Introduction
Rapidly progressive dementia (RPD) presents a significant diagnostic challenge in clinical neurology. Characterized by a swift decline in cognitive function, RPD necessitates prompt and thorough investigation to differentiate between various underlying etiologies. While Creutzfeldt-Jakob disease (CJD) remains the archetypal and most feared cause, it’s crucial to recognize that CJD constitutes only a fraction of RPD cases. The concept of RPD, though lacking a universally accepted definition, serves as a vital clinical framework to distinguish a group of conditions distinct from the more common, slowly progressive dementias. While some definitions propose dementia onset within a year of symptom emergence, the insidious nature of initial symptoms often makes precise onset determination difficult. Nevertheless, the RPD designation effectively highlights a subset of neurological disorders demanding urgent diagnostic attention. In the context of CJD, the disease course is tragically rapid, with approximately 90% of patients progressing from initial symptoms to death within a year. Clinicians encountering suspected CJD cases witness a stark and accelerating decline in cognitive and neurological function, evolving over weeks to a month, contrasting sharply with the more gradual changes observed in typical dementias.
Population-based studies on RPD are notably absent, and the experiences documented by specialized prion disease referral centers may not accurately reflect the broader spectrum of RPD encountered in general clinical practice. Referral patterns are influenced by geographical factors and the availability of specialized services, leading to variations in the proportion of RPD cases ultimately diagnosed as prion disease, ranging from 20% to over 80% in specialized settings. This variability reflects the pre-referral diagnostic filtering performed by local healthcare providers.
It is undeniable that many patients presenting with rapid functional decline and dementia are experiencing delirium. Delirium is characterized by acute or subacute disturbances in attention, concentration, and orientation, alongside cognitive impairment and an identifiable underlying physiological stressor such as toxic, metabolic, or infectious etiologies, as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Crucially, a detailed patient history often reveals a pre-existing, more insidious cognitive decline preceding the acute delirium. Similarly, conditions such as multiple strokes, viral encephalitis, and brain tumors, while potentially fitting an RPD definition, are typically identifiable early in the diagnostic process. This discussion will focus on the more diagnostically challenging cases, those that have navigated initial clinical filters and present a significant differential diagnostic dilemma with CJD, emphasizing the critical aspects of Cjd Differential Diagnosis.
Phenotypic Spectrum of Creutzfeldt-Jakob Disease in Differential Diagnosis
Prion diseases, including CJD, are remarkably heterogeneous, encompassing diverse causes, clinical manifestations, and disease durations. Sporadic CJD (sCJD), with unknown etiology, accounts for approximately 85% of annual cases. Acquired CJD forms, while less common, can have identifiable causes such as prior treatment with cadaveric pituitary-derived human growth hormone (before 1985) or dura mater grafts (before 1992). Variant CJD (vCJD), linked to bovine spongiform encephalopathy (BSE) transmission to humans, has involved wider population exposure, with specific at-risk groups, such as recipients of blood transfusions from donors who later developed vCJD, being identifiable. Genetic prion diseases, while suspected in familial cases, often present without a clear family history due to late-age onset and incomplete penetrance of certain genetic mutations. The clinical spectrum of inherited prion diseases extends beyond RPD, and diagnostic investigations are often less specific than in sCJD. Therefore, genetic screening of the prion protein gene (PRNP) is a standard practice in undiagnosed RPD cases to rule out inherited prion etiologies.
In advanced stages, prion diseases converge on a similar clinical picture: akinetic mutism. Patients in this state are immobile, often with open but unseeing eyes, exhibiting occasional myoclonus (spontaneous or startle-induced), incontinence, and minimal verbal output. With supportive care including feeding, patients can survive in this state for weeks or even years. In sCJD, progression to akinetic mutism can occur rapidly, within weeks in the most aggressive cases, or over a year in approximately 10% of patients. Typically, patients are admitted for urgent inpatient evaluation following initial hospital assessment, with diagnostic investigations conducted during a single hospital stay. Many patients are discharged directly to palliative care or hospice following this initial hospitalization.
