (RPD) is a patients are referred.
clinical syndrome that is not well defined Undoubtedly, many patients with rapid
and little studied. There are some excel- changes in their function and dementia
lent and comprehensive reviews,1–3 have a delirium, recognised by acute or
including by Murray,4 in this journal. The subacute deficits in attention; concentra-
archetypal diagnosis is Creutzfeldt–Jakob tion and orientation; a cognitive disorder
disease (CJD), and most experiences have and an explanatory toxic, metabolic or
been reported from specialist prion infective physiological problem (Diag-
disease referral centres and from a small nostic and Statistical Manual of Mental
number of specialist cognitive clinics. Disorders, Fifth edition). A key feature
Some have used a definition of a diag- here is the identification through history
nosis of dementia within 1 year of taking of a pre-existing and more insidi-
symptom onset, although this is problem- ously progressive cognitive disorder.
atic, as initial symptoms are often non- Similarly, multiple strokes, viral encepha-
To cite: Mead S, Rudge P. specific and merge with highly prevalent litis and brain tumours might meet our
Pract Neurol complaints in the population; therefore, working definition of RPD but are
2017;17:113–121.
the exact time of onset is hard to readily identified at initial assessments.

Mead S, Rudge P. Pract Neurol 2017;17:113–121. doi:10.1136/practneurol-2016-001571 113

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Here, we focus more on particularly difficult cases more CJD-specific symptoms are diverse and lead to
that have made it through the filters of local physi- distinct initial differentials (figure 1). In half of
cians and were therefore challenging to differentiate the cases, the more typical picture of CJD is present
from CJD. on exploring the history further or reveals itself
during examination or shortly after an initial assess-
ment. In its classical presentation (figure 1), the
What are the phenotypes of CJD?
clinical syndrome of CJD comprises an RPD (wide-
Prion diseases are highly heterogeneous disorders
spread cognitive domains: memory, dysexecutive,
with distinct causes, clinical features and durations.7
behaviour disturbance, abnormalities of calculation
Most commonly (~85% of the annual incidence), the
and spelling and dysphasia9) associated with cerebellar
cause is unknown, termed ‘sporadic’ CJD. Acquired
ataxia, myoclonus, pyramidal and extrapyramidal
causes are sometimes immediately obvious, such as
motor signs and often evidence of a disorder of
treatment with cadaveric pituitary-derived human
growth hormone (before 1985), or using cadaver- higher visual functions. Aside from rapid forms of
derived dura mater to repair defects during neurosur- common neurodegenerative diseases, the main differ-
gery (before 1992). Variant CJD, caused by the entials are limbic, corticosteroid-responsive or
human transmission of the cattle prion disease bovine infective encephalitis, paraneoplastic conditions,
spongiform encephalopathy, involved much more Wernicke’s encephalopathy, neurosarcoidosis, hypo-
widespread exposure of the UK and other popula- thyroidism, non-convulsive status epilepticus, hypoxic
tions, although specific at-risk groups, such as those encephalopathy, a toxic/metabolic syndrome or a
patients who received a blood transfusion derived functional disorder.
from a donor who later developed variant CJD, are Atypical presentations cause more difficulty,
identifiable. These individuals may have been notified including pure cognitive presentations (~15%) that
of their increased risk status. The recognition of might be mistaken for rapid forms of Alzheimer’s
genetic causes may be prompted by evidence of a disease, frontotemporal dementia or dementia with
familial disorder; however, family history is often Lewy bodies; ataxic presentations (~10%) are often
negative in definite cases, because for example, associated with acquired CJD and might be mistaken
several causal genetic mutations typically manifest in for disorders of the cerebellum and its brainstem
old age and are partially penetrant. The range of clin- connections, including vascular, neoplastic, paraneo-
ical phenotypes of inherited prion disease extends far plastic or inflammatory conditions. The visual
beyond RPD, and investigation results are much less presentation or Heidenhain variant (~5%) is particu-
specific than for CJD; consequently, our practice for larly distressing for patients with hemianopia or
all undiagnosed cases that we see is to screen the only scotoma, misperceptions, hallucinations, distortions
gene that contains mutations that cause inherited and palinopsia. Progression tends to be rapid, even
prion disease, the prion protein gene (PRNP). relative to other presentations of CJD. The condition
In advanced stages, all prion diseases look very often presents to ophthalmologists or optometrists
similar: the patients have akinetic mutism. They lie as an ocular disorder, for example, suspected cata-
still in a hospital bed, often have eyes open but not ract.10 Psychiatric presentations (~5%) also occur;
tracking a face moving across the visual field,
thus, in variant CJD, depression and personality
have occasional spontaneous or startle-related myoc-
change are common early in the evolution of the
lonus, are incontinent and silent or make only
disease, while paranoia, visual hallucinations and
incomprehensible noises. If swallowing is retained and
aggression occasionally occur during the initial phase
depending on other aspects of supportive care,
of the disease in sporadic CJD, suggesting a primary
patients can survive in this state for several weeks,
even years, with tube feeding. In sporadic CJD, psychiatric diagnosis of psychosis or depression.11
patients deteriorate to this state as rapidly as in a few Very rare presentations include those that mimic a
weeks in the fastest cases or over a year in 10%.8 In stroke (~2%) or corticobasal syndrome (~2%). The
the vast majority of cases, patients are admitted for thalamic presentation (~2%) includes sleep
urgent inpatient assessment following the first inter- disturbance and distal pain and may include abnor-
view in the hospital, and investigations leading to malities of the autonomic nervous system:
diagnosis are organised in a single hospital stay. Many palpitations, temperature dysregulation, hypertension
patients are discharged from this first hospital stay or postural hypotension. This presentation is well
into 24-hour care or a hospice. known as fatal familial insomnia and is typically asso-
The first symptoms of sporadic CJD are usually ciated with the inherited prion disease caused by the
non-specific: headache, malaise, cough, dizziness D178N missense mutation in PRNP, usually linked to
and change in personality, mood or memory. The first a methionine allele at polymorphic codon 129;

