Differential Diagnosis in Neurology

1.3. Medical Causes of Stroke

The medical causes of stroke occur in younger patients are associated with cardiac disease, autoimmune vasculitis, infection, mitochondrial deficits or clotting factor dysfunction. Dissection from trauma or in association with collage vascular disease and migraine is also common. Specific symptoms such as cerebral autosomal dominant arteriopathy with subcortical infarction and stroke (CADASIL), hereditary endoheliopathy, neuropathy, renal disease and stroke as well as mitochondrial disease and named syndromes such as Susac, Eales, Sneddon's, Cogan's and Grönblad–Strandberg Disease, all test the diagnostic acumen of the examiner. Clotting disorders of deficiency, inhibition of activated coagulation factors or hereditary fibrinolytic defects are AD, AR or acquired. The examiner needs to elicit the sentinel characteristic of each entity to diagnose the category of medical illness and then the specific disease.

Genetic causes of embolic stroke are:

• AD, MVP
• Tuberous sclerosis
• Familial atrial myxoma (AD; AR)
• Hereditary cardiac conduction defects (long QT)
• Hereditary cardiomyopathies
• Mitochondrial disease

Mitral valve prolapse has a prevalence rate of 5–21% in the population. It occurs occasionally in an AD form and rarely causes a cerebral embolus. Auscultation reveals a mid-systolic click-systolic murmur and 2D-ECHO cardiography determines greater than 2 mm or more abnormal movement of the anterior or posterior leaflets.

Tuberous sclerosis patients are easily diagnosed by their characteristic skin manifestations, seizures and mental retardation. Rhabdomyosarcoma may be the cause of cerebral emboli. Heredity is AD.

Hereditary long QT defects most frequently presents with syncope especially provoked by drugs that decrease cardiac conduction or with rare sudden death during strenuous athletics.

Hereditary cardiomyopathies with a dilated myocardium occur in mitochondrial disease, limb-girdle muscular dystrophy, congenital myopathies, DMD, BMD, and myotonia type; all of these entities have characteristic physical findings such as proximal weakness, calf hypertrophy contracture of elbows, arms and ankles (Emery–Dreifuss muscular dystrophy); rigid spine syndrome.

Mitochondrial disease should be suspected in short patients with undue fatigue with exercise, sensorineural hearing loss, diabetes and dilated cardiomyopathy.

Atrial myxomas with emboli may present with fevers of unknown origin, petechiae across the chest wall, pial vessel emboli and peripheral cerebral aneurysm that bleed (myxomatous material grows through the walls of the affected arteries).

Genetic causes of thrombotic stroke are:

• Homocystinuria (marfanoid habitus) and dislocated arm
• Dyslipoproteinemias such as Tangier disease with orange tonsils, alpha hypolipoproteinemia and intermittent neuropathy
• Hemoglobinopathies particularly SS disease have relevant telangiectasis and arachnodactyl; while neurofibromatosis type I with characteristic coast of Maine spots and abnormalities of renal vasculature

Clotting disorders secondary to polycythemia vera occur primarily in the posterior greater than anterior circulation and tend to thrombose large cerebral vessels. Retinal venous occlusion in coagulopathies from clotting factor deficiency are characteristically seen in young patients whose parents have had a fetal wastage, protein losing enteropathy, nephrotic syndrome or migraine with aura. Protein S deficiency and stroke occurs in middle aged women. Protein C deficiency often occurs concomitantly with the Factor V Leiden mutation. Antithrombin III deficiency should be suspected in the setting of severe resistance to heparin anticoagulation. Anticardiolipin antigen and lupus anticoagulant often are associated with migraine with visual aura. Cerebral sinus thrombosis is common in all defects of inhibitors of clotting.

Platelet abnormalities and stroke should be suspected in a setting of petechiae particularly of the lower extremities. The primary anti-phospholipid antibody syndrome is associated with spontaneous abortion and fetal wastage. Valve cusps are affected and the syndrome may be associated with cerebral emboli. The lupus anticoagulant is an antibody to phospholipids (on platelets) which blocks the formation of the prothrombin activator and is associated with clotting and not hemorrhage. There is usually evidence of systemic venous clotting.

In general, platelet counts greater than one million/mm³ are associated with hypercoagulability. Functional platelet abnormalities rather than absolute number may be the important parameter. This may occur in a small group of migraine patients and in essential thrombocythemia.

Heparin induced thrombocytopenia and thrombosis occurs as a transitory and asymptomatic reduction in platelet count or as an immunopathologic condition. The later (Type II) usually occurs after the 5th day of treatment and causes both arterial and venous thrombosis. Gangrene of a limb, thrombosis and stroke is the usual triad. White clots are noted in blood vessels.

Disseminated intravascular coagulation occurs in a setting of gram negative sepsis, cancer and obstetrical emergency. It is announced by oozing from all venipuncture sites and acrocyanosis. Arterial and venous clotting as well as hemorrhage dominate the clinical profile.

The following discussion highlights the major characteristics and differential features of the genetic causes of embolic and thrombotic stroke, coagulopathies and rheological abnormalities that are seen in clinical practices.

Genetic Causes of Embolic Stroke

• Mitral valve prolapse (MVP) – AD
• Tuberous sclerosis – AD
• Familial atrial myxoma (AD, AR)
• Hereditary cardiac conduction defects (long QT) AD
• Hereditary cardiomyopathy AD, AR, X-linked
• Mitochondrial disease (maternal inheritance)

• MVP
  • Associated with:
    • Osteogenesis imperfecta
    • Ehlers Danlos syndrome
    • Marfan's Syndrome disease
    • Duchenne MD
    • Becker MD
    • Van Willebrand's
    • Fragile X syndrome
• Tuberous Sclerosis
  • Cardiac rhabdomyomas that cause emboli
  • 80% are new mutations
  • Abnormalities of cerebral arteries and aorta also occur
• Atrial Myxoma
  • AD/AR forms; most atrial myxomas are sporadic
  • 20% of familial atrial myxoma are associated with an AD heredity
  • Associated with:
    • Myxoid fibroadenoma
    • Lentiginous blue nevi
    • Large cell calcifying Sertoli cell tumors
    • Primary adrenocortical nodular dysplasia
    • Pituitary growth hormone tumors

Cardiac Dysrhythmia with Emboli

• Idiopathic Hypertrophic Subaortic Stenosis (IHSS)
  • Syncope after exercise
    • Muscle constricts subaortic outlet; epinephrine dilates blood vessels in muscle. Severe hypotension results after strenuous exercise
  • Atrial fibrillation late in the course of the illness
    • Emboli during the arrhythmia
  • Female > male at risk for stroke
  • Hypertension a cause of stroke
  • Other stroke mechanisms:
    • Associated mitral annulus calcification
    • AV conduction defect
• mt DNA Cardiomyopathy
  • Kearns–Sayre syndrome
    • Heart/block (bundle branch block; AV node block)
    • Ophthalmoplegia
    • Hearing loss (VIIIth nerve)
    • Diabetes mellitus
    • Dilated cardiomyopathy with emboli (poor flow; clot formation)
    • Decreased ventricular ejection fraction
    • Endocardial thickening
    • Intellectual decline
    • Cerebellar ataxia
    • Stroke like episodes after seizure
• Dilated cardiomyopathy (DCM)
  • DCM with and without conduction-system disease
  • Familial DCM with CSD (conduction syndrome) chromosome 1 p1-q21
  • X-linked dystrophinopathy (Becker's; Duchenne)
  • Female carrier of BMD and DMD
  • Sporadic and AR limb-girdle muscular dystrophy
  • Emery Dreyfus Muscular Dystrophy
  • Adhalinopathies
  • Barth Syndrome
  • Rigid Spine Syndrome
  • Welander's distal myopathy
  • Distal vacuolar myopathy
  • Systemic carnitine deficiency

Genetic Causes of Thrombotic Stroke

• Homocystinuria (AR)
  • Homocysteine to cystathionine; deficient enzyme is cystathionine beta synthase (most common defect)
  • Homocystinuria
    • Severe atherosclerotic changes
    • Increased levels of homocysteine injuries endothelium
  • Clinical Features:
    • Marfanoid habitus
    • Osteoporosis
    • Mental retardation
    • Premature atherosclerosis
    • Venous and arterial occlusions
    • High myopia
    • Dislocated lens
  • Heterozygosity
    • Incidence 1:200 persons
    • Increased stroke risk
    • Oral methionine load causes increased homocysteine level in the serum
• Dyslipoproteinemias
  • Familial hypoalphalipoproteinemia (Tangier Disease)
    • Tangier Disease:
      • AR
      • Low HDL
      • Increased triglycerides
      • Orange tonsils
      • Intermittent neuropathy
      • Premature atherosclerosis with stroke
      • Increased carotid artery intima-media thickness in subjects with primary hypoalphalipoproteinemia
      • ABCA1 Gene Mutation
        • Cell membrane protein is deficient

Hemoglobinopathies

• General Vascular Features
  • Small and large vessel thrombosis
  • Sickling in the vaso-vasorum (blood supply of the vessel wall)
  • SAH
  • ICH
  • Embolic disease

Sickle Cell Hemoglobinopathies

SS Disease

• General Characteristics
  • Scleral telangiectasia
  • Arachnodactyly
  • Auto splenectomy
  • Pneumococcal peritonitis
  • Meningitis
  • Bone marrow infarction
  • Severe joint and abdominal pain

• Occlusive disease:
  • Large intracranial arteries
  • Small penetrating vessels
  • Dilated and ectatic arteries
  • Moya-Moya collateral pattern
  • SAH
• MRI/CT Evaluation
  • Subcortical infarction
  • Cortical infarction
  • Border-zone infarction
• Pathology
  • Thickened arterial walls from intimal and subintimal proliferation
  • Rare thrombosis of veins and cerebral sinuses
• Sickled Cells
  • Adhere to the endothelium
  • Activate inflammatory cells and clotting factors that form the nidus for thrombosis
  • Small vessel sludging
  • Deficiency of nitric oxide decreases compensatory vasodilatation
• TCD
  • Velocities above 200 cm/second may occur in large vessels

SSA Disease

• Stroke propensity

SC Disease

• "Sea fan" macular sign (abnormal collection of blood vessels)
• Propensity of strokes during pregnancy
• Aseptic necrosis of the hip

Neurofibromatosis I

• General Characteristics
  • Associated with abnormalities of the renal and cerebral circulation
• Abnormalities of the Intracranial Vasculature
  • Beading of blood vessels
  • Aneurysms and arterial stenosis
    • Intracerebral carotid artery
      • at the level of the ophthalmic artery
    • Moya-Moya like syndrome occurs with carotid occlusion
    • Hypertensive vascular disease secondary to renal artery stenosis
      • Rarely secondary to associated pheochromocytoma

Polycythemia Vera

• General Characteristics
  • AD form
  • Variants:
    • High oxygen affinity variant
    • Mutant hemoglobin
    • Mutant receptor for erythropoietin
    • Increased erythropoietins (E)
    • Abnormal metabolism of 2,3-diphosphoglyceride
• Neurologic Features
  • Thrombotic events occur in 20–50% of patients
  • Thrombosis of large cerebral vessels
    • Posterior greater than anterior circulation thrombotic stroke
    • Scattered lesion pattern:
      • Suggestive of embolic microcirculation strokes
    • Retinal venous occlusions
    • Risk factors for thrombosis:
      • Age
      • Use of phlebotomies
      • Rate of phlebotomies
      • Prior history of thrombosis
      • Platelet counts not definitively linked to increased risk of thrombosis
      • Risk of stroke occurs with > 1.5 million platelets/mm³
    • Thrombotic events:
      • Most frequently occur 2 years preceding diagnosis
      • Thrombosis 3.4% per year
      • Overall mortality of 2.9/100 patients/year
      • patients receiving chemotherapy have higher mortality

Hereditary Cause of Hemorrhagic Stroke

• X-linked VIII and IX deficiency
• AR-afibrinogenemia
• Factor VII, X, XI, XIII deficiency

• Clinical Features:
  • Rare bleeding in factor XI deficiency
  • VIII deficiency less than 10% of normal values are necessary to bleed
  • Latent period of deficits prior to stroke

