Creutzfeldt-Jakob disease (CJD)a fatal neurodegenerative illness, is one form of transmissible spongiform encephalopathies (TSE) affecting humans. The suspected causal agent of these diseases is the priona proteinaceous infectious particle. Designated as PrPSC, this infectious protein is unique in that it does not contain nucleic acid, which is different from a virus, yet has the capability of replication and being transmitted to other hosts. This capability of transmission poses a major problem in that the detection of the disease caused by this prion while the individual is in the incubation phase is not currently possible. Hence the disease may be accidentally transmitted to another individual through medical proceduresas seen in the case study presented.
Throughout the 20th century, various case studies evolved and were compiled to form a sketchy descriptive pattern for Creutzfeldt-Jakob disease. However, as time progressed, new forms of CJD emergedusually as an epidemic, presenting similar yet distinct prodromal and clinical patterns. Accumulation of data has led to a finer delineation of symptomology and sub-type classification of the disease. Yet a test to definitively show that the individual has the disease during incubation is not currently available.
With different methods of transmission and completion of the incubation periods, various epidemics have erupted. Those points in time have been reflected within the literature, e.g. iatrogenic CJD through growth hormone (HgH). Current known forms of CJD are sub-typed as sporadic (spontaneous), familial (genetic), new variant and iatrogenic (acquired by accidental medical introduction).
Documentation of the transmission of Creutzfeldt-Jakob disease through blood products and other similar tissues is very limited. Currently, there are no cases found in the literature reflecting the onset of the disease via immune gamma globulin (IgG) treatment. One major reason for this may be due to the fact that even if the disease is transmitted, the incubation period may span beyond an individuals lifespan. Therefore, the individual will die incubating the disease, never entering the clinical phase.
Each of the different categories of the disease presents various clinical and neuropathological symptoms and patterns at onset and throughout the course of the disease. The prion strain, codon 129 and method of infectivity (exposure) are contributing factors in the incubation period and clinical presentation of Creutzfeldt-Jakob disease.
Prion strains present various protein sizes which are currently described as type I-IV. Each type is associated with a specific subtype of the disease, e.g. type I and II are associated with sporadic Creutzfeldt-Jakob disease. Heterozygosity on codon 129 has shown to act as a protective barrier to the disease by prolonging the incubation period or may prevent acceptance for transmission. Homozygosity on codon 129, however, places an individual at a higher risk level for contraction, produces a shorter incubation period and more severe symptomology and/or pathology. Codon 129 may also affect the age for onset of the disease.
Currently, sporadic CJD (sCJD) is the most prevalent strain occurring in humans, representing 80-85% of the reported cases of Creutzfeldt-Jakob disease. Hypothetically, this particular strain occurs spontaneously, i.e. idiopathic, and may be transmitted to other humans medically through use of tissue/blood products/procedures.
Familial CJD (fCJD), however, may be genetically traced through family lines. Various specific mutations on the prion gene (PRNP) create a predisposition for family members as to the onset, course and severity of the disease.
Knowledge of the symptoms and course of the disease has become more urgent due to the recent epidemic of bovine spongiform encephalopathy (BSE) in cattle in the United Kingdom and the link to new variant CJD (vCJD) in humans as a possible species-barrier crossover. Since one possible link for transmission is that of consumption of infected beef, a possible epidemic of vCJD may be seen to emerge in the next few years. Another concern related to vCJD is the transfer or transmission to another individual through tainted medical supplies, e.g., blood products, while the individual is in the incubation period or prodromal phase of the disease.
Transmission of this type would be recognized or categorized as iatrogenic, i.e. acquired from another source outside of the host through tainted medical supplies/procedures. Normal or generally accepted sterilization methods that destroy bacteria or viruses do not work on prions. Inactivation of prions requires extremely rigorous methods that would destroy tissues and many surgical instruments in the process. Individuals incubating any of the previous forms of CJD may inadvertently transmit the disease through blood/tissue donor products or through contamination of surgical instruments during a surgical procedure. This is the final known form of Creutzfeldt-Jakob disease and is dependent on the other forms of the disease for existence. The course of the disease may be presented with a short or lengthy incubation period depending on the method of transmission, i.e. centrally or peripherally.
To further complicate the transmission of the disease, many of these products are not held within an individuals community but are processed as a batch and become exported to other countries. Therefore, the possibility of transmission through tissue products is not restricted to one specific region or population due to economic globalization and interdependency.
This has been the case and continues to be the case for the transmission being reported in various areas of the world. The case study currently presented is one such incident where the contaminated product was imported into the United States from Canada. Through that producttainted immune globulin gamma (IgG), transmission of Creutzfeldt-Jakob disease occurred during peripheral medical procedures.
