Inga Zerr, Department of Neurology, Georg-August University, Robert-Koch-Str. 40, 37075 Göttingen, Germany. e-mail: IngaZerr@aol.com
The most widely distributed form of transmissible spongiform encephalopathy, sporadic Creutzfeldt-Jakob disease, typically affects patients in their sixties. Rapidly progressive dementia is usually followed by focal neurological signs and typically myoclonus. The disease duration in sporadic CJD is shorter than in variant CJD (6 months and 14 months, respectively). The clinical diagnosis in sporadic CJD is supported by the detection of periodic sharp and slow wave complexes in the electroencephalogram, hyperintense signals in basal ganglia on magnetic resonance imaging and elevated levels of neuronal proteins in the cerebrospinal fluid (such as 14-3-3). In contrast to the sporadic form, hyperintense signals in the posterior thalamus (``pulvinar sign'') are seen in variant CJD. Following recent developments in diagnostic premortem techniques, clinical criteria for probable sporadic and probable variant CJD were established. Clinicopathological studies on sporadic CJD revealed different phenotypes which are characterized by neuropathological lesion profile, clinical syndrome, codon 129 genotype and type of proteinase K-resistant core of the prion protein. Alzheimer's disease and Lewy body dementia are the most frequent differential diagnoses in sporadic CJD in elderly patients, whereas chronic inflammatory disorders of the central nervous system have to be considered in younger patients.
In the early 1920s, Hans Gerhard Creutzfeldt and Alfons Jakob were the first to describe the human spongiform encephalopathies as rare neurodegenerative diseases (later also designated as transmissible spongiform encephalopathies or prion diseases) (1, 2). For many decades, human Creutzfeldt-Jakob disease was considered to be an exclusively neurodegenerative disorder. Later on, hereditary forms (familial/genetic CJD, Gerstmann-Sträussler-Scheinker syndrome (GSS), fatal familial insomnia, FFI) were identified. Transmitted cases (either by ritual cannibalism as kuru or due to iatrogenic exposure) have been identified in recent decades. During the past 6 years, a new form of human CJD (variant CJD, vCJD), which is linked to the BSE epidemic in Europe, has been identified (3).
Human spongiform encephalopathies were considered to be rare diseases of the central nervous system and, in addition, many neurologists believed that the diagnosis is difficult during life time because of overlapping clinical syndromes in other neurodegenerative diseases. According to currently used diagnostic criteria, definite diagnosis of CJD is still considered to be possible only after autopsy (4, 5). However, in recent years advances in the clinical characterisation of different CJD phenotypes have been made and many diagnostic techniques are under development, helping to achieve a precise diagnosis of this disorder during life time (6, 7). The clinical diagnosis of typical sporadic CJD is supported by a variety of clinical tests (cerebrospinal fluid, electroencephalogram, magnetic resonance images). In contrast, many of these tests do not give positive results in genetic cases. As the family history of a neurodegenerative disorder is known only by 30% of relatives, analysis of the PRNP gene is necessary for the diagnosis of genetic prion disease in many of these patients (8). A very special situation arises in the diagnosis and differential diagnosis of variant CJD. Among non-invasive tests, only magnetic resonance imaging seems to support the clinical diagnosis (9). As the pathological form of the prion protein is detectable in peripheral tissues in these patients (tonsil, lymph nodes, appendix, spleen), tonsil biopsy has been suggested for diagnostic purposes (10).
CLINICAL FEATURES OF SPONGIFORM ENCEPHALOPATHIES
Sporadic Creutzfeldt-Jakob disease
CJD usually occurs in middle and old age, and typically affects patients in the seventh decade of life (11, 12). Women are slightly more often affected than men. There are no specific symptoms at disease onset. Most often, depressive personality changes, sleep disorders and loss of weight occur. Impairment of cognitive functions or behavioural abnormalities are key symptoms and are found in most patients (Fig. 1). Psychiatric features are frequent, and about 12% of sporadic CJD patients are reported to epidemiological surveillance studies by psychiatrists. Visual disturbances are often observed in CJD patients (in 126 out of 238 fully analysed cases in the German CJD Surveillance study). Patients complain of blurred vision and poor eyesight. In some cases, cortical anopsia can be verified. Visual hallucinations occur in both patients with and without other visual disturbances and are more frequently reported at the beginning of the disease (Fig. 2). They are usually composed of complex visual phenomena (many different forms, visions of people, images of animals, inanimate objects) and scenic hallucinations. Auditory hallucinations are less common. In most cases there are delusions of suspicion and persecution and patients are alarmed that strange things are happening around them and in their home and that non-existent people are living in or entering the house. Television images are misidentified as being real. In most cases these symptoms are present only for a short time at the initial stage of the disease.
