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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
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
Sporadic Creutzfeldt–Jacob disease (sCJD) is a
neurodegenerative, uniformly fatal prion disease characterised pathologically by spongiform change within the brain. The cause is
unknown. It is rare, with an annual incidence
in the UK of 1–1.5/million, meaning that on
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
Correspondence to
Dr K Murray, Specialist Registrar,
Department of Clinical
Neurosciences, Western General
Hospital, Crewe Road South,
Edinburgh EH4 2XU, UK;
[email protected]
www.practical-neurology.com
20 Practical Neurology
Most infective
encephalopathies
are too acute to be
confused with CJD
differential diagnoses, particularly those disorders which are amenable to treatment.
THE DIAGNOSTIC POSSIBILITIES
There is a wide differential for subacute encephalopathy (table 1). However, a large number of
Table 1 Differential diagnosis of subacute encephalopathy
Metabolic/endocrine
Drug/toxic/nutritional
Infection
Systemic
CNS
In immunocompromised
Autoimmune antibody
associated
Malignancy (nonparaneoplastic)
Inflammatory
Vascular
Neurodegenerative
Other
Uraemic encephalopathy
Hepatic encephalopathy
Hypo/hyperthyroid
Hypoglycaemia
Hyponatraemia (including central pontine
myelinolysis)
Hypercalcaemia
Chemotherapy (eg, methotrexate)
Lithium toxicity
Alcohol
Chronic carbon monoxide poisoning
Wernicke–Korsakoff syndrome
Vitamin B12 deficiency
Pneumonia, urinary tract
HSV1/2, enterovirus, varicella zoster, Epstein–
Barr, Lyme, HIV, TB, listeria
Syphilis, HHV 6, cytomegalovirus,
measles, JC virus (progressive multifocal
leukoencephalopathy), fungal/parasitic
Paraneoplastic
Non-paraneoplastic—antivoltage gated
potassium channel antibodies
Malignant meningitis
Primary CNS malignancy
Cerebral metastases
Vasculitis
Sarcoid
Systemic lupus erythematosus
Sjögren’s syndrome
Hashimoto’s encephalopathy
Multiple sclerosis/acute disseminated
encephalomyelitis
Intracranial venous thrombosis
Behcet’s disease
Prion disease—sporadic, variant, genetic and
iatrogenic CJD
Rarely rapid presentations of other
neurodegenerative diseases such as Alzheimer’s
disease, and dementia with Lewy bodies
Mitochondrial cytopathy
Psychiatric such as schizophrenia and severe
depression
Irradiation
CJD, Creutzfeldt–Jakob disease; HHV, human herpes virus; HSV, herpes
simplex virus; TB, tuberculosis.
10.1136/jnnp.2010.235721
potential causes can be confirmed or excluded
fairly quickly with a detailed history, including of drug and alcohol use, and some simple
investigations such as routine bloods, CSF and
CT brain imaging (eg, drug/toxic encephalopathy, 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 common causes of encephalitis, such as herpes
simplex virus (HSV) 1 and 2, can present as a
subacute encephalopathy. Clearly, if there is
concern about herpes simplex encephalitis it is
prudent to treat with acyclovir until the diagnosis is excluded (usually by a negative HSV
PCR on CSF). However, the clinical picture of
fever, headache, reduced consciousness with
CSF pleocytosis in addition to sometimes focal
changes on MRI usually makes the diagnosis
of an infective process relatively straightforward. The situation becomes more complicated in the immunocompromised patient or
returning travellers, with a much wider differential diagnosis which is beyond the scope of
this article.1
SPORADIC CJD
The mean age of sCJD disease onset is 66 years
with most cases presenting between the ages
of 50 and 75 years although patients as young
as 142 and as old as 863 have been reported.
There is no gender difference. Disease duration
is typically short, with a median of 6 months
from onset to death. Only 14% of cases survive longer than a year and only 5% live for
2 years or more.4
Clinical picture
The characteristic clinical picture in sCJD is
one of rapidly progressive dementia with
associated neurological features, particularly
cerebellar ataxia, pyramidal signs and myoclonus. Visual disturbance, ocular movement
disorders, extrapyramidal signs and hallucinations are also well recognised. The final stages
are characterised by an akinetic mute state.
The illness may be preceded by a non-specific prodrome, including fatigue, low mood,
weight loss and headache for a few months.
Although the commonest sCJD presentation is
with a subacute encephalopathy, other onsets
include pure cerebellar, visual, psychiatric and
stroke-like syndromes. The rapidity of deterioration in sCJD usually helps distinguish it
Katherine Murray 21
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 normal 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 sensitivity 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 pathologically atypical, with a younger age of onset
and prolonged disease duration. The value of
the test is much less when used as a screening 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 conditions, including stroke, paraneoplastic disease,
inflammation and post-seizure activity.