Initial symptoms of sCJD are often nonspecific, including headache, malaise, cough, dizziness, and changes in personality, mood, or memory. The emergence of more specific CJD symptoms is variable, leading to distinct initial differential considerations (Figure 1). In approximately half of cases, a more classic CJD presentation becomes apparent upon further history taking, clinical examination, or shortly after initial assessment. The classical presentation of CJD (Figure 1) involves RPD (affecting multiple cognitive domains such as memory, executive function, behavior, calculation, spelling, and language) combined with cerebellar ataxia, myoclonus, pyramidal and extrapyramidal signs, and often visual-spatial dysfunction. The differential diagnosis at this stage includes rapid forms of other neurodegenerative diseases, limbic encephalitis, corticosteroid-responsive encephalitis, infectious encephalitis, paraneoplastic syndromes, Wernicke encephalopathy, neurosarcoidosis, hypothyroidism, non-convulsive status epilepticus, hypoxic encephalopathy, toxic/metabolic encephalopathies, and functional neurological disorders.
Figure 1: Clinical features and progression of Creutzfeldt-Jakob disease (CJD). The diagram illustrates clinical variants of CJD, with arrow widths representing the proportion of cases for each presentation. Over time, CJD presentations converge, with almost all patients progressing to akinetic mutism before death.
Atypical CJD presentations pose greater diagnostic challenges. Pure cognitive presentations (~15%) may mimic rapid-onset Alzheimer’s disease, frontotemporal dementia, or dementia with Lewy bodies. Ataxic presentations (~10%), more common in acquired CJD, can be mistaken for cerebellar or brainstem disorders, including vascular, neoplastic, paraneoplastic, or inflammatory conditions. The visual presentation or Heidenhain variant (~5%) is marked by visual disturbances like hemianopia, scotoma, visual misperceptions, hallucinations, distortions, and palinopsia. These patients may initially present to ophthalmologists with suspected ocular disorders such as cataracts. Psychiatric presentations (~5%) are also recognized; in vCJD, early symptoms often include depression and personality changes, while in sCJD, paranoia, visual hallucinations, and aggression may occur initially, suggesting a primary psychiatric disorder. Rare presentations include those mimicking stroke (~2%) or corticobasal syndrome (~2%). The thalamic presentation (~2%), notably fatal familial insomnia, involves sleep disturbances, distal pain, and potential autonomic dysfunction (palpitations, temperature dysregulation, hypertension, postural hypotension), typically linked to the D178N PRNP mutation.
While neurologists consider a broad range of conditions in the initial differential diagnosis of RPD, the rapid progression often necessitates urgent and comprehensive investigation. In some cases, the rapid decline may not be immediately apparent due to lack of history or obscuring comorbidities. Therefore, certain interventions are warranted while awaiting initial test results. Suspected viral encephalitis should be promptly treated with intravenous acyclovir. Patients with weight loss, alcohol abuse, or malnutrition should receive intravenous vitamin supplementation. Standard initial investigations for RPD include a blood screen (hematology, biochemistry, thyroid function, vitamin B12, neurosyphilis serology, paraneoplastic and limbic encephalitis antibody panels), brain MRI (dementia protocol including DWI and FLAIR sequences), EEG, and CSF analysis (basic constituents, 14-3-3 protein, S100b, amyloid-beta and tau proteins, and RT-QUIC assay) (Table 1).
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Table 1: Initial Investigations for Rapidly Progressive Dementia
Diagnostic Investigations for CJD in Differential Diagnosis
Neuroimaging: MRI in CJD Differential Diagnosis
Magnetic Resonance Imaging (MRI) of the brain is an invaluable tool in the CJD differential diagnosis due to its accessibility and non-invasive nature. Classic MRI findings in CJD include hyperintensity on diffusion-weighted imaging (DWI) or FLAIR sequences in the striatum, cerebral cortex, and/or thalamus (Figure 2). These signal changes can occur in isolation or combination. Cortical signal abnormality is often patchy and widespread, affecting multiple cortical regions beyond areas prone to artifacts (e.g., frontal poles), and should not exhibit enhancement or mass effect. Thalamic signal changes may be diffuse or dorsomedially predominant but should not exceed striatal signal intensity in sCJD. MRI sensitivity for sCJD diagnosis is reported to be >90% in many centers. The pathological correlate of these imaging abnormalities in CJD is likely the presence of small vacuoles within neuronal cell bodies, axons, and dendrites in gray matter. Cortical signal changes often correlate with clinical findings, such as contralateral frontal lobe involvement in hemiparesis or occipital cortex changes in visual variants of CJD. Post-gadolinium MRI can help exclude conditions like lymphoma and neuroinflammatory disorders by demonstrating blood-brain barrier disruption, which is typically absent in CJD.
