Pract Neurol: first published as 10.1136/jnnp.2010.235721 on 14 January 2011. Downloaded from http://pn.bmj.

com/ on December 16, 2023 at Portsmouth Hospitals University NHS Trust.

Katherine Murray 19

REVIEW Pract Neurol 2011; 11: 19–28

Creutzfeldt–Jacob disease
mimics, or how to sort out
the subacute encephalopathy
patient
Katherine Murray

Protected by copyright.
Sporadic Creutzfeldt–Jacob disease (CJD) is a rare untreatable neurodegenerative
disease which every neurologist will occasionally encounter during their career.
However, it is likely to appear on their differential diagnosis list significantly more
frequently. Numerous conditions can present with subacute encephalopathy which
might be sporadic CJD and this article explores these diagnoses. It includes the
commonest sporadic CJD mimics which are neurodegenerative, and highlights the
relatively rare treatable mimics which must not be missed. It discusses relevant
investigations, including serum antibodies, CSF, electroencephalography and MR brain
imaging, and strategies when preliminary investigations fail to support sporadic CJD
but no alternative diagnosis is readily apparent.

A 44-year-old woman was admitted under the neurology department with a 4 week history
of rapid cognitive decline and mild gait unsteadiness. Her only history was of classical
migraine but immediately prior to presentation she had experienced 5 weeks of persistent
migrainous headache with left-sided sensory disturbance. On examination she scored 47/100
on the Addenbrooke’s Cognitive Examination with deficits in all domains; she had myoclonic
jerks, truncal ataxia and subtle left-sided pyramidal weakness. Initial investigation revealed
normal routine bloods, normal MR brain imaging, CSF with 22×109/ mm3 lymphocytes
(decreasing to 6 on repeat CSF a week later), protein of 0.62 g/l, normal glucose, red blood
cell count and cytology, and positive unpaired oligoclonal bands. EEG showed bursts of
frontally predominant slow wave activity. The initial concern was that she had a subacute
encephalopathy, possibly sporadic CJD……..

INTRODUCTION in the UK of 1–1.5/million, meaning that on Correspondence to

Sporadic Creutzfeldt–Jacob disease (sCJD) is a
neurodegenerative, uniformly fatal prion dis-
ease characterised pathologically by spongi-
form change within the brain. The cause is
unknown. It is rare, with an annual incidence
average an individual UK neurologist may
encounter a new case only once every 5 years.
However, far more patients present with a
subacute encephalopathy which might be
CJD. Here I will discuss such patients and their
Dr K Murray, Specialist Registrar,
Department of Clinical
Neurosciences, Western General
Hospital, Crewe Road South,
Edinburgh EH4 2XU, UK;
kmurray12@doctors.org.uk

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20 Practical Neurology

Most infective
encephalopathies
are too acute to be
confused with CJD
Table 1 Differential diagnosis of subacute encephalopathy
Metabolic/endocrine
Drug/toxic/nutritional
Infection
differential diagnoses, particularly those dis- potential causes can be confirmed or excluded
orders which are amenable to treatment. fairly quickly with a detailed history, includ-
ing of drug and alcohol use, and some simple
THE DIAGNOSTIC POSSIBILITIES investigations such as routine bloods, CSF and
There is a wide differential for subacute enceph- CT brain imaging (eg, drug/toxic encephalopa-
alopathy (table 1). However, a large number of thy, brain metastases, systemic and common
CNS infections and many metabolic causes).
Most infective encephalopathies are too acute
to be confused with CJD but rarely even com-
mon causes of encephalitis, such as herpes
Uraemic encephalopathy simplex virus (HSV) 1 and 2, can present as a
Hepatic encephalopathy subacute encephalopathy. Clearly, if there is
Hypo/hyperthyroid concern about herpes simplex encephalitis it is
Hypoglycaemia prudent to treat with acyclovir until the diag-
Hyponatraemia (including central pontine nosis is excluded (usually by a negative HSV
myelinolysis)
PCR on CSF). However, the clinical picture of
Hypercalcaemia
fever, headache, reduced consciousness with
Chemotherapy (eg, methotrexate)
Lithium toxicity CSF pleocytosis in addition to sometimes focal
Alcohol changes on MRI usually makes the diagnosis
Chronic carbon monoxide poisoning of an infective process relatively straightfor-
Wernicke–Korsakoff syndrome ward. The situation becomes more compli-
Vitamin B12 deficiency cated in the immunocompromised patient or
returning travellers, with a much wider differ-

