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– Two falls at work while walking in hallway– Grandfather and grandmother with Alzheimer’s

Disease onset in their 80’s

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

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

Give a one sentence summary of case

Summary

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

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

• Mental status change, generalized ataxia, upper motor neuron signs

• Localization to the bilateral cerebral and cerebellar hemispheres

• Time course?– Rapid!

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

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

Workup: blood testsGeschwind, 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

Workup: UrineGeschwind, 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)

Workup: CSFGeschwind, 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

Workup: Other testsGeschwind, 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

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

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.

14-3-3sCJD = 218RPD = 90

Neuron-specific enolase

sCJD = 86RPD = 58

Total TausCJD = 61RPD = 35

Sensitivity 55% 57% 64%

Specificity 74% 89% 95%

sCJD = sporadic Creutzfeldt-Jakob disease; RPD = nonprion rapidly progressive dementia

Neuron-specific enolase is considered positive if level is > 35 ng/mlTotal 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%

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

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)

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

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

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

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

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.

CJD Links

• Autopsy H&E• Biopsy H&E