The case has created numerous diagnoses, complications and confusion among those involved. Resources available continue to be maximized to minimize the effects that maintaining appointments and traveling have on the individual. Involvement with the individual and the family will be continued until the diagnosis/results are definitive and support or participation are no longer desired.
This research project follows an individual through the course of events surrounding the progression of a possible onset of iatrogenic Creutzfeldt-Jakob disease transmitted through tainted immune gamma globulin (IgG). The treating physician informed the individual about the infectivity after several months of treatment. Approximately 6 years later, the individual has begun to rapidly display symptoms of the disease.
The purpose of the research is to:
Provide a detailed account of the symptomology, duration and severity displayed at onset and throughout the course of the disease presented;
Identify polymorphisms on codon 129 or PRNP mutations, if any; and
Extend or enhance the existing database of the disease through differential diagnosis or actual iatrogenic CJD information.
Information gathered in a case study is intense for a particular individual which may place limitations on the extrapolation of findings to the general population. There will be no other person exhibiting the exact symptoms with the same degree of severity or duration. Comparative analysis will be made from other peripheral iCJD cases since there is no known case for IgG iCJD. Re-enactment of the research data obtained cannot be replicated. Researcher bias may also be present though not intentional. Responses from the individual may not reflect the true degree or level of symptomology being experienced, i.e. the individual generally minimizes actual events occurring which may be out of denial, fear, hope, optimism, etc.
Question 1: If the case is iCJD, then what prodromal and clinical patterns will evolve during the course of the disease?
Question 2: Will this case follow peripheral transmission patterns similar to HgH or be unique in duration and degree of severity?
Question 3: If a polymorphism has occurred on codon 129, what is encoded?
Question 4: Are any mutations occurring in the open reading frame (ORF) of the prion protein gene (PRNP)?
Question 5: What differential diagnoses will be ruled out?
Definition of Terms
Ataxiarefers to the physical movements of the individual which are presented as a staggering gait and imbalance. This symptom is one of the triad associated with Creutzfeldt-Jakob disease.
Bovine Spongiform Encephalopathies (BSE): is a prion disease affecting the bovine or cattle populations that has possibly crossed the species barrier to humans through contaminated meat products and has been transmitted to zoo animals and domestic cats via contaminated food products.
Codon 129: refers to the 129th marker or segment of the prion gene and is encoded with methionine and valine. This area may entail a non-disease causing polymorphism that may increase the risk factors and symptomology of Creutzfeldt-Jakob disease.
Dementia: is one of the three symptoms generally associated with Creutzfeldt-Jakob disease characterized by cognitive decline (thought processes and memory) that is not reversible.
Dura mater graft: is the membrane surrounding the brain that has an enormous flexion and durability. This tissue is used to repair other areas of body tissue, organs, or neurological damage. The membrane has been implicated as one form of iatrogenic transmission.
Electroencephalogram (EEG): is a procedure which measures the electrical impulses or activity within the brain. In various forms of Creutzfeldt-Jakob disease, this activity is characterized by a triphasic wave pattern, i.e. 3 pattern stages.
Endogenous: refers to the process of the disease to be formed from within without external sources. Sporadic CJD is such a form of disease.
Exogenous: is the antonym of endogenous, i.e. the disease originated outside of the body and has gained entrance (transmission). Iatrogenic and new variant CJD are examples that reflect this process.
Familial Creutzfeldt-Jakob disease (fCJD): a form of Creutzfeldt-Jakob disease that is inherited or has a genetic basis of origin.
Heterozygous: refers to the amino acids encoded on codon 129. The pair which would be present is methionine and valine and may act as the human species barrier for this disease. Also implicated with heterozygosity is increased length of the incubation period and the decreased severity and duration of the disease.
Homozygous: represents the polymorphism that has occurred at codon 129 and is presented as methionine/methionine pairing or valine/valine pairing instead of the heterozygous pairing of methionine/valine. This change decreases the incubation period and increases the risk, duration, and severity of the disease.
Iatrogenic: is a condition which has been accidentally caused by medical personnel or a medical procedure. Within the medical community, this condition or act is sometimes referred to as therapeutic misadventure.
Iatrogenic Creutzfeldt-Jakob disease (iCJD): is the form of the disease which has been caused by a medical procedure due to contaminated material or equipment.
Immunoglobulin G (IgG): represents one of 5 different antibodies manufactured by the body. This antibody protects or establishes a defense against harmful bacterial, viral, and fungal agents. Also known as immune globulin gamma.
Intraperitoneal: refers to the area within the peritoneum cavity (abdominal cavity).
Lymphoreticular system (LRS) : includes the spleen, lymph nodes, and tonsils. The system transports blood components used to fight infections and diseases and has been associated with the clearing and possible transporting of the prion protein.
Macrophage: refers to a specialized cell that is capable of phagocytosis, i.e. to eat or destroy microorganisms or other diseased or dead cells.
