- Last edited on February 15, 2022
Rapidly Progressive Dementias (RPDs)
Primer
Rapidly Progressive Dementias (RPDs) are dementias that progress quickly – over the course of weeks to months. In some cases, it 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:
- Prion disease (e.g. - Creutzfeldt-Jakob Disease (CJD))
- Neurodegenerative diseases (e.g. - early onset Alzheimer's Disease (AD))
- Autoimmune
- Infectious
- Psychiatric
- Neoplastic
- Toxic-Metabolic
- Vascular
- 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 mnemonicVITAMINS can be used to remember the
V- VascularI- InfectiousT- Toxic-MetabolicA- AutoimmuneM- Metastasis/NeoplasticI- IatrogenicN- NeurodegenerativeS- Systemic/Seizures
Rapid vs. Early-Onset
- Although there can be some overlap between rapid and early-onset dementias, there are different diagnostic considerations. Not all early-onset dementias are rapid, and not all rapidly progressive dementias have an early-onset.[2]
Approach
See also:
Vascular
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 |
Infectious
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 necrosis | Lymphocytic pleocytosis, [RBC, HSV-1 PCR1 | EEG: focal abnormalities, PLEDs | IV acyclovir for 14–21 days (start early if suspected) |
| Cryptococcal meningitis | A/S | Any age, immunocompromised | Cognitive decline, subacute headache | Leptomeningeal enhancement on neuroimaging | Typical CSF features include a raised opening pressure (i.e. - elevated intracranial pressure), lymphocytic pleocytosis (increased white blood cells), and evidence of inflammation. |
Toxic-Metabolic
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 |
Autoimmune
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 | Subtle MTL hyper on FLAIR in 85%; MRI might be normal in 50% of cases. Individuals with LGI may have unilateral or bilateral hippocampal swelling with subtle hyperintensities on T2 and FLAIR sequences (a classic appearance).[3] | 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) |
- A basic rheumatologic screen may include, ESR, CRP, C3, C4, CH50, ANA, RF, anti-SSA, anti-SSB, P-ANCA, and C-ANCA, with other testing depending on results of this initial screen.
Metastasis/Neoplasia
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 |
Iatrogenic/Inborn Errors
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 |
Neurodegenerative
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 |
Systemic/Seizures
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 |
Investigations
- 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.[4]
- 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
Resources
References
1)
Paterson, R. W., Takada, L. T., & Geschwind, M. D. (2012). Diagnosis and treatment of rapidly progressive dementias. Neurology: Clinical Practice, 2(3), 187-200.
2)
Paterson, R. W., Takada, L. T., & Geschwind, M. D. (2012). Diagnosis and treatment of rapidly progressive dementias. Neurology. Clinical practice, 2(3), 187–200.