INTRODUCTION:

Creutzfeldt-Jakob disease (CJD) belongs to a family of fatal degenerative disorders of the nervous system known as transmissible spongiform encephalopathies or prion diseases, which affect both animals and humans¹. The term prion, derived from proteinaceous infectious particle, was coined by Stanley prusiner after the identification of the disease-associated protein². The normal prion protein, PrP^c, is present in all mammalian species and is encoded by the prion gene (PRNP) on human chromosome 20.

The function of prion protein has not yet been established. Prion diseases are characterized by the deposition of PrP^Sc, an abnormally misfolded isoform of the native prion protein, within the nervous system.

Triggering of abnormal prion protein leads to neuronal degeneration, spongiform change and astrocyticgliosis which finally results in fatal neurological disorder³.

The human prion disorders are heterogeneous with different phenotypes, epidemiology and pathogenesis. Sporadic CJD (sCJD) is the commonest human prion disease, around 85% of the cases; 10-15% is associated with mutations of PRNP and 1% is iatrogenic, most frequently associated with prion treatment with human pituitary-derived hormones or human dura matter grafts.

Variant CJD (vCJD) is a unique human prion disease which occurs on consumption of beef products contaminated with the agent of the cattle disease or bovine spongiform encephalopathy (BSE)^4-6sCJD has a very rapid disease course and mean survival is six months. Over 90% of the patients die within a year of symptoms of onset. The peak incidence is in the seventh decade⁷.

HISTORY:

What is CJD?

Jacob first described this illness in 1921 in an article by creutzfeldt and was retrospectively and mistakenly included which we now call as CJD⁸. Scientific developments have led to the changes in the nosology of CJD over years, with other diseases of humans and animals being found to be related which is shown in Table 1.

Table 1: Prion diseases

Disease	Notes
Animal
Scrapis	Naturally occurring disease of sheep and goats
TME	Disease of farmed mink
BSE	Disease of cattle, first reported in1987
BSE-related disease	Transmission of BSE to cats (FSE) and other animals
Humans
Kuru	Confined to Papua New Guinea
CJD	The most common human prion disease, existing in the following forms: Sporadic, genetic, iatrogenic, and variant (described in 1996)
Genetic prion disease	Rare autosomal dominant inherited disease, including GSS and FFI
NOTE: BSE-bovine spongiform encephalopathy; CJD,-Creutzfeldt-Jacob disease; FFI-Fatal familiar insomnia; GSS-Gerstmann, Straussler, Scheinker syndrome; TME-Transmissible mink encephalopathy

Two of the most important findings were the transmissibility and the central role of the prion protein (PrP) hence the term “prion diseases” ^{9, 10}.

The neuropathological features of the prion disease are neurodegenerative, loss of neurons, astrocytic proliferation, spongioform change and deposition of an abnormal disease related form of PrP in tissues^{11, 12}. All the prion diseases are brain illness typically involving dementia, which are universally progressive, fatal and presently incurable.

What is PrP?

PrP is a normal cellular protein performs certain functions in humans, is encoded by the PrP gene (PRNP), which is located on chromosome 20. In prion disease, there are post-translational conformational changes, from the normal α-helical structure (PrP^c) to a more β-sheeted form (PrP^Sc).

The precise mechanism of this change is unclear, and its cause is to vary with different prion diseases. Once the process begins, PrP^Sccontinues to cause PrP^c to convert in an auto-catalytic amplification. PrP^Scand PrP^c have different physico-chemical properties. PrP^Sc is relatively insoluble, resistant to protease degradation, tends to accumulate in tissues and forms amyloid deposits. PrP^Sc is related to disease pathogenesis and infectivity, but the precise relationship are unclear^13,
14.

There are different glycosylation patterns of the disease-related protein (A and B). Thus the underlying PrP found in disease can be classified (eg. as IIB)^15-17. The resultant protein types vary between different forms of prion disease; thus they help to distinguish them. Figure 1 shows the structure of PrP^cand PrP^Sc.

