Differential Diagnosis in Neurology

Topic 1. Vascular Disease

1.4. Cerebral Emboli

The general clinical features of cerebral emboli are a sudden neurological deficit maximum at onset. There is usually some degree of recovery within 24 hours. Carotid crescendo TIA's are caused by emboli from an area of critical stenosis associated with a burst plaque. The lipid core of the burst plaque activates platelets and the coagulation cascade with consequent detachment of platelet plugs and red cell fibrin material into the carotid territory. Frequently, the crescendo carotid TIA from emboli results in repeated monocular blindness described as blurry vision or dimness which is different from a patient with severe carotid stenosis. Sudden exposure to light in these patients may cause scotomata due to failure of replenishment of retinal pigments. Distal field ischemia with blindness, contralateral sensory loss or weakness may occur with postural lowering of perfusion pressure. These attacks are more frequent than those that occur following a burst plaque. Distal field ischemia may be manifest by shaking of the contralateral area with decreased perfusion. Similar attacks occur in the posterior circulation. These are rapid and clear quickly without a clinical deficit.

Emboli most often occur during the usual activities of daily living. Often an embolus occurs during a Valsalva maneuver which suggests a PFO, atrial septal defect or ventricular septal defect. Getting up to urinate in the middle of the night is often a common time for the occurrence of emboli. Cardiac emboli (red-fibrin dependent) are larger than cholesterol or platelet fibrin aggregates and the deficits last> 30 minutes to hours. Deficits from the smaller cholesterol platelet-fibrin emboli in general last from 30 seconds to five minutes. Fluctuations and deterioration within specific territorial involvement occurs with distal migration of embolic material. Approximately 90% of emboli migrate in 2–3 weeks or recanalize. Emboli from the heart or venous system have no prior TIA in the affected arterial territory but may have caused TIA's in another arterial territory.

The most common symptoms of emboli are non-specific headaches or dizziness which are hard to document. Seizures occur in 10–15% of patients, 25% of patients have focal symptoms. The sudden onset of a pure Wernicke's aphasia in the setting of AF suggests an embolus to the inferior division of the left MCA. Muteness may be caused by an embolus to the stem of the MCA or an ACA embolus that affects the supplementary motor area. Thalamic aphasia may occur with a top of the basilar embolus. Ten percent of patients suffer loss of consciousness at ictal onset. Many cerebral emboli are asymptomatic which has been clearly demonstrated by evidence of old lesions at presentation during the first ictus and by multiple emboli detected by TCD during carotid endarterectomy. Simultaneous involvement of ACA and MCA territories suggest a top of the carotid siphon localization.

In approximately 50% of patients there are RBC's in the CSF (80–100/mm3) at presentation.

Cardiogenic Embolic

The majority of patients that suffer cerebral cardiogenic emboli have ischemic heart disease, non-valvular atrial fibrillation, prosthetic heart valves and various forms of dilated cardiomyopathy. The rarer causes of cerebral cardiogenic emboli are heart tumors, congenital right to left shunts, subacute bacterial endocarditis, mitral annulus calcification, mitral valve prolapse, venous clots that pass through a patent foramen ovale (PFO), atrial septal aneurysm, fat, air, septic material and fibromyxomatous degeneration of heart valves.

Clinical Features of Cardiac Emboli

  • An abrupt onset of hemiparesis, aphasia (particularly Wernicke's in a setting of AF), sensory deficit or hemianopic visual field loss.
  • MCA > PCA > ACA are the most frequent territories affected
    • Some lacunar strokes may be embolic (several vessels affected that produce large lacunes)

Preceding Symptoms and Signs

  • 10% may have prodromal symptoms prior to the presenting ictus:
    • Stuttering focal deficits occur due to:
      • Distal movement of prior embolus
      • Collateral circulation
      • Recanalization
    • Cerebral infarction from cardiac emboli may be preceded by TIA's that are longer with a more severe neurologic deficit than artery to artery emboli.
      • Cardiogenic emboli cause minutes to hours of deficit
      • Artery to artery <2 minutes of deficit
  • Anterior Circulation Clinical Pattern:
    • Focal motor, sensory deficits with or without aphasia
    • Muteness
      • Stem MCA
      • ACA (supplementary motor area)
    • Seizures in approximately 10%
    • <10% loss of consciousness at ictus
    • Several vascular territories may be involved simultaneously
      • Multifocal neurologic deficits
    • Evidence by imaging of prior embolic events

Vertebrobasilar Signs and Symptoms of Cardiac Emboli

  • Most often the embolus lodges at the top of the basilar artery with midbrain, thalamic, parietal and occipital lobe symptomatology
    • Diplopia
    • Ataxia
    • Vertigo
    • Crossed or bilateral sensory or motor deficits
    • Rarely coma at onset

Myocardial Infarction and Ischemic Heart Disease as a Source of Emboli

  • Arterial emboli occur in 2–4% of patients after myocardial infarction
  • Time of occurrence
    • 10% in the first week
    • 35% in the second week
    • 15% in the third week
    • 5% in the 3rd month
    • Newer studies suggest the first 5 days are the major time of risk
  • Mural thrombi occur with higher incidence in:
    • Large infarctions
    • Transmural infarction involving the intraventricular septum
    • Associated congestive failure
    • Anterior > posterior wall
    • Severe apical wall dyskinesia
    • 75% of major anterior transmural infarctions have dyskinesias
    • Most mural thrombi identified by TEE (transthoracic echocardiography) can be seen in 3–5 days
      • Embolize at 4 days
      • Rare after 4–6 weeks to embolize
  • Thrombi within cardiac chambers are due to:
    • Stasis of blood that initiates:
      • Activation of factor XII and endothelin from the cardiac surface
    • Endothelial cardiac wall injury
      • Loss of endothelium
      • Change of negative to positive charge on the cardiac endothelial surface and exposed collagen
      • Platelet aggregation at the site of charge change
    • Prothrombotic State is initiated:
      • Low shear rate of circulating RBC within the cardiac chambers
    • Echocardiographic correlates of ventricular dysfunction
      • Spontaneous ECHO contrast ("smoke")
        • Swirling haze within cardiac chambers
        • Interaction of plasma protein, erythrocytes and shear rate
      • Determinants of "smoke"
        • Slow intracardiac flow
        • Hematocrit
        • Fibrinogen level