Coagulopathies

• General Categories:
  • Decreased inhibitors of activated coagulation factors
  • Hereditary fibrinolytic deficits
  • Clotting factor deficiencies
• Autosomal Dominant Defects
  • Heparin co-factor II
  • Protein C deficiency
  • Decreased release of plasminogen activator
  • Homozygote XII deficits (thrombotic tendency)
  • Prothrombin gene defect
• AR Defects:
  • Prekallikrein deficiency (Fletcher factor)
• Propensity for Thrombosis
  • Antithrombin III defects
  • Protein S deficiency
  • Plasminogen defects
  • Factor V Leiden defect
• Acquired Causes of Hypercoagulability
  • Diabetes mellitus
  • Hyperlipidemic states
  • DIC (consumption with fibrinolysis)
  • Platelet disorders
  • Vasculitis
  • Malignancy (thromboplastin-like substances released into circulation)
  • Hyperagreeable (sticky) platelets
  • Endothelial damage
  • Cardiopulmonary bypass:
    • Increased fibrinolytic activity
    • Decreased coagulant activity
    • Increased plasminogen activator inhibitor level
    • Platelets >1,000,000 – 7× risk of bleeding
  • Antiphospholipid antibody
  • Anticardiolipin antibody
  • Lupus anticoagulant
  • Heparin induced thrombosis
  • Rheological Abnormalities
    • Hyperviscosity
    • Deficits in laminar and pulsatile flow

General Categories of Coagulopathies

• Comprehensive Procoagulant Screen
  • Common gene mutations
    • Factor V (R1691A) mutation
    • Prothrombin (G20210A) mutation
    • MTHFR (C677T); methyl tetrahydrofolate reductase mutation
  • Rare Genetic Deficiencies
    • Protein C
    • Protein S
    • Antithrombin III
    • Plasminogen
  • Putative candidates for genetic thrombophilia
    • Elevated lipoprotein
    • Homocysteine

• Probable genetic risk factors
  • Increased:
    • Fibrinogen
    • Factor IX
    • Factor VIII
    • Decreased factor XII

Platelet Dysfunction

• General Features
  • Increased platelet counts – above 1 million
    • Associated with hypercoagulability
  • Increased coagulability may occur with increased adhesion and aggregation
    • Functional platelet abnormality > than absolute number may be the important parameter
      • Sticky platelets
• Essential Thrombocythemia
  • Associated with stroke and digital artery infarction
  • Transient ischemic attacks
  • Major ICH

Leukemia

• General Characteristics
  • Rheological abnormalities occur with WBC > 250,000/mm³
    • Capillary sludge
      • Infarction
      • Small brain hemorrhages
  • SAH
    • Vaginal bleed prior to cerebral bleed at approximately 30,000 platelets

Decreased Natural Inhibitors of Coagulation

• Antithrombin III
• Low levels of heparin releasable tissue factor inhibitor in young patients with thrombosis
  • Coincidence of defect with thrombosis is putative
• Pre-Kallikrein deficiency
  • Severely prolonged activated partial thromboplastin time (a PTT)
  • Due to Factor XII activation
  • No increased bleeding risk
  • Bleeding risks occur in association with hereditary defects of:
    • VIII, IX, XI

Most Common Deficiencies of Inhibitors of Clotting

• Antithrombin III
• Protein C
• Protein S
• Factor V Leiden

Antithrombin III Deficiency

• General Characteristics
  • Usually AD inheritance
  • Defect may be qualitative as well as quantitative
  • Reduced synthesis in the liver
  • May be lost in the nephrotic syndrome or by protein losing enteropathy

• Clinical Features
  • Strong family history of venous thrombosis
  • Approximately 50% of patients with deficiency suffer:
    • Venous thrombosis
    • Pulmonary embolism
    • Rarely myocardial infarction
    • Rarely peripheral arterial disease
    • Occasional stroke
    • Other thrombolic risk factors potentiated in this setting

Protein C

• General characteristics:
  • AD
  • Most common functional defect occurs with concomitant Factor V Leiden mutation:
    • Causes resistance to activated protein C which prevents degradation of factor V
• Clinical features
  • Cerebral venous thrombosis
  • Occasional arterial thrombosis
  • Rare cerebral emboli from the heart

Protein S

• General Characteristics
  • Increases affinity of protein C for phospholipid
  • Protein C inhibits procoagulant activity of Factor V and VIII
  • 65% of plasma protein S is bound to c4b-binding protein which increases during infection
  • Levels of protein S are low with:
    • Nephrotic syndrome
    • Protein losing enteropathy
    • Failure of synthesis with liver disease
    • Antibodies to protein S occur with post varicella purpura fulminans
    • Lower levels in women than men
  • A particularly important risk factor for stroke in middle aged women
• Clinical Features
  • Dural venous thrombosis
  • Arterial stroke
  • Stroke in young patients with the concomitant risk factor of smoking

Factor V Leiden

• Most common cause of decreased protein C function
• Mutation of the gene that codes coagulation factor V (factor V G1691A)
• Factor V Leiden prevalence in population:
  • heterozygotes 7.7%
  • hemo zygotes 0.2%
• Risk for ischemic stroke
  • heterozygotes + hemo zygotes – 0.92%
  • control population – 0.68%
• Clinically correlated with:
  • thromboembolism in pregnancy
  • venous thromboembolism of lower extremity
  • cerebral venous and dural sinus thrombosis

Prothrombin Gene Defect

• Second most common gene mutation causing prothrombotic state
  • AR (G20210A mutation)
  • Substitution, deletion or insertion of single nucleotides in the prothrombin gene
• Two phenotypes:
  • hypoprothrombinemia
    • low levels of coagulant activity
    • antigen type 1
  • dysprothrombinemia
    • low coagulant activity
    • borderline or normal antigen levels

• Clinical Manifestation
  • Cerebral venous thrombosis
  • Recurrent peripheral venous thromboembolism
  • Rare arterial clotting
• Factor VIII Alteration
  • Deficiency causes bleeding into:
    • joints
    • skin
    • abdomen
    • cranium
      • SDH
      • ICH
  • Increased Factor VIII in patients associated with:
    • Thrombophlebitis
    • Spontaneous abortion
    • Increased incidence of stroke
    • May be associated with:
      • Infections (preceding occlusive disease)
      • Crone's disease and ulcerative colitis

Crohn's Disease and Ulcerative Colitis

General Characteristics

• Associated with:
  • Increased factor VIII
  • Elevated factor V
  • Reduced levels of antithrombin III
  • Platelet dysfunction
• Clinical associations:
  • Venous dural sinus occlusion
  • Ischemic arterial stroke
  • Thrombophlebitis
  • Putative mechanism for increased coagulability:
    • concomitant endothelial and valve injury
  • patients with high IgG antibody titers in the presence of APLA syndrome
    • higher probability of stroke

Primary Antiphospholipid Antibody Syndrome

• General Characteristics
  • IgG, IgA, IgM are formed against phospholipids. Those on platelets include:
    • Phosphatidylethanolamine
    • Phosphatidylserine
  • No identified autoimmune disease is present
• Clinical features:
  • Thrombophlebitis
  • Small and large vessel arterial stroke
  • Spontaneous abortions and fetal wastage
  • Thrombotic endocarditis
    • Organized thrombus with marked fibrosis of the valves
      • Valve cusps are involved
      • Lesions embolize

APLA Syndrome Associations

• SLE found in 1/3 of patients
• SLE like syndrome in 5% of patients
• Most patients have a higher frequency of:
  • Myocardial infarction
  • Arterial thrombosis of the lower extremities
  • After age 50 males > females

Infections Preceding Stroke and Relationship to Clotting

• General Characteristics
  • May occur days to weeks prior to the stroke
  • Evidence most convincing for chlamydia infection
  • Putative mechanisms are increased levels of:
    • Acute phase reactants
    • Factor V
    • WBC
    • Factor VII, VIII
    • Fibrinogen
  • May require prior endothelial injury

Circulating Lupus Anticoagulant

• General Characteristics
  • High levels with the appropriate clinical symptomatology constitutes the antiphospholipid antibody syndrome
  • Lupus anticoagulant:
    • Is an antibody to phospholipids
    • Blocks the formation of the prothrombin activator
      • Causes a prolonged activated partial thromboplastin time (APPT) that is not corrected by added plasmin
    • Most patients with the antibody do not have SLE
    • Associated with increased clotting and not bleeding
    • Anti IgA, IgG or IgM anticardiolipin (antiphospholipid antibodies) are found without concomitant autoimmune disease-the process is a primary APLA syndrome.

• Clinical manifestations:
  • evidence of systemic venous clotting
  • large and small artery occlusions
  • mitral and aortic valve lesions

Neurologic Manifestations

• Amaurosis fugax
• Chorea
• Migraine
• Transverse myelitis
• Stroke may be the initial presentation
• Intracranial occlusive disease
• Venous and dural thrombosis
• Atypical extracranial occlusions
• Binswanger's leukoencephalopathy

Heparin Induced Thrombocytopenia and Thrombosis

General Characteristics

• Two types of heparin-induced thrombocytopenia (HIT)
  • Type I
    • Transitory and asymptomatic reduction in platelet count
    • Rarely < 100,000 platelets
    • Resolves spontaneously
    • Does not require cessation of the drug
    • Putative mechanism: heparin induced platelet clumping
    • Rare clinical manifestations
  • Type II
    • Immunologic pathophysiology
    • Occurs after the 5th day
    • <30,000 platelets mm³
    • Resolves 5–15 days after cessation of heparin
      • May take months to resolve
• Epidemiology
  • <5% from bovine heparin
  • 1% porcine heparin
  • <1% due to heparin prophylaxis
• Pathophysiology
  • Antibody to PF4 complex of the platelet
  • Ab binds to FC receptor
• Clinical Manifestation of HIT II
  • Thrombocytopenia independent of:
    • Type of heparin
    • Dosage
    • Route of administration
    • Higher risk:
      • Elderly patients
      • Post surgical prophylaxis for deep vein thrombosis (orthopedic and cardiovascular surgery)
      • Prothrombotic concomitant risks associated in 60%
  • Associated cutaneous allergic and skin necrosis
  • Major clinical neurological complications:
    • Arterial and venous thrombosis
    • May occur in the absence of thrombocytopenia and arterial thrombosis
    • Greater occurrence in cardiovascular disease
    • Arterial complications most common in large vessels
      • Gangrene of limb
      • Cardiac thrombosis
      • Stroke
      • Myocardial infarction
    • Venous complications
      • Deep vein thrombosis
      • Pulmonary embolism
      • Clotting of dialysis shunts
      • Cerebral sinus thrombosis
      • Rare complications
        • Hemorrhagic adrenal necrosis
        • DIC
      • "white" clots in blood vessels
• Laboratory Diagnosis
  • SRA Test
    • Heparin-dependent HIT antibodies release 14e-serotonin from platelets
  • Heparin-induced platelet aggregation test

Disseminated Intravascular Coagulation

• General Characteristics
  • Simultaneous clotting and activation of the fibrinolytic system
  • Causative disease entities:
    • Sepsis
    • Obstetrical emergencies (amniotic fluid emboli)
    • Cancer (release of thromboplastic-like substances)
    • Damage to blood vessel endothelium
    • Severe brain injury or surgery
    • Heat stroke (platelet activation)
    • Treatment of leukemia and lymphoma (after IV chemotherapy)
    • SAH
    • Vascular malformations (Kasabach–Merritt Syndrome)
  • Abnormal activation of intravascular thrombin
    • Deposition of thrombin throughout systemic and intracranial vasculature
• Neurological Manifestations
  • Large and small vessel arterial thrombosis
  • SAH
  • SDH (subdural hematoma)
  • NBTE (emboli) in cancer patients
  • Intracranial hemorrhage in non hypertensive areas
  • Multifocal encephalopathy
  • Severe acrocyanosis
  • Bleeding from prior venipuncture sites
• Laboratory Diagnosis
  • Low Platelets (thrombocytopenia)
    • <30–50,000/mm³
    • Decreased factors V and VIII
    • Decreased fibrinogen levels
    • Prolonged PT and partial thromboplastin time
    • d-dimer (new antigen) appears in the blood

