Medicine – Creutzfeldt–Jakob Disease

Creutzfeldt–Jakob disease (CJD) is a rare, rapidly progressive and fatal prion disease of the central nervous system. It is characterised by rapidly worsening cognitive decline, myoclonus, ataxia and other neurological abnormalities.

Prion diseases are unusual because the infectious agent is not a virus, bacterium or fungus. Instead, disease results from abnormal folding of a naturally occurring prion protein.

1. Prion Disease

CJD belongs to the group of disorders known as:

Transmissible spongiform encephalopathies.

These are neurodegenerative diseases caused by accumulation of abnormal prion protein within the CNS.

The abnormal protein induces normally folded prion proteins to adopt the abnormal configuration.

Therefore:

Abnormal prion protein → conversion of normal prion protein → progressive accumulation → neuronal injury and death.

2. Prion Protein

The normal cellular prion protein is often referred to as:

PrPᶜ.

The abnormal disease-associated form is commonly referred to as:

PrPˢᶜ.

The abnormal form is resistant to normal protein degradation and tends to accumulate within nervous tissue.

3. Effect on the Brain

Accumulation of abnormal prion protein produces progressive neurodegeneration.

Characteristic pathological changes include:

Neuronal loss.

Gliosis.

Spongiform change.

The term spongiform refers to the microscopic appearance of numerous tiny vacuoles within brain tissue, giving it a sponge-like appearance.

4. Main Forms of CJD

CJD can occur in several forms.

The major categories are:

Sporadic CJD.

Familial or genetic CJD.

Acquired CJD.

Variant CJD is usually considered a distinct acquired prion disease.

5. Sporadic CJD

Sporadic CJD is the most common form.

It occurs without a clear family history or known exposure.

The exact trigger for spontaneous abnormal prion folding is unknown.

It typically presents in later adulthood with rapidly progressive neurological deterioration.

6. Familial CJD

Familial CJD results from pathogenic variants in the:

PRNP gene.

Inheritance is usually:

Autosomal dominant.

Therefore, an affected individual may have a significant family history of prion disease or rapidly progressive neurological illness.

7. Genetic Prion Diseases

Familial CJD is one of several inherited prion disorders.

Other important genetic prion diseases include:

Fatal familial insomnia.

Gerstmann–Sträussler–Scheinker syndrome.

These are also associated with mutations in the PRNP gene.

8. Acquired Prion Disease

Prion disease can rarely be acquired from exposure to abnormal prion protein.

Important examples include:

Kuru.

Iatrogenic CJD.

Variant CJD.

These differ from sporadic and familial forms because transmission has occurred from an external source.

9. Kuru

Kuru was historically seen among the Fore people of Papua New Guinea.

It was transmitted through ritualistic consumption of human nervous tissue during mortuary practices.

The disease became an important demonstration that prion diseases could be transmissible.

Kuru is now extremely rare.

10. Iatrogenic CJD

Iatrogenic CJD has occurred through medical exposure to contaminated biological material.

Historical examples include:

Cadaveric human growth hormone.

Dura mater grafts.

Contaminated neurosurgical instruments.

Because prions are unusually resistant to standard sterilisation methods, special infection-control procedures are required when prion contamination is suspected.

11. Variant CJD

Variant CJD is linked to exposure to the agent causing:

Bovine spongiform encephalopathy – BSE.

BSE is commonly known as:

Mad cow disease.

Variant CJD differs clinically from typical sporadic CJD.

12. Clinical Features

The major clinical features of CJD include:

Rapidly progressive dementia.

Myoclonus.

Ataxia.

Behavioural or psychiatric disturbance.

Sleep abnormalities.

Visual or cerebellar abnormalities.

Pyramidal or extrapyramidal signs.

The disease usually progresses rapidly over months.

13. Rapidly Progressive Dementia

One of the most important features is:

Rapid cognitive decline.

Patients may develop:

Memory impairment.

Poor concentration.

Disorientation.

Language difficulty.

Executive dysfunction.

Unlike most common dementias, which progress over years, CJD often progresses over a much shorter period.

Therefore:

Rapid dementia over weeks to months → consider CJD among the differential diagnoses.

14. Myoclonus

Myoclonus is a classic feature.

It consists of:

Brief, sudden, shock-like involuntary muscle jerks.

These movements may be spontaneous or triggered by:

Sound.

Touch.

Movement.

Myoclonus is particularly characteristic when it develops in a patient with rapidly progressive dementia.

15. Ataxia

Cerebellar involvement can produce:

Gait ataxia.

Limb incoordination.

Dysarthria.

Unsteadiness.

Ataxia may appear early or develop during disease progression.

16. Visual Disturbance

Some patients develop visual abnormalities.

These may include:

Blurred vision.

Visual-field abnormalities.

Visual hallucinations.

Cortical visual impairment.

Prominent visual and cerebellar features may occur in some subtypes of sporadic CJD.

17. Pyramidal and Extrapyramidal Features

As the disease progresses, patients may develop:

Rigidity.

Bradykinesia.

Tremor.

Spasticity.

Hyperreflexia.

Extensor plantar responses.

This reflects widespread CNS involvement.

18. Sleep Abnormalities

Sleep disturbances can occur in prion disease.

These may include:

Insomnia.

Disrupted sleep–wake cycles.

Reduced sleep quality.

Severe progressive insomnia is particularly characteristic of fatal familial insomnia, although sleep abnormalities can also occur in CJD.

