Creutzfeldt-Jacob Disease
This is a 58 year old woman who presented with a six week history of swallowing difficulty, blurry vision, tremor, gait ataxia, while initially denying any cognitive changes. However, symptoms progress very rapidly within the subsequent one week, including emergence of paranoia, visual hallucinations, and very rapid decline in mental status eventually developing akinetic mutism by her second admission. The patient had three brain MRIs within two weeks period. While her first two brain MRIs were mostly unremarkable, her third brain MRI showed diffusion restriction in right temporal/parietal/occipital cortices and in bilateral head of caudate and putamen. This overall presentation was characteristic of Creutzfeldt-Jacob disease.
Primary neurodegenerative processes: Most neurodegenerative dementias present with a protracted clinical course of gradual decline in cognitive functions. However, some neurodegenerative dementias may present much more rapidly than their prototypical presentations. Early-onset dementias typically manifest a shorter time course. Those with genetic mutation of presenilin-1 can present with early-onset Alzheimer's disease. Lewy body dementia has a rapid decline with average survival of three years. Lewy body dementia usually manifests with fluctuating of cognition, recurrent visual hallucination, and parkinsonism. Frontotemporal dementia has a quicker symptom progression than Alzhiemer's disease, and typically presents with prominence of personality changes and impaired self-monitoring. Because corticobasal degeneration (CBD) may present with rapidly progressive dementia and has some common features with CJD (e.g., alien hand syndrome and myoclonus), it is important to distinguish these two conditions. Imaging of CBD may have atrophy of caudate nucleus, putamen and some cortical regions, usually in an asymmetric pattern. Progressive supranuclear palsy (PSP) and Multiple-system atrophy (MSA) can also have rapid courses. PSP usually presents with dementia, vertical gaze palsy, parkinsonism, and frequent falls. Classical MRI finding includes "humming bird" sign which is related to atrophy of the midbrain, pons, thalamus, and the superior cerebellar peduncle. MSA has classic clinical findings of autonomic dysfunction, parkinsonism, and ataxia. Classic MRI finding of "hot cross bun sign" in MSA is due to the atrophy of the lower brain stem, middle cerebellar peduncles, cerebellum and putamen.
Infectious: Viral agents, including HSV 1 and 2, CMV, EBV, enteroviruses, and West Nile virus can manifest with rapid cognitive decline. AIDS-dementia tends to occur in later stages of HIV, and its incidence has decreased since the introduction of HAART therapy. Rapidly progressive dementia can develop during HIV seroconversion and even during immune reconstitution. It is also important to rule out CNS lymphoma, progressive multifocal leukoencephalopathy or toxoplasmosis in immunocompromised patients. Bacterial agents, such as Bartonella henselae, Mycoplasma pneumonia, Whipple's disease, syphilis, Cryptococcus neoformans, subacute scleorsing panencephalitis can present as rapidly progressive dementia. Prion diseases are rare diseases in which the pathophysiologic entity is the prion, a misfiled form of normal protein within the brain, which propagates itself by promoting changes in the conformation of the normal prion proteins. The most common prion disease is Creutzfeld-Jakob disease.
Autoimmune/inflammatory processes: Antibody-mediated limbic encephalitis associated with cancer (paraneoplastic) or without cancer (nonparaneoplastic) can also manifest with rapidly progressive dementia. Antibody-mediated limbic encephalitides are associated with antibodies directed against the brain, including anti-Hu and anti-CV2 antibodies which are associated with small-cell lung cancer, anti-Ma2 with testicular cancer, and anti-NMDA with ovarian teratomas. Hashimoto encephalopathy is a rare, but treatable condition and is associated with markedly increased levels of anti-thyroglobulin or anti-thyroperoxidase. CNS involvement is common in sarcoidosis. Brain MRI of neurosarcoidosis can show periventricular T2 hyperintense lseions, enhancing granulomas, and leptomeningeal enhancement. CSF can be normal, but increased protein and pleocytosis are common. CSF angiotensin-converting enzyme lacks specificity and sensitivity. Definitive diagnosis requires biopsy of affected tissue. Primary CNS vasculitis is a rare entity, but can be differentiated from many other dementias in that there are frequently concomitant cerebrovascular accidents. FLAIR and T2 hyperintensities are prevalent in vasculitis, while thickening of vessel and extramural enhancement are more definitive findings.
Toxic metabolic causes: Porphyria, an inherited disorder of metabolism leading to build-up of porphyrins, can cause psychosis and pain. Vitamin deficiencies (thiamine, vitamin E) occur in patient with history of alcoholism or malabsorption. Heavy mental intoxication of arsenic, mercury, lithium or lead can cause cognitive decline. Bismuth intoxication presents with confusion, ataxia, myoclonus, or psychosis.
