Creutzfeldt-Jakob Disease Flashcards
CJD Disease
Creutzfeldt-Jakob disease (CJD) is rapidly progressive neurological condition caused by prion proteins. These proteins induce the formation of amyloid folds resulting in tightly packed beta-pleated sheets resistant to proteases.
Features
- dementia (rapid onset)
- myoclonus
Investigation
CSF is usually normal
EEG: biphasic, high amplitude sharp waves (only in sporadic CJD)
MRI: hyperintense signals in the basal ganglia and thalamus
Sporadic CJD vs New Variant CJD
Sporadic CJD
accounts for 85% of cases
10-15% of cases are familial
mean age of onset is 65 years
New variant CJD
- younger patients (average age of onset = 25 years)
- psychological symptoms such as anxiety, withdrawal and dysphonia are the most common presenting features
- the ‘prion protein’ is encoded on chromosome 20 - it’s role is not yet understood
- methionine homozygosity at codon 129 of the prion protein is a risk factor for developing CJD - all patients who have so far died have had this
- median survival = 13 months
Other Prion Diseases
Other prion diseases
kuru
fatal familial insomnia
Gerstmann Straussler-Scheinker disease
CJD Diagnosis - Example Question
A 58 year old female is brought into hospital by her husband with recurrent falls associated with cognitive decline noted by her husband over the past 8 weeks. The patients husband reports a possible cough and cold about 3 months ago, during which she took 2 days off work as a personal assistant to a FTSE 100 company CEO but otherwise has no significant past medical history, is a non-smoker and drinks minimal alcohol.
On examination, she is alert and orientated to time and place but appears easily startled every time you start a sentence. You note significant bilateral finger-nose and heel-shin dysmetria, mild postural tremor and mild speech slurring. The remainder of her neurological examination was unremarkable.
Her blood tests are as follows:
Hb 12.4 g/dl
Platelets 282 * 109/l
WBC 4.8 * 109/l
Na+ 143 mmol/l K+ 4.7 mmol/l Urea 6.7 mmol/l Creatinine 86 µmol/l CRP 3 mg/l TSH 8.0 mu/l Free T4 12.0 pmol/l Anti-TPO negative HIV negative Glucose 6.5 mmol/l
A lumbar puncture was performed with results as follows:
WCC <1 /mm³ RBC 28 /mm³ Protein 0.71 g/l Glucose 3.4 mmol/l Culture no organisms grown Viral PCR awaited Cytology awaited 14-3-3 positive
An EEG demonstrated brief periodic spikes but were not correlated to any seizure activity clinically. A MRI head demonstrated no parenchymal abnormalities except mild increased signal in the cortical sulci.
What is the most likely diagnosis?
> Creutzfeld Jakob disease Viral encephalitis Acute disseminated encephalomyelitis (ADEM) Progressive multifocal leucoencephalopathy (PML) Hashimoto's encephalopathy
This middle aged female demonstrates a number of worrying features suggestive of Creutzfeld Jakob disease (CJD): rapid cognitive decline, myoclonus, extrapyramidal signs (ataxia), startle response, positive 14-3-3 on CSF and periodic spiking on EEG. The MRI findings likely represent ‘cortical ribboning’, with high signal on the cortical sulci surfaces, which along with increased signal in putamen and caudate head, is suggestive of CJD.
She is also in the expected age group for CJD, typically presenting between 57 and 62 years old.
A number of features in the history and investigations are red herrings: it is unusual for a viral encephalitis, related to a probable viral respiratory tract infection, to be indolent for 8 weeks and continuing to progress in a non-immunosuppressed patient. The MRI findings and time course are also not suggestive of ADEM, which produces many focal areas of central demyelination within 1 to 3 weeks of a viral illness.
PML results in central demyelinating and is caused by activation of JC papovirus in immunosuppressed patients, typically HIV positive individuals, and hence unexpected in this patient. The raised TSH likely represents subclinical hypothyroidism in this patient: while Hashimoto’s encephalopathy can produce personality change, aggressive and disorientation, myoclonus and ataxia, 14-3-3 is typically negative in CSF with positive anti-TPO antibodies. A diagnosis of CJD is thus most likely diagnosis, with the patient progressing along a typically fatal clinical course.
Creutzfeldt Jakob Disease
A 64 year old man is referred to you from a psychiatrist for a second opinion. He initially presented with a 3 month history of low mood, apathy and suicidal ideation. In addition he was asked to retire early from his job as an accountant as he was performing poorly at work. He is also sleeping an average of 14 hours per day.
When the psychiatrist assessed him he noted abnormal jerky movements in the lower limbs as well as a broad based gait. An MMSE was performed and he scored 15/30. This is corroborated by your examination and you also note hyperreflexia in the lower limbs and nystagmus.
He has no history of cognitive impairment or any psychiatric history. There is no family history of any neurological or psychiatric conditions and his only past medical history is an appendectomy 20 years ago which was complicated by a large intraperitoneal bleed.
Which findings are you most likely to find on investigation?
> Increased T2 and FLAIR signal intensity in the putamen and head of the caudate on T2 weighted MRI, 14-3-3 protein on CSF CAG trinucleotide repeats on the short arm of chromosome 4 Increased T2 and FLAIR signal intensity in the putamen and head of caudate on T2 weighted MRI and oligoclonal bands on CSF CAG trinucleotide repeats on the short arm of chromosome 12 Cortical atrophy, most prominent in the frontal lobes
The diagnosis here is Sporadic Creutzfeld Jakob Disease. CJD is characterised by a rapidly progressive dementia along with neuropsychiatric changes. Death usually occurs within a year of diagnosis. Most common psychiatric symptoms are depression and apathy although euphoria, anxiety and emotional lability can also be seen. Myoclonus, ataxia, nystagmus and hyperreflexia are the most common neurological symptoms.
