© 1998 by European Society of Cardiology
Copyright © 1998, European Society of Cardiology
Oh, dura dear! What can the mater be?
Elizabeth Conrad and the children had eagerly awaited the Mediterranean cruise that would take them to Greece and the Greek Isles. Theodore Conrad had been invited to lecture in Athens and this would mean opportunities to visit the Acropolis, Parthenon and Agora</CNY > then traveling to Rhodes to see its Colossus, the Asclepion, a renowned center of healing, and finally Kos, the birthplace of Hippocrates, the father of medicine. They would cruise the Archipelago and perhaps the Adriatic Sea as well. The day of their journey had arrived and their anticipation buoyed even further by the splendor of the cruise ship and its many offerings. They departed on Tuesday, June 10, 1992.
Seated in one of the ship's dining rooms, the Conrads enjoyed a panoramic view of Italy's coastline as they shared a champagne toast prior to dinner. Elizabeth remarked that it would be good to meet up with their dear friend Dominic in Athens. Dominic Marconi, an endocrinologist in Genoa, had become their close friend during his residency training in the States. Dinner featured a broad array of fine fish and was complemented by the elegant flavors of a vintage port and creamy gorgonzola. Theodore remarked that the mention of his friend's name brought back a memory of an interesting case Dominic had shared with him whey they last met. Elizabeth smiled and grasped Theodore's hand. "Will this be another Conrad Conundra?" Theodore nodded. "And what will it be called?" she asked. In a singsong voice he announced, "Oh, Dura Dear! What can the mater be?" The children burst out laughing at the familiar sounding melody of the nursery. Another voyage into a public health dilemma followed.
Sunday afternoon, May 3, 1981, and the skies over Genoa were clear and cobalt blue. Luigi and Carmen Petricelli were at home celebrating their 25th wedding anniversary with daughter, Ramona. Brothers and sisters had traveled from central and northern Italy to join them for the occasion. Carmen, sister Celeste, and Celeste's youngest daughter Dolores were busy in the kitchen preparing a special meal for the occasion. There would be several of their favorite Ligurian dishes: a shellfish and octopus stew; and bell peppers stuffed with olives, pine nuts and rice. The entire Petricelli clan was soon assembled at the dining room table. As was his custom, Luigi was seated at the head of the table with Carmen to his left and Ramona to his right. He offered everyone a toast and words of affection for Carmen. To begin there would be pasta that he ladled for each family member family from a large bowl. Luigi found it strange that the dish of pasta he offered Ramona went unnoticed. Perhaps it was simply her involvement in the lively discussion. However, he observed that when Dolores, seated to Ramona's right, provided her an offering of bread, it too went unheeded. It was as if Ramona's lateral vision had become faulty. This had not been the case one month ago when they celebrated Ramona's 21st birthday. Today she also seemed to have difficulty holding her fork, complaining of pain on the palmar surface of her right thumb, index and middle fingers. A secretary at a nearby accountant's office, Ramona had recently complained she was unable to work the typewriter for any length of time. Headaches and fatigue seemed to have become her constant companion.
With dinner completed, Carmen invited everyone to join her and Luigi in the living room. Ramona slowly and deliberately rose from the table, grimacing from pain in her left knee. As she advanced toward the living room, she shielded her eyes and asked that Dolores draw the window shades to eliminate brilliant beams of sunlight that showered the room. Carmen beckoned Ramona, "Come, sit with me and papa on the couch." The occasion of her anniversary had prompted Carmen to extricate the family album from its usual resting place in the closet. It was time to reminisce and with pride she would review her daughter's growth and development. With the album nestled on her lap, Carmen sought to cheer up Ramona. She excitedly pointed to Ramona's school photograph taken at age 7. "And here," she beamed, "your picture when you completed grade school at age 11." Ramona had experienced a remarkable growth spurt between the ages of 13 and 15. Carmen reminded Ramona how she towered over her classmates. Ramona suddenly began to weep uncontrollably. "What's wrong with me?" she sobbed while holding her forehead confronting another headache. Carmen and Luigi comforted her until she fell asleep on the couch and the family quietly dispersed to the backyard. The rapid procession of their daughter's photographs had struck Carmen and Luigi with the changes in her appearance. Together with her apparent recent loss of vision and other complaints, they were convinced that prompt medical attention was necessary.
