Vol

DEPARTMENT OF PATHOLOGY
The Johns Hopkins Medical Institutions

Vol. 20, No. 31
THE JOHNS HOPKINS MICROBIOLOGY NEWSLETTER
Tuesday, July 31, 2001

A. Provided by Leslie Edwards Reger, Division of Outbreak Investigation, Maryland Department of Health and Mental Hygiene.

Four outbreaks were reported to the DHMH during MMWR week 29:

1 outbreak of hepatitis A at a food-service facility (Baltimore City)
1 outbreak of salmonellosis at a food-service facility (Baltimore County)
1 outbreak of salmonellosis at a daycare facility (Howard Co.)
1 outbreak of food-borne gastroenteritis with unknown etiology at a food-service facility (Washington County) B. The Johns Hopkins Hospital. Information provided by Robert W. Allan, M.D., Department of Pathology and Laboratory Medicine. Case Report: The patient was a 60 year old white female with a medical history significant for a left modified mastectomy for infiltrating ductal breast carcinoma that was metastatic to one of fifteen axillary lymph nodes treated by left modified mastectomy, chemotherapy and tamoxifen with no evidence of recurrence on follow up visits. She developed the gradual onset of gait unsteadiness followed by mild dysarthria, upper extremity ataxia and markedly impaired visual pursuit. Workup for paraneoplastic cerebellar degeneration was negative. Electroencephalogram at that time showed generalized slowing and diffuse cortical irritability. Magnetic resonance imaging of the brain revealed no significant abnormality. Full body imaging showed no evidence of recurrence of breast carcinoma or evidence for a second primary carcinoma. Over the course of six months the patient’s neurologic condition deteriorated with severe dysarthria, mental slowing, and myoclonic jerks. Small bowel biopsy was negative for Whipple’s disease. There was no familial history of dementia. A right frontal lobe biopsy revealed a mild reactive gliosis with no vacuolization, spongiform change, malignant cells or neurofibrillary tangles. The patient continued to deteriorate and became mute and bedridden with no voluntary movements of her extremities. She died nine months after the onset of her neurologic symptoms. An autopsy was performed which revealed mild cerebral atrophy with marked spongiform change and neuronal vacuolization of the cerebral cortex and mild spongiform change of the cerebellum with pyriform cell loss and degeneration of the granular cell layer with associated reactive astrocytic proliferation. The neuropathologic changes were diagnostic of Creutzfeldt-Jakob disease. Creutzfeldt-Jakob disease, sporadic Background: Creutzfeldt-Jakob disease is one of many spongiform encephalopathies that afflict humans and animals and is grouped under the penumbra of prion diseases. The common thread of prion diseases is abnormal metabolism of a 33-35 kd sialoglycoprotein that is transmissable, the so-called prion protein. The normal cellular counterpart, designated PrP^c, has been implicated in synaptic transmission, neuronal maintenance, neural copper metabolism and Cu/Zn dismutase activity to name a few. The precise function has yet to be determined. The transmissible (infectious) agent is designated either PrP^SC (SC because prions have been implicated in causing scrapie- a spongiform encephalopathy in sheep) or PrP^RES, because unlike viruses and bacteria, the agent is quite resistant to proteolytic destruction, formalin and alcohol fixation and treatment with nucleases. The disease causing properties are conferred by post-translational modification ( alpha-helix to beta-pleated sheet) of two protein domains (H1 and H3) of PrP^c leading to relative insolubility and resistance to proteolytic digestion and accumulation in neurons and extracellular tissues.

The causative agent is the prion. The transmissible agents have spread across species (mink encephalopathy, possibly new variant Creutzfeldt-Jakob disease from bovine spongiform encephalopathy); through the food chain (bovine spongiform encephalopathy, kuru in humans who practiced cannibalism) or by inheritance of mutations in the PrP^C gene (familial Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker disease, familial fatal insomnia). Many of the details of the pathogenesis of the disease need to be determined including incubation periods, strain diversity, species specificity and the basic question of how introduction of an abnormal protein (PrP^res) can lead to increasing amount of native PrP^C protein being converted to the aberrant disease causing form. However, it is known that human spongiform encephalopathy can be transmitted to mice expressing human PrP^C genes and that mice who overexpress mutant PrP^res develop the behavioral and neuropathological evidence of the disease.

Epidemiology: Creutzfeldt-Jakob disease was initially described in the 1920s in a patient described by Creutzfeldt and five patients described by Jakob. The disease occurs worldwide with an estimated incidence of 0.5 to 1.5 cases per million people per year. Seasonal distribution, geographic clustering or increasing incidence have not been noted. Case-control studies including dietary factors, animal exposures, and occupational hazards (surgeons, cooks, abattoir workers and pathologists) have failed to identify at risk populations. Iatrogenic outbreaks of the disease have occurred in the past due to use of contaminated pooled cadaveric human pituitary growth hormone, human dura mater grafts and improperly sterilized stereotactic implanted electroencephalogram electrodes.

The outbreak of cases of so-called new variant Creutzfeldt-Jakob disease in Great Britain are strongly suspected to be caused by the same agent responsible for an outbreak of bovine spongiform encephalopathy in Great Britain in the late 1990s. It is believed to be a distinct entity from the traditional, sporadic Creutzfeldt-Jakob disease. Ruminations on this topic are abundant in both the lay press and medical literature; a concise summary paper is referenced.

Clinical Manifestations: Most cases of sporadic Creutzfeldt-Jakob disease are diagnosed in persons 50 to 70 years of age. Initially patients may describe altered sleep, increased fatigue, confusion or altered behavior. Up to one-third can have focal neurologic signs such as ataxia, aphasia, visual disturbances or hemiparesis. The disease follows an inexorable progression with cognitive decline, development of myoclonic jerks and ultimately akinesia. The mean survival time is five months and 80 percent die within one year of the development of symptoms.

Diagnosis: The diagnosis of Creutzfeldt-Jakob disease depends heavily on the synthesis of the clinical history with supportive laboratory data. Early in the course of the disease periodic sharp wave complexes superimposed on background slow rhythm have been reported to be 67% sensitive and 86% specific for the detection of Creutzfeldt-Jakob disease. Abnormal protein patterns detected in the cerebrospinal fluid have proved powerful in confirming the diagnosis. Elevations of a normal brain protein, termed 14-3-3, which in conjunction with an absence of pleocytosis and a clinical history of progressive, rapid dementia have reported sensitivities and specificities of 96% and 99%, respectively. However, some argue that the test is neither sensitive nor specific. The gold standard for diagnosis remains brain biopsy or necropsy demonstrating the characteristic spongiform change with neuronal loss and gliosis. Immunohistochemical stains for the aberrant PrP^RES have been developed and show striking synaptic and perivacuolar staining.

Treatment: There is no effective treatment for Creutzfeldt-Jakob disease. Therapies that have been tried include antiviral drugs (amantadine, idoxuridine, methisoprinol, cytarabine, vidarabine and acyclovir), antibacterials, interferon, anticonvulsants, amphotericin B, and corticosteroids.

References:

1. Johnson RT and Gibbs CJ. Creutzfeldt-Jakob disease and Related Transmissible Spongiform Encephalopathies. New England Journal of Medicine 1998; 339 (27): 1994-2004.

2. S Collins et al. Recent advances in the pre-mortem diagnosis of Creutzfeldt-Jakob disease. Journal of Clinical Neurosciences 2000; 7(2):195.

3. Brown P. Bovine Spongiform Encephalopathy and variant Creutzfeldt-Jakob disease. British Medical Journal 2001; 322, April 7, p. 841-844.