The disease may start with exclusively neurological deficits, mostly with cerebellar dysfunction (gait ataxia) or cortical visual impairment. Patients develop a gradual decline in memory and a loss of higher functions. In rare cases, paraesthesia or myoclonus may be the initial symptom of the disease. Apart from rapidly progressive dementia, myoclonus (involuntary muscle twitching without unconsciousness) typically develops, which often raises the suspicion of CJD for the first time. Typically, myoclonus can be elicited by loud noise or tactile stimuli (startle response). Pyramidal dysfunction (spastic paresis with pyramidal tract signs) and extrapyramidal dysfunction occur as a consequence of the involvement of many nuclei and tracts of the central nervous system (Table 1).
Table 1. Clinical symptoms and signs at disease onset and during course in sporadic CJD (n=725 definite and probable CJD, German CJD surveillance)
Variant Creutzfeldt-Jakob disease
The clinical course in variant CJD (vCJD) is characterised by distinct features: psychiatric abnormalities (behavioural abnormalities, depression, anxiety) are the initial symptoms during early-stage disease (Table 2).. With some exceptions, almost all patients with vCJD exhibit psychiatric features in the early stages of the disease (13) (Table 3) Symptoms may occur in isolation in the majority of cases. In many patients, pain in the limbs or joints or painful paraesthesia or dysaesthesia is present. The first signs of cognitive decline are noted at a median of 5 months after disease onset. The first neurological deficits such as ataxia or involuntary movements are usually observed 6 to 7 months after onset. Following a median disease duration of 9 months, myoclonus or choreatic movements develop. Akinetic mutism is usually present after a median disease duration of 12 months (14). In contrast to sporadic CJD, the disease duration (median 14 months) is almost twice as long as in sporadic CJD patients. Initially, the disease was observed mainly in young patients at a median age at onset of 29 years (range 14–74). Since the first vCJD case in a 74-year old man this disorder will also be a differential diagnosis of rapid progressive dementia in older patients (15).
Table 2. Clinical signs in vCJD during clinical course (n=14) (14)
Table 3. Psychiatric features of new variant CJD
Withdrawal Delusions Aggression/irritability Anxiety Hallucinations Depression First rank symptoms Forgetfulness at onset Suicidal ideation
Genetic prion diseases
Early studies revealed a familial accumulation of CJD in about 5–10% of patients. In these patients, mutations in the open reading frame of the human prion protein gene (PRNP) were identified. The human prion protein gene is located on the short arm of chromosome 20. More than 20 different point mutations and insertion mutations have been described up to now. The insertion mutations are located within the octapeptide repeat region in the N-terminal half of the protein, while the point mutations are concentrated in the C-terminal moiety of the protein. The most frequent mutations are located at codons 200, 178 and 102.
Familial CJD with codon 200 mutation. The clinical syndrome in patients with a mutation at codon 200 (glutamic acid to lysine) resembles clinical features usually observed in sporadic CJD. Clusters of patients with this mutation have been identified worldwide, with the earliest descriptions coming from Slovakia, Libya and Israel. Patients carrying this mutation develop the disease earlier than sporadic cases (median 50–60 years vs 60–70 years). The clinical syndrome is characterized by progressive cognitive decline, visual hallucinations and/or cortical blindness. Psychosis or depression at onset are frequently reported, similar to other CJD forms. Cerebellar ataxia, myoclonus, pyramidal tract signs and extrapyramidal signs gradually evolve during the disease course and tonic-clonic seizures are also reported (16, 17).
Fatal familial insomnia (FFI). The term fatal familial insomnia was first used in 1986 to describe a neurodegenerative illness in five members of a large Italian family (18). PRNP analysis revealed a mutation in codon 178 of the gene, which results in the substitution of asparagine with aspartic acid. This condition was considered to be very rare until systematic studies revealed that it might be the most common genetic prion disease in some countries (8).