Rheology

• General Characteristics
  • Cerebral blood flow (CBF) dependent upon:
    • Viscosity of the blood
      • Erythrocyte quantity and quality
      • Fibrinogen level
      • Immunoglobulins (particularly IgM)
    • Perfusion pressure
    • Cerebral vascular resistance
• Pathologic Increases in Blood Viscosity and Stroke occur with:
  • Polycythemia vera
  • Leukemia and lymphoma >250,000 WBC/mm³
  • Hyperfibrinogenemia
  • Waldenstrom macroglobulinemia
  • Myoglobulinemia
  • Multiple myeloma
  • High concentrations of serum lipids
• Clinical Manifestations of Hyperviscosity Syndromes
  • Lower leg petechia (Waldenström's)
  • Poor perfusion of distal extremities; acrocyanosis
  • Bleeding gums
  • Dilated and tortuous retinal veins
  • "Box car" formation of RBC's in retinal veins (abnormal clumping)
• Neurological Manifestations of Hyperviscosity
  • Encephalopathy
  • Headache
  • Seizures
  • Ataxia
  • Decreased vision
  • Stupor
  • Bing Neel Syndrome
  • Encephalopathy with slow processing
• Laboratory Evaluation
  • Serum viscosity compared to water is normally 1.8
  • Serum viscosity of 5–6:
    • Associated with encephalopathy
  • Hematocrit > 60–65 associated with poor cerebral perfusion
    • Tetrad attacks in tetralogy of Fallot (Hct > 67)
  • Sickled cells
    • Poor laminar flow through capillaries
  • Endothelial factors putative cause of poor microcirculatory flow

Autoimmune Disease and Stroke

Almost all autoimmune diseases are associated with stroke, especially during exacerbations of the dysimmune process. The patient's symptoms and signs may be dominated by organ system failure or by the other aspects of cerebral involvement such as seizures, dementia or movement disorder. The specific pattern of organ, central and peripheral nervous system involvement are the clinical clues that differentiate the entities

Neurologic manifestations and stroke frequently occur in the setting of:

Systemic Lupus Erythematosus (SLE) is generally dominated by renal, cardiac and serosal surface involvement. If there is a rash in the hand it is between the interphalangeal joints as opposed to dermatomyositis where the rash is over the joint (Groton's sign). The malar rash is characteristic. Periungual telangiectasia and fingertip pain occur with disease activity. Pial vessel strokes occur although seizures, psychosis and proximal myopathy are the most common neurologic features. A vasculopathy rather than a vasculitis is the predominant pathology of cerebral blood vessels.

Periarteritis nodosa usually affects the peripheral nervous system with mononeuritis multiple or a multiradicular pattern of involvement. Renal medullary artery involvement with severe hypertension dominates the active phase of the disease. Late onset asthma, testicular and hepatic artery infarctions occur. Eosinophilia is common. Stroke is rare.

Microscopic polyangiitis is a variant of periarteritis nodosa that affects venules, arterioles and small arteries. It is the most common pulmonary-renal vasculitic syndrome. It, like periarteritis nodosa, most commonly affects the peripheral nervous system, but ischemic and hemorrhagic infarction may be seen secondary to hypertension.

Sarcoid affects both the PNS and CNS. It usually comes to medical attention from its diffuse infiltrative or periaortic node involvement, Ankle pain is characteristic as are cardiac conduction abnormalities. MRI evaluation demonstrates posterior hypothalamic, chiasmatic and parenchymous granulomata. Characteristically, the dura is involved. It is associated with a cerebral vasculitis and retinal inflammation (a periphlebitis). A VIIth nerve palsy in association with uveitis (Heerfordt's Syndrome) is diagnostic.

Sjögren's Syndrome is very prevalent in the population and is most often associated with rheumatoid arthritis. Its cardinal diagnostic feature is keratoconjunctivitis sicca and xerostomia (dry mouth). Peripherally there is a large fiber sensory loss with dorsal column spinal cord involvement. Both conducting and pial vessels may be involved in the CNS.

Rheumatoid arteritis is most often associated with a severe motor neuropathy of the hands that causes intrinsic muscle wasting in association with CTS. Subluxation (atlantoaxial) at C2–C3 is a feared complication. Localized vasculitis is rare.

Scleroderma produces a microvascular pathology that produces characteristic fibrosis of multiple organ systems. Gastrointestinal tract and renal involvement as well as its skin manifestations are characteristic. It frequently affects the Vth cranial nerve (as does Sjögren's syndrome). A disseminated cerebral vasculitis has been noted.

Churg–Strauss Syndrome should be considered in a patient presenting with asthma, eosinophilia and pituitary infarction. A CNS small vessel necrotizing arteritis may accompany the medical triad.

Henoch–Schönlein is usually a disease of childhood and presents with abdominal pain, arthritis and prominent purpura. Allergies to drugs may be a precipitant. Rare small vessel stroke has been reported.

Wegener's granulomatosis should always be borne in mind in the setting of refractory chronic sinus disease. The usual medical evaluation reveals upper respiratory tract necrotizing vascular lesions. Orbital involvement is common with extraocular muscle paresthesia. A cerebral arteritis with pial vessel infection occurs.

Hypersensitivity vasculitis primarily affects the skin in the form of a purpuric skin rash. Specific allergies trigger the process (particularly sulfa). The extremities are symmetrically swollen, erythematous and painful. Stroke is rare.

Mixed collagen vascular disease is an overlap of SLE, scleroderma and polymyositis. Encephalopathy, seizure and aseptic meningitis are much more common CNS manifestations than stroke from vasculitis. Peripheral nerve involvement is more common than are CNS manifestations.

Thrombotic thrombocytopenic purpura often has a dramatic explosive onset manifested by seizures, hallucinations, fever and renal failure. Transient focal neurologic deficits dominate its course. Multifocal microinfarctions of the cortex are seen pathologically.

Reiter's syndrome should be suspected in a patient with diarrhea and heel pain associated with optic neuritis, encephalitis and pial artery stroke.

Relapsing polychondritis is an autoimmune disease of cartilage. It may present with inflamed sore ear lobes (also occurs in ochronosis) conjunctivitis, lip scleritis and laryngotracheal involvement. Stroke is rare.

Ulcerative colitis and regional enteritis are associated with both venous and cerebral sinus thrombosis as well as large vessel stroke.

Celiac disease presents most commonly with severe diarrhea. Its neurologic manifestations are proximal myopathy and ataxia. Occasionally, patients suffer conducting vessel and pial strokes.

The following is a detailed description of the major neurologic and general medical features that differentiate the autoimmunize entities that cause stroke.

Systemic Lupus Erythematosus

• General neurologic manifestations
  • Psychosis
  • Proximal myopathy
  • Sensorimotor neuropathy
  • Mononeuritis multiplex
  • Migraine headaches
  • Chorea
  • Seizures
  • Stroke (pial arteries; multifocal)
  • Retinal findings:
    • Cytoid bodies
    • Increased nicking of arterioles
• Arteritis:
  • Vasculopathy more common than arteritis. Change in the vascular wall rather than WBC invasion
• Hematologic Abnormalities in SLE
  • Clinical signs and symptoms of Lupus anticoagulant:
    • Miscarriage
    • Recurrent thrombophlebitis
    • Small vessel ischemic stroke
  • Thrombocytopenia
  • Platelet abnormalities
  • Thrombotic thrombocytopenic like syndrome
    • Platelet thrombi in arteries and capillaries
    • Subendothelial hyaline deposits
    • Arterial microaneurysms
• Source of Cardiac Emboli in SLE:
  • Libman Sachs (verrucous) endocarditis
  • Marantic endocarditis
  • Mural thrombi
  • Endocarditis (infectious)
• Prognosis
  • Approximately 30% of patients die from cerebral thrombosis
  • Anti-ds double stranded DNA and antiphospholipid antibodies have predictive value for development of SLE

Stroke Mechanisms

• Libman Sachs endocarditis with emboli
• Coagulopathy
  • lupus anticoagulant
  • anticardiolipin antibody
• Noninflammatory vasculopathy
• Small deep infarcts
  • associated HCVD
• Intracranial branch artery occlusion
• Cortical and subcortical infarcts (arteritis)
• Large Vessel Stroke
  • in approximately 86% of patients the disease is active at stroke occurrence
  • stroke occurs after 4–5 years of disease
  • headache is common at onset
  • often associated with low protein S activity
  • antiphospholipid antibody associated with Libman–Sachs endocarditis
  • global depression of left ventricular function
    • cardiac small vessel arteritis
    • poor ejection fraction and embolus
• Unusual Vascular Manifestations:
  • vertebrobasilar territory infarction at presentation
  • vascular monocular or binocular optic neuropathy
  • posterior ischemic optic neuritis

Periarteritis Nodosa

• General Characteristics
  • Multisystem involvement:
    • Late onset asthma
    • Testicular infarction
    • Lobar hepatic infarction
    • Eosinophilia
    • Severe hypertension from renal involvement
    • Palpable arteriolar enlargement in the skin
    • May occur with hepatitis B and C
• Neurological Manifestations:
  • Peripheral nerve involvement
    • Mononeuritis multiplex
    • Guillain Barré-like syndrome
• CNS involvement
  • Occurs in 20–40% of patients late after onset of systemic and PNS disease
• Stroke
  • Occurs late in the illness
  • Often secondary to renal induced hypertension
  • Illness never presents with stroke
• Ocular manifestations
  • Any orbital structure may be involved
  • Conjunctivitis
  • Episcleritis
  • Extraocular muscle palsy
  • Optic neuritis
  • Orbital pseudotumor
• Pathology
  • Involvement of medium sized arteries
    • Disease occurs at branch points
    • Necrotizing arteritis:
      • Increased levels of adhesion molecules
      • Invasion of arterial wall by leukocytes and monocytes
      • Fibrinoid necrosis
      • Endothelial proliferation with thrombosis
    • Rare ANCA antibodies (pANCA); antinuclear cytoplasmic antibodies
    • Multiple microaneurysms and stenosis of medullary renal arteries

Microscopic Polyangiitis (Periarteritis nodosa variant)

• General Features
  • A form of necrotizing small vessel vasculitis
    • Affects venules, arterioles and small arteries
    • Rarely medium-sized arteries are affected
  • Absence of or minimal immunoglobulin location in vessel walls distinguishes it from:
    • Henoch–Schönlein purpura
    • Cryoglobulinemic vasculitis
  • Associated medical conditions:
    • Immune necrotizing and crescentic glomerulonephritis
    • Hemorrhagic, pulmonary capillaritis
    • Most common cause of pulmonary-renal vasculitic syndrome
  • Pathologically vasculitis similar to:
    • Wegener's
    • Churg–Strauss
  • Associated with circulating pANCA antibodies
  • Putative role for neutrophiles/monocytes in vascular injury
• Systemic Features
  • Fever, weight loss and fatigue in majority of patients
  • pANCA is antibody seen
    • Myeloperoxidase is in the epitope that pANCA binds
  • Elevated C-reactive protein and sedimentation rate prominent at diagnosis
• Neurological Signs
  • Optic neuritis
  • Peripheral nervous system involvement
    • GBS
    • Mononeuritis multiplex
    • Vasculitic induced sensorimotor neuropathy
  • Ischemic and hemorrhagic infarction from hypertension

Sarcoid

• General Characteristics:
  • Pulmonary periaortic node involvement
  • Diffuse infiltrative lung pattern
  • Cardiac conduction abnormalities
  • Rheumatologic manifestations (ankle involvement prominent)
  • Skin manifestations (neck and nose)
• PNS Involvement:
  • Cranial nerve VII (with uveitis is Heerfordt's syndrome)
  • Optic nerve (compression by meningeal infiltration)
  • Sensorimotor neuropathy
  • Myopathy
  • Chiasmatic involvement
• CNS Involvement
  • Chiasm
  • Parenchymatous granuloma occur in the:
    • Posterior hypothalamus
    • Pituitary
    • Hemisphere
  • Meningeal involvement; may compress optic nerves
  • Compressive myelopathy
  • Meningitis:
    • Glucose 30–40 mg%
    • Slightly elevated protein 60–80 mg%
    • Lymphocytic pleocytosis (30 cells mm³)
  • Stroke:
    • Cerebral vasculitis
    • Associated with pleocytosis
    • Retinal inflammation (periphlebitis)
    • Spread of inflammatory cells from the meninges through the Virchow–Robin spaces to pial vessels
    • Predilection for veins (phlebitis)
  • Stroke pattern
    • TIA
    • Superficial pial artery stroke
  • Retinal changes:
    • Periphlebitis (diffuse sheathing of retinal veins)
    • Hard exudates ("taches de bougie"; candle wax dripping)
    • Chorioretinal scars

Sjögren's Syndrome

General Characteristics

• May affect 3% of population; women > men
• 50% of patients it is secondary (occurring with other processes)
  • Most often associated with rheumatoid arthritis
• characterized by:
  • Keratoconjunctivitis sicca
  • Xerostomia
  • Associated with other connective tissue diseases
• Lymphoid invasion of exocrine tissues of the body:
  • Otitis (eustachian tube dysfunction)
  • Recurrent bronchial infection
  • Dryness of genital mucosa
  • Atrophic gastritis
  • Atrophy of the oral mucosa
• Raynaud's phenomena
• 50% of patients have arthralgias
• Renal interstitium involved
• Muscle, skin, nerve, vasculitis
  • Usually involved with RA (rheumatoid arthritis)