Left Ventricular Thrombi

  • Occur in 20–40% of patients with anterior wall myocardial infarction
  • Form in the apical wall of the left ventricle
  • Mechanisms
    • Low ejection fraction
    • Left ventricular aneurysm
    • Dyskinesia from decreased contractibility

Mural Thrombi in Ventricular Aneurysms

  • 7.6% of patients develop intraventricular aneurysms after an MI
  • Mural thrombi occur in 50% of ventricular aneurysms
  • Clinical emboli occur in 1–3% of patients per year
  • Usually occur within 4–6 weeks after MI

Impaired Left Ventricular Contraction

  • Risk of stroke is 4.6%
  • Ejection fraction of less than 28% is the highest risk
  • Asymptomatic or unexpected cardiac ventricular thrombi
    • Patient with stroke is noted to have cardiac thrombi without known coronary artery disease
    • Known cardiac thrombi may regress

Arrhythmia and Cerebral Emboli

  • Most common arrhythmias associated with stroke:
    • Chronic atrial fibrillation
    • Intermittent atrial fibrillation
    • Sick sinus syndrome
  • The majority of cardiogenic emboli are cerebral

Cardiac Arrthymia

Atrial Fibrillation (AF)

  • General characteristics:
    • 2–5% of the population > 60 have AF
    • 35% of patients with AF will have an ischemic stroke over their life time
    • Approximately 4% of AF patients suffer a stroke each year
    • AF with no associated risk factors <2% of stroke per year
  • AF with known risk factors:
    • Approximately 6% strokes per year
    • AF and stroke; 75% have had an ischemic event secondary to AF
    • AF plus RHD
      • 17 fold increase of stroke risk
    • AF without RHD
      • 5.6 fold increase of stroke risk
    • AF increases risk of stroke with age
    • AF increases the risk of silent infarction
    • 25% of stroke patients >70 years of age have non-valvular AF
    • NVAF -- 3× greater risk of stroke related death
    • Left atrial enlargement and decreased function causes increased risk of cardiac emboli
    • Embolus rate highest after the onset of dysrhythmia
    • 12% of patients' cardioverter for AF suffer an embolus within the first few days of the procedure.
  • Causes of AF:
    • 10–30% of AF no identifiable cardiovascular disease
    • Identified causes
      • Dilated left atrium in mitral stenosis
      • Thyrotoxicosis
      • Pericarditis
      • Ischemic cardiac disease
  • Origin of embolic material:
    • Left atrium or the left atrial appendage
      • 15–50% of valvular atrial fibrillation (VAF) have thrombi in the left atrium
      • Autopsy evidence of arterial emboli in 40% of non-valvular atrial fibrillation (NVAF)
    • Valvular disease with AF
      • 9–29% have left atrial thrombi

Clinical Features of AF

  • Acute Wernicke's aphasia as sole clinical finding:
    • Embolus to the temporal-parietal occipital branch of the inferior division of the MCA
  • Highest risk for embolization:
    • Evidence of rheumatic heart disease
    • Onset of AF within the preceding 3 months
    • An enlarged left atrium

Recurrent Embolism in Non-Valvular AF (NVAF)

  • 50% of patients with cerebral embolism from AF suffer a second embolic stroke
  • Recurrence is greatest the first days to weeks (15–20% of patients); some evidence that the greatest risk is at 12–24 hours

Paroxysmal Atrial Fibrillation

  • Cerebral emboli occur during a paroxysm of AF
  • Thrombi form during the arrhythmia
  • Cerebral rather than peripheral arteries are affected
  • 2% may occur at the time of cardioversion

Sick Sinus Syndrome

  • Chaotic atrial activity
  • Changing p wave contour
  • Bradycardia with:
    • Multiple recurrent ectopic beats
    • Runs of atrial and nodal tachycardia
  • Associated arrhythmias:
    • AF or atrial flutter with slow rate of response (70 beats per minute)
    • Sinoatrial arrest
    • Atrial tachycardia
    • Sinus bradycardia
  • 29.9% of men and 1.5% of women >75 years may suffer the syndrome
    • 14–18% of patients suffer cerebral emboli
  • The sinoatrial disease at greatest risk for embolism is the brady-tachy syndrome. A greater risk than sinoatrial disease without tachycardia or atrioventricular block
    • Emboli are more common with prolonged atrial asystole
    • Tachyarrhythmias > bradyarrhythmias are more likely to embolize

Rare Causes of Emboli with Arrhythmia

  • Romano Ward Syndrome (AD)
  • Long QT Syndrome
    • Jervell
    • Lang–Nielsen

Rheumatic Heart Disease

  • Majority of RHD patients with cerebral emboli have mitral stenosis (10–20%)
  • Mitral insufficiency (MI) and aortic valve disease are the second most common cause of cerebral emboli in RHD
  • Mitral stenosis:
    • Thrombi form in the left atrium
    • Rarely on the valve
  • 50–75% of RHD patients have AF or other arrhythmias at the time of an embolus
  • Majority of RHD patients with mitral stenosis have a normal sinus rhythm
    • AF greatly increase stroke risk
  • Systemic emboli occur in 10–49% of patients with RHD

