Creutzfeldt-Jakob Disease

Etiology

A prion protein (PrP) is a normal neuron protein with a predominantly α-helical and random coil composition. Proteinaceous infectious particles known as "prions" are self-propagating proteins lacking nucleic acids and are primarily comprised of proteinase K-resistant β-pleated sheet aggregates. Prions reproduce by associating with normal PrP cellular isoforms, converting α-helices into indigestible β-pleated sheets. These particles cause CJD and other transmissible spongiform encephalopathies, such as bovine spongiform encephalopathy (also known as mad cow disease), kuru, and scrapie. 

CJD can be classified based on the mode of transmission. Sporadic CJD is the most common type of the disease (∼85%) and is due to misfolding of normal PrP isoforms with no apparent triggers. Subtypes of sporadic CJD include sporadic fatal insomnia and variably protease-sensitive prionopathy. Genetic CJD is the second most common type (∼10-15%) and arises from a heritable genetic mutation. Subtypes of this condition include familial CJD, fatal familial insomnia, and Gerstmann-Sträussler-Scheinker syndrome.

Infectious CJD accounts for less than 1% of cases and results from the transmission of prions through an external source. Subtypes include kuru, iatrogenic CJD, and variant CJD. Kuru is a disease of the FORE people of Papua New Guinea who consumed the brains of dead relatives as part of ritualistic cannibalism before the practice was banned in the 1950s. Iatrogenic CJD arises from inadvertent prion inoculation during surgical procedures or through blood transfusion.[6] Variant CJD is associated with the ingestion of infected beef by a mechanism similar to the development of bovine spongiform encephalopathy. Most documented cases of variant CJD have occurred in the United Kingdom and France.[7][8][9]

Epidemiology

CJD affects about 1 individual per million per year worldwide. Approximately 350 cases are diagnosed annually in the United States. Sporadic CJD is the most common form of human prion disease. The condition has a mean age of onset of 62 years, although it has also been reported in younger and older age groups.[10][11] Sporadic CJD has a 1:1 male-to-female ratio. Approximately 1 to 2 new sporadic CJD cases occur per 1,000,000 individuals worldwide each year.[12] Death occurs in nearly 70% of patients within a year of onset. The mean survival of sporadic CJD is 4 to 8 months, with 90% of patients dying within a year.

Genetic CJD is the second most common type of this condition. Patients often have a family history of the disease and mutations in the autosomal-dominant PRNP gene. Acquired cases are rare, occurring in less than 1% of cases, and typically affect young adults with a mean age of 29 years.

Pathophysiology

Normal cellular prion protein (PrP^c) transforms into the disease-causing form PrP scrapie (PrP^Sc) either spontaneously or as a result of PrP^Sc infection. PrP^Sc self-propagates and accumulates throughout the brain. The highly chemically stable β-pleated aggregates cause derangements in intracellular protein folding, ubiquitination, and trafficking in affected neurons. Additionally, astrocytes may swell and degrade in reaction to prion-induced injury. Neurodegeneration results from these changes.[13]

Histopathology

Gross pathological examination of affected brains may not reveal any abnormalities. However, the following features are commonly observed during light microscopy (see Image. Neuropathological Confirmation of Creutzfeldt-Jacob Disease):

• Vacuolation or spongiform degeneration, most notably in the cerebral cortex, caudate nucleus, thalamus, putamen, and the molecular layer of the cerebellum
• Neuronal loss
• Astrocytic gliosis or fibrous proliferation of the astrocytes, primarily in the gray matter

Amyloid plaques can be found in some individuals.

History and Physical

CJD presents in variable ways, depending on the subtype. The manifestations arise from the involvement of various parts of the CNS. The table below summarizes the symptoms that may manifest in patients with CJD.

Table. Symptoms of Creutzfeldt-Jakob Disease

Atypical features include cranial nerve abnormalities, peripheral nervous system involvement, and vestibulocochlear dysfunction. Although found rarely in association with CJD, these manifestations should raise suspicion of another potential diagnosis. The neurologic examination must be as detailed as possible for all patients suspected of CJD.

Sporadic CJD

In the early stages of sporadic CJD, patients may develop nonspecific symptoms like vertigo, headache, fatigue, and sleep disorders. However, memory problems, agitation, irritability, depression, apathy, mood swings, and sensory changes such as visual loss can also occur. As the disease progresses, patients may develop rapidly worsening confusion, disorientation, and cognitive problems. Most patients display coordination and movement abnormalities, including ataxia, involuntary jerky movements, myoclonus, muscle stiffness, and involuntary muscle twitching. Myoclonus persists during sleep and may be elicited by loud sounds or bright lights.

Extrapyramidal symptoms can include bradykinesia, dystonia, and rigidity. Patients gradually lose mobility, the ability to speak, and progress into a comatose state. Certain infections, such as pneumonia, can be fatal.

Patients with sporadic CJD are typically between 55 and 75 years of age. Death occurs within a year of onset, with the median duration of illness being 4 to 5 months. The median age of death in individuals with sporadic CJD is 68 years. Sporadic CJD is similar to dementia in its presentation, but progresses much more rapidly.