Dr. Oliveri, internist at University Clinic, greeted the Petricelli's in his office on Monday morning. He noted Ramona's coarse facial features; her prominent nose, nasolabial folds and mandible. As he shook her hand, he found her handshake quite distinctive. It was bulky, doughy and sweaty; fingers were blunt and spadelike. Dr. Oliveri listened intently to Carmen and Luigi's anxious recounting of Ramona's history of faulty vision, headache, sensitivity to sunlight, painful knee and difficulty typing. She had no prior illnesses and other members of the family were in good health. Physical examination revealed bitemporal hemianopsia and evidence of median nerve compression. He formulated his thoughts and reached a diagnosis: acromegaly due to pituitary adenoma with the consequences of growth hormone excess evident in soft tissues, including carpal tunnel syndrome. His concern for Ramona's recent visual defect, likely due to compression of the optic nerve chiasm, prompted immediate referral to endocrinologist Dr. Dominic Marconi for further evaluation and management.
The next morning Dominic saw Ramona in his office and ordered several studies. Excess circulating growth hormone was confirmed. Skull radiograph demonstrated: thickening of the calvarium; enlargement of the frontal and paranasal sinuses; prognathism of the mandible; and dilatation of the sella turcica with thinning of the posterior clinoid process. Because the tumor was compressing the optic nerve and causing loss of vision, he recommended neurosurgery and discussed the serious nature of the illness with the Petricellis. The following week Ramona had her operation. A large tumor extending into the right middle fossa and adherent to its dura was found. Subtotal removal was performed followed by duraplasty to the right temporal area using lyophilized cadaveric dura mater. Transsphenoidal microsurgery and conventional irradiation followed in the hopes of addressing remnant neoplasia. In the weeks following surgery, serum growth hormone levels normalized and Ramona's vision gradually improved and her headaches resolved. Ensuing summers between 1981 and 1984, found the Petricelli's traveling extensively throughout western Italy. Together with Ramona, they visited such seaports as Gulf di Follonica, Gaeto, and Salerno.
It was over breakfast in April, 1985, and while they were planning their next trip, that Carmen noted Ramona had developed slurred speech and difficulty in remembering guests that had attended her recent birthday party. Her gait was unsteady as she carried dishes to the sink. Carmen immediately telephoned Dr. Marconi. Ramona was admitted to the hospital for evaluation. Lumbar tap and cerebrospinal fluid examination were normal, including cell count, protein, glucose, immunoglobulins and viral titers. EEG demonstrated generalized slowing, particularly over the right hemisphere while CT scan did not reveal a recurrence of the tumor. Over the next several weeks, Ramona became increasingly dysarthric, disoriented and confused; generalized choreoathetoid movements appeared and there was an inability to control the range of her muscular movements. She became progressively bedridden, akinetic and mute. In August, 1985, a second EEG showed generalized, bilaterally synchronous triphasic waves with sharp and slow wave complexes. CT scan now demonstrated cerebral and cerebellar atrophy. Twenty-one months after the onset of these symptoms, Ramona succumbed to respiratory infection.
What is your diagnosis and what is its causality?
Answer:
The sadness and introspection that had befallen the Conrad table was allayed when Elizabeth, a former critical care nurse, commented on Ramona's unfortunate postoperative course. "An example of a therapeutic misadventure," she quipped, "based on the use of cadaveric tissue. The duraplasty likewise provided a central inoculum of prion protein that led to rapid spongiform encephalopathy or iatrogenic Creutzfeldt–Jakob disease (CJD)." She further remarked, "this is not dissimilar from children and adolescents who received growth hormone, harvested from cadaveric pituitary glands between 1963 and 1969, for the management of their hypopituitary growth failure and who then presented with CJD 15–20 years later." Theodore nodded. "We are dealing with a worrisome modern-day health problem," he added.