Figure 2: Typical MRI features of Creutzfeldt-Jakob disease (CJD). (A and B) Sporadic CJD showing typical basal ganglia signal return on fluid-attenuated inversion recovery (FLAIR) (A), which is more obvious on diffusion-weighted sequences (B). (C) Diffusion-weighted imaging sequence showing striking cortical ribboning with normal basal ganglia in sporadic CJD. (D) Variant CJD showing pulvinar sign on the FLAIR sequence.
Electroencephalography (EEG) in CJD Differential Diagnosis
With the advent of highly sensitive MRI and CSF assays, the role of electroencephalography (EEG) in CJD differential diagnosis has become less central. Periodic sharp wave complexes (PSWCs), a classic EEG finding in sCJD, develop in approximately half of patients, particularly in later stages. EEG is most valuable in identifying findings atypical for CJD, suggesting alternative diagnoses. These include periodic lateralized epileptiform discharges (PLEDs) in encephalitis, frontal intermittent rhythmic delta activity (FIRDA) in toxic-metabolic or structural disorders, status epilepticus, or 2–3 second runs of polyphasic slow/sharp waves (subacute sclerosing panencephalitis – SSPE). The “extreme delta brush” pattern may be seen in autoimmune encephalitis.
Cerebrospinal Fluid (CSF) Analysis in CJD Differential Diagnosis
Pleocytosis in CSF is uncommon in CJD. For two decades, CSF analysis for surrogate markers of neuronal damage, such as 14-3-3 protein, S100b, and neuron-specific enolase (NSE), has been utilized in CJD differential diagnosis. While these proteins are elevated in over 80% of CJD cases, they lack specificity, reflecting rapid neuronal damage and can be abnormal in various CJD mimics. Newer CSF assays, particularly the real-time quaking-induced conversion (RT-QUIC) assay, offer significantly improved specificity for prion disease detection. RT-QUIC involves cyclic shaking of CSF samples to disrupt prion protein aggregates, followed by incubation with recombinant prion protein, inducing misfolding and aggregation, detected by increased thioflavin T fluorescence. CSF angiotensin-converting enzyme (ACE) levels can be helpful in diagnosing neurosarcoidosis.
Prion Protein Gene (PRNP) Sequencing in CJD Differential Diagnosis
Prion protein gene (PRNP) sequencing is a critical component of the diagnostic workup in CJD differential diagnosis and should be considered routinely in all suspected cases. The phenotypic spectrum of inherited prion diseases is broader than sCJD, and family history is often absent. The codon 129 polymorphism of PRNP influences sCJD phenotype; methionine homozygosity is associated with faster disease progression, while methionine-valine heterozygosity is linked to slower progression. However, the primary rationale for PRNP sequencing is to exclude inherited prion disease. Genetic testing has implications for blood relatives, necessitating careful consideration and genetic counseling.
Other Tissues and Biofluids in CJD Differential Diagnosis
Tonsillar biopsy or blood-based assays (Direct Detection Assay) are useful in diagnosing vCJD but not sCJD. Emerging prion protein amplification or capture technologies using olfactory brushings, urine, or blood are under research development for sCJD but are not yet in routine clinical use. Brain biopsy is rarely indicated for CJD diagnosis and is reserved for cases where a treatable condition is strongly suspected, particularly when a specific lesion requires targeted biopsy. Prion precautions are essential in neurosurgical procedures when CJD is suspected.
Mimics of CJD After Initial Investigation: Navigating the Differential Diagnosis
Even after initial investigations, some RPD cases remain diagnostically challenging, often with abnormalities on key tests, particularly a positive CSF 14-3-3 protein. Differentiating CJD from its mimics is crucial for appropriate patient management and prognosis.
