克雅病常被误诊

《神经病学文献》9月24日在线发表的一项研究显示，只有少数克雅病患者在首次就诊时得到正确诊断，许多患者在疾病进展至中晚期、经历多次误诊后才最终被正确诊断。在97例该病患者中，仅17例(18%)在首次就诊时被正确诊断；在获得正确诊断之前，人均被误诊4次，历时8个月 (Arch. Neurol. 2012 Sept. 24 [doi:10.1001/2013.jamaneurol.79])。

克雅病患者通常在1年内死亡，该病的早期症状和体征多变且易被误认为其他神经变性疾病，因此难以诊断。这项研究由加州大学旧金山分校(UCSF)神经病学科的Ross W. Paterson博士及其同事进行，目的是回顾性探讨在该病检查过程中常做出的错误诊断是什么、谁做了这些诊断及一般需多久才得到正确诊断。研究对象是UCSF 2001~2007年收治的40例女性和57例男性克雅病患者，平均年龄为62岁(26~83岁)。

共76%患者的首次诊断是由内科医生(40%)或神经科医生(36%)作出的，这些医生也在作出错误诊断的医生中占据绝大部分。在73%的患者中，神经科医生是进行评估的首位专科医生。其他在患者首次就诊时作出错误诊断的医生包括：6名眼科医生、4名精神科医生、4名心脏科医生、2名耳鼻喉科医生、2名整形外科医生和1名神经肿瘤科医生。

在获得正确诊断前，患者被误诊的总次数为373个，平均每例患者4个。研究者发现克雅病被误诊为16类疾病，最常见为神经变性、自身免疫性、感染性、毒性/代谢性和“不明原因痴呆”。最常见的单个错误诊断为病毒性脑炎，这很可能是因为克雅病具有多灶性、急性和症状迅速发生等特点。

该研究结果表明，对于已被给予多个诊断(如神经变性、自身免疫性、感染性或毒性/代谢性)的快速进行性痴呆患者，应考虑偶发克雅病的可能。如果缺乏支持诊断病毒性脑炎、副肿瘤性疾病、抑郁、外周性眩晕、阿尔茨海默病、卒中、痴呆(非特指型)、CNS血管炎、外周神经病变或桥本氏脑病的证据，临床医生应考虑进行弥散加权成像/表现弥散系数序列MRI来观察与偶发克雅病相关的改变。弥散加权MRI在鉴别克雅病和其他脑病方面的敏感性为91%~96%，特异性为91%~95%。此外，由于许多放射学报告会遗漏克雅病的特异病征性MRI表现，因此临床医生应对这种朊病毒病的MRI表现有所了解，并能够自行解读患者的MRI图片。医生做出正确诊断有助于避免该病的传播，特别是避免通过污染的手术器械或医学操作传播。

从另一个角度看，将患有不同病因所致的快速进行性痴呆患者误诊为克雅病同样具有危害。近期一项研究显示，32%因疑似克雅病而进行尸检的患者实际上所患的是其他疾病。共7%患者的病因是可以治疗的，但却因被误诊为克雅病而未接受治疗。

上述研究获美国老衰老研究所等多家机构支持。一名研究者声明与TauRx制药公司等多家药企存在联系。

随刊述评：确诊姗姗来迟

Richard J. Caselli博士

梅奥医院的神经科教授Richard J. Caselli博士表示，许多常见疾病具有与克雅病相同的特征，甚至在MRI表现上也相同，包括缺氧/缺血、病毒性脑炎(急性)和局灶性癫痫持续状态，通过临床表现可对这些疾病和克雅病进行鉴别。要确保正确诊断及控制医疗费用，除了依赖于医生之外，还需要患者及其家属具备相应的疾病知识，这样才能尽快地确立诊断，并最大程度地提高患者的生活质量(Arch. Neurol. 2012 [doi:10.1001/2013.jamaneurol.1])。

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By: MARY ANN MOON, Internal Medicine News Digital Network

Few patients with sporadic Creutzfeldt-Jakob disease appear to receive a correct diagnosis when first assessed by a physician, and many receive multiple misdiagnoses until finally being correctly diagnosed two-thirds of the way through the course of the fatal disease.

In a case series of 97 patients with the disease, only 17 (18%) were correctly diagnosed when first assessed by a physician. The average patient received four misdiagnoses and endured 8 months of evaluation before Creutzfeldt-Jakob disease (CJD) was finally identified, according to the report, published online Sept. 24 in Archives of Neurology.

CJD, which is almost always fatal within 1 year, can be difficult to diagnose because early symptoms and signs are so variable and are easily mistaken for those of other neurodegenerative conditions. But the "lack of recognition of this condition in the medical community" is also to blame, especially the fact that many physicians aren’t aware that diffusion-weighted MRI has a sensitivity of 91%-96% and a specificity of 91%-95% in differentiating CJD from other brain disorders, said Dr. Ross W. Paterson of the department of neurology, University of California, San Francisco, and his associates.