114 Mead S, Rudge P. Pract Neurol 2017;17:113–121. doi:10.1136/practneurol-2016-001571

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Figure 1 Creutzfeldt-Jakob disease (CJD) clinical features and progression. The boxes describe clinical variants of CJD. The width of
each arrow relates to the proportion of cases with the presentation. Patients with CJD become more similar over time, and almost all
enter a phase of ‘akinetic mutism’ before death.

however, there have been cases without this or any proteins, and the real-time quaking-induced conver-
gene mutation. sion assay (RT-QUIC) (table 1).
While we list the obvious conditions that a neurolo-
gist would consider after an initial assessment, it is
Investigation features of CJD
usually clear that the patient warrants urgent and
Imaging
comprehensive investigation. At an initial assessment,
MR imaging of brain is an extremely useful investiga-
the rapidity of progression may not be evident, either
tion in CJD, because it is readily available at short
because there is no witness account available or
notice and non-invasive.12 Classical abnormalities
because comorbidities or prodromal symptoms are high signal on diffusion-weighted imaging or
obscure the underlying disease. Some interventions FLAIR in the striatum, cerebral cortex and/or thal-
are therefore indicated immediately while waiting for amus (figure 2). Changes at these three sites may
initial test results. Suspect cases of viral encephalitis occur in isolation or combination. Cortical signal
should be treated with intravenous acyclovir. Cases change is often patchy and extensive but should
associated with weight loss, alcohol excess or other involve more than one cortical region and areas that
evidence of malnutrition should be treated with intra- are not vulnerable to artefactual signal change (eg, the
venous vitamins. In all patients, we recommend frontal pole) and should not enhance or show mass
a blood screen, including routine haematology, effect. Thalamic signal change may be diffuse or have
biochemistry, thyroid function, vitamin B12, serology emphasis in dorsal and medial aspects but should not
for neurosyphilis, paraneoplastic antibodies and be of greater signal intensity than in the striatum in
serology for limbic encephalitis; MR scan of brain sporadic CJD. Most units report a sensitivity of
(dementia protocol), including axial diffusion- MRI>90% in the diagnosis of sporadic CJD. In grey
weighted imaging and fluid-attenuated inversion matter, CJD is associated with small vacuoles in
recovery (FLAIR); electroencephalograph (EEG) and neuronal cell bodies, axons or dendrites, which are
cerebrospinal fluid (CSF) examination for basic most probably the pathological substrate for imaging
constituents, 14-3-3 protein, S100b, abeta and tau abnormalities. Often, cortical signal change correlates

