Sporadic Creutzfeldt-Jakob Disease Case File

Sporadic Creutzfeldt-Jakob Disease Case File

Eugene C. Toy, MD, Ericka Simpson, MD, Pedro Mancias, MD, Erin E. Furr-Stimming, MD

CASE 29

A 53-year-old woman presents with loss of balance, mood swings, and memory loss. She had not noticed these symptoms until her coworkers and family pointed them out to her. Although these symptoms presented 4 months ago, she did not seek medical attention until now, when these began interfering with her daily activities. Her ataxia has progressed to the point that she is stumbling and falling. She has noticed difficulty with problem-solving, and her boss has witnessed inappropriate behavior. Her family reports that over the past month her memory has quickly deteriorated to the point that she is unable to recognize friends, unable to drive, unable to work, and forgets if she has eaten. She has also developed slurred speech and has been witnessed to “jerk” during the day. The neurologic examination reveals a Mini-Mental State Examination (MMSE) score of 17/30, and she had difficulty with orientation, object recall, calculations, naming, concentration, and drawing the intersecting polygons. There is horizontal nystagmus, moderate dysarthria, and anomia. Her strength appears to be normal; however, she has dysmetria and a wide-based gait. Her deep tendon reflexes (DTRs) are hyperreflexic, and she has evidence of myoclonus. A computed tomography (CT) scan of the brain is performed and shows no abnormalities.

▶ What is the most likely diagnosis?

▶ What is the next diagnostic step?

▶ What is the next step in therapy?

ANSWERS TO CASE 29:

Sporadic Creutzfeldt-Jakob Disease                                                    

Summary: A 53-year-old woman presents with a 4-month history of rapidly progressive memory loss, ataxia, mood swings, inappropriate behavior, and dysarthria. Her examination is notable for a markedly abnormal MMSE with global abnormalities, moderate dysarthria, and anomia. She additionally has nystagmus, dysmetria, ataxia, myoclonus, and hyperreflexia.

• Most likely diagnosis: Sporadic Creutzfeldt-Jakob disease (CJD).
• Next diagnostic step: Serologic studies including comprehensive metabolic panel (CMP), complete blood count (CBC), HIV, erythrocyte sedimentation rate (ESR), thyroid-stimulating hormone (TSH), thyroxine (T4), triiodothyronine (T3), vitamin B12, rapid plasma reagin (RPR), international normalized ratio (INR), magnetic resonance imaging (MRI) of the brain, lumbar puncture for protein, glucose, cell count with differential, Gram stain and cultures, and 14-3-3 protein. Additionally, an electroencephalograph (EEG) may be requested.
• Next step in therapy: Supportive and symptomatic therapy since there is no specific treatment.

ANALYSIS

Objectives

1. Be familiar with the clinical presentation of sporadic CJD and its variants.
2. Recognize the differential diagnosis for CJD.
3. Identify the recommended evaluations to make the diagnosis of CJD.

Considerations

This 53-year-old woman presents with a rapidly progressive set of neurologic symptoms including memory loss, ataxia, behavioral changes, poor coordination, and myoclonus. These abnormalities are consistent with a rapidly progressive dementia and typical for CJD. Initially, patients experience problems with muscular coordination, personality changes including impaired memory, judgment, and thinking, and impaired vision. The CT scan rules out a structural etiology such as a stroke or brain tumor. Most other causes of dementia are insidious in onset and progression. Nevertheless, in this patient, treatable causes of dementia should be sought with the laboratory studies and neuroimaging mentioned previously.

APPROACH TO:

Creutzfeldt-Jakob Disease                                        

CLINICAL APPROACH

Clinical Features and Epidemiology

CJD is a rare, neurodegenerative, invariably fatal brain disorder. It affects approximately 1 person in every 1 million people per year worldwide; in the United States, there are approximately 200 cases per year. CJD usually appears later in life and has a rapid course. Typically, the onset of symptoms occurs at approximately 60 years, and about 90% of patients die within 1 year. In the early stages of disease, patients can have failing memory, behavioral changes, lack of coordination, and visual disturbances. As the illness progresses, mental deterioration becomes pronounced, and involuntary movements, blindness, weakness of extremities, and coma can occur.

There are four major categories of CJD:

• In sporadic CJD, the disease appears even though the person has no known risk factors for the disease. This is by far the most common type of CJD and accounts for at least 85% of cases.
• In hereditary CJD, the person has a family history of the disease and/or tests positive for a genetic mutation associated with CJD. Approximately 5% to 10% of cases of CJD in the United States are hereditary.
• In acquired CJD, the disease is transmitted by exposure to the brain or nervous system tissue, usually through certain medical procedures. There is no evidence that CJD is contagious through casual contact with a CJD patient. Since CJD was first described in 1920, fewer than 1% of cases have been acquired CJD.
• In variant CJD, the disease is likely transmitted by ingestion of meat products from cattle infected with bovine spongiform encephalopathy (BSE). It presents at a younger age compared to sporadic CJD and has a more protracted course. Psychiatric disturbances are more likely to be the initial presentation compared to rapidly progressing dementia in sporadic CJD.

