DECRYPTING Matt Starr MD Stroke CRYPTOGENIC · PDF filePresents to OSH with aphasia 6/14 New...
Transcript of DECRYPTING Matt Starr MD Stroke CRYPTOGENIC · PDF filePresents to OSH with aphasia 6/14 New...
Matt Starr MDStroke Attending
DECRYPTING CRYPTOGENIC STROKE
50yoM9/13 left hand
numb clumsyNo past medical
historyHypercoag panel
NegTEE negativeLoop recorder
placed
CASE
Presents to OSH with aphasia 6/14New left hemisphere
infarctsLoop with “possible
afib” on itStarted apixaban
CASE
7/14 expressive aphasia and right hand weakOn apixabanNew infarctLoop recorderWith no afibSwitched toWarfarin
CASE
WHAT IS THE ETIOLOGY??
The UnknownAs we know, There are known knowns. There are things we know we know. We also know There are known unknowns. That is to say We know there are some things We do not know. But there are also unknown unknowns, The ones we don't know We don't know.
—Donald Rumsfeld, Feb. 12, 2002, Department of Defense news briefing
STROKE CLASSIFICATIONS
TOAST Criteria-Large Vessel-Cardioembolic-Small Vessel-Other Known
Cryptogenic- the known unknowns and the unknown unknowns
CRYPTOGENIC STROKE
Determining the etiology of stroke lets you determine
appropriate secondary prevention
ETIOLOGY
In the literature, usually means stroke with no clearly definable cause even after some type of work up.
This could mean: 1. the cause is reversible and work up was not performed at
appropriate time 2. cause of stroke not fully investigated 3. some causes of stroke remain unknown 4. there are multiple concomitant risk factors that force the
physician to be unable to determine the final diagnosis
CRYPTIC DEFINITION
Goals 1. Learn about epidemiology of “cryptogenic” stroke 2. Diagnostic work up 3. Potential etiologies
PURPOSE OF THE LECTURE
Intraparenchmalhemorrhage 10%Subarachnoid
Hemorrhage 3% Ischemic 87%2 most common
subtypes are LVO and Cryptogenic
TYPES OF STROKES
Cryptogenic stroke accounts for 23-40% of all stroke ~1/3 of strokes are cryptogenic, ~200,000 per year More frequent in younger patients Hard to know what prognosis for recurrence is
CRYPTOGENIC
German Stroke Data Bank-5017 patients, cryptogenic stroke made up 23%, 40% under age 50.
South Korean study found recurrent stroke rate of 30% in cryptogenic patients within 1 year of initial stroke
Helsinki Young Stroke Registry, age 15-49, followed for 5 years, 807 patients, 267 with cryptogenic stroke. Found to have 3% rate of stroke at 1 year, 8.2% rate at 5 years.
MORE LIKELY TO AFFECT THE YOUNG
Follow-Up of Transient ischemic attack and stroke patient and Unelucidated Risk factor Evaluation
Studies 722 patients between age 18-50 with first TIA, ischemic stroke or ICH
Patients followed for 9.1 years 226 had undetermined cause of stroke (99 TIAs, 127 Ischemic
stroke, no ICH) Overall, 32% had poor functional outcome (mRS >2) Ischemic stroke patients had poor outcome 36.5% TIA patient 16.8%
Stroke in young can cause debilitation
FUTURE STUDY
Older patients with cryptogenic stroke are also at increased risk of recurrent stroke and death
Study from Neurology 8/17 pooled patients with cryptogenic stroke from 11 stroke registries in Europe and America
Ages <60, 60-80, >80, looked at recurrent stroke/TIA and death per 100 patient-years
<60 2.46 and 1.01 60-80 5.76 and 5.23 >80 7.88 Patients >80 had ~3-fold higher risk of recurrent event and 8-
fold higher risk of death compared to Patients <60
AGE
Study out of South Korea followed 3278 patients with stroke, subtype undetermined in 37%. 21.2% had negative evaluation10.6% had multiple causes so not able
to determine exact mechanism4.8% had incomplete work up
COMPLETE INVESTIGATION
The incompletely investigated patient: Not every patient had carotid imaging Only TTE or only Holter The incompletely investigated patient in this series had the
highest mortality rate and most likely to have poor outcome at 3 months
Mortality 12.7% within 30 days, 25.5% within 1 year, and 35.7% within 3 years
Poor 3 month Functional Outcome (mRS 3 or higher) 49.6%
INCOMPLETE INVESTIGATION
Patients in this series who underwent complete work up which was stil l negative had second lowest poor outcome rate and similar mortality rate compared to other known stroke subtypes.