Neurological manifestations

• peripheral nervous system:
  • Large fiber sensory loss
  • Dorsal column involvement
  • Autonomic impairment
    • Adies pupil (tonic pupil)
    • Anhidrosis
    • Orthostatic hypotension
  • Vth nerve involvement
    • Gasserian ganglionitis
  • Central nervous system involvement:
    • Myelitis
    • Seizure
    • Dementia
    • Meningoencephalitis
    • Focal brain infiltrates
  • Stroke:
    • Pial vessels
    • Large vessels
    • Hemiparesis, aphasia, ataxia
    • Cognitive and behavioral deficits
  • Associated with primary progressive multiple sclerosis
  • CSF:
    • Lymphocytic pleocytosis < 30 cells mm³
    • Mildly elevated protein 60–80 mg%
  • MRI evaluation
    • Lesions resemble those of MS
    • Dorsal column spinal cord lesions
    • Discrete cortical lesions that resemble infarcts

Rheumatoid Arthritis

General features

• Crippling arthritis associated with:
  • Ocular manifestations (keratoconjuctivitis)
  • Cardiac involvement
  • Vasculitis of the bowel
• Possibly affects 1% of the population
• Associated neurological manifestations:
  • Myopathy (proximal)
  • Neuropathy (severe atrophy of intrinsic hand muscles)
  • Atlantoaxial subluxation (C2–C3; spinal cord compression)
  • Rheumatoid pachymeningitis
  • Rheumatoid dural nodules (seizures)
  • Encephalopathy
  • Generalized sensorimotor neuropathy
  • Rare mononeuritis multiplex
  • C2 pannus with spinal cord compression
  • CTS
• Cerebral rheumatoid vasculitis occurs:
  • Concomitantly with aggressive systemic rheumatoid vasculitis
  • Rarely in isolation
  • Ischemic stroke associated with:
    • Localized vasculitis (rare)
    • Rheumatoid pachymeningitis
    • Cardiac emboli
    • Multifocal small infarcts
  • Cerebral hyperviscosity syndrome due to:
    • High titers of circulating rheumatoid factor
    • Increased levels of fibrinogen, and fibrinogen depredation products

Scleroderma

• General Features:
  • Microvascular pathology and diffuse tissue fibrosis that affects:
    • Skin
    • Gastrointestinal tract
    • Lungs
    • Heart
    • Kidneys
  • Neurological Manifestation
  • Peripheral nervous systems:
    • Myopathy in 17% of patients
    • Cranial nerve involvement
      • Vth nerve most often involved
      • Possibly at the ganglion level
    • Sensorimotor neuropathy
    • Mononeuritis multiplex
    • Carpal tunnel syndrome
    • Cranial neuropathies (Vth nerve)
    • Autonomic neuropathy
    • Myelopathy (rare)
  • CNS Features: stroke
    • Disseminated cerebral arteritis
    • Hemorrhage from renal hypertension
    • SAH (rare)
    • Cardiac emboli (rare)

Churg–Strauss Syndrome

• General Characteristics
  • Asthma
  • Eosinophilia
  • Previous allergic disorder
  • Lung involvement
  • Pituitary infarction
  • >60% of patients have CNS involvement
  • May be relapsing
• Primary Vascular Involvement
  • venules
  • capillaries
  • arterioles
  • small vessel necrotizing vasculitis
• Neurological Manifestations
  • Encephalopathy
  • Peripheral neuropathy
    • Distal motor sensorimotor
  • Rare small vessel stroke
  • Pachymeningitis

Henoch–Schönlein

• General characteristics:
  • Predominant IgA meningeal deposits
    • Small vessel necrotizing arteritis
  • Clinical associations:
    • Purpura
    • Abdominal pain
    • Arthritis
    • Renal involvement
    • Carcinoma of respiratory and GI tract
    • Adult involvement
      • Preceded by mucosal infection of the upper respiratory tract
• Neurological complications
  • Occasional small vessel stroke
    • Primarily in children
    • ICH (children)
      • Factor XIII deficiency
  • Allergic reactions to drugs are a precipitant

Wegener's Granulomatosis

• General characteristics
  • Necrotizing vasculitis of:
    • Sinuses
    • Lungs
    • Upper respiratory tract
    • Kidneys
  • Neurological manifestation
    • Optic nerve ischemia
    • Orbital involvement
    • Extraocular muscle palsies
    • Retinal involvement
    • Posterior ischemic optic neuropathy
  • Eosinophilic fasciitis (rarely associated)
  • Jaw claudication (rare)
  • Rarely associated with temporal arteritis
  • Stroke
    • Cerebral arteritis
    • Pial vessel infarcts
  • Laboratory evaluation
    • Sed rate a good measure of disease activity
    • pANCA elevated
    • Overlap with other serum markers of hypersensitivity disease

Hypersensitivity Vasculitis

• General characteristics:
  • Rash
  • Palpable purpuric skin lesions
  • Legs more commonly affected than arms
  • Extremities may be symmetrically swollen and erythematous
• Etiology
  • Specific allergens
  • Penicillin and sulfa drugs
  • Post infectious
• Henoch–Schönlein: General manifestations:
  • Joint pain may be prominent
• Mixed cryoglobulinemia
  • Acrocyanosis
  • Cold induced acroparesthesias
  • Sensorimotor neuropathy
  • Increased IgM

Peripheral Nervous System Manifestation

• Sensorimotor neuropathy
• Plexopathy
• More common than CNS manifestations

Stroke

• Diffuse petechiae in centrum semiovale
  • Secondary to low platelets

Mixed Collagen Vascular Disease

• General characteristics
  • Features of:
    • SLE
    • Scleroderma
    • Polymyositis
  • Concomitant high titers of antibody to:
    • RNase-sensitive ribonucleic complex
      • small RNPC (ribonucleic protein)
• Neurological manifestations:
  • Headache
  • Seizure
  • Psychosis
  • Encephalopathy
  • Transverse myelitis
  • Ataxia
  • Aseptic meningitis
  • Monocular blindness
  • Vth nerve involvement
  • Sensorimotor neuropathy
  • Entrapment neuropathy
• Stroke
  • Rare
  • Secondary to cerebral vasculitis
• Neurologic features are dependent on the dominant clinical syndrome, i.e., SLE vs scleroderma vs polymyositis

Thrombotic Thrombocytopenic Purpura (Moschowitz Syndrome)

• General characteristics
  • Female 2:1 > male
  • Fever (interleukin I)
  • Renal failure
  • Thrombocytopenia
  • Microangiopathic hemolytic anemia
• Associated with:
  • Pregnancy
  • Bone marrow transplantation
  • HIV
  • SLE
  • Ticlopidine
  • Sjögren's Syndrome
  • Rheumatoid arthritis
  • Influenza vaccination
  • D-penicillamine
  • Cyclosporine
  • Citomycin
• Neurological manifestations
  • Diffuse encephalopathy
    • Visual hallucinations
    • Headache
    • Seizures
    • Visual loss
  • Transient focal deficits
  • Aphasia
  • Papilledema
  • Relapsing course
  • Posterior leukoencephalopathy
• Pathology
  • Arteriolar and capillary involvement
  • Platelet rich thrombi
  • Multifocal microinfarctions
• Pathogenesis
  • Non-familial form
    • Inhibitor of Von Willebrand factor cleaving protease
  • Familial form (constitutive deficiency of the protease)
  • Large multimeres of Von Willebrand Factor adhere to and aggregate platelets

Reiter's Disease

• General characteristics:
  • May follow G.I. illness
  • Severe heel pain
• Neurologic complications:
  • Optic neuritis
  • Encephalitis
  • Ascending motor paralysis (GBS like syndrome)
  • Seizures
  • Brainstem dysfunction
  • Acute transverse myelitis
  • Neuralgic amyotrophy
  • Superficial pial stroke

Relapsing Polychondritis

• General characteristics
  • Episodic inflammation of cartilage throughout the body
• Clinical characteristics
  • Pain and tenderness of cartilaginous portions of the ear in 85% of patients
  • 40% suffer inner ear disease with:
    • Hearing loss
    • Tinnitus
    • Vertigo
    • Rarely deafness
  • Ocular involvement:
    • Conjunctivitis, episcleritis, scleritis
    • Iritis and iridocyclitis
    • Keratoconjunctivitis sicca
    • Choroiditis
    • Orbital pseudotumor (proptosis)
    • Optic neuritis
    • Retinal vasculitis
  • Nasal cartilage inflammation
    • 70% of patients
    • Saddle nose deformity
  • Aortic insufficiency
  • Laryngotracheal involvement in 50%
  • 10% of patients develop PAN
• Associated Diseases:
  • Rheumatoid Arthritis
  • Systemic lupus erythematosus
  • Reiter's syndrome
  • Ankylosing spondylitis
  • Ulcerative colitis
  • Hashimoto's thyroiditis
  • 25% have myelodysplastic syndrome
• Neurologic Signs and Symptoms:
  • Occur in 3% of patients
  • Extraocular muscle palsy
  • Optic neuritis
  • Bilateral VIIth nerve
    • Associated with inner ear disease
  • Mononeuritis multiplex
    • Associated with PAN
  • CNS manifestations:
    • Meningoencephalitis
    • Headache
    • Altered consciousness
    • Papilledema
    • Meningeal signs
    • Seizure
    • Ischemic stroke

Ulcerative Colitis and Regional Enteritis

• General characteristics
  • Dominant bowel symptoms
  • Large joint arthritis
  • Keratoconus
• Neurological Manifestations
  • Cerebral venous and sinus thrombosis
  • Large vessel strokes
  • Loss of protein C and S (protein losing enteropathy)

Celiac Disease

• General characteristics:
  • Severe diarrhea
  • Gluten sensitivity
  • Antibodies to gliadin
• Neurologic manifestations:
  • Proximal myopathy
  • Sensorimotor peripheral neuropathy
  • Spinal cord dysfunction
  • Cerebellar degeneration with ataxia
• Stroke
  • Large conducting and pial vessel stroke

Giant Cell Arteritis

• General characteristics
  • Incidence of 17.4/100,000 people
  • Superficial temporal and occipital arteries are most frequently involved
  • Internal carotid, extracranial vertebral arteries, coronary, femoral and rarely intracranial arteries may be affected
  • Extracranial vessels most commonly involved in giant cell arteritis are:
    • Aortic arch (dissection)
    • Rupture of an aortic aneurysm
    • Annuloaortic ectasia
  • Presents as a systemic illness:
    • Low grade fever
    • Iching of proximal muscles
    • Weight loss
    • Onset of headache
      • Painful burning scalp
      • Not pulsatile
    • Jaw claudication
    • Perforated nasal septum
    • Ischemic tongue lesions (similar appearance to carcinoma)
    • Painful cord like superficial temporal arteries (only 30–40% positive by biopsy)
      • ESR is increased in greater than 90% of patients'; biopsy negative in at least 50% of patients
    • Sites of arterial involvement causing stroke:
      • Distal extracranial ICA at the carotid siphon
  • Rare sites of involvement:
    • Pial and brainstem arteries
  • Extracranial giant cell arteritis:
    • Occurs in 10–15% of patients with polymyalgia rheumatica
  • Relapses may occur after successful treatments

Neurological Manifestations

• Blindness from:
  • Occlusion of the posterior ciliary arteries (derived from the internal carotid) or their collaterals (from the external carotid)
  • Central retinal artery occlusion
  • Ischemic optic neuropathy from infarction at the optic disc
  • Visual loss occurs suddenly
    • may occur in the second eye within minutes or at approximately 2 months
    • men > women with severe ocular problems
    • visual loss is permanent due to infarction of the optic nerve head and retina
• Visual field deficits
  • Altitudinal rather than central
• Anterior optic nerve involvement:
  • Mild papilledema
  • Infrequent disk hemorrhage
  • Resolves over 10 days
• Retrobulbar ischemic optic neuropathy:
  • Gradual optic pallor and atrophy
• Diplopia:
  • 2–14% of patients
  • Vasculitis of extraocular muscles with total ophthalmoplegia (rare)
• Cranial nerve palsies:
  • Rare that VIII th nerve is involved
  • Infarction of the internal auditory artery (origin is AICA)
• Tongue:
  • Hemianesthesia of the tongue
  • Lingual paralysis
  • Ischemic tongue lesion
    • Similar to squamous cell carcinoma in appearance
• Facial pain:
  • Arteritis of the facial branch of the external carotid artery
• Myelopathy:
  • Vasculitis of the vertebral and anterior spinal artery with cervical cord infarction
• Peripheral neuropathy:
  • Distal symmetrical sensorimotor neuropathy
  • Mononeuritis multiplex
  • One month after onset
• Myopathy:
  • Steroid related proximal myopathy