Sites of Origin of Artery-to-Artery Emboli

  • Site of Origin
    • Artery-to-artery embolism
      • Carotid System
        • Bifurcation of common and external carotid arteries
        • T-portion (ACA and MCA) at the siphon
        • From giant distal aneurysms (carotid; MCA)
        • Embryologic connections from the basilar artery to the carotid (rare cause of posterior circulation embolus to reach the anterior circulation)
          • Trigeminal
          • Otic
          • Hypoglossal
          • Proatlantal
      • Intimal tears from dissection of the carotid are a source of emboli
        • repair of carotid ulcers or stenosis
    • Vertebrobasilar system sources:
      • Arch of the aorta (mobile plaques)
      • Vertebral artery
      • Basilar artery
      • Dolichoectatic vertebral basilar artery
      • Giant aneurysms
      • 1. Tip of the basilar
    • Predilection for specific sites of embolic termination
      • Arterial bifurcations
      • Pial superficial MCA branches
      • Upper and lower trunks of the MCA
      • Distal basilar artery (top of the basilar)
      • Posterior cerebral arteries
      • Areas of greatest CBF:
      • 1. 40% of anterior circulations emboli go to MCA territory
      • Tendency to affect same location within an arterial territory
      • 1. Laminar flow
      • Aortic arch is the source of 25% of posterior circulation emboli
      • 25% of emboli go to VB system (less than 20% of blood flow goes to this circulation)

Cardiogenic Site of Origin

General Features

  • Ejection fraction less than 40%:
    • Contact factors of clotting mechanisms are activated (slow blood flow)
    • Large atria
    • Areas of muscle hypokinesia in the ventricles
  • Valve leaflets:
    • Activation of platelets by shear forces
    • Consequent dilatation of left atrium with arrhythmia
    • Nidus for infection
    • Platelet fibrin deposition from prothrombotic conditions
      • Non-bacterial thrombotic emboli
    • Myxomatous valve and chordae tendinea degeneration
    • Calcific aortic valve degeneration
  • Patent foramen ovale (PFO)
  • Atrial septal aneurysm (ASA)
  • Combination of PFO + ASA
  • Cardiac tumors:
    • Primary
    • Metastatic
  • Less common types and sources of emboli:
    • Lodge in the carotid artery (Calcium; cartilage)
    • Vertebrobasilar arteries at sites of narrowing

Valvular Heart Disease as a Source of Emboli

General Characteristics:

  • Approximately 10–20% of patients with valvular heart disease embolize
  • Valvular outlet obstruction is caused by:
    • Commisural adhesions
    • Leaflet dystrophic calcification
  • Functional properties of stenotic valves:
    • Decreased pliability
    • Irregular surfaces
    • Turbulent blood flow
  • Platelets are activated by turbulence
  • Thrombus formation is related to valve device turbulence
  • Abnormalities of blood flow distal to stenotic or incompetent valves cause:
    • Prolonged contact of blood and platelets
    • Formation of platelet and red cell fibrin thrombi
  • Atrial and ventricular enlargement from stenotic or incompetent valves:
    • Enlarged left atria (mitral stenosis or incompetence)
    • Prolonged contact of blood and platelets with cardiac and valve surfaces induces thrombus formation

Cause of Valvular Heart Disease Associated with Emboli

  • Rheumatic mitral and aortic valve stenosis and incompetence
  • Bicuspid aortic valve (congenital)
  • Mitral annulus calcification
  • Calcific aortic stenosis
  • Mitral valve prolapse
  • Bacterial endocarditis
  • Non-bacterial thrombotic endocarditis
  • Prosthetic heart valves
  • Left ventricular assist devices (LVAD)
  • Anti-phospholipid syndrome
  • Fibrin valvular excressences

Aortic Valve Disease

  • General Characteristics
    • Progressive calcific aortic stenosis:
      • Develops in patients with congential bicuspid valves; becomes symptomatic in the 4–5th decade
      • Rheumatic valvulitis
      • Idiopathic
        • Develops in 6–8th decade
        • An atherosclerotic degenerative process
    • Microthrombi in 53% of stenotic valves at necropsy
    • Neurologic complications
      • Emboli possibly as high as 33% of patients with calcific stenosis
      • Associated emboli to:
        • Retina (white and irregular, calcium deposits)
        • Coronary arteries
        • Renal arteries
      • Embolization more common after cardiac catheterization or surgery than spontaneously
      • Mitral valve > aortic valve embolization
      • Incidence and clinical features of aortic insufficiency are unknown

Mitral Valve Disease

  • Valve most often involved in rheumatic fever
    • Often concomitant aortic valve disease
  • Embolism in mitral stenosis:
    • Occurs in 10–20% of patient's; approximately 50–75% of these are to the brain
    • Atrial fibrillation greatly increases the risk of embolism
    • Incidence of embolization possibly 1.5% per year
  • Mitral insufficiency is a rare cause of cerebral embolism:
    • Increased risk occurs with atrial enlargement and AF

Idiopathic Hypertrophic Subaortic Stenosis

  • Asymmetric hypertrophy of the left ventricular septum that causes:
    • Variable obstruction of left ventricular outflow from systolic anterior displacement of the mitral valve
    • Concomitant structural abnormality of the mitral valve
  • Clinical Features
    • Syncope with prolonged exercise:
      • Release of norepinephrine that constricts the myocardial septum
      • Epinephrine release from the adrenal that dilates skeletal muscle arteries; norepinephrine constricts the hypertrophied segment
      • Combination of peripheral vasodilation and ventricular outflow obstruction that induces hypotension after exercise
    • Atrial fibrillation associated with left atrial enlargement occurs late in the course of the disease with a low rate of cerebral embolization
    • Rare concomitant SBE of mitral valve or of the annulus calcification or may be causative

