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Rapid dementia

Rapid dementia. Richard Lukose PGY-3 Neurology . 54 y/o male accountant presents to PCP 2 months progressively “ acting strangely ” per wife Cannot remember where he parked his car No longer interested in fantasy football games Difficulty completing routine tasks at work

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Rapid dementia

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  1. Rapid dementia Richard Lukose PGY-3 Neurology

  2. 54 y/o male accountant presents to PCP • 2 months progressively “acting strangely” per wife • Cannot remember where he parked his car • No longer interested in fantasy football games • Difficulty completing routine tasks at work • Two falls at work while walking in hallway • Grandfather and grandmother with Alzheimer’s Disease onset in their 80’s

  3. Physical Exam • Vitals: 36.8, 18, 84, 132/82 • General: NAD, afebrile • Head: atraumatic • Neck: no nuchal ridgidity, no bruits • Chest: CTA • Heart: RRR, no murmurs • Abdomen: No masses, BS present • Extremities: No C/C/E

  4. Neurologic Exam • Mental Status: • Alert, oriented to name only • Poor recall of three objects • Poor insight • Poor judgment • Thoughts fragmented • CN’s intact • Motor 5/5 throughout • Reflexes ¾ b/l patellar, toes extensor • Sensation: intact for pin/temp/vib/propioception, startle myoclonus • Cerebellar: mild b/l ataxia on finger to nose and heel to shin • Gait: ataxic with positive Rhomberg test

  5. Give a one sentence summary of case

  6. Summary • A 54 y/o male without significant medical history with a rapid progression of cognitive decline

  7. Summary • A 54 y/o male without significant medical history with a rapid progression of cognitive decline • Neurological exam shows impaired mental status, generalized ataxia, upper motor neuron signs and myoclonus

  8. Mental status change, generalized ataxia, upper motor neuron signs • Localization to the bilateral cerebral and cerebellar hemispheres • Time course? • Rapid!

  9. Rapidly Progressive DementiaDifferential Diagnosis • VITAMINS: • Vascular: multi-infarct, CNS vasculitis, intravascular lymphoma • Infectious: Encephalitis (bacterial, viral, fungal, rickettsial); Infectious in older adults (UTI, PNA); Progressive multifocal leukoencephalopathy (PML), HIV dementia, Creutzfeldt-Jakob disease; • Toxic/Metabolic: heavy metals, bismuth, drug rxn, electrolytes, Wilson’s disease, vitamin deficiencies, uremic/hepatic encephalopathy

  10. Rapidly Progressive DementiaDifferential Diagnosis • Autoimmune: CNS vasculitis, Hashimoto encephalopathy, sarcoid • Metastasis (neoplasm):lymphoma, paraneoplastic, primary tumor • Iatrogenic: medications, hospitalization • Neurodegenerative: CJD, Alzheimer disease, obstructive hydrocephalus • Systemic: delirium, hypertensive encephalopathy, mitochondrial

  11. Workup: blood testsGeschwind, 2010. RPD: Prion diseases and other RPDs. Continuum 16 (2) 31-56. Required Sometimes Helpful Cancer screen Blood smear Coagulation profile Hypercoagulability testing Homocysteine Copper and ceruloplasmin Methylmalonic acid Additional rheumatologic tests • CBC • BMP w/ Ca, Mg, Phosphorus • LFTs • RPR • ESR, CRP, antinuclear antibody • TSH and free T4 • Antithyroglobulin and antithyroperoxidase antibodies • B12 • HIV • Lyme titer • Paraneoplastic antibodies • Autoimmune antibodies

  12. Workup: UrineGeschwind, 2010. RPD: Prion diseases and other RPDs. Continuum 16 (2) 31-56. Required Sometimes Helpful Urine culture Copper (24 hrs if Wilson disease suspected) Heavy metal screen (24 hrs) • Urine analysis