Cerebrovascular Disease

• TIA of anterior and posterior arterial systems
• Encephalopathy
  • Arteritis of pial and superficial arteries
• Multiinfarct dementia
• Infarction of major branches of both anterior and posterior circulations
• arotid bruits noted in 10–20% of patients:
  • Bilateral bruits:
    • 60% of these patients have associated involvement of the aortic arch
• Vertebrobasilar arterial involvement may present with:
  • Acute confusional state
  • Coma

Laboratory Evaluation

• Elevated sedimentation rate
• Mild normocytic anemia
• Mild peripheral leukocytosis

Isolated Angitis of the CNS

• General features:
  • This is putatively and immune mediated arteritis of strictly cerebral blood vessel
  • Other names for the process:
    • Isolated granulomatous angiitis
    • Giant cell granulomatous angiitis of the CNS
  • Mean age of onset 49; any age can be affected
  • Male predominance 2:1
  • Vasculitis isolated to the CNS:
    • Exclusion of systemic inflammation, infection or other causes of CNS vasculitis; rarely associated with angioid angiopathy
  • Segmental necrotizing granulomatous vasculitis that involves:
    • Cortical arteries
    • Spinal arteries
    • Leptomeningeal arteries
    • Usual vessel size involved is 200–500 μm (microns)
      • Any size vein or artery may be involved
      • Precapillary arterioles < 200 μm are involved
    • Intima and adventitia of arteries are infiltrated with:
      • Lymphocytes, giant cells, and granulomas
      • Granulomas may invade the cortex
    • Veins may be affected in 50% of patients
• Neurologic Manifestations
  • Earliest symptoms:
    • Headache
    • Phonophobia
    • Photophobia
    • Unusual stroke-like presentation
    • Diffuse encephalopathy (usual presentation)
    • Gradual onset
  • Later signs and symptoms:
    • Altered mental status
    • Dementia
    • Myelopathy
    • Hemiparesis
    • Diffuse encephalopathy
    • Rare territorial stroke
    • Pathology of intracranial vessels
      • Thrombosis
      • Small aneurysms develop on arteries
    • Myelopathy may precede encephalopathy
    • Seizures occur
    • Usual progression
      • Step-like deterioration of a progressive encephalopathy
    • Rare SAH
• Imaging Evaluation
  • MRI
    • Positive 68% of the cases
    • Infarcts demonstrated (ischemic)
    • Rarely hemorrhagic infarction
    • Small hematoma (rare)
    • Rare intracerebral aneurysm
  • Arteriogram
    • Positive in approximately 50% of patients; involved vessels <500 μm
    • Segmental narrowing, dilatation and beading
  • Laboratory Evaluation
    • Elevated sed rate in 2/3 of patients
    • CSF
      • Mononuclear and lymphocytic pleocytosis
      • CD4+ lymphocytes involved
      • Protein elevated in 80%of patients > 100 mg/dl

Nongranulomatous Angiitis of the CNS

• General characteristics:
  • Segmental necrotizing angiitis without granulomata
  • Male: female 1.8 to 1
  • Multiple small but occasionally large foci of infarction throughout the CNS
  • Mean age at onset 49
• Neurological Manifestations:
  • Acute presentation
    • Stupor or coma within days to weeks
  • Classic presentation:
    • Fever and weight loss uncommon
    • Mental status change
    • Headache
    • Hemiparesis
    • Impairment of consciousness
    • Focal, multifocal or diffuse encephalopathy
  • Rare vascular presentation:
    • TIA
    • large vessel stroke
    • SAH
    • Multiinfarct stroke
  • Rare neurologic presentation
    • Increased ICP
    • Chronic meningitis or arachnoiditis
    • Cerebral hemorrhage
    • Radiculopathy
• Evolution of the Disease
  • Stepwise occurrence of focal neurologic deficits
• Laboratory Evaluation
  • Mild elevation of ESR in 2/3 of patients
  • CSF mononuclear pleocytosis (mean of 70 monocytes/mm³)
• Imaging Evaluation:
  • MRI:
    • White and grey matter involvement
    • Occasional hemorrhage
    • Bilateral subcortical lesions
    • Enhanced meninges
  • Arteriography
    • Abnormal in approximately 60%
      • Segmental narrowing and sausage shaped dilatation (beading)
      • Rarely: avascular mass or intracerebral aneurysm
      • Affected vessels < 500 μm
  • Leptomeningeal biopsy more often positive than brain biopsy

Benign Angiitis of the CNS

• General Characteristics
  • Affects young women
  • Setting of intermittent hypertension
• Neurologic Manifestations
  • Transient reversible neurologic deficits
  • Multi-segmental arterial narrowing
  • Self limited course
• Course, setting and favorable prognosis differentiate this entity from isolated angiitis of the CNS

Post Partum Cerebral Angiopathy

General Characteristics

• May occur up to two days after delivery
• Associated with
  • Bromocriptine
  • Sympathomimetic drugs
  • Ergotamines
• May be recurrent
• Mean age of onset:
  • PACNS with amyloid angiopathy (65 years)
  • PACNS (44.8 years)
  • Cerebral angioid angiopathy (CAA) (76 years)

Neurological Manifestations

• Transient bilateral parieto-occipital high signal intensity lesions on MRI (T2)
• Frontal intracranial hemorrhage
• Primary angiitis of the central nervous system associated with cerebral amyloid angiopathy
• Multifocal neurological signs and symptoms
• Headache
• Hallucinations
• Subacute cognitive deficits

CSF Evaluation

• Eosinophilic pleocytosis
• Xanthochromia >40% of patients

Differential Diagnosis of Conditions Mimicking Vasculitis

• Dissecting aneurysm
• Antiphospholipid syndrome
• Drugs
  • Methamphetamine
  • Sympathomimetic drugs
  • Ginseng
  • Ephedrine
  • Propyl ethanolamine
  • Cocaine
• Cholesterol emboli
• Intravascular lymphomatosis
• Coll.'s syndrome

Differential Diagnosis of Arteritis Associated with Autoimmune Diseases

• SLE
• PAN
• Sarcoid
• Sjögren's
• Rheumatoid arthritis
• Scleroderma
• Churg–Strauss
• Wegener's granulomatosis
• Hypersensitivity arteritis
• Mixed collagen vascular disease
• Giant cell arteritis
• Reiter's Syndrome
• Relapsing polychondritis
• Ulcerative colitis
• Regional enteritis
• Celiac Disease
• Serum sickness
• Henoch–Schönlein purpura
• Cryoglobulinemia

Differential Diagnosis of Systemic Necrotizing Arteritis

• Wegener's granulomatosis
• Lymphomatoid granulomatosis
• Sarcoid
• Hairy cell leukemia

Differential Diagnosis of Arteritis with Neoplasia

• Hodgkin's disease
• Non-Hodgkin's lymphoma
• Neoplastic angioendotheliosis
• Hairy cell leukemia
• Angiocentric endothelial lymphomatosis

Differential Diagnosis of Isolated Angiitis of the CNS

• Necrotizing vasculitis
• HZ
• Hodgkin's disease
• HIV
• Sarcoid
• Hypersensitivity arteritis
• PAN
• Lymphomatoid granulomatosis
• Methamphetamine
• Sympathomimetic drugs
• Coll.'s Disease
• Wegener's granulomatosis

Differential Diagnosis of Systemic Vasculitis Resembling Isolated Angiitis of the CNS

• Vasculitis with connective tissue disease
• PAN
• Wegener's granulomatosis
• Giant cell arteritis
• Takayasu's Disease
• Behçet's Disease

Differential Diagnosis of Vasculitis Associated with Granulomatous Parenchymal Lesions

• Wegener's granulomatosis
• Sarcoid
• Lymphomatoid granulomatosis
• Granulomatous angiitis

Differential Diagnosis of Granulomatous Angiitis of the CNS

• Hodgkin's Disease
• Sarcoid
• HZ
• Methamphetamine
• Sympathomimetic drugs
• Coll.'s Disease

Differential Diagnosis of Vasculitis By Characteristic Sites of Involvement

• Takayasu's Disease:
  • Arch of the aorta
  • Mid common carotid artery
  • Mid descending aorta
• Sneddon's Syndrome
  • Skin (livedo reticularis)
• Köhlmeier–Degos Syndrome
  • Atrophic skin lesions
• Giant cell arteritis
  • Primarily external carotid system
  • May affect the ICA, and arch of the aorta

Differential Diagnosis of Vasculitis by Topography

• Focal
  • Herpes Zoster
    • Proximal MCA; ACA (side of the skin lesions)
• Multifocal
  • SLE
  • Primarily separate areas of the cortex
• Disseminated
  • Isolated or primary angiitis of the CNS

Differential Diagnosis of Vasculitis of Medium Sized Arteries

• PAN
• SLE
• RHA
• Sjögren's Syndrome
• Buerger's Disease

Differential Diagnosis of Vasculitis of Small Sized Arteries

• Churg–Strauss
• Polyarteritis nodosa (microangiopathic variant)
• Wegener's granulomatosis
• Hypersensitivity arteritis

Differential Diagnosis of Segmental Narrowing of Cerebral Arteries on Arteriogram

• Arteritis (infective; inflammatory; necrotizing)
• Leptomeningitis (infective, chemical, carcinomatous)
• Vasospasm (SAH, migraine, hypertensive encephalopathy)
• Atherosclerosis
• Fibromuscular dysplasia
• Recanalization of emboli
• Sickle cell disease
• Sympathomimetic drug abuse
• Neoplasms (angioendotheliosis, glial and meningeal tumors, atrial myxoma)
• Closed head injury
• Radiation therapy (X-RT)
• Neuroectodermal dysplasia (neurofibromatosis; tuberous sclerosis)

Differential Diagnosis of Infections that Cause Stroke

The differential diagnosis of the infections that cause stroke rests on the specific pathologic mechanisms induced or associated with each infection. The neurology of each infection is different and often the extracranial manifestation of the infection provides the clue to the specific diagnosis. Bacteria viruses and fungi cause stroke as due spirochetes and protozoa.

Stroke may occur in the setting of bacterial meningitis. Pus may directly involve the pial vessels that encase them on the cortex. Pneumococcus may concomitantly infect heart valves and mycotic aneurysm with hemorrhage and stroke may occur 6–8 weeks after the primary infection.

Meningococcal infection occurs frequently in settings in which young healthy adults are living in close quarters. The speed of the infection (headache to coma) within hours is characteristic. The course is dominated by the meningitis. Stroke is rare.

Listeria infections occur following head and neck surgery and during pregnancy and delivery. The seminal feature is brainstem infarct with dorsal pontine involvement. Bartonella henselae infection follows exposure or inoculation from cats. Seizures and retinitis are the seminal features following extremity lymphadenitis.

Syphilis has made a comeback as a serious cause of infection due to HIV. It may be telescoped where all three stages are seen within a short period of time. In the past, brainstem strokes were noted in the meningovascular stage. This pattern persists, but may be more associated with gumma formation and less with clonic syphilitic optic nerve and pretectal involvement (Argyl Robertson pupils). If meningitis is seen concomitantly the CSF sugar is usually normal.

Lyme disease is the most common vector borne infection in the United States and has protein manifestations. If VIIth nerve palsy and characteristic rash and large joint arthritis is present diagnosis is straight forward. Unfortunately, many patients present in later stages with asthenia and low grade encephalopathy weeks or months after the infection. Strokes are rare, but are described.

Tuberculosis causes strokes because of cortical and basilar exudates. It is a more chronic illness in Western countries and is often seen as a low grade dementing illness. It should always be suspected in HIV infected patients with lower cranial nerve abnormalities (particularly the VIIIth nerve).

Fungal infections occur most frequently in the immunocompromised host. Disorders of B-lymphocyte function are associated with encapsulated bacterial pathogens. Impaired T-lymphocyte or macrophage function causes infection by intracellular pathogens such as aspergillus and fungi, nocardia (bacterial) viruses and parasites (toxoplasmosis gondii).

