Rapidly Progressive Dementia
R. Ryan Darby
Alireza Atri
Definition: Deterioration of intellectual/behavioral/cognitive/psychiatric fxn (dementia) usually over several weeks to months but <2 yr.
Epidemiology (UCSF data: 178 rapidly progressive (RPD) referrals, most “r/o CJD,” Ann Neurol 2008;64:97): 62% prion (75% sporadic, 22% genetic, 3% acquired); 15% neurodegenerative (i.e., classically “chronic” degenerative dzs); 8% autoimmune; 4% infectious; 2% each psychiatric, cancer, toxic-metabolic, vascular; 4% undetermined (often leukoencephalopathy/encephalopathy of unknown origin). Other studies suggest 6%-27% from reversible causes.
DIFFERENTIAL DIAGNOSIS & WORKUP FOR RPD
DDx of RPD “VITTAMMNIINSSSS” (modified from Neurol Clin 2007;25:783): Vascular, Infectious, Toxic & Trauma, Autoimmune, Metabolic & Metastases/neoplasm, Iatrogenic & Illicit/drugs, Neurodegenerative, Systemic, Seizure, Structural & Sleep disorders.
Vascular: Infarcts (large vessel, thalamic, multifocal) or ischemic encephalopathy; TTP (2/2 microangiopathic thromboses), hyperviscosity (e.g., polycythemia, paraproteinemias—monoclonal gammopathy, Waldenstrom), cerebral venous thrombosis, dural AV fistulas, inflammatory cerebral amyloid angiopathy (I-CAA), CADASIL.
Infectious: Viral encephalitis, HIV dementia, PML, subacute sclerosing panencephalitis (SSPE), fungal infxns, syphilis, parasites/amebiasis, Lyme dz, Balamuthia, Whipple dz.
Toxic & trauma: Toxicities/poisoning: Lead, CO, bismuth, lithium, mercury, arsenic, toluene, cyanide. Trauma: Postconcussion & chronic traumatic encephalopathy (CTE), chronic SDH, diffuse axonal injury, & hemorrhage.
Autoimmune: Hashimoto encephalopathy/SREAT, nonparaneoplastic autoimmune (e.g., NMDA, VGKC), lupus cerebritis, 1° or 2° CNS vasculitis, sarcoidosis, paraneoplastic limbic encephalopathy, ADEM, Susac, Behcet, celiac dz.
Metabolic & metastases/neoplasm: Metabolic: Electrolyte/metabolic abnls; uremia, hypoxic-ischemic or hypercapnic encephalopathy, Wilson dz, mitochondrial dz, portosystemic encephalopathy, porphyria, acquired hepatocerebral degeneration, lysosomal storage dz, leukodystrophies, methylmalonic acidemia. Metastases/neoplasm: Nonautoimmune paraneoplastic limbic encephalitis, frontal meningioma, gliomas, CNS mets, primary CNS lymphoma, intravascular lymphoma (IVL), lymphomatoid granulomatosis (LYG), gliomatosis cerebri.
Iatrogenic-illicit drugs: Iatrogenic: Medication & supplement side effects, neurosurgery, chemoRx, XRT. Illicit/drugs: Chronic alcohol (Wernicke-Korsakoff, Marchiafava-Bignami), leukoencephalopathy from inhaled heroin, MDMA, methanol.
Neurodegenerative: Creutzfeldt-Jakob dz (CJD; sporadic, iatrogenic, familial, new variant), AD, vascular dementia (VAD), DLB, FTD syndromes, primary progressive aphasia (PPA) syndromes, PD w/dementia, CBD, MSA, ALS-FTD-parkinsonism, PSP, Huntington dz, CTE.
Systemic, seizure, structural, & sleep disorders: Systemic: Thyroid, parathyroid, & adrenal abnls, HTN/PRES. Seizure: Chronic sequelae or interictal encephalopathy. Structural: NPH, sagging brain syndrome. Sleep Disorders: OSA, sleep deprivation.