MR brain imaging characteristically demonstrates 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
most sensitive, with diffusion weighted imaging being particularly good at detecting early
changes in both the striatum and cortex.9 The
differential diagnosis for high signal in the
basal ganglia includes Wilson’s disease, carbon monoxide poisoning, mitochondrial disorders and variant CJD (although in the last
the posterior thalamic hyperintensity is more
pronounced than the caudate/putamen signal
change). However, most of these conditions
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 periodic, triphasic sharp wave complexes at a frequency of 1/s, usually generalised throughout
the trace (figure 2). Objective criteria have been
published and when these are applied, the sensitivity 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
positive EEGs are recognised in Alzheimer’s
disease, Lewy body dementia, vascular dementia11–13 and other less likely to be confusing clinical scenarios, such as lithium toxicity.
sCJD can only be confirmed by pathology but brain biopsy is rarely required in life
because of the characteristic clinical phenotype plus supportive investigations (box 1).14
The EEG lacks
sensitivity in the
early stages of sCJD
and serial traces
may be required to
detect the typical
pattern
Issues in diagnosis
The usual difficulty in diagnosis lies in atypical presentations, or those with negative
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).
www.practical-neurology.com
22 Practical Neurology
Figure 2
Typical EEG in sporadic Creutzfeldt–Jacob disease showing generalised periodic triphasic complexes.
Box 1 Current WHO criteria for sporadic Creutzfeldt–Jacob disease
(sCJD): Rotterdam 1998*
I Rapidly progressive dementia
II (A) Myoclonus
(B) Visual or cerebellar problems
(C) Pyramidal or extrapyramidal features
(D) Akinetic mutism
III Typical EEG
1.0 Definite: Neuropathologically/immunocytochemically confirmed
2.0 Probable: I + 2 of II + III or I + 2 of II + positive 14-3-3 CSF protein
3.0 Possible: I + 2 of II + duration <2 years
4.1 Unclear diagnosis, not meeting sCJD criteria
4.2 Clinical diagnosis not sCJD
*Soon to be amended to incorporate brain MRI changes8
investigations, in particular cases where the
diagnosis may be CJD but there is a nagging
doubt that a potentially treatable condition
may have been overlooked. No single clinical
feature distinguishes CJD. Myoclonus, while
typically prominent in CJD, also occurs in
many other conditions, including Alzheimer’s
disease, corticobasal degeneration and
immune mediated encephalopathies, so it is
not specific. One study found presentation
with visual disturbance was the most useful
feature distinguishing sCJD from CJD mimics (positive predictive value 93%) but in a
highly selected population referred to a CJD
unit, whereas extrapyramidal signs and early
10.1136/jnnp.2010.235721
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 representative 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 presenting with a rapidly progressive dementia
or subacute encephalopathy where readily
identifiable alternative diagnoses have been
excluded and sCJD is suspected but subsequently disproven.11–13 15
In the UK, the two UK CJD surveillance centres perform CSF 14-3-3 testing and genotyping for genetic CJD. All suspected cases of any
form of CJD should be discussed with them by
faxing the National CJD referral form (downloaded from www.uclh.nhs.uk or www.cjd.
ed.ac.uk) to the National CJD Surveillance Unit,
Edinburgh and National Prion Clinic, London.
NEURODEGENERATIVE sCJD
MIMICS
The commonest sCJD mimics are neurodegenerative, including Alzheimer’s disease, dementia with Lewy bodies (DLB), frontotemporal
dementia and the tauopathies such as corticobasal degeneration and progressive supranuclear palsy.17 18
Alzheimer’s disease
Alzheimer’s disease can be mistaken for sCJD
for a number of reasons. While an individual
with Alzheimer’s disease typically survives
anywhere between 4 and 8 years, there are
more aggressive cases dying after just a year
or two. Myoclonus is well recognised and
reported in 10%, particularly in the later stages.
Investigations can confuse matters, with periodic triphasic waves being seen occasionally
on EEG and positive CSF 14-3-3 results.
Dementia with Lewy bodies (DLB)
DLB can also mimic sCJD. The classic DLB phenotype, as defined in the diagnostic criteria, of
progressive dementia with particular attentional, visuospatial and subcortical deficits,
Katherine Murray 23
marked fluctuations, visual hallucinations
and parkinsonism is unlikely to be misdiagnosed.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 distinguishing feature although in DLB hallucinations 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.
