CME INDIA Presentation by Dr. Manan Mehta, MD, DM Neurology, Mehta Neurology Center, Vadodara.

Stroke stands as the fifth leading cause of death. In US it presents as two primary subtypes: hemorrhagic, constituting 17%, and ischemic, making up 83% of cases. Cryptogenic strokes, accounting for 15-40% of all strokes, add complexity to the landscape.

Notably, women face a higher lifetime risk of stroke compared to men. Additionally, racial disparities emerge, with Blacks and Hispanics experiencing a greater incidence of ischemic strokes than Caucasians. Historically, cryptogenic stroke incidence skewed towards older patients, but recent findings from the Northern Manhattan Stroke Study (NOMASS) challenge this trend, suggesting a higher incidence. Here we present few eye-opening cases of cryptogenic stroke.

Cryptogenic Stroke - What Physicians Must Know?

First see this case

  • 65/F
  • HTN – Well controlled
  • No cardiac Illness
  • Normal Lipids
  • Acute onset altered sensorium – with quadriparesis (right > left)
  • RBS – 200
  • ECG – Sinus rhythm, Normal
Cryptogenic Stroke - What Physicians Must Know?
Cryptogenic Stroke - What Physicians Must Know?

What happened later?

  • Holter – WNL
  • Negative ANA
  • Transesophageal ECHO – normal
  • DSA – normal Angio and Veno

Diagnosis

  • Embolic Stroke of Undetermined Source
  • Treatment with Antiplatelet and statin
  • Patient is doing very well

Need to know 3 terms

  • Etiology
  • Risk factors
  • Mechanism

Toast Classification

Cryptogenic Stroke - What Physicians Must Know?

Classifying Ischemic Stroke, from TOAST to CISS. Courtesy: Chen PH, Gao S, Wang YJ, Xu AD, Li YS, Wang D. Classifying Ischemic Stroke, from TOAST to CISS. CNS Neurosci Ther. 2012 Jun;18(6):452-6

(A) Large Vessel Occlusion

  • ICA, MCA(M1) or Vertebro-Basilar
  • More deficits
  • Poor outcome
  • Smoking, DM, Hyperhomocystenemia
  • Thrombolysis and Mechanical Thrombectomy
Cryptogenic Stroke - What Physicians Must Know?

Brain MRI findings. (A) MR angiography demonstrates loss of flow distal to the right middle cerebral artery bifurcation. (B) Axial diffusion-weighted image showing hyperintensity in the territory of right middle cerebral artery

(B) Cardio Embolic

  • Atrial Fibrillation
  • Valvular Heart Disease
  • Severe LV dysfunction
  • LAA thrombus/ LV clot
  • Infective endocarditis
  • Anticoagulation is the treatment of choice
Cryptogenic Stroke - What Physicians Must Know?

(C) Small Vessel Arteriosclerosis

  • Lacunar strokes – Basal ganglia, Internal Capsule and Pons
  • Hypertension
  • Dyslipidemia
  • DM
  • Double Antiplatelets and Statins
  • Risk Factor Modifications
Cryptogenic Stroke - What Physicians Must Know?

Lacunar infarct MRI

D) Stroke of Other determined Etiology

  • Vasculitis  
  • Dissection
  • Drug Abuse
  • Arteritis
  • Vasospasm

(E) Brain infarction – not attributable to

  • Any source of definite cardio-embolism
  • Large artery atherosclerosis
  • Small artery disease
  • Despite a standard vascular, cardiac, and serologic evaluation
  • Embolic stroke of undetermined source — (ESUS) represents a subset of cryptogenic stroke
  • 20-30%

Possible Mechanisms for Cryptogenic Stroke

Paroxysmal AF
Aortic Arch Atheromas
Hypercoagulable States (Occult malignancy, Post Pregnancy, Genetic)
Paradoxical Embolism (PFO, ASD)
Sub stenotic (<50%) Atherosclerotic vessels
Others

Paroxysmal AF

Usually missed on ECG and short-term cardiac monitor
Requires at least 72 hours of Holter
Loop Recorder devices – 7-30 days (ambulatory)
Anticoagulation is a reasonable choice once AF detected
Usually missed on ECG and short-term cardiac monitor
Requires at least 72 hours of Holter
Loop Recorder devices – 7-30 days (ambulatory)
Anticoagulation is a reasonable choice once AF detected

Arch of Aorta – Plaques

  • Common source of Embolus
  • Complex plaque – Ulcerated or > 4mm
Cryptogenic Stroke - What Physicians Must Know?