Mitral Annulus Calcification (MAC)

  • General characteristics
    • Degeneration of the fibrous support of the valve
    • Common in the elderly
    • Women > men
  • Clinical symptomatology:
    • Increased risk of stroke
      • Each millimeter of thickening on the echocardiogram increases the relative risk of stroke (RR) by 1.24
    • Calcification occurs
      • Posterior portion of the mitral annulus ring
      • May project into the cavity of the left ventricle
    • Often MAC is accompanied by MI and AF
    • May develop superimposed SBE

Mitral Valve Prolapse

  • Mid Systolic murmur
    • Failure of mitral valve leaflet to coapt
    • Some patients have abnormal left ventricular contractions
  • Most commonly diagnosed cardiac valve lesion:
    • Prevalence of 5–20% in the general population
    • Women > men
  • Pathology
    • Disruption of valve collagen by infiltration of myxomatous material
    • Thickened and elongated chordae tendinea
    • Infiltration of the mitral valve annulus
    • Fibrosis and thickening of the endocardial surface of the valve leaflets
  • Clinical symptomatology:
    • Small percentage of patients develop severe mitral insufficiency with CHF
    • AF may develop in elderly patients with MI and enlarged left atria
    • Associated with Marfan's syndrome, osteogenesis imperfecta and Ehlers–Danlos syndrome
    • Rare endocarditis on myxomatous valves
    • Low rate of cerebral embolization
  • Echocardiographic evaluation
    • 2 mm or greater movement of the coapted anterior or posterior valve leaflets
    • Valve leaflets are displaced into the left atrium during systole
    • Mitral valve thickening or redundancy
    • Regurgitation

Neurologic Features

  • Emboli occur in young patients often without other associated risk factors
  • Strokes and TIA occur
  • Approximately 10% of patients have AF concomitantly with the stroke
  • Platelet dysfunction is reported in some patients with MVP:
    • Shortened survival time
    • Increased levels of beta-thromboglobulin and platelet factor IV
  • Recurrent embolic stroke is rare

Prosthetic Heart Valves

  • General Characteristics
    • Dacron rings are a nidus for platelet activation and adhesion
    • Prosthetic material activates intrinsic clotting cascade; erythrocyte-fibrin thrombi form
    • Degeneration of bioprosthetic valves:
      • Deposition of white platelet fibrin thrombi
      • Cusp sinuses of bioprosthetic mitral valves:
        • Undergo fibrosis and calcification
        • Nidus for thrombi
  • Mechanical valves are:
    • Metal and carbon alloys
    • Bioprosthetic valves:
      • Heterography from pig and cow pericardium or valves
  • Non-tissue valves:
    • Thrombus forms at the component tissue interface or in areas of stenosis
  • Incidence of embolization is related to the degree of thrombogenicity:
    • Non cloth covered prosthetic valves > cloth covered prosthetic valves > tissue valves
  • Increased risk for embolization:
    • Caged ball valve prosthesis
    • Mitral valve (associated with AF)
    • Multiple prosthetic valves
    • Age > 70b years
    • AF
    • Decreased left ventricular ejection fraction
    • SBE
    • Pregnancy and the puerperium
  • Mitral valve embolize > aortic valves
  • Risk of bioprosthetic valve embolization equals that of mechanical valves that are adequately anti-coagulated
  • Size of the cerebral infarction is due to:
    • Size of the embolus
    • Stability of the embolus
    • Adequacy of the collateral circulation

Subacute Bacterial Endocarditis

  • General Characteristics:
    • Natural valves: staph aureus and group D streptococcus are the most common organisms
    • Prosthetic valves: aspergillus most common for early emboli; strep viridans for late emboli
  • New epidemiology:
    • Older patients
    • Intravenous drug abuse patients
    • Tricuspid valve is more frequently involved
  • 20% of patients with endocarditis suffer cerebral emboli:
    • Small cortical or subcortical bland infarcts
    • Large infarcts are secondary often to staph aureus
  • Valve pathology:
    • Calcified valves
    • Prosthetic valves
    • Rheumatic valves
    • Mitral valve prolapse
    • Myxomatous mitral valves
  • 30–40% of emboli may occur from normal valves
    • Aortic > mitral
  • 50% of infected prosthetic valves cause cerebral emboli
  • Neurologic complications are similar for native and prosthetic valves

Clinical Characteristics

  • Systemic symptoms:
    • Intermittent fever and fatigue
    • Backache is common, early
    • Embolization to other organs; large artery occlusion suggests fungus
    • Sterile vegetations may embolize

Systemic Symptoms

  • Intermittent fever and fatigue
  • Backache
  • Loss of weight and appetite

Neurologic Signs and Symptoms

  • Cerebral and retinal TIA
    • Most common early in the course of the infection
  • Brain ischemia
    • 15–19% of patients
  • Ischemic stroke may occur after treatment has started
  • Intracranial Hemorrhage
    • 2.8–7% of patients
    • Hemorrhagic transformation of bland infracts
    • Large hemorrhages occur:
      • Concomitant use of anticoagulants
    • Rupture of septic arteritis
    • Rupture of mycotic aneurysms
      • Occur in peripheral subpial vessels
    • ICH occurs at or near time of presentation
      • May have had a preceding TIA
    • Mycotic aneurysms may rupture after bacterial treatment

Encephalopathy

  • Most common with staph aureus:
    • Toxic metabolic factors
    • Secretion of interleukins (IL-6) with subsequent cerebral edema
    • Associated brain infarcts and microabscesses

Meningitis

  • Embolization of bacteria to meningeal arteries:
    • Presentation with neck and back pain prior to neurologic symptoms
    • 1.1–6.4% of patients with endocarditis have meningitis