Common Neurodegenerative Disorders in CJD Differential Diagnosis
In over half of CJD mimic cases seen at specialized prion clinics, the final diagnosis is another neurodegenerative disease. These conditions, far more prevalent than CJD, can present with rapid progression, particularly in the context of comorbid conditions like infections causing delirium or medication changes. Rapidly progressive Alzheimer’s disease and dementia with Lewy bodies are key considerations in the CJD differential diagnosis. Witness accounts of pre-existing, albeit milder, cognitive symptoms prior to the acute presentation are crucial differentiating features. MRI evidence of focal or generalized atrophy, or CSF biomarkers suggestive of Alzheimer’s pathology (amyloid-beta and tau), are also informative. Clinical stabilization or improvement, which is exceedingly rare in CJD even with supportive care, strongly favors an alternative diagnosis. Vascular disease affecting the striatum, cortex, or thalamus can also mimic CJD, particularly on initial imaging. Myoclonus, ataxia, and motor signs can occur in other neurodegenerative disorders and may be exacerbated by certain medications (e.g., tricyclic antidepressants and myoclonus, antiepileptic drugs and ataxia, neuroleptics and dementia with Lewy bodies).
While disease-modifying therapies for CJD are lacking, accurate diagnosis is essential for symptomatic management, patient and family counseling, and end-of-life care planning. Genetic etiologies in other neurodegenerative diseases, such as C9orf72 expansions, can also lead to rapid progression and motor features, further complicating the CJD differential diagnosis. The increasing availability of gene panel diagnostics aids in identifying specific genetic diagnoses in RPD.
Potentially treatable CJD mimics are of particular clinical importance and can be broadly categorized as follows.
Immune-Mediated Encephalitis in CJD Differential Diagnosis
Immune-mediated encephalitis represents a critical category of treatable CJD mimics. These recently characterized antibody-mediated inflammatory CNS disorders are paramount in the CJD differential diagnosis. While some are paraneoplastic, and FDG-PET can help identify underlying tumors, a significant proportion involves antibodies targeting neuronal surface ion channels and receptors without an identifiable malignancy. Many patients with immune-mediated encephalitis exhibit dramatic responses to immunotherapy.
N-methyl-D-aspartate receptor (NMDAR) antibody encephalitis is the most frequently recognized type, initially linked to ovarian teratomas in young women but occurring across demographics. Similar to CJD, NMDAR encephalitis often presents with a nonspecific prodrome, progressing to behavioral and psychiatric symptoms, and early seizures (generalized and focal), which are atypical for CJD. Movement disorders are common in both CJD and NMDAR encephalitis, but the characteristic facial dyskinesias of NMDAR encephalitis are a key differentiating feature. Diagnostic clues favoring NMDAR encephalitis over CJD include CSF pleocytosis, CSF oligoclonal bands, and specific MRI findings (Table 3). MRI in NMDAR encephalitis may show T2/FLAIR hyperintensity in the striatum, thalamus, and cortex, similar to CJD (Figure 3), but more typically involves other regions, particularly the mesial temporal lobes, hippocampus, brainstem, cerebellum, and white matter, often with contrast enhancement or mass effect indicative of inflammation. Antibody testing (serum and CSF) for NMDAR encephalitis is recommended in all suspected CJD cases, particularly those with clinical or investigation “red flags.”
Figure 3: Brain MRI in four patients mimicking prion disease. (A) C9orf72 mutation showing severe generalized atrophy without abnormal parenchymal signal. While severe atrophy occurs late in CJD, DWI typically shows restricted diffusion. (B) B-cell lymphoma confined to the brain, showing extensive white matter signal change with normal cortex. Leukoencephalopathic CJD is rare and associated with gray matter destruction. (C) N-methyl-D-aspartate antibody encephalitis with the pulvinar sign, typically seen in variant CJD but rare in other pathologies. (D) Voltage-gated potassium channel (Casp-1) antibody encephalitis showing unilateral basal ganglia DWI hyperintensity without ADC restriction, and caudate swelling, not seen in CJD.
