Rapidly Progressive Dementias (RPDs)

Rapidly Progressive Dementias (RPDs) are dementias that progress quickly – over the course of weeks to months (in rarer cases, may be over a period of 1-2 years).[1] Treatment of an RPD is dependent on the etiology of the dementia, some of which are fully treatable. This makes early recognition critical. Broadly, RPDs can be broken down into different etiologies:

  1. Prion disease (e.g. - Creutzfeldt-Jakob Disease (CJD))
  2. Neurodegenerative diseases (e.g. - early onset Alzheimer's Disease (AD))
  3. Autoimmune
  4. Infectious
  5. Psychiatric
  6. Neoplastic
  7. Toxic-Metabolic
  8. Vascular
  9. Leukoencephalopathies (e.g. - Multiple Sclerosis (MS), Progressive Multifocal Leukoencephalopathy)

Mnemonic

Evaluating for RPDs requires a detailed and systematic approach, and a mnemonic can be useful to do this. The mnemonic VITAMINS can be used to remember the

  • V - Vascular
  • I - Infectious
  • T - Toxic-Metabolic
  • A - Autoimmune
  • M - Metastasis/Neoplastic
  • I - Iatrogenic
  • N - Neurodegenerative
  • S - Systemic/Seizures

RPDs: Vascular

Adapted from Paterson, R. et al. (2012). Diagnosis and treatment of rapidly progressive dementias. Neurology: Clinical Practice, 2(3), 187-200.
Onset Demographics Clinical Features MRI CSF Other Tests Treatment
Multi-infarct vascular dementia A/S >50 years, risk factors for vascular disease Stepwise cognitive decline, with localizing motor, visual, or sensory signs Multiple regions of T2/FLAIR hyper in vascular territories Nondiagnostic - Secondary prophylaxis, treatment of risk factors, AChI
Strategic infarct dementia A >50 years, risk factors for vascular disease Sudden onset of cognitive impairment, memory loss Hippocampal, thalamic, angular gyrus, PCA/ACA territory infarct(s) Nondiagnostic - Secondary prophylaxis, treatment of risk factors, IV high- dose corticosteroids
Inflammatory CAA S >40 years, M = F Subacute cognitive decline, headache, seizures Microbleeds on T2, large/ confluent hyper T2 lesions (hypo on T1) - Homozygous APOE e4 genotype; biopsy for confirmation -
Primary CNS angiitis A Peaks at ~50 years, M = F Cognitive decline, multifocal neurologic symptoms Multiple grey or white matter T2-hyper Might show pleocytosis or elevated protein CNS angiogram or brain and meningeal biopsy IV high-dose corticosteroids; immunosuppression
Cerebral venous sinus thrombosis (CVST) A/S Adults, F > M, pregnancy, hypercoagulable states Cognitive decline, confusion, focal neurologic signs, headache Venous clot; T2-hyper in adjacent GM and WM; possible restricted diffusion or hemorrhage Normal MRV, hypercoagulable tests Anticoagulation

RPDs: Infectious

Adapted from Paterson, R. et al. (2012). Diagnosis and treatment of rapidly progressive dementias. Neurology: Clinical Practice, 2(3), 187-200.
Onset Demographics Clinical Features MRI CSF Other Tests Treatment
Neurosyphilis S Consider risk factors Cognitive decline, psychosis, depression, pupillary abnormalities Nonspecific atrophy, may be normal CSF VDRL Serum EIA/RPR Crystalline IV penicillin G for 10–14 dayse3
Whipple disease S Adults; rare in older adults Dementia, psychiatric symptoms, movement disorder, ophthalmoplegia, myoclonus, GI disturbance Normal vs FLAIR hyper in MTL, midbrain, diencephalon (+/- CE) Tropheryma whippelii PCR Jejunal biopsy (PAS + staining or PCR) Ceftriaxone 2 g/d x 2 weeks, then co- trimoxazole (>1 year)
Lyme disease S Any age; prevalence variable in different regions Dementia, cranial neuropathy, meningitis, psychosis, polyradiculopathy; neurologic manifestations are late Normal in most cases Lymphocytic pleocytosis; intrathecal production of Abs Serology Ceftriaxone 2 g/d x 14 days
HIV dementia A/S Seroconversion, older HIV-positive adults, low CD4 Psychomotor slowing, executive dysfunction, depression, movement disorders Cortical atrophy; nonspecific white matter changes Increased protein, mild pleocytosis HIV serology; serum and CSF viral loads CNS penetrating HAART
Herpetic meningoencephalitis A Any age Altered level of consciousness, focal deficits, seizures, behavioral changes; fever Medial temporal lobe hyper on FLAIR, asymmetric; later hemorrhagic necrosie6 Lymphocytic pleocytosis, [RBC, HSV-1 PCR1 EEG: focal abnormalities, PLEDs IV acyclovir for 14–21 days (start early if suspected)