CJD subtyping is based on genetic polymorphism, prion protein characteristics, and the associated symptoms. Methionine/methionine type 1 (MM1) and methionine/valine type 1 (MV1) comprise 70% of cases and correlate with the classic CJD phenotype. The condition has a mid- to late-life onset and presents with rapidly progressive dementia (RPD) and early myoclonus and ataxia. 

Methionine/valine type 2 (MV2) is the kuru plaque variant, accounting for approximately 10% of sporadic CJD cases. The condition presents with progressive dementia with prominent psychiatric features and has a longer duration of approximately 17 months.[19] The valine/valine type 2 (VV2) variant is also known as the ataxic variant. This condition presents with ataxia at the onset or as an isolated feature. The VV2 subtype has a duration of illness of around 7 to 9 months.[20]

The methionine/methionine type 2 (MM2) subtype may be classified as either thalamic or cortical. The thalamic MM2 subtype is also known as sporadic fatal insomnia and is present in 2% of cases. The mean disease duration is 15.6 months. The most frequent symptoms include psychomotor hyperactivity, ataxia, insomnia, and cognitive impairment, resembling fatal familial insomnia.[21] The cortical MM2 subtype also comprises 2% of sporadic CJD cases. Dementia is the predominant clinical manifestation of this subtype. The average disease duration is 15.7 months. Visual and cerebellar signs are rarely described at presentation.[22]

The valine/valine 1 (VV1) subtype accounts for 1% of cases and typically has a younger age of onset. Individuals with this condition present with progressive dementia. The VV1 subtype has an average duration of 15.3 months.[23]

Inherited CJD

Genetic CJD has phenotypic variability that may be attributed to the low penetrance of PRNP mutations. Patients with genetic CJD are usually younger than individuals with sporadic CJD, manifesting behavioral and cognitive changes initially, and incoordination and movement abnormalities over the next few months. A family history of similar neurologic manifestations may be elicited.

Inherited CJD is fatal, though the duration of illness varies among individuals. For example, Gerstmann–Straussler–Scheinker syndrome has a slow progression, and death may be delayed for up to 10 years.[32]

Variant CJD

Patients with variant CJD are often younger than patients with sporadic CJD, initially presenting with psychiatric symptoms, behavioral changes, and painful dysesthesias. Movement disorders may develop early, but dementia is usually a late sign. A history of having a neurosurgical procedure or ingestion of infected meat may be elicited. The median duration of illness is between 13 and 14 months, while the median age at death is 28 years. 

Evaluation

Creutzfeldt-Jakob disease is often a diagnostic challenge as it presents similarly to other conditions presenting with rapidly progressive dementia (RPD). The following are the recommended initial screening tests for evaluating RPD:

• Complete blood count
• Complete metabolic panel
• Blood magnesium level
• Rapid plasma reagin
• Erythrocyte sedimentation rate
• Antinuclear antibody
• C-reactive protein
• Thyroid function tests
• Vitamin B12 level
• HIV test
• Lyme disease titer
• Autoimmune antibodies
• Urinalysis
• CSF studies, including glucose, oligoclonal bands, and cell count with differential
• CSF 14-3-3 protein (a specific test for prion disease)
• Venereal disease research laboratory (VDRL) test

Among imaging studies, computed tomography (CT) may be ordered initially. However, brain magnetic resonance imaging (MRI) with or without contrast, along with related modalities such as fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted imaging (DWI), can provide more detailed information about the involved regions. CJD may be diagnosed when imaging is combined with clinical, laboratory, and electroencephalogram (EEG) findings.[24][25][26]

The World Health Organization published diagnostic criteria for CJD in 1998, which relied on the clinical, EEG, and CSF findings. However, advanced diagnostic procedures, such as MRI and genetic testing, have rendered those criteria obsolete.

Brain MRI is a more sensitive and specific test for variant CJD than the CSF 14–3–3 protein and was found to be accurate in about 90% of cases (see Image. Brain MRI of a Patient with Early-Stage Creutzfeldt-Jakob Disease).[27] Brain MRI with T2-weighted scanning, DWI, and apparent diffusion coefficient (ADC) sequences can often reveal abnormalities in the cortical gray matter, like cortical ribboning, and in the deep nuclei in sporadic CJD. MRI with DWI or 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 indicates variant, infectious, or acquired CJD, although it is also seen in other forms of CJD. CSF 14-3-3 can be more sensitive for CJD than other prion diseases when combined with the typical EEG findings.

CSF protein biomarkers, including the 14–3–3 protein, total tau (T-tau), and neuron-specific enolase (NSE), are markers of rapid neurodegeneration. While these tests can support the diagnosis of CJD, they are not specific to the disease. An elevated tau level (greater than 1150 picograms/mL) has greater accuracy and specificity than the 14-3-3 protein as a diagnostic test for CJD, although both tests can produce significant false-negative and false-positive results.[28]

In 2012, the American Academy of Neurology recommended ordering CSF 14-3-3 only when CJD is strongly suspected. A recent comparison of these non-prion-specific CSF biomarkers with MRI revealed that DWI had a diagnostic accuracy of 97%, surpassing that of the T-tau (79.6%), 14-3-3 protein (70.4%), and NSE (71.4%) tests. Detection of these traditional surrogate marker proteins is accurate in approximately three-fourths of cases. Routine CSF analysis, which includes glucose, total protein, white blood cell count, total cell count, and oligoclonal IgG, is generally unremarkable in CJD patients.

