Jawaharlal Nehru Technological University, Kakinada, Andhra Pradesh 533003
Creutzfeldt-Jakob Disease (CJD) is a rare, lethal neurodegenerative disorder observed due to accumulation of malformed prion proteins in brain. This review presents an updated synopsis of CJD, focusing on its pathophysiology, clinical manifestations, diagnostic challenges, and emerging treatment strategies. CJD includes quickly advancing dementia, myoclonus, ataxia, leading to fatality within months. There are several types of CJD: sporadic (sCJD), which is the reason for the majority of cases; hereditary (hCJD), observed due to genetic mutations in the prion protein gene; iatrogenic (iCJD), resulting from medical procedures like contaminated transplants or surgical instruments; and variantCJD (vCJD), linked to eating infected beef in cases of Bovine Spongiform Encephalopathy(BSE). Diagnostic techniques such as electroencephalography (EEG), magnetic resonance imaging(MRI), and cerebrospinal fluid (CSF) analysis for 14-3-3 proteins has a important role in confirming the disease. Despite advances in understanding prion misfolding and genetic variants, no cure exists, and treatment remains supportive. Recent case reports highlight challenges in early diagnosis and clinical variability, underscoring the importance of improving awareness. This review also discusses the critical case reports which aids in future research and clinical practices.
Creutzfeldt-Jakob disease is subacute spongiform encephalopathy or neurocognitive impairment caused by prion disease. Decreasing the quality of life of data subjects is fatal neurodegenerative disease (Creutzfeldt-jakob disease.,2018). Degenerative brain disorders lead to dementia and mortality. Creutzfeldt-Jakob disease can occur unprompted, hereditary, or become infected by getting in touch with polluted tissue. B. Meat contaminated during transplantation or through food. This condition usually causes individuality, nervousness, sadness and forgetfulness within a few month. A lot of population falls into coma. With no effective treatment, the spotlight is on relieving ache and lessen indications. Symptoms consist of remembrance problems, behavioral changes, visual impairment (Manix et al.,2015). The indications afterwards include dementia, unintentional movements, loss of sight , tiredness and blackout (Manix et al.,2015). Approximately 70% of population died within one year after identification (Manix et al.,2015). CJD is caused by the malformed protein known as a prion (sitammagari KK et al.,2024) contagious prions also fold misfolded proteins that can lead to normal folded proteins(Manix et al.,2015). Approximately 85% of cases of CJD happen due to unspecified cause, and approximately 7.5% of cases are legally bred by CAR(Manix et al.,2015). Exposure to the brain or backbone tissue of an infected person can also lead to widespread (Manix et al.,2015). There is no definite treatment for CJD. Opioids can employ to aid pain, but clonazepam or sodium valprote helps in inadvertent movements(Manix et al.,2015). CJD affects approximately one person per year(Manix et al.,2015) . It usually starts for more than 60 years(Manix et al.,2015). This state has been primarily depicted in 1920 (Manix et al.,2015). It is classified as a kind of mobile spongiform encephalopathy. Inherited CJD accounts for approximately 10% of cases of prion disease(https://www.nhs.uk). Sporadicated CJD differs from Spongiform-encephalopathy (mad cow disease) and Creutzfeldt's Jakob's disease (VCJD)(Parchi P et al.,1999). The disease has an estimated rate of approximately one case per million people global annually, predominantly affecting older adults (Will, R.G.,et al.,1996).
CJD manifests in four primary forms: sporadic CJD (sCJD), which accounts for about 85% of cases and has no known cause; familial CJD (fCJD), which is inherited and accounts for around 7.5% of cases (Mead., 2006); iatrogenic CJD (iCJD), caused by medical procedures for example contaminated neurosurgical instruments / dura mater grafts (Brown, P., et al.,2012) and variant CJD (vCJD), linked to ingestion of prion-contaminated beef and associated with bovine spongiform encephalopathy (BSE), or “mad cow disease” (Will, R.G.,et al.,1996).The pathogenesis of CJD involves abnormal prion proteins (PrP^Sc) inducing the misfolding of normal cellular prion proteins (PrP^C) in the brain, leading to neuronal injury, spongiform changes, and astrocytosis (Prusiner,S.B..,1998) Unlike conventional infectious agents, prions lack nucleic acids, making them resistant to standard sterilization procedures and immune responses (Collinge J.,2001). scientifically, CJD is characterized by behavioral changes, motor dysfunction, including myoclonus, ataxia, and akinetic mutism (Geschwind,M.D.,2015). Diagnosis is challenging due to its rapid progression and symptomatic overlap with other dementias, but advanced diagnostic tools, including MRI, CSF biomarkers ( 14-3-3 protein, RT-QuIC assays), and electroencephalograms (EEG) showing periodic sharp wave complexes, aid in identifying the disease (Zerr,I et al.,2011). Despite extensive research, there is no known cure or helpful treatment for CJD. Management focuses on palliative care to alleviate symptoms such as pain and agitation (Aplleby,B.S.,2011). The disease is universally fatal, with majority sufferers succumbing within a year of disease onset (Masters, C. L., et al.,1979). Given the transmissible nature of CJD, strict biosafety protocols are essential to prevent iatrogenic spread, particularly in surgical and medical procedures involving nervous system tissues (Brown P et al.,2012). The emergence of vCJD in the 1990s underscored the risks associated with prion-contaminated food sources, leading to enhanced regulatory measures to protect public health In conclusion, Creutzfeldt-Jakob Disease remains a devastating and enigmatic disorder with significant public health implications. While advances in molecular diagnostics have improved early detection, the absence of curative treatments underscores the urgent need for further research into prion biology and therapeutic interventions.