Protected by copyright.
Systemic Pneumonia, urinary tract ential diagnosis which is beyond the scope of
CNS HSV1/2, enterovirus, varicella zoster, Epstein– this article.1
Barr, Lyme, HIV, TB, listeria
In immunocompromised Syphilis, HHV 6, cytomegalovirus, SPORADIC CJD
measles, JC virus (progressive multifocal The mean age of sCJD disease onset is 66 years
leukoencephalopathy), fungal/parasitic
with most cases presenting between the ages
Autoimmune antibody Paraneoplastic
of 50 and 75 years although patients as young
associated Non-paraneoplastic—antivoltage gated
potassium channel antibodies as 142 and as old as 863 have been reported.
Malignancy (non- Malignant meningitis There is no gender difference. Disease duration
paraneoplastic) Primary CNS malignancy is typically short, with a median of 6 months
Cerebral metastases from onset to death. Only 14% of cases sur-
Inflammatory Vasculitis vive longer than a year and only 5% live for
Sarcoid 2 years or more.4
Systemic lupus erythematosus
Sjögren’s syndrome Clinical picture
Hashimoto’s encephalopathy The characteristic clinical picture in sCJD is
Multiple sclerosis/acute disseminated one of rapidly progressive dementia with
encephalomyelitis
associated neurological features, particularly
Vascular Intracranial venous thrombosis
cerebellar ataxia, pyramidal signs and myo-
Behcet’s disease
Neurodegenerative Prion disease—sporadic, variant, genetic and clonus. Visual disturbance, ocular movement
iatrogenic CJD disorders, extrapyramidal signs and hallucina-
Rarely rapid presentations of other tions are also well recognised. The final stages
neurodegenerative diseases such as Alzheimer’s are characterised by an akinetic mute state.
disease, and dementia with Lewy bodies The illness may be preceded by a non-spe-
Other Mitochondrial cytopathy cific prodrome, including fatigue, low mood,
Psychiatric such as schizophrenia and severe weight loss and headache for a few months.
depression Although the commonest sCJD presentation is
Irradiation with a subacute encephalopathy, other onsets
CJD, Creutzfeldt–Jakob disease; HHV, human herpes virus; HSV, herpes include pure cerebellar, visual, psychiatric and
simplex virus; TB, tuberculosis. stroke-like syndromes. The rapidity of dete-
rioration in sCJD usually helps distinguish it
10.1136/jnnp.2010.235721

from other dementias and neurodegenerative
conditions.
Investigations
There are no specific findings on blood
tests; their primary value is to exclude other
diagnoses.
The CSF is usually unremarkable with nor-
mal glucose and no cells although protein may
be modestly raised (usually less than 1 g/l).5 A
raised white cell count virtually excludes sCJD.
The most valuable CSF test is analysis of the
neuronal protein 14-3-3 which has a sensitiv-
ity of 90–97% and specificity of 87–100% in
patients with suspected sCJD referred to a CJD
surveillance unit.6 7 Confirmed sCJD cases with
a normal 14-3-3 are often clinically and patho-
logically atypical, with a younger age of onset
and prolonged disease duration. The value of
the test is much less when used as a screen-
ing tool for unselected patients with dementia
because when sCJD is unlikely most positives
are false positives. False positive results occur
with acute neuronal damage in diverse condi-
tions, including stroke, paraneoplastic disease,
inflammation and post-seizure activity.
MR brain imaging characteristically dem-
onstrates hyperintensity of the putamen and
caudate head (figure 1A), usually bilaterally.
Cortical hyperintensity also occurs (figure 1B).
Both sensitivity and specificity based on either
bilateral basal ganglia changes or cortical
hyperintensity in at least two areas is up to
80%.8 Fluid attenuated inversion recovery and
diffusion weighted imaging sequences appear
A B
Figure 1
(A) MR brain scan in sporadic Creutzfeldt–Jacob disease demonstrating hyperintensity of the putamen and caudate
heads (arrows). (B) MR brain scan showing cortical hyperintensity (arrows).
Pract Neurol: first published as 10.1136/jnnp.2010.235721 on 14 January 2011. Downloaded from http://pn.bmj.com/ on December 16, 2023 at Portsmouth Hospitals University NHS Trust.
Katherine Murray 21
most sensitive, with diffusion weighted imag- The EEG lacks
ing being particularly good at detecting early
changes in both the striatum and cortex.9 The sensitivity in the
differential diagnosis for high signal in the early stages of sCJD
basal ganglia includes Wilson’s disease, car-
bon monoxide poisoning, mitochondrial dis- and serial traces
orders and variant CJD (although in the last may be required to
the posterior thalamic hyperintensity is more
pronounced than the caudate/putamen signal detect the typical
change). However, most of these conditions pattern
should be readily clinically distinguishable. The
WHO diagnostic criteria for sCJD are currently
being modified to incorporate MRI features.8
Electroencephalography (EEG) is a useful
investigation in sCJD, classically showing peri-
odic, triphasic sharp wave complexes at a fre-
quency of 1/s, usually generalised throughout
the trace (figure 2). Objective criteria have been
published and when these are applied, the sen-
sitivity of the EEG is about 65% and specificity
about 80%.10 However, the EEG lacks sensitivity
in the early stages of sCJD and serial traces may
be required to detect the typical pattern. False
Protected by copyright.
positive EEGs are recognised in Alzheimer’s
disease, Lewy body dementia, vascular demen-
tia11–13 and other less likely to be confusing clini-
cal scenarios, such as lithium toxicity.
sCJD can only be confirmed by pathol-
ogy but brain biopsy is rarely required in life
because of the characteristic clinical pheno-
type plus supportive investigations (box 1).14
Issues in diagnosis
The usual difficulty in diagnosis lies in atypi-
cal presentations, or those with negative
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22 Practical Neurology

