Diagnostic challenges in Creutzfeldt-Jakob disease: case report.

Abstract: Sporadic Creutzfeldt-Jakob disease (CJD) is the most common prion disease. The diagnosis can be confirmed only by histological examination of brain tissue obtained at biopsy or at autopsy. Because of the transmissible nature of the disease, autopsy or brain biopsy cannot be performed at many institutions, which poses numerous challenges in confirming the diagnosis. We report the case of a patient with CJD in which autopsy to confirm the diagnosis was performed after overcoming numerous obstacles and advocating with hospital leadership. This case illustrates the numerous challenges that exist in achieving a definitive diagnosis of CJD and in postmortem disposition of the body, and we provide recommendations to clinicians who face similar challenges.

Key Words: autopsy, brain biopsy, challenges, Creutzfeldt-Jakob disease

**********

Key Points

* Sporadic Creutzfeldt-Jakob disease is the most common prion-related neurodegenerative disorder in humans.

* Diagnosis can only be confirmed by histological examination of brain tissue obtained either by the brain biopsy or after autopsy.

* Autopsy to confirm the tissue diagnosis of Creutzfeldt-Jakob disease cannot be performed at many institutions due to the transmissible nature of the disease.

* Because numerous efforts are required to arrange for an autopsy to confirm the diagnosis, more specific protocols, adequately equipped autopsy sites, trained pathologists, guidelines for healthcare professionals, funeral homes, and families to handle such cases are needed to overcome these obstacles.

Case Report

A 68-year-old woman was admitted to a geriatric psychiatric center because of acute psychosis and rapidly declining cognitive function. The patient had been well until approximately 2 months before this admission, when she presented to her primary care physician with vague symptoms of headache, tinnitus, impaired hearing, and unsteady gait. During the course of a few weeks, she developed delusions, inappropriate behavior, and agitation. She was admitted to the local county hospital with the diagnosis of acute psychosis and was treated with antipsychotic medications. Despite treatment, the patient became increasingly withdrawn, mute, and catatonic. Because of a rapid decline in her mental status, she was transferred to a geriatric psychiatric center. The patient's medical history was unremarkable for previous episodes of psychosis, corneal transplants, administration of human growth hormone, or blood transfusions. Family members denied any family history of neurologic diseases.

The physical examination revealed the patient to be awake but unable to communicate and follow verbal commands. She had a low-grade fever, pulse 80 beats/min, respiration 20 breaths/min, and blood pressure 130/75 mm Hg. She was noted to demonstrate myoclonic jerks and a dramatic startle reflex. The neurologic examination revealed spastic quadriparesis and hyperreflexia. The patient's gait and memory could not be tested. The rest of the physical examination was unremarkable. The possibility of CJD was considered. Computed tomography and magnetic resonance imaging (MRI) of the brain revealed mild cerebral atrophy. CSF analysis showed elevated protein of 45, normal glucose, and no pleocytosis. CSF cultures were negative. Analysis for CSF protein 14-3-3 was not performed. The initial electroencephalogram (EEG) revealed diffuse slowing consistent with metabolic or toxic encephalopathy. The positron emission tomographic scan was unrevealing. An EEG obtained 2 weeks later revealed bilateral synchronous periodic epileptiform discharges characteristic of spongiform encephalopathy. At that time, the patient's family pressed for confirmation of the diagnosis of CJD on the basis of a brain biopsy. They communicated many concerns regarding the mode of transmission of CJD and handling of the corpse after death.

Neurosurgical consultation was sought to perform the brain biopsy. The neurosurgeon was reluctant to perform the brain biopsy because of a fear of "contaminating" the operating room and instruments. The patient continued to deteriorate clinically and was transferred to a hospice unit, where she died as a result of pneumonia and sepsis. The autopsy could not be performed at the hospital at which she was originally admitted because of the pathologist's lack of training and enthusiasm, an inadequately equipped morgue, and cost. The hospice also could not perform the autopsy, because the hospice Medicare benefit would not cover the cost.