HISTORY:
The title "Creutzfeldt–Jakob disease" was presented by Walther Spielmeyer in 1922, after the German neurologists Hans Gerhard Creutzfeldt and Alfons Maria Jakob (Creutz-feldt jakob disease@WHO). In 1920, German neuropathologist Alfons Maria Jakob depicted a arrangement of 6 patients with spasticity and dynamic dementia related with neural degeneration. Without further ado from there on, in 1921, another German neuropathologist, Hans Gerhardt Creutzfeldt, freely distributed a comparative case. Jakob gave credit to Creutzfeldt for depicting the disorder to begin with, without realizing he had moreover revealed the modern disorder. Walther Spielmeyer to begin with utilized the term “Creutzfeldt-Jakob disease” (CJD) in 1922. CJD happens around the world as a uncommon, scattered malady, with hereditary and iatrogenic shapes. A zoonotic shape, variant CJD (vCJD), is caused by disease with a prion inferred from bovines and happens overwhelmingly in the Joined together Kingdom(Henry R et al.,2017).CJD is comparative to other neurodegenerative illnesses such as kuru (influenced generally ladies in New Guinea who ate the brains of dead relatives as portion of a burial service custom), a human clutter, and scrapie, which happens in sheep and goats. All three illnesses are sorts of transmissible spongiform encephalopathies, so called since of the characteristic sponge like design of neuronal pulverization that takes off brain tissue filled with gaps.
Certain clinical observations noted in their initial publications do not align with the present standards for diagnosing Creutzfeldt–Jakob disease, leading to speculation that a minimum of two individuals involved in the early research may have had an alternative condition(Ironside JW.,1996). An initial account of hereditary CJD originates from the German psychiatrist and neurologist Friedrich Meggendorfer, who worked from 1880 to 1953 (Meggendorfer F.,1930;Gambetti P et al.,2003). A research study released in 1997 identified over 100 instances globally of transmissible CJD, with new occurrences still being reported during that period (Ricketts MN et al.,1997). The first documented case of suspected iatrogenic CJD emerged in 1974. Research involving animals demonstrated that the corneas of those infected could transfer CJD, with the infectious agent following visual pathways. Another case of CJD linked to a corneal transplant was noted, but specifics were not included. In 1977, it was first documented that CJD transmission resulted from silver electrodes that had been used in the brain of a CJD patient. This dissemination occurred even though the electrodes had been sanitized using ethanol and formaldehyde. Retrospective investigations revealed four additional cases likely caused by a similar mechanism. The level of transmission from a single contaminated tool is uncertain, although it is acknowledged to be less than 100%. In some instances, exposure was noted to happen weeks after the tools had been utilized on a CJD-afflicted individual (Ricketts MN et al.,1997). During the 1980s, it was determined that Lyodura, a product used for dura mater transplantation, could convey CJD from donor to recipient. Consequently, this product was prohibited in Canada but continued to be utilized in countries like Japan until 1993. A review article published in 1979 remarked that by that point, there had been 25 dura mater-related cases reported in Australia, Canada, Germany, Italy, Japan, New Zealand, Spain, the United Kingdom, and the United States. Stanley B. Prusiner from the University of California, San Francisco, received the Nobel Prize in Physiology or Medicine in 1997 for his identification of prions, marking a new biological principle of infection. Yale University neuropathologist Laura Manuelidis has questioned the prion protein (PrP) theory regarding the disease (Stanley B. Prusiner.,1997). In January 2007, she and her team indicated that they discovered a particle similar to a virus in both naturally and experimentally infected animals. “The high infectivity of similar, isolated virus-like particles that display no intrinsic PrP through antibody labeling, along with their loss of infectivity when nucleic acid–protein complexes are disrupted, suggests that these 25-nm particles are likely the causative TSE virions” (Manuelidis L et al.,2007).
ETIOLOGY:
CJD occurs mostly for unknown reasons in 85% cases and 7.5% cases are inherited in autosomal dominant manner. It is caused due to the abnormal folding of a protein called prion. Infectious prions are the misfolded proteins that can cause normal folded proteins to become misfolded. Onset may be observed around 60 years of age. Parts of the brain may resemble a sponge where the prions were infecting the brain. Hence it is known as spongiform encephalopathy. A prion protein (PrP) could be a ordinary neuron protein with a overwhelmingly α-helical and arbitrary coil composition. Proteinaceous infectious particles, also called "prions," are self-propagating proteins lacking nucleic acid and are mostly comprised of proteinase K-resistant β-pleated sheet aggregates (Sitammagari KK et al.,2024). Prions replicate by partner with ordinary PrP cellular isoforms, changing over α-helices into toxic β-pleated sheets. It is mainly initiated due to a misfolded prion which will increase the number of misfolded prions (protein molecules) and leads to the formation of large quantity of insoluble proteins in affected cells. This mass will disrupts neuronal cell function and cell death. CJD symptoms are similar to the other progressive neurological diseases like alzheimer's disease and Huntington's disease. But in case of CJD, symptoms tends to worsen faster within 6 months and leads to the death. Proteins are molecules made up of amino acids that help the cells in our body function They start as a string of amino acids that at that point crease themselves into a 3-dimensional shape. This "protein collapsing" permits them to perform valuable capacities inside our cells. Typical (safe) prion proteins are found in nearly all body tissues, but are at the most noteworthy levels in brain and nerve cells. The precise part of typical prion proteins is obscure, but it's thought they may play a part in transporting messages between certain brain cells. Mistakes sometimes occur during protein folding and the prion protein can't be used by the body. Normally, these misfolded prion proteins are recycled by the body, but they can build up in the brain if they aren't recycled. Prions are misfolded prion proteins that construct up within the brain and cause other prion proteins to misfold as well. This causes the brain cells to die, releasing more prions to contaminate other brain cells. Inevitably, clusters of brain cells are slaughtered and stores of misfolded prion protein called plaques may show up within the brain. Prion contaminations too cause little gaps to create within the brain, so it gets to be sponge-like. The harm to the brain causes the mental and physical disability related with CJD, and in the long run leads to passing (https://www.nhs.uk/conditions/creutzfeldt-jakob-disease-cjd/causes/).