RPDs: Toxic-Metabolic

Adapted from Paterson, R. et al. (2012). Diagnosis and treatment of rapidly progressive dementias. Neurology: Clinical Practice, 2(3), 187-200.
Onset Demographics Clinical Features MRI CSF Other Tests Treatment
Wernicke-Korsakoff Syndrome A Risk factors: alcoholism, malnutrition Cognitive impairment, eye movement abnormalities, ataxia T2 hyper in medial thalamus and mammillary bodiese7 Nondiagnostic - Thiamine
Extrapontine myelinolysis A Rapid correction of electrolyte disturbance (e.g., hyponatremia) May take few days to develop symptoms; encephalopathy, movement disorders, para/quadriparesis Hyper T2 lesions (CE) in pons, cerebellum, basal ganglia, thalamus; may take days to appeare8 Nondiagnostic - Symptomatic
Vitamin B12 deficiency S Older adults, pernicious anemia, veganism, fad diets Cognitive impairment (infrequent, but treatable), sensory ataxia, paresthesias Nondiagnostic Nondiagnostic Vitamin B12, MMA, homocysteine Vitamin B12
Acquired hepatocerebral degeneration, hepatic encephalopathy S Cirrhosis (portosystemic shunting) Apathy, inattention, parkinsonism, cranial dyskinesia Pallidal T1 hyper, T2 normal Nondiagnostic Ammonia level Treatment of liver disease, but might be irreversible; liver transplant
Acute intermittent porphyria A/S 20s–30s; F > M Abdominal pain, autonomic dysfunction, behavioral changes, altered consciousness Normal Nondiagnostic Elevated PBG/ALA in urine Carbohydrates, intravenous haem arginate; avoid certain medications and metabolic disturbances

RPDs: Autoimmune

Adapted from Paterson, R. et al. (2012). Diagnosis and treatment of rapidly progressive dementias. Neurology: Clinical Practice, 2(3), 187-200.
Onset Demographics Clinical Features MRI CSF Other Tests Treatment
anti-NMDAR encephalitis A/S Median 19 years, F > M Flu-like prodrome, prominent psychiatric features (psychosis), hyperkinesias, autonomic instability Normal in 45%. T2 hyper in cerebral/ cerebellar cortex with meningeal CE Lymphocytic pleocytosis, OCB frequent Screening for tumor (mostly ovarian teratoma) See main article
Encephalopathy with VGKC antibodies (LGI1 antigen) S Median 60 years Limbic encephalitis, hyponatremia, seizures, myoclonus, ataxia, unilateral brachial-facial spasms MTL hyper on FLAIR in 85%; might be normal Normal/elevated protein, OCB infrequent <20% with tumors (SCLC, thymoma) EEG slowing See main article
Paraneoplastic Encephalitis and Syndromes S Any age (depends on antibody) Neuropsychiatric symptoms (anxiety, hallucinations), seizures, cognitive decline, headache, tremor, subacute onset, fluctuating course MTL hyper on T2/ FLAIR; might be normal Lymphocytic pleocytosis, normal/elevated protein +/- OCB Most frequent Abs: anti-CV2/CRMP5, Hu, Ma2 (10% seronegative) EEG slowing See main article
Acute demyelinating encephalomyelitis A More frequent in children Flu-like prodrome, post vaccination/viral infection; encephalopathy with multifocal neurologic signs Multifocal T2/FLAIR hyper, sometimes with CE Mild pleocytosis, protein <100 mg/ dL - IV corticosteroids (or PE, immunoglobulin)

RPDs: Metastasis/Neoplasia

Adapted from Paterson, R. et al. (2012). Diagnosis and treatment of rapidly progressive dementias. Neurology: Clinical Practice, 2(3), 187-200.
Onset Demographics Clinical Features MRI CSF Other Tests Treatment
Primary CNS lymphoma S Most 50–70 years Neuropsychiatric symptoms, focal neurologic deficits, seizures Focal hypo or hyper T2 lesions with CE; seldom DWI hyper Lymphocytic pleocytosis; flow cytometry for lymphoma cells High LDH, ESR; biopsy Specific lymphoma treatment
Gliomatosis cerebri S Older adults AMS, dementia, seizures, headache, focal deficits T2/FLAIR hyper in 2+ lobes; +/- mass effect; +/- CE - Brain biopsy Radiation +/- chemotherapy

RPDs: Iatrogenic/Inborn Errors

Adapted from Paterson, R. et al. (2012). Diagnosis and treatment of rapidly progressive dementias. Neurology: Clinical Practice, 2(3), 187-200.
Onset Demographics Clinical Features MRI CSF Other Tests Treatment
Medications A/S Older adults Attention to temporal relationship between initiating drug use and cognitive symptoms Nondiagnostic Nondiagnostic Nondiagnostic Discontinuation

Although most of the common neurodegenerative disorders do not present as rapidly progressive, they can present with this phenotype in certain cases.