Voltage-gated potassium channel (VGKC) complex antibody encephalitis is another crucial CJD mimic to exclude in CJD differential diagnosis. Pathogenic antibodies are often directed at specific proteins within the VGKC complex, such as LGI1, facilitating more specific antibody testing. VGKC-complex encephalitis presents with diverse clinical syndromes, but the most CJD-mimicking presentation includes peripheral features (neuromyotonia, autonomic disturbances) and central manifestations (faciobrachial dystonic seizures, insomnia, memory impairment, behavioral changes, encephalitis). Diagnostic pointers include hyponatremia and MRI abnormalities of the mesial temporal lobe and hippocampus, potentially extending to the basal ganglia (Figure 3).
Other immune-mediated encephalitis subtypes involve antibodies against glutamic acid decarboxylase (GAD), associated with limbic encephalitis or cerebellar ataxia; AMPA receptor antibodies, often linked to tumors, psychosis, and limbic encephalitis; GABAA or GABABR antibody limbic encephalitis; glycine receptor antibodies, seen in progressive encephalomyelitis with rigidity and myoclonus (PERM); and metabotropic glutamate receptor antibodies, reported in subacute cerebellar degeneration.
Hashimoto’s encephalitis is frequently mentioned in the CJD differential diagnosis, although it is rarely encountered in specialized prion clinics. Thyroid function tests and antithyroperoxidase antibody assays are readily available, but many reported cases are euthyroid. The pathogenesis and distinctness of Hashimoto’s encephalitis from other immune-mediated encephalitides remain unclear.
Infections in CJD Differential Diagnosis
Infections, while often clinically distinct, must be considered in the CJD differential diagnosis.
Progressive multifocal leukoencephalopathy (PML), an opportunistic brain infection caused by JC virus, predominantly affects immunocompromised individuals (immunosuppressant use, HIV, Hodgkin’s lymphoma, chronic lymphocytic leukemia). PML can mimic CJD due to rapid neurological decline and frequent involvement of visual pathways or cerebellum. Generalized seizures, occurring in about half of PML cases, are less typical in CJD. MRI in PML typically shows parieto-occipital demyelinating lesions at the gray-white matter junction, less commonly affecting the corpus callosum, thalamus, and basal ganglia, differing from typical CJD imaging. CSF PCR for JC virus confirms the diagnosis. CSF pleocytosis, if present, is also more suggestive of PML than CJD.
Subacute sclerosing panencephalitis (SSPE), a rare late complication of childhood measles infection, can resemble CJD clinically. Early symptoms include lethargy and behavioral changes, followed by characteristic “hung-up” myoclonus, seizures, cognitive decline, and later motor signs and reduced consciousness. SSPE should be considered in children and young adults and may be suggested by EEG findings of bilaterally synchronous, repetitive sharp complexes. CSF measles antibody titers are diagnostic.
Other viral encephalitides typically present acutely with fever, elevated inflammatory markers in serum and CSF, seizures, meningismus, and coma, making them usually distinguishable from CJD. However, subacute presentations can pose diagnostic confusion.
A broad range of bacterial, fungal, and parasitic infections can cause RPD and should be included in a differential diagnosis checklist (Table 2), although they are less frequent CJD mimics in specialized clinic settings.
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Table 2: Differential Diagnosis Checklist for Rapidly Progressive Dementia
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Table 3: Red Flags: Clinical Features Suggestive of CJD Mimics
Toxic-Metabolic Syndromes in CJD Differential Diagnosis
Toxic-metabolic encephalopathies are critical considerations in the CJD differential diagnosis and are often identified through initial laboratory testing (serum biochemistry, calcium, magnesium, glucose, thyroid function).
Wernicke encephalopathy, caused by thiamine deficiency, is an acute neurological emergency characterized by ophthalmoplegia, ataxia, and confusion, requiring urgent intravenous thiamine replacement. Imaging features may overlap with CJD. Encephalopathy associated with hepatic failure has also mimicked CJD, with negative myoclonus in comatose patients resembling late-stage CJD. Elevated serum ammonia levels (hyperammonemia) in liver failure, urea cycle disorders, or certain drug therapies are diagnostic clues. T1-weighted MRI signal hyperintensity in the lentiform nucleus due to manganese deposition is highly suggestive of hepatic encephalopathy.
