Rapidly Progressive Dementia

VERSION: 1.0 CREATED: January 27, 2026 STATUS: Approved

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DIAGNOSIS: Rapidly Progressive Dementia (RPD)

ICD-10: F03.90 (Unspecified dementia without behavioral disturbance), G31.9 (Degenerative disease of nervous system, unspecified), A81.00 (Creutzfeldt-Jakob disease, unspecified), G30.9 (Alzheimer's disease, unspecified), G31.09 (Other frontotemporal dementia)

CPT CODES: 85025 (CBC with differential), 80053 (CMP), 84443 (TSH), 82607 (B12), 82746 (Folate), 85652 (ESR), 86140 (CRP), 86592 (RPR or VDRL), 87389 (HIV 1/2 antigen/antibody), 81003 (Urinalysis), 82947 (Blood glucose), 86235 (ANA), 86334 (Serum protein electrophoresis (SPEP)), 84425 (Thiamine (B1) level), 82390 (Copper), 84630 (Zinc level), 82533 (Cortisol), 83655 (Heavy metals: lead), 83519 (14-3-3 protein (CSF)), 70553 (MRI brain with and without contrast), 95816 (EEG), 70450 (CT head without contrast), 72141 (MRI spine), 95700 (Continuous EEG (cEEG)), 78608 (FDG-PET brain), 78816 (PET-CT body), 89051 (Cell count with differential), 84157 (Protein), 82945 (Glucose with paired serum), 83916 (Oligoclonal bands), 96374 (Thiamine (B1) IV), 96365 (IV methylprednisolone)

SYNONYMS: Rapidly progressive dementia, RPD, rapidly progressive cognitive decline, subacute dementia, prion disease evaluation, CJD workup, Creutzfeldt-Jakob disease, rapid onset dementia, fast progressing dementia, subacute encephalopathy, prion disease, fast dementia

SCOPE: Urgent evaluation of cognitive decline progressing over weeks to months (typically <1-2 years from symptom onset to severe disability). Covers comprehensive workup to identify treatable causes including autoimmune encephalitis, infectious etiologies, toxic-metabolic causes, CNS malignancy, and prion disease (CJD). The key principle: assume a treatable cause exists until proven otherwise. Excludes typical slowly progressive dementias (Alzheimer's, FTD) unless presenting atypically fast, and acute delirium (<days).

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PRIORITY KEY: STAT = Immediate | URGENT = Within hours | ROUTINE = Standard | EXT = Extended/atypical cases | - = Not applicable to this setting

═══════════════════════════════════════════════════════════════ SECTION A: ACTION ITEMS ═══════════════════════════════════════════════════════════════

1. LABORATORY WORKUP

1A. Essential/Core Labs

Test	ED	HOSP	OPD	ICU	Rationale	Target Finding
CBC with differential (CPT 85025)	STAT	STAT	ROUTINE	STAT	Infection screen; hematologic malignancy; B12 deficiency (macrocytosis)	Normal
CMP (CPT 80053)	STAT	STAT	ROUTINE	STAT	Hepatic encephalopathy (ammonia); renal failure (uremia); electrolyte abnormalities (Na, Ca); hypo/hyperglycemia	Normal
TSH (CPT 84443), free T4 (CPT 84439)	URGENT	ROUTINE	ROUTINE	URGENT	Hypothyroid encephalopathy (Hashimoto encephalopathy); hyperthyroidism	Normal
B12 (CPT 82607), methylmalonic acid (MMA) (CPT 83921)	URGENT	ROUTINE	ROUTINE	URGENT	B12 deficiency — reversible cause of cognitive decline and myelopathy	B12 >300 pg/mL; MMA normal
Folate (CPT 82746)	-	ROUTINE	ROUTINE	-	Deficiency associated with cognitive impairment	Normal
ESR (CPT 85652)	URGENT	ROUTINE	ROUTINE	URGENT	Vasculitis screen; inflammatory conditions; infection; malignancy	Normal (<20 mm/h age-adjusted)
CRP (CPT 86140)	URGENT	ROUTINE	ROUTINE	URGENT	Inflammatory marker	Normal
RPR or VDRL (CPT 86592)	URGENT	ROUTINE	ROUTINE	URGENT	Neurosyphilis — treatable cause; "the great imitator"	Non-reactive
HIV 1/2 antigen/antibody (CPT 87389)	URGENT	ROUTINE	ROUTINE	URGENT	HIV-associated neurocognitive disorder (HAND); opportunistic infections	Negative
Ammonia	URGENT	ROUTINE	ROUTINE	URGENT	Hepatic encephalopathy	Normal (<35 µmol/L)
Urinalysis (CPT 81003) + urine culture	STAT	ROUTINE	ROUTINE	STAT	UTI causing delirium (especially elderly)	Negative
Urine drug screen	URGENT	ROUTINE	ROUTINE	URGENT	Substance-related cognitive impairment; prescription drug toxicity	Negative or expected medications only
Blood glucose (CPT 82947)	STAT	STAT	ROUTINE	STAT	Hypoglycemia; diabetic encephalopathy	Normal

1B. Extended Workup (Second-line)

