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Creutzfeldt–Jakob Disease


Quick Start: Creutzfeldt–Jakob Disease

Definition

  • Creutzfeldt–Jakob disease (CJD) is one of several prion transmissible neurodegenerative diseases characterized by a rapid cognitive decline that can progress to akinetic mutism over weeks.

  • Creutzfeldt–Jakob disease is the most common type of prion disease; prion diseases are also called transmissible spongiform encephalopathies.

  • Prion diseases have a specific neuropathology characterized by spongiform changes, neuronal death, astrocytosis, and accumulation of a pathological protein (PrP Sc ) in the brain and sometimes other organs.

  • Other forms of Creutzfeldt–Jakob disease include genetic and acquired. Acquired forms include iatrogenic and variant.

  • Variant Creutzfeldt–Jakob disease is similar biochemically and histopathologically to bovine spongiform encephalopathy (aka “mad cow disease”).

Prevalence

  • Sporadic Creutzfeldt–Jakob disease has an incidence of approximately 1 to 2 per million.

  • The usual age of onset of sporadic Creutzfeldt–Jakob disease is from 55 to 75 years; variant Creutzfeldt–Jakob disease often presents in younger individuals.

Genetic and transmission risk

  • Prion diseases are transmissible, meaning an inoculation with the pathological protein can cause the disease in another individual.

  • There are a number of mutations of the gene PRNP (located on the short arm of chromosome 20), which codes for the pathological protein (PrP Sc ), leading to familial, autosomal dominant Creutzfeldt–Jakob disease, Gerstmann–Sträussler–Scheinker syndrome, and fatal familial insomnia.

Cognitive, behavioral, and other symptoms

  • Cognitive and behavioral changes include impairment of memory and executive function, as well as depression and sometimes personality changes.

  • Cerebellar signs and myoclonus are frequent, and can worsen over a period of days.

Diagnostic criteria
  • 1.

    Rapid cognitive decline

  • 2.

    Two of the following six signs/symptoms:

    • Myoclonus

    • Pyramidal/extrapyramidal dysfunction

    • Visual dysfunction

    • Cerebellar dysfunction

    • Akinetic mutism

    • Focal cortical signs (e.g., neglect, aphasia, acalculia, apraxia)

  • 3.

    Typical electroencephalogram and/or magnetic resonance imaging (MRI)

    • MRI shows diffusion-weighted imaging (DWI) brighter than fluid-attenuated inversion recovery (FLAIR) hyperintensity in the cingulate, striatum, and/or greater than one neocortical gyrus, ideally with sparing of the precentral gyrus and apparent diffusion coefficient map supporting restricted diffusion.

  • 4.

    Other investigations should not suggest an alternative diagnosis

Treatment

  • Treatment for Creutzfeldt–Jakob disease is supportive.

Top differential diagnoses

  • Slow progression: common degenerative diseases

    • Dementia with Lewy bodies

    • Frontotemporal dementia

    • Corticobasal degeneration

    • Progressive supranuclear palsy

    • Alzheimer’s disease (particularly when associated with cerebral amyloid angiopathy)

  • Rapidly progressing dementias

    • Cerebrovascular disease

    • Vasculitis

    • Autoimmune encephalopathies

    • Collagen vascular and granulomatous disease

    • Infectious disease

    • Malignancies

    • Paraneoplastic disorders

    • Toxic and metabolic disorders

    • Psychiatric disorders

A 68-year-old man presented to our clinic for evaluation of a 5-month history of memory problems. Memory loss, feeling “funny,” and loss of appetite were initial symptoms. At the first visit the daughter reported that the problems appeared to be accelerating, and were much worse over the last two weeks. He now had difficulty getting dressed, using the toilet, and finding his way around his own house. He had emotional lability and paranoia. He complained of blurry vision and was noted to be very drowsy at times.

His neurologic examination was notable for myoclonus and a coarse intention tremor in both upper extremities due to ataxia. He had perseveration, anomia, and apraxia. He was unable to complete the Montreal Cognitive Assessment (MoCA) because of perseveration. Cerebrospinal fluid 14-3-3 was within normal limits. Electroencephalogram (EEG) showed diffuse slowing and occasional triphasic complexes. Magnetic resonance imaging (MRI) showed significant atrophy, along with abnormal diffusion signal in the thalami and bilateral parietal lobes. He died seven months after symptom onset.

Prevalence, Prognosis, and Definition

Creutzfeldt–Jakob disease (CJD) (also known as Jakob-Creutzfeldt disease, JCD) is the most common type of prion disease. Prion diseases, also called transmissible spongiform encephalopathies, are progressive neurodegenerative diseases characterized by a specific neuropathology and a rapid cognitive decline that can progress to akinetic mutism over weeks. Cerebellar signs and myoclonus are frequent. EEG recordings often show a characteristic periodic sharp-wave complex. Sporadic Creutzfeldt–Jakob disease (making up 85%–90% of prion diseases) has an incidence of approximately 1 to 2 per million, with a usual age of onset from 55 to 75 years (average 67 and median 64 years) ( ). Average survival is about six months. Other forms of Creutzfeldt–Jakob disease include genetic (gCJD; 10%–15% of prion diseases) and acquired (1%–3% of prion diseases). Acquired forms include iatrogenic (iCJD) and variant (vCJD). Age of onset of variant Creutzfeldt–Jakob disease is generally younger, sometimes presenting in the second decade of life. Creutzfeldt–Jakob disease can be confirmed neuropathologically by biopsy or at autopsy, although these are rarely performed given the risk of transmission.

Criteria

Two commonly used sets of criteria are the University of California, San Francisco (UCSF) Criteria ( Box 16.1 ; ) and those of the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition ( Box 16.2 ).

Box 16.1
University of California, San Francisco Creutzfeldt–Jakob Criteria
Modified from Geschwind, M. D. (2015). Prion diseases. Continuum (Minneapolis, Minn.), 21(6 Neuroinfectious Disease),1612–1638.

  • 1.

    Rapid cognitive decline

  • 2.

    Two of the following six signs/symptoms:

    • a.

      Myoclonus

    • b.

      Pyramidal/extrapyramidal dysfunction

    • c.

      Visual dysfunction

    • d.

      Cerebellar dysfunction

    • e.

      Akinetic mutism

    • f.

      Focal cortical signs (e.g., neglect, aphasia, acalculia, apraxia)

  • 3.

    Typical electroencephalogram and/or magnetic resonance imaging (MRI)

    • a.

      MRI shows diffusion-weighted imaging brighter than fluid-attenuated inversion recovery hyperintensity in the cingulate, striatum, and/or greater than one neocortical gyrus, ideally with sparing of the precentral gyrus and apparent diffusion coefficient map supporting restricted diffusion.

  • 4.

    Other investigations should not suggest an alternative diagnosis.

Box 16.2
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition Criteria for Major or Mild Neurocognitive Disorder Caused by Prion Disease
From American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders (DSM-5) (5th ed.). Arlington, VA: American Psychiatric Publishing, Inc.

  • A.

    The criteria are met for major or mild neurocognitive disorder.

  • B.

    There is insidious onset, and rapid progression of impairment is common.

  • C.

    There are motor features of prion disease, such as myoclonus or ataxia, or biomarker evidence.

  • D.

    The neurocognitive disorder is not attributable to another medical condition and is not better explained by another mental disorder.

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