Wolfe, Keith MS*; Leach, James L. MD*†‡; Kissela, Brett MD†‡; Fortuna, R. Brian MD*
There are a wide variety of infectious causes of encephalopathy. Some, such as herpes encephalitis or pyogenic abscess, have a definite etiology, typical imaging features, and specific treatments. Prion-based disease is an unusual but increasingly recognized cause of encephalopathy and can have imaging manifestations that, in the proper clinical scenario, will lead to the correct diagnosis. We present a case of sporadic Creutzfeldt-Jakob disease (sCJD) in a patient presenting with rapid mental status and neurological decline. The evolution of imaging findings was crucial in making the proper diagnosis.
A 68-year-old right-handed, previously neurologically intact white woman presented with a 3-week history of intermittent difficulty in talking and ataxia. Some episodes resulted in her being unable to express herself in words. She noticed that she was running into objects at home. Episodes would last for 1 to 2 hours then spontaneously resolve. One day before admission, she had a more pronounced episode of difficulty in speaking and walking, which only partially resolved, prompting her to seek medical attention. Her medical history included non-insulin-dependent diabetes, hypertension, hypothyroidism, and hyperlipidemia. A coronary stent had been placed one year previously for coronary atherosclerotic disease. The patient's blood pressure was 165/83, and temperature was 99.2°F.
Her initial neurological examination was remarkable for mildly nonfluent speech with occasional paraphasic errors and abnormal finger-to-nose testing in the right upper extremity. Her strength and gait were normal.
Initial white blood cell count was 10.4 × 103 with a normal differential. Renal profile was normal. Urinalysis was normal. Erythrocyte sedimentation rate was mildly elevated at 61 mm/h (0-30). C-reactive protein was elevated at 3.9 mg/dL (0.0-0.5). Cerebrospinal fluid (CSF) analysis revealed a mildly elevated protein (57 mg/dL) and glucose (107 mg/dL); 1 red blood cell and 1 white blood cell were noted on cell count. Extensive CSF analysis was performed, including assessment for cytomegalovirus DNA, herpes simplex virus polymerase chain reaction, and VDRL which venereal desease research laboratory were negative. All CSF cultures were negative.
Initial computed tomography of the head was normal. A magnetic resonance imaging (MRI) of the brain without and with contrast was obtained 2 days after admission (Fig. 1). The MRI demonstrated areas of increased signal in the right medial and lateral occipital lobe and bilateral parafalcine frontoparietal lobes on the fluid-attenuated inversion recovery (FLAIR) sequences (Fig. 1A). More extensive abnormalities were identified on the diffusion-weighted images (DWIs), with areas of diffusion restriction involving the right inferior frontal lobe cortex and right caudate head, and in the areas of cortical abnormality seen on the FLAIR sequences. A magnetic resonance angiogram of the intracranial and extracranial circulation was normal.
An electroencephalogram (EEG) was performed that demonstrated focal slowing and intermittent polymorphic delta activity in the left frontal and central head region. This was interpreted as being consistent with a focal disturbance of cerebral function and possible structural abnormality.
At this point, the differential diagnosis included vasculitis, multiple infarcts, and encephalitis. A transesophageal echocardiogram was performed that showed mild atheromatous plaque in the arch and descending thoracic aorta but was otherwise normal. A transthoracic echocardiogram and a 4-vessel cerebral catheter angiogram were normal.
Based on the abnormal echocardiogram, the working diagnosis was thought to be multiple embolic infarcts as the most likely cause of the signal abnormalities. The patient was started on anticoagulation therapy (coumadin). At discharge, mild expressive aphasia remained.
The patient returned 18 days later (24 days after initial presentation and initial magnetic resonance), with worsening symptoms. The patient had worsening right-sided weakness, dysphagia, and dysarthria. Repeat MRI (not shown) demonstrated persistent parenchymal signal abnormalities and diffusion restriction in the areas previously noted on the prior MRI. A new focus of diffusion restriction was noted in the left caudate head. The examination was significantly motion degraded. Repeat CSF analysis was normal, including assessment for acid-fast bacillus, cytomegalovirus, Epstein-Barr virus, and JC virus. A complete autoimmune and rheumatologic serological work-up was negative. A repeat EEG was performed that showed generalized slowing with periodic synchronous wave discharges (PSWDs).