Figure 1: Proposed structure of PrP^cand PrP^Sc

What is the role of PRNP gene?

PRNP gene is important in all the disease process. In genetic forms, the role is direct but it has effects in all forms of CJD. In particular, there is a common polymorphism at codon 129, whereby either methionine (M) or valine (V) may be encoded. This genotype affects the susceptibility to prion diseases, which may influence the incubation period in acquired cases and can affect the clinic-pathological phenotype of the resulting disease¹⁸. The replication of PrP^Sc is shown in figure 2.

Figure 2: Replication of PrP^Sc

What is the nature of the transmissibility?

CJD has characteristics which are not unique but other neurodegenerative illness or disease such as Alzheimer disease involves the deposition of an abnormally folded protein, however, CJD is transmissible. The precise nature of the infective agent is uncertain. PrP^Sc is generally associated with infectivity and the “prion theory” holds that PrP^Sc is either itself the agent or a major component of it and no specific DNA or RNA is involved in it^19,
20.

Genetics:

PrP^cis encoded by the prion protein (PRNP) gene on human chromosome 20²¹. All familial forms of the disease are characterized by the mutations in the gene. PRNP has a normal genetic polymorphism at codon 129, where either meithionine (M) or valine (V) may be encoded. It is very important because the genotype imparts genetic susceptibility in all types of prion diseases. The most sudden and striking example of this is that all cases of vCJD are in individuals homozygous for methionine (MM)²².

Parchi et al¹⁶ classified sCJD into 6 different molecular strains based on the genotype and biochemical properties. When PrP^Sc is cleaved by proteinase K under certain conditions, there are 2 truncated forms that result: the 21-Kd fragment (Type 1) and one that is 19kD (Type2).

The importance of this classification into MM1, MM2, MV1, VV1 and VV2 is that different strains correlate with different pathological and clinical presentations, which implies that the conformational variant determines the phenotypic or molecular “strain”.

The changes in the protein structure are by a confirmation-dependent immunoassay (CDI). This test identifies PrP^Sc by exposing specific epitopes of the protein which are unmasked with progressive denaturation and antibodies specific to these areas bind and elicit a positive result or response. It is 100% specific for the disease and recent data show sensitivity which is equal to other diagnostic tests.

Type of CJD:

Sporadic CJD:

The most common form of the disease is sporadic type of sCJD which occurs at an incidence of 1 case in 1 million per annum and it accounts for 85% of the CJD cases. Researchers speculate that it results from a spontaneous neurodegenerative illness or disease and the postulate is that it results from either a somatic mutation in the gene or a random structural change in the PrP protein causing the formation of PrP^Sc.

Onset usually occurs in the 7^th decade of life and the average time to death is 5 months with 90% of patients dead by 1 year²³. Unlike vCJD, the clinical and pathological findings are more heterogeneous and it is probably due to the different molecular phenotypes present.

Familial CJD:

Familial CJD is the result of known mutations of PRNP, which accounts for approximately 10% of all the cases of prion disease 25 and split into the 3 phenotypic categories of Gertsmann-Straussler-Scheinker (GSS) syndrome, fatal familial insomnia (FFI) and fCJD. There are more than 50 mutations described and the disease is transmitted in an autosomal dominant pattern with high penentrance and with an incidence which increases with age. fCJD has similar clinical, radiographic and test findings as sCJD, whereas GSS and FFI are well described variants²⁴.

Iatrogenic CJDL:

Iatrogenic CJD is simply CJD (most likely sporadic CJD) that is transmitted from one person to another by medical or surgical treatment (Table 2)²⁵.

Table 2: Iatrogenic Creutzfeldt-Jakob disease (CJD): recognized causes and worldwide occurrence.