NEGATIVE WORK UP
Study out of Calgary TIA or minor stroke (NIHSS <4) Determined to be cryptogenic after standard evaluation MRI at 24hrs, then either 30 days or 90 days 3 month clinical evaluation
MRI PROGNOSIS
333 patients, 207 who had follow up imaging 30 day cohort—5 of 76 (6.6%) patients had new lesions on
MRI 90 day cohort—19 of 131 (14.5%) had new lesions on MRI At 90 days for both cohorts, only 4 patients had clinical
recurrent stroke (1.2%)
What else is happening in these people to cause new clinically silent lesions?
MRI PROGNOSIS
AF AND SILENT CEREBRAL INFARCTS (SCI)
MRI study of 71 patients with AF vs 71 controls
-number of SCIs, severity of periventricular hyperintensities and deep/subcortical WM hyperintensities were significantly increased the AF group
-higher CHADS2 score associated with more lesions on MRI in the AF group
SCI
Meta-analysis of 11 studies found SCIs in patients with AF 40% of the time on MRI and 22% of the time on CTH.-AF doubles the risk of SCIs
SCI leads to decreased cognitive performance
-cognitive impairment on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) test was significantly impaired in persistent and paroxysmal AF patients with SCIs compared to controls
Embolic Stroke of Undetermined/Unknown Source—ESUS A relatively new name Embolic appearing non-lacunar stroke in patient without
proximal artery stenosis or obvious cardioembolic source
The possible sources are subclinical afib, paradoxical embolus from venous side across a PFO, non-occlusive atherosclerotic plaques in the aortic arch, cervical, or cerebral arteries, and inherited thrombophilias
Must consider further work up for these etiologies.
ESUS
The presumed treatment would be anticoagulation.
Several studies are underway to look at this. NavigateESUS—Rivaroxaban vs antiplatelet for ESUS RESPECT ESUS—Dabigatran vs antiplatelet for ESUS ATTICUS ESUS—Apixaban vs antiplatelet for ESUS
UPMC will be participating in upcoming ARCADIA study for ESUS and atrial cardiopathy with apixaban vs antiplatelet
ESUS
Lacunar ESUS
LACUNAR VS ESUS
Basic stuff—neurovascular imaging, TTE, holter
HOW DO YOU MAKE DIAGNOSIS?
12 lead ECG24hrs or more of
telemetryTEE if TTE negativeScreening for
hypercoagulability (patients <55)
MRA/CTA/DSAConsider ct
chest/abd/pelv
May not be feasible for all patients or centers
TO DETERMINE IF TRULY CRYPTOGENIC
1. paroxysmal atrial fibrillation 2. patent foramen ovale 3. aortic arch atheromatous disease 4. inherited thrombophilia
POSSIBLE ETIOLOGIES AND WORK UP
Risk of stroke and TIA is thought to be the same in chronic and paroxysmal afib
Current guidelines recommend telemetry for first 24 hours after stroke. Might be reasonable to monitor for 1 month
24hr Holter may be inferior to serial ECG for 3 days in detecting afib
Detection of PAF greatly changes management, very important to detect
PAROXYSMAL AFIB (PAF)
HOW DO YOU FIND AF?