The most prominent and striking clinical feature in these patients is the complete disruption of the normal sleep-wake cycle, which can be seen in polysomnography as a complete disorganisation of the electroencephalographic pattern of sleep. Autonomic disturbances (sympathetic overactivity) and disruption of the circadian oscillations of endocrine functions are observed early in the disease. A variety of hallucinations may occur which resemble dreamlike oneiroic states. Later in the disease progression, other abnormalities such as myoclonus, pyramidal and extrapyramidal signs are found at clinical examination (19).
Gerstmann-Sträussler-Scheinker syndrome. This syndrome was originally described in a large Austrian family. Patients were described as suffering from slowly progressive cerebellar ataxia and late cognitive decline. Genetic studies revealed the linkage to codon 102 mutation (prolin to leucine). Patients are usually affected in their fifth or sixth decade. In contrast to sporadic CJD, the disease progresses more slowly and the overall disease duration may span between several months to several years (median 5 years, up to 13 years). At disease onset, many patients develop unsteady gait, limb ataxia, dysmetria, dysdiadochokinesia and dysarthria. As the symptoms slowly progress, other motor abnormalities (pyramidal tract signs, extrapyramidal abnormalities and myoclonus) are observed. Dementia is usually apparent later in the disease, but cases with prominent dementia at onset are also reported (19).
Codon 129 genotype. The methionine/valine polymorphism at amino acid position 129 (either homomozygosity for methionine (MM) or valine (VV) or heterozygosity (MV) of the prion protein gene influences the neuropathological characteristics of the sporadic and hereditary variants of human transmissible spongiform encephalopathies (20–25). Homozygosity at codon 129 is considered to be a predisposing risk factor for sporadic CJD (Table 4). VV patients with sporadic CJD tend to be younger than patients who are either MM or MV at codon 129 (23). All patients with vCJD examined so far have been homozygous for methionine at codon 129 (26). Homozygous patients with iatrogenic CJD have shorter incubation periods than heterozygous patients (the first MM and VV cases occurred in 1989, MV cases in 1994) (27). In homozygous patients with kuru, the disease occurred earlier than in heterozygous patients and a shorter disease duration was observed (28).
Table 4. Codon 129 genotype in CJD and controls
a Population in Germany. b Alpérovitch 1999 (24). c Brown 2000 (47). d Will 2000 (26).
In general, codon 129 genotype is considered to affect the susceptibility (sporadic, variant, iatrogenic CJD), influence incubation time (kuru, iatrogenic CJD and possibly variant CJD) and correlate with the clinicopathological phenotypes of sporadic CJD and genetic prion diseases. (See also: “Classification of sporadic CJD on a molecular basis”).
Prion diseases cause different degrees of brain atrophy. The three classical neuropathological findings of CJD are spongiform degeneration, nerve cell loss and astrocytic gliosis. The immunohistochemical detection of the pathological form of the prion is the basis of the current neuropathological diagnosis of prion disease.
Standard investigations. The cerebrospinal fluid (CSF) parameters in standard investigations (cell count, barrier function and inflammatory reactions) in patients with CJD are in general normal. In patients with neuropathologically confirmed CJD (n=148), a slight pleocytosis (between 5 and 11 cells/mm3) and mildly impaired brain-blood-barrier function in 25% of the cases is observed ((29)). Oligoclonal bands are detected only in exceptional cases (7%). In individual cases, an intrathecal synthesis of antibodies against herpes simplex (3/18) or varizella zoster virus (2/18) is detected. The origin of these abnormalities and the detection of oligoclonal bands in the CSF is not known, but may represent a residuum of earlier inapparent infections. There are only a few studies on these parameters CSF in non-neurological controls; in these patients, similar changes in the CSF were reported (30, 31).