Her condition worsened during the hospitalization, with progression to complete aphasia and inability to follow commands. Her neurological status continued to decline over the next week, and she began to show signs of increased startle response and continued dense aphasia. At this time, a repeat MRI of the head was performed (31 days after her initial MRI) (Fig. 2). This demonstrated progressive signal abnormalities in the areas previously involved and new areas of signal abnormality in the left caudate head and left putamen and both occipital lobes (Fig. 2A). Progressive areas of diffusion restriction were noted in the right frontal lobe, right parietal lobe, and paramedian frontoparietal areas near the vertex. New areas of diffusion restriction were noted in the left caudate head, left putamen, right parietal lobe, and right inferior frontal lobe (Fig. 2B). There was no enhancement abnormality. Given the progression of signal abnormalities, the progressive and persistent diffusion restriction in several areas, and suggestive clinical progression and EEG findings, the diagnosis of CJD was suggested.
Repeat EEGs were performed that again showed generalized slowing with more prominent periodic epileptiform discharges. The CSF analysis for neuron-specific enolase (Mayo Medical Laboratories) was abnormal with a value of 37 ng/mL (normal < 20 ng/mL; suggestive of CJD > 35 ng/mL). Immunoassay for the 14-3-3 protein was not available from our laboratory system. The family was counseled to the likelihood of the diagnosis of CJD and-based upon the extensive previous work-up for other causes, lack of effective treatment of this disease, and poor prognosis-opted to place the patient under hospice care.
Diagnosis: Creutzfeldt-Jakob disease.
Creutzfeldt-Jakob disease is a progressive and uniformly fatal neurodegenerative disorder that is believed to be caused by the conversion of the normal prion protein (PrPC) to PrPSc. PrPSc is a protease-resistant protein that has been proven to be an isoform of PrPC, a protease-sensitive normal host cellular protein. In the pathological process of CJD, PrPC undergoes posttranslational change in conformation to become PrPSc. This change involves the conversion of the predominantly alpha-helical structure of the normal prion protein into a large β-sheet confirmation. Accumulation of the abnormal protease-resistant form of the protein in and around neurons leads to vacuolization, cell death, and progression of the disease process.1,2
The worldwide incidence of CJD is approximately 1 per 1 million population per year after middle age, affecting slightly more women than men.2 Approximately 85% of cases of CJD are considered sporadic in nature, and no identifiable etiology can be found.3 Eighty percent of sporadic cases of CJD are diagnosed in individuals aged 50 to 70 years.1 Genetic cases or familial CJD account for 15% of cases and are thought to represent a mutation in the prion protein gene (PRNP). The PRNP gene, which encodes the PrP protein, is located on chromosome 20 in humans. The PRNP is expressed at its highest levels on neurons and various other cells of the central nervous system. Based on molecular analysis, the PRNP gene is polymorphic at codon 129. At this codon, the gene encodes either a valine or methionine residue.4 Homozygosity for methionine seems to constitute a risk factor for developing sCJD. Parchi et al5 reported an allelic distribution for codon 129 in a population of sCJD subjects significantly different from the normal US and European populations, with almost 90% of patients with sCJD being homozygous at codon 129-most for the methionine homozygosity (MM) genotype. Iatrogenic (corneal transplants, dural grafts, human growth hormone, and improperly cleaned surgical instruments) cases typically compromise less than 1% of all CJD cases.3
Sporadic Creutzfeldt-Jakob disease is typically characterized by a triad of rapidly progressive dementia, periodic synchronous discharge on EEG, and myoclonus.6,7 Often, the classical triad is not found in patients with CJD especially early in the course of the disease. Some reports indicate that the classic triad will not be present in as many as 25% of all patients. One third of all patients initially show vague symptoms including fatigue, disordered sleep patterns, or loss of appetite. Another one third of patients initially show focal neurological signs, such as aphasia, ataxia, vision loss, amyotrophy, or hemiparesis. The final one third of patients suffer more global neurological dysfunction, such as memory loss, uncharacteristic behaviors, or confusion.1 Classically, PSWD on EEG associated with a progressive