After numerous and relentless efforts were made, an autopsy was performed at the university hospital only after it was advocated by the hospital's leadership. The histological examination revealed marked spongiform changes and gliosis predominantly involving the cerebral and cerebellar cortices. Immunostaining studies for PrSc performed with the use of antiprion protein monoclonal antibodies revealed a granular pattern of staining, which is characteristic of CJD. The funeral home director was unfamiliar with World Health Organization infection control guidelines for transmissible spongiform encephalopathies and refused to accept the corpse, stating that embalming the patient would put him and his family at risk. He stated that he would accept the body only if it were cremated or if a "direct burial" could be performed. The funeral home agreed to accept the body after cremation.

Prion diseases have generated increasing public concern since the identification of the relationship between bovine spongiform encephalopathy and new variant Creutzfeldt-Jakob disease (CJD). (1,2) Sporadic CJD remains the most common prion-related neurodegenerative disease in humans. (3) Older adult patients may present with common nonspecific clinical manifestations such as falls, psychiatric illness, or loss of memory, which causes diagnostic difficulty. (4-6) Although rare, CJD may present at any hospital at any time, and physicians' lack of familiarity with it may lead to unfounded fears about the transmissibility of the disease. Although significant progress has been made in neuroradiologic and cerebrospinal fluid (CSF) tests to establish the clinical diagnosis, the definitive diagnosis of CJD can be confirmed only by performing histological examinations of brain tissue. We report the case of a patient with classic clinical features of CJD. We discuss challenges that clinicians face in confirming the diagnosis, address the fears of involved personnel and the postmortem handling of the corpse, and provide recommendations to clinicians.

Discussion

CJD accounts for more than 85% of all cases of prion disease. (7) The worldwide annual incidence is approximately 1 per 1 million people. (8) The disease occurs sporadically in 90% of cases, is inherited in less than 15% of cases, and is transmissible in less than 5% of cases. Patient age at onset ranges from 16 to 86 years, with an average of 61.5 years. (9,10) The disease is always fatal, with a mean interval of 8 months and a median interval of 4.5 months between onset and death. (10) From 1979 through 1998, 4,751 deaths as a result of CJD were reported in the United States. The average annual age-adjusted death rate was 0.97 per 1 million population, ranging from 0.78 in 1980 to 1.13 in 1997. The overall annual rates have been stable since 1985. The median patient age at death is 68 years. (11) Recently, significant progress has been made in establishing the antemortem diagnosis in suspected cases of CJD. These include MRI and 14-3-3 protein immunoassay in CSF. MRI has been shown to be a valuable tool in the clinical diagnosis of CJD. MRI shows bilateral areas of increased signal intensity predominantly affecting the basal ganglia (ie, caudate nuclei, putamina) in CJD. In a recent study, (12) T2-weighted MRI scans were found to have sensitivity of 67% and specificity of 93%. The presence and persistence of protein 14-3-3 has been shown to be of great value in differentiating CJD from other forms of rapidly progressive dementia. In a recent prospective study of 364 patients initially suspected of having CJD, 14-3-3 protein was found to be superior to MRI and electroencephalography in discriminating CJD from other rapidly progressive dementias. (13) The sensitivity and specificity of protein 14-3-3 in CSF were determined to be 95 and 93%.

Our patient met Masters et al's (8) criteria for probable CJD, such as inappropriate behavior, ataxia, myoclonic jerks, akinetic mutism, and rapid decline in cognitive function during a 3-month period. In this case, T2-weighted MRI failed to show characteristic findings of CJD. Unfortunately, 14-3-3 protein analysis was not performed because of the lack of availability of the test at the hospital. However, characteristic findings of bilateral synchronous epileptiform periodic activity seen on repeat EEGs supported the clinical diagnosis in this case. Although current guidelines suggest that individuals with clinically probable CJD may not need biopsy of the brain to establish antemortem diagnosis, given its greater than 97% accuracy, efforts were made in this case to establish a definitive antemortem diagnosis at the insistence of the family. Unfortunately, brain biopsy could not be performed, because of several concerns of the neurosurgeons who were consulted. In this instance, the risk to surgeons and pathologists was much lower because of the already high index of suspicion for CJD. Appropriate infection control measures could have been implemented so that surgical or pathology staff would have incurred minimal risk. Had this case been more atypical, appropriate infection control measures would have been less likely to be instituted, and inappropriate decontamination procedures could have proved more hazardous than the disease itself to health care personnel. (14) Eventually, the diagnosis was confirmed at autopsy on the basis of histologic and immunostaining studies.