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Table 1 Investigations/work-up
Screen in all CJD mimic patients Second-line test

Basic blood tests: routine haematology, biochemistry, calcium, Serum ammonia, drug levels (as appropriate)
magnesium, vitamin B12, HIV serology, thyroid function, antinuclear
antibody, antineutrophil cytoplasmic antibody, inflammatory markers
Serology: Voltage-gated K-channel antibodies, NMDA-R antibodies, Serology for specific infections (eg, Lyme), paraneoplastic
TPHA (neurosyphilis) antibodies
Imaging: MR scan of brain, dementia protocol, including diffusion- Angiography (vasculitis, dural arteriovenous fistula, intravascular
weighted axial images and post-gadolinium imaging for lymphoma/ lymphoma)
inflammatory CNS conditions
EEG: routine recording Electromyography and nerve conduction studies
CSF: for cells, biochemistry, oligoclonal bands, 14-3-3 protein, S100b CSF serology for NMDA-R encephalitis, measles serology, PCR for
protein, RT-QUIC assay, amyloid beta protein (1–42), total tau JC virus and for viruses associated with other encephalitides
PRNP: gene analysis Dementia gene panel diagnostics
Urine: test for infection Brain biopsy
CJD, Creutzfeldt–Jakob disease; CNS, central nervous system; CSF, cerebrospinal fluid; EEG, electroencephalogram; JC, John Cunnigham, NMDA-R, N-
methyl-D-aspartate; PRNP, prion protein gene; RT-QUIC, real-time quaking-induced conversion assay.

with clinical features, for example, contralateral in the Post-gadolinium imaging can help identify blood–
frontal lobe in patients with hemiparesis or occipital brain barrier breakdown in lymphoma and neuroin-
cortex signal change in the visual variant of CJD. flammatory conditions, which is not seen in CJD.

Electroencephalogram
The EEG is less useful with the availability of very
specific imaging and CSF tests. Periodic sharp wave
complexes develop in half of the patients with
sporadic CJD, particularly in the later stages. It is
most useful when showing unexpected findings that
would be unusual in CJD and provide suggestive
evidence for alternative diagnoses. These include peri-
odic lateralising epileptiform discharges in
encephalitis, frontal intermittent delta activity in
toxic–metabolic or structural abnormalities (if asym-
metrical), status epilepticus or runs of 2–3 s of
polyphasic slow/sharp waves (subacute sclerosing
panencephalitis). The extreme delta brush sign may
occur in autoimmune encephalitis.