seizures were relatively more common in

non-CJD cases.15
The differential diagnosis of sCJD has proved
challenging to study because of referral bias;
so much of the literature is based on patients
referred to specialised CJD units who are highly
selected before they get there and not represen-
tative of the average subacute encephalopathy
patient in a district general hospital or even in
a regional neurology unit. In addition, a number
of CJD mimics die with no diagnosis and even
autopsy may fail to provide an answer.16 17
Table 2 summarises the most frequent
‘filtered’ sCJD mimics—that is, patients pre-
senting with a rapidly progressive dementia
or subacute encephalopathy where readily
identifiable alternative diagnoses have been
excluded and sCJD is suspected but subse-
quently disproven.11–13 15
In the UK, the two UK CJD surveillance cen-
Figure 2 tres perform CSF 14-3-3 testing and genotyp-
Typical EEG in sporadic Creutzfeldt–Jacob disease showing generalised periodic triphasic complexes.
ing for genetic CJD. All suspected cases of any
form of CJD should be discussed with them by

Protected by copyright.
faxing the National CJD referral form (down-
Box 1 Current WHO criteria for sporadic Creutzfeldt–Jacob disease
(sCJD): Rotterdam 1998* loaded from www.uclh.nhs.uk or www.cjd.
ed.ac.uk) to the National CJD Surveillance Unit,
I Rapidly progressive dementia Edinburgh and National Prion Clinic, London.
II (A) Myoclonus
(B) Visual or cerebellar problems NEURODEGENERATIVE sCJD
(C) Pyramidal or extrapyramidal features MIMICS
(D) Akinetic mutism The commonest sCJD mimics are neurodegen-
III Typical EEG erative, including Alzheimer’s disease, demen-
1.0 Definite: Neuropathologically/immunocytochemically confirmed tia with Lewy bodies (DLB), frontotemporal
2.0 Probable: I + 2 of II + III or I + 2 of II + positive 14-3-3 CSF protein dementia and the tauopathies such as corti-
3.0 Possible: I + 2 of II + duration <2 years cobasal degeneration and progressive supra-
4.1 Unclear diagnosis, not meeting sCJD criteria nuclear palsy.17 18
4.2 Clinical diagnosis not sCJD
*Soon to be amended to incorporate brain MRI changes8 Alzheimer’s disease
Alzheimer’s disease can be mistaken for sCJD
investigations, in particular cases where the for a number of reasons. While an individual
diagnosis may be CJD but there is a nagging with Alzheimer’s disease typically survives
doubt that a potentially treatable condition anywhere between 4 and 8 years, there are
may have been overlooked. No single clinical more aggressive cases dying after just a year
feature distinguishes CJD. Myoclonus, while or two. Myoclonus is well recognised and
typically prominent in CJD, also occurs in reported in 10%, particularly in the later stages.
many other conditions, including Alzheimer’s Investigations can confuse matters, with peri-
disease, corticobasal degeneration and odic triphasic waves being seen occasionally
immune mediated encephalopathies, so it is on EEG and positive CSF 14-3-3 results.
not specific. One study found presentation
with visual disturbance was the most useful Dementia with Lewy bodies (DLB)
feature distinguishing sCJD from CJD mim- DLB can also mimic sCJD. The classic DLB phe-
ics (positive predictive value 93%) but in a notype, as defined in the diagnostic criteria, of
highly selected population referred to a CJD progressive dementia with particular atten-
unit, whereas extrapyramidal signs and early tional, visuospatial and subcortical deficits,
10.1136/jnnp.2010.235721