Courtsey:https://www.stroke-manual.com/aortic-arch-atherosclerosis/

Paradoxical Embolism

  • PFO, ASD
  • Determined mainly on TEE and Bubble study
  • RoPE score
Cryptogenic Stroke - What Physicians Must Know?

Courtsey: https://www.stroke-manual.com/patent-foramen-ovale-pfo/

  • The RoPE score evaluates the likelihood that a detected PFO in the context of an otherwise cryptogenic stroke is causally linked to the stroke rather than being an incidental discovery. The RoPE score has a scale of 0 to 10, where scores of 0 to 3 suggest a minimal likelihood of the stroke being attributed to the PFO, and a score of 10 indicates an approximately 90% probability of the stroke being linked to the PFO.
  • PASCAL integrates the RoPE score with the presence or absence of high-risk PFO features to assess the probability of the PFO being causally associated with the index stroke.
Cryptogenic Stroke - What Physicians Must Know?

Courtesy: The RoPE Score and PASCAL Classifications. Available from: https://www.ncbi.nlm.nih.gov/books/NBK592989/table/tbl001

ASA, atrial septal aneurysm; LS, large shunt; PASCAL, PFO-Associated Stroke Causal Likelihood; PFO, patent foramen ovale; RoPE, Risk of Paradoxical Embolism.

SCOPE Study (2023): It showed that among patients aged 18 to 60 years with PFO-associated stroke, risk reduction for recurrent stroke with device closure varied across groups classified by their probabilities that the stroke was causally related to the PFO.

Sub-Stenotic Atherosclerosis

  • < 50% stenosis
  • But – Unstable plaque, Intraplaque hemorrhage, > 3mm, Rupture of Plaque
  • Vessel Wall Imaging
Cryptogenic Stroke - What Physicians Must Know?

VW-MR imaging to differentiate among causes of intracranial arterial stenosis when angiography findings are inconclusive. This patient had multiple recent infarcts in the pons. MR angiogram

Courtsey: American Journal of Neuroradiology February 2017, 38 (2) 218-229; DOI: https://doi.org/10.3174/ajnr.A4893

Others

  • Occult Malignancy
    • Elderly, Raised D-Dimer, constitution symptoms
    • Hypercoagulable state
    • APLA, hyperhomocytenemia, other genetic
  • RVCS
    • Eclampsia, Vasospasm, Drugs (tacrolimus, vincristine, cocaine)
  • Dissection
    • Neck Manipulation, Trauma
  • Vasculitis
    • Lupus, Takayasus, Primary CNS vasculitis

See this case

  • Orthopedic Resident
  • Sudden jerk during Fracture reduction
  • Heard an abnormal sound in the neck
  • Acute Ataxia with vomiting
  • Smoked very occasionally
  • No family history of stroke
  • All traditional work up was negative

Right Cerebellar Infarct – Right VA Dissection

Cryptogenic Stroke - What Physicians Must Know?

Case

  • Post Renal Transplant
  • Day 18
  • Sudden Confusion and vision loss
  • On Tacrolimus
  • S. Tac level – 22 ng/ml
  • Post Renal Transplant
  • Day 18
  • Sudden Confusion and vision loss
  • On Tacrolimus
  • S. Tac level – 22 ng/ml
Cryptogenic Stroke - What Physicians Must Know?

RCVS – Reversible Vasoconstriction Syndrome

Case

  • 18-year-old Boy
  • DOI – 7 Months
  • Failed in 12th
  • Depression – suicidal attempts
  • Headache
  • Change of Personality

Acute right Hemiparesis – 3 days

Cryptogenic Stroke - What Physicians Must Know?