EKGs, Holter monitors, 24hr telemetry had been standard
Detection was in range of 1-10%
Can be seen on interrogation of most implantable pacemakers and AICDs
2 recent studies in NEJM show that looking for AF longer increases odds of detection
EMBRACE and CRYSTAL-AF
EMBRACE
572 patients, 55 years or older with cryptogenic stroke
30 day event monitor vs conventional 24hr monitor
Followed for 90 days
AF recorded in monitor group 16.1% vs 3.2% in control group
Number needed to screen was 8
CRYSTAL-AF
441 patients 40 or older with cryptogenic stroke
Randomized to insertablecardiac monitor (REVEAL XT) or Conventional treatment)
At 6 months, AF detected in 8.9% of loop patients vs 1 .4% in control
Median time to detection 41 days
At 12 months 12.4% in loop vs 2.0% in control
At 36 months 30% vs 3% in control
Number needed to screen at 6 months= 14, at 12 months= 10, at 36 months = 4.
Safety— 5 devices, or 2.4%, explanted due to infection or pocket erosion
LOOP RECORDER
CRYSTAL AF was done with the REVEAL XT
The Reveal LINQ is the new device
The LINQ is smaller, easier to implant, downloads information wirelessly
Both devices are MRI compatible
Looking longer for AF increases likelihood of finding it
The majority of patients diagnosed with AF in EMBRACE and CRYSTAL-AF were started on anticoagulation
Subclinical AF increases risk of stroke, heart failure and death just like symptomatic AF
SUBCLINICAL AF
GUIDELINES
PFO—PATENT FORAMEN OVALE
Fetal Cardiac development-septum Primum-septum secundum
Pathway for placental oxygenated blood to enter left heart
With first breath pressures change with increase in LA pressure favoring closure of PFO
PFO AND CRYPTOGENIC STROKE
Lechat et al NEJM 1988; 318:1148-52-evaluation of patients with ischemic stroke-PFO present in 56% of patient with no identified cause-Present in 40% with risk factors (migraine, MVP, OCPs)-Present in 21% of patients with identifiable cause
Petty et al. Arch Neurology 1997;54:819-22-TEE study of 116 patient-PFO in 40% with cryptogenic stroke-Present in 25% of patients with known etiology
MAJOR CLINICAL TRIALS FOR PFO CLOSURE
CLOSURE trial- used STARFlex device-patients 60 or younger with stroke or TIA-5.9% closure vs 7.7% for primary endpoint, P value 0.30.
RESPECT trial- use Amplatzer PFO Occluder device-patients 18-60 with cryptogenic stroke-9 strokes in closure group vs 16 in medical group (HR 0.49; 95% CI 0.22-1.11; P=0.08)
PC trial – used amplatzer PFO occluder-patient 18-60, verified stroke-3.4% in closure vs 5.2% control (HR 0.63; 95% CI 0.24-1.62; P=0.34)
META ANALYSIS OF RCTS OF PFO CLOSURE
EXTENDED FOLLOW UP—POST-HOC ANALYSIS
Long term follow up of RESPECT group Majority of recurrent strokes had known mechanism that PFO
closure could not prevent For cryptogenic strokes in Amplatzer PFO patients there was a
54% RRR, p=0.042 If device verified to be in place that reduction went to 70% for
cryptogenic stroke recurrence. If PFO and ASA, 75% RRR for cryptogenic stroke, HR 0.245,
p=0.007
AAN GUIDELINES 7/16
Do not close PFO outside of research setting If recurrent strokes on maximal medical therapy could
consider Amplatzer PFO Occluder
May 2017 European Stroke Conference 2 studies presented—CLOSE and Gore-REDUCE New data regarding PFO closure
NEW DATA
663 patients with cryptogenic stroke and PFO + ASA or PFO with large shunt randomized PFO closure vs antiplatelet therapy, and antiplatelet therapy vs anticoagulation
Followed for 5 years PFO closure vs Antiplatelet
0 vs 4 recurrent strokes(hazard ratio, 0.03; 95% confidence interval [CI] , 0 - 0.25; P < .001)
Antiplatelet vs Anticoagulation7 vs 3 recurrent strokes(hazard ratio, 0.43; 95% CI, 0.1 - 1 .45; P = .17)
Patients with ASA 2% recurrent strokes, large PFO 0.5% recurrent strokes
Safety:Major procedural complications occurred in 14 patients (5.9%) of the closure group. These were AF (n = 9) , atr ial f lutter (n = 1) , supraventricular tachycardia (n = 2) , air embolism (n = 1) , and hyper thermia (n = 1) .
