Creutzfeldt-Jakob Disease

  A sizable percentage of my audience happen to be people from Brazil. As is well known there, youtuber Lito Sousa was recently diagnosed with Creutzfeldt-Jakob disease, a very rare neurodegenerative illness that strikes between 1-2 per 1 million people. This recent event has increased awareness of the disease in Brazil and peaked the public's curiosity about the nature of this illness. While I am not a doctor or neuropathologist, this is a disease that I have studied extensively, and as this blog is educational in nature, it seemed appropriate to provide a post for readers who are curious as to the nature of this disease. With that in mind, this post provides a summary of the illness, its pathology, its signs and symptoms, its cause, its prognosis and other closely related diseases. It should be noted that the purpose of this post is not to direct negative attention to Lito or those associated with him. My heart and sympathies extend to Lito and his family. This post is merely for educational and awareness raising purposes.

With that being established, let’s begin our discussion.

                            The Disease

Creutzfeldt-Jakob disease is a rare and invariably fatal neurodegenerative disease affecting 1-2 in 1 million people worldwide. It is a member of a group of diseases known as transmissible spongiform encephalopathies; rare but invariably fatal diseases that attack the central nervous system. Spongiform encephalopathies are so named due to microvacuole accumulation in brain tissue, giving histopathological brain findings a “sponge” appearance. The first of these diseases to be discovered was that of scrapie, a spongiform encephalopathy affecting sheep, so named for its tendency to cause afflicted sheep to scrap their skin to the point of wool loss. That being said, by far the best well known is bovine spongiform encephalopathy (BSE), perhaps better well known by its informal name, mad cow disease. Though currently very rare, BSE is famous for a wide outbreak in Britain during the 1980’s and 90’s, in which hundreds of thousands of cows were infected and invariably died from the disease, resulting from enforced cannibalism from the British meat industry. Other spongiform encephalopathies which have been discovered include chronic wasting disease in deer and elk, transmissible mink encephalopathy and feline spongiform encephalopathy in cats. Transmissible spongiform encephalopathies in humans include the titular Creutzfeldt-Jakob disease (CJD), variant Creutzfeldt-Jakob disease (which shall also be explored in this article), fatal familial insomnia, Gerstmann-Straussler-Sheinker syndrome, kuru and variable protease-sensitive prionopathy. 

                         Symptoms

Creutzfeldt-Jakob disease can present with several variations and symptomatological manifestations. Further atypical presentations are also not uncommon. Be that as it may, official subtypes are recognized, being defined by their symptomatology, histopathology and cause. While we shall examine these subtypes in more detail, let us settle for now with a general overview of symptoms.

Creutzfeldt-Jakob disease typically begins with rapidly progressive dementia, producing memory loss, confusion and personality changes over a course of months. Unsteady gait, balance problems and impaired coordination (ataxia) typically occur. Myoclonus (involuntary jerking movements) are seen in 90% of cases, but may not appear until later stages. Speech deterioration may appear and insomnia is not uncommon. Visual disturbances are common and may include difficulty understanding what one is perceiving, blurred or double-vision. Hallucinations occur frequently. Hearing impairments can also sometimes occur. Psychiatric symptoms can appear in the early stages, including anxiety, depression, paranoia, obsessive-compulsive symptoms or psychosis.

As the disease progresses, dementia becomes much more pronounced and severe. Myoclonus is usually quite prominent during this stage. Self-coordination becomes impossible, with the patient frequently being bed-ridden, unable to stand, even with assistance. Cortical blindness is not infrequent, and deafness may occur. Hallucinations, if experienced, tend to become more prominent, especially if blindness is present. Akinetic mutism is frequently the final manifestation, a state in which patients appear conscious but do not respond to environmental cues. Urinary and fecal incontinence are invariably seen at this stage.

Death typically results from pneumonic secondary bacterial infections due to impaired coughing reflex. Sometimes, it may result from skin ulcers developed through prolonged periods in a single position. Should the patient survive long enough, the disease will eventually reach the brain stem, destroying neuronal subsystems associated with respiration.

                                Subtypes

Sporadic CJD: This is by far the most common type, encompassing over 85% of CJD patients. It typically manifests within the seventh decade of life, with 68 being the usual age of onset. The cause of this subform is not known, but is thought to be related to alterations associated with the aging process.

Familial CJD: Also called inherited CJD, this form of the disease encompasses over 10% of patients and is associated with genetic mutation passed down through an allele dominant manner. Parents with the gene have a fifty/fifty chance of passing the gene to their offspring. This form typically has a slower course than the sporadic variant.

Iotragenic CJD: A rare form encompassing 1-2% of all CJD cases, this form is acquired through medical procedures contaminated with infectious prion protein. Presentation of symptoms can vary wildly between cases.

Variant CJD: A very rare form of CJD, this form is acquired through the consumption of contaminated cow products. Variant CJD is believed to be the human equivalent of bovine spongiform encephalopathy, transmitted to humans by consumption of the cow’s organic material. Psychiatric symptoms are more pronounced than in other forms of CJD. Deterioration is typically slower than sporadic CJD and sometimes familiar CJD, and electroencephalogram results are atypical when compared to the sporadic form.