Surrogate marker. In 1986, a research group headed by M. Harrington identified two CSF proteins using two-dimensional gel electrophoresis in CJD that were, however, also present in about 50% of the patients with herpes simplex encephalitis (32). Microsequencing showed that these two CSF proteins belong to the family of the 14-3-3 proteins (11, 23). Their detection was facilitated by the use of Western blot assays. Other brain proteins such as neuron-specific enolase (NSE), S-100 protein, brain-specific creatine kinase, G0-protein and tau protein were measured at high concentrations in the CSF of patients with CJD. Follow-up examinations revealed an increase of these proteins with disease progression as well as a decrease in end-stage disease (33). Similar to findings in Alzheimer's disease, levels of Aβ-amyloid are decreased in the cerebrospinal fluid (34). A detection of the proteinase K-resistant form of the prion protein, typical of CJD, in the CSF would make it possible to perform a diagnostic test when the patients are still alive and such a test is presently still under development.
14-3-3 proteins. Several studies have demonstrated that the detection of 14-3-3 in the CSF is sensitive for the diagnosis of sporadic CJD. Levels of these proteins are high in 95% of sporadic CJD patients (sensitivity) (35). In familial CJD patients bearing codon 200 and codon 210 mutations, the 14-3-3 assay has a similar diagnostic value. In contrast, 14-3-3 proteins are constantly absent in the CSF of patients with fatal familial insomnia and are uncommon in GSS (Table 5). The sensitivity is low in patients with iatrogenic CJD (60%), but may increase when the CSF is taken in later stages of the disease (36). In variant CJD, only half of the patients examined so far were reported to have elevated 14-3-3 levels (37).
Table 5. Detection of 14-3-3 proteins in the cerebrospinal fluid in CJD and controlsa
a German CJD surveillance and BIOMED study (11, 35).
Elevation of 14-3-3 proteins is not specific for Creutzfeldt-Jakob disease. This phenomenon is believed to be due to acute neuronal damage that occurs in several conditions. Therefore, elevated levels are expected also in other acute illnesses with extensive neuronal damage (see Table 6). Usually, these disorders can be diagnosed correctly and differentiated from CJD by means of detailed clinical history and other neurological tests, such as brain imaging, cerebrospinal fluid examination, etc. It should be emphasised that, in the differential diagnosis of neurodegenerative disorders, only rare cases are positive for 14-3-3. In a group of patients reported to CJD surveillance units throughout Europe, only 7% were positive for 14-3-3 (specificity in this particular differential diagnosis 93%).
Table 6. Elevated 14-3-3 levels in neurological disorders
Single cases were reported in: Alzheimer's disease, metabolic, Hashimoto's encephalopathy. (See also: (48)).
CJD Vascular: stroke/hypoxia, haemorrhage Inflammation (acute and chronic) Paraneoplastic Cerebral neoplasia (tumour, metastasis) Shortly after epileptic fits
Among currently available techniques, analysis of CSF is the most sensitive method for substantiating the suspected diagnosis of CJD. Although indicative of acute neuronal damage or astrocytosis, detection of abnormal concentrations of the brain proteins 14-3-3, NSE and S-100 in the CSF alone is not sufficient to reach a diagnosis of CJD and should always only be used in the clinical context (see diagnostic criteria). The identification of the 14-3-3 proteins in CSF, in particular, has proved to be a useful method for discriminating CJD from other forms of dementia. In doubtful cases, lumbar puncture repeated at least 2 weeks after the initial lumbar puncture may be of help in the clinical setting: in sporadic CJD patients, usually a further increase in the 14-3-3 levels is observed. In patients with acute neuronal damage, which may be caused by hypoxia, inflammation, epileptic fit and/or other acute pathological events, a decrease in 14-3-3 levels is frequently seen.
Periodic sharp and slow wave complexes (PSWCs) have since the fifties been regarded as a characteristic electroencephalographic pattern that may point to the diagnosis of CJD. Bilateral alpha activity with generalised irregular theta and delta waves may be found in the EEG in early-stage disease. In addition, intermittent, high-amplitude rhythmic delta wave activity is seen on the EEG. Some patients show periodic sharp and slow wave complexes as early as 3 weeks after onset of the disease. In most cases, however, they occur about 12 weeks after onset, in a few isolated cases even later. In about 60–70% of the patients with sporadic CJD, EEG recordings reveal PSWCs in the course of the disease. In genetic cases, PSWCs are seen in patients with codon 200 and codon 210 mutation, but are absent in fatal familial insomnia and GSS. The EEG is not informative in iatrogenic human growth hormone cases and no PSWCs have so far been observed in patients with vCJD (14, 36).