Increase in AF in the closure group (4.6% vs 0.9%; P = .02).
CLOSE
664 patients randomized 2:1 PFO closure vs antiplatelet Outcomes:
recurrent stroke 24 monthsnew clinical stroke or silent brain infarct on MRI at 24 months
6 vs 12 clinical strokes in closure vs medical group
GORE-REDUCE
These new studies will change practice The complete data has not been published yet
For patients ischemic stroke with Large PFO or PFO with ASA it might make sense to close PFO
Unclear if this data will apply to small PFO, PFO without ASA, patients with TIA and not ischemic stroke, or patients >60 years old
PFO
PELVIS study evaluated young stroke patients with MRV of pelvis to look for pelvic DVT
95 patients, 46 cryptogenic, 49 known etiology 9 patients found to have pelvic DVT on MRV in cryptogenic
arm 2 patients found to have pelvic DVT in the other arm
Pelvic DVT found more often in cryptogenic stroke patients but was not significant.
Small number of patients evaluated Could be reasonable to obtain in young patient with PFO and
otherwise cryptogenic stroke
PELVIC THROMBI
ILIAC VEIN DVT
Autopsy study of patients with AA Atheroma-26% of patients with stroke had ulcerated plaque
AORTIC ARCH ATHEROMA
IMAGING FOR AAA
Atheromas that are >4mm in thickness, ulcerated or mobile, located at proximal or arch of aorta more likely to cause stroke/TIA
Patent Foramen Ovale in Cryptogenic Stroke Study (PICSS) trial, aspirin vs warfarin, followed for recurrent stroke/tia
Patients had TEE Plaque >4mm had increased recurrent events (adjusted
hazard ratio [HR], 2.12; 95% confidence interval [CI], 1 .04 to 4.32)
Event rates similar for warfarin and aspirin groups in the overall study population (16.4% versus 15.8%; P=0.43).
AORTIC ATHEROMA
To assess cryptogenic stroke patients, TEE is the gold standard, even though TTE is used as screening.
TTE identifies abnormality in 0.7% of patients without known cardiac disease
TTE is basically useless in determining cause of stroke in a young person without heart disease
PARADOXICAL AND AORTOGENICEMBOLISM
Goal to see what is optimal antithrombotic strategy 349 patients, Age >18, mRS <4 with stroke, TIA or peripheral
embolism Found to have atherosclerotic plaque in thoracic aorta on TEE Exclusions: no other cardiac source of embolism, no
extracranial or intracranial stenosis, no arterial dissection, no contraindication to anticoagulation, aspirin or plavix.
Randomized 1:1 to aspirin plus clopidogrel OR warfarin (INR 2-3)
ARCH TRIAL
ARCH TRIAL
ARCH TRIAL
A + C (n=172) Warfarin (N=177)
Sex, male 119 (69.2) 131 (74.0)
Qualifying event
Stroke 113 (65.7) 122 (68.9)
TIA 58 (33.7) 55 (31.1)
Peripheral Embolus 1 (0.6) 0
Results: Primary endpoint is combination of stroke, MI, peripheral
embolism, vascular death, intracranial hemorrhage A+C
13 events Warfarin
20 events Hazard ratio 0.76 (0.30-1.6.1) P= 0.5 TTR 67% Non-significant 24% reduction in endpoint from dual
antiplatelet vs warfarin
ARCH RESULTS
Stopped for futility after 8 years Trouble recruiting patients Sample size they thought they needed would be 744 patients
per arm Actual size was 172 and 177 for A+C and Warfarin
respectively
Still not sure what to do for Arch atheroma Unless they have a flopping thrombus, I usually use
antiplatelet plus high dose statin
ARCH TRIAL
HYPERCOAG & ASSOCIATION WITH STROKE
Inherited thrombophilias (eg, protein C, protein S, or antithrombin III deficiency; factor V Leiden; prothrombinG20210A mutation), and MTHFR Rarely contribute to adult stroke May play a larger role in pediatric stroke
Studies in younger patients (<55 years of age) have shown an association between prothrombotic genetic variants and ischemic stroke Remains controversial in an older population with vascular risk factors
Even in the young, results have been inconsistent Small study of cryptogenic stroke patients <50 years of age Increased risk associated with the PT G20210A mutation No significant association with FVL
2 other studies of young (<50 years) patients Found no association between ischemic stroke and the FVL, PT G20210A, or
MTHFR The association between APL antibodies and stroke is strongest
for young adults (<50 years of age)
Furie KL, et al. Guidelines for the Prevention of Stroke in Patients with Stroke or Transient Ischemic Attack: A Guideline for Healthcare Professionals. Stroke. 2011;42:227-276.