Cerebrospinal fluid
Pleocytosis in CJD can occur but is rare. For 20 years,
the main CSF tests have been the detection of
proteins released into the spinal fluid, as the disease
process damages glia and neurones; these include 14-
3-3, S100b and neurone-specific enolase.13 Over 80%
of patients with CJD have abnormalities of these
proteins, but importantly, they are not specific to the
Figure 2 Typical MRI features of Creutzfeldt-Jakob pathogenesis of CJD; rather, they reflect rapid tissue
disease (CJD). (A and B) Sporadic CJD showing typical basal damage, and therefore, may also be abnormal in many
ganglia signal return on fluid-attenuated inversion
of the mimic conditions. New CSF tests, such as the
recovery (FLAIR) (A), which is more obvious on diffusion-
weighted sequences (B). (C) Diffusion-weighted imaging
real-time quaking-induced conversion assay (RT-
sequence showing striking cortical ribboning with normal basal QUIC), are entering routine clinical use and initial
ganglia in sporadic CJD. (D) Variant CJD showing pulvinar sign evidence suggests these are much more specific.14 The
on the FLAIR sequence. RT-QUIC protocol involves disruption of prion

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protein aggregates in a test sample by rounds of rapidly progressing end of the spectrum of Alzheimer’s
shaking, followed by incubation in an excess of disease or dementia with Lewy bodies. Comorbidities,
recombinant prion protein and induction of recombi- such as infection, leading to delirium, or drug changes
nant prion protein misfolding, detected by an increase are often a factor. Key features enabling recognition
thioflavin T fluorescence through the protocol (hence here are evidence from the witness account of pre-
real time). CSF angiotensin-converting enzyme can existing symptoms before the acute or subacute presen-
help diagnose neurosarcoidosis. tation. MR imaging evidence of focal or generalised
atrophy or CSF abnormality of abeta or tau proteins
Prion protein gene sequencing are also instructive. The diagnosis becomes clear when
Prion protein gene sequencing should, in our opinion, patients stabilise or improve, which hardly ever
be routinely considered in all cases. The phenotypic happens in patients with CJD despite treatment of
spectrum of inherited prion disease is more diverse intercurrent infection. Vascular disease in the striatum,
than CJD, and family history is often absent due to cortex or thalamus can also contribute to diagnostic
old-age presentations/partial penetrance. Most confusion, because at first glance, this might suggest
patients with CJD are homozygous at the common prion disease. Myoclonus, ataxia and motor signs can
polymorphism at codon 129 of the gene. The fastest develop in common neurodegenerative diseases and
declining patients with CJD are typically methionine can worsen with drug treatments, for example, tricy-
homozygous at this site, whereas the more slowly clics and myoclonus, antiepileptic drugs and ataxia,
changing patients are usually methionine–valine neuroleptics and dementia with Lewy bodies.
heterozygous. While this is a powerful effect, ruling Although there are no specific disease-modifying
out inherited prion disease is the most important therapies, accurate diagnosis of CJD can lead to mean-
purpose for gene sequencing. Gene testing has impli- ingful management decisions about symptomatic
cations for blood relatives, who must be involved in therapies and choices for the patient and carers. All
the decision to proceed. neurodegenerative disorders have Mendelian genetic
causes, which (eg, in the case of C9orf72 expansion)
can be associated with rapid progression and motor
Other tissues and biofluids
signs that bring CJD into the differential. The avail-
Tonsillar biopsy or a blood test (the Direct Detection
ability of gene panel diagnostics will identify an
Assay, from the National Prion Clinic) can be used in
increasing proportion of cases with a specific genetic
the diagnosis of variant CJD but has no use in the
diagnosis.17
sporadic form. Prion protein amplification or capture
We are particularly interested in potentially treatable
diagnostic technologies may be used in the future, with
mimics, which may be grouped into the following
material from olfactory brushings or using urine or
categories.
blood, but for the time being, these tools are in research
development for sporadic CJD.15 16 Brain biopsy is
seldom used to make a diagnosis of CJD, because it is
Immune-mediated encephalitis
reserved for circumstances when a reversible diagnosis
Probably, the most important CJD mimics are the
seems possible, in particular where a specific lesion is to
recently characterised antibody-mediated inflamma-
be targeted. It is essential to take prion precautions
tory disorders of the central nervous system.18 19
before neurosurgery in suspect cases. For more detailed
While some are paraneoplastic and fluorodeoxyglucose
guidance, see https://www.gov.uk/government/publica-
PET is useful in locating the underlying tumour, a
tions/guidance-from-the-acdp-tse-risk-management-
substantial proportion is not associated with antibodies
subgroup-formerly-tse-working-group.
directed to a range of neuronal surface ion channels
and membrane receptors. Many cases have dramatic or
Mimics of CJD after initial investigation significant recovery following immune therapies.
Once initial investigations are done, patients N-methyl-D-aspartate receptor (NMDAR) antibody
who cause ongoing difficulty usually have abnormality encephalitis is the most commonly recognised type,
of at least one of the key initial tests. Most frequently, initially linked to ovarian teratoma in young women,
this is a positive 14-3-3 protein in CSF. which remains a prompt to consider the diagnosis.
Like in patients with CJD, the history often includes a
Common neurodegenerative disorders non-specific prodromal stage, developing into behav-
In over half of the mimics that the National Prion ioural and psychiatric features, and early generalised
Clinic sees, the eventual diagnosis is another neurode- and focal seizures that would be very unusual in CJD.
generative disease. These conditions are much more Movement disorders commonly develop in CJD, but
prevalent than CJD and are also heterogeneous, with the specific facial dyskinesia of NMDAR encephalitis
confusion only likely to occur with the very most would prioritise the disorder. Other flags for the