dementia, with at least 2 of the 4 features of myoclonus, cerebellar or visual signs, pyramidal or extrapyramidal signs, and akinetic mutism, suggested the diagnosis of a case of sCJD.8 More recently, several CSF markers of neurodegeneration have been used to help support clinical diagnoses of CJD. These markers include neuron-specific enolase, S-100, and 14-3-3 protein.7 Of these markers, 14-3-3 protein has shown the most promise based on sensitivity and specificity, but comparison of multiple studies evaluating 14-3-3 protein as a marker for CJD indicate wide ranges of sensitivity of 53% to 100% and specificity of 84% to 100%. Electroencephalogram changes are often only seen late in the course of the disease and can have a variable sensitivity of 65% to 85%.3 Current criteria for the diagnosis of CJD include the characteristic neurological symptoms, characteristic EEG changes, or the presence of the 14-3-3 protein in the CSF. Ultimately, definitive diagnosis of CJD can only be obtained by neuropathologic or biochemical examination of the brain by either biopsy or autopsy (postmortem examination).3,7-9 Because of the lack of classical symptoms in the early stages of the disease and the variable sensitivity of EEG and CSF analysis, CJD can be very difficult to diagnose until patients have advanced stage disease.
Magnetic resonance imaging is an important tool in helping to identify probable cases of CJD especially earlier in the course of the disease process. Before MRI, neuroradiological examinations were considered to be relatively unhelpful in the diagnosis of CJD, because computed tomography findings are usually falsely negative, although nonspecific brain atrophy is often indicated late in the course of the disease. Newer MRI sequences, particularly FLAIR and DWI, are beginning to show significant promise as possible alternatives to brain biopsy in helping to confirm the diagnosis of CJD. This is particularly important when considering the significant morbidity and mortality of performing a brain biopsy on these patients, in addition to the risks of surgical instrument contamination and potential accidental inoculation of healthy patients.
Early reports of MRI showed poor sensitivity in established cases of CJD. However, as FLAIR and DWI became available in the 1990s, reports evaluating these modalities showed greatly improved sensitivity and specificity. By the year 2000, small-sized retrospective studies evaluating DWI in cases of established CJD were starting to be published. One large-sized retrospective analysis of the sensitivity and specificity of FLAIR and DWI in evaluating cases of confirmed or probable CJD was published in 2005. This study, involving 40 patients with confirmed or probable CJD and 53 control subjects with other forms of dementia, demonstrated 91% sensitivity and 95% specificity for the diagnosis of CJD using FLAIR and DWI. Tschampa et al performed another large retrospective analysis of T2-weighted MRI, FLAIR, DWI, and proton-density weighted MRI in the evaluation of suspected sCJD. This study demonstrated an overall sensitivity of 59.7% of MRI in the diagnosis of sCJD, based on the combined results of 3 separate observers. In addition, specificity of MRI in the diagnosis of sCJD was found to be 84.2%, 89.5%, and 81.6% for 3 separate observers.
Ukisu et al demonstrated the use of serial DWI in the evaluation of sCJD from early stages before the onset of myoclonus or PSWD on EEG to terminal stages of the disease process. Abnormal high-signal intensity in the cortex on DWI was observed before the onset of myoclonus or PSWD in 6 of 6 patients. In addition, high-signal intensity on DWI was also noted in the caudate nucleus in 5 of 6 patients early in the course of the disease. By the terminal stage of CJD, disappearance of cortical and basal ganglia signal abnormalities was observed in one case, suggesting that DWI may have good use in the earlier stages of CJD but may show some limitation in later stages of the disease.
Abnormal signal intensities on MRI have been observed throughout various neocortical areas in cases of sCJD, including abnormal signal in areas of the parietal, temporal, frontal, and occipital cortices. In addition, abnormal signal on MRI is commonly seen in the striatum, involving both the caudate nucleus and putamen. The head of the caudate and the anterior aspect of the putamen seem to be more commonly involved than the body of the caudate or the posterior portion of the putamen. Thalamic involvement is less frequently seen on MRI in cases of sCJD, but when thalamic abnormalities are seen, they typically involve medial and posterior portions of the thalamus.