Cause	Comment	Approximate total no. of cases worldwide
Human growth hormone	Related to use of cadaveric-derived human growth hormone from pituitary glands	165
Human dura matter	Related to use of cadaveric-derived human dura matter in surgery	136
Neurosurgical and depth electroencephalogram electrodes	Transmission via contaminated instruments and/or depth electrodes	6
Human gonadotropin	Transmission via human-cadaveric derived hormone	5
Ophthalmological	Transmission via corneal transplants	3
Blood	Probable instances of infection via blood donated by donors with variant CJD	2

Creutzfeldt-Jakob disease can be acquired iatrogenically; several outbreaks over last few decades were associated with intracerebral electrodes, corneal transplantation, dura matter grafts and growth hormone injections. The first case report, in the year1974, was in a patient who had received a corneal transplant from an infected cadaver²⁶.

Dura matter grafts with contaminated material led to more than 60cases of CJD, with an incubation periods lasting between 1 to 4 years²⁷. Pooled cadaveric growth hormone was used for injections and led to CJD 5-30 years after the injections. The clinical symptom is similar to sCJD as of the MRI and EEG findings²⁸. Iatrogenic has a clinical presentation and is similar to sCJD.

It is clear that incubation time is reflective of the inoculation site. Those with contaminated electrodes placed directly on the brain had short incubation periods of 16-28 months, whereas the peripheral injections of growth hormone took 50 to 30 years for the symptoms to begin²⁹.

There are 3 cases of probable transmission of CJD to individuals who received the blood transfusions from donor with vCJD and that is the reason there was a ban on donors who lived in the United Kingdom (UK) during the epidemic of Bovine Spongiform Encephalopathy (BSE)³⁰.

Variant CJD:

Variant CJD was first described in 1996 and occurs from the contaminated food with BSE which was a major problem in the late 1980s through the early 1990s in the UK³¹. There have been 4 total cases in the US, with 3 of the 4, having a history of residence in the UK³². The clinical and pathological findings differ from other types of CJD.

The median age of onset is much younger than in the sporadic or familial types and the mean survival is also longer at 14 months. It is unclear if the survival increase is as a result of age differences, but recent epidemiological studies suggest that exposure alone is not sufficient to explain the higher incidence and that the age is an important risk factor for contracting the disease³³.

Epidemiology:

The incidence of sCJD is one per million populations per annum. However, there has been a gradual increase in the mortality rates in UK and in many other countries in which systematic surveillance is undertaken, which may relate to the changes in population demographics, with an increase in the number of individuals in the age cohorts with a high incidence of sCJD and improved case ascertainment as a result of increased awareness and more sensitive diagnostic investigations. Mortality rates of 1.5-2 cases per million may be more realistic on current evidence.

The vCJD epidemic is in decline both in UK and internationally. UK population were exposed to a significant level of BSE infectivity in the food chain in the 1980s and early 1990s and relatively small scale of the vCJD epidemic is evident of significant barrier to infection between bovines and humans³⁴.

Secondary transmission of vCJD through blood transfusion is established with three clinical cases of vCJD which is linked to the transfusion of non-leucodepleted red blood cells derived from the individuals who themselves went to develop vCJD³⁵.

The prevalence of vCJD infection in the UK population has been studied by examining routine appendectomy samples by immunoctochemistry. Positive samples were identified in 19 out of 33, 115 appendices, leading to an estimated prevalence of 1 in 4000 in general population ³⁶.

Recent study examined appendix samples before 1980, prior to the presumed start of the BSE epidemic and those born after 1996 after which human exposure to BSE was minimal and surprisingly, 7 out of 15,959 of those samples were positive, suggesting either a more extended period of human exposure to BSE or perhaps that positivity may not imply infection with vCJD³⁷.

Pathophysiology:

To understand the clinical findings of the disease, one must first analyze the pathophysiology of how a healthy protein becomes abnormal and destructive to the brain. PrP^c is found on the cell surface of normal brains. The function of the protein is unknown, prion protein (PRNP) knockout mice lacking the protein does not show any abnormalities and have a normal brain development³⁸.