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which may give more specific tests. While associated

with a wide range of clinical syndromes, the most
commonly confused picture with CJD is one that may
include both peripheral manifestations—neuromyo-
tonia, a twitching or stiffness related to spontaneous
motor nerve excitability, and autonomic disturbances—
and central manifestations, such as brief and frequent
seizures affecting ipsilateral face and arm (termed
‘faciobrachial dystonic’), insomnia, memory
impairment and behavioural disturbances or more
florid manifestations of an encephalitis. Investigation
prompts to the diagnosis include hyponatraemia and
MR imaging abnormalities of the mesial temporal lobe
and hippocampus, which can also involve the basal
ganglia (figure 3).
Other protein targets in immune-mediated encephalitis
are proliferating and include glutamic acid decarbox-
ylase, which can be associated with limbic encephalitis or
cerebellar ataxia; AMPA receptor antibody encephalitis,
often associated with tumours, psychosis and limbic
encephalitis; GABAA or GABABR antibody limbic enceph-
alitis; glycine receptor antibodies, which may occur in
Figure 3 MR scan of brain in four patients presenting as progressive encephalopathy with generalised stiffness,
mimics of prion disease. (A) C9orf72 mutation showing severe autonomic abnormalities and myoclonus (progressive
generalised atrophy with no parenchymal abnormal signal.
encephalomyelitis with rigidity and myoclonus);
Severe atrophy does occur late in some cases of Creutzfeldt-
Jakob disease (CJD), but usually diffusion-weighted sequences and metabotropic glutamate receptor antibodies, which
reveal restricted diffusion. (B) B-cell lymphoma confined at have been reported in subacute cerebellar degeneration.
the time of presentation to the brain. Note the extensive white- Hashimoto’s encephalitis is commonly referred to as
matter signal change with the normal cortex. Occasionally, the a key differential of CJD, but we have never seen this
leukoencephalopathic form of CJD has white-matter signal at the Prion Clinic. Testing of thyroid function and
alteration, but this is associated with grey matter destruction. antithyroperoxidase antibodies is simple to do,
(C) N-methyl-D-aspartate antibody encephalitis with MR
although many patients reported to have the disorder
imaging showing the pulvinar sign. This sign develops in most
cases of variant CJD and has rarely been described with other are euthyroid. The pathogenesis of this disorder and
pathologies. (D) Voltage-gated potassium channel (Casp-1) its distinction from other immune-mediated encepha-
antibody encephalitis showing unilateral basal ganglia high litides is unclear.
signal on diffusion-weighted imaging but not on the apparent
diffusion coefficient map (scan not shown). Note that the
swelling of the caudate is a feature that does not occur in CJD.
Infections
Progressive multifocal encephalopathy is an opportu-
disorder are a CSF pleocytosis, CSF oligoclonal
nistic brain infection associated with the polyoma JC
bands, and MR imaging findings (Table 3). These can virus infection, almost exclusively in immunocompro-
include T2 or FLAIR hyperintensity of the striatum, mised people. There is usually a history of
thalamus and cortex as might occur in CJD (figure 3) immunosuppressive drug use, HIV, Hodgkin’s
but more typically include abnormalities in other lymphoma or chronic lymphocytic leukaemia. The
areas, particularly the mesial temporal lobe and condition is hard to link to a specific symptom,
hippocampus, and also the brainstem, cerebellum and although it is mistaken for CJD because of rapid
white matter, often with enhancement or mass effect progression of disability and its common involvement
from inflammation. We recommend testing at least of visual pathways or cerebellar ataxia. As for enceph-
serum in all patients suspected to have CJD and CSF alitis, the occurrence of generalised seizures in half of
in patients with flags for the disorder. the cases would be unusual for CJD. Imaging features
Voltage-gated potassium channel (VGKC) complex should be distinct from CJD, with a propensity for
antibody encephalitis is similarly a crucial mimic of parieto-occipital demyelinating lesions at the junction
CJD to exclude. Importantly, we now know that patho- of grey and white matter, less commonly seen in the
genic antibodies are directed at individual members of corpus callosum, thalamus and basal ganglia. CSF is
the VGKC multiprotein complex, for example, LGI1, used to confirm diagnosis with PCR for JC virus, but