Extra CNS sites of infection suggest aspergillus and nocardia that may present subacutely or chronically. T-lymphocyte dysfunction with meningitis is Listeria or cryptococcus. Aspergillus can present as a CNS mass lesion or stroke but most often as meningitis.

Mucormycosis is associated with all forms of immunosuppression, but particularly with diabetic ketoacidosis and renal failure. The fungus is associated with sinus infection and venous infarction. It should be suspected in this circumstance in a patient with ophthalmoplegia.

Aspergillosis infects isolated lung abcesses and is associated with osteomyelitis of the base of the skull. It is notorious for fungal hyphae occluding cerebral conducting vessels. Fungal balls from valve leaflets are large enough to occlude peripheral extremity arteries.

Cryptococcus usually presents as a chronic dementia in the setting of immunocompromise. It spreads through the Virchow–Robin spaces to involve the basal ganglia. This is most helpful in setting of stroke and T2 enhancement of the caudate and putamen. Proximal MCA branches and vessels in the posterior perforated substance are most frequently involved.

Coccidiomycosis is common in the American SW. Extracranially it affects lungs and joints. Sacral involvement is frequent as is involvement of the jaw. Proximal MCA and the arteries of the perforated posterior substance are most often involved.

Histoplasmosis is most often encountered in the Mississippi Valley. It may be associated with adrenal failure with concomitant splenic calcification. Arteries are inflamed in the chronic basilar exudate.

Viral infections cause stroke by direct invasion of the vessel wall or its endothelium, an immune response triggered by vessel epitopes or immune complex deposition.

Herpes Zoster causes a middle cerebral artery stroke of the ipsilateral MCA on the side of the Vth nerve involvement. This characteristically occurs 6–8 weeks following the rash, but has been seen within two weeks. Both anterior and posterior circulation large vessels may be involved. Immune compromised HIV patients may suffer small vessel disease. One mechanism is involvement of vessel wall endothelial antithrombotic systems.

HIV itself is associated with stroke from various mechanisms:

• Immune complex formation
• Cell mediated vasculitis
• Inflammation from direct viral invasion
• Associated infections that cause stroke

Most often the pathology is in medium sized arteries. The clinical manifestations of severe HIV infection suggest the diagnosis.

Cerebral malaria may be the most widespread CNS infection with stroke as a consequence. It most often occurs with plasmodia falciparum and occurs due to obstruction of main capillaries by parasitized RBC.

The following is a more detailed description of the various infections that cause stroke.

Infections that cause stroke

• Bacterial meningitis
  • Pneumococcus:
    • Early hematogenous spread from the lung
    • Simultaneous infection of the heart valve (may occur); later SBE
    • Stroke of superficial pial vessels
    • Course clinically dominated by meningitis
  • Meningococcal infection:
    • Early headache, nausea and vomiting; "flu-like"
    • Rapid progression to lethargy in 6–12 hours
    • Pial artery strokes
    • Adrenal failure (Waterhouse–Frederickson Syndrome)
    • Clustered infection
      • Close living quarters (army barracks' camp, college dormitories)
    • Bacteria may be seen in cerebral spinal fluid prior to neutrophils
  • Listeria monocytogenes
    • Head and neck cancer patients
    • Abrupt onset of symptoms
    • Clinical involvement of:
      • Medulla
      • Pontine tegmentum (seminal feature)
      • Lower cranial nerve palsies
      • Arteritis of the brainstem with multiple infarcts
      • Focal encephalitis
      • Monocytic cerebral spinal fluid pleocytosis
  • Bartonella henselae (cat-scratch fever)
    • Lymphadenopathy in drainage area of the scratch
    • Seizures (generalized)
    • Retinitis
    • Intracranial stenosis and arteritis

Syphilis

• Arteritic attacks occur in stage II disease (meningovascular syphilis)
  • Many brainstem syndromes were originally described in patients with syphilis
  • "Heubner's arteritis"
• A proliferative endarteritis
• Primarily occurs in small penetrating vessels of the brainstem
• Pupillary abnormalities:
  • Oval pupil
  • Argyle–Robertson pupil
  • Paralytic tabetic pupil
• Associated retinitis pigmentosa
  • Pigmentary migration around choroidal blood vessels
• Concomitant neurologic manifestations:
  • Progressive encephalomyelitis
  • Meningovasculitis (syphilitic)
  • Peripheral unilateral > bilateral VII nerve palsies (Bernhardt's disease)
  • Peripheral neuropathy
  • Headache with meningitis
    • Skin rash involving the palms and soles
  • VDRL in cerebral spinal fluid is positive
    • Sugar is normal
    • Acute meningitis with neutrophiles
    • Protein moderately elevated
  • Spinal cord strokes occur
  • Infection more virulent in HIV patients:
    • Telescoped spinal fluid (3rd stage CSF, lymphocytes, may be seen early in infection)

Lyme Disease

General Features

• The most common vector borne infection in the United States:
  • 15,000 cases/year
  • Three distinct foci
    • Maine to Maryland
    • Wisconsin and Minnesota
    • Northern California and Oregon
• Borrelia burgdorferi:
  • Tick borne spirochete
    • Ixodes ricinus complex
  • Vectors are:
    • Deer; white footed mice; dusky footed wood rats
• Medical Complications:
  • Early infection
    • Localized erythema migrans (stage 1)
    • Disseminated infection (stage 2)
      • Nervous system
      • Heart
      • Joints
      • Occurs within days or weeks of infection
    • Late or persistent (stage 3)
      • Weeks or months after infection
• Medical system involvement:
  • Skin
    • Erythema migraines
  • Cardiac
    • AV block; subtle myocarditis
  • Joints
    • Oligoarticular arthritis
    • Treatment resistant arthritis in 10% of patients
  • Asymptomatic infection about 10% of patients
• Neurological complications:
  • Acute phase:
    • Severe headaches
    • Meningitis (lymphocytic)
    • Neck stiffness
    • Radiculoneuritis
    • Mononeuritis multiplex
    • Cerebellar ataxia
    • Myelitis
  • Chronic phase:
    • Uni or bilateral VII nerve palsy
    • Encephalopathy
    • Cognitive dysfunction
    • Sensory polyneuropathy
      • No acrodermatosis

Laboratory evaluation:

• An antibody response to B. burgdorferi by enzyme-linked immunosorbent assay (ELISA)
• Western blotting of CSF (positive)
• Intrathecal production of IgM, IgG or IgA antibody
• After antibody treatment:
  • Antibody titers fall slowly and may persist for years

Tuberculosis

• Infarction of arteries within cortical and basilar exudates
  • Superficial pial arteries most often affected
• Exudates at the base of the brain
• Seizures (focal or generalized)
• Cranial nerve VIII and lower cranial nerves most frequent affected
• Frequently associated with HIV
• Chronic dementia

Cerebral Nervous System (CNS) Infections in the Immunologically Compromised Host

• General neurological manifestations:
  • Meningeal signs
  • Mass lesions
  • Encephalopathy
  • Seizures
  • Stroke-like presentation
• Presentation depends on specific characteristics of the organism
• CNS mass lesions
  • Subacute or chronic presentation
• Meningitis and encephalitis
  • Acute presentation
• Disorders affecting B-lymphocyte function:
  • Meningitis caused by encapsulated bacterial patho-gens
  • Bacterial meningitis similar presentation in normal and compromised hosts
• Impaired T-lymphocyte or macrophage function:
  • Infection caused by intracellular pathogens
    • Aspergillus and fungi
    • Nocardia (bacteria)
    • Viruses
      • HSV
      • JC
      • CMV
      • HH-6
    • Parasites
      • Toxoplasmosis gondii
• Extra-CNS sites of infection
  • Lung and brain infection
    • Aspergillus
    • Nocardia
    • Subacute or chronic presentation
• T-lymphocyte dysfunction with meningitis:
  • Listeria
  • Cryptococcus
• Failure of anti-toxoplasmosis on the therapy for a mass lesion:
  • Probable central nervous system lymphoma
• Aspergillus presentation:
  • Mass lesion
  • Stroke
  • Rare as meningitis

Fungus Infections

• Mucormycosis
  • Associated with ethmoid, sphenoid, maxillary sinus infection
  • Ophthalmoplegia (cavernous sinus involvement)
  • Black palate (associated with lateral sinus thrombosis with cyanotic congested palate)
  • Occurs in immunocompromised patients:
    • Diabetic ketoacidosis
    • Renal failure
    • HIV
  • May have indolent cause with ophthalmoplegia
  • Basilar arteritis
    • Pontine infarction
    • Skull base involvement
  • Intracranial hemorrhage
  • Large vessel stroke
  • Involvement of intracranial vessels
• Aspergillosis
  • Immunocompromised patients
    • Inhalation of spores
    • Aspergillomas in lung cavities
    • Disseminated after bone marrow transplantation
    • Common after ENT surgery (paranasal sinus)
    • Involves blood vessels
    • Associated mycotic aneurysms
    • Intraluminal extension of fungal hyphae with ischemic stroke
    • Aspergillomas occur in sphenoid sinus
      • Associated skull base osteomyelitis
      • Cranial nerve involvement
      • Cavernous sinus thrombosis
      • Rare spinal cord involvement
• Cryptococcus
  • Meningitis
    • Sugar 30–40 mg%
    • Lymphocytic pleocytosis
    • PCR positive
    • Moderate protein elevation of 50–80%
  • Chronic dementia with headache
  • Common in all immunocompromised patients (especially those with HIV)
  • Affects cranial nerve II accumulate (under optic nerve dura)
  • Basal ganglia and midbrain involvement (spreads through Virchow Robin space)
  • Proximal MCA and arteries in the posterior perforated substance most frequently involved
  • Occasional pial artery stroke
• Coccidia mycosis (coccoides immitis)
  • Spores inhaled from the soil
  • Endemic in deserts of SW USA
  • Pulmonary route of infection
    • "flu-like" illness
  • Propensity to invade bone
    • Jaw
    • Lumbosacral area
  • Chronic basilar meningitis
    • Inflammation of arteries within the inflammatory exudate
    • Proximal MCA and arteries of the posterior perforated substance involved

Histoplasmosis

• Endemic in the Mississippi Valley
• Pulmonary route of infection
• Adrenal failure (rare)
• Skin manifestations
• Central Nervous System:
  • Basilar meningitis
  • Proximal great vessel involvement

Fungal Aneurysms

• Fusiform in shape
• Involve longer and more proximal segments of intracranial vessels
• Intradural portion of the carotid artery most common site of fungal neurysm
• Vessel invasion occurs from extension of the hyphae into the lumen which cause:
  • In situ thrombosis
  • Embolization of hyphal masses
  • Major portions of vessels involved
    • Large infarctions

CT Signs of Fungal Infection of a Sinus

• Sclerotic thickening
• Erosion
• Remodeling
  • All rare in bacterial infections
• Central area of high density within the sinus cavity
• Low signal on MRI in all sequences
  • paramagnetic substances within fungal mycetomas
• Aggressive extension of fungus form the sinus to:
  • Orbit
  • Facial tissues
  • Intracranial cavity
• Vascular invasion

Viral Infections and Stroke

• General features:
  • Vasculitis from a viral infection effected by:
    • Direct invasions of central nervous system vessels
    • Triggering an immune response to epitopes of the vessel wall
    • Immune complex deposition

Herpes Zoster

• General vascular manifestations
  • Delayed brain infarction following infection
    • Contralateral hemiplegia form ipsilateral MCA involvement
    • Days to 6–8 weeks following onset of the rash
    • Occlusion or stenosis of the carotid siphon, ACA or MCA
      • May be preceded by a TIA
      • Usual clinical onset in that of an abrupt stroke
    • Concomitant encephalitis
    • Recurrent and multiple infarcts
    • rash may occur in V2, V3 or vertebrobasilar territory
    • Rare involvement of PCA or vertebrobasilar territory
    • Infarct and stenosis may occur in young adults
  • Arteriographic evaluation
    • Stenosis of proximal MCA and basilar artery
      • Induce large infarction
    • Occlusion of the supraclinoid ICA
    • Stenosis of intracranial large conducting vessels