Diagnostic workup: Generic & “As Indicated” Tests
Essential (all pts presenting w/RPD)
Blood: CBC, PT, PTT, chem7, Ca, Mg, phos, LFTs, NH3, LDH, vitamin B12, Hcy, MMA, TSH, free-T4, “rheum screen” (ESR, CRP, ANA, RF, SS-A, SS-B), RPR, HIV Ab, Lyme Ab, anti-TG abs, anti-TPO abs, paraneoplastic/autoimmune abs [minimum: anti: NMDA, Hu (ANNA-1), Ma2 (Ta), CV2 (CRMP-5), amphiphysin, AMPA-R, & VGKC (LGI1, CASPR2); GABAb; consider: anti: Yo, nCMAg, Ma1, Ri (ANNA-2), GAD65].
CSF: Cell count + differential, protein, glucose, IgG index, oligoclonal bands, VDRL, paraneoplastic/autoimmune abs.
Urine: UA. Others: MRI brain (w/FLAIR, DWI, ±gadolinium), CXR, EEG.
As indicated (directed toward specifically suspected dxs)
Blood: Tumor markers (CEA, Ca-125, PSA), vitamin E, Cu, ceruloplasmin, anti-ds DNA, anti-smith, p-ANCA, c-ANCA, C3, C4, CH50, antiendomysial abs, antigliadin IgA & IgG, ACE, anti-GAD Ab, other paraneoplastic abs, HIV viral load, T-cell subsets, smear, viscosity, lactate & pyruvate, hypercoagulability tests, Notch3 gene (CADASIL), VLC fatty acids, arylsulfatase, galactosidases, genetic tests (e.g., HD, AD, FTD, SCAs).
CSF: Cryptococcal Ag, viral PCRs & cultures. Cultures: Bacterial, fungal, AFB, AFB stain, cytology & flow cytometry, PCR IgH gene rearrangement, Whipple PCR, 14-3-3 protein, NSE (neuron-specific enolase), amyloid-beta42, tau (total & phosphorylated).
Urine: Cu (24 h collection, if ? Wilson dz), heavy metal screen (24 h collection, for lead, arsenic, mercury, bismuth, aluminum, lithium), PBG/ALA (24 h collection if ? porphyria).
Others: Brain FDG-PET (AD vs. FTLD), amyloid PET (AD), DAT PET (DLB, PD), MR spectroscopy, body PET + CT (cancer screen), mammogram, conventional angio, EMG/NCS, Bx: brain/meninges, jejunum (Whipple dz), skin (IVL); carotid U/S, TTE.
VASCULAR CAUSES OF RPD
Inflammatory cerebral amyloid angiopathy (Neurology 2013;81:1596)
Def: CAA a/w (1) perivascular inflamm. (CAA-RI, 13%-17% of CAA) or (2) Aβ-related angiitis (ABRA, 36% of CAA) ? response to deposits of β-amyloid. More common w/APOE ε4/ε4.
P/w: RPD (cognitive ↓ over 1-4 mo), szs (90% CAA-RI), HA, leukoencephalopathy.
Dx: Clinical history + MRI findings, ±biopsy, MRI: multiple microhemorrhages on GRE/SWI; patchy or confluent WM ↑ T2/FLAIR lesions, +meningeal enhancement (57%). CSF: mild-moderate ↑ protein (nonspecific). Brain bx: CAA-RI: perivascular inflammatory response. ABRA: granulomatous angiitis similar to 1° CNS vasculitis.
Rx: steroids +/- cyclophosphamide; avoid antiplatelet & anticoagulant meds.
CADASIL (Lancet Neurol 2009;8:643)
Def: Genetic, AD dz affecting small cerebral vessels causing strokes & leukoencephalopathy.
Epid: Prev 2% age <65, 11% age <50 in pts w/lacunar stroke + leukoaraiosis.
P/w: Migraine w/aura (20%-40%), TIA/stroke (60%-85%), mood d/o (20%), progressive cog impairment in 10% (executive, attn, memory, near 100%), szs 5%-10%.