Test	ED	HOSP	OPD	ICU	Rationale	Target Finding
Anti-thyroid antibodies (anti-TPO, anti-thyroglobulin)	-	ROUTINE	ROUTINE	-	Hashimoto encephalopathy (SREAT) — treatable with steroids even if euthyroid	Negative (positive + encephalopathy = consider SREAT)
ANA (CPT 86235)	-	ROUTINE	ROUTINE	-	Lupus cerebritis; systemic autoimmune disease	Negative
dsDNA antibodies	-	ROUTINE	ROUTINE	-	Lupus cerebritis (specific)	Negative
Complement levels (C3, C4)	-	ROUTINE	ROUTINE	-	Lupus; complement-mediated disease	Normal
ANCA (c-ANCA, p-ANCA)	-	ROUTINE	ROUTINE	-	CNS vasculitis (granulomatosis with polyangiitis, microscopic polyangiitis)	Negative
ACE level (serum)	-	ROUTINE	ROUTINE	-	Neurosarcoidosis	Normal
Serum protein electrophoresis (SPEP) (CPT 86334) + immunofixation	-	ROUTINE	ROUTINE	-	Multiple myeloma; POEMS; Waldenström; M-protein-associated neuropathy/encephalopathy	Normal pattern
LDH	-	ROUTINE	ROUTINE	-	Lymphoma; hemolysis; intravascular lymphoma	Normal
Peripheral blood smear	-	ROUTINE	-	-	Intravascular lymphoma (schistocytes); TTP (schistocytes + thrombocytopenia)	Normal
Thiamine (B1) level (CPT 84425)	-	ROUTINE	ROUTINE	-	Wernicke encephalopathy — reversible with treatment; alcoholism, malnutrition, bariatric surgery	Normal (>70 nmol/L)
Copper (CPT 82390) and ceruloplasmin (CPT 82390)	-	ROUTINE	ROUTINE	-	Wilson disease (young patients <50); acquired copper deficiency (zinc excess, gastric surgery)	Normal
Zinc level (CPT 84630)	-	ROUTINE	ROUTINE	-	Zinc excess causes copper deficiency → myeloneuropathy + cognitive decline	Normal
Cortisol (CPT 82533)	-	ROUTINE	ROUTINE	-	Adrenal insufficiency causing encephalopathy	Normal (>18 µg/dL AM)
Heavy metals: lead (CPT 83655), mercury (CPT 83825), arsenic (CPT 82175)	-	EXT	EXT	-	Occupational/environmental exposure	Normal
Paraneoplastic panel (serum) — comprehensive	-	ROUTINE	ROUTINE	-	ANNA-1 (Hu), ANNA-2 (Ri), CRMP-5 (CV2), amphiphysin, PCA-1 (Yo), PCA-2, PCA-Tr (DNER), GAD65	Negative
Autoimmune encephalitis panel (serum) — NMDAR, LGI1, CASPR2, GABA-B, GABA-A, AMPA, DPPX, IgLON5	-	ROUTINE	ROUTINE	-	Treatable autoimmune encephalitis — most important reversible cause to identify	Negative

1C. Rare/Specialized (Refractory or Atypical)

Test	ED	HOSP	OPD	ICU	Rationale	Target Finding
14-3-3 protein (CSF) (CPT 83519)	-	ROUTINE	ROUTINE	-	CJD biomarker; elevated in rapid neuronal destruction. Sensitivity ~90% but NOT specific (also elevated in stroke, encephalitis, seizures)	Negative (positive supports CJD in right clinical context)
RT-QuIC (CPT 86235) — CSF	-	ROUTINE	ROUTINE	-	MOST SPECIFIC test for prion disease; sensitivity 92%, specificity 99-100%. Gold standard CSF prion test	Negative (positive = prion disease essentially confirmed)
Tau protein (CSF — total tau) (CPT 83519)	-	ROUTINE	ROUTINE	-	Markedly elevated in CJD (>1150 pg/mL); also elevated in AD but less extreme	Normal (<400 pg/mL; CJD often >10,000)
Neuron-specific enolase (NSE) — CSF	-	ROUTINE	-	-	Elevated in CJD (>35 ng/mL); marker of neuronal damage	Normal
AD biomarkers (CSF Aβ42, p-tau, t-tau) (CPT 83519)	-	ROUTINE	ROUTINE	-	Rapidly progressive Alzheimer disease (rpAD) is the most common misdiagnosis of CJD; AD biomarker pattern distinguishes	Aβ42/Aβ40 ratio normal; p-tau/t-tau ratio helps distinguish
Neurofilament light chain (NfL) (CPT 83519) — CSF or serum	-	ROUTINE	ROUTINE	-	Non-specific marker of neuronal damage; markedly elevated in CJD, moderately in many RPDs	Baseline for comparison
Whipple disease PCR (CSF and duodenal biopsy)	-	EXT	EXT	-	Tropheryma whipplei — rare but treatable cause of RPD with oculomasticatory myorhythmia; GI symptoms, arthralgia	Negative
PRNG gene analysis (blood)	-	EXT	EXT	-	Genetic prion disease (familial CJD, fatal familial insomnia, GSS); family history of early dementia or movement disorder	No mutation
QuantiFERON-TB Gold / PPD	-	ROUTINE	ROUTINE	-	TB meningitis with cognitive decline	Negative
Bartonella serology	-	EXT	EXT	-	Cat-scratch disease encephalitis	Negative
Brucella serology	-	EXT	EXT	-	Neurobrucellosis (occupational exposure)	Negative
Lyme antibody (ELISA, Western blot)	-	ROUTINE	ROUTINE	-	Lyme encephalopathy (endemic areas)	Negative
Celiac antibodies (tTG IgA, deamidated gliadin)	-	ROUTINE	ROUTINE	-	Gluten ataxia / celiac encephalopathy	Negative