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Table 2 Differential diagnosis checklist

Common disorders with rare presentation Rare but potentially treatable/reversible mimics Rare and untreatable mimics
that mimic CJD of CJD

Rapidly progressive forms of common Limbic and other immune-mediated encephalitis Unusual infections: subacute
neurodegenerative diseases sclerosing panencephalitis
Delirium and pre-existing dementia Metabolic and endocrine conditions Mitochondrial cytopathy
(hyperammonaemia, electrolyte disturbance,
hypoglycaemia/hyperglycaemia, uraemia)
Viral encephalitis Primary CNS vasculitis Diffuse neoplastic disease (eg,
carcinomatous meningitis,
gliomatosis cerebri)
Hepatic failure and encephalopathy Neurosarcoidosis
Cerebrovascular disease (single or multiple Primary CNS and intravascular lymphoma
strokes) or hypoxic encephalopathy
Wernicke’s encephalopathy and related Unusual infections: progressive multifocal
manifestations of alcohol-related dementia (eg, leukoencephalopathy, fungal encephalitis, Lyme disease,
extrapontine myelinolysis) Whipple’s disease, neurosyphilis
Thyroid dysfunction Large dural arteriovenous fistula
HIV-related dementia
Subacute combined degeneration
CNS manifestations of autoimmune disorders (eg, lupus,
sarcoidosis)
Heavy metal toxicity (eg, lithium, mercury)
Toxicity related to medications (eg, lithium, valproate)
Non-convulsive status epilepticus
Psychiatric conditions: functional disorders, catatonia,
depression
CJD, Creutzfeldt–Jakob disease; CNS, central nervous system.