CJD can be transmitted through the restorative strategies that utilize contaminated instruments, or due to transplanted human corneal and brain tissues. Variation CJD is related with the ingestion of contaminated hamburger, a component comparable to bovine spongiform encephalopathy. It can be acquired by family individuals through genes (https://www.nhs.uk/conditions/creutzfeldt-jakob-disease-cjd/causes/).
TYPES OF CJD:
CJD mainly observed in four forms. Those types include sporadic CJD, Iatrogenic CJD, Familial CJD, Variant CJD.
Sporadic CJD:
Sporadic Creutzfeldt-Jakob disease (sCJD) is a rapidly-progressive neurodegenerative illness caused by an irregular isoform of the human prion protein (Navid J et al.,2019). Intermittent CJD, the most common sort (85%), is due to misfolding of typical PrP isoforms with no clear triggers. Illness creates in somebody when cause is obscure. Subtypes of sporadic CJD incorporate sporadic lethal sleep deprivation and dynamically protease-sensitive prionopathy. Patients with sporadic CJD are regularly between 55 and 75 years old. Passing happens within a year of onset, with the middle term of sickness being 4 to 5 months. The middle age of passing in people with sporadic CJD is 68 years. Sporadic CJD is comparable to dementia in introduction but advances much more rapidly.
CJD subtyping is based on hereditary polymorphism, prion protein characteristics, and related side effects. Methionine/methionine sort 1 (MM1) and methionine/valine type 1 (MV1) contain 70% of cases and relate with the classic CJD phenotype. The condition has a mid- to late-life onset and presents with rapidly progressive dementia (RPD) and early myoclonus and ataxia. Methionine/valine sort 2 (MV2) is the kuru plaque variation, comprising 10% of scattered CJD cases. The condition presents with dynamic dementia with conspicuous psychiatric highlights and has a longer length (around 17 months) (PUoti G et al.,2012). The valine/valine sort 2 (VV2) variation is moreover known as the ataxic variation. The condition presents with ataxia at the onset or as an disconnected highlight. The VV2 subtype has a length of ailment of almost 7 to 9 months (Head MW et al.,2012). The methionine/methionine sort 2 (MM2) subtype may be classified as either thalamic or cortical. The thalamic MM2 subtype is too known as scattered deadly sleep deprivation and is show in 2% of cases. The mean infection length is 15.6 months. The most visit side effects incorporate psychomotor hyperactivity, ataxia, a sleeping disorder, and cognitive disability, taking after deadly familial insomnia (Mead S et al.,2009). The cortical MM2 subtype moreover comprises 2% of scattered CJD cases. Dementia is the overwhelming sign of this condition. The normal infection length is 15.7 months. Visual and cerebellar signs are once in a while depicted at presentation (Colombo R et al.,2006). The valine/valine 1 (VV1) subtype comprises 1% of cases and has a more youthful age of onset. People with this condition show with dynamic dementia. The VV1 subtype has an normal term of 15.3 months (Schelzke G et al.,2005).
Inherited CJD:
It is watched in the patients through which the disease was inherited from their family individuals through genes. Subsequently moreover referred as Familial CJD. There may be a known gene transformation that happens in a family. Almost 10-15% cases of CJD in the US are genetic. Inherited CJD is deadly, in spite of the fact that the term of ailment changes separately. For illustration, Gerstmann–Straussler–Scheinker disorder has a moderate movement, and passing may be postponed for up to 10 years (Oppenheim C et al.,2004). Indications include need of coordination, adjust and walking issues, memory and considering impedance, behavior changes, discouragement, uneasiness, and mood swings. Indications are caused by the dynamic passing of brain nerve cells. If one parent has the changed gene, there's a 50% chance of passing it on to their children. The change is not on the sex chromosomes, Hereditary CJD can have a survival time of one to ten years.
It shows in a assortment of distinctive shapes caused by changes to PRNP on chromosome 20 that may happen with deletion, addition, or point mutations—all in autosomal overwhelming designs of legacy. PRNP changes are profoundly penetrant, meaning that the nearness of a PRNP change all but ensures the possible movement of CJD in an person. In any case, past pathognomonic PRNP transformations (for which specific sorts of familial CJD are named), there are moreover polymorphic codons somewhere else inside the quality. One area in specific is the codon 129, which codes for either methionine or valine and is the target of atomic symptomatic tests of CJD (Creutzfeldt-jakob disease@WHO). This codon is habitually included in all shapes of CJD, and methionine homozygosity shows up to constitute the most common polymorphism related with an expanded chance for CJD (Henry R et al.,2017). More later work contends for a defensive impact of heterozygosity at codon 129 as assurance against kuru (an unusual form of prion infection related with cannibalism in a particular population of Papua New Guinea)(Sitammagari KK et al.,2024). In this way, change in CJD introductions turns fundamentally on the nature of the PRNP transformation and at that point is further adjusted by polymorphisms inside codon 129 on both the changed and wild alleles. most common frame of acquired CJD includes the E200K (lysine [K] in lieu of the glutamate [E]) transformation, which has been famous in an grouping familial clusters counting Libyan Jews (most conspicuously) and families in Slovakia and South America—this sign offers extraordinary similitude to intermittent CJD both clinically and on demonstrative imaging (Navid J et al.,2019). The another most common transformation is V210I (isoleucine [I] in lieu of valine [V]), but this condition does not have a clear pattern (Navid J et al.,2019;Collins SJ et al.,2006). To date, around 30 transformations related with acquired prion infection have been distinguished in a different bunch of populations, and it is likely that, with expanded awareness and improved atomic devices, more transformations will be observed (Navid J et al.,2019).