CJD belongs to a family of human and animal diseases known as the transmissible spongiform encephalopathies (TSEs). Spongiform refers to the characteristic appearance of infected brains, which become filled with holes until they resemble sponges under a microscope. CJD is the most common of the known human TSEs. Other human TSEs include kuru, fatal familial insomnia (FFI), and Gerstmann-Straussler-Scheinker (GSS) disease. Kuru was identified in people of an isolated cannibalistic tribe in Papua, New Guinea, and has now almost disappeared. FFI and GSS are extremely rare hereditary diseases found in just a few families around the world. Other TSEs are found in specific kinds of animals. These include BSE, which is found in cows and is often referred to as “mad cow” disease; scrapie, which affects sheep and goats; mink encephalopathy; and feline encephalopathy. Similar diseases have occurred in elk, deer, and exotic zoo animals.

CJD is characterized by rapidly progressive dementia. Initially, patients experience problems with muscular coordination, personality changes including impaired memory, judgment, thinking, and vision. Affected patients also can experience insomnia, depression, or unusual sensations. CJD does not cause a fever or other flu-like symptoms. As the illness progresses, the patients’ mental impairment becomes severe. They often develop involuntary muscle jerks called myoclonus and may lose vision. They eventually lose the ability to move and speak and enter a coma. Pneumonia and other infections often occur in these patients and can lead to death.

Some symptoms of CJD can be similar to symptoms of other progressive neurologic disorders, such as Alzheimer or Huntington disease. However, CJD causes unique changes in the brain tissue that can be seen on autopsy. It also tends to cause more rapid deterioration of a person’s abilities than Alzheimer disease or most other types of dementia.

Etiology and Pathogenesis

CJD and the other TSEs are caused by a type of protein called a prion. Prion proteins occur both in a normal form, which is a harmless protein found in the body’s cells, and in an infectious form, which causes disease. The harmless and infectious forms of the prion protein have the same sequence of amino acids (the “building blocks” of proteins), but the infectious form of the protein takes a different folded shape than the normal protein. Sporadic CJD may develop because some of a person’s normal prions spontaneously change into the infectious form and then alter the prions in other cells in a chain reaction. Once they appear, abnormal prion proteins aggregate, or clump together. Investigators think these protein aggregates may lead to the neuron loss and other brain damage seen in CJD. However, they do not know exactly how this damage occurs.

Approximately 5% to 10% of all CJD cases are inherited. These cases arise from a mutation in the gene that controls formation of the normal prion protein. Although prions themselves do not contain genetic information and do not require genes to reproduce themselves, infectious prions can arise if a mutation occurs in the gene for the body’s normal prion protein. If the prion protein gene is altered in a person’s sperm or egg cells, the mutation can be transmitted to the person’s offspring. Several different mutations in the prion gene have been identified. The particular mutation found in each family affects how frequently the disease appears and what symptoms are most noticeable. However, not all people with mutations in the prion protein gene develop CJD.

CJD cannot be transmitted through the air, through touching, or through most other forms of casual contact. Spouses and other household members of sporadic CJD patients have no higher risk of contracting the disease than the general population. However, exposure to brain tissue and spinal fluid from infected patients should be avoided. In some cases, CJD has spread to other people from grafts of dura mater, transplanted corneas, implantation of inadequately sterilized electrodes in the brain, and injections of contaminated pituitary growth hormone derived from human pituitary glands taken from cadavers. Since 1985, all human growth hormone used in the United States has been synthesized by recombinant DNA procedures, thereby eliminating the risk of transmitting CJD by this route.

DIAGNOSIS

There is currently no single diagnostic test for CJD. CJD is distinguished from the more common forms of dementia by its rapid progression, presence of myoclonus, and gait disorder. When CJD is suspected, the first concern is to rule out treatable forms of dementia, such as encephalitis (inflammation of the brain); meningitis; autoimmune disorders such as paraneoplastic syndrome, demyelinating disease, sarcoidosis, or vasculitis; malignancy; metabolic disorders such as B12 deficiency or folate deficiency; or endocrine disorders such as hypothyroidism or Hashimoto encephalopathy. Standard diagnostic tests will include a spinal tap to rule out more common causes of dementia and measure biomarkers of neuronal damage and an EEG to record the brain’s electrical pattern. The EEG often shows periodic sharp wave complexes, which has a sensitivity of 66% and a specificity of 74% for CJD (Figure 29–1). CT of the brain can help rule out the possibility that the symptoms result from other problems such as a stroke or brain tumor. MRI scans of the brain can also reveal characteristic patterns of brain degeneration that can help diagnose CJD, such as hyperintense lesions in the brain cortex, caudate nucleus, and putamen on T2, fluid-attenuated inversion recovery (FLAIR), and diffusion-weighted imaging (DWI).

The only way to confirm a diagnosis of CJD is by brain biopsy or autopsy. Because a correct diagnosis of CJD does not help the patient, a brain biopsy is discouraged unless it is needed to rule out a treatable disorder. In an autopsy, the whole brain is examined after death. Both brain biopsy and autopsy pose a small but definite risk that the surgeon or others who handle the brain tissue can become accidentally infected by self-inoculation. Special surgical and disinfection procedures can minimize this risk. A fact sheet with guidance on these procedures is available from the National Institute of Neurological Disorders and Stroke (NINDS) and the World Health Organization.