Methionine (Met): an amino acid encoded on codon 129. If homozygous, then listed as Met/Met; if heterozygous, listed as Met/Val.
Mutation: refers to the permanent change of a codon on the prion gene (PRNP) that is disease related.
Myoclonus: is characterized by spasms within a group of muscles. These spasms may occur sparingly or frequently within the disease.
Phagocytosis: is a process that a specialized cell initiates in removing a microorganisms, diseased, dead or dying cell, or debris from an internal system within the body. The literal translation from Greek is to eat.
Plaques: used in this context refers to the neurological condition from the build-up seen within the various parts of the brain due to the prion protein.
Prion: designates the term given to proteinaceous infectious particle which is the primary disease causing-agent of CJD. The term is pronounced pree-on.
PrPC: is the abbreviation given to the cellular nonpathogenic prion isoform.
PrPSC: designates the pathogenic prion isoform.
PRNP: refers to the prion gene.
Prodromal: is an element of time which refers to the symptoms/characteristics of the disease that occur prior to the clinical phase. Symptoms that commonly occur or are seen in the general population are included in this phase, e.g. depression, forgetfulness or irritability.
Species barrier: is a phenomenon that prevents or deters the transmission of disease occurring in one species to another. In the case of CJD, if a crossover does occur, then the length of incubation is seen to typically increase and the areas of tissue in the brain affected also differ.
Sporadic Creutzfeldt-Jakob disease (sCJD): the most common form of the disease that occurs idiopathically, i.e. without a known cause.
Transmissible spongiform encephalopathy (TSE): is the name given to the category of prion diseases effecting animals and humans. The disease is capable of being transmitted within the species, and destroys brain tissue which takes on the characteristic of a natural sponge, i.e. full of holes.
Valine (Val): one of the amino acids found on codon 129.
Variant Creutzfeldt-Jakob disease (vCJD): the form of CJD associated with the species barrier crossover from BSE or mad cow disease found in Europe. This form is also known as nvCJD or new variant CJD.
Primary Approach for Data Collection
A qualitative design using observation, interviews with the individual and medical personnel involved, as well as reviews and analysis of written reports/tests and literature was the primary approach for data collection. The individual case study provided the opportunity to find answers to questions or solutions to a problem since human experiments involving CJD are unethical. This method provided a comprehensive, detailed account of the progression/characteristics of the disease being experienced. A compassionate outlet was provided for the individual in that his/her concerns or fears were openly discussed and clarified. Therefore insight into a thought process or emotional aspect that others with this disease may also have experienced may be provided. Also, the individual may find relief or comfort in talking and being heard. The data collected was analyzed according to the previous established patterns displayed by other types of CJD, i.e. was a relationship established. Implementing qualitative methodology in this case study, took an individuals specific concerns to larger social issues surrounding concerns of medical risks associated with supplies and procedures and identification of the characteristics/symptomology of the disease itself.
Selection of Research Population
The original research project did not revolve around this individual even after the accidental discovery that CJD had been transmitted many years ago. At that time, the individual displayed no clinical signs of the disease and was relatively healthy. Within a few weeks, the entire health related picture began to change.
A very complex scenario began to emerge for everyone involved, as did uncertainty as to whether to even approach what was being seen. I was skeptical due to the rarity of the disease, the mimicking symptoms presented by other diseases, and the lack of specificity of diagnostic tests. After careful deliberation with various professionals, the decision was made to go forward following the course of this individual.
The disease could not be ruled out, but also could not be positively diagnosed since this required postmortem brain tissue biopsy or premortem brain biopsy. The later procedure placed this individual at risk. A final comment cemented the course of the dissertation: regardless if this is iCJD or not, you will be gathering information that will be important for disease identification. If you choose not to proceed, the complete intricate package of information will be lost
Benefits Derived from Study
This case study of an individual with possible onset of Creutzfeldt-Jakob disease via IgG has been done to provide:
Beneficial information which expands or enhances the data base on the disease since the information is rich in detail and may be an index case;
The interaction of factors at play within the disease which included incubation period, method of transmission, codon 129 and the prodromal, clinical and differential diagnostic characteristics of the disease; and
An awareness as to the risk factors of transmission which may have bearing on public health policies.
The objective of the research was to determine if the peripheral transmission of Creutzfeldt-Jakob disease via contaminated IgG would follow the same or similar disease course characteristics as other types of peripheral iatrogenic CJD cases. Research focused on the behavioral, cognitive and motor functions in relation to those seen in various forms of CJD at various stages of the diseasewhether typical or atypical.
Medical records, literature reviews and interviews/consultations with the individual and medical personnel were made to gather and analyze data. All of the data was compiled to determine whether the disease characteristics displayed indeed followed the distinct patterns of the disease or if surprises waited around the corner.