HZ Cerebral Infarctions in HIV-Infected Patients

• HZ ophthalmicus:
  • Delayed contralateral hemisphere stroke
    • Granulomatous arteritis
    • Patient's may have no preceding rash prior to stroke
    • Similar pathology to non-infected patients
      • Segmental arteritis of the carotid siphon
    • Concomitant acute retinal necrosis
• Immune competent HZ patients
  • Large vessel disease
• HIV patients
  • Small vessel diseases
  • Leukoencephalitis
  • Ventriculitis
• Children with concomitant HIV and HZ
  • Dilatation arteriopathy with fusiform aneurysms of intracranial arteries
  • Subarachnoid hemorrhage
• Children with non-HIV, VZV stroke
  • Typical delayed proximal intracranial arteritis

HIV

• General features:
  • Approximately 25% of HIV infected patients have cerebrovascular involvement
    • Concomitant infections that cause vasculitic syndromes are:
      • Ebstein–Barr virus
      • CMV
      • Hepatitis B
      • HZ
• Vasculitis due to:
  • Infections (viral, bacterial, fungal, parasitic)
  • Lymphoma
  • Lymphomatoid granulomatosis
    • Primarily affects the lungs
    • Angiocentric mixed inflammatory infiltration of central nervous system vessels
    • May involve into non-Hodgkin's lymphoma
• Mechanism of vasculitis in HIV:
  • Immune complex formation
  • Cell mediated vasculitis
  • Inflammation due to direct injury
• Clinical associations with HIV vasculitis
  • Encephalitis
  • Myelopathy
  • Peripheral neuropathy
  • Myopathy
• Types of vasculitis with HIV infection
  • Necrotizing
  • Eosinophilic
  • Granulomatous
• MRA evaluation of HIV arteritis:
  • Vascular abnormalities seen in medium sized blood vessels
    • Aneurysmal dilatation
    • Thickening and contrast enhancement of vessel walls
• Primary angiitis of the central nervous system in an HIV infected patient:
  • All other etiologies ruled out
  • Clinical features:
    • Acute or subacute recurrent focal deficits
    • Background of global central nervous system dysfunction

Parasitic Infections

Cysticercosis

• General features:
  • Infection with the larvae (cysticerci) of Taenia solium (pork tapeworm)
• Types of infection
  • Ventricular cysts (racemose form)
  • Parenchymal involvement
  • Subarachnoid space
• Vascular manifestations
  • Occurs primarily in the subarachnoid form of the disease
    • Meningitic spread to basal intracranial blood vessels
      • Endarteritis of small vessels in the vicinity of the parasite
• Patterns of infarction
  • MCA > PCA > ACA infarcted
  • Rarely involves the basilar territory
  • Subcortical small infarcts
  • Large cortical-subcortical strokes
  • Intracranial hemorrhage (rare)
• Clinical features:
  • Stenosis of arteries may spontaneously improve
  • Stroke may be precipitated by treatment with praziquantel
  • Treatment may precipitate an inflammatory response that exacerbates the endarteritis

Cerebral Malaria

• General manifestations:
  • Plasmodium falciparum
  • Neurologic manifestations occur in 2% of all malarial infections
  • RBC's parasitized by P₁ falciparum
    • Occurs maximally in brain capillaries
    • Clinical manifestations
      • Prodrome of fever and headache
      • Intracranial hypertension
        • Distention of capillaries and vessels
        • Cerebral edema
      • Generalized petechial brain hemorrhages
      • Hemiparesis and seizures most common neurological focal complications
    • Focal infarctions more common in children than adults
• CT findings
  • Severely ill patients demonstrate:
    • Thalamic and cerebellar attenuation
    • Cerebral edema
  • Mildly affected patients may have normal initial CT scans
  • Angiography and TCD in children
    • Demonstrate focal stenosis of the basal intracranial arteries
  • Areas of petechial hemorrhage
    • Hallmark of cerebral malaria pathologically
    • Not demonstrated by CT
  • Focal infarcts of the ophthalmic and major cerebral arteries are rare in adults

MRI Evaluation of Cerebral Malaria

• Cortical infarcts
• T2-weighted and FALIR hyperintense lesions
  • Diffuse or symmetrical

Stroke in Association with Named Syndromes

It is surprising how many named stroke syndrome have seminal skin manifestations. Köhlmeier Degos syndrome is associated with characteristic whitish or erythematous papules with a porcelain white center. Associated severe gastrointestinal symptoms are diagnostic. Mencke's syndrome has diagnostic course, stiff hair associated with severe hypotonia, seizures, and branch artery occlusion. There is often survival to early adulthood. Vogt–Koyanagi disease is distinguished by a white forelock, eye lashes and eyebrows. The skin manifestations are noted with a uveal meningeal presentation, ocular and brainstem signs and symptoms of the VIIIth nerve is involved the syndrome becomes Voigt–Koyanagi–Harada.

Sneddon's syndrome is characterized by severe livedo reticularis in the extremities and is associated with stroke in young adults. Divry Von Bogaert disease is seen in older patients has livedo reticularis and is associated with seizures and dementia.

The skin is clearly hyperelastic in pseudoxanthoma elastica (Grönblad–Strandberg disease) and has a characteristic cigarette paper thinness in the posterior neck area. Hyperelastic skin may also be noted in Ehlers Danlos Type I and IV as well as Marfan's Syndrome. Characteristic dissections of extracranial arteries (often bilateral), aortic disease and aneurysms distinguish these entities. Fabry's disease has characteristic angioma in the bathing suit distribution and other seminal feature of heat sensitivity, renal failure, premature coronary artery disease and painful neuropathy.

Hemorrhage rather than stroke syndrome are characteristic of Van Hippel Lindau disease, Sturge Weber, Cobb's disease and Klippel–Ternary–Weber Syndrome. The strawberry hemangioma must cover the upper eyelid (V1) distribution in Sturge–Weber Syndrome. Its most characteristic features are intractable seizures, mental retardation and trans-track calcification of the parieto occipital cortex. Von-Hippel Lindau has characteristic retinal artery venous malformations with lesions also noted in the cerebellum and spinal cord. Associated renal carcinoma is expected. Wyborn–Mason is characterized by strawberry hemangioma on the face or trunk with a midbrain hemangioma Cobb's Syndrome presents with massive truncal hemangioma and hemispheric AVM. Osler Weber Rendu often presents with telangiectasia of the lower lip, conjunctiva and nasal mucous membrane. Stroke may be emboli from pulmonary shunts.

Thrombophlebitis with dilated veins in the upper extremity or chest wall (Mondor's syndrome) suggests nonbacterial thrombophlebitis from an underlying malignancy. Well known in this regard is pancreatic cancer.

Petechiae and purpura are frequently associated with syndromic stroke. Thrombotic thrombocytopenic purpura (Moschowitz's syndrome) presents with generalized purpura, seizures, hallucinations, focal neurologic signs and renal failure. Waldenström's macroglobulinemia may be associated with rheological causes of stroke difficulty with perfusion of capillaries, due to high concentrations of IgM. The petechiae are characteristically noted below the knee. Cryoglobulinemia may present similarly, but often with acrocyanosis. The Bing Neel Syndrome is inclusive of all disease processes that interfere with cerebral perfusion. Bleeding from the gums, petechiae and depressed consciousness are diagnostic. Small cortical strokes may occur. Kawasaki's disease frequently presents with an explosive course and mucous membrane involvement. Unusual coronary artery occlusion and stroke occur. Behçet's Syndrome may present with painful erythematous, well demarcated skin lesions and stroke. Most frequently mouth and genital ulcers are seen concomitantly.

Eye findings and named stroke syndromes are common. Susac disease is a combination of retinitis and VIIIth nerve involvement with stroke. It is a microangiopathy of the main vestibulocochlear complex and retina. There is striking obliteration and amputation of retinal vessels. Acute posterior multifocal placoid pigment epitheliopathy affects young adults and is a putative autoimmune process. The patients may suffer arteritic strokes. The major pathology is in the retinal pigment epithelium although the optic nerve may be involved concomitantly.

Cogan's syndrome and its variants affect young adults and cause an acute interstitial keratitis as well as vestibular and auditory dysfunction. Central retinal artery or vein occlusion occurs in association with pial artery stroke. Atypical variants have vasculitis and systemic manifestations.

Eales disease occurs in young men and is prevalent in the Middle East and India. Retinal periphlebitis and vitreous hemorrhage are common with occasional large vessel stroke. The ophthalmologic symptoms predominate.

Eye findings in association with stroke occur in osteogenesis imperfecta (robin's egg blue sclera); PXE (angioid streaks-disruption of Bruch's membrane), homocystinuria and Marfan's syndrome (lens dislocation), cat scratch fever (infectious retinitis) syphilis (retinitis pigmentosa, argyle Robertson pupil, optic atrophy).

The defects in Ehler Danlos disease cause arterial dissection, intracerebral an extracranial aneurysm and cavernous sinus fistula. Gastric hemorrhage, skin manifestations, mitral valve prolapse due to elongated chordae tendinea and aortic root ectasia occur. Marfan's osteogenesis imperfecta, Ehlers Danlos type I and IV are the primary named entities.

Strokes and bowel defects are related most often due to protein losing enteropathy known as Ménétriér's syndrome. Ulcerative colitis and regional enteritis are associated with large vessel stroke due to loss of protein C and S. Behçet's may affect the gastrointestinal tract with mucosal ulcers. Köhlmeier–Degos disease frequently is initiated by abdominal pain and diarrhea. Henoch–Schönlein purpura may be attended by early and severe joint and abdominal pain.

Loeffler's syndrome and Churg–Strauss disease are associated with pulmonary intersitial disease, eosinophilia and stroke. Pituitary infarction is peculiarly common with Churg–Strauss disease. Vasculitic sarcoid affects the lung and cerebral vessels as does the hyper eosinophil syndrome (20,000 eosinophil/mm³).

Arterial involvement as the primary disease process occurs in both Moya-Moya syndrome and Buerger's syndrome. In Moya-Moya disease there is progressive relentless occlusion of the origin of the carotid arteries. The resulting collateral circulation and exuberance of lenticulostriate arteries produce the characteristic "puff of smoke" on arteriograms. In the United States it is seen with sickle cell disease, tuberculosis that affects the origin of the great vessels as well as X-ray therapy. Frequently it is idiopathic. Surprisingly, it may present in elderly patients and as a primary subarachnoid hemorrhage rather than occlusive ischemic stroke. Buerger's disease often presents with severe occlusive disease below the knee rather than the distal 1/3 of aorta or iliac arteries that is characteristic of atherosclerosis. A dementia secondary to a generalized granular cortical atrophy is more common than conducting vessel stroke.

Erdheim–Gesell syndrome is medial cystic necrosis. Dissection of the great vessel is common. Arterial thickening of the radial artery at the wrist and aortic insufficiency bolster the diagnosis. As noted above, osteogenesis imperfecta, Marfan's syndrome and homocystinuria (accelerated atherosclerosis) all present as primary disease of blood vessels. May Turner Disease is iliofemoral deep vein thrombosis that is associated with embolus to the top of the basilar artery.

Takayasu's disease dramatically affects the blood vessels emanating from the aortic arch and the aorta itself. Subclavian steal is prominent arteriographically, but rarely clinically significant. Cataracts and facial atrophy are prominent due to loss of nutritive blood supply to the face. The strokes are primarily in the anterior circulation. Claudication of vision occurs with head position and walking due to the tenuous blood supply to the retina. It occurs with rheumatic diseases as reported from Scandinavia.

HERNS disease is a hereditary stroke syndrome associated with endotheliopathy, renal disease neuropathy and stroke. Polyarteritis and polyangiitis are the other vascular arteritides which is associated with renal disease.

Cerebral autosomal dominant arteriopathy with subcortical infarction and leukoencephalopathy is a named disease associated with dementia. Severe migraines are common. Binswanger small vessel microangiography also is associated with dementia. Mitochondrial encephalomyopathy, lactic acidosis and stroke like episodes are also associated with dementia and migraine. Posterior leukoencephalopathy is characteristic in parietal occipital areas. In a similar syndrome reported in French Canadians Saquenay Lac St. John Syndrome, the leukoencephalopathy is frontal rather than parieto occipital. Divry Von Bogaert's disease is also associated with dementia.