The central pathological event is the information of the abnormal PrP^sc from cellular form of PrP^c. It occurs in a pathway where PrP^sc acts as the template for PrP^c to fold abnormally into the pathogenic conformation. It is an autolytic process which is poorly understood, but the change in the protein shape is characteristic of the pathology³⁹.

Both forms have an identical amino acid sequence (primary structure) but the post translational changes cause the PrP^c (40% alpha helix) to refold into a form with 45% beta sheet composition 40 and this makes the protein highly insoluble, but also resistant to proteinase digestion.

As the subsequent multimerization accumulates, it spreads throughout the brain parenchyma which induces the classic spongiform change by microglia activation and neuronal loss, leading to progressive neurodegeneration and astrogliosis.

Clinical signs and symptoms:

The characteristic of CJD is rapidly progressive dementia which is of unknown origin and numerous atypical neurological findings are commonly seen. Myoclonus, visual changes leading to cortical blindness, ataxia and usually a kinetic mutism in the last changes of the disease.

Myoclonus is the most common sign, but there are atypical findings such as sleep disturbances, chorea, psychiatric symptoms and peripheral neuropathy⁴⁰. The clinical examination highlight the heterogeneity of CJD phenotypes but the common factor is progressive decline in the neurological status.

Other signs and symptoms include extra pyramidal dysfunction manifested as rigidity masklike face, choreotheoid movements, pyramidal signs (usually mild) seizures (usually major motor) and vegetative signs such as changes in weight, temperature, sweating or menstruation. vCJD patients also display unusual psychiatric problems.

Diagnosis:

In 1998 WHO published diagnostic criteria for CJD with the diagnosis relying on clinical examination, EEG and CSF findings. This is somewhat out dated in contemporary medicine because it does not take into account MRI findings, genetic testing or modern laboratory tests for confirmation of the diagnosis.

The genotype at codon 129 can be methionine homozygous (MM), valine homozygous (VV) or heterozygous (MV). The normal codon 129 distribution has been reported as 39% MM, 50% MV and 11% VV⁴¹.

The diagnosis of CJD is dependent upon assessment of clinical features. There has been an evolution in the diagnosis of CJD in the recent years with the identification of newer diagnostic tests and reflected in changes to the formal diagnostic criteria for sCJD.

Magnetic Resonance Imaging:

Magnetic resonance imaging in sporadic Creutzfeldt-Jakob disease:

Magnetic resonance imaging (MRI) is the most useful investigation in sCJD as it is highly sensitive and specific as well as widely available and relatively non-invasive⁴². The classic MRI findings in sCJD including high signal in the caudate, putamen or cortex on Diffusion weighted images (DWI) and Fluid–attenuated inversion recovery (FLAIR) sequences, are present in about 80% of cases⁴³.

DWI is more sensitive at detecting early cortical and sub cortical changes. DWI at the level of the basal ganglia demonstrates marked symmetrical hyper intensity in the caudate head and putamen with less marked affection of the thalami.

Magnetic resonance imaging in variant Creutzfeldt-Jakob disease:

Symmetrical hyper intensity in the posterior thalamus, relative to the anterior putamen, on T2-weighted or FLAIR MRI is characteristic of vCJD and is known as the pulvinar sign. Figure 4 shows the MRI scanning of brain.

Figure 3: Brain MRI showing gyriform hyper intensity on FLAIR (A) and diffusion-weighted images (B) involving the left cortical ribbon and the posterior cingulated gyrus.

Pulvinar sign of vCJD:

Axial fluid-attenuated inversion recovery image show symmetrical hyper intensity of the posterior thalamic nuclei and is very rare in the types of prion disease ⁴⁴ and have a sensitivity of 70-80% and a specificity of 100% for vCJD in the right clinical setting. The mediodorsal thalamic nucleus is involved and in combination with pulvinar hyper intensity appears such as ‘hockey stick sign’.