Acquired CJD:
Disease transmission is watched due to presentation to brain or apprehensive framework tissues as a rule through certain therapeutic strategies such as surgical joins of dura mater, transplanted corneal, implantation of insufficiently sterilized cathodes in the brain or by contamination with human development hormone(hGH) and gonadotrophins (https://www.ninds.nih.gov/). It is moreover alluded to Iatrogenic CJD. Less than one percent of cases has been obtained CJD. This shape of CJD transmission by means of restorative misadventures was to begin with recognized in 1974. Nowadays, as it were incidental CJD cases with outstandingly long brooding periods still show up. The fundamental sources of the biggest episodes were tissues from human cadavers with unsuspected CJD that were utilized for dura mater joins and development hormone extricates. A few extra case brought about from neurosurgical instrument defilement, corneal joins, gonadotrophic hormone, and auxiliary diseases from blood transfusions. In spite of the fact that the last arrangement to the issue of iatrogenic CJD is still not accessible (a research facility test to distinguish potential benefactors who harbor the irresistible operator), certain other measures have worked well: applying extraordinary sterilization of entering surgical rebellious, lessening the irresistible potential of benefactor blood and tissue, and barring givers known to have higher than ordinary hazard for CJD. In differentiate to sCJD, iCJD regularly presents with cerebellar ataxia or maybe than cognitive dysfunction. The presentation of recombinant GH in 1985 disposed of this issue. Iatrogenic CJD has moreover happened in over 100 patients who gotten dura mater joins gotten from a single producer whose preparative strategies were lacking to decontaminate specimens, and as a result of utilizing a pericardium join to repair a punctured eardrum. Other cases of iCJD incorporate two cases related to corneal transplants, at slightest five cases in ladies after accepting human pituitary gonadotropin, and two patients uncovered to disgracefully purified brain electrodes. blood transfusions have moreover been an iatrogenic source of illness transmission. Neuropathologic examination uncovers spongiform alter, neuronal misfortune and gliosis, and testimony of irregular prion protein (https://www.orpha.net/en/disease/detail/576379).
Variant CJD:
Ailment is evolved in the humans with the aid of consuming meat from farm animals suffering from a disorder similar to CJD known as bovine spongiform encephalopathy (BSE) or mad cow disorder. vCJD was first described in 1996 in the UK. Strict controls were put in region to prevent meat from infected cattle getting into the meals chain. The average time it takes for the signs and symptoms of vCJD to arise after initial infection is uncertain vCJD is a Transmissible Spongiform Encephalopathy (TSE) it may take years for someone to increase vCJD symptoms once they had been exposed to BSE. however, once signs and symptoms begin, it is always deadly. The general public with vCJD stay with the contamination for one to 2 years, with a mean time of 13-14 months. Humans with vCJD have obvious psychiatric (mental, emotional, behavioral) symptoms. regularly, this consists of despair, tension and withdrawal. They will even have a painful situation known as dysesthesia. this can experience like itching, burning, pins and needles or different sensations on their body. Later within the infection, sufferers generally have dementia and neurologic symptoms together with poor coordination. Prp's bring conformational changes in the regular shape. This produces huge range of unusual groups that gather in lymphoreticular tissue before invading neural cells ,disrupts neural function and ends in loss of life.Those prp's are resistant to established sterilization approaches and may best be identified on the time of postmortem. It appears to arise in more youthful population (imply age at death 29years) (https://www.cdc.gov/variant-creutzfeldt-jakob/about/index.html)
Signs and symptoms of different types of CJD:
CJD occurs in different forms where each form show different signs and symptoms and differ in diagnosis results.[Table 1]
Table 1: Signs and symptoms of different types of CJD
|
Sporadic CJD |
Inherited CJD |
Acquired CJD |
Variant CJD |
|
vertigo, headache, fatigue, and sleep disorders memory problems agitation, irritability depression, apathy, mood swings, vision loss rapidly worsening confusion disorientation, and cognitive problems coordination and movement abnormalities ataxia, involuntary jerky movements myoclonus muscle stiffness and involuntary muscle twitching bradykinesia, dystonia, and rigidity lose mobility and speech May progress into a comatose state. |
lack of coordination balance and walking problems memory and thinking impairment behavior changes depression anxiety mood swings |
rapidly progressive cognitive impairment myoclonus visual or cerebellar problems pyramidal or extrapyramidal features akinetic mutism EEG examination may show characteristic generalized periodic sharp wave complexes. |
psychiatric (mental, emotional, behavioral) symptoms depression anxiety and withdrawal dysesthesia itching, burning, pins and needles or other sensations on their body dementia neurologic signs such as poor coordination. |
DIAGNOSIS OF CREUTZFELDT-JAKOB DISEASE:
Creutzfeldt-Jakob sickness is usually a diagnostic task because it presents similarly to different situations presenting with RPD. Early and correct prognosis of Creutzfeldt–Jakob disease (CJD) is vital to keep away from iatrogenic transmission and to distinguish CJD from potentially treatable dementias. Diagnosis of CJD in residing sufferers is difficult, specially because the disorder phenotypes are enormously heterogeneous, and detection of the misfolded protein within the brain tissue is frequently no longer possible. The United nation of the us's facilities for centers for disease control and Prevention (CDC) defines the following diagnostic criteria (Zanusso G et al.,2016).
