Creutzfeldt-Jakob disease (CJD) is a rapidly progressive, rare, transmissible, universally fatal, neurodegenerative condition caused by prion proteins. This condition was first described in 1920 by Hans Creutzfeldt, later described in 1921 and 1923 by Alfons Jakob. Later, Clearance J. Gibbs started using the term Creutzfeldt-Jacob disease (CJD) because the acronym was closer to his initials.
CJD belongs to a family of prion diseases or transmissible spongiform encephalopathies which can cause several fatal neurodegenerative disorders in humans and animals. The infectious agent is “prion” (a protein) that can be transmitted either by direct contact with contaminated tissue (iatrogenic) or via inheriting a mutation in the prion protein gene (familial). However, most cases of CJD are sporadic. The word “prion” derives from the words “proteinaceous” and “infectious,” in reference to the previously unknown form of infection due to protein misfolding in 1982. Prions were named and discovered by Stanley Prusiner, who received the 1997 Nobel Prize in physiology or medicine for his work on prions.
Types of CJD
A Variant Form of CJD
Acquired by consuming infected beef resulting in a bovine disease similar to human CJD called bovine spongiform encephalopathy (BSE) or “mad cow” disease. The majority of cases have occurred in the United Kingdom and France.
Creutzfeldt-Jakob disease (CJD) affects about 1 individual per million per year worldwide. Approximately 350 cases are diagnosed annually in the United States. Sporadic CJD is the commonest form of human prion disease, and the mean age of onset is 61 years. Death occurs in nearly 70% of patients within 1 year of onset.
Normal cellular prion protein (PrP) is found on the membranes of cells throughout the body even in healthy people and animals. It has complex functions that are yet to be fully discovered. CJD is caused by the transformation of the normal cellular prion protein PrP into an abnormal, structurally changed, disease-causing form called the prion PrP scrapie, (the prion disease of sheep and goats) which then self-propagates and accumulates throughout the brain. The infectious isoform known as PrP scarpie triggers the normal PrP proteins to convert into the infectious isoform (PrP) scarpie by inducing a structural change in native prion proteins, which accounts for its infective capacity. It is believed that both, the transformation of prion proteins into prions and the accumulation of prions lead to neurodegeneration.
Sporadic CJD is the commonest prion disease affecting humans and usually manifests as a rapidly progressing dementia with ataxia and myoclonus leading to death usually within one year, sometimes even quicker. It usually affects older individuals with a peak age of onset between 55 to 75 years old, the median age of death is 68 years, and a median duration of illness is 4 to 5 months. It presents similar to dementia with early neurological signs but progresses very rapidly. In the early stages of the sporadic CJD, patients may develop vertigo, headache, fatigue, and sleep disorders. However, memory problems, behavioral changes like agitation, irritability, depression, apathy and mood swings, sensory changes like incoordination, and vision loss can also occur. As the disease advances, rapidly worsening confusion, disorientation, problems with memory/thinking/planning/judgment become more pronounced and involuntary jerky movements, myoclonus, muscle stiffness, and muscle twitching can develop. Extrapyramidal symptoms like bradykinesia, dystonia, rigidity and sometimes blindness can occur. Patients gradually lose mobility, speech and develop into a comatose state. Certain infections such as pneumonia can lead to death.
Variant CJD (vCJD) occurs in young patients with a median duration of illness between 13 to 14 months and the median age at death is 28 years. It usually begins with psychiatric symptoms, behavioral symptoms, and painful dysesthesias. Neurological signs are delayed and have a longer than usual duration from onset of symptoms to death. As prions have been detected in blood and urine of patients with symptomatic vCJD, until the potential infectivity of these prions is established, caution should be exercised when handling body fluids and tissues from patients with vCJD.
Recommended initial screening tests for evaluation of a rapidly progressive dementia are complete blood count (CBC), basic metabolic panel including magnesium level, liver function tests, rapid plasma reagin, erythrocyte sedimentation rate, antinuclear antibody, C-reactive protein, thyroid function tests, vitamin B-12, HIV, Lyme disease titer, autoimmune antibodies, urinalysis, cerebrospinal (CSF) studies including glucose, oligoclonal bands, cell count and differential, VDRL, MRI brain (including FLAIR and DWI) with and without contrast, and EEG. With summation of clinical presentation and supportive diagnostic studies, Creutzfeldt-Jakob disease can be diagnosed.
In 1998, the WHO published diagnostic criteria for CJD with the diagnosis relying on clinical examination, EEG and CSF findings. However, due to advances in medicine with newer testing like MRI, genetic testing, and other modern laboratory tests, the diagnostic criteria perhaps need to be updated.
Several tests can help diagnose CJD including MRI brain, CSF based tests, and EEG.
For vCJD MRI brain is a more sensitive and specific test than CSF 14–3–3 protein and found to be accurate in about 90% of cases. Brain MRI with T2-weighted, diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) sequences often reveal abnormalities in the cortical gray matter (cortical ribboning) and deep nuclei in sCJD. MRI with DWI/FLAIR imaging has a sensitivity of 98% and specificity of 93%. DWI typically demonstrates hyperintensities within the basal ganglia, thalamus, and cortex. The “hockey stick” or “pulvinar” sign is indicative of variant (infectious acquired) CJD, but also seen in other forms of CJD. For CJD, CSF 14-3-3 is more sensitive followed by typical EEG findings.