marked fluctuations, visual hallucinations
and parkinsonism is unlikely to be misdiag-
nosed.19 However, it can present more acutely
with rapidly progressive dementia, myoclonus
and minimal motor features of parkinsonism.
Hallucinations occur in approximately 40%
of sCJD patients so this is not a reliable dis-
tinguishing feature although in DLB halluci-
nations are typically visual and well formed,
involving animals or people, whereas in CJD
they are more variable. EEG in DLB can rarely
show periodic complexes, further confusing
the issue. However, MRI does not show the
typical sCJD caudate/putamen signal change.
Corticobasal degeneration
One study found that corticobasal degenera-
tion was the most frequent single condition
masquerading as CJD despite its relative rarity,
although it was not population based.17 This
probably reflects the selected patient group
and frequent occurrence of dementia, myo-
clonus, alien limb and parkinsonism in cortico-
basal degeneration (all features well recognised
in CJD) in addition to the lack of supportive
investigations as corticobasal degeneration is
essentially a clinical diagnosis.
Genetic CJD
Genetic CJD should be considered in both typi-
cal and atypical sCJD presentations. It refers to
autosomal dominantly inherited prion disease
with mutations in the prion protein (PRNP) gene.
Only 30–50% of inherited cases have a family
history, emphasising the need to offer genetic
sequencing in all CJD suspects (with informed
consent). Depending on the precise mutation,
it can present differently to classic sCJD, often
in younger individuals with slower disease
progression, and sometimes as an alternative
clinical phenotype (eg, fatal familial insomnia,
Gerstmann–Straussler–Scheinker syndrome).20
ANTIBODY MEDIATED
ENCEPHALITIS
Paraneoplastic encephalitis
Paraneoplastic encephalitis includes limbic
encephalitis (typically presenting with memory
impairment, behavioural change and seizures)
and less frequently brainstem encephalitis.
Patients may also have other neurological signs
secondary to overlap paraneoplastic antibody
effects—for example, a cerebellar syndrome
or polyneuropathy. A key feature is the rapidly
Pract Neurol: first published as 10.1136/jnnp.2010.235721 on 14 January 2011. Downloaded from http://pn.bmj.com/ on December 16, 2023 at Portsmouth Hospitals University NHS Trust.
Katherine Murray 23
Table 2 ’Filtered’ differential diagnosis of sporadic Creutzfeldt–
Jacob disease
Neurodegenerative Alzheimer’s disease
Dementia with Lewy bodies
Frontotemporal dementia +/− motor neuron disease
Corticobasal degeneration
Progressive supranuclear palsy
Other prion disease (genetic, iatrogenic, variant CJD)
Immune mediated Cerebral vasculitis
Autoimmune limbic encephalitis (antivoltage gated
potassium channel antibody, anti-GAD, anti-NMDA
receptor)
Paraneoplastic encephalitis (anti-Hu, Ma, Ta,
ANNA-3, CV2, amphiphysin, NMDA receptor,
glutamate receptor)
Hashimoto’s encephalopathy/steroid responsive
encephalopathy
Infective Viral encephalitis (enterovirus, HSV 1 or 2,
cytomegalovirus, Epstein–Barr virus, HIV, West Nile
(not UK), Japanese encephalitis B)
Lyme disease (Borrelia)
Protected by copyright.
Whipple’s disease (Tropheryma whippelii)
Subacute sclerosing panencephalitis
Other CNS lymphoma/intravascular lymphoma
Vascular dementia
Not CJD but no diagnosis made (patients either
improve, or die but autopsy not diagnostic)
Those in bold represent potentially treatable conditions which must not be
missed.
CJD, Creutzfeldt–Jakob disease; HSV, herpes simplex virus; NMDA, N-methyl
D-aspartate.
progressive nature of the neurological syn-
drome—symptoms evolving slowly over more
than a few months are unlikely to be paraneo-
plastic. The commonest underlying malignancy
is small cell lung carcinoma with the individual
mounting an antibody response to one or more
of their tumour antigens, which then cross react
with neuronal antigens. A variety of onconeu-
ronal antibodies have been associated with
paraneoplastic encephalitis, including anti-Hu,
anti-CV2, anti-Ma and anti-Ta (Ma2), ANNA-3,
anti-amphiphysin, anti- N-methyl D-aspartate
(NMDA) receptor, anti-glutamate receptor and
various other antibodies directed against the Genetic CJD should
neuropil of the hippocampus21:
be considered in
• Anti-Hu is the commonest and these
patients often have other, non-limbic both typical and
neurological features such as ataxia and atypical sCJD
sensory neuronopathy, in addition to
small cell lung cancer. presentations
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24 Practical Neurology
• Anti-amphiphysin syndromes occur with
breast cancer and small cell lung cancer,