Table 2 ’Filtered’ differential diagnosis of sporadic Creutzfeldt–
Jacob disease
Neurodegenerative
Immune mediated
Corticobasal degeneration
One study found that corticobasal degeneration 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, myoclonus, alien limb and parkinsonism in corticobasal degeneration (all features well recognised
in CJD) in addition to the lack of supportive
investigations as corticobasal degeneration is
essentially a clinical diagnosis.
Infective
Other
Genetic CJD
Genetic CJD should be considered in both typical 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
Alzheimer’s disease
Dementia with Lewy bodies
Frontotemporal dementia +/− motor neuron disease
Corticobasal degeneration
Progressive supranuclear palsy
Other prion disease (genetic, iatrogenic, variant CJD)
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
Viral encephalitis (enterovirus, HSV 1 or 2,
cytomegalovirus, Epstein–Barr virus, HIV, West Nile
(not UK), Japanese encephalitis B)
Lyme disease (Borrelia)
Whipple’s disease (Tropheryma whippelii)
Subacute sclerosing panencephalitis
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 syndrome—symptoms evolving slowly over more
than a few months are unlikely to be paraneoplastic. 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 onconeuronal 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
neuropil of the hippocampus21:
•
Anti-Hu is the commonest and these
patients often have other, non-limbic
neurological features such as ataxia and
sensory neuronopathy, in addition to
small cell lung cancer.
Genetic CJD should
be considered in
both typical and
atypical sCJD
presentations
www.practical-neurology.com
24 Practical Neurology
•
•
•
•
Up to 40% of
paraneoplastic
limbic encephalitis
cases have
no detectable
antibodies
10.1136/jnnp.2010.235721
Anti-amphiphysin syndromes occur with
breast cancer and small cell lung cancer,
often with stiff person syndrome in conjunction 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 underlying 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 immunotherapy.23 It is also reported without associated tumour.24
Investigations in paraneoplastic limbic
encephalitis are usually abnormal, with brain
MRI showing atrophy or mesial temporal signal change in the majority, and CSF pleocytosis 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 current testing although this figure will shrink as
more antibodies are identified. In these cases
the diagnosis is based on the clinical phenotype 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 paraneoplastic syndromes, discovery of the underlying
malignancy frequently postdates the neurology, sometimes by several years. This means
that if initial cancer screening investigations
(eg, mammography, tumour markers, testicular
ultrasound, CT chest/abdomen/pelvis or whole
body positron emission tomography depending on availability) are negative they should be
repeated after an interval. The frequency and
duration of these malignancy screening tests
are debated but a pragmatic approach might
be after 6–12 months initially, and subsequently 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 clinical and immunological features of 10 cases of
VGKC associated limbic encephalitis was published.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 recognised, including sleep disorders (loss of rapid
eye movement (REM) sleep, REM sleep behaviour disorder), tremor and refractory epilepsy.
Hyponatraemia is common secondary to the
syndrome of inappropriate antidiuretic hormone secretion and this may help distinguish it
from paraneoplastic limbic encephalitis.
The antibody assay uses binding of radio-iodine labelled α-dendrotoxin to specific potassium 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 intermediate antibody levels (100–400 pM) is unclear.
According to one study, just under half the
patients have mild lymphocytosis or raised protein 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 potentially 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 presenting in middle age with a fluctuating encephalopathy including rapid cognitive decline,
seizures, neuropsychiatric manifestations and
Katherine Murray 25
sometimes movement disorders such as tremor
or myoclonus, ataxia, stroke-like episodes and
even coma.30 31 However, the clinical phenotype is variable.32 Individuals may be euthyroid,
hypothyroid or less often hyperthyroid.
The CSF is frequently abnormal but nonspecific with modestly raised protein (generally 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 demonstrate non-specific white matter changes,
which interestingly frequently resolve with
treatment, as do the EEG abnormalities.31
The diagnosis is based on an appropriate clinical phenotype with other conditions
excluded in addition to raised antithyroid
antibodies (antithyroglobulin and thyroid peroxidase 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 antibody 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 inflammatory state.30 For this reason many believe
Hashimoto’s encephalopathy should be relabelled ‘steroid responsive encephalopathy
associated with autoimmune thyroiditis’. 31
Treatment is with corticosteroids, at least initially, 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, frequently suspected but seldom confirmed. It typically 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 angiography may be helpful but is of low specificity
and sensitivity so the diagnosis requires brain
and meningeal biopsy. The importance of this
rare condition, and one reason it appears so
frequently on differential diagnosis lists, is the
potential for improvement with immunotherapy (corticosteroids and cyclophosphamide).34
Cerebral amyloid angiopathy related inflammation may represent one subset of CNS vasculitis. It refers to a distinct subtype of amyloid
angiopathy that presents with a subacute
encephalopathy, headache, seizures and focal
neurological deficits, rather than the more
common amyloid angiopathy related haemorrhages. 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
The commonest
malignancies
misdiagnosed
as prion disease
are primary CNS
lymphoma and
intravascular
lymphoma
MALIGNANCIES
The commonest malignancies misdiagnosed
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, particularly 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 chemoradiotherapy 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 vessels. It typically presents with symptoms secondary to CNS or skin involvement, or with
fever of unknown origin, but can involve virtually any organ. Relapsing stroke-like presentations are classical but subacute dementia
can occur. Brain MRI may provide a clue to the
diagnosis with acute ischaemic lesions in addition 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
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 abnormality 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.