Stroke in Association with Named Syndromes

• Eales disease
• Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)
• Buerger's disease (thromboangiitis obliterans)
• Ehlers–Danlos syndrome (type IV)
• Homocystinuria
• Moyamoya disease
• Antiphospholipid antibody syndrome (aPL)
• Sneddon's syndrome
• Susac syndrome (microangiopathy of the retina, inner ear, and brain)
• Takayasu's disease
• Divry von Bogaert syndrome
• Grönblad–Strandberg Disease (pseudoxanthoma elasticum) PXE
• Kohlmeier–Degos disease (malignant atrophic papulosis)
• Behçet's Disease
• Moschowitz syndrome (thrombotic thrombocytopenic purpura) TTP
• Disseminated intravascular coagulation (DIC)
• Sturge–Weber Disease
• Osler Weber Rendu
• Bing Neel syndrome
• Kawasaki syndrome
• Loeffler's syndrome
• Ménétriér's syndrome
• Acute posterior multifocal placoid pigment epitheliopathy
• Voigt Koyanagi disease
• Hereditary endotheliopathy renal neuropathy syndrome (HERNS)
• Fabry's disease
• Sanguinary Lac St. John Syndrome
• Erdheim–Gesell Syndrome (medial cystic necrosis)
• May Turner Syndrome
• Cogan's Syndrome
• Churg–Strauss

Eales Disease

• General characteristics
  • Disease of young men
  • Prevalent in the Middle East and India
  • No systemic symptoms
  • Eye symptomatology is dominant
• Ophthalmological Manifestations
  • Retinal periphlebitis
  • Vitreous hemorrhage
  • Retinal capillary ischemia
  • Retinal revascularization
  • Perivenous and periarterial sheathing
  • Macular arteries are less severely affected
    • relative sparing of central vision
  • Uveitis
• CNS Manifestation
  • Meningitis
  • Stroke
    • Focal infarcts
    • Occasional large vessel involvement

CADASIL

General characteristics

• AD inheritance chromosome: 19q12
• Onset 30–50 years of age; notch 3 gene mutation
• Migraine like headaches
• Depression
• Diffuse leukoencephalopathy (MRI)
• Recurrent stroke-like episodes
• Basophilic granular material replaces the smooth muscle cells of the media
  • Small medium sized vessels
• Strokes in basal ganglia; thalamus, brainstem, meninges and cerebellum
• Blood vessel changes: myocardium, spinal cord, muscle
• Unusual neurologic features:
  • Seizures
  • Small cortical infarcts
• Gradient ECHO sequence demonstrates the hemosiderin of old infarcts
• APOE e2 allele
  • More hemorrhage
  • Vasculopathy
• May involve external capsule
  • Longest penetrating blood vessels
• A3243G mutation
  • Occipital infarcts are prominent

Neurologic manifestations

• Small lacunar infarcts; brainstem, thalamus, basal ganglia, meninges and spinal cord
• Ischemic atherosclerotic white matter changes with posterior predominance
• Strokes may involve the external capsule (longest penetrating arteries)
• Recurrent stroke-like episodes
• Most frequent presentation is hemorrhage
  • Lobar (superficial)
  • White matter
  • Recurrent
• Progressive
  • Gradual
  • Step-wise
• Gait disturbances
• Seizures and small cortical infarcts are rare

Japanese variant

• Occurs in young men
• Alopecia
• Back pain
• Affects small arteries
  • Hyalinosis
  • Deterioration of internal elastic membrane

MRI evaluation

• Diffuse leukoencephalopathy (posterior predominance)
• T2 weighted lesions may be seen prior to symptoms
• Gradient ECHO sequences demonstrate hemosiderin from prior bleeds

Differential diagnosis

• Binswanger
• MS
• HIV
• Neurosyphilis
• Vasculitis
• Hexosaminidase A deficiency
• Adrenomyeloneuropathy (AMN)
• Adrenoleukodystrophy (ALD)

Mitochondrial Encephalomyelopathy with Lactic Acidosis Stroke-Like Episodes (MELAS)

• General features:
  • Ischemic brain lesions
    • Metabolic dysfunction of mitochondria
    • Decreased COX activity (mitochondrial complex III)
    • Arteries supplying (ischemic areas) are open
• Maternal mutation of mtDNA
• Clinical features:
  • Short stature
  • High incidence of diabetes
  • Migraine – like headaches
  • Sensorineural hearing loss
  • Visual dysfunction
  • Hemiparesis
  • Seizures
  • Ataxia
  • Fatigue with exercise
• Point mutation A3243G
  • Severe occipital infarcts
• Laboratory evaluation:
  • Elevated resting pyruvate/lactate levels
  • Ragged red fibers; COX deficiency on muscle biopsy
• MRI evaluation:
  • Multifocal lesions
  • Parieto-occipital predominance
  • Cortex and underlying white matter affected
  • High incidence of basal ganglia calcification
• Other MtDNA diseases such as MERFF and KSS
  • Demonstrate leukoencephalopathy

Buerger's Disease (Thromboangiitis Obliterans)

• General Manifestations:
  • Severe peripheral vascular disease. Extremity lesions are typically below the knee in the posterior and anterior arteries rather than the distal 1/3 of the aorta or the iliac arteries
  • Intermittent claudication often presenting in the medial foot (in step)
  • Coronary and renal arteries may be affected
• Neurological Manifestations
  • Large vessel stroke
  • Granular cortical atrophy
    • Dementia

Susac Syndrome

• General Characteristics
  • Microangiopathy of the brain, vestibulo-cochlear complex and retina
  • Affects young women
  • Most prevalent in second to fourth decade
• Clinical manifestations:
  • Retina
    • Large retinal arteries are involved:
      • Obliteration and amputation of vessels
      • Increased light reflex
      • Narrow attenuated arteries
  • Bilateral visual loss
  • Tinnitus and hearing loss
  • Bilateral pyramidal tract dysfunction
  • Cerebellar ataxia
  • Dementia
  • Gradual or step wise progression
• Laboratory evaluation
  • CSF
    • Minor lymphocytic pleocytosis
    • High protein 1g/dl
• Pathology
  • Obliteration of small intracranial arteries
  • No inflammation or granuloma formation

Acute Posterior Multifocal Placoid Pigment Epitheliopathy

• General characteristics:
  • Affects young adults
  • Precedent flu-like febrile illness
• Clinical features:
  • Both eyes are affected simultaneously; ocular involvement may occur seriatim
  • Visual blurring; scotoma and distortion of vision
  • Vision recovers after several weeks; deficits may be permanent
  • Funduscopic examination
    • Pathology in the retinal pigment epithelium
    • Well circumscribed grey-white flat lesions
• Neurologic features:
  • Optic neuritis
  • Headache
  • Stroke
    • May have arteritis pattern
• Pathology
  • Focal granulomatous inflammation of medium sized blood vessel (one patient)

Takayasu's Disease

• General characteristics
  • Most common in Asia; may be seen sporadically in the West
  • Prodrome of fever and night sweats
  • High sedimentation rate; anemia
  • Gradual obliteration of:
    • Major arterial branches of the arch of the aorta
    • Vertebral arteries are relatively spared
• Neurological manifestations
  • Loss of extremity and neck pulses
  • Asymptomatic subclavian steal
  • Intermittent claudication of vision
    • Tenuous blood supply to the optic nerve and retina
  • Early onset of cataracts
  • Facial atrophy
  • Headache
  • Dizziness
  • Hypothyroidism
    • Increase thyrocervical trunk collaterals destroy the gland
  • Arm and leg claudication
• Stroke
  • Ischemic stroke
    • Less frequent than expected from the radiologic evaluation
    • Media and adventitia of blood vessels involved in an inflammatory response
    • Late stage fibrosis
    • Etensive collateral circulation associated with
      • SAH
      • ICH
• Arteriographic evaluation:
  • Occlusion, stenosis, ectasia, aneurysm formation at vessel origins of the aortic arch
  • Most common sites of involvement:
    • Mid portion of the left common carotid artery
    • Left and right subclavian arteries
    • Mid portion of the innominate artery

Behçet's Disease

• General Characteristics
  • Relapsing remitting course
  • Major features
    • Oral ulcers
    • Genital ulcers
    • Uveitis
  • High incidence in Turkey and Japan
    • World-wide distribution
  • Systemic involvement:
    • Skin:
      • Aphthous mouth ulcers
      • Folliculitis
      • Erythema nodosum
  • Ulcerative lesions of bowel/bowel mucosa
  • Stomach ulcers
  • Synovitis
  • Large joint arthritis
  • Thrombophlebitis
  • Affects young adults
  • Male > female 2:1
  • Neurologic involvement <10%
• Neurological manifestations include:
  • Retinal vasculitis
  • Demyelinative and/or ischemic foci in:
    • Midbrain (most extensive)
    • Basis pontis
    • Medulla
    • Optic nerve
    • Globus pallidus
    • Spinal cord
    • Hypothalamus
• Pattern of involvement:
  • Ocular
    • Uveitis
    • Optic nerve inflammation
  • Brainstem
    • Cranial nerve inflammation
  • Cortical:
    • Subcortical dementia
  • Stroke:
    • Large artery stroke
    • Vasculitis
    • Cerebral venous thrombosis in 10%
      • Hetero or homozygous for Factor V Leiden defect
  • Dementia:
    • Frontal lobe type
    • Subcortical
    • Rarely accompanied by:
      • Seizures
      • Aphasia
  • Late stage disease
    • Quadriparesis
    • Pseudo bulbar palsy
• Cerebral infarction:
  • Branch occlusion > large vessel
  • Dural venous sinus thrombosis
  • Primarily ocular manifestations
  • Brainstem syndrome (rhombencephalitis)
  • Neurologic signs and symptoms are frequently relapsing and remitting
  • Spinal cord may be involved
• MRI Evaluation:
  • Topography of involvement
    • Pons > midbrain > basal ganglia > thalamus
  • Small well delineated T2 weighted lesions
    • Brainstem lesions
      • Not in arterial territories
    • Grey and white matter lesions
    • 10 mm sharply marginated irregular and confluent lesions in affected areas

Cogan's Syndrome

• General Characteristics
  • Occurs in young adults
  • Clinical features:
    • Acute interstitial keratitis
    • Vestibular auditory dysfunction
      • Inflammation of the labyrinths
    • Stroke (pial arteries)
• Typical Cogan's
  • Photophobia, lacrimination, eye pain
  • Blurred vision
  • Intermittent symptoms for years
  • Méniére's like attacks may precede eye pain
  • Total deafness and absence of vestibular function
• Atypical Cogan's Syndrome
  • Vasculitis and systemic manifestations
  • Eye pathology includes:
    • Retinal hemorrhage
    • Papilledema
    • Orbital pseudotumor
    • Central artery or vein occlusion
  • Vestibula auditory dysfunction may occur >2 years after onset of eye symptoms
  • Vasculitis
    • Occurs in atypical disease
    • Aortitis and aortic insufficiency in the classic syndrome
    • Neurologic symptoms
      • Stroke
      • Encephalopathy
      • Seizure
      • Myelopathy
      • Mononeuritis multiplex
      • Cavernous sinus thrombosis
    • Differential diagnosis includes syphilis

Buerger's Disease (Thromboangiitis Obliterans)

• General Characteristics
  • Vasculitis of medium and small vessels
  • Primary involvement in distal extremity vessels
  • Rarely affects veins
  • Onset prior to age 45
• Brain vessel topography:
  • Watershed zones between ACA/MCA and MCA/PCA territories
  • Possibly two vessel size involved:
    • Arteries <1 mm
    • Large proximal arteries
• Systemic characteristics
  • Intermittent claudication of the legs
    • Involvement of the in-step rather than the calf
  • Upper extremity claudication of the arms as the disease progresses
  • Claudication particularly prevalent in smokers
    • Regresses with cessation of tobacco use
• Neurological features:
  • Monoparesis
  • Hemiparesis
  • Visual field deficits

Ehlers Danlos Syndrome

• General features
  • Hyperelastic skin
  • Hyperextensible joints
  • Increased scarring after injury
  • Platelet dysfunction
  • Cardiac defects
• Nine subtypes of the syndrome
  • Major types are I, II, or III (approximately 50% of patients)
• Subtype IV most important for cerebrovascular lesions:
  • Decreased synthesis of type III collagen
    • All of these patients demonstrate AD inheritance
    • COL 3A1 gene (mutations); chromosome 2
      • Codes for alpha-1 chain of type III collagen
• Neurological features:
  • Aneurysms (IV; rarely type I)
    • Intra and extracranial aneurysms
    • Multiple aneurysms
    • Most common aneurysm is of the ICA
      • In the cavernous sinus
      • At the site of emergence from the sinus
    • Presentation of aneurysms:
      • SAH
      • Carotid cavernous fistula (rupture of the cavernous sinus aneurysm)

Differential Diagnosis between Marfan's Syndrome and Ehlers Danlos

• Marfan's syndrome fewer cerebrovascular aneurysms
• Aortic arch and pulmonary arteries affected more in