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 prion—a 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 procedures—as 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 emerged—usually 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 individual’s 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 individual’s 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 product—tainted 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.
Purpose
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.
Limitations
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.
Research Questions
Primary Question
Question 1: If the case is iCJD, then what prodromal and clinical patterns will
evolve during the course of the disease?
Secondary Questions
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
Ataxia—refers 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 individual’s
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.
Summary
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
disease—whether 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.