“HYPERCOAG W/U”
Common causes of venous thrombosis are unlikely to cause stroke Activated Protein C resistance/Factor V Leiden Protein C, Protein S, Antithrombin III Prothrombin mutation This “typical” hypercoagulable panel is low yield in arterial stroke These tests are more high yield in CVT
In young patients without known etiology/risk factors anticardiolipin and lupus anticoagulant are high yield Should also order beta-2 glycoproteins
MTHFR and homocysteine are not helpful-DO NOT ORDER Testing in the acute phase can be misleading—need to
repeat at 12 weeks Testing should be done off of heparin or warfarin or NOAC
This is not clear. Recommendations I have seen from Heme many times in past: If heterozygous (or homozygous) for FVL and no prior clot then
aspirin If positive for LAC/APL and no prior clot then aspirin If LAC/APL persistently positive and no prior clot then aspirin
or clopidogrel If recurrent events sometimes clopidogrel or anticoagulation
The utility of ordering these studies for arterial stroke is low for the most part.
WHAT IF IT’S POSITIVE?
15% of cancer patients had thromboembolic complication during the course of treatment
Stroke in cancer patients can be unrelated to cancer (conventional stroke mechanism), cancer-related (hypercoagulable state), or treatment related
Cancer leading to venous thromboembolism is well known Thrombophlebitis migrans may appear months or years before
malignancy is discovered Could cryptogenic stroke be related to undetected malignancy
OCCULT CANCER RELATED COAGULOPATHY
Study out of South Korea, looked at patients with neurologic symptoms, DWI lesion, sufficient diagnostic work up, and D-Dimer
They excluded all cases that were not cryptogenic They divided them into cryptogenic strokes with active cancer
(diagnosis in 6 months previous), and cryptogenic without active cancer
348 patients, 71 in active cancer group, 277 in just cryptogenic group
OCCULT CANCER
The two cryptogenic groups were compared with a Cancer-control group that did not have stroke
Plasma levels of D-dimer were significantly higher in the cancer-stroke group than in the cancer control group.
D-dimer levels were 20x higher in cancer-stroke group than in non-cancer cryptogenic group
Cancer-stroke group also had dif ferent infarct pattern on MRI, multiple infarcts in multiple vascular territories
The non-cancer cryptogenic group usually had single or multiple lesions in a single vascular territory
OCCULT CANCER
OCCULT CANCER
10 patients in the non-cancer stroke group who had elevated d-dimer and characteristic MRI patternAll 10 were found to
have occult malignancy during hospitalization
OCCULT CANCER
Stroke, cancer, cancer treatment can all cause D-dimer elevation so it isn’t very specific by itself
Another study following cancer patients with MCA stroke used TCD monitoring for embolic signals
Patients without conventional stroke mechanisms were more likely to have embolic signal on TCD
Embolic signals also more likely to be found in patients with elevated D-dimer
Elevated D-dimer and presence of adenocarcinoma more likely to have embolic signals
D-dimer levels decreased with use of anticoagulation
D-DIMER
What must you do? Vessel imaging, LDL, hgba1c for all TTE for almost everyone, TEE for some, cardiac