often with stiff person syndrome in con-
junction with limbic encephalitis.
• Anti-Ma patients are typically middle aged
with a range of underlying tumours and
frequently a poor neurological response
to treatment.
• In contrast, anti-Ta (Ma2) classically
occurs in young men with testicular germ
cell tumours (including extragonadal sites)
who respond well to immunotherapy and
treatment of the underlying testicular
malignancy. 22
• Anti-NMDA receptor encephalitis has
a well defined phenotype of psychotic
encephalopathy, seizures, dyskinesias
and autonomic instability with underly-
ing ovarian teratoma. Brain MRI is often
normal. It classically presents acutely in
young females so is rarely confused with
sCJD but it is important as it responds to
removal of the teratoma and immuno-
therapy.23 It is also reported without asso-
ciated tumour.24
Investigations in paraneoplastic limbic
encephalitis are usually abnormal, with brain
MRI showing atrophy or mesial temporal sig-
nal change in the majority, and CSF pleocy-
tosis and raised protein. However, normal CSF
does not exclude the diagnosis. Treatment is
aimed primarily at the underlying malignancy,
supplemented with immunosuppression in
some cases.
It is important to remember that up to
40% of paraneoplastic limbic encephalitis
cases have no detectable antibodies with cur-
rent testing although this figure will shrink as
more antibodies are identified. In these cases
the diagnosis is based on the clinical pheno-
type evolving over a maximum of 12 weeks
with radiological or pathological evidence of
limbic system involvement and discovery of
an appropriate cancer.25 As with all paraneo-
plastic syndromes, discovery of the underlying
malignancy frequently postdates the neurol-
ogy, sometimes by several years. This means
Up to 40% of that if initial cancer screening investigations
paraneoplastic (eg, mammography, tumour markers, testicular
ultrasound, CT chest/abdomen/pelvis or whole
limbic encephalitis body positron emission tomography depend-
cases have ing on availability) are negative they should be
repeated after an interval. The frequency and
no detectable duration of these malignancy screening tests
antibodies are debated but a pragmatic approach might
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be after 6–12 months initially, and subse-
quently annually up to 5 years.
Voltage gated potassium channel
associated limbic encephalitis
This has only recently entered the literature as
a sCJD mimic.26 Anti-voltage gated potassium
channel (VGKC) antibodies were first recognised
in association with limbic encephalitis in 200127
but they are not specific, being associated with
the peripheral nerve excitability syndromes of
acquired neuromyotonia (Isaac’s syndrome)
and cramp fasciculation syndrome, in addition
to Morvan’s syndrome (peripheral and central
involvement). In 2004 a review of the clini-
cal and immunological features of 10 cases of
VGKC associated limbic encephalitis was pub-
lished.28 Since then a large number of patients
have been identified with an expanding clinical
phenotype. Characteristically it presents with
a subacute amnesic syndrome plus seizures,
but increasingly other presentations are rec-
ognised, including sleep disorders (loss of rapid
Protected by copyright.
eye movement (REM) sleep, REM sleep behav-
iour disorder), tremor and refractory epilepsy.
Hyponatraemia is common secondary to the
syndrome of inappropriate antidiuretic hor-
mone secretion and this may help distinguish it
from paraneoplastic limbic encephalitis.
The antibody assay uses binding of radio-io-
dine labelled α-dendrotoxin to specific potas-
sium channels. The normal reference range
is less than 100 picomolar (pM), with limbic
encephalitis being associated with titres greater
than 400 pM. The significance of intermedi-
ate antibody levels (100–400 pM) is unclear.
According to one study, just under half the
patients have mild lymphocytosis or raised pro-
tein in the CSF but oligoclonal bands are rare.
The CSF was entirely normal in approximately
a quarter.29 Similar to paraneoplastic limbic
encephalitis, MRI characteristically reveals
temporal lobe signal change but can be normal.
EEG abnormalities include focal temporal sharp
waves and generalised slowing.25 It is poten-
tially treatable with immunosuppression.
Hashimoto’s encephalopathy
This rare CJD mimic is particularly important
because, like VGKC encephalitis, it is treatable.
It is commoner in women, typically present-
ing in middle age with a fluctuating enceph-
alopathy including rapid cognitive decline,
seizures, neuropsychiatric manifestations and