Dx: MRI: T2/FLAIR WM lesions, esp external capsule, ant temp lobes. Other: Notch3 gene mutation, skin bx w/granular osmiophilic material in vessel walls.
Rx: ? donepezil for cog impairment, CV risk modification, migraine Rx.
INFECTIOUS CAUSES OF RPD
Most infectious RPD cases are atypical (i.e., uncharacteristically slow) presentations of common CNS infxns. Most common causes: HSV, CMV, EBV, enteroviruses, WNV, EEE.
Rabies: P/w behavioral & neuropsychiatric Δs (e.g., agitation, bizarre behavior, hallucinations, extreme excitability); usu rapidly progresses to coma.
Polyomaviruses (JVC, BKV): Usu p/w multifocal neuro deficits or meningoencephalitis.
HIV: Four associations w/RPD: (1) AIDS-dementia complex (usu advanced AIDS); (2) during seroconversion; (3) neuro-IRIS (neuroimmune reconstitution inflamm synd) on starting HAART; (4) opportunistic infxns. Amphetamine + HIV → accelerated HIV dementia.
SSPE (2/2 CNS infxn w/measles virus): In pts from countries where measles is common; children >> adults. P/w: Dementia (chronic progressive or RPD), szs, myoclonus, ataxia, rigidity, visual Δs. Later: spastic quadriparesis, diffuse hyperreflexia & upgoing toes, coma. Dx: (1) ↑ measles abs (serum & CSF) in approp clinical setting; (2) EEG: Periodic complexes & 3-10 Hz sharp waves a/w myoclonic jerks.
CNS Whipple dz: Rare but treatable bacterial infxn 2/2 Tropheryma whippelii. Epid: Onset: Any age, typically 40-70s (median 50). P/w: Typically diarrhea, abd pain, ↓ wt, arthralgias, wasting, fever, lymphadenopathy; 15% w/o GI si/sx. CNS involvement: ˜5% p/w neuro si/sx; subclinical dz in ˜45% cases. 70% cognitive impairment, 40% psychiatric si/sx. Other common si/sx: Eye mvmt palsies, myoclonus, sz, aseptic meningitis, hypothalamic involvement, ataxia, focal signs. “Classic triad”: Dementia, ophthalmoplegia, myoclonus (<10% cases, but very specific). Oculomasticatory myorhythmia: Pathognomonic (but uncommon). Dx: CSF: ↑ protein, ↑ lymphs 50% cases. MRI: Nonspecific. PAS+ inclusions or T. whippelii in foamy macrophages on jejunal bx; PCR on jejunal bx or CSF. Rx: TMP/SMX 160/800 mg PO bid × 1-2 yr, w/folate. Second line: penicillin G, penicillin VK, amoxicillin.
TOXIC-METABOLIC CAUSES OF RPD
Niacin deficiency: Pellagra (“rough skin”): See Poisons and Vitamin Def chapter.
Heavy metals (arsenic, mercury, aluminum, lithium, lead): Usu p/w florid acute encephalopathy (hours-days; usu faster than RPD [weeks-months]); can present as RPD.
Manganese toxicity: Mostly in miners. Parkinsonism a dominant feature; can p/w RPD.
Bismuth toxicity: W/overuse of bismuth-containing meds, e.g., Pepto-Bismol (for PUD, diarrhea). Typically p/w apathy, mild ataxia, HA; can progress to myoclonus, dysarthria, severe confusion, hallucinations, sz, death. Toxic range: >50 µg/L.
Adult onset or presentation of pediatric metabolic disorders
Common features: Weakness, spasticity, ataxia; progression usu slow, but rarely rapid.
Porphyria: GI si/sx, unexplained pain, worse si/sx w/new meds; fluctuating course.
Adult-onset metachromatic leukodystrophy (AoMLD): Rarely p/w RPD; other leukodystrophies also rarely p/w adult-onset RPD (e.g., X-linked adrenoleukodystrophy).
Kufs dz: Rare; adult form of neuronal ceroid lipofuscinosis. Presentation: Early adulthood onset, progressive myoclonic epilepsy, ±psychiatric si/sx, ±catatonia.