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2. DIAGNOSTIC IMAGING & STUDIES

2A. Essential/First-line

Study	ED	HOSP	OPD	ICU	Timing	Target Finding	Contraindications
MRI brain with and without contrast (CPT 70553) + DWI	STAT	STAT	ROUTINE	STAT	Within 24h. DWI is CRITICAL — cortical ribboning on DWI is highly suggestive of CJD	CJD: cortical ribboning (DWI/FLAIR high signal in cortex), caudate/putamen signal. Autoimmune: mesial temporal T2/FLAIR. Vasculitis: multifocal white matter lesions. Lymphoma: enhancing mass. Wernicke: mamillary body/thalamic signal. MS: periventricular/juxtacortical lesions	Pacemaker, metallic implants
EEG (CPT 95816)	URGENT	URGENT	ROUTINE	URGENT	Within 24h	CJD: periodic sharp wave complexes (PSWCs) at 1-2 Hz — sensitivity ~65% (higher in sCJD-MM1). Seizures: electrographic activity. NCSE: subclinical seizures. Autoimmune: extreme delta brush (NMDAR)	None significant
CT head without contrast (CPT 70450)	STAT	STAT	-	STAT	Immediate if acute presentation or focal deficit	Mass lesion, hydrocephalus, hemorrhage, large infarct	Pregnancy (relative)

2B. Extended

Study	ED	HOSP	OPD	ICU	Timing	Target Finding	Contraindications
MRA/MRV brain	-	ROUTINE	ROUTINE	-	If vasculitis or venous thrombosis suspected	CNS vasculitis (beading); dural sinus thrombosis	Same as MRI
MRI spine (CPT 72141)	-	ROUTINE	ROUTINE	-	If concurrent myelopathy (B12 deficiency, copper deficiency, neurosarcoidosis)	Cord signal change (posterior columns in B12/copper); sarcoid enhancement	Same as MRI
Continuous EEG (cEEG) (CPT 95700)	-	URGENT	-	STAT	If altered consciousness; suspected NCSE	Non-convulsive seizures; subclinical status	None
FDG-PET brain (CPT 78608)	-	EXT	ROUTINE	-	Differentiate neurodegenerative patterns; detect occult malignancy; autoimmune encephalitis (mesial temporal hypermetabolism)	AD: temporoparietal hypometabolism. FTD: frontal/temporal. CJD: cortical/striatal. Lymphoma: hypermetabolic mass. Autoimmune: mesial temporal hypermetabolism	Pregnancy; uncontrolled diabetes
PET-CT body (CPT 78816)	-	EXT	ROUTINE	-	Occult malignancy search (paraneoplastic); lymphoma staging	Primary tumor identification	Same as FDG-PET
CT chest/abdomen/pelvis with contrast	-	ROUTINE	ROUTINE	-	Cancer screening (paraneoplastic); sarcoidosis (hilar adenopathy)	Mass, lymphadenopathy	Contrast allergy, renal impairment
Conventional cerebral angiography (DSA)	-	EXT	EXT	-	If CNS vasculitis suspected (MRA normal does not exclude small-vessel vasculitis)	Beading (alternating stenosis/dilation)	Contrast allergy, coagulopathy
Testicular ultrasound (males)	-	ROUTINE	-	-	Testicular germ cell tumor (paraneoplastic; anti-NMDAR in males)	Normal	None
Pelvic ultrasound/MRI (females)	-	ROUTINE	ROUTINE	-	Ovarian teratoma (anti-NMDAR encephalitis — present in 50% of young women)	Normal	None

2C. Rare/Specialized

Study	ED	HOSP	OPD	ICU	Timing	Target Finding	Contraindications
Brain biopsy	-	-	EXT	-	Last resort when all non-invasive testing inconclusive; suspected CNS vasculitis, intravascular lymphoma, or prion disease where RT-QuIC unavailable	Vasculitis (vessel wall inflammation); lymphoma (atypical cells); prion disease (spongiform change, PrP immunostaining)	Surgical risk; coagulopathy
Meningeal biopsy	-	-	EXT	-	Chronic meningitis of unknown etiology	Granulomas (sarcoid, TB); malignancy	Same as brain biopsy
Bone marrow biopsy	-	EXT	EXT	-	If intravascular lymphoma, hemophagocytic lymphohistiocytosis (HLH), or hematologic malignancy suspected	Abnormal cells; hemophagocytosis	Coagulopathy
Upper endoscopy with duodenal biopsy	-	EXT	EXT	-	Whipple disease (PAS-positive macrophages)	Normal (PAS-negative)	Standard GI endoscopy risks
Sleep polysomnography	-	-	EXT	-	Fatal familial insomnia (FFI) — complete loss of sleep architecture	Absent sleep spindles; disrupted sleep architecture	Cooperation

LUMBAR PUNCTURE

Indication: Essential in ALL RPD evaluations. Multiple studies needed — collect adequate volume.