Primary CNS Vasculitis

  • Raised ESR, CRP
  • Normal Routine profile
  • Normal ECHO
  • Normal TEE
  • Negative ANA
  • DSA – Classical Stenosis and Ballooning (Beaded Appearance)
Cryptogenic Stroke - What Physicians Must Know?

Work up in Cryptogenic Stroke

Traditional Work up: DM, HTN, Lipids, ECG, Echo, Doppler
High suspicion of embolism
Holter or Long-term Ambulatory Recorders
Transesophageal ECHO with Bubble study
Atheromatous Plaques
Arch of Aorta
Vessel Wall Imaging (unstable Plaques)
Other depending on the history
ANA, APLA, Homocysteine, Sickle cell, Look for dissection, Drugs
Cryptogenic Stroke - What Physicians Must Know?

Treatment for Cryptogenic Stroke

  • Acute Therapy remains same – IV TPA/TNK and Mechanical Thrombectomy
  • For long term
    • Depends on the etiology that we establish
    • Also – BASICS remain the same
      • Smoking, Tobacco, Sugar, BP and Lipids
  • ESUS/Cryptogenic – Single stroke – Antiplatelet > Anticoagulation
  • ESUS/Cryptogenic – Recurrent – Anticoagulation (DOAC)
  • Presence of AF – Anticoagulation (DOAC)
  • PFO – Closure
  • Compared with other stroke subtypes, cryptogenic stroke tends to have a better prognosis and lower long-term risk of recurrence.

CME INDIA Tail Piece

Cryptogenic Stroke - What Physicians Must Know?

Another Important Article by Author

Editor’s Choice:

https://www.stroke.org/-/media/Stroke-Files/Cryptogenic-Professional-Resource-Files/Cryptogenic-Stroke-Education-Deck.pdf

References:

  1. Chen PH, Gao S, Wang YJ, Xu AD, Li YS, Wang D. Classifying Ischemic Stroke, from TOAST to CISS. CNS Neurosci Ther. 2012 Jun;18(6):452-6. doi: 10.1111/j.1755-5949.2011.00292.x. Epub 2012 Jan 24. PMID: 22268862; PMCID: PMC6493455.
  2. Kent DM, Saver JL, Kasner SE, et al. Evaluating Therapies to Prevent Future Stroke in Patients with Patent Foramen Ovale-Related Strokes — The SCOPE Study [Internet]. Washington (DC): Patient-Centered Outcomes Research Institute (PCORI); 2023 Apr. Table 1, The RoPE Score and PASCAL Classifications. Available from: https://www.ncbi.nlm.nih.gov/books/NBK592989/table/tbl001/ doi: 10.25302/04.2023.RS.SCOPE2019001
  3. Kent DM, Saver JL, Kasner SE, et al. Evaluating Therapies to Prevent Future Stroke in Patients with Patent Foramen Ovale-Related Strokes — The SCOPE Study [Internet]. Washington (DC): Patient-Centered Outcomes Research Institute (PCORI); 2023 Apr. Available from: https://www.ncbi.nlm.nih.gov/books/NBK592989/ doi: 10.25302/04.2023.RS.SCOPE2019001
  4. Benjamin EJ, Muntner P, Alonso A, et al. Heart disease and stroke statistics-2019 update: a report from the American Heart Association. Circulation 2019;139:e56-e528.
  5. White H, Boden-Albala B, Wang C, et al. Ischemic stroke subtype incidence among whites, blacks, and hispanics: the Northern Manhattan Study. Circulation 2005;111:1327-31.
  6. Williams LS, Garg BP, Cohen M, Fleck JD, Biller J. Subtypes of ischemic stroke in children and young adults. Neurology 1997;49:1541.
  7. American Journal of Neuroradiology February 2017, 38 (2) 218-229; DOI: https://doi.org/10.3174/ajnr.A4893
  8. Acampa, M., Lazzerini, P.E., Lattanzi, S. et al. Cryptogenic stroke as a working diagnosis: the need for an early and comprehensive diagnostic work-up. BMC Neurol 23, 153 (2023). https://doi.org/10.1186/s12883-023-03206-6


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