In neuropathologic cases, involvement of the caudate nucleus on FLAIR MRI was shown in 40% and putamen was shown in 23% and peri aqueductal grey matter was in 83%. Neuropathologic cases of vCJD are with heterozygous genotype at the codon 129⁴⁵.

The MRI of this case has shown diffusion which is restricted in the basal ganglia, insular cortexes, hypo-thalamus and medial thalami but not in the pulvinar nuclei.

Blood and urine tests in variant Creutzfeldt - Jakob disease (vCJD):

In pre-mortem test for vCJD several studies has detected abnormal PrP^Sc in vCJD in the blood and urine samples by using protein misfolding cyclic amplification (PMCA).

Moda et al. in the year 2014 has detected PrP^Sc in the urine of the patients with vCJD⁴⁶. The study has examined at 238 samples from the patients with vCJD, sCJD or genetic prion disease and healthy controls in a blinded study.

All the sCJD and control samples were negative. Similar studies using PMCA have led to the detection of PrP^Sc in plasma from clinical vCJD as well as in pre-clinical blood samples taken from 2 vCJD who had donated blood prior to the onset of symptoms^47-48.

Electroencephalogram:

With the advent of MRI and CSF tests EEG is less useful, despite it is an important non-invasive for sCJD. The EEG appearances in sCJD are periodic, triphasic with sharp wave complexes. These changes in the right clinical setting have 90% specificity for CJD^{42 but} are known to occur in other conditions, such as end stage Alzheimer’s disease, lewy body dementia and metabolic encephalopathy^{49, 50}.

It is vital to recognize that EEG patterns associated with CJD are sensitive to disease timing, benzodiazepines and external stimulation. Benzodiazepines mask Periodic Sharp Wave Complexes (PSWC) finding on EEG for patients with sCJD. Seizures, especially status epilepticus treated with benzodiazepines are typically found in 15% patients with CJD and may cloud the utility of EEG in diagnosis.

Treatment:

Despite all the advances in the understanding of the disease, the prognosis remains grim-CJD is incurable or untreatable disease. The mainstay of treatment is symptomatic and supportive, for example using clonazepam for the treatment of myoclonus. CJD symptoms such as anxiety and depression can be treated with sedatives and depressants and muscle jerks or tremors are treated with clonazepam and sodium valproate.

Otto et al. has shown improvement in cognitive function in CJD patients when treated with flupiritine and this is the only study which shows symptom improvement with the use of medication⁵¹. Future targets of the therapy may develop which involve preventing the conversion of PrP^c to PrP^Sc.

CONCLUSION:

CJD is a very rare illness or disease which is acquired by infection or secondarily transmitted. The most common form, sporadic CJD affects approximately 1-2 people per million per year, most of them are middle aged or elderly and possible under ascertainment of cases among people with older age. The illness profile is usually a distinctive or striking one, but most of the clinicians had much previous experience with cases, and there is no simple, non-invasive diagnostic test for living patients.

To help prevent spread of CJD, pre-hospital emergency care providers is must, within their education programs, highlight the single use of medical items wherever possible and adequate cleaning and disinfection of all non-disposable equipments and to mitigate the infection risks with CJD patients. The diagnosis of CJD has improved in the recent years with the advent of improved brain imaging (MRI) and the development of specific CSF tests in sCJD and diagnostic tests for plasma and urine in vCJD.

There have been many medical advances towards a cure for CJD but no definitive drug or therapy has been identified for the disease. Scientific developments are encouraging clinical trials, but further research needs to be conducted. Training and education programs should be made available for pre-hospital workers to prevent further spread of infections. As the search for the cure continues, it is clear that this important research needs to be conducted and enhanced in order to reduce the mortality and morbidity.

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Received on 04.05.2018 Modified on 20.06.2018

Res. J. Pharmacology and Pharmacodynamics.2018; 10(3): 134-140.

DOI: 10.5958/2321-5836.2018.00025.3