Brain MRI:
MRI is the modality of desire to assessing patients with suspected Creutzfeldt-Jakob disease. The maximum sensitive collection to pick out function modifications is diffusion-weighted imaging (e.g. b=a thousand) which demonstrates expanded sign, that is greater conspicuous than both T2/aptitude adjustments and ADC abnormalities eight (Kovacs GG et al.,2005). signal abnormalities may be diffused to begin with but turn out to be extra suggested as the ailment progresses. Assessment of sequential studies additionally generally demonstrates rapidly modern cerebral atrophy. An MRI of a CJD affected person usually demonstrates hyperintense sign adjustments in the striatum or thalamus on T2-weighted pics. it could additionally display lesions in the periventricular white remember and diffuse cortical atrophy (Creutzfeldt–Jakob Disease .,2018; About CJD.,2017). it's miles a useful imaging technique for CJD. It generally shows an extraordinary signal inside the putamen and head of the caudate. Early CJD is characterised by means of an increased diffusion-weighted imaging (DWI) sign in the cortex or deep grey depend. Intermediate CJD is identified by way of greater symmetrical involvement and progression of lesions to involve the putamen. late CJD is characterised by generalized atrophy and ventricular dilatation (Creutzfeldt–Jakob Disease .,2015). The position of serial MRI has now not been properly mounted as a diagnostic tool for CJD. however, proof indicates it can not handiest help in the prognosis but also resource in tracking the sickness (Creutzfeldt–Jakob disease@WHO ). In 2011, Kono, et al. mentioned that serial MRI in a CJD affected person should show the progression of abnormal lesions starting from the left cerebral cortex, head of caudate and the putamen to the right cerebral cortex. They ultimately spread to the occipital lobes inside the terminal degree (Kono S.,2011). Others have commented on the advancement of abnormalities from the basal ganglia to cerebral gray and white matter as confirmed in a follow-up MRI. Oppenheim, et al. pointed out the correlation of the patient’s scientific and pathological progression to the hyperintense sign MR abnormalities (Oppenheim C et al.,2005). The examine mentioned that because the affected person declined to a close to vegetative nation, the odd hyperintense lesions had been now not really apparent. This become thought to arise due to the fact terminal pathological cortical changes within the form of fibrillary gliosis and gross neuronal loss had taken region (Sitammagari KK et al.,2005). Other case reports have also showed the use of serial MRI to perceive CJD and its progression (https://www.nhs.uk/conditions/creutzfeldt-jakob-disease-cjd/causes/). In our affected person, the endurance of diffusion abnormality involving the lentiform nucleus and cerebral cortex with growth changed into a high-yield clue in the diagnosis of CJD as discovered in our patient. brain MRI with T2-weighted scanning, DWI, and obvious diffusion coefficient (ADC) sequences regularly monitor abnormalities inside the cortical gray rely (cortical ribboning) and deep nuclei in sporadic CJD. MRI with DWI or flair imaging has a sensitivity of 98% and specificity of 93%. DWI commonly demonstrates hyperintensities in the basal ganglia, thalamus, and cortex. The "hockey stick" or "pulvinar" signal shows variation, infectious, or obtained CJD, even though it is also visible in other types of CJD (Sitammagari KK et al.,2005).
CSF analysis:
CSF evaluation became performed for the dedication of CSF protein 14-3-3.CSF protein 14-3-3 changed into accelerated at 13 instances the higher limit of regular. The 14-3-3 protein in CSF has been discovered to be a sensitive and particular marker for sporadic CJD (sCJD). it's far used as an adjunctive test together with different findings for the analysis of prion diseases (Navid J et al.,2019). CSF 14-3-3 can be more sensitive for CJD than other prion sicknesses whilst combined with the everyday EEG findings. CSF protein biomarkers, consisting of the 14–3–3 protein, total tau (T-tau), and neuron-particular enolase (NSE), are markers of speedy neurodegeneration. These exams can assist diagnose CJD but are not precise to the circumstance. An accelerated tau stage (greater than 1150 picogram/mL) has greater accuracy and specificity than 14-3-3 protein as a diagnostic test for CJD, even though each tests can produce enormous false-negative and fake-positive outcomes (Zanusso G et al.,2016). CSF 14-3-3 most effective while CJD is strongly suspected. A recent comparison of these non-prion-unique CSF biomarkers with MRI observed that DWI had a diagnostic accuracy of 97%, better than the T-tau (79.6%), 14-three-three protein (70.4%), and NSE (71.4%) tests. Detection of those traditional surrogate marker proteins is correct in approximately three-fourths of instances. Habitual CSF evaluation that consists of glucose, total protein, white blood cellular count, overall cellular count, and oligoclonal IgG are normally unremarkable in CJD sufferers (Sitammagari KK et al.,2024).
RT-QuIC:
The country wide Prion disease Pathology Surveillance center launched a brand new diagnostic test in April 2015 referred to as "2d-technology real Time-Quaking-triggered Conversion (RT-QuIC)," that is noticeably sensitive and unique for CJD. RT-QuIC can accurately stumble on pathogenic prion protein inside the CSF of patients with CJD. RT-QuIC directly detects the pathogenic prion protein, in assessment to the 14-3-3 protein, T-tau, and NSE, which might be indirect tests. a few research display that RT-QuIC has modest sensitivity (more than 80%) however high specificity (about 98%) for sporadic CJD. most sufferers with the VV2 sporadic CJD subtype have bad CSF RT-QuIC checks. RT-QuIC might be extra sensitive the usage of olfactory epithelium brushings than the CSF as a specimen. current studies have shown that RT-QuIC is corresponding to brain biopsy in phrases of accuracy in diagnosing CJD. RT-QulC is much less invasive as compared to brain biopsy (Sitammagari KK et al.,2025). real-time quaking-brought on conversion (RT-QuIC) become defined in 2010, a brand new technique to detect small amounts of PrPSc (Henry R et al.,2017). This approach exploits the capacity of PrPSc to result in PrPC to misfold in a cyclical fashion to shape aggregates of PrPSc fibrils. The formation of those aggregates is monitored in real time by way of their capability to bind a fluorescent dye, namely thioflavin T (determine 1). In short, CSF from a patient suspected of having CJD is introduced to a mixture of recombinant PrP (rPrP) and thioflavin T. Any PrPSc present in the CSF binds to the rPrP and induces it to trade form and form fibrils. This system can soak up to 30 hours and is called the lag phase, after which period the fibrils begin to combination and bind thioflavin T, which starts to fluoresce (figure 2). This fluorescence is monitored in real time. The aggregation kinetics are monitored and display a function sigmoidal curve (https://www.clinlabnavigator.com). the first studies used both complete-duration hamster rPrP (23-231) or complete-length human rPrP and pronounced sensitivities among 69% and 89% for neuropathologically showed sCJD, and specificities between 99% and 100% (desk 1).6 eight–thirteen no matter the call, RT-QuIC is definitely a protracted manner taking ninety hours to reach completion. There may be now an version of RT-QuIC called either stepped forward RT-QuIC (IQ) or 2d-era RT-QuIC using truncated hamster rPrP (90-231) as substrate. This has the equal order of sensitivity (70%–96%) as the traditional RT-QuIC however a far shorter analytical time of about 30 hours (Rhoads DD et al.,2020;Puoti G et al.,2012). The specificity of this substrate is 98%–100% (Parchi P et al.,1999).