Timing: URGENT. Perform early in workup.

Volume Required: 20-30 mL (many specialized tests required; save extra frozen)

Study	ED	HOSP	OPD	Rationale	Target Finding
Opening pressure	URGENT	ROUTINE	ROUTINE	Elevated ICP in mass, hydrocephalus, venous thrombosis	Normal (10-20 cm H2O)
Cell count with differential (CPT 89051)	URGENT	ROUTINE	ROUTINE	Pleocytosis suggests infection, autoimmune, or lymphoma; normal in CJD	Normal in CJD; elevated in autoimmune/infectious
Protein (CPT 84157)	URGENT	ROUTINE	ROUTINE	Elevated in infection, inflammation, malignancy; mildly elevated or normal in CJD	Normal or mildly elevated in CJD; elevated in infection/autoimmune
Glucose with paired serum (CPT 82945)	URGENT	ROUTINE	ROUTINE	Low in bacterial/TB/fungal meningitis, carcinomatous meningitis	Normal in CJD, autoimmune; low in infectious/malignant
Gram stain and culture	URGENT	ROUTINE	ROUTINE	Exclude chronic bacterial infection	No organisms
RT-QuIC (CPT 86235)	-	ROUTINE	ROUTINE	Most sensitive and specific CSF test for prion disease (sensitivity 92%, specificity 99-100%)	Negative
14-3-3 protein (CPT 83519)	-	ROUTINE	ROUTINE	CJD biomarker; rapid neuronal destruction marker	Negative
Total tau protein (CPT 83519)	-	ROUTINE	ROUTINE	Markedly elevated in CJD (>1150 pg/mL); moderately elevated in AD	Normal (<400 pg/mL)
NSE (neuron-specific enolase)	-	ROUTINE	ROUTINE	CJD biomarker	Normal
Autoimmune encephalitis panel (CSF) — NMDAR, LGI1, CASPR2, GABA-B, GABA-A, AMPA, DPPX	-	ROUTINE	ROUTINE	CSF more sensitive than serum for NMDAR antibodies; identifies treatable autoimmune etiology	Negative
Paraneoplastic antibodies (CSF)	-	ROUTINE	ROUTINE	More sensitive than serum for some antibodies	Negative
Oligoclonal bands (CPT 83916), IgG index	-	ROUTINE	ROUTINE	Intrathecal antibody synthesis (MS, autoimmune, neurosarcoidosis)	Negative
Cytology (send 10 mL minimum; repeat x3 for sensitivity)	-	ROUTINE	ROUTINE	Leptomeningeal carcinomatosis/lymphoma; sensitivity improves with volume and repeat	Negative
Flow cytometry	-	ROUTINE	ROUTINE	CNS lymphoma (B-cell clonality)	Normal
HSV 1/2 PCR	-	ROUTINE	ROUTINE	HSV encephalitis; post-HSV autoimmune encephalitis	Negative
VZV PCR	-	ROUTINE	ROUTINE	VZV vasculopathy / encephalitis	Negative
EBV PCR	-	ROUTINE	ROUTINE	CNS lymphoma (EBV-driven)	Negative
JC virus PCR	-	ROUTINE	ROUTINE	PML (immunocompromised)	Negative
VDRL (CSF)	-	ROUTINE	ROUTINE	Neurosyphilis	Non-reactive
Cryptococcal antigen	-	ROUTINE	ROUTINE	Cryptococcal meningitis (immunocompromised)	Negative
AFB smear and culture	-	ROUTINE	ROUTINE	TB meningitis	Negative
ACE level (CSF)	-	ROUTINE	ROUTINE	Neurosarcoidosis	Normal
Whipple PCR (T. whipplei)	-	EXT	EXT	Whipple disease	Negative
Beta-2 microglobulin (CSF)	-	ROUTINE	-	CNS lymphoma marker	Normal
Alzheimer biomarkers (Aβ42, Aβ40, p-tau 181, t-tau) (CPT 83519)	-	ROUTINE	ROUTINE	rpAD pattern: low Aβ42, elevated p-tau; helps distinguish from CJD (where p-tau is NOT as elevated relative to t-tau)	Context-dependent
Neurofilament light chain (NfL) (CPT 83519) — CSF	-	ROUTINE	ROUTINE	Non-specific neuronal damage; very elevated in CJD	Baseline

Save 5-10 mL of CSF frozen at -80°C for future studies.