With progression from early- to late-stage disease, the cortical signal abnormalities may be stable or less prominent, and the striatal involvement may become more pronounced. Thalamic involvement is uncommon in sCJD (12% of patients) but can be seen in late-stage disease.
The progression of signal abnormalities in our case and the persistence of diffusion restriction in areas over 31 days, as in the presented case, would be highly unusual for arterial ischemia and suggested ongoing brain injury. In studies evaluating serial DWI in the diagnosis of CJD, persistence and evolution of areas of diffusion restriction can be seen over periods ranging from 3 to 13 months. Although abnormalities on DWI may become less conspicuous in advanced stages of disease, the abnormalities do persist usually until patients succumb to the disease process.
Over the past decade, interest in infectious CJD has grown significantly in large part because of the outbreak of variant CJD (vCJD) and its relationship to bovine spongiform encephalopathy (BSE). In 1994, the first cases of vCJD were recognized in the United Kingdom. As of July of 2004, there have been 147 cases of definite or probable vCJD reported in the United Kingdom, 142 of whom have died. This form of the disease process was named vCJD because of the apparent differences in its clinical course and neuropathologic findings as compared with the classical sCJD. The early stages of vCJD are characterized by psychiatric and behavioral changes that precede the neurological symptoms (myoclonus, ataxia, speech problems, and memory problems) in several months. In addition, the mean age of onset of vCJD is 28 years, which lies in stark contrast to the much older age of onset of sCJD, and the time course of vCJD before death ensues is also significantly longer. The causal relationship between BSE in cattle and vCJD in human subjects remains difficult to prove, although the geographical and temporal clustering of both diseases in the United Kingdom is highly suggestive.
All patients affected by vCJD seem to be MM homozygotes at codon 129. Based on molecular analysis using protease digestion and Western blot, there are between 3 and 6 different types of the abnormal PrP protein, and one specific PrP type is found in patients with vCJD, which is identical to the PrP type found in BSE. Conversely, multiple PrP types are found in sCJD.
In suspected cases of vCJD, the best differentiating imaging feature is the presence of the "pulvinar sign," which is much less commonly seen in cases of sCJD. Originally, the World Health Organization had defined the pulvinar sign as simply bilateral high-signal intensity in the pulvinar (posterior medial aspect of the thalamus) on MRI. This sign was found to be relatively specific for vCJD, but cases of sCJD have been found that show similar high-signal intensity in this region. Since that time, the World Health Organization has revised their definition of the pulvinar sign as bilateral, symmetrical pulvinar high-signal intensity on MRI greater than the high-signal intensity of other deep gray matter nuclei or cortical gray matter. With this new working definition, this sign has become more specific for differentiating cases of vCJD from sCJD. Abnormal hyperintensity is often seen in the periaqueductal gray matter and posterior deep white matter tracts in cases of vCJD.
Currently, CJD and all other human prion diseases (kuru, Gerstmann-Sträussler-Scheinker disease, fatal familial insomnia) are uniformly fatal, with no effective treatment available at this time. The hurdles to developing effective treatments for prion diseases are significant because of the protein nature of the infectious agent, the necessity of effective treatments to be able to transverse the blood-brain barrier, and continued uncertainty about the exact pathological mechanisms of the disease process. Some initial work have begun to investigate potential treatment of prion diseases. The use of animal models for development of active and passive immunization techniques has been started. Drug therapy trials with quinacrine, chlorpromazine, and amphotericin B have shown some possible effect in animals but have shown no definite therapeutic effects in humans. If such treatments are developed for humans, early diagnosis may be important in starting therapy before insurmountable neurological damage occurs. Early diagnosis is helpful to avoid unnecessary and potentially harmful treatments (such as coumadin in this case), properly take infectious precautions (if brain biopsy was to be considered as part of the work-up, for example), and provide the patient and their family with appropriate information regarding prognosis. Therefore, the use of MRI as the most sensitive and specific method of early detection of CJD will continue to evolve as we learn more about prion-associated diseases.
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