Tonsil biopsy:
A tonsil biopsy may be used to diagnose variant Creutzfeldt-Jakob disorder (vCJD), a specific form of CJD, as it may discover the presence of extraordinary prion proteins (PrPSc) in the tonsil tissue, probably doing away with the need for a brain biopsy to verify the diagnosis; however, a tonsil biopsy isn't typically used for diagnosing different kinds of CJD. Tonsils include lymphoid tissue where the atypical prions related to vCJD can acquire, making them a potential site for detection. A small piece of tissue can be taken from the tonsils and checked for the peculiar prions determined in variation CJD (they're not found in different sorts of CJD)
Electroencephalogram (EEG):
Electroecenphalography (EEG) is an imperative a part of the diagnostic manner in patients with Creutzfeldt–Jakob disease (CJD). The EEG has consequently been covered in the world fitness company diagnostic type standards of CJD. In sporadic CJD (sCJD), the EEG famous feature adjustments depending on the stage of the disorder, starting from nonspecific findings which include diffuse slowing and frontal rhythmic delta activity (FIRDA) in early ranges to disorder-normal periodic sharp wave complexes (PSWC) in middle and overdue ranges to areactive coma lines or maybe alpha coma in preterminal EEG recordings. PSWC arise in sufferers with methionine homozygosity and methionine/valine heterozygosity however only hardly ever in sufferers with valine homozygosity at codon 129 of the prion protein gene. PSWC generally tend to disappear at some point of sleep and can be attenuated by way of sedative medication and external stimulation. Seizures are an uncommon locating, happening in less than 15% of sufferers with sCJD. In patients with iatrogenic CJD, PSWC generally present with extra local EEG findings similar to the site of inoculation of the transmissible agent. In genetic CJD, PSWC in its traditional shape are uncommon, occurring in approximately 10%. No PSWC occur in EEG recordings of sufferers with variant CJD.In nV CJD Diffuse slowing of historical past activity to delta variety turned into determined (Wieser HG et al.,2006).
Brain biopsy:
Applying the technique of open brain biopsy, the sample of about 1.5cm in diameter containing each the cortex and subcortical white matter was received from the left temporal lobe. The tissue become treated as a result to the universally established techniques for dealing with tissue suspected of being “infected” with a pathogenic prion pressure, which includes 1h immersion in formic acid. Histopathological investigations consisting of immunohistochemistry were made on sections of samples embedded din paraffin blocks. Hematoxylin and eosin (H&E) staining confirmed vacuolization inside the neuropil and neuronal loss indicating spongiform degeneration. Immunohistochemical staining for PrP verified immunopositive deposits round spongiform modifications immune to autoclaving and proteinase k digestion. These results showed the prognosis of CJD in our patient (Adrian Andrez Chroak et al.,2016).
TREATMENT AND MANAGEMENT OF CJD:
PRN100
A primary-in-human treatment designed specially for Creutzfeldt–Jakob disease (CJD) has proven encouraging early effects and may contribute to the improvement of new remedies for different neurodegenerative diseases. CJD is a rare and fatal disorder that causes brain damage and for which there's currently no certified treatment. maximum patients die within some months of prognosis (https://www.uclhospitals.brc.nihr.ac.uk/news). There are several capacity remedy alternatives inside the pipeline together with retailers that concentrate on the healthy form of the prion protein (PrP). There's widespread proof for effectiveness and protection of antibody treatments which bind to PrP. Antibodies are proteins observed within the blood and made via immune cells. they're used by our immune gadget to assist fight infections. As PrP is one of the body’s own proteins we do now not naturally make antibodies towards prions. But we have been capable of make antibodies in mice after which, via genetic engineering, make human versions of those antibodies. Antibodies that bind to PrP can treat prion-infected nerve cells growing in the laboratory. It was supposed that the treatment works with the aid of disposing of the normal shape of PrP required for prions to grow. Antibodies additionally have potent hobby in animal models of prion sickness, certainly if treatment is began early, before symptoms have started, the infection may be cured. PRN100 could be a human counter acting agent made from the mouse counter acting agent ICSM18. PRN100 binds extraordinarily tightly to PrP. In prion-inflamed mice PRN100 can amplify survival time from much less than two hundred days to a ordinary lifespan (>six hundred days), with these lengthy surviving mice showing no proof of prion contamination whilst their organs are tested after loss of life; basically those mice are cured. As prion sicknesses can be transmitted between mammalian species, resulting in almost identical functions, we anticipate that remedy may even translate properly. In October 2018, university college London Hospitals NHS basis agree with commenced treating patients with PRN100, and went directly to treat 6 sufferers in general, all of whom were at exceptional tiers in their sickness once they started treatment, earlier than our stocks were in the end exhausted in 2019. While the drug become nicely tolerated, unluckily all 6 sufferers succumbed to the disorder. we are now taking time to examine the huge quantity of medical statistics and records we've amassed considering that we commenced treating patients, and can be trying to determinate if, or to what quantity, the drug had an effect at the patients conditions (https://www.ucl.ac.uk/national-prion-clinic/drug-treatments).