19. Behavioural Disturbance

Behavioural and psychiatric symptoms may occur in CJD.

These can include:

Anxiety.

Depression.

Irritability.

Withdrawal.

Personality change.

They are particularly important in variant CJD.

20. Variant CJD Presentation

Variant CJD tends to affect younger patients than classic sporadic CJD.

Early manifestations often include prominent psychiatric symptoms such as:

Depression.

Anxiety.

Behavioural change.

Social withdrawal.

Painful sensory symptoms.

Neurological deterioration, ataxia and dementia then develop.

Therefore:

Early psychiatric symptoms are particularly characteristic of variant CJD.

21. Investigation

Diagnosis is based on the clinical picture together with:

MRI brain.

EEG.

CSF biomarkers.

Definitive confirmation requires demonstration of prion pathology, but in practice diagnosis is usually made using validated clinical and laboratory criteria.

22. MRI Brain

MRI is one of the most useful investigations.

Typical sporadic CJD may show restricted diffusion involving:

Cerebral cortex.

Caudate nucleus.

Putamen.

This cortical signal abnormality is often called:

Cortical ribboning.

23. Cortical Ribboning

Cortical ribboning refers to high signal along the cerebral cortex, particularly on:

Diffusion-weighted imaging.

and

FLAIR sequences.

This finding is strongly supportive of CJD when combined with the appropriate rapidly progressive clinical syndrome.

24. Variant CJD MRI

Variant CJD is associated with a characteristic MRI abnormality involving the:

Pulvinar of the thalamus.

This is known as the:

Pulvinar sign.

Historically it has also been called the hockey-stick sign when dorsomedial thalamic involvement accompanies the pulvinar abnormality.

25. EEG

EEG in sporadic CJD may demonstrate:

Periodic sharp-wave complexes.

These are classically repeated at roughly regular intervals.

However, they are not present in every patient and may appear later in the illness.

26. CSF Biomarkers

CSF may be tested for markers of rapid neuronal injury.

Historically important tests include:

14-3-3 protein.

Total tau.

These support the diagnosis but are not completely specific, because they may also be elevated in other causes of rapid brain injury.

27. RT-QuIC

A more specific modern investigation is:

RT-QuIC – real-time quaking-induced conversion.

This test detects abnormal prion-seeding activity in samples such as CSF.

A positive RT-QuIC result strongly supports a diagnosis of prion disease.

28. Differential Diagnosis

Because CJD causes rapidly progressive dementia, important alternative diagnoses must be excluded.

These include:

Autoimmune encephalitis.

HSV encephalitis.

Other CNS infections.

Metabolic encephalopathy.

Toxic disorders.

Malignancy.

Vasculitis.

Rapidly progressive neurodegenerative disease.

Some of these conditions are treatable, making early exclusion important.

29. Treatment

There is currently no established curative treatment for CJD.

Management is mainly:

Supportive.

Treatment focuses on:

Control of myoclonus.

Management of behavioural symptoms.

Nutrition and hydration.

Mobility and pressure-area care.

Palliative and family support.

30. Management of Myoclonus

Myoclonus may be treated symptomatically.

Drugs that may be used include:

Clonazepam.

Valproate.

Other antiseizure medications may be considered depending on the clinical situation.

31. Prognosis

CJD is relentlessly progressive and usually fatal.

In sporadic CJD, progression is typically rapid, often occurring over:

Months rather than years.

This rapid course is one of its most distinguishing features compared with more common dementias.

32. Sporadic CJD – Note Form

Most common form.

No known exposure.

No necessary family history.

Rapidly progressive dementia.

Myoclonus.

Ataxia.

MRI cortical ribboning / basal ganglia abnormalities.

EEG may show periodic sharp-wave complexes.

RT-QuIC supports diagnosis.

33. Familial CJD – Note Form

Cause: PRNP gene mutation.

Inheritance: autosomal dominant.

Mechanism: genetically determined abnormal prion protein folding.

May have: positive family history.

34. Acquired Prion Disease – Note Form

Important acquired forms include:

Kuru.

Iatrogenic CJD.

Variant CJD.

These involve transmission of abnormal prion protein from an external source.

35. Variant CJD – Note Form

Association: bovine spongiform encephalopathy.

Patients: typically younger than those with sporadic CJD.

Early features: psychiatric and behavioural symptoms.

Later features: ataxia + cognitive decline + neurological deterioration.

MRI: pulvinar sign.

36. Classic Clinical Pattern

The characteristic combination is:

Rapidly progressive dementia.

Myoclonus.

Ataxia.

These may be accompanied by:

Behavioural disturbance.

Visual abnormalities.

Pyramidal/extrapyramidal signs.

Sleep disturbance.

37. Important Investigation Pattern

For examination purposes:

MRI → cortical ribboning ± caudate/putamen involvement.

EEG → periodic sharp-wave complexes.

CSF → RT-QuIC positive ± elevated 14-3-3/tau.

Key Clinical Pattern

Think of CJD when you see:

RAPIDLY PROGRESSIVE DEMENTIA + MYOCLONUS + ATAXIA.

Then remember:

Prion accumulation → spongiform neurodegeneration.

Sporadic = most common.

Familial = autosomal dominant PRNP mutation.

Acquired = kuru / iatrogenic / variant CJD.

Variant CJD = younger patient + early behavioural/psychiatric disturbance + BSE association.

And the classic investigations are:

MRI cortical ribboning + EEG periodic sharp waves + CSF RT-QuIC.