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 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 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

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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).

The EEG lacks sensitivity in the early stages of sCJD and serial traces may be required to detect the typical pattern

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.

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Figure 2

Typical EEG in sporadic Creutzfeldt–Jacob disease showing generalised periodic triphasic complexes.

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

Issues in diagnosis

The usual difficulty in diagnosis lies in atypical presentations, or those with negative 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 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.

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, 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.

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.

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

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 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.

• 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

Genetic CJD should be considered in both typical and atypical sCJD presentations

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.

Up to 40% of paraneoplastic limbic encephalitis cases have no detectable antibodies

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 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 non-specific 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.