The investigators described their study as the first large-scale examination "of pathologically proven cases of spontaneous CJD that retrospectively determines what misdiagnoses are made in the work-up of [the disease], who makes these misdiagnoses, and how long it takes to reach the correct diagnosis."

A total of 76% of the patients in this study were first assessed by internists (40%) or neurologists (36%), comprising "the vast majority of the physicians making the misdiagnoses," the researchers noted. In 73% of the cases, a neurologist was the first specialist to perform an assessment.

Dr. Paterson and his colleagues studied the issue because they had observed that many families of patients referred to the UCSF Memory and Aging Center complained about the typical delay in diagnosis. Their loved ones had been subjected to extensive and costly evaluations for other conditions, and the families had failed to be protected from a transmissible prion disease. And the delay had deflected both patients and families from focusing on palliative care and end of life planning for this incurable disease.

The 40 female and 57 male subjects were treated at UCSF in 2001-2007. Their ages ranged from 26 to 83 years, with a mean age of 62 years.

Before being correctly diagnosed, the study subjects had received 373 misdiagnoses, with an average of approximately 4 per patient. Of 16 possible categories of disease under which they were misdiagnosed, the most frequent categories were neurodegenerative, autoimmune, infectious, toxic/metabolic, and "unknown dementia."

The most common individual misdiagnosis was viral encephalitis, most likely because of "the multifocality, acuity, and rapidity of symptoms seen in CJD," Dr. Paterson and his associates said (Arch. Neurol. 2012 Sept. 24 [doi:10.1001/2013.jamaneurol.79]).

In addition to internists and neurologists, a smattering of other physicians also misdiagnosed CJD when patients first presented with symptoms. These included six ophthalmologists, four psychiatrists, four cardiologists, two otolaryngologists, two orthopedists, and one neuro-oncologist.

The results of this study indicate that sporadic CJD should be considered "in any patient with a rapidly progressive dementia who has been given multiple potential diagnoses," such as those with neurodegenerative, autoimmune, infectious, or toxic/metabolic etiologies, the investigators wrote. And "if evidence to support a diagnosis of viral encephalitis, paraneoplastic disorder, depression, peripheral vertigo, Alzheimer’s disease, stroke, dementia (nonspecified), CNS vasculitis, peripheral neuropathy, or Hashimoto encephalopathy is lacking, then the clinician should think about requesting an MRI with diffusion-weighted imaging/apparent diffusion coefficient sequences to look for changes associated with sporadic CJD," they noted.

Moreover, since many radiology reports miss the pathognomonic MRI findings of CJD, "it is critical that physicians be aware of MRI findings in prion disease and read their patients’ MRIs [themselves]," Dr. Paterson and his associates added.

Although this study targeted patients with CJD, misdiagnosing CJD in a patient who has a different etiology for their rapidly progressive dementia is just as harmful, because many of these other dementias are treatable. A recent study demonstrated that 32% of patients referred to the National Prion Disease Pathology Surveillance Center for autopsy because of suspected CJD were actually found to have other diagnoses. A total of 7% had had a treatable etiology but went untreated because they were mistakenly diagnosed as having CJD, Dr. Paterson and his associates noted.

It is also incumbent on physicians to make the correct diagnosis so that transmission of this prion disease is avoided – particularly transmission via contaminated surgical equipment or medical procedures, they added.

This study was supported by the National Institute on Aging, the National Institute of Neurological Disorders and Stroke, the Michael J. Homer Family Fund, the National Center for Research Resources, and the John Douglas French Alzheimer’s Foundation. One of Dr. Paterson’s associates reported ties to TauRx Pharmaceuticals, Bristol-Myers Squibb, Siemens Molecular Imaging, and Allon Therapeutics.

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"A Final and Very Unfortunate Diagnosis"

Dr. Paterson and his associates at a major referral center for patients with suspected Creutzfeldt-Jakob disease should be commended for illustrating the diagnostic journey these patients and their families must travel "on their way to a final and very unfortunate diagnosis," said Dr. Richard J. Caselli.

Many of the most common alternative diagnoses can share many of the same features of CJD, including even MRI mimics, such as "anoxia/ischemia, viral encephalitis (acutely), and focal status epilepticus," which can usually be distinguished from CJD by the clinical context, he wrote.

"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," he said.

RICHARD J. CASELLI, M.D., is a professor of neurology at the Mayo Clinic in Scottsdale, Ariz. He reported no financial conflicts of interest. These remarks were taken from his editorial accompanying Dr. Paterson’s report (Arch. Neurol. 2012 [doi:10.1001/2013.jamaneurol.1]).