Vegetations

  • Millimeters to centimeters in size
    • fungi are the largest
  • Potential for embolization is related to:
    • Size
    • Friability
  • Valve most like to embolize
    • Mitral > aortic > tricuspid

Endocarditis on Prosthetic Valve

  • Occurs in 3–6% of patients:
    • Early endocarditis <60 days; from perioperative bacteremia: skin, wound or contaminated valves; organisms: staph epidermidis or aureus, gram negative bacteria, diphtheroids, fungi, mycobacteria, legionella.
    • Late prosthetic valve endocarditis >60 days post operatively; streptococci, staph epidermidis.
    • The risk of endocarditis is similar for mechanical and bioprosthetic valves.
    • Most common symptoms and signs; fever, new or changing murmur, systemic embolization or congestive heart failure.
    • Early endocarditis: rapid hemodynamic deterioration, conduction defects, poor peripheral perfusion
    • Mortality for prosthetic valve endocarditis is 30–80% for the early form and 20–40% for the late form.
    • Infection with organisms other than streptococcus usually results in valve replacement.

CSF

  • Pleocytosis < 300 cells/mm3 neutrophilic early and lymphocytic late
  • Slight increase of protein
  • Normal sugar
  • May have normal CSF

Non-Infective Endocardial Lesions

  • General Characteristics
    • Occur primarily in SLE, the APLA syndrome and NBTE
    • Probable similar pathogenesis
    • All three entities are associated with:
      • Hypercoagulability
      • Thrombocytopenia
      • Embolic stroke
      • Platelet thrombi on valve and endocardial tissues
  • Noninfective valve lesions are associated with:
    • Ergotamine
    • Methysergide
    • Dexfenfluramine
    • Phentermine
    • Carcinoid (high serotonin levels)
    • Leukemia
  • Strands
    • Trans esophageal echo cardiography may demonstrate:
      • Strands of mobile tissue attached to valve and endocardial surfaces
    • Filamentous strands are known as Lambl excrescences:
      • Located on the atrial surfaces of mitral valves or the ventricular surfaces of aortic valves
      • Strands are composed of:
        • Cellular connective tissue core covered by epithelium
        • 1–10 mm in length
        • May be related to fibrinous deposits on valve surfaces
        • May spread to the endocardium and papillary muscles
      • Prevalence by TEE (transesophageal echocardiography)
        • Approximately 4% on mitral valves
        • 1.7% on aortic valves
        • Incidence possibly 10% in patients who have suffered embolization
      • Association of stroke and strands:
        • Young patients
        • Mitral and aortic strands
        • Low recurrent stroke risk
        • Patients with SLE, APLAS and NBTE

Antiphospholipid Antibody Syndrome

  • General Characteristics
    • Associated with:
      • Recurrent abortion
      • Phlebothrombosis (including the upper extremities)
      • Myocardial infarction
      • Thrombocytopenia
      • Pulmonary emboli
    • Cardiac valvular lesions:
      • High frequency
      • Similar to the verrucous lesion of SLE
      • Mitral > aortic valves
  • Phospholipids are important constituents of:
    • Platelets
    • Cardiac valve endothelium
    • Coagulation factors
  • Laboratory evaluation:
    • Patients demonstrate lupus anticoagulant
    • Anticardiolipin antibody (IgG or IgM)
    • Patients with clinical features of APLAS may have embolic stroke and a negative screen for antibodies

Non-Bacterial Thrombotic Endocarditis

  • Associated most often with cancer (particularly mucinous adenocarcinoma, prostate, lung, or melanoma)
  • Other Associations:
    • SLE
    • APLAS
    • Pneumonia
    • Perforated ulcer
    • Wasted, immunosuppressed patients
    • Severe gram negative infection
    • Pheochromocytoma
  • Order of valve involvement:
    • Mitral > aortic > tricuspid > pulmonary
    • Deposits are along lines of valve coaptation and consist of degenerating platelets, fibrin and leukocytes
    • Bivalvular lesions occur
    • Vegetations are bland and less than 5 mm in size
  • Both small and large vessel occlusions occur in the cerebral or systemic circulation
    • Cerebral emboli with stroke occur in 50% of patients with valve lesions
  • Often associated with DIC but also occur concomitantly with SAH, ICH and thrombotic stroke
    • Elevated D-dimer seen in this context

Lupus Verrucous Endocarditis

  • Fibrous thickening of valves
  • Vegetations prominent along valvular closure lines and leaflets
  • Spread to the papillary muscles and endocardium
  • Associated with cerebral embolism

Cardiomyopathy

  • General Characteristics
    • Embolism most common in dilated cardiomyopathies; ejection fraction less than 50%
    • Loss of normal subendocardial trabeculations
    • Stasis of blood; prolonged contact of platelets and contact factor XIII
    • Mural thrombi form within the trabeculae carnea of the cardiac apex
    • Embolism less frequent in hypertrophic cardiomyopathy unless there is concomitant AF
    • Associated with the stasis of CHF
  • Cardiomyopathies associated with emboli:
    • Idiopathic
    • Post partum
    • Viral
    • Myocarditis (idiopathic)
    • Ischemic cardiomyopathy
    • Sarcoidosis
    • Amyloidosis
    • Endocardial fibroelastosis
    • Mitochondrial myopathies
    • Dystrophinopathy (DMD; Becker's)
    • Inflammatory muscle disease (IBM; DM/PM)
    • Nemaline myopathy
    • Glycogen: storage disease (debrancher)
    • scapuloperoneal dystrophy with mental retardation
    • Desmin myopathy
    • Myofibrillar lysis
    • Fabry's disease
    • Cocaine
    • Endocrinopathies (acromegaly, hypothyroidism, adrenal insufficiency)
    • Congenital myopathy