Magnetic resonance imaging
Magnetic resonance imaging was recently considered to be useful for substantiating the clinical diagnosis of CJD. Atrophy of various brain regions is not a major consistent finding in these patients. However, in 63% of patients hyperintensities in basal ganglia (nucleus caudatus and putamen) are observed and are most prominent in FLAIR (fluid-attenuated inversion recovery) and diffusion-weighted images (see Table 7). In a few isolated cases, these MRI changes may become apparent as early as some weeks or a few months after disease onset. MRI plays a particularly important role in the diagnostic process, as it may allow the discrimination of vCJD from sporadic CJD. The most pronounced signal enhancements in vCJD are observed in the posterior thalamus (“pulvinar sign”) (9, 26). As this signal pattern is present in 78% of the vCJD cases observed, MRI has been included in the diagnostic criteria for vCJD (26).
Table 7. Hyperintensities in the MRI in CJD
a In sporadic CJD, changes in the thalamus are usually less pronounced than in the nucleus caudatus and putamen and can therefore be differentiated from those seen in vCJD.
Nucleus caudatus, putamen
Thalamus (“pulvinar sign”)
Positron emission tomography[18F] FDG-PET
A widespread change in the metabolism in brains of patients with CJD is observed using 18F-2-fluoro-2-deoxy-D-glucose (FDG) and positron emission tomography (PET). All patients investigated so far have reduction of cerebral glucose metabolism in at least one temporal or parietal region (38, 39). The occipital lobe, cerebellum and basal ganglia are involved too. Changes are widespread, often markedly asymmetric and differ from the typical pattern seen in Alzheimer's disease or other neurodegenerative disorders (38) (Table 8). The usefulness of this technique has not so far been evaluated in a large number of patients with CJD.
Table 8. Typical patterns of hypometabolism ([18F]FDG-PET-findings) in dementing diseases
The evolution of clinical symptoms and signs is the basis for the diagnosis of sporadic CJD. To further substantiate the clinically suspected diagnosis, CSF analysis represents the most sensitive of diagnostic tests available at present (Table 9). The set of diagnostic criteria for the classification of CJD has been expanded to include biochemical parameters (35, 40) (Table 10).
Table 9. Sensitivity and specificity of diagnostic techniques in sporadic CJD
a In neurological/psychiatric conditions which are relevant in the differential diagnosis.
Table 10. Clinical diagnostic criteria for sporadic CJD
– Progressive dementia and
– At least two out of four of the following: 1. myoclonus 2. visual/cerebellar 3. pyramidal/extrapyramidal 4. akinetic mutism
– PSWCs in EEG or 14-3-3 in CSF in patients with disease duration <2 years ↓ probable CJD
– No PSWCs in EEG no 14-3-3 in CSF, disease duration <2 years ↓ possible CJD
Growing experience with the new variant of CJD meant that it was also possible to establish clinical criteria for this condition (26) (Table 11). Besides a number of clinical signs, they include MRI as the sole technique, allowing the detection of hyperintensities in the thalamus in 78% of patients with vCJD.
Table 11. WHO criteria for variant CJD
a Depression, anxiety, apathy, withdrawal, delusions. b This includes both frank pain and/or dysaesthesia. c Generalised triphasic periodic complexes at approximately one per second. d Tonsil biopsy is not recommended routinely, nor in cases with EEG appearances typical of sporadic CJD, but may be useful in suspected cases in which the clinical features are compatible with vCJD and MRI brain scan does not show bilateral pulvinar high signal. e Spongiform change and extensive PrP deposition with florid plaques throughout the cerebrum and cerebellum.
Progressive neuropsychiatric disorder
Duration of illness >6 months
Routine investigations do not suggest an alternative diagnosis
No history of potential iatrogenic exposure
No evidence of familial prion disease
Early psychiatric symptomsa
Persistent painful sensory symptomsb
Myoclonus or chorea or dystonia
EEG does not show the typical appearance of sporadic CJDc (or EEG not performed)
Bilateral pulvinar high signal on MRI brain scan
Positive tonsil biopsydDEFINITE
I and 4/5 of II and III A and III B OR I and IV Ad
I and 4/5 of II and III A
CLASSIFICATION OF SPORADIC CREUTZFELDT-JAKOB DISEASE ON A MOLECULAR BASIS
In previous studies, attempts were already being made to distinguish between the different subtypes of CJD based on neuropathological lesion profile and clinical features. However, based on new molecular classification criteria, previous results have had to be revised. The molecular basis for phenotypic heterogeneity in sporadic CJD was recently established (6, 41). According to this, distinct clinicopathological phenotypes are characterised by codon 129 genotype and type of proteinase K-resistant core of the prion protein (either PrP type 1 or type 2) (41).