Investigations are being conducted to create laboratory tests for CJD. One such test, developed at 

NINDS, is performed on a person’s CSF and detects a protein marker, 14-3-3 protein, which indicates neuronal degeneration. 14-3-3 proteins in the CSF have been found to correlate with the clinical diagnosis with a 94% sensitivity and a specificity of 84%. The protein assay in combination with EEG findings further increases the sensitivity but decreases the specificity. However, these tests can help diagnose CJD in people who already show the clinical symptoms of the disease. CSF analysis for the protein is much easier and safer than a brain biopsy. The false-positive rate is approximately 5% to 10%. Scientists are working to develop this test for use in commercial laboratories. They are also working to develop other tests for this disorder.

Treatment and Prevention

There is no treatment that can cure or control CJD. Researchers have tested many drugs, including amantadine, steroids, interferon, acyclovir, antiviral agents, and antibiotics. Studies of a variety of other drugs are now in progress. However, so far none of these treatments has shown any consistent benefit in humans. Current treatment for CJD is aimed at alleviating symptoms and making the patient as comfortable as possible. Opiate drugs can help relieve pain if it occurs, and the drugs clonazepam and sodium valproate can help relieve myoclonus. During later stages of the disease, changing the person’s position frequently can keep him or her comfortable and helps prevent bedsores. A catheter can be used to drain urine if the patient cannot control bladder function, and intravenous fluids and artificial feeding also can be used.

Figure 29–1. EEG of a patient with Creutzfeldt-Jakob disease. (Reproduced, with permission, from Aminoff MJ, Greenberg DA, Simon RP. Clinical Neurology. 6th ed. New York, NY: McGraw-Hill; 2005:53.)

CASE CORRELATION

• See also Case 20 (Alzheimer Dementia) and Case 21 (Lewy Body Dementia)

COMPREHENSION QUESTIONS

29.1 A 61-year-old woman presents to the emergency room (ER) for several days of jerking limb movements. Her daughter notes 2 months of progressive memory loss. Assuming the patient has a degenerative disease, which of the following is most likely?

A. Alzheimer disease

B. Lewy body dementia

C. Progressive supranuclear palsy

D. CJD

29.2 For the patient in Question 29.1, which of the following methods is the most accurate for diagnosing her condition?

A. Serum serology

B. Serum polymerase chain reaction (PCR)

C. Serum viral culture

D. Brain biopsy

29.3 The patient’s daughter asks if there is any disease-modifying treatment available for her mother. Which of the following should be offered?

A. Acyclovir

B. Plasma exchange

C. Donepezil

D. None of the above

ANSWERS

29.1 D. The scenario describes a rapidly progressing cognitive impairment (over 2 months). CJD is the only rapidly progressive condition listed. The other answer choices are of slower onset, usually years.

29.2 D. Brain biopsy and histologic analysis is the only definitive method of diagnosis. Although there are investigational laboratory tests being evaluated, at this time, none are available.

29.3 D. There is no known treatment to reverse or slow progression of CJD; only supportive treatment can be offered.

    CLINICAL PEARLS    

▶ Ninety percent of patients diagnosed with CJD die within 1 year. ▶ The annual rate of CJD is approximately 3.4 cases per million. In recent years, the United States has reported fewer than 300 cases of CJD a year. ▶ CJD is caused by a prion, which is a misfolded protein. ▶ CJD is distinguished from the more common forms of dementia by its rapid progression, presence of myoclonus, and gait disorder. ▶ Elevated 14-3-3 proteins in the CSF and periodic sharp waves on the EEG in a patient with rapidly progressive dementia are supportive of CJD. ▶ Treatment of CJD consists of supportive care.

REFERENCES

Collie DA, Summers DM, Sellar RJ, et al. Diagnosing variant Creutzfeldt-Jakob disease with the pulvinar sign: MR imaging findings in 86 neuropathologically confirmed cases AJNR Am J Neuroradiol. 2003;24:1560-1569. 

Duhamel A, Solomon E. Role of the biomarkers for the diagnosis of Creutzfeldt-Jakob disease. J Med Life. 2016;9(2):211-215. 

Geschwind MD. Rapidly progressive dementia: prion diseases and other rapid dementias. Continuum (Minneap Minn). 2010;16(2 Dementia):31-56. 

Geschwind MD. Rapidly progressive dementia. Continuum (Minneap Minn). 2016;22(2):510-537. 

National Institute of Neurological Disorders and Stroke. Creutzfeldt-Jakob disease fact sheet. http://www.ninds.nih.gov/disorders/cjd/detail_cjd.htm. Accessed Jan 1, 2017. 

Zerr I, Pocchiari M, Collins S, et al. Analysis of EEG and CSF 14–3-3 proteins as aids to the diagnosis of Creutzfeldt–Jakob disease. Neurology. 2000;55:811-815.

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