CSF protein biomarkers including 14–3–3 protein, total tau (t-tau) and neuron-specific enolase (NSE) are markers of rapid neurodegeneration, so they assist in CJD diagnosis, but these are not CJD specific. Routine CSF studies including glucose, total protein, white blood cell count, total cell count, and oligoclonal IgG are generally unremarkable in CJD patients. In 2012, the American Academy of Neurology recommended ordering CSF 14-3-3 only when CJD is strongly suspected. A recent comparison of these three non-prion-specific CSF biomarkers and MRI found that DWI MRI had a higher diagnostic accuracy of 97%, more than any or all of these three CSF biomarkers like t-tau (79.6%) or 14-3-3 protein (70.4%) or NSE (71.4%). Detection of these traditional surrogate marker proteins is accurate in approximately three-fourths of cases.
The National Prion Disease Pathology Surveillance Center in April 2015 developed a new diagnostic test called second-generation Real Time-Quaking-Induced Conversion (RT-QuIC) which is very sensitive and specific for CJD. RT-QuIC can detect pathogenic prion protein in the cerebrospinal fluid of CJD patients with high accuracy. RT-QuIC directly detects the pathogenic prion protein, whereas the existing indirect markers of rapid neurodegeneration like protein 14-3-3 and tau proteins cannot do this.
A few studies have demonstrated modest sensitivity (>80%) but high specificity (approximately 98%) of CSF RT-QuIC for sCJD. Although it does not have as high sensitivity as MRI, it is often positive in many forms of genetic prion disease (gPrD), some of which usually do not show the classic MRI findings identified in most sporadic CJD cases. RT-QuIC in CSF is more specific than protein 14-3-3, probably NSE and t-tau also. RT-QuIC appears to be a highly specific test for human prion disease and might be more sensitive using olfactory epithelium (from nasal brushings) than CSF. Recent studies have shown that the RT-QuIC technique is the most sensitive and specific diagnostic test that can replace brain biopsy for accurate diagnosis of CJD. Because RT-QulC is less invasive compared to brain biopsy, this should be the first test to do in the workup of a patient with suspected CJD. However, the existing CJD guidelines do not include newer less invasive diagnostic modalities, and probably need to be updated.
EEG is the least sensitive test compared to MRI brain or CSF studies, and typical periodic sharp wave complexes can be seen.
Brain tissue biopsy or postmortem exam of the brain confirms the diagnosis of CJD. However not all areas in the brain are affected by the disease, so neurosurgeons target the areas that are abnormal on imaging studies which are most often in deep-seated subcortical structures. The surgery can be risky, and it may not always obtain the affected brain tissue. As the confirmatory diagnosis of CJD does not change the clinical outcome of the patient, a brain biopsy is only indicated when a reversible condition is suspected in the differential.
Few societies and organizations including CDC have proposed updated diagnostic criteria for CJD.
Figure 1 MRI-CJD Consortium criteria for sporadic Creutzfeldt–Jakob disease.
There is no definitive treatment for CJD. The mainstay of treatment is symptomatic and supportive care. A few drug trials were done on CJD, but none of them have shown any clear benefit so far. More research is needed to find the treatment for this fatal condition.
Rapidly progressive dementia (RPD) has a broad differential including vascular, neurodegenerative, autoimmune, infectious, thromboembolic, metastasis/neoplasm, iatrogenic and toxic metabolic conditions. Vascular conditions like strokes or multiple infarcts or cerebral myeloid angioplasty or hypertensive encephalopathy can lead to rapidly progressive dementia. Vasculitis and intravascular lymphoma can also lead to rapidly progressive dementia. Brain MRI, as well as vascular imaging studies such as MRI angiography and CT angiography, can help diagnose vascular etiologies. Infectious causes like viral encephalitis including herpes simplex virus, HIV dementia, progressive multifocal leukoencephalopathy, fungal infections like central nervous system (CNS) aspergillosis, syphilis, Lyme disease, subacute sclerosing panencephalitis can cause rapidly progressive dementia. Appropriate blood and serological studies can help diagnose infectious causes of RPD. Neurodegenerative conditions like Creutzfeldt-Jakob disease (iatrogenic, familial), Alzheimer's disease, dementia with Lewy bodies, progressive supranuclear palsy, corticobasal degeneration, neurofilament inclusion body disease, and progressive subcortical gliosis can also cause RPD.
Despite all the advances that have helped in understanding this disease, the prognosis is extremely poor. CJD is invariably fatal. Death often occurs within 1 year of symptom onset.
Creutzfeldt-Jakob disease (CJD) affects about 1 person in every 1 million individuals per year worldwide. Rapidly progressive dementias can occur due to neurodegenerative, toxic-metabolic, infectious, autoimmune or neoplastic etiologies, and extensive workup for reversible and treatable causes is needed. CJD and other prion diseases should be considered in the differential, during the workup of rapidly progressive ataxia or hemiparesis with cognitive deficit within weeks to months.
The diagnosis and management of CJD are with an interprofessional team that includes a neurologist, pathologist, internist, ICU nurses, and an intensivist. The disorder is very rare and is very rapidly progressive. Most of these patients need ICU admission but there is no specific treatment. Most patients are deceased within a few weeks/months. Counseling of the family is important because no treatment works and death is inevitable.
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