Neoplastic and Paraneoplastic Conditions (Excluding Limbic Encephalitis) in CJD Differential Diagnosis
Neoplastic conditions without prominent mass lesions on MRI are among the most challenging to differentiate from CJD. These include primary CNS lymphoma, carcinomatous meningitis, and intravascular lymphoma. Imaging findings are often crucial for diagnosis. Primary CNS lymphoma typically presents with contrast-enhancing lesions in contact with CSF. Large-volume CSF cytology prior to corticosteroid treatment may obviate brain biopsy. Serum tumor markers and whole-body imaging can also be helpful. Intravascular (B-cell) lymphoma, a rare and diagnostically elusive condition, can cause rapid cognitive decline, seizures, upper motor neuron signs, and peripheral neuropathy. Imaging may resemble primary CNS vasculitis.
Vascular Disorders in CJD Differential Diagnosis
Vascular conditions such as large vessel stroke, dural arteriovenous fistula, posterior reversible encephalopathy syndrome (PRES), and primary CNS vasculitis can mimic CJD. In each case, careful review of MRI features is paramount for accurate diagnosis.
Mimics Relevant to Genetic and Iatrogenic Prion Diseases in CJD Differential Diagnosis
Genetic and iatrogenic prion diseases often progress more slowly than sCJD, leading to distinct differential diagnoses. A common phenotype in inherited prion diseases is slowly progressive cerebellar ataxia, often with distal sensory neuropathy, absent ankle reflexes, and extensor plantar responses. Iatrogenic CJD frequently presents with ataxia and relatively preserved cognitive function, progressing more slowly than typical sCJD. Other inherited prion disease forms may present with predominantly cognitive symptoms, behavioral disturbances, mimicking frontotemporal dementia, Huntington’s disease (in familial cases), or Alzheimer’s disease.
Conclusions and Future Directions in CJD Differential Diagnosis
RPD mimicking CJD is uncommon but clinically significant, requiring urgent investigation and presenting diagnostic challenges. However, the pursuit of a diagnosis in RPD is often more rewarding than in slowly progressive dementia due to the wider range of potentially treatable conditions. Specialized prion disease services, such as national prion clinics, play a crucial role in assessment, diagnostic guidance, access to specialized testing (molecular genetics, RT-QUIC), follow-up, and supportive care. Early referral, particularly after MRI findings suggestive of CJD, is highly encouraged.
Research in rare disorders like CJD is most effective when concentrated in national centers with sustained funding, integrated with specialized patient care, and in collaboration with local physicians. Significant progress has been made in prion disease diagnostics, with blood and CSF-based assays transitioning from research to clinical practice in recent years. While effective treatments remain elusive, this is a major focus of current research efforts. Continued referral of RPD cases by clinicians is essential for advancing research and improving patient care in this challenging area.
Key Points for CJD Differential Diagnosis
- Creutzfeldt-Jakob disease (CJD) is a rapidly progressive and clinically heterogeneous condition that can mimic a wide array of potentially reversible or treatable neurological disorders. Accurate CJD differential diagnosis is therefore paramount.
- Highly sensitive and specific diagnostic tests are available for CJD, notably diffusion-weighted MRI and CSF RT-QUIC assay. While clinical syndromes may overlap with mimics, appropriate investigations should rapidly clarify the diagnosis in most cases.
- Investigations are less definitively diagnostic in genetic forms of prion disease, necessitating a low threshold for genetic testing to rule out inherited prion etiologies in RPD.
- Clinical “red flags” should raise suspicion for CJD mimics, including unexplained fever, generalized seizures, hyponatremia, facial movement disorders, slower progression (>1 year duration), CSF pleocytosis, contrast-enhancing MRI lesions, and white matter lesions outside the typical CJD distribution (striatum, thalamus, cortex).
Acknowledgments
We extend our sincere gratitude to the patients, their families, and caregivers, as well as the dedicated staff of the National Prion Clinic, past and present, for their invaluable contributions to the National Prion Monitoring Cohort study. We acknowledge the numerous consultant neurology colleagues throughout the UK for their prompt referrals to specialist services. We also thank the National CJD Research and Surveillance Unit for their ongoing collaboration in addressing this rare disease. Mr. Richard Newton is acknowledged for his assistance with figure design.