sometimes movement disorders such as tremor
or myoclonus, ataxia, stroke-like episodes and
even coma.30 31 However, the clinical pheno-
type is variable.32 Individuals may be euthyroid,
hypothyroid or less often hyperthyroid.
The CSF is frequently abnormal but non-
specific with modestly raised protein (gener-
ally less than 1g/l) and white cell count ranging
from normal to a mild lymphocytic pleocytosis
(5–30 × 109/mm3). EEG is usually abnormal with
generalised slowing or less frequently showing
focal slowing, triphasic waves or epileptiform
changes. Brain MRI can be normal or dem-
onstrate non-specific white matter changes,
which interestingly frequently resolve with
treatment, as do the EEG abnormalities.31
The diagnosis is based on an appropri-
ate clinical phenotype with other conditions
excluded in addition to raised antithyroid
antibodies (antithyroglobulin and thyroid per-
oxidase antibody, or TPO previously known
as antimicrosomal antibody). The difficulty is
that antithyroid antibodies are not specific to
Hashimoto’s encephalopathy and are common
in normal elderly people, so if they are raised
other mimics must still be excluded.
There is no correlation between anti-
body level and disease severity or reliable
decline with clinical improvement, and none
of the implicated antithyroid antibodies has
a well defined antigenic target in the brain.
Therefore, it is likely that the antibodies are
not pathogenic but simply an epiphenomenon
reflecting an underlying autoimmune inflam-
matory state.30 For this reason many believe
Hashimoto’s encephalopathy should be rela-
belled ‘steroid responsive encephalopathy
associated with autoimmune thyroiditis’. 31
Treatment is with corticosteroids, at least ini-
tially, and virtually all patients improve (44 out
of 45 in one series).33 Lack of response should
prompt review of the diagnosis.
PRIMARY CNS VASCULITIS
Primary CNS vasculitis is a rare condition, fre-
quently suspected but seldom confirmed. It typ-
ically presents in middle age, more commonly
in men, with headache, encephalopathy and
sometimes strokes. Serological inflammatory
markers and autoimmune bloods (antinuclear
antibody, extractable nuclear antigens, etc) are
usually normal. CSF and brain MRI are often
abnormal but non-specific. Cerebral angiog-
raphy may be helpful but is of low specificity
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Katherine Murray 25
and sensitivity so the diagnosis requires brain The commonest
and meningeal biopsy. The importance of this
rare condition, and one reason it appears so malignancies
frequently on differential diagnosis lists, is the misdiagnosed
potential for improvement with immunother-
apy (corticosteroids and cyclophosphamide).34 as prion disease
Cerebral amyloid angiopathy related inflam- are primary CNS
mation may represent one subset of CNS vasc-
ulitis. It refers to a distinct subtype of amyloid lymphoma and
angiopathy that presents with a subacute intravascular
encephalopathy, headache, seizures and focal
neurological deficits, rather than the more
lymphoma
common amyloid angiopathy related haem-
orrhages. MRI reveals white matter changes,
sometimes with vasogenic oedema mimicking
a space occupying lesion. If biopsied there is
evidence of an inflammatory process around
vascular deposits of amyloid-β. Unlike other
amyloid deposition diseases this is reported to
respond to immunosuppression.35
MALIGNANCIES
The commonest malignancies misdiagnosed
Protected by copyright.
as prion disease are primary CNS lymphoma
and intravascular lymphoma, both rare and
challenging to diagnose without brain biopsy.
Primary CNS lymphoma comprises high
grade, non-Hodgkin B cell-type lymphoma.
Immunosuppression is a risk factor but most
still occur in immunocompetent individuals. It
can present as a progressive focal neurological
deficit or as a subacute encephalopathy, par-
ticularly in HIV positive patients. CSF cytology
is often negative and brain MRI appearances
are highly variable but characteristically
demonstrate solitary or multifocal contrast
enhancing lesions. Previously it was invariably
fatal but recent advances in chemoradiother-
apy result in prolonged survival in 20–40%.36
Intravascular lymphoma is an even rarer
manifestation of non-Hodgkin’s lymphoma
where the lymphocytes are restricted to the
lumen of small and medium sized blood ves-
sels. It typically presents with symptoms sec-
ondary to CNS or skin involvement, or with
fever of unknown origin, but can involve vir-
tually any organ. Relapsing stroke-like presen-
tations are classical but subacute dementia
can occur. Brain MRI may provide a clue to the
diagnosis with acute ischaemic lesions in addi-
tion to raised serum lactate dehydrogenase,
especially if there is clinical or subclinical skin
involvement, but the diagnosis is often only
made at autopsy.37
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26 Practical Neurology

