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
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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
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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 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
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
Workup: blood tests
Geschwind, 2010. RPD: Prion diseases and other RPDs. Continuum 16 (2) 31-56.
Required
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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
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Sometimes Helpful
Cancer screen
Blood smear
Coagulation profile
Hypercoagulability testing
Homocysteine
Copper and ceruloplasmin
Methylmalonic acid
Additional rheumatologic
tests
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)
Workup: CSF
Geschwind, 2010. RPD: Prion diseases and other RPDs. Continuum 16 (2) 31-56.
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Required
Cell count and differential
Glucose
IgG index
Oligoclonal bands
VDRL
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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 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
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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
EEG: GPEDs
MRI: basal ganglia/cortical ribbon on FLAIR
WHAT’s YOUR DIAGNOSIS?
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
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/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%
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-StrausslerScheinker 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:
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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:
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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