RPDs: Neurodegenerative

Adapted from Paterson, R. et al. (2012). Diagnosis and treatment of rapidly progressive dementias. Neurology: Clinical Practice, 2(3), 187-200.
Onset Demographics Clinical Features MRI CSF Other Tests Treatment
Creutzfeldt-Jakob Disease (CJD) S Mostly 50–70 years; M = F Subacute cognitive decline with behavioral, pyramidal, extrapyramidal, cerebellar, myoclonus, or visual symptoms Cortical or subcortical hyper on DWI Increased Total-tau, increased 14- 3-3, and increased NSE EEG: slowing; PSWCs See main article
Alzheimer's Disease (AD) S 60 years Early short-term memory impairment Hippocampal atrophy, later spreading to temporal, parietal, and frontal regions Decreased Aβ42, increased phospho-tau, increased total tau PET with amyloid ligand See main article
Lewy Body Dementia (LBD) S >50 years Cognitive dysfunction, parkinsonism, visual hallucinations, behavioral changes, fluctuations Normal or non- specific atrophy Nondiagnostic FDG-PET: occipital hypo See main article
Frontotemporal Dementia (FTD) S 40–70 years Behavioral changes (apathy, disinhibition, loss of empathy/sympathy, repetitive behaviors), executive dysfunction Frontal or temporal atrophy Nondiagnostic FDG-PET: frontal/ temporal hypo See main article
Corticobasal Syndrome (CBS) S 50-70 years Cognitive dysfunction, asymmetric motor abnormalities, or aphasia Asymmetric atrophy, parietal or frontal In AD etiology, decreased Aβ42, increased phospho-tau, increased total tau - See main article

RPDs: Systemic/Seizures

Adapted from Paterson, R. et al. (2012). Diagnosis and treatment of rapidly progressive dementias. Neurology: Clinical Practice, 2(3), 187-200.
Onset Demographics Clinical Features MRI CSF Other Tests Treatment
Hypertensive encephalopathy A Uncontrolled hypertension, eclampsia, chemotherapy Headaches, confusion, visual changes, seizures, coma FLAIR hyper in occipitoparietal WM Nondiagnostic - Treatment of hypertension
Seizures A Older adults Cognitive dysfunction, fluctuations in alertness DWI hyper in cortical or subcortical GM Might have mild pleocytosis EEG AEDs
  • Bloodwork
    • CBC
    • Electrolytes, extended electrolytes
    • Liver function tests (including ammonia)
    • Renal function
    • Thyroid function
    • Anti-Tg (anti-thyroglobulin) and Anti-TPO (anti-thyroperoxidase) antibodies
    • Vitamin B12, MMA, homocysteine
    • Rheumatology screen (ESR, CRP, ANA (antinuclear antibody), RF (rheumatoid factor), C-ANCA (anti-neutrophil cytoplasmic antibody), P-ANCA, SSA, SSB)
    • Rapid plasma reagin (RPR)
    • HIV serology
    • Paraneoplastic/autoimmune antibodies
  • CSF
    • Cell count and differential
    • Protein
    • Glucose
    • IgG index
    • Oligoclonal bands
    • VDRL
    • 14-3-3/NSE (neuron-specific enolase)/total tau
  • Neuroimaging
    • Brain MRI (FLAIR, DWI, ADC sequences) +/- contrast
    • SPECT (to examine areas of hypoperfusion)
  • Other
    • Urinalysis
    • EEG

In Select Cases...

  • Other Bloodwork Considerations
    • Lyme disease (in endemic regions)
    • Cancer screening
    • Blood smear
    • Coagulation profile
    • Hypercoagulability testing
    • Copper, ceruloplasmin
    • Heavy metals screening (arsenic, lead, mercury, copper, aluminum and bismuth), in those with a history of exposure, or in those using herbal supplements.[2]
    • Additional rheumatological screen (complement, dsDNA, anti-Sm, anti-RNP, anticardiolipin, anti-SCL 70, anti-Jo, anti-centromere antibodies)
  • CSF
    • Bacterial, fungal, acid-fast bacilli stains and cultures
    • Cytology
    • Flow cytometry
    • Whipple PCR
    • Cryptococcal antigen
    • Viral PCRs and cultures
  • Imaging
    • Cancer screen (CT chest abdo pelvis +/- contrast)
    • MRI angiography or brain angiogram
    • MR spectroscopy
    • Carotid ultrasound
    • Echocardiogram
  • Urine
    • Heavy metal screen
    • Copper (24 hour urine)
    • Porphobilinogen (PGB)/delta-aminolevulinic acid (ALA)
    • EMG/nerve conduction study
    • Brain biopsy