Iatrogenic Creutzfeldt–Jakob disease (CJD) is a rapidly progressive neurodegenerative disorder with flagrant defects of cognitive and affective functions. It is a serious health problem in today's technology-driven practice of medicine. Considered to be of infectious origins, transmission of iatrogenic CJD has been associated with intracerebral introduction of the pathogen. Escaping eradication by conventional sterilization procedures for common pathogens, such fomites have included: cross-contaminated neurosurgical instruments; electrodes used in stereotactic EEG recordings; and implantation of homografts consisting of cadaveric dura mater following neurosurgery or pericardial tissue for eardrum perforation. The first case of iatrogenic CJD was reported in 1974 after corneal transplant surgery. Following central inoculation, incubation has been measured in months and is expressed as a rapidly appearing dementia similar to sporadic CJD. Peripheral transmission of CJD has accompanied use of human growth and gonadotrophin hormones extracted from pooled human cadaveric pituitary glands for respective management of hypopituitarism or infertility. In these cases, incubation is measured in years or even decades and is expressed as a cerebellar syndrome with ataxia similar to kuru, a neurodegenerative disorder found in parts of the world where cannibalism is practiced. Mental deterioration with peripheral inoculation is a late manifestation; it tends to be mild in severity and to evolve gradually. Deaths from CJD have been reported in a neurosurgeon, a neuropathologist, and histology technicians and has raised awareness of medically related risk in the workplace and the need for appropriate precautions.
The clinical similarity between centrally infected and sporadic CJD suggests the brain is the site of origin for infection in sporadic cases. Contrariwise, similarities between kuru and CJD in recipients of human pituitary-derived growth hormone suggests the route of infection could be via organs (e.g., gastrointestinal tract) in contact with the environment. Transmission of CJD has been demonstrated by intracerebral inoculation of nonhuman primates with infected tissue. This leads to induction of an amyloid protein in the brain. Infectivity has not been detected in external bodily secretions or excretions and therefore does not appear to be contagious. Usual routes of spread by a contagion are inhibited by epidermal and mucosal surfaces since the protein lacks receptors for cell surface attachment. The intestinal mucosa would appear to be an imperfect barrier. Transmission occurs through introduction into the body of an altered protein molecule that then induces production in the brain of the amyloid protein and has led to the concept of infectious amyloidosis. The amyloid protein is referred to as proteinase-resistant protein (PrP) and prion protein (for proteinaceous infectious particle). Amyloid enhancing factors include polypeptides which serve as nuclei for accelerating their own production and formation of amyloid.
When a protein is implicated in the pathogenesis of disease, encoded by a host gene, a genetic component to the disease is suggested. Therapeutic misadventures associated with iatrogenic CJD and the discovery of mutations in the CJD amyloid precursor gene on chromosome 20, the prion protein gene, has been linked to familial disease. This has called into question predisposing genetic factors in infectious amyloid. Homozygosity at codon 129 enhances susceptibility to iatrogenic infections of either central or peripheral sites of inoculation. The predisposing nature of the codon 129 genotype may reside in the influence of encoded amino acid on the three-dimensional pattern of folding of the polypeptide chain and which favors formation of insoluble amyloid fibrils that are characteristic of the spongiform encephalopathies.There is a small but finite risk of iatrogenic CJD infection attendant with the use of any human tissue or tissue extract. This is compounded by difficulties posed in its detection in preclinical cases, homograft tissue and by the high resistance of the infectious agent to ordinary sterilization procedures. The potential merits of disposable instruments, a rigorous selection of tissue donors and use of synthetic materials over homografts needs to be carefully addressed. Potentially similar catastrophes associated with today's zeal for xenograft tissues and organs will require scrutiny and reasoned judgement.
Postscript: Human prion disease is rare. Nonetheless, its importance to public health is clear. In this connection, the potential for the agent responsible for bovine spongiform encephalopathy (BSE) to cross species barriers as a result of occupational or dietary exposure has caused considerable controversy and is of major concern to human health. During the past 3 years in Great Britain, 23 cases of a new variant of CJD have occurred that are considered a consequence of the consumption of BSE-contaminated beef. In early December, 1997, and based on its concern for the transmission of BSE via bone marrow, the British government announced there would be no beef on the bone for the holidays. Britons reacted promptly to this news that undermined the kitchen and threatened thousands of years of cooking tradition. It was with an extension of the digit and a flexion of the legs that they crowded local butcher shops in search of the traditional roast. Identification of the infectious particles consisting of warped protein as the source of illnesses, such as BSE and new variant CJD, earned Stanley Prusiner the Nobel Prize in Medicine on October 7, 1997.
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