Hereditary Cardiomyopathies

  • General Characteristics:
    • Categories of familial dilated cardiomyopathies (FDCM)
      • Mutations in contractile protein genes
      • Dystrophinopathy
        • Affected boys and men
        • Women carriers of Becker or Duchenne mutations
        • Mitochondrial disorders
        • Sarcoglycanopathies
          • Limb girdle myopathies
        • Rare disorders
  • Genetics of FDCM
    • Allelic and locus heterogeneity
  • Usual clinical features:
    • Syncope
    • Palpitations
    • Dyspnea
    • Heart failure
    • Exertion induced sudden death
    • Angina
  • Neurologic features:
    • Cerebral emboli occur in patients with:
      • Ejection fractions of <30%
      • Trans echo cardiogram that demonstrate:
        • "smoke" (echoic signals that signal altered intracardiac blood flow)

Familial Hypertrophic Cardiomyopathy (IHCM)

  • General Characteristics:
    • Clinical onset from fetal life to adulthood
    • Mutations in genes that encode cardiac contractile proteins
      • Most frequent mutations:
        • B-myosin heavy chain
        • High penetrance
        • High incidence of sudden death
      • Less common mutations in genes for:
        • Essential light chain protein
        • Regulatory light chain protein
        • Myosin binding protein
  • Clinical Manifestations by Mutation Characteristics
    • Penetrance
      • B-myosin high penetrance
        • High incidence of sudden death
      • B-myosin low penetrance
        • Benign course
    • Mutation specific cause of sudden death:
      • Myocardial ischemia that cause:
        • Syncope
        • Pre-syncope
        • Sudden death
      • Heart block
      • Preexcitation syndrome
    • Mutations causing functional deficits:
      • B-myosin heavy chain
        • Affects head-rod junction
      • Expression of mutations in skeletal muscle with:
        • Decreased isometric force
    • Mutations expressed in skeletal muscle
      • Heart and skeletal muscle affected concomitantly
      • B-myosin heavy chain; myosin light chains, tropomyosin affected

Clinical Syndromes of ICHM

  • Variance in degree of heart muscle pathology
    • Focal heart muscle pathology vs generalized heart muscle involvement
  • AD in some families
  • Penetrance is age dependent
  • Clinical heterogeneity within families

Dystrophinopathy

  • General Characteristics
    • More limited the patients exercise tolerance the less symptomatic cardiomyopathy
    • EKG abnormalities in BMD and DMD increase dramatically with age
    • DMD carrier women
      • 38% abnormal cardiograms
    • BMD carrier women
      • 34% abnormal cardiograms
    • 8% of DMD carries suffer dilated cardiomyopathy
    • X-linked cardiomyopathy
      • Similar dystrophin gene type gene mutation in some; others are new mutations
        • High CPK
        • Dystrophic myopathy by skeletal muscle biopsy
    • Sarcoglycanopathy
      • Patients with dilated cardiomyopathy:
        • Point mutation in gene for alpha sarcoglia

Mitochondrial Cardiomyopathy

  • General Characteristics:
    • Dilated cardiomyopathy
      • More common in patients with maternally inherited point mutations
      • Mutations most common in:
        • mt DNA-encoded t RNA's
  • MELAS-3243 mutation
    • Dilated cardiomyopathy
  • Progressive external ophthalmoplegia (PEO)
    • Dilated cardiomyopathy
    • Multiple mt DNA deletions
    • Eastern Arabian Peninsula (most common)
  • Kearns–Sayre Syndrome:
    • Dilated cardiomyopathy
    • Adolescents with stroke
    • Predominant cardiac feature is heart-block
  • Patients with dilated cardiomyopathy identified with:
    • Complex I, III, and IV mitochondrial complex deficits

Rare Myopathies with Emboligenic Cardiomyopathy

  • Myofibrillar lysis
  • Scapuloperoneal dystrophy with mental retardation
  • Glycogen debrancher deficiency
  • Nemaline myopathy
  • Desmin myopathy

Hereditary Dysrhythmias with Embolic Stroke

Prolonged QT Syndromes

  • General Characteristics:
    • Prolongation of the QT interval
      • Corrected for heart rate
    • T-wave abnormalities
    • Brachycardia
    • Ventricular tachyarrhythmias
    • Polymorphic ventricular tachycardiac
    • Torsades de pointes
    • Defects of cardiac repolarization
  • Usual Clinical Presentation
    • Syncope
    • Seizure
    • Sudden death
  • Triggers:
    • Exercise
    • Emotion
    • Noise
    • Rarely sleep
  • Romano Ward Syndrome
    • AD
    • Most common form
  • Jervell
    • Rare
    • AR
    • Sensorineural deafness
  • Lang Nielsen
    • Cardiac defect is AD
    • Deafness is recessive

Mechanism

  • Heterogeneous genetic defects
    • Mutation in the cardiac potassium channel HERG (KCNH2)
    • Reduces the delayed rectifier KCN currents
    • A trafficking defect that cause failure of delivery of the mutant protein to the plasma membrane

Cardiac Tumor and Cerebral Emboli

  • Atrial myxoma:
    • Arise from either side of the atrial septum in the region of the fossa ovalis
    • Left atrium > left ventricle: may have simultaneous origin from both atria
    • Attached to atrial wall or are pedunculated and cause valve obstruction
    • Gelatinous round, polypoid masses covered with platelet fibrin clots
    • Emboli: Tumor fragments or thrombi
    • Cardiac symptoms:
      • Syncope (change of cardiac output)
      • Tripopnea
        • Right atrial myxoma
        • Shortness of breath with position change (blockage of right ventricle outflow)
      • Heart murmur usually MI > MS (with mitral valve disease)
      • Occasionally a cardiac "plop" can be auscultated. Tumor falls into the valve and obstructs it
    • Rare bilateral myxomas
      • Project from right atrium to left and through a PFO
    • Less than 10% are in the ventricles