SUBACUTE SCLEROSING include more extensive blood tests, MR brain

PANENCEPHALITIS
Subacute sclerosing panencephalitis is due
to a mutated, slow but persistent form of
the wild measles virus. Although rare and
usually a paediatric illness it can be seen in
young adults and the clinical phenotype of
prominent myoclonus, progressive cognitive
decline, visual disturbance, and pyramidal and
extrapyramidal signs can easily be mistaken
for CJD (although the age of onset is against
sporadic prion disease). The typical EEG abnor-
mality in subacute sclerosing panencephalitis
is periodic triphasic complexes but usually at a
lower frequency than in sCJD. The diagnosis is
confirmed by raised antimeasles antibody titre
in the CSF.38 It is invariably fatal, usually within
1–3 years of onset, with less than 10% having
more prolonged survival.
INVESTIGATIONS AND MAKING
THE DIAGNOSIS
Box 2 summarises the recommended investi-
imaging, CSF examination and usually EEG.
The precise sequence of these tests depends
on their availability and the clinical scenario
in practice, they often occur simultaneously,
and frequently a positive result in one area (eg,
anti-VGKC antibody or anti-TPO antibody) does
not negate the need for other tests (brain MRI,
CSF). In most cases a diagnosis is reached but
if not there are a number of options.
If the neurology team feel sCJD remains
likely despite the lack of overwhelmingly sup-
portive investigations then:
• The patient can be discussed and referred
to one of the two national UK CJD surveil-
lance teams.
• Alternatively, a watch and wait approach
can be taken, particularly if the patient
is elderly with disease duration over 12
months; in such instances the final diag-
nosis is likely to be neurodegenerative and
hence not curable. This approach needs to
be discussed carefully with relatives, with

