Author Affiliation: Department of Neurology, Mayo Clinic Arizona, Scottsdale, Arizona.
I recall, as a young resident in the 1980s, that Creutzfeldt-Jakob disease (CJD) seemed much easier to diagnose than it seems to me now. How can that be? Graying synapses aside, I suspect it reflects the progress that has been made in the past 30 years, particularly in the area of autoimmune encephalopathy. Although CJD at one time seemed to have a monopoly on rapidly progressive dementia, the increasing recognition of autoimmune encephalopathy has made us less confidant about pronouncing the “death sentence.” Patients with autoimmune encephalopathy can be highly responsive to steroids; however, that is not always the case. Paraneoplastic cases typically are not at all responsive and usually end in death. New antibodies continue to be found, making us further wary of the CJD pronouncement only to find, weeks later, that a new antibody not previously sought has been identified. So, increasingly, our attention is focused on not missing reversible causes with somewhat reduced concern for the timely diagnosis of an invariably fatal disease. In this issue of Archives of Neurology, however, Paterson and colleagues1 remind us of perhaps a more traditional perspective.
The University of California, San Francisco, Memory and Aging Center is a major referral center for patients with suspected CJD, and Dr Michael Geschwind and his colleagues there have previously reported that roughly 38% of referred patients have a nonprion-related condition that is most often degenerative; however, in a significant proportion of cases, it is a condition that is potentially reversible.2 Unquestionably, when confronted with the syndrome of rapidly progressive dementia, our first concern must be the search for reversible causes, a point that Paterson et al1 discuss in this issue of Archives, but their main point is to illustrate the diagnostic journey patients with CJD travel on their way to a final and very unfortunate diagnosis.
This journey has important implications for neurologists, the first of which is that in the year of life left to them, patients spend nearly 8 months undergoing various forms of evaluation and treatment before a final diagnosis is reached. Up to that point, an average of nearly 4 alternative diagnoses are entertained with the added physical and emotional toll that any incorrect diagnosis invariably takes on families, especially when confronted with such a serious illness. In only 18% of cases was the correct diagnosis of CJD the initial diagnosis (almost always made by a neurologist).1 However, neurologists and other early evaluators may be forgiven for these types of delays in diagnosis because the initial symptoms of the patient may have been nonspecific or may have suggested a more common and less lethal alternative diagnosis. Rabinovici et al3 found that 76% of patients initially present with merely a single symptom (with roughly half not even falling within the dementia heading) and that 19% of patients present with 2 initial symptoms. The most common are cognitive (40%), cerebellar (22%), “constitutional” (vertigo, fatigue, and sleep disorder [21%]), and behavioral (irritability and depression [20%]), with other symptoms less common (including visual [7%]).3 Furthermore, genetic variants of CJD can present with a myriad of focal presentations, including but not limited to simultanagnosia, aphasia, apraxia, and ataxia,4 which explains the frequent misjudgment of a neurodegenerative or vascular etiology.
Turning to the most common alternative diagnoses, we can further understand the pitfalls that we face in CJD diagnosis. Alzheimer disease is far more common, has a variety of variant syndromes, can occasionally be rapidly progressive, and, in such cases, may even be associated with elevations of the 14-3-3 protein.5 Autoimmune encephalopathy typically presents as a subacute delirium or rapidly progressive dementia that can occasionally result in electroencephalographic periodic complexes, yet the patient may be exquisitely responsive to steriods.6 In a large autopsy series of 1106 brains of patients clinically diagnosed with CJD, 32% of the patients (n = 71) had an alternative diagnosis that was thought to be potentially reversible.7 Because such conditions as acute disseminated encephalomyelitis, leptomeningeal carcinomatosis, and paraneoplastic syndromes were included in this category, the actual number of reversible cases may have been somewhat overestimated, but, even more conservatively, there were roughly 38 cases (3.4% overall) that might have had a reasonable chance for meaningful improvement if diagnosed antemortem.
Magnetic resonance imaging has greatly facilitated the diagnosis of CJD, and in a recent study, the sensitivity and specificity of magnetic resonance imaging for sporadic CJD were 96% and 93%, respectively. Familial CJD had overlapping features, including most prominently the cortical ribbon and basal ganglia and thalamic hyperintensities on diffusion-weighted imaging and fluid-attenuated inversion recovery sequences.8 Nonetheless, even magnetic resonance imaging mimics occur, including anoxia/ischemia (Figure), viral encephalitis (acutely), focal status epilepticus, and others, but the clinical circumstances usually help to distinguish these entities from CJD.
Figure. Diffusion-weighted images of anoxic-ischemic encephalopathy in a 17-year-old girl demonstrating a cortical ribbon pattern most prominently in occipital-temporal and paracentral cortices.
Although our first priority is to save lives when at all possible, we are also responsible for protecting others from harm and for mitigating suffering. Paterson and colleagues1 appropriately cite these priorities as compelling us to a prompt and accurate diagnosis of CJD. Regarding the safety of others, CJD is a transmissible disease. To date, there have been 226 known cases associated with contaminated growth hormone derived from infected pituitary extracts and 228 known cases associated with infected dura mater grafts, more than half of which occurred in Japan.9 With the greater recognition of risk and the appropriate decontamination procedures, the number of future cases is expected to be much lower, but past experience underscores the real risk posed by patients with undiagnosed conditions who may donate human tissue for medical use, as well as the risk posed by surgical equipment contaminated with prion-infected tissue. As to the mitigation of suffering, CJD is a challenging management problem, which is all the more reason why professional palliative care should be sought.10
There is also a societal dimension to the timely diagnosis of CJD. At this time of global economic crisis, national health care reform, escalating medical expenditures, and an aging population (creating projections of accelerating health care–driven financial gloom and doom), the financial burden posed by prolonged and duplicative testing that results from diagnostically ambiguous cases of rapidly progressive dementia must also be considered. Most health care expenditures occur during the final year of life, and CJD is no exception to this general rule. As we attempt to rein in health care costs while sacrificing no degree of medical accuracy or compassion, we owe it to our patients and to society to have the necessary knowledge to consider the diagnosis, establish the diagnosis as efficiently as possible, and then work with patients, families, and palliative care providers to maximize the quality of life for our dying patients. Paterson and colleagues1 are to be commended for highlighting this important but sometimes underappreciated dimension of neurologic practice.
Correspondence: Dr Caselli, Department of Neurology, Mayo Clinic Arizona, 13400 E Shea Blvd, Scottsdale, AZ 85259 (email@example.com).
Published Online: September 24, 2012. doi:10.1001/2013.jamaneurol.1
Conflict of Interest Disclosures: None reported.
Caselli RJ. The (Mis)diagnosis of Creutzfeldt-Jakob Disease. Arch Neurol. 2012;69(12):1554-1555. doi:10.1001/2013.jamaneurol.1