Researchers at the NIHR UCLH Biomedical research Centre (BRC) advanced a monoclonal antibody, called PRN100, that changed into given to 6 patients with CJD between October 2018 and July 2019. The results, posted in Lancet Neurology, display the treatment is safe and able to get right of entry to the mind. In 3 patients, disease progression seemed to stabilize whilst dosing levels had been in goal range. none of the six patients skilled side results even as receiving the treatment however all alas died due to their circumstance. CJD has no authoritative treatment, and strong care is the pillar of administration. most trial tablets for CJD have not demonstrated any clear advantage to this point. but, intraventricular pentosan polysulfate has been shown in rodent research to inihibit PrPSc formation. An apparent survival extension of 37 to 114 months changed into observed in four sufferers. greater research is needed to locate the remedy for this fatal situation (https://www.uclhospitals.brc.nihr.ac.uk/news).
Early detection of a PRNP mutation can also assist households at threat for the genetic shape of CJD. patients affected by the circumstance could make in advance preparations for end-of-existence worries. Psychosocial support and supportive care may additionally improve patients' high-quality of existence. Genetic counseling and circle of relatives making plans assist prevent disorder transmission to the offspring of individuals with PRNP mutation.
Pentosan polysylphate (PPS):
PPS is a semi-artificial chemical derived from shavings of beech wood. it is used as an anti-coagulant in continental Europe whilst injected below the skin. within the USA, PPS given by using mouth is used for an inflammatory ailment of the bladder known as interstitial cystitis. There are numerous studies that have shown that PPS can put off the onset of prion sickness in infected mice, and might therapy infection in cells developing in culture. PPS has been given to numerous sufferers with version CJD and some with sporadic CJD inside the united kingdom. In a number of these patients PPS has been given as an instantaneous infusion into the brain the use of a pump positioned beneath the skin. This became done because PPS isn't expected to go from blood into the brain because of its chemical homes. Placement of the pump calls for neurosurgery (https://www.ucl.ac.uk/national-prion-clinic/drug-treatments).
Tsuboi et al. 22 the increased survival with PPS infusion become investigated. at some stage in the research, 7 of the patients died with infectious complications and the closing 4 endured receiving the treatment. in keeping with the consequences of the take a look at, all sufferers had multiplied survival instances when compared with comparable instances, at an average time of 24.2 months. All handled instances reported deterioration of cognitive functions to various levels, in addition to subdural fluid collection. No different aspect outcomes had been observed inside the sufferers of the organization, although aspect results consisting of thrombocytopenia and coagulation disturbances are not unusual in the management of this drug (Tsuboi Y et al.,2009).
Scientific trials of PPS for patients with prion disorder had been performed in Japan and the UK (Navid J et al.,2019;Collins SJ et al.,2006). although there's a document of 1 case in which postmortem exam confirmed a significantly reduced stage of PrP-res within the brain compared with levels in brains with out PPS treatment, there was no apparent improvement in medical symptoms anyhow of familial, ectopic, or sporadic CJD handled with PPS in Japan. Notably, in two clinical studies of united kingdom sufferers with version CJD, 3 out of 4 and 4 out of 5 patients survived longer than people who did no longer get hold of PPS treatment. These variations may additionally end result from variations within the efficacy of PPS depending at the subtype of CJD.
Tetracyclic Compounds
Tetracyclic compounds have also been studied experimentally. The antibiotics tetracycline and doxycycline were proven to lengthen the incubation period in experimentally prion-inflamed mice. Tetracycline additionally reduces the formation of ordinary prions in test-tube experiments. Doxycycline has been studied via randomised scientific trials in Italy and Germany (Doxycycline in Creutzfeldt-Jakob ailment: a section 2, randomised, double-blind, placebo-managed trial ) however the results were bad (https://www.ucl.ac.uk/national-prion-clinic/drug-treatments).
Flupirtine
The antipsychotic drug flupirtine has been used in one moderately sized randomised scientific trial in Germany. No survival advantage became seen, although the opportunity of small blessings for questioning abilties become raised by means of this look at in addition work was encouraged with this drug but no medical trials are active at present (https://www.ucl.ac.uk/national-prion-clinic/drug-treatments).
Symptom management
A variety of specific signs, which include jerking of limbs termed myoclonus, behavioural or sleep disturbance, also can be supressed by capsules even though no survival gain is expected (https://www.ucl.ac.uk/national-prion-clinic/drug-treatments).
Palliative care
There are no established guidelines for the palliative care of this uncommon illness. A comprehensive approach involving a diverse team is crucial (Harrison KL et al.,2022). Patients may exhibit rapid changes, necessitating daily reassessment of management techniques in numerous instances (Harrison KL et al.,2022;Majeed S et al.,2022). It is critical to evaluate for treatable sources of agitation, like urinary retention. If no treatable sources are identified, strategies may include non-drug interventions, such as creating a soothing, familiar atmosphere and implementing behavioral techniques, followed by the introduction of medication (Harrison KL et al.,2022). Antipsychotic drugs, including olanzapine, or benzodiazepines like clonazepam, or a combination thereof, may be necessary. Preparing for a shift to subcutaneous treatments when swallowing is compromised is essential. Continual palliative care assistance is beneficial, especially during the transition to medication aimed at alleviating end-of-life symptoms. Support for bereavement is advised (Mead S et al.,2022). Studies indicate that families prefer a multidisciplinary team and assistance from healthcare professionals experienced with CJD. In this study, backing from a group knowledgeable about the condition, such as CJDSGN, helped reduce some of the stress associated with caring for an individual afflicted by this rare and swiftly advancing disease (Mead S et al.,2022).