The National Prion Disease Pathology Surveillance Center launched a new diagnostic test in April 2015 called "second-generation Real Time-Quaking-Induced Conversion (RT-QuIC)," which is highly sensitive and specific for CJD. RT-QuIC can accurately detect pathogenic prion protein in the CSF of patients with CJD. RT-QuIC directly detects the pathogenic prion protein, in contrast to the 14-3-3 protein, T-tau, and NSE, which are indirect tests.

Several studies have revealed that RT-QuIC exhibits modest sensitivity (greater than 80%) but high specificity (approximately 98%) for sporadic CJD.[29] Most patients with the VV2 sporadic CJD subtype have negative CSF RT-QuIC tests. Although it is not as sensitive as MRI, RT-QuIC is often positive in many forms of genetic prion disease, some of which lack the classic MRI findings of sporadic CJD.

RT-QuIC may be more sensitive using olfactory epithelium brushings as a specimen rather than CSF. Recent studies have shown that RT-QuIC is comparable to brain biopsy in terms of accuracy in diagnosing CJD.[30] RT-QulC is less invasive compared to brain biopsy. However, the existing CJD guidelines do not include newer, less invasive diagnostic modalities.

EEG is not as sensitive as brain MRI or CSF studies in detecting CJD; however, the typical findings associated with the condition in its late stages include periodic sharp wave complexes (PSWCs). Bi- or triphasic PSWC is found in 67% to 95% of patients with sporadic CJD. This finding is considered supportive rather than diagnostic and is characterized by the following features:

• Generalized or lateralized complexes
• A minimum of 5 repetitive intervals with a duration difference of less than 500 milliseconds to exclude semiperiodic activity
• Strictly periodic cerebral potentials, the majority with an intercomplex interval of 500 to 2000 milliseconds and a duration of 100 to 600 milliseconds

Among patients with sporadic CJD, the MM1 and MV2 subtypes frequently manifest with PSWCs, while the MV2 subtype exhibits PSWCs infrequently. PSWCs are not found in patients with Gerstmann-Sträussler-Scheinker syndrome, variant CJD, kuru, or fatal familial insomnia. PSWCs are occasionally observed in patients with genetic CJD, particularly in those with the codon 200 mutation.[31]

Brain tissue biopsy or postmortem examination of the brain confirms the diagnosis of CJD. However, not all areas of the brain are affected by the disease. Imaging studies should target subcortical structures, where abnormal features are most likely to be found. Surgery has inherent risks and may not always be able to access the area of involved brain tissue. CJD confirmation does not alter the clinical outcome of the patient. Therefore, a brain biopsy is only indicated when a reversible condition is suspected in the differential diagnosis. 

Prions have been detected in the blood and urine of patients with symptomatic variant CJD. Caution should be exercised when handling body fluids and tissues from patients with variant CJD until prion infectivity has been excluded.

Treatment / Management

CJD has no definitive treatment, and supportive care is the mainstay of clinical management.[32] Most trial drugs for CJD have not demonstrated any clear benefit to date. However, intraventricular pentosan polysulfate has been shown in rodent studies to inhibit PrP^Sc formation. An apparent survival extension of 37 to 114 months was observed in four patients.[33] More research is needed to find a cure for this fatal condition.(A1)

Early detection of a PRNP mutation may help families at risk for the genetic form of CJD. Patients affected by the condition can make earlier arrangements for end-of-life planning. Psychosocial support and supportive care may improve patients' quality of life. Genetic counseling and family planning help prevent the transmission of disease to the offspring of individuals with the PRNP mutation.

Differential Diagnosis

Rapidly progressive dementia (RPD) has a broad differential diagnosis that includes vascular, neurodegenerative, autoimmune, infectious, thromboembolic, neoplastic, iatrogenic, and toxic metabolic conditions. Vascular conditions like stroke, multiple infarcts, cerebral amyloid angiopathy, or hypertensive encephalopathy can likewise lead to RPD. Vasculitis and intravascular lymphoma may also manifest as RPD.

These conditions may be distinguished from CJD by a thorough medical evaluation. Imaging studies can help exclude vascular and neoplastic causes of RPD. Blood and CSF examinations can detect autoimmune, infectious, metabolic, and neurodegenerative conditions.[34][35]

Prognosis

The prognosis for CJD is extremely poor despite all the advances that have helped to understand this disease. The condition is invariably fatal. Death occurs within one year of symptom onset, except in some rare cases.

Complications

CJD's complications encompass both physical and psychosocial difficulties. Individuals affected by CJD often withdraw from friends and family and ultimately lose their ability to recognize or relate to them. Patients also lose their capacity for self-care and often gradually progress into a coma. CJD has a 100% fatality rate.