a pleocytosis often occurs and would be another checklist (table 2) but have not caused diagnostic
feature against a diagnosis of CJD. confusion with CJD at our clinic.
Subacute sclerosing panencephalitis is a rare late
complication of measles infection in early childhood. Toxic–metabolic syndromes
The clinical picture can look quite similar to CJD, Most of these syndromes are picked up in the initial
with early lethargy and behavioural change followed laboratory testing, which should include basic serum
by a ‘hung-up’ type of myoclonus, seizures, cognitive biochemistry, calcium, magnesium, glucose and
impairment, later motor signs and reduced level of thyroid function. It is important to emphasise the
consciousness. The diagnosis should be considered in importance of Wernicke’s encephalopathy, an acute
children or young adults and may be prompted by neurological disorder, precipitated by thiamine defi-
EEG findings of bilaterally synchronous and repetitive ciency, characterised by the clinical triad of
sharp complexes lasting a few seconds. CSF antibody ophthalmoplegia, ataxia and confusion, which should
titres for measles are diagnostic. be treated with urgent intravenous B vitamin replace-
Other viral encephalitides usually present acutely ment. Imaging features may partially overlap those of
and are immediately recognised by general features CJD. The encephalopathy associated with hepatic
such as fever and raised inflammatory markers in failure has mimicked CJD on a couple of occasions at
serum and CSF, along with more specific features of our clinic, with the associated negative myoclonus (a
brain infection like seizures, meningism and coma. sudden loss of muscle tone) in comatose patients
Occasionally, its more subacute presentations may mimicking the end stages of CJD. The detection of
cause some confusion with CJD. hyperammoninaemia either as part of rare genetic
A wide range of bacterial, fungal and parasitic infec- urea cycle disorders, drug therapy or liver failure can
tions that can cause an RPD should be on a reference be crucial in the diagnosis of a toxic encephalopathy.

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Table 3 Red flags: clinical features that might indicate a CJD mimic
Feature Indicates

Fever Infections, lymphoma

Seizures Implies less likely to be CJD, infective and immune encephalitis, neoplasia, many
other mimics
Hyponatraemia VGKC encephalitis
Facial movement disorder NMDA-R encephalitis, CNS Whipple’s disease
Modest progression Implies less likely to be CJD, more likely to be a common neurodegenerative
disorder
CSF pleocytosis Infections, lymphoma, inflammatory, neoplastic
Contrast-enhancing lesions Infections, lymphoma, inflammatory, neoplastic
MRI hyperintensities on T2-weighted imaging outside the Vascular diseases, lymphoma, progressive multifocal leukoencephalopathy,
striatum, thalamus and cortex encephalitis, extrapontine myelinolysis, others
CJD, Creutzfeldt–Jakob disease; CNS, central nervous system; CSF, cerebrospinal fluid; NMDA-R, N-methyl-D-aspartate; VGKC, voltage-gated potassium
channel.