The most frequent phenotypes of sporadic CJD are designated as MM1/MV1, VV2 and MV2:
– MM-1/MV-1: The most common phenotype with comparatively short disease duration (median 5 months) and the peak incidence is in the seventh decade of life. Most often the onset of disease is characterised by cortical visual impairment (41%) and rapidly progressive dementia, which, in more than two-thirds of the patients, is often already present at disease onset, while ataxia is rarely seen at this stage. The clinical syndrome is accompanied by severe involvement of the pyramidal and extrapyramidal systems, and most patients develop myoclonus in the course of the disease (Table 12).
Table 12. Clinical characteristics, neuropathological lesion profile and most useful clinical tests in sporadic CJD
Codon 129 genotype
Most prominent clinical sign/symptom
Most affected brain region
Most useful clinical test
Ataxia, dementia, extrapyramidal
Focal involvement of cortex, basal ganglia, thalamus, cerebellum, detection of kuru plaques
Ataxia, late dementia
Basal ganglia, thalamus, cerebellum, deep cortical layers
– VV-2: These patients are younger (median 62 years), and their disease duration is longer (median 8 months). Progressive ataxia is often the first clinical sign, while visual symptoms are less frequent at onset and usually manifest as blurred vision or diplopia. Dementia is rarely found at this stage, although all patients become demented during the course of the disease. Neuropathological examination typically shows pronounced involvement of the cerebellum and brain stem and spongiform changes in the deep layers of the cerebral cortex.
– MV-2: The third most frequent group comprises patients with the MV-2 phenotype. The long disease duration (median 17 months) and diverse symptomatology are remarkable features. Dementia is the first clinical sign in about half the cases. However, the disease can also start with ataxia or extrapyramidal signs. Neuropathologically, this phenotype is characterised by so-called kuru plaques. Focal lesions are distributed in the cortex, although they are also found in the basal ganglia, thalamus and cerebellum.
The three most frequently occurring phenotypes of CJD do not only differ in clinical presentation and neuropathology. One striking observation is the different sensitivity of the clinical diagnostic tests. Typical EEG changes seem to occur most often in patients with the MM-1/MV-1 phenotype. The detection of the 14-3-3 protein represents the technical investigation that can be used for patients with a VV-2 phenotype as well as for a MM1/MV1 phenotype (sensitivity 95%). There are no typical EEG changes in patients with the VV-2 phenotype. The clinical diagnosis of patients with the MV-2 phenotype is particularly difficult to establish, not only because of the prolonged disease duration. In this case too, no typical EEG changes can be observed, and the sensitivity of 14-3-3 protein detection in CSF is low. MRI helps to fill the diagnostic gap. According to results obtained so far, almost all patients show hyperintensities in their basal ganglia, which emphasises the important diagnostic role of MRI in this phenotype (7).
The differential diagnosis of sporadic CJD includes a large number of neurological and psychiatric diseases (Table 13). The most important differential diagnosis in elderly patients is Alzheimer's disease. The rapid disease courses, in particular, can rarely be discriminated from CJD when myoclonus is present. The detection of the 14-3-3 protein in CSF helps to distinguish between CJD and Alzheimer's disease, as increased concentrations of this protein are only found in exceptional cases in Alzheimer's disease (42). Dementia with Lewy bodies and vascular dementias are further diagnoses that are frequently found in elderly patients (43, 44), while chronic encephalitis is often the differential diagnosis among patients of younger age (45). Encephalitis associated with Hashimoto's disease is one form of dementia for which the treatment prospects are particularly good (46).
In variant CJD, other differential diagnoses have to be considered because of the different age at disease onset (Table 14). However, sporadic CJD is still the most frequent differential diagnosis of vCJD.