Neurological Signs and Symptoms of Myxoma

  • Superficial pial MCA territory most commonly affected
  • Peripheral aneurysm of superficial blood vessels:
    • Small
    • Multiple
    • Rupture with SAH or hemorrhagic infarctions
      • Myomatous tissue grows through the vessel wall
    • Rarely large peripheral aneurysms are seen
  • Delayed progressive neurologic signs are seen (rare)
  • 30–50% of cardiac myxomas embolize
  • Rare embolization to the spinal cord
  • Sudden death (possible coronary artery embolus)

Constitutional Symptoms and Signs of Myxoma

  • CHF
  • Polyarthralgia
  • Fever
  • Weight loss
  • Anterior chest wall petechiae

Papillary Fibroelastoma

  • General characteristics
    • Multiple papillary bands that are attached to an avascular fibrocartilaginous core
    • Arise from the aortic valve
  • Clinical symptomatology
    • Angina due to embolization of the coronary arteries
    • Multiple brain infarcts

Rhabdomyoma

  • General characteristics
    • Often are multiple
    • Arise from the ventricular myocardium with projection into the ventricular chamber
    • Associated with tuberous sclerosis and neurofibromatosis (NFI)
  • Emboli consist of tumor fragments

Differential Diagnosis of Cardiac Tumors

  • Rhabdomyoma
  • Atrial and ventricular myxomas
  • Fibroelastoma
  • Histiocytoma
  • Hemangioma
  • Hamartoma
  • Undifferentiated
  • Fibroma
  • Metastatic tumors

Differential Diagnosis of Intracardiac Lesions

  • Cardiac tumors
  • Metastatic tumors to the heart
    • Hypernephroma (through the inferior vena cava)
    • Squamous cell lung carcinoma (through the pericardium)
    • Malignant melanoma (able to attach to the endocardium)
  • Ball valve thrombus
  • Mural thrombus
    • Following myocardial ischemia
    • Within ventricular aneurysm
  • Thrombi within septal aneurysms

Paradoxical Cerebral Embolus

  • General characteristics
    • Definition: embolus entering the arterial circulation from the venous side through a right to left shunt
  • Predisposition:
    • Patent foramen ovale (20–25% of the population)
    • Atrial septal defect's, VSD, pulmonary AV fistulas
    • Anovulatory drugs
    • Lower extremity injury
    • Prothrombotic states
    • Jugular vein catheterization
    • Cancer
    • Obesity
    • Prolonged bed rest
    • Any increased source of right heart pressure
    • Occurs in some patients with no evidence of right heart disease, thrombophlebitis or increased pulmonary pressure
    • Valsalva maneuvers
  • Less than 1% of cerebral emboli are paradoxical
  • The clinical setting:
    • Thrombosis of leg or pelvic veins
    • Prothrombotic state
    • Valsalva maneuvers
    • Associated pulmonary embolism
  • Neurological signs and symptoms
    • Most common stroke territory is that of the MCA
    • Higher than expected vertebrobasilar embolization

Patent Foramen Ovale

  • General characteristics:
    • Present to some degree in approximately 30% of patients
    • Declines approximately 10% with age
    • Average size is 4–5 mm; gradually increases with age
  • Neurologic signs and symptoms:
    • MCA territory most frequently involved
    • Approximately 1/3 involve the VB system which receives approximately 20% of CBF. MCA territory receives approximately 40% of CBF
    • Predisposition for paradoxical embolus is the setting
  • Increased risk of paradoxical embolus with PFO by TEE
    • Concomitant atrial septal aneurysm
    • Larger PFO
    • More microbubbles insonated in MCA territory

Atrial Septal Aneurysm

  • General characteristics
    • Bulging of septum primum tissue of the atrial septum through the fossa ovalis
      • Into the right or left atria
    • Association of atrial septal aneurysms and interatrial shunts
    • High incidence of PFO with atrial septal aneurysms
    • Atrial septal aneurysm with 10 mm excursion greater chance of embolization
    • Thrombi may form within the aneurysm
  • Recurrence rate of stroke for PFO and atrial septal aneurysm when combined is approximately 2% per year; may have severe stroke at onset

Differential Diagnosis of Cardiac Sources of Emboli

  • Ischemic Heart Disease
    • Mural thrombus
    • Congestive heart failure
    • Ejection fraction of less than 30%
    • Ventricular aneurysm
    • Akinetic or hypokinetic segments
  • Cardiac Arrhythmia
    • Chronic or paroxysmal atrial fibrillation
    • Sick sinus syndrome
    • Brady-tachyarrhythmia
    • Long QT interval syndrome
    • Ward Romano Syndrome (AD)
    • Jervell Syndrome (AD)
    • Lang–Nielsen Syndrome (AR)
  • Valvular heart disease
    • Rheumatic mitral stenosis
    • Rheumatic mitral insufficiency (rare)
    • Rheumatic aortic stenosis
    • Bicuspid aortic valve (congenital)
    • Calcific aortic stenosis
    • Mitral annulus calcification
    • Bacterial endocarditis
    • NBTE (marantic endocarditis)
    • SLE (verrucous endocarditis)
    • Antiphospholipid syndrome (APLS)
    • Left ventricular assist devices
    • Prosthetic heart valves
    • Fibrous and fibrinous endocardial lesions
  • Cardiomyopathy
    • All dilated cardiomyopathies
    • Idiopathic
    • Post partum
    • Viral
    • Idiopathic myocarditis
    • Ischemic cardiomyopathy
    • Sarcoidosis
    • Amyloidosis
    • Endocardial fibroelastosis
    • Multiple mitochondrial myopathies
    • Duchenne muscular dystrophy
    • Becker's muscular dystrophy
    • Idiopathic dilated cardiomyopathy
    • Variants of dystrophinopathy
    • Inclusion body myositis
    • Dermatomyositis/polymyositis complex
    • Nemaline myopathy
    • Debrancher glycogen storage disease
    • Scapuloperoneal dystrophy with mental retardation
    • Desmin myopathy
    • Myofibrillar lysis
  • Intracardiac Lesions
    • Cardiac tumors (primary)
      • Myxoma
      • Fibroma
      • Fibroelastoma
      • Hamartoma
      • Hemangioma
      • Histiocytoma
      • Rhabdomyoma (sarcoma)
      • Undifferentiated
    • Metastatic tumors
      • Hypernephroma
      • Melanoma
      • Squamous cell carcinoma of the lung
    • Ball valve thrombus
    • Mural thrombus
    • Ventricular aneurysm with thrombus
    • Septal aneurysm with thrombus
  • Intracardiac defects with paradoxical embolus
    • Atrial septal defects
    • Ventricular septal defects
    • Patent foramen ovale (PFO)
    • Atrial septal aneurysms
    • PFO plus atrial septal aneurysm