MRI/CCTA not very often Telemetry, holter on d/c, 30 day event monitor with
autotrigger algorithm, consider loop recorder Hypercoagulable panel—usually only for younger
patient or venous thrombosis CT chest/abd/pelv—if suspicion for occult
malignancy is high
LASER FOCUS OR KITCHEN SINK
The number of strokes that are “cryptogenic” is high Cryptogenic stroke seen more often in young people Young people are likely to be debilitated by stroke and have
recurrence of stroke Determining mechanism of stroke leads to changes in
secondary prevention Work up for AF, PFO treatment, Aortic arch atheroma or
inherited thrombophilia may lead to decreased recurrent cryptogenic stroke
The ideal treatment for ESUS is currently being studied
CONCLUSIONS
THANK YOU
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P a t t o n K K , H e c k b e r t S R , A l o n s o A , B a h r a m i H , L i m a J A , B u r k e G , e t a l . N - t e r m i n a l p r o - B - t y p e n a t r i u r e t i c p e p t i d e a s a p r e d i c t o r o f i n c i d e n t a t r i a l f i b r i l l a t i o n i n t h e M u l t i - E t h n i c S t u d y o f A t h e r o s c l e r o s i s : t h e e f f e c t s o f a g e , s e x a n d e t h n i c i t y . H e a r t . 2 0 1 3 ; 9 9 : 1 8 3 2 – 1 8 3 6 .
K i m S J , R y o o S , H w a n g J , N o h H J , P a r k J H , C h o e Y H , e t a l . C h a r a c t e r i z a t i o n o f t h e i n f a r c t p a t t e r n c a u s e d b y v u l n e r a b l e a o r t i c a r c h a t h e r o m a : D W I a n d m u l t i d e t e c t o r r o w C T s t u d y . C e r e b r o v a s c D i s . 2 0 1 2 ; 3 3 : 5 4 9 – 5 5 7 .
A m a r e n c o P , D a v i s S , J o n e s E F , C o h e n A A , H e i s s W D , K a s t e M , L a o u é n a n C , Y o u n g D , M a c l e o d M , D o n n a n G A ; A o r t i c A r c h R e l a t e d C e r e b r a l H a z a r d T r i a l I n v e s t i g a t o r s . C l o p i d o g r e l p l u s a s p i r i n v e r s u s w a r f a r i n i n p a t i e n t s w i t h s t r o k e a n d a o r t i c a r c h p l a q u e s . S t r o k e . 2 0 1 4 M a y ; 4 5 ( 5 ) : 1 2 4 8 - 5 7
K i r c h h o f P , B e n u s s i , S , K o t e c h a D , e t a l . 2 0 1 6 E S C G u i d e l i n e s f o r t h e m a n a g e m e n t o f a t r i a l f i b r i l l a t i o n d e v e l o p e d i n c o l l a b o r a t i o n w i t h E A C T S . E u r H e a r t J . P u b l i s h e d o n l i n e A u g u s t 2 7 , 2 0 1 6 . A c c e s s e d o n l i n e A u g u s t 3 1 , 2 0 1 6 a t : h t t p : / / e u r h e a r t j . o x f o r d j o u r n a l s . o r g / c o n t e n t / e a r l y / 2 0 1 6 / 0 8 / 2 6 / e u r h e a r t j . e h w 2 1 0
A m a r e n c o P , D u y c k a e r t s C , T z o u r i o C , H é n i n D , B o u s s e r M G , H a u w J J . T h e p r e v a l e n c e o f u l c e r a t e d p l a q u e s i n t h e a o r t i c a r c h i n p a t i e n t s w i t h s t r o k e . N E n g l J M e d . 1 9 9 2 ; 3 2 6 : 2 2 1 – 2 2 5
D i T u l l i o M R , R u s s o C , J i n Z , S a c c o R L , M o h r J P , H o m m a S ; P a t e n t F o r a m e n O v a l e i n C r y p t o g e n i c S t r o k e S t u d y I n v e s t i g a t o r s . A o r t i c a r c h p l a q u e s a n d r i s k o f r e c u r r e n t s t r o k e a n d d e a t h . C i r c u l a t i o n . 2 0 0 9 ; 1 1 9 : 2 3 7 6 – 2 3 8 2
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