A represents the most likely findings for sporadic CJD. Sporadic CJD normally has a longer clinical course than nvCJD and is normally seen in older people (although nvCJD is possible in this individual as he may have has a blood transfusion 20).
B represents a finding seen in Huntingtons chorea. The lack of family history makes this diagnosis less likely. The oligoclonal bands in C are seen in association with Multiple Sclerosis not CJD. D is not a recognised investigation finding and E would be more consistent with a diagnosis of Picks Disease. The very rapid onset of symptoms and presence of myoclonic jerks make this answer less likely.
Iatrogenic CJD
The use of prion-contaminated medication, grafts and instruments may result in iatrogenic CJD. The current worldwide total of growth-hormone-associated cases of CJD is 226. Most cases occurred in France (119 cases/1,880 recipients; attack rate 6.3%), the United Kingdom (65 cases/1,800 recipients; attack rate 3.6%), and the United States (29 cases/7,700 recipients; attack rate 0.4%). No new case has been identified since 2008 but would be important to recognise this condition and how it presents if it did, as it is invariably fatal -so patients need to be made aware of their prognosis.
The clinical features of the disease vary according to the route of inoculation.
Central inoculation, eg from infected neurosurgical instruments, results in a rapidly progressive neurodegenerative disease similar to sporadic CJD, characterised by ataxia, dementia, myoclonus, rigidity, and akinetic mutism. Survival is 2-12 months.
Peripheral inoculation, eg from the use of the old human growth hormone products, results in a slightly less acute disease -characterised by progressive cerebellar ataxia and dementia. Survival is 8-18 months.
Example Question:
A 32-year-old man had a compressive pituitary macroadenoma surgically removed in France 4 weeks ago and has been on pituitary hormone replacement since, including growth hormone. Surgery was uncomplicated and he initially made a good recovery. He has no other past medical history. He has now developed, over the last 1-2 weeks, poor balance, with a broad-based gait. He has also become extremely forgetful. On examination, he has an ataxic gain and you also observe occasional myoclonic limb movements. His MMSE score is 22/30. Clinical examination is otherwise unremarkable, as are routine blood investigations. Given the likely diagnosis, what might you expect to find on his MRI brain?
Areas of demyelination in the cerebellum An area of high T2 signal in the right middle cerebral artery territory with restricted diffusion on diffusion-weighted sequences > High T2 signal in the posterior thalamus Leptomeningeal enhancement Loss of grey-white matter differentiation
The diagnosis is Creutzfeldt-Jakob disease (CJD) from an iatrogenic source.
Iatrogenic CJD - Example Question
A 46 year-old man is admitted to hospital after he is found wandering the streets, unable to remember who he his or how he got there. After a collateral history is obtained, he is referred to the neurologists for further investigation.
Over the last two months he has become increasingly forgetful and clumsy, and his behaviour has become progressively more bizarre. His speech has become confused, and he struggles with daily tasks. Others have commented that he has become very ‘twitchy’, and he sometimes drops things out of his hands without meaning to.
He was previously fit and well and the main carer for his father who suffers from motor neuron disease. His sister who previously helped him care for their father was recently killed in a car accident.
His only past medical history is that at age 22 he underwent extensive surgical resection of a large parafalcine meningioma which was discovered after investigation of chronic headache. Since the operation he has been free of headache.
On examination he is completely disoriented in time, place, and person. His gait is broad-based and uncoordinated, and during the examination you notice several shock-like jerks of his arms. Tone, power, reflexes, and sensation are otherwise normal, and cranial nerve examination is unremarkable.
What is the most likely diagnosis?
Viral encephalitis > Creutzfeld-Jakob disease Frontotemporal dementia Alzheimer's disease Dissociative fugue
The history of rapidly progressive dementia, ataxia, and myoclonus is highly suggestive of Creutzfeld-Jakob disease (CJD). The previous neurosurgery may have required the use of a dural graft and if so this is the likely method of transmission of the prion protein (iatrogenic CJD).
Viral encephalitis is unlikely over a two month period.
Frontotemporal dementia causes a dementia with prominent personality change and behavioural disturbance, which may progress rapidly over months to years. There is an association with motor neuron disease.
Alzheimers disease would not typically occur at such an early age, or cause such a rapid deterioration. Ataxia would be unusual, and although myoclonus can occur in advanced dementia, this would not be typical early in the disease.
Dissociative fugue is a psychiatric condition characterised by disintegration of personality and memory, typically precipitated by a stressful event, and accompanied by wandering.
CJD
Example Presentation:
‘This middle aged female’ demonstrates a number of worrying features suggestive of Creutzfeld Jakob disease (CJD): rapid cognitive decline, myoclonus, extrapyramidal signs (ataxia), startle response, positive 14-3-3 on CSF and periodic spiking on EEG.
Example Ix:
An EEG demonstrated brief periodic spikes but were not correlated to any seizure activity clinically. A MRI head demonstrated no parenchymal abnormalities except mild increased signal in the cortical sulk. These MRI findings likely represent ‘cortical ribboning’, with high signal on the cortical sulci surfaces, which along with increased signal in putamen and caudate head, is suggestive of CJD.
Expected age group for CJD = between 57 and 62 years old.
CJD Investigations
Increased T2 and FLAIR signal intensity in the putamen and head of the caudate on T2 weighted MRI
14-3-3 protein on CSF
CJD
RAPIDLY PROGRESSIVE DEMENTIA + ATAXIA + MYOCLONUS
PSHx - Neurosurgery - ?iatrogenic