The Aorta as a Source of Emboli

General characteristics

  • Average diameter of an aortic plaque is 19 mm
  • Plaques are frequently on the anterior or posterior right side of the ascending aorta
  • The upper and lower half of the ascending aorta are equally involved
  • Aortic arch plaques
    • At the edifice of the innominate artery
  • Plaque grading system
    • 0 mm – 0
    • 1 mm – grade 1
    • 2 mm – grade 2
    • 3 mm – grade 3
    • 4 mm – grade 4
    • 5 mm – grade 5; mobile complex
  • Complex thick or mobile plaques are most likely to embolize
  • Plaques have disappeared after anti-coagulant therapy
  • Anticoagulants theoretically could potentiate cholesterol emboli by:
    • Blocking protective clot thrombi that cover plaque ulceration

Neurologic Signs and Symptoms

  • Protruding atheroma
    • Related to emboli
  • Ulcerated plaque in the aortic arch may not correlate with atheromatous carotid disease
  • Ascending aorta and arch junction
    • Important site for plaque that embolize as is the origin of the innominate artery
  • Frequency of brain infarction correlated with thickness of the aortic wall
  • Complex, thick or mobile plaques > 5 mm have 3× greater incidence of stroke than patients with plaques <5 mm

Differential Diagnosis of Artery-to-Artery Embolism

  • Proximal extracranial and intracranial arteries
    • Ulcerated and stenotic lesions
  • Dissection of arteries
    • Thrombus at the site of the intimal tear
  • Post surgical sites (flaps, sutures)
  • Inflammatory arterial disease
    • Giant cell arteritis
    • Takayasu's Disease
    • Infectious arteritis
    • Autoimmune arteritis
  • Thrombi within aneurysms
    • Dolichoectatic arteries
    • Saccular (giant aneurysms)
    • Fusiform aneurysms
  • Fibromuscular dysplasia
  • Cancer:
    • Direct invasion of arteries
    • Promotion of clots within arteries encased by tumor
  • Hypercoagulable states
  • Aortic arch atherosclerosis with embolus:
    • Infarcts MCA territory and brachial plexus
    • Supraclavicular portions of the plexus supplied by ascending deep and transverse arteries
    • Infraclavicular portions of the plexus supplied by 3–4 branches of the axillary arteries
  • Multiple brain gas embolisms:
    • Ingestion of H2O2
      • O2 embolism
      • Predominantly to grey matter
    • Air embolism
      • Vascular surgical procedures:
        • Open heart surgery
        • Head and neck surgery in the sitting position. Air enters the jugular vein
    • Pelvic vein insufflation (air) during pregnancy
  • Spectacular shrinking deficit
    • Profound hemispheric ischemia
    • Resolves over hours to days
    • Minimal residual deficits
    • Rapid embolic lysis and fragmentation
    • 90% of emboli migrate or are recanalized within 2–3 weeks
  • Fat embolism
    • Broken long bones in young patients
    • Hip replacement surgery (even in elderly patients)
    • Acute syndrome:
      • Interstitial lung involvement with low pO2
      • Petechiae across the anterior chest wall
      • Predilection for emboli
        • Retina (fat globules visible)
        • Corpus callosum
        • Centrum semiovale
        • Superficial pial vessels
      • Fat globules noted in the urine
      • Mechanism
        • Emboli pass through the lungs into the arterial circulation
        • Precipitation of fat from chylomicra
    • Late syndrome
      • 4–7 days following the event
      • Acute confusion

Differential Diagnosis of Unusual Emboli

  • Air (cardiac and neck surgery, diving accidents)
  • Fat emboli (diabetic ketoacidosis, trauma, pancreatitis)
  • N2O (bends) diving, pressure from underwater construction (Caisson's Disease)
  • Calcium (calcific aortic valves, calcified mitral valve annulus)
  • Fungus balls (SBE: aspergillus)
  • Bullets (shot gun pellets; rare bullet fragments)
  • Ectatic arteries
  • Aneurysms (giant > 1 cm; tip of the basilar, carotid, middle cerebral artery)
  • Tumor material
  • Thrombolytic therapy (lysis of clots that then expose underlying collagen which then forms new less adherent clots)
  • Iatrogenic occlusive therapy (embolization of AVM's; Gelfoam)
  • Catheters
  • Defoaming agents
  • MAC attack (esophageal fistula to veins-McDonald hamburger fragments to veins)
  • Talc (addicts; increased right heart pressure from pulmonary fibrosis; paradoxical embolus)
  • Fibrocartilage (following orthopedic procedures)
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