Rapidly progressing dementias

Dementias which progress from normal cognition to severe dementia in less than 2 years (unofficial definition) (Salardini 2019).

• In addition to cognitive decline, they often have behavioral problems, pyramidal or extrapyramidal symptoms, EEG changes, and myoclonus.

Categories (Salardini 2019)

1. Prion disease – misfolded prions are infectious proteins which cause devastating neurodegenerative illness
   1. Creutzfeldt-Jakob disease (CJD)
      1. Most common form of prion disease
      2. Presents with cognitive symptoms, pyramidal / extrapyramidal motor symptoms, ataxia, myoclonus, and psychiatric symptoms
   2. Fatal familial insomnia (FFI)
      1. Presents with insomnia, dysautonomia, cognitive problems
   3. Gerstmann-Straussler-Schinker syndrome (GSS)
      1. Cerebellar and/or extrapyramidal symptoms
      2. Slow progression over 10-20 years
   4. Kuru
   5. Variant CJD
      1. Caused by eating contaminated meat of livestock with bovine spongiform encephalopathy
2. Atypical presentation of other primary dementias
3. Autoimmune diseases including autoimmune encephalitis
4. Secondary encephalopathies (toxic metabolic encephalopathy)

Diagnostic approach (Geschwind, 2016)

• Initial evaluation
  • establish time course, highlight initial symptoms, r/o delirium
    • autoimmune encephalopathies often affect limbic areas and may present with memory and/or behavioral symptoms
    • viral encephalopathies or acute demyelinating encephalomyelitis may present after flu-like illness
  • screening tests
    • blood studies: CBC, BMP, LFTs, RPR, rheum screen (ESR, ANA, CRP), B12, HIV, medication levels
    • urine studies: u/a, utox (if indicated)
    • Imaging: (typically done prior to CSF, as it can help direct what CSF studies to order) brain MRI (w/ and w/o contrast - T1, T2, FLAIR, DWI, SWI), CXR if indicated
    • CSF: cell count/differential, protein, glucose, IgG index, oligoclonal bands, VDRL, 14-3-3 protein western blot, Total tau ELISA, neuron specific enolase ELISA, RT-QuIC, cryptococcal antigen, viral PCRs/antibodies/cultures, bacterial/fungal/acid-fast bacilli stains/cultures, cytology, flow cytometry
      • note: 14-3-3, t-tau, and neuron-specific enolase are not necessarily diagnostic tests for prion diseases but are general markers of rapid neuronal injury. If prion disease is in the differential, RT-QuIC should be included. If Alzheimer disease is in differential, send for p-tau and amyloid beta 42.
    • EEG
• Secondary tier depending on initial screen
  • undiagnosed rapidly progressive dementia after initial screen should consider whole body CT scan (w/ and w/o contrast) for malignancy, sarcoid, or other. If whole body CT is not feasible, can start with CXR
  • if paraneoplastic antibodies are present, consider aggressive cancer workup w/ FDG-PET/CT or ultrasounds depending on antibody
  • depending on initial screen and workup, additional tests may include:
    • blood studies: cancer screen (serum protein electrophoresis, serum immunoelectrophoresis, cancer antigen 125), blood smear, coagulation profile, hypercoagulability testing, homocysteine, MMA, additional rheumatological tests (cytoplasmic antineutrophil cytoplasmic antibody, perinuclear antineutrophil cytoplasmic antibody, DS DNA, smith antigen ribonucleoprotein, SCL-70, SSA/SSB, RA, C3, C4, CH50), antithyroglobulin/anti-TPO, Lyme, paraneoplastic/autoimmune ab, additional endocrinological tests (eg cortisol), lymphoma markers
    • urine studies: urine culture, heavy metal screen
    • CSF: Whipple PCR, metagenomic deep sequencing (CSF, biopsy tissue), p-tau, AB42, CSF B2-microglobulin and EBV PCR

Imaging

DWI images of 2 patients with suspected CJD (Salardini 2019)

• In axial view of patient A there is characteristic increased cortical signal (cortical ribboning) suggesting cortical cytotoxic edema
• In axial view of patient B there is characteristic increased signal in caudate and mesial thalamus (hockey stick)

References

Geschwind MD. Rapidly progressive dementia. Continuum. Apr:22(2 Dementia):510-537 (2016). https://pubmed.ncbi.nlm.nih.gov/27042906/

Salardini A. An Overview of Primary Dementias as Clinicopathological Entities. Semin. Neurol. 39, 153–166 (2019). https://pubmed.ncbi.nlm.nih.gov/30925609/