Protected by copyright.
regular reviews scheduled. Obviously mak-
gations in subacute encephalopathy patients ing a diagnosis remains the aim, if only to
where sCJD is suspected. Assuming no diagnosis guide prognosis and minimise unneces-
is apparent after preliminary screening bloods sary procedures.
and imaging, the secondline investigations • Thirdly, further investigations can be
undertaken, including repeating earlier
tests such as the EEG and brain MRI, par-
Box 2 Investigation algorithm
ticularly if the patient has significantly
progressed, in addition to considering
Initial screening tests
brain biopsy. This last option carries signif-
Bloods: urea, electrolytes, full blood count, liver function, thyroid
icant risk, including haemorrhage, infec-
function, glucose, C reactive protein, erythrocyte sedimentation rate,
tion, permanent focal deficit and seizures.
vitamin B12, folate
An analysis of 90 biopsies undertaken to
Urinalysis
investigate dementia where a reversible
Chest x ray
cause was suspected found 57% were
CT brain
diagnostic (the most common diagno-
Secondline investigations
ses being neurodegenerative) but in only
Bloods: ammonia, antithyroid antibodies, paraneoplastic antibody screen,
10 of the 90 cases (11%) did the pathol-
ANA (antinuclear antibody), ENA (extractable nuclear antigens), ANCA
ogy result directly modify treatment.39
(antinuclear cytoplasmic antibody), anticardiolipin antibodies, Borrelia
Generally, in suspected CJD biopsy is not
serology, HIV, neurosyphilis screen, angiotensin converting enzyme,
necessary or recommended, with possible
lactate dehydrogenase
exceptions being younger cases where
CSF: cell count, protein, glucose, cytology, oligoclonal bands, viral PCR,
CNS vasculitis or another inflammatory
14-3-3
process is strongly suspected but cannot
MRI brain (including DWI, FLAIR and contrast examination)
be confirmed with less invasive investiga-
EEG
tions. Neurosurgical instruments used in
Thirdline investigations (variably indicated depending on other results)
suspected CJD patients should generally
Cerebral angiography (digital subtraction angiography)
be destroyed and not reused.
CSF: AAFB (acid and alcohol fast bacilli) stain, antimeasles antibody titre,
• A fourth option often raised is an empirical
Whipple’s PCR, JC virus PCR
trial of corticosteroids. While many argue
CT chest/abdomen/pelvis or whole body positron emission tomography
this is unlikely to cause harm, steroids do
Prion protein genotyping
have potentially serious adverse effects,
Jejunal biopsy (Whipple’s disease)
and a blind trial raises difficult questions;
Brain biopsy
if there is no prompt improvement how
10.1136/jnnp.2010.235721
 Pract Neurol: first published as 10.1136/jnnp.2010.235721 on 14 January 2011. Downloaded from http://pn.bmj.com/ on December 16, 2023 at Portsmouth Hospitals University NHS Trust.
Katherine Murray 27

long do you continue for, at what dose

and do you try alternatives such as intra-
venous immunoglobulin (bearing in mind
even Hashimoto’s encephalopathy does
not always respond to steroids immedi-
ately and this is especially true for anti-
body mediated limbic encephalitis)? Even
if patients do appear to improve, one still
needs a diagnosis to guide future manage-
ment. Generally, empirical immunosup-
pression is only recommended if there is a
significant chance of a steroid responsive
encephalopathy, as suggested by inflam-
matory CSF, raised antibody titres or serum
markers supporting a diagnosis of a ste-
roid responsive condition like Hashimoto’s
encephalopathy or VGKC encephalitis.
PRACTICE POINTS
• Most sCJD mimics are neurodegenerative and rarely is there a treatable
alternative; the minority with potentially reversible pathology tend to be
younger, with inflammatory CSF or positive serum antibodies.
• Disease duration is the most reliable distinguishing feature18; the diagnosis
of sCJD should be reviewed in patients surviving over a year and particularly
over 2 years.
• CSF examination and EEG are useful but relatively non-specific investiga-
tions in the work-up for sCJD and its mimics.
• MR brain imaging has emerged as an increasingly valuable tool in identify-
ing sCJD, particularly because most of the main differential diagnoses do
not show the same caudate/putamen high signal.

....the case continued

The 44-year-old woman initially described in this article had ongoing fluctuating confusion
and developed auditory and visual hallucinations but no other new features. Further
investigation revealed a strongly positive anti-La titre of 132 (normal range 0–25) and weakly
positive thyroid peroxidase antibody level of 109 (normal range 0–50 IU/ml). All other blood
tests were normal or negative, including thyroid function, antinuclear antibodies, anti-

Protected by copyright.
VGKC antibody, anti-NMDA receptor antibody and paraneoplastic screen. Based on these
results suggesting an immune mediated process and her inflammatory CSF, she was treated
with 1 g/day of methyl prednisolone for 3 days followed by oral prednisolone. Within a week
there was a marked improvement in her cognition with resolution of the neurological signs
although visual misperceptions persisted. A presumptive diagnosis of a steroid responsive
encephalopathy was made. She continued to improve on oral prednisolone, deteriorating
when the dose dropped to 30 mg daily and improving again when the dose was increased
to 40 mg, and is now leading a normal life.

ACKNOWLEDGEMENTS transmissible spongiform encephalopathies.

Thanks to Robert Will for his helpful sug-
gestions after reading this article, and David
Simpson for the case update. This article was
reviewed by Geraint Fuller, Gloucester.
Patient consent Obtained.
Provenance and peer review Commissioned;
externally peer reviewed.
Competing interests None.
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