The sporadic form of CJD disease (sCJD), which typically manifests with dementia and myoclonus, accounts for approximately 85% of all cases of prion disease in humans. Infectious and inherited prion diseases account for the rest. The new variant CJD (nvCJD) is believed to arise from the consumption of infected cattle.
sCJD is a rare disease caused by prion proteins that undergo conformational changes, resulting in a fatal transmissible spongiform encephalopathy. The worldwide annual incidence is estimated to be 1 in a million. Affected individuals usually manifest as rapidly progressing dementing illness in the sixth or seventh decade of life. The mean life span from the symptom onset is less than one year (3-9 months).
The differential diagnosis of a patient presenting with rapid progressive dementia is broad, and the wide spectrum of clinical manifestations in sCJD makes determining the diagnosis yet more difficult. The hallmark feature of advancing sCJD is dementia. One third of patient will manifest psychiatric symptoms such as paranoia, self-neglect, depression, hallucinations. Another one-third of patients, in addition to dementia, manifest pyramidal or extrapyramidal, cerebella, or visual changes. There is progressive impairment such that patients eventually become globally demented, mute, and akinetic/bed bound.
CSF may be normal or show only slightly protein elevation. For patients with suspected CJD, CSF protein 14-3-3 has a diagnostic sensitivity of 92% and specificity of 80%. The usefulness of 14-3-3 depends on pre-test probability. The test is more useful when the pretest probability of CJD ranges from 20% to 90%. Whereas a negative 14-3-3 may be useful in reducing the suspicion for sCJD, a positive 14-3-3 may be found in other, potentially treatable causes of dementia. The use of other ancillary test may influence the pretest probability. Periodic sharp and slow wave complexes (PSWC) on EEG have a sensitivity of 66% and specificity of 74%. PSWC tend to occur in older patients, and in half of the patients 6 months or more into the disease course, with prevalence tending to decrease as the condition progresses. In some cases, there can be a temporal (time-locked) correlation between PSWC and the myoclonic jerking exhibited by some patients. Other frequent EEG findings in sporadic CJD cases include triphasic sharp waves, recurring every 0.5-2.0 seconds on an abnormal, diffusely slow background.
Imaging studies are emerging as valuable tools in diagnosing CJD. Diffuse weighted imaging (DWI) and fluid attenuation inversion recovery (FLAIR) sequences are very useful. The sensitivity and specificity of DWI and FLAIR in diagnosing CJD was found to be 91-92% and 93.8-95%, respectively. The most common sites for CJD-associated MRI changes were cerebral cortex, caudate, and thalamus to a less frequent extent. The shortest period reported in literature from symptom onset to the appearance of characteristic radiological features on MRI was three weeks. Reduced diffusivity of apparent diffusion coefficient images in the basal ganglia and cortical regions have been demonstrated and can last as long as two months. Matoba et al. noted that the hyperintensity in the basal ganglia and cortex during the early and intermediate stages was more extensive and conspicuous, with the cortical hyperintensity tending to wane as the disease approaches the terminal stage. Brain MRI is a useful tool in the diagnosis of CJD, but the characteristic changes are often not identified at initial scan in the early stage of disease. Diagnosis of CJD on the basis of a single brain MRI can be difficult to establish. However, there is curently no specific guideline or recommendation regarding when to repeat brain MRI in cases suspicious for CJD, should the initial brain MRI be negative. The clinical course presented in this case report underscores the usefulness of serial brain MRI (even when across relatively short time intervals) in cases of suspected CJD.
Definitive diagnosis of CJD requires brain biopsy or autopsy confirmation. Prion diseases are associated with four common histopathological features. Spongiform degeneration, atrophy, loss of nerve cells, and astrocytic gliosis are the typical histological features. Spongiform change is characterized by a fine vacuole-like appearance in the neutrophils, with vacuoles ranging from 2-200 um in diameter. These vacuoles are usually most prominent in cerebral cortex, basal ganglia, thalamus, and cerebellar. Brain biopsy has been shown to be diagnostic in around 95% of patients who were confirmed as having CJD on post-modern examination. Studies have suggested that brain biopsy can be avoided in patients with a typical clinical presentation and confirmatory screening tests. The CDC has diagnostic criteria for definite, probable, and possible diagnosis of CJDs.
CJD is invariably fatal. Clinically, course is usually progressive until death at about seven months.
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