RECENT CASE REPORTS:
Atypical young case of MV1 Creutzfeldt-Jakob disease with unusually long survival
A 21-yr-old woman who died with a sporadic prion sickness. She presented with psychiatric signs and symptoms accompanied by a swiftly progressive neurocognitive and motor decline. EEG was poor for periodic sharp wave complexes; however, brain MRI was suggestive of prion disease. The cerebrospinal fluid (CSF) real-time quaking-brought on conversion (RT-QuIC) assay turned into indeterminate. Neuropathologic examination at autopsy discovered extreme neuronal loss and gliosis with secondary white remember degeneration but minimal spongiform adjustments and PrP deposits within the cerebellum and neocortex by using immunohistochemistry. Absence of pathogenic mutations and methionine/valine heterozygosity at codon 129 of the prion protein gene (PRNP), extraordinary type 1 protease-resistant PrP that lacks or indicates underrepresentation of the diglycosylated PrP isoform by western blot analysis, and no acquired prion sickness chance factors ended in a final prognosis of atypical sCJD. Very younger onset sCJD often has odd clinical shows and ailment progression, neuropathological examination outcomes, and/or laboratory check outcomes which can confound diagnosis. it's far important to carry out thorough, complete critiques to make an correct diagnosis, which incorporates autopsy confirmation with histology, prion protein typing and prion gene sequencing (Ahn LY et al.,2025).
A case report of Heidenhain Variant of Creutzfeldt-Jakob Disease
A 72-yr-old female with a past clinical records widespread for hypertension and chronic kidney disease presented as a trauma transfer from some other medical institution for assessment following a fall. The patient's own family had reportedly found her at domestic at the floor near a staircase careworn and with a couple of bruises. preliminary imaging was great for a couple of axial and appendicular bone fractures, a small right frontal subarachnoid hemorrhage, and a small hemorrhage inside the right frontoparietal area on computed tomography (CT) of the head. She ultimately evolved blurred vision several months prior and became evaluated via several ophthalmologists who recognized her with cataracts. She then underwent surgical treatment two months prior to this admission. notwithstanding this, her vision loss advanced, with suspected lens dislocation as the underlying reason. She additionally developed vertigo and unsteady gait. She presented to an emergency room a month previous and underwent CT of the head which became mentioned as normal. She did no longer have cognitive deficits prior to this hospitalization. On preliminary neurologic evaluation, the patient changed into awake but poorly attentive and not able to provide records. in addition neurologic testing became acquired inside the sanatorium together with routine electroencephalogram (EEG) and magnetic resonance imaging (MRI) of the brain. EEG was ordinary with nonspecific findings which includes mild diffuse history slowing and generalized rhythmic delta interest (parent 2). MRI turned into abnormal with restrained diffusion within the bilateral parieto-occipital cortex (cortical ribboning ). Early remoted visible symptoms can be explained by means of the stated involvement of the parietal and occipital lobe as seen on MRI (Creutzfeldt-jakob disease.,2015), in assessment to the extra normally worried regions with CJD which include the advanced frontal gyrus, superior parietal lobule, cingulate gyrus, and insular cortex. Our patient’s MRI established cortical ribboning preferentially concerning the bilateral parieto-occipital lobes. MRI has 95% sensitivity and 93% specificity prices in diagnosing HvCJD (Sitammagari KK et al.,2025). CSF assessment indicates comparable findings to regular CJD which includes nonspecific elevation of protein, the presence of 14-three-3 protein, and positive RT-QuIC, the latter of which became visible in our affected person (Creutzfeldt-jakob disease@WHO). RT-QuIC is eighty%-90% sensitive and 100% precise for CJD (Sitammagari KK et al.,2025). The ailment duration of the HvCJD averaged 5.7 months with various 2.3-14.1 months in comparison to 7.5 months with various 1.3-32.4 months in other instances (Creutzfeldt-jakob disease.,2015). this can be because of preliminary nonspecific visible signs and symptoms and behind schedule development of different neurologic signs and symptoms till later in ailment path. Our affected person’s cognitive symptoms were best evident following traumatic brain harm, and she or he had fast cognitive decline at some point of hospitalization (Madjer N et al.,2024).
Creutzfeldt-Jakob Disease: Case Report
A 62 yr age lady provided to ER with modern decline in cognitive characteristic during the last 3 months, inclusive of ataxia, reminiscence loss, and disorientation. all through her health facility visit, CT of the head and chest/abdomen/pelvis were done first of all, which were poor for malignancy, infarction or hemorrhage. more than one exams were achieved to exclude reasons along with infection, toxic or metabolic sicknesses, and autoimmune encephalitis. MRI of the head become done which established diffusion limit and T2/aptitude hyperintensities within the bilateral basal ganglia (caudate and putamen), bilateral thalami, hippocampi, and bilateral frontal and temporal cortices in a gyriform pattern. No corresponding enhancement or mass impact become seen. Lumbar puncture turned into done, which validated expanded ranges of 14-3-3 protein in the cerebrospinal fluid. EEG become carried out, which showed slowing hobby and periodic sharp wave complexes (PSWC). overall, the outcomes of head MRI, EEG, and CSF trying out were regular with CJD. within a few weeks of admission, the affected person had worsening of cognitive feature and loss of speech output, and died away peacefully with own family at bedside. An autopsy was finished which tested spongiform modifications, neuronal loss, and astrogliosis, consistent with CJD (Fahad Rasool Butt et al.,2018).
DECLARATION OF CONFLICT OF INTEREST
The authors declared no potential conflict of interest with respect to the research, authorship and/or publication of this article.
FUNDING STATEMENT: None
REFERENCES
Athkuri Jishnu Sri, Gundega Yugandhar, Bolem Dinesh Teja, D. C. S. Manga Devi, Dr. S. Ashok Krishnan, S. K. Kamar Jaha, Creutzfeldt-Jakob Disease: An analysis on pathophysiology, Diagnosis, Treatment with Case report Highlights, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 7, 3072-3094. https://doi.org/10.5281/zenodo.16313757
10.5281/zenodo.16313757