include more extensive blood tests, MR brain
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 supportive investigations then:
•
•
INVESTIGATIONS AND MAKING
THE DIAGNOSIS
Box 2 summarises the recommended investigations in subacute encephalopathy patients
where sCJD is suspected. Assuming no diagnosis
is apparent after preliminary screening bloods
and imaging, the secondline investigations
Box 2
•
Investigation algorithm
Initial screening tests
Bloods: urea, electrolytes, full blood count, liver function, thyroid
function, glucose, C reactive protein, erythrocyte sedimentation rate,
vitamin B12, folate
Urinalysis
Chest x ray
CT brain
Secondline investigations
Bloods: ammonia, antithyroid antibodies, paraneoplastic antibody screen,
ANA (antinuclear antibody), ENA (extractable nuclear antigens), ANCA
(antinuclear cytoplasmic antibody), anticardiolipin antibodies, Borrelia
serology, HIV, neurosyphilis screen, angiotensin converting enzyme,
lactate dehydrogenase
CSF: cell count, protein, glucose, cytology, oligoclonal bands, viral PCR,
14-3-3
MRI brain (including DWI, FLAIR and contrast examination)
EEG
Thirdline investigations (variably indicated depending on other results)
Cerebral angiography (digital subtraction angiography)
CSF: AAFB (acid and alcohol fast bacilli) stain, antimeasles antibody titre,
Whipple’s PCR, JC virus PCR
CT chest/abdomen/pelvis or whole body positron emission tomography
Prion protein genotyping
Jejunal biopsy (Whipple’s disease)
Brain biopsy
10.1136/jnnp.2010.235721
•
The patient can be discussed and referred
to one of the two national UK CJD surveillance 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 diagnosis is likely to be neurodegenerative and
hence not curable. This approach needs to
be discussed carefully with relatives, with
regular reviews scheduled. Obviously making a diagnosis remains the aim, if only to
guide prognosis and minimise unnecessary procedures.
Thirdly, further investigations can be
undertaken, including repeating earlier
tests such as the EEG and brain MRI, particularly if the patient has significantly
progressed, in addition to considering
brain biopsy. This last option carries significant risk, including haemorrhage, infection, permanent focal deficit and seizures.
An analysis of 90 biopsies undertaken to
investigate dementia where a reversible
cause was suspected found 57% were
diagnostic (the most common diagnoses being neurodegenerative) but in only
10 of the 90 cases (11%) did the pathology result directly modify treatment.39
Generally, in suspected CJD biopsy is not
necessary or recommended, with possible
exceptions being younger cases where
CNS vasculitis or another inflammatory
process is strongly suspected but cannot
be confirmed with less invasive investigations. Neurosurgical instruments used in
suspected CJD patients should generally
be destroyed and not reused.
A fourth option often raised is an empirical
trial of corticosteroids. While many argue
this is unlikely to cause harm, steroids do
have potentially serious adverse effects,
and a blind trial raises difficult questions;
if there is no prompt improvement how
Katherine Murray 27
long do you continue for, at what dose
and do you try alternatives such as intravenous immunoglobulin (bearing in mind
even Hashimoto’s encephalopathy does
not always respond to steroids immediately and this is especially true for antibody mediated limbic encephalitis)? Even
if patients do appear to improve, one still
needs a diagnosis to guide future management. Generally, empirical immunosuppression is only recommended if there is a
significant chance of a steroid responsive
encephalopathy, as suggested by inflammatory CSF, raised antibody titres or serum
markers supporting a diagnosis of a steroid 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 investigations in the work-up for sCJD and its mimics.
MR brain imaging has emerged as an increasingly valuable tool in identifying 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, antiVGKC 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
Thanks to Robert Will for his helpful suggestions 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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