Mitochondrial d/o: Include MELAS, MERRF, Kearns-Sayre dz. Rarely p/w RPD. Other sx: Migraines, psych sx, weakness, n/v/GI sx, hearing/vision impairment. Dx: Lactacte/pyruvate, plasma AAs, urine organic acids, MR spect, muscle bx, genetic testing. Rx: CoQ10, mitochondrial cocktail
Wilson Dz (Lancet 2007;369:397)
Def: AR d/o of copper metabolism.
Epid: Prev 1:30-100 K, age onset 5-35.
P/w: Neuropsych (40%-50% initial presentations): Parkinsonism, tremor, dystonia, behavioral, psychiatric. Other sx: Cirrhosis, Kayser-Fleischer rings.
Dx: ↑ LFTs, serum ceruloplasmin, serum Cu, 24 h Cu, liver Bx, ATP7B gene test.
Rx: Chelators (penicillamine, trientine, Zn); liver transplant.
AUTOIMMUNE CAUSES OF RPD
HASHIMOTO ENCEPHALOPATHY/STEROID RESPONSIVE ENCEPHALOPATHY ASSOCIATED WITH AUTOIMMUNE THYROIDITIS, “SREAT”
Epid (J Neuropsychiatry Clin Neurosci 2011;23:384): Prev ˜2/100,000. Age of onset: 45-55 yr. 80% female. A/w autoimmune thyroid dz, SLE, DM 1, Sjögren.
P/w: Nonspec course. Rapid improvement w/steroids is required (96%). Prodrome (not always present): Depression, personality Δs, psychosis. Progressive or fluctuating encephalopathy w/inattention, exec/memory dysfxn, agitation or lethargy (65%), szs (59%), psychosis (27%), myoclonus (42%), stroke-like episodes (18%), hallucinations.
Dx: 86% w ↑ antithyroid peroxidase (anti-TPO) abs, 48% w ↑ antithyroglobulin (anti-TG) abs. Most cases are euthyroid or subclinically hypothyroid. Levels of anti-TPO abs don’t correlate w/severity. Rare cases of anti-TPO neg dz. Anti-TPO abs ↑’d in 10% gen population; % ↑’s w/age, F gender. MRI (abnl 45%), EEG (abnl 89% usu slowing, sometimes sharps), CSF (abnl 71% usu ↑ TP), & brain bx findings nonspecific.
Rx: Corticosteroid responsiveness a defining feature. Start w/high-dose IV methylpred (Solu-Medrol) 1 g/day × 3-5 days. Too short course → relapse. Follow w/maint PO prednisone 1-2 mg/kg/d; taper slowly. Repeat methylpred pulses for relapses. Rx duration varies (4-6 mo-10 yr). In relapsing-remitting dz, can use steroid-sparing agents, e.g., IVIg, plasma exch, azathioprine, cyclophosphamide, hydroxychloroquine, methotrexate, cyclophosphamide, rituximab.
LIMBIC ENCEPHALITIS (LE)
Epid: Up to 8% of pts p/w RPD.
P/w: Subacute amnesia (↓ antegrade short-term memory (STM), ±↓ retrograde memory), psychosis, hyperreligiosity, hallucinations, szs, personality Δs, sleep disturbances, +/- brainstem involve.
Cancer: SCLC (75%; of these, 50% a/w anti-Hu abs), germ cell (ovarian, testicular), thymoma, Hodgkin lymph, breast Ca. LE may precede Ca dx by weeks-months; rarely years.
Abs: Intraneuronal: Anti-Hu, anti-Ma2/Ta, anti-CV2/CRMP-5, antiamphiphysin. Extracellular: Anti-NMDA, anti-AMPA, anti-GABAb, anti-VGKC (LGI1, CASPR2).
Dx: MRI: T2/FLAIR Δs in mesial temporal lobes (MTL). EEG: Slowing, szs. LP: Mild ↑ prot, WBCs. Serum/CSF: LE ab panel. Cancer screen: CT-PET c/a/p, pelvic/testicular US, mammogram.
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