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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