                        Cause

Creutzfeldt-Jakob disease shares a common cause with all other spongiform encephalopathies, a misfolding of the PrP protein, a naturally occurring protein found in the central nervous system. This protein needs to exist in a constituent form for it to function naturally, reliably and in a manner that is conducive to overall brain health. Normally, this protein in its native form (PrPC) is composed of 45% alpha-helices, and very little beta-sheet. Though, for reasons still unknown, the shape of this protein can change. Exact formations of the distortion in shape vary, though it is often composed of 40% alpha-helices and 45% beta-sheet. This form of the protein is highly stable, being resistant to solubility and decontamination. Bizarrely, it is also infectious, functioning as a transmissible agent. This form of the protein (PrPRes) was affirmed by neurologist Stanley Prusiner, naming the agent a prion, a derivative for “infectious protein.” The prion, through mechanisms not fully understood, is able to convert healthy

PrPC protein into the disease-causing variant, forming aggregates that are unable to be broken down by cellular enzymes. Accumulation of these aggregates are toxic to neurons, bringing in excessive amounts of calcium transportation into the neuron and ultimately leading to apoptosis of the cell. The continuous cascade of these prion proteins results in cellular death, leading to the formation of microvacuoles reminiscent of holes in a sponge, which are responsible for the onset of symptoms.

Some forms of Creutzfeldt-Jakob disease have an origin point that can be tied to external prion infection. Variant CJD is acquired through exposure to abnormal prion protein found in cow products (though this is extremely rare). Iotragenic CJD results from exposure to contaminated transplant tissue or medical equipment. Familial CJD results from mutation to codon 129 of the PRNP gene, being the gene associated with manufacturing of PrP protein. While these forms have an origin story, they encompass a maximum of 15% of CJD cases. Sporadic CJD on the other hand, does not have a clear origin point in terms of prion formation. We do know that specific alleles on codon 129 increase one’s risk. Each person in the world expresses either an MM, MV or VV variation of codon 129, MM encompassing 1/3rd of people, MV just over 50% and the remaining being the VV genotype. Research has confirmed that 63% of patients with sporadic CJD possess the MM variation, suggesting this is a risk factor for the disease. Furthermore, alterations to the body associated with the aging process are thought to be involved. Be that as it may, these alone do not explain the onset of sporadic CJD. While these risk factors were identified, no definitive cause is known as of yet.

            Diagnosis

There are various diagnostic methods to confirm Creutzfeldt-Jakob disease. The presence of rapidly progressive dementia combined with ataxia, myoclonus and other neurological symptoms leads to a conclusion of possible CJD. Spinal taps and testing of cerebral spinal fluid lead to a probable diagnosis. However, the definitive method of diagnosis is through examining histopathology via use of a brain biopsy. For reasons of invasiveness, this is almost never performed, leading doctors and families with merely a “probable” or “possible” labeling until after the death of the patient. When death occurs, the presence of microvacuoles in brain tissue will confirm the diagnosis with certainty. Vacuole presentation is variable among subforms of the disease.

                                Prognosis

Creutzfeldt-Jakob disease carries a poor prognosis, being neurodegenerative and invariably fatal. Disease courses are highly variable depending on the subtype, but onset of symptoms to death is generally a rapid progression. Seventy percent of patients die within the first year of onset.

Sporadic CJD has the most rapid progression, with patients rarely surviving longer than a year. The average course from onset to death typically averages between 2-6 months, with death usually occurring four months after onset. Sometimes, disease progression can occur extremely rapidly, killing the individual weeks after symptom onset. 

Familial CJD typically has a longer course, with deterioration happening between 8 months to 2 years. Iotragenic CJD is the most volatile, ranging enormously in terms of presentation and speed of deterioration.

Variant CJD typically lasts longer than its sporadic counterpart, but is more rapid than the familial form. Psychiatric symptoms tend to be the first clinical presentation, a striking contrast to the immediate memory deterioration present in sporadic CJD. Victims of this form survive an average of 13 months.

In all cases, patients will inevitably die as a result of the neural deterioration or its associated consequences.

                                 Treatment

There is no cure, treatment, preventative or slowing of progression for Creutzfeldt-Jakob disease. Medications may be used for diminishing myoclonus. SSRIs may be prescribed to deal with depression or anxiety. After diagnosis, palliative care and end-of-life preparation should be prepared.

                                Summary

Creutzfeldt-Jakob disease is a devastating neurodegenerative disease belonging to the category of Transmissible Spongiform Encephalopathies, being one of several to occur in humans. The disease is caused by prions, misfolded proteins naturally found in the brain that act as infectious agents, converting healthy proteins into the misfolded form. The resulting aggregates are toxic to nerve cells, leading to destruction of brain tissue. 

There is no cure or treatment for Creutzfeldt-Jakob disease, having a one-hundred percent mortality rate. Treatment includes palliative care and end-of-life preparation.

For all Brazilian readers, please show support for Lito Sousa and his family. As the author of this blog, I extend my sympathies to this wonderful man who has been struck by this cruel disease.

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