Prion diseases are transmissible and invariably fatal. Because of its transmissible nature, care of patients with CJD is challenging and a cause of concern among family physicians, surgeons, pathologists, and nursing staff. Patients with CJD might be refused care because of clinicians' lack of knowledge and their concern about contracting the disease, similarly to patients with human immunodeficiency virus infection and those with acquired immunodeficiency syndrome when these epidemics first emerged in the 1980s. (15)

The numerous challenges that we faced in arranging the autopsy and rendering the pathologic diagnosis are summarized in Figure 1. These challenges included concerns raised by the family, the pathologist, the neurosurgeon, and the funeral home. The family was concerned about how the disease was contracted, the risk of transmission to other family members and close relatives, the cost of an autopsy, and burial of the body after autopsy. The neurosurgeons were concerned about contaminating the operating room and the surgical instruments. The pathologist's concerns were mainly due to lack of training and a morgue inadequately equipped to handle the bodies of patients with emerging transmissible infectious diseases such as CJD. Funeral home staff were concerned about contracting the disease and transmitting the disease to their family members.

[FIGURE 1 OMITTED]

Recommendations

Adherence to the following measures may help in making the definitive diagnosis, may assist with physician-patient family communication, and may help in the proper care of patients with CJD and their burial after autopsy:

* Local continuing medical education programs should be arranged to educate professionals in various disciplines, such as family physicians, surgeons, and pathologists, about CJD. The educational material should include the pathophysiology of CJD, its mode of transmission, its clinical features, and, of course, the diagnosis and treatment of the disease. (16-18)

* Precautions need to be taken to perform the brain biopsy or autopsy and when handling the tissues and body fluids of patients suspected of having CJD.

* Methods of decontamination and sterilization of instruments and operating and autopsy rooms, including appropriate types and duration of autoclaving and the use of sodium hydroxide, need to be implemented.

* Health care professionals need to be treated after exposure to patients with CJD.

* The body of the deceased patient with CJD needs to be buried appropriately.

* Morgues should be adequately equipped, and pathologists should be trained to perform autopsies on patients who have died as a result of emerging transmissible diseases such as CJD.

* In-service training programs should be provided to educate nursing staff about CJD and the precautions needed to care for patients with the disease.

* Meetings should be arranged with the family and health care professionals, such as physicians, social workers, and pastoral staff, to address the anxiety and concerns of family members and close relatives. The discussion should include issues such as how the disease was contracted, its communicability, and possible hereditary transmission. Families should be informed that superficial contact such as touching or kissing the patient's face need not be discouraged. (19)

* The patient's family members and close relatives should be given literature containing current information and research regarding the disease.

* Statewide multidisciplinary task forces should be developed to communicate consensus guidelines for funeral homes regarding the proper burial of the bodies of patients with CJD after autopsy.

The American Association of Neuropathologists has established a National Prion Disease Pathology Surveillance Center at Case Western Reserve University in collaboration with the Centers for Disease Control and Prevention. The objective of this project is to determine the true prevalence and incidence of CJD and its variants in the United States. Further information regarding participation in the project is available at http://members.aol.com/larmstr853/ajdvoice/AANP.htm and http://members.aol.com/larmstr853/cjdvoice/cdcprog.htm

Conclusions

This case highlights the numerous barriers to rendering the diagnosis of CJD, including initially nondiagnostic EEGs as well as positron emission tomographic and MRI scans, the lack of wide availability of CSF immunoassays for 14-3-3 protein, the lack of understanding of the need for diagnosis in patients' families, the resistance of consultants to obtaining a tissue diagnosis, the lack of training and enthusiasm of pathologists and a properly equipped morgue, economic barriers to performing an autopsy, and obstacles to burial of the body after autopsy. Autopsies cannot be performed at many institutions because of the transmissible nature of the disease. Increased educational efforts, specific protocols, and additional testing sites are needed to address these obstacles, because enormous efforts are currently required to arrange for an autopsy to confirm the diagnosis.

References

(1.) Knight R. The relationship between new variant Creutzfeldt-Jakob disease and bovine spongiform encephalopathy. Vox Sang 1999;76:203-208.