  13. Workup: CSFGeschwind, 2010. RPD: Prion diseases and other RPDs. Continuum 16 (2) 31-56. Required Sometimes Helpful Cryptococcal antigen Viral PCRs and cultures Vacterial, fungal, acid-fast bacilli stains and cultures Cytology Flow cytometry Whipple PCR 14-3-3 test Total tau Neuron-specific enolase • Cell count and differential • Glucose • IgG index • Oligoclonal bands • VDRL

  14. Workup: Other testsGeschwind, 2010. RPD: Prion diseases and other RPDs. Continuum 16 (2) 31-56. Required Sometimes Helpful CT head CT chest, abdomen, pelvis with and without contrast MR angiography brain and neck Mammogram Body PET scan MR spectroscopy Echocardiogram EMG/NCS Brain biopsy • MRI brain (FLAIR and DWI) with and without contrast • EEG

  15. Significant Results MRI: basal ganglia/cortical ribbon on FLAIR WHAT’s YOUR DIAGNOSIS? EEG: GPEDs • CSF • Negative for 14-3-3 protein • Negative for Neuron-specific enolase • Positive for Total Tau

  16. Sensitivity and Specificity of CSF Biomarkers in UCSF Rapidly Progressive Dementia CohortfromGeschwind, 2010. RPD: Prion diseases and other RPDs. Continuum 16 (2) 31-56. sCJD = sporadic Creutzfeldt-Jakob disease; RPD = nonprion rapidly progressive dementia Neuron-specific enolase is considered positive if level is > 35 ng/ml Total Tau is considered positive if level is > 1200 pg/ml False positive rate (FPR) is defined as 1 minus the specificity. FPR 14-3-3 is 26%; NSE is 11% and Total Tau is 5%

  17. Creutzfeldt-Jakob Disease • Caused by the transformation of a normal cellular prion protien (PrPc) into a disease causing prion (PrPSc) • Accumulation of PrPSc leads to neurodegeneration

  18. 3 CJD Subtypes • Sporadic CJD (sCJD) • 85% of CJD cases • No known cause • Survival 4-8 months • 90% mortality at 1 year • Onset 55-75 years (median age 68, mean 61) • Include sporadic fatal insomnia (very rare)

  19. 3 CJD Subtypes • Genetic CJD (gCJD) • Include: familial CJD, Gerstmass-Straussler-Scheinker syndrome and fatal familial insomnia • Mutation makes PrP more susceptible to change to PrPSc Familial CJD presents exactly like sCJD 60% of genetic CJD cases have no family history

  20. 3 CJD Subtypes • Variant Creutzfeldt-Jakob disease (vCJD) • Bovine Spongiform Encephalopathy (BSE) has been strongly linked to the occurrence of vCJD in humans. • 175 cases in UK and Ireland from October 1996 to March 2011; 3 cases in US. • Containment of the BSE epidemic in cattle resulted in decline of cases of vCJD

  21. Criteria for Probably Sporadic CJD WHO revised 1998 USCF Modified (2007) Rapid cognitive decline with any two of: Myoclonus Pyramidal/extrapyramidal Visual Cerebellar Akinetic mutism Other focal higher cortical sign AND typical MRI and/or EEG AND no other condition to explain • Progressive dementia with any two of: • Myoclonus • Pyramidal/extrapyramidal • Visual/cerebellar • Akinetic mutism • AND typical EEG or if < 2 year duration, positive CSF 14-3-3 AND no other condition to explain

  22. CJD MRI findings now thought to be best test for CJD sCJD and gCJD – cortical riboning and basal ganglia involvement on DWI vCJD – Pulvinar sign on DWI and FLAIR is said to be 90% sensitive for vCJD

  23. Definitive diagnosis of CJD can only be made through autopsy • spongiform change in the gray matter • the presence of many round vacuoles in all six cortical layers or cortex or with diffuse involvement of the cerebellar molecular layer • vacuoles appear glassy or eosinophilic and may coalesce • Neuronal loss and gliosis are also seen • Plaques of amyloid-like material can be seen in the neocortex in new-variant CJD.

  24. CJD Links • Autopsy H&E • Biopsy H&E

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