What are the causes of rapidly progressive dementia?

Causes of Rapidly Progressive Dementia

Rapidly progressive dementia (RPD) developing over weeks to months requires urgent evaluation to identify potentially reversible causes before considering neurodegenerative etiologies, with infections, autoimmune encephalopathies, and prion diseases representing the most critical diagnostic considerations. 1

Immediate Priority: Exclude Reversible Causes

The most critical first step is excluding acute conditions that can mimic RPD:

Delirium and Acute Medical Conditions

• Infections are the most common reversible cause, particularly urinary tract infections, pneumonia, and sepsis in elderly patients 2
• Metabolic derangements including hypoglycemia, hyperglycemia, hyponatremia, hypercalcemia, and hepatic or renal failure must be ruled out immediately 2
• Medication toxicity or interactions, especially anticholinergic agents, benzodiazepines, and opioids, frequently cause acute cognitive decline 2
• Delirium requires urgent or emergent evaluation and management in all settings 1

Acute Cerebrovascular Events

• Stroke (ischemic or hemorrhagic) involving strategic areas such as thalamus, hippocampus, or frontal lobes can present as sudden cognitive decline 2
• Multiple lacunar infarcts or extensive white matter disease may manifest as RPD 2

Structural Brain Lesions

• Subdural hematoma, particularly with recent head trauma history, is a critical reversible cause 2
• Brain tumors or metastases can present with rapid cognitive deterioration 2

Primary RPD Etiologies (After Excluding Acute Causes)

Autoimmune and Immune-Mediated Encephalopathies

• Autoimmune encephalitides represent 18% of RPD cases and are potentially treatable, making early recognition essential 3
• These conditions often present with prominent psychiatric symptoms, seizures, or movement disorders alongside cognitive decline 4, 5
• High-dose steroid therapy may be both diagnostic and therapeutic in clinically ambiguous cases 5

Infectious Causes

• Infections account for approximately 39% of RPD cases in some series, making them the leading identifiable cause 3
• Specific infectious etiologies include:
  • Subacute sclerosing panencephalitis (SSPE) - 41% of infectious RPD cases 3
  • Neurosyphilis - 17.9% of infectious cases 3
  • Progressive multifocal leukoencephalopathy (PML) - 15.3% of infectious cases 3
  • HIV-associated dementia 4, 5

Prion Diseases

• Creutzfeldt-Jakob disease (CJD) is the prototypical RPD, with median survival of approximately 5 months from symptom onset 1, 2
• Sporadic CJD typically affects individuals aged 55-75 years, while variant CJD affects younger patients 6
• RT-QuIC testing in cerebrospinal fluid has become the gold standard diagnostic test, with high sensitivity and specificity 1
• CSF 14-3-3 protein (>20,000 AU/mL) and elevated tau protein (>1,300 pg/mL) support the diagnosis 1
• MRI showing restricted diffusion in cortical regions and/or basal ganglia is highly characteristic 1

Atypical Neurodegenerative Presentations

• Rapidly progressive Alzheimer's disease can occur in 20-43% of patients with mild to moderate dementia 2
• Atypical presentations of other neurodegenerative diseases (frontotemporal dementia, Lewy body dementia) may progress rapidly 1, 4
• These patients often have substantially different care needs than typical presentations 1

Neoplastic Causes

• Primary CNS lymphoma, paraneoplastic syndromes, and metastatic disease can present as RPD 3, 7
• Neoplastic disorders tend to present earlier (<6 months from onset) compared to neurodegenerative causes 3

Vascular Causes

• Dural arteriovenous fistulas have been increasingly recognized as RPD causes 7
• Cerebral vasculitis (primary or secondary) can manifest as rapid cognitive decline 4, 5

Diagnostic Approach Algorithm

Clinical Evaluation

• Obtain detailed history focusing on exact timeline of decline onset - sudden decline over days is atypical for primary neurodegenerative disease and mandates searching for acute causes 2
• Document new medications, head trauma, infectious symptoms, and vascular risk factors 2
• Assess for atypical features including prominent language abnormalities, apraxia, sensory/motor dysfunction, mood/behavioral disturbances, or fluctuating course 1

Laboratory Testing

• Complete blood count, comprehensive metabolic panel, liver and kidney function, thyroid hormones, vitamin B12, and urinalysis 2, 8
• Lumbar puncture for CSF analysis including cell count, protein, glucose, 14-3-3 protein, tau protein, and RT-QuIC when prion disease is suspected 1
• Consider autoimmune encephalitis antibody panels, paraneoplastic antibodies, and infectious serologies based on clinical presentation 4, 5

Neuroimaging

• MRI is strongly preferred over CT for detecting vascular changes, structural lesions, and patterns characteristic of specific RPD etiologies 2, 8
• Essential sequences include FLAIR, diffusion-weighted imaging (DWI), and T1-weighted images with contrast 1

Electroencephalography

• EEG may show periodic sharp wave complexes (PSWCs) in CJD, though these are not always present, particularly in atypical subtypes 1
• Continuous focal epileptiform patterns may be seen in some cases 1

Specialist Referral Criteria

Patients with early-onset (<65 years), atypical presentations, or rapidly progressive symptoms should be referred expeditiously to a dementia subspecialist 1

Specific indications for urgent specialist referral include:

• Rapidly progressive course (weeks to months) 1
• Prominent language, social-behavioral, or sensory-motor abnormalities 1
• Young age of onset (<65 years) 1
• Uncertainty in diagnosis or atypical examination findings 1
• Suspected prion disease requiring complex evaluation 1

Critical Clinical Pitfalls to Avoid

• Never attribute acute cognitive decline to progression of existing dementia without excluding reversible causes - this is the most common and dangerous error 2
• Do not delay neuroimaging - structural lesions and vascular events require immediate identification 2
• Failing to perform lumbar puncture when prion disease or autoimmune encephalitis is suspected delays diagnosis 1, 5
• Overlooking medication review as a potential cause of rapid decline 2
• Not obtaining corroborative history from reliable informants, which is essential for accurate timeline assessment 8
• Delaying specialist referral when atypical features are present - delays in diagnosis cause substantial harm, especially in working-age patients with families 1