(2.) Lorains JW, Henry C, Agbamu DA, et al. Variant Creutzfeldt-Jakob disease in an elderly patient. Lancet 2001;357:1339 1340.

(3.) Prusiner SB. Shattuck Lecture: Neurodegenerative diseases and prions. N Engl J Med 2001;344:1516-1526.

(4.) Sivakumar R, Barrett JA, Ironside JW, et al. Creutzfeldt-Jakob disease presenting as recurrent falls in an older person. Age Ageing, 2001;30: 356-357 (letter).

(5.) Jiang TT, Moses H, Gordon H, et al. Sporadic Creutzfeldt-Jakob disease presenting as major depression. South Med J 1999;92:807 808.

(6.) Pachalska M, Kurzbaner H, MacQueen BD, et al. Neuropsychological features of rapidly progressive dementia in a patient with an atypical presentation of Creutzfeldt-Jakob disease. Med Sci Monit 2001 ;7:1307-1315.

(7.) DeArmond SJ, Prusiner SB. Etiology and pathogenesis of prion diseases. Am J Pathol 1995;146:785-811.

(8.) Masters CL, Harris JO, Gajdusek DC, et al. Creutzfeldt-Jakob disease: Patterns of worldwide occurrence and the significance of familial and sporadic clustering. Ann Neurol 1979;5:177-188.

(9.) Brown P, Gibbs CJ Jr, Rodgers-Johnson P, et al. Human spongiform encephalopathy: The National Institutes of Health series of 300 cases of experimentally transmitted disease. Ann Neurol 1994;35:513-329.

(10.) de Silva R, Findlay C, Awad I, et al. Creutzfeldt-Jakob disease in the elderly. Postgrad Med J 1997;73:557-559.

(11.) Gibbons RV, Holman RC, Belay ED, et al. Creutzfeldt-Jakob disease in the United States: 1979-1998. JAMA 2000;284:2322-2323 (letter).

(12.) Schroter A, Zerr I, Henkel K, et al. Magnetic resonance imaging in the clinical diagnosis of Creutzfeldt-Jakob disease. Arch Neurol 2000;57: 1751-1757.

(13.) Poser S, Mollenhauer B, Kraubeta A, et al. How to improve the clinical diagnosis of Creutzfeldt-Jakob disease. Brain 1999;122:2345-2351.

(14.) Whittle IR, Will RG, Ironside JW. Brain biopsy and patients with atypical presentations of sporadic Creutzfeldt-Jakob disease. J Neurol Neurosurg Psychiatry 1997;63:547-548 (letter).

(15.) Shapiro MF, Hayward RA, Guillemot D, et al. Residents' experiences in, and attitudes toward, the care of persons with AIDS in Canada, France, and the United States. JAMA 1992;268:510-515.

(16.) Steelman VM. Creutzfeldt-Jakob disease: Recommendations for infection control. Am d Infect Control 1994;22:312-318.

(17.) Ironside JW, Bell JE. The "high-risk" neuropathological autopsy in AIDS and Creutzfeldt-Jakob disease: Principles and practice. Neuropathol Appl Neurobiol 1996;22:388-393.

(18.) Budka H, Aguzzi A, Brown P, et al. Tissue handling in suspected Creutzfeldt-Jakob disease (CJD) and other human spongiform encephalopathies (prion diseases). Brain Pathol 1995;5:319-322.

(19.) World Health Organization. WHO Infection Control Guidelines for Transmissible Spongiform Encephalopathies: Report of a WHO Consultation, Geneva Switzerland, 2326 March 1999 (WHO/CDS/CSR/APH/ 2000.3). Geneva, World Health Organization, 1999. Available at: http:/ who.int/emc-documents/tsc/docs/whocdscsraph2003.pdf. Accessed June 17, 2003.

Division of Geriatrics, University of Louisville School of Medicine, Louisville, KY.

Reprint requests to Christine S. Ritchie, MD, MSPH. Division of General Internal Medicine, Geriatrics, and Health Policy Research, University of Louisville School of Medicine, Medcenter One, Suite 320, 501 E. Broadway, Louisville, KY 40202. Email: [e-mail]

Accepted January 30, 2003.