In addition, a high signal in the lentiform nucleus on and normal or near-normal cognitive function and is
T1 MRI sequences due to manganese deposition slightly slower in progression than typical sporadic
strongly suggests hepatic encephalopathy. CJD. Other forms of inherited prion disease have
pure cognitive presentations, often with behavioural
Neoplastic and paraneoplastic conditions (other than limbic encephalitis) disturbance and are mistaken for the frontal variant
The conditions hardest to distinguish are those with no of Alzheimer’s disease, Huntington’s disease (as
or only subtle mass lesions on MRI. Typically, these there is an autosomal dominant family history) or
include primary CNS lymphoma, carcinomatosis and frontotemporal dementia.
intravascular lymphoma. In these cases, the imaging
findings are usually the crucial diagnostic. Primary Conclusions and possible developments
CNS lymphoma is usually associated with enhancing RPD mimicking CJD is rare but requires urgent inves-
lesions in contact with CSF. Large-volume CSF tigation and can be difficult to diagnose. This can be
sampling for cell analysis before a trial of corticoste- more rewarding than the investigation of insidiously
roids may avoid brain biopsy. Serum tumour markers progressing cognitive dysfunction, as there is a wide
and whole-body imaging may also help. Intravascular range of potentially treatable disorders. Specialist
(B-cell) lymphoma is a rare and notoriously difficult services for prion disease, including the NHS National
diagnosis. It leads to rapid cognitive decline, seizures, Prion Clinic at the National Hospital for Neurology
upper motor neurone signs and peripheral signs such as and Neurosurgery (University College London Hospi-
those of a neuropathy. Imaging findings overlap those tals NHS Trust) and the National CJD Research and
of primary CNS vasculitis. Surveillance Unit at Edinburgh University, are here to
help for assessment, to advise about local
Vascular investigation and to provide access to molecular
We have seen cases of large vessel stroke, dural arte- genetics and other diagnostics, follow-up and
riovenous fistula, posterior reversible encephalopathy supportive care. We like to hear about cases as early
syndrome and primary CNS vasculitis as mimics of as possible, certainly immediately after a scan showing
CJD. In each case, the MR imaging review was the changes compatible with CJD.
main indicator of the diagnosis. With such rare disorders, clinical research can
most effectively be done when concentrated in
Mimics relevant to other types of prion disease national centres with long-term funding and
Genetic and iatrogenic forms of prion disease often provided alongside specialist care in partnership
do not progress as rapidly as CJD and therefore with local physicians. Research is delivering mean-
have distinct differentials. A common phenotype of ingful improvements, with specific blood and CSF
several inherited prion disease mutations is a prion disease diagnostics moving from the laboratory
modestly progressive (over the years) cerebellar to clinical use in the last 5 years. It is hard to
ataxia, often with a distal leg sensory disturbance, predict when we shall see any meaningful treat-
absent ankle jerks and extensor plantar responses. ments, but this is certainly a major focus of activity
Iatrogenic CJD also commonly presents with ataxia at the moment. Progress in this area will not be

120 Mead S, Rudge P. Pract Neurol 2017;17:113–121. doi:10.1136/practneurol-2016-001571

 REVIEW

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Acknowledgements We thank the patients, their families and
clinical phenotype of the "Heidenhain variant". Br J Ophthalmol
carers, and staff at the National Prion Clinic, past and present, for
contributing to the National Prion Monitoring Cohort study. 2005;89:1341–2.
Numerous consultant neurology colleagues in the UK contributed 11 Thompson A, MacKay A, Rudge P, et al. Behavioral and
by making prompt referrals to specialist services. We also thank the psychiatric symptoms in prion disease. Am J Psychiatry
National CJD Research and Surveillance Unit for ongoing joint 2014;171:265–74.
working in this rare disease. Mr Richard Newton assisted with 12 Zerr I, Kallenberg K, Summers DM, et al. Updated clinical
the figure design.
diagnostic criteria for sporadic Creutzfeldt-Jakob disease. Brain
Competing interest None declared. 2009;132(Pt 10):2659–68.
Funding Both authors are funded by the Medical Research Council 13 Zerr I, Bodemer M, Weber T. The 14-3-3 brain protein and
(MRC), UK. The National Prion Clinic is funded by MRC UK, the transmissible spongiform encephalopathy. N Engl J Med
Biomedical Research Centre at University College London Hospitals 1997;336:874.
NHS Foundation Trust and the NHS. 14 Peden AH, McGuire LI, Appleford NE, et al. Sensitive and
Provenance and peer review Commissioned; externally peer specific detection of sporadic Creutzfeldt-Jakob disease brain
reviewed. This paper was reviewed by Colin Doherty, Dublin, prion protein using real-time quaking-induced conversion.
Republic of Ireland.
J Gen Virol 2012;93(Pt 2):438–49.
15 Zanusso G, Bongianni M, Caughey B. A test for Creutzfeldt-
Jakob disease using nasal brushings. N Engl J Med
2014;371:1842–3.
16 Luk C, Jones S, Thomas C, et al. Prospective diagnosis of
sporadic CJD by the detection of abnormal PrP in patient urine.
JAMA Neurol 2016;73:1454–60.
17 Beck J, Pittman A, Adamson G, et al. Validation of next-
generation sequencing technologies in genetic diagnosis of
dementia. Neurobiol Aging 2014;35:261–5.
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