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 Dementia Differential 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 Dementia Differential 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 tests Geschwind, 2010. RPD: Prion diseases and other RPDs. Continuum 16 (2) 31-56. Required 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 Sometimes Helpful Cancer screen Blood smear Coagulation profile Hypercoagulability testing Homocysteine Copper and ceruloplasmin Methylmalonic acid Additional rheumatologic tests

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

13. Workup: CSF Geschwind, 2010. RPD: Prion diseases and other RPDs. Continuum 16 (2) 31-56. Required Cell count and differential Glucose IgG index Oligoclonal bands VDRL 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

14. Workup: Other tests Geschwind, 2010. RPD: Prion diseases and other RPDs. Continuum 16 (2) 31-56. Required MRI brain (FLAIR and DWI) with and without contrast EEG 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

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

16. Sensitivity and Specificity of CSF Biomarkers in UCSF Rapidly Progressive Dementia Cohort from Geschwind, 2010. RPD: Prion diseases and other RPDs. Continuum 16 (2) 31-56. 14-3-3 sCJD = 218 RPD = 90 Neuron-specific enolase sCJD = 86 RPD = 58 Total Tau sCJD = 61 RPD = 35 Sensitivity55%57%64% Specificity74%89%95% 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 (PrP c ) into a disease causing prion (PrP Sc ) Accumulation of PrP Sc 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 PrP Sc 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 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 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

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