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3. TREATMENT

3A. Empiric / Treatable Causes — TREAT WHILE AWAITING RESULTS

Treatment	Route	Indication	Dosing	Contraindications	Monitoring	ED	HOSP	OPD	ICU
Thiamine (B1) IV (CPT 96374)	IV	Empiric for Wernicke encephalopathy if ANY suspicion (alcohol, malnutrition, bariatric surgery); treat before glucose	500 mg :: IV :: TID :: 500 mg IV TID x 3-5 days, then 250 mg IV daily x 3-5 days, then 100 mg PO daily ongoing	None significant	Clinical response (confusion, ataxia, ophthalmoplegia should improve)	STAT	STAT	-	STAT
IV methylprednisolone (CPT 96365)	IV	Suspected autoimmune encephalitis, Hashimoto encephalopathy (SREAT), neurosarcoidosis, CNS vasculitis	1000 mg :: IV :: daily :: 1000 mg IV daily x 3-5 days. Consider when autoimmune etiology suspected and workup pending. Document pre-treatment baseline exam.	Active infection (rule out first); uncertain prion disease (steroids do not help CJD and may mask diagnosis)	Glucose q6h; BP; GI prophylaxis; response assessment	-	URGENT	-	URGENT
IVIG (empiric immunotherapy trial)	-	Suspected autoimmune encephalitis; concurrent with steroid trial	0.4 g/kg :: - :: daily x 5 days :: 0.4 g/kg/day x 5 days (total 2 g/kg). Add to steroids or as alternative if steroid-intolerant	IgA deficiency; renal failure; thrombotic risk	Renal function; headache; thrombotic events	-	URGENT	-	URGENT
Acyclovir IV (CPT 96365)	IV	Empiric while awaiting HSV PCR; fever + encephalopathy	10 mg/kg :: IV :: q8h :: 10 mg/kg IV q8h. Continue until HSV PCR confirmed negative	Renal impairment (dose adjust)	Cr daily; hydration	STAT	STAT	-	STAT

3B. Targeted Treatments (Once Diagnosis Established)

Treatment	Route	Indication	Dosing	Contraindications	Monitoring	ED	HOSP	OPD	ICU
IV methylprednisolone (CPT 96365) → oral prednisone taper	IV	-	1g :: IV :: - :: 1g IV x 5d → prednisone 1 mg/kg/day with slow taper over 3-6 months	-	Glucose, BP, bone density, weight, mood	-	-	-	-
IVIG	PO	-	0.4 g/kg :: PO :: monthly :: 0.4 g/kg/day x 5 days; repeat monthly for maintenance	-	Renal function; IgG levels	-	-	-	-
Rituximab (CPT 96365)	IV	-	375 mg/m2 :: IV :: - :: 375 mg/m2 IV weekly x 4 weeks OR 1000 mg IV x 2 doses (2 weeks apart)	-	CD19/20 counts; immunoglobulins; infection risk; PML risk	-	-	-	-
Cyclophosphamide (CPT 96365)	IV	-	750-1000 mg/m2 :: IV :: monthly :: 750-1000 mg/m2 IV monthly x 6 months (pulse) OR oral 1-2 mg/kg/day	-	CBC (nadir at 10-14 days); urinalysis (hemorrhagic cystitis — give MESNA); fertility preservation discussion	-	-	-	-
Penicillin G IV (CPT 96365)	IV	-	18-24 million units :: IV :: q4h :: 18-24 million units/day IV (3-4 MU q4h) x 14 days	-	RPR titer follow-up q3-6 months (4-fold decline expected)	-	-	-	-
Tumor-directed therapy	-	-	N/A :: - :: per protocol :: Per oncology	-	Clinical response; antibody titers	-	-	-	-
Teratoma resection	-	-	N/A :: - :: once :: Surgical removal	-	Repeat imaging; antibody titers	-	-	-	-
B12 replacement	IM	-	N/A :: IM :: daily :: Cyanocobalamin 1000 µg IM daily x 7 days, then weekly x 4, then monthly long-term	-	B12 and MMA levels at 3 months	-	-	-	-
Antifungals (amphotericin B + flucytosine) (CPT 96365)	IV	-	0.7-1 mg/kg :: IV :: - :: Amphotericin B 0.7-1 mg/kg/day IV + flucytosine 100 mg/kg/day x 2 weeks (induction)	-	Renal function; electrolytes; LFTs	-	-	-	-
Anti-TB regimen	-	-	N/A :: - :: per protocol :: RIPE: rifampin + isoniazid + pyrazinamide + ethambutol	-	LFTs; visual acuity (ethambutol); drug interactions	-	-	-	-
No disease-modifying treatment	-	-	N/A :: - :: per protocol :: Supportive care only; no effective treatment exists	-	Comfort care; goals of care discussion	-	-	-	-

3C. Symptomatic Treatments

Treatment	Route	Indication	Dosing	Pre-Treatment Requirements	Contraindications	Monitoring	ED	HOSP	OPD	ICU
Levetiracetam (CPT 96374)	IV	Seizures	500-1500 mg :: IV :: BID :: 500-1500 mg PO/IV BID; max 3000 mg/day	-	Severe renal impairment (dose adjust)	Renal function; behavioral changes	-	-	-	-
Lorazepam (CPT 96374)	IV	Agitation, myoclonus (CJD)	0.5-1 mg :: IV :: PRN :: 0.5-1 mg PO/IV q6-8h PRN	-	Respiratory depression	Sedation; respiratory status	-	-	-	-
Clonazepam	PO	Myoclonus (CJD)	0.5 mg :: PO :: BID :: 0.5 mg PO BID; increase to 1-2 mg TID	-	Respiratory depression; fall risk	Sedation; fall prevention	-	-	-	-
Valproic acid	PO	Myoclonus (adjunctive); seizures	250-500 mg :: PO :: BID :: 250-500 mg PO BID; target level 50-100 µg/mL	-	Hepatic disease; pancreatitis; pregnancy	LFTs; ammonia; drug level; CBC	-	-	-	-
Quetiapine	PO	Agitation, psychosis, behavioral disturbance	25-50 mg :: PO :: qHS :: 25-50 mg PO qHS; increase by 25 mg/day; max 200-400 mg/day	-	QT prolongation; Parkinson disease (avoid all antipsychotics in Lewy body)	QTc; metabolic panel; sedation	-	-	-	-
Trazodone	PO	Insomnia, behavioral disturbance	25-50 mg :: PO :: qHS :: 25-50 mg PO qHS; max 150 mg	-	Priapism (rare); orthostatic hypotension	Sedation; orthostasis	-	-	-	-
Melatonin	PO	Insomnia	3-10 mg :: PO :: qHS :: 3-10 mg PO qHS	-	None significant	Sleep quality	-	-	-	-

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4. OTHER RECOMMENDATIONS

4A. Referrals & Consults

Recommendation	ED	HOSP	OPD	ICU	Indication
Neurology (behavioral/cognitive subspecialty if available)	STAT	STAT	STAT	STAT	All RPD cases; diagnostic workup direction; empiric treatment decisions
Neuro-immunology	-	URGENT	ROUTINE	URGENT	Suspected autoimmune encephalitis; immunotherapy management
Infectious disease	-	ROUTINE	ROUTINE	-	Suspected CNS infection (neurosyphilis, TB, HIV, fungal, Whipple)
Oncology	-	ROUTINE	ROUTINE	-	Paraneoplastic syndrome; CNS lymphoma; brain metastases
Neurosurgery	-	ROUTINE	-	ROUTINE	Brain biopsy consideration; hydrocephalus management
Rheumatology	-	ROUTINE	ROUTINE	-	Suspected CNS vasculitis; lupus cerebritis; sarcoidosis
Psychiatry	-	ROUTINE	ROUTINE	-	Behavioral management; depression; capacity assessment
Neuropsychology	-	-	ROUTINE	-	Formal cognitive testing; baseline and follow-up
Palliative care	-	ROUTINE	ROUTINE	ROUTINE	Goals of care (especially if CJD suspected); symptom management
Social work	-	ROUTINE	ROUTINE	-	Family support; advance directive planning; caregiver resources
Genetic counseling	-	-	ROUTINE	-	If genetic prion disease suspected; family implications
Ethics consultation	-	ROUTINE	-	-	End-of-life decisions; capacity evaluation for untreatable conditions
National Prion Disease Pathology Surveillance Center (Cleveland)	-	ROUTINE	ROUTINE	-	If CJD suspected: contact for diagnostic guidance and potential brain autopsy
Speech-language pathology	-	ROUTINE	ROUTINE	-	Dysphagia; communication strategies
Physical/Occupational therapy	-	ROUTINE	ROUTINE	-	Safety; mobility; ADLs; fall prevention

4B. Patient and Family Instructions

Recommendation	ED	HOSP	OPD
RPD has many TREATABLE causes — aggressive workup is justified	-	ROUTINE	ROUTINE
Return to ED if: new seizure, sudden worsening, falls, inability to swallow, fever	STAT	STAT	ROUTINE
Do NOT drive	-	ROUTINE	ROUTINE
Ensure 24/7 supervision at home (fall risk, wandering, impaired judgment)	-	ROUTINE	ROUTINE
Advance directives / healthcare power of attorney should be completed early while patient can still participate	-	ROUTINE	ROUTINE
If CJD is diagnosed: no cure exists; disease is uniformly fatal; focus on comfort and quality of life	-	ROUTINE	ROUTINE
CJD is NOT contagious through casual contact; standard precautions are sufficient; no isolation needed for family	-	ROUTINE	ROUTINE
CJD surgical instruments: notify any surgical/dental providers about diagnosis (special sterilization or instrument destruction required)	-	ROUTINE	ROUTINE
Family support resources: CJD Foundation (www.cjdfoundation.org); Autoimmune Encephalitis Alliance	-	ROUTINE	ROUTINE
Follow-up with neurology frequently (weekly to monthly depending on trajectory)	-	ROUTINE	ROUTINE

4C. Lifestyle & Safety

Recommendation	ED	HOSP	OPD
Fall prevention (remove tripping hazards, grab bars, non-slip surfaces)	-	ROUTINE	ROUTINE
No driving, no operating machinery	-	ROUTINE	ROUTINE
Medication management by caregiver (patient cannot reliably self-administer)	-	ROUTINE	ROUTINE
Home safety evaluation (OT)	-	ROUTINE	ROUTINE
Caregiver support and respite care	-	ROUTINE	ROUTINE
Nutritional support (swallowing may decline; SLP evaluation)	-	ROUTINE	ROUTINE
Medical ID bracelet	-	ROUTINE	ROUTINE

═══════════════════════════════════════════════════════════════ SECTION B: REFERENCE (Expand as Needed) ═══════════════════════════════════════════════════════════════

5. DIFFERENTIAL DIAGNOSIS

Alternative Diagnosis	Key Distinguishing Features	Tests to Differentiate
Creutzfeldt-Jakob disease (CJD)	Weeks-months; myoclonus; startle; akinetic mutism late; MRI cortical ribboning + caudate/putamen DWI signal; PSWCs on EEG	RT-QuIC (CSF); 14-3-3; total tau >1150; MRI DWI; EEG
Autoimmune encephalitis (anti-NMDAR)	Subacute; psychiatric symptoms → seizures → movement disorder → autonomic → decreased consciousness; young women; ovarian teratoma	NMDAR antibody (CSF > serum); pelvic imaging
Autoimmune encephalitis (anti-LGI1)	Faciobrachial dystonic seizures; hyponatremia; memory loss; >40 years	LGI1 antibody (serum > CSF); serum Na
Hashimoto encephalopathy (SREAT)	Euthyroid or hypothyroid; high anti-TPO; steroid-responsive; diagnosis of exclusion	Anti-TPO elevated; response to steroids; exclude other causes
Rapidly progressive Alzheimer disease (rpAD)	Most common misdiagnosis of CJD; positive AD biomarkers (low Aβ42, high p-tau); no myoclonus typically; MRI shows atrophy, no DWI ribboning	CSF AD biomarkers (Aβ42/Aβ40 ratio low, p-tau elevated); MRI (atrophy without DWI cortical signal); RT-QuIC negative
CNS lymphoma (primary or intravascular)	B symptoms; enhancing mass (primary); multifocal white matter changes with LDH elevation and no mass (intravascular)	MRI with contrast; CSF cytology + flow cytometry; EBV PCR; brain biopsy; LDH; peripheral smear
Leptomeningeal carcinomatosis	Known malignancy; cranial neuropathies; communicating hydrocephalus; CSF cytology positive	CSF cytology (repeat x3); MRI with contrast (leptomeningeal enhancement)
Neurosyphilis	RPR/VDRL positive; Argyll Robertson pupils; psychiatric symptoms; may have prior STI history	RPR/VDRL (serum); CSF VDRL; FTA-ABS
Wernicke encephalopathy	Acute confusion + ophthalmoplegia + ataxia triad (only 10% have all three); alcoholism, malnutrition	Thiamine level (draw before treatment); MRI (mamillary body, thalamic signal); clinical response to thiamine
CNS vasculitis	Headache; multifocal deficits; strokes; CSF pleocytosis	MRA (beading); DSA; brain/meningeal biopsy; ESR/CRP elevated
Neurosarcoidosis	Cranial neuropathies (CN VII); leptomeningeal enhancement; hilar adenopathy; elevated ACE	Chest CT; serum/CSF ACE; biopsy (granulomas)
Normal pressure hydrocephalus (NPH)	Triad: gait disorder (predominant) + urinary incontinence + dementia; "wet, wobbly, and wacky"; ventricular enlargement disproportionate to atrophy	Large-volume LP (30-50 mL) with pre/post gait assessment; MRI (Evans index >0.3)
Toxic/metabolic encephalopathy	Medication toxicity (lithium, methotrexate, chemotherapy); substance abuse; hepatic/uremic encephalopathy	Drug levels; LFTs; ammonia; BUN/Cr; UDS
Depression/Pseudo-dementia	Depressive symptoms predominant; subjective cognitive complaints > objective deficits; onset correlates with depressive episode	Neuropsychological testing; psychiatric evaluation; may improve with antidepressant
Whipple disease	Oculomasticatory myorhythmia (pathognomonic); GI symptoms; arthralgia; chronic diarrhea	T. whipplei PCR (CSF, duodenal biopsy); PAS-positive macrophages on biopsy
PML (progressive multifocal leukoencephalopathy)	Immunocompromised; multifocal white matter lesions (no enhancement typically); progressive deficits	JC virus PCR (CSF); MRI pattern; clinical context
Fatal familial insomnia	Genetic prion disease; progressive insomnia → autonomic dysfunction → motor signs → dementia; family history	PRNP gene testing (D178N mutation with 129M); polysomnography (absent sleep spindles)

6. MONITORING PARAMETERS

Parameter	ED	HOSP	OPD	ICU	Frequency	Target/Threshold	Action if Abnormal
Cognitive assessment (MMSE, MoCA, or bedside exam)	STAT	STAT	ROUTINE	STAT	Baseline; weekly inpatient; each visit outpatient	Stable or improving (if treatable cause)	Document trajectory; adjust treatment
Neurologic exam (focal signs, myoclonus, gait, cranial nerves)	STAT	STAT	ROUTINE	STAT	Daily inpatient; each visit outpatient	Stable or improving	If new focal signs: repeat MRI; if myoclonus: add clonazepam
Seizure monitoring	STAT	STAT	ROUTINE	STAT	Clinical observation; EEG if suspicious	No seizure activity	AED initiation/adjustment
Swallowing assessment	-	ROUTINE	ROUTINE	ROUTINE	Weekly; SLP evaluation	Safe oral intake	Modified diet; NG/PEG if progressive
Weight	-	ROUTINE	ROUTINE	-	Weekly	Stable	Nutritional support
Serum sodium	-	ROUTINE	ROUTINE	-	q12-24h initially; then per clinical indication	135-145 mEq/L	SIADH management if low; LGI1 encephalitis associated with hyponatremia
Renal function	-	ROUTINE	ROUTINE	-	Daily if on acyclovir or nephrotoxic drugs; weekly otherwise	Stable	Dose adjustments
Response to immunotherapy	-	ROUTINE	ROUTINE	-	Assess at day 5 of steroids/IVIG; then weekly	Objective improvement in cognition or exam	If no response: consider second-line (rituximab); reconsider diagnosis
Autoimmune antibody titers (follow-up)	-	-	ROUTINE	-	q3-6 months if positive	Declining titers	If rising: relapse risk; adjust immunotherapy
Safety assessment (fall risk, wandering, capacity)	-	ROUTINE	ROUTINE	-	Daily inpatient; each visit outpatient	Safe	Increase supervision; facility placement if needed

7. DISPOSITION CRITERIA

Disposition	Criteria
Discharge home	Stable cognition; safe home environment with 24/7 caregiver; outpatient workup can be completed; no active seizures; swallowing safe; outpatient follow-up arranged within 1-2 weeks
Admit to hospital	Acute/subacute decline requiring urgent workup; unable to safely manage at home; seizures; empiric immunotherapy trial; cannot complete workup as outpatient
Admit to ICU	Status epilepticus; respiratory failure; autonomic instability; severe agitation requiring sedation; ICP management
Transfer to tertiary center	Complex workup (brain biopsy, specialized autoimmune testing); prion disease expertise; clinical trial access
Memory care / Long-term care	Progressive untreatable dementia (CJD, advanced neurodegenerative); unable to care for self; caregiver unable to manage
Hospice	Confirmed CJD or other untreatable rapidly fatal diagnosis; focus on comfort

8. EVIDENCE & REFERENCES

Recommendation	Evidence Level	Source
RT-QuIC for CJD diagnosis (sensitivity 92%, specificity 99-100%)	Class I, Level A	McGuire et al. (Ann Neurol 2012); Atarashi et al. (Nat Med 2011)
MRI DWI cortical ribboning for CJD	Class I, Level A	Vitali et al. (Neurology 2011); Young et al. (AJNR 2005)
CSF 14-3-3 protein for CJD (sensitivity ~90%, lower specificity)	Class IIa, Level B	WHO diagnostic criteria; Muayqil et al. (2012)
Comprehensive autoimmune antibody testing in RPD	Class I, Level B	Graus et al. (Lancet Neurol 2016) — diagnostic criteria for autoimmune encephalitis
Empiric immunotherapy trial for suspected autoimmune encephalitis	Class IIa, Level C	Expert consensus; Dalmau & Graus (NEJM 2018)
Anti-NMDAR encephalitis: immunotherapy + teratoma resection	Class I, Level B	Titulaer et al. (Lancet Neurol 2013)
Anti-LGI1: steroids as first-line	Class IIa, Level B	Irani et al. (Brain 2010)
Hashimoto encephalopathy (SREAT): steroid-responsive	Class IIb, Level C	Castillo et al. (Arch Neurol 2006); diagnosis of exclusion
Thiamine for Wernicke: high-dose IV (500 mg TID)	Class I, Level B	Thomson & Marshall (2006); Galvin et al. (2010)
Neurosyphilis: IV penicillin G x 14 days	Class I, Level A	CDC STI Treatment Guidelines
CJD: no effective treatment; supportive care only	Class I, Level A	No disease-modifying therapy exists; multiple trials failed
Brain biopsy when non-invasive workup inconclusive	Class IIa, Level C	Expert consensus; diagnostic yield 57-65% in RPD
Save CSF frozen for future studies	Class I, Level C	Standard practice; new biomarkers emerging

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APPENDIX: RPD DIAGNOSTIC APPROACH — "VITAMINS" MNEMONIC

Category	Examples
Vascular	CNS vasculitis, cerebral amyloid angiopathy, CADASIL, intravascular lymphoma
Infectious	CJD (prion), neurosyphilis, HIV, Whipple disease, TB, fungal, PML
Toxic / Metabolic	Drug toxicity (lithium, methotrexate, chemobrain), hepatic/uremic encephalopathy, heavy metals, B12/thiamine deficiency, copper deficiency
Autoimmune	Anti-NMDAR, anti-LGI1, Hashimoto (SREAT), neurosarcoidosis, lupus cerebritis, CNS vasculitis
Metastatic / Neoplastic	Leptomeningeal carcinomatosis, CNS lymphoma, paraneoplastic, brain metastases, gliomatosis cerebri
Iatrogenic	Medication side effects, radiation injury, post-surgical
Neurodegenerative	Rapidly progressive AD, DLB, FTD, corticobasal degeneration
Systemic / Seizure	NPH, non-convulsive status epilepticus, depression (pseudo-dementia)

APPENDIX: CJD DIAGNOSTIC CRITERIA (CDC — PROBABLE sCJD)

Requires: Progressive neuropsychiatric disorder AND at least ONE of: 1. Positive RT-QuIC (CSF or nasal brushing) 2. Positive 14-3-3 CSF + duration <2 years 3. Typical MRI signal (caudate/putamen or ≥2 cortical regions on DWI/FLAIR) 4. Typical EEG (periodic sharp wave complexes)

PLUS at least TWO of: myoclonus, visual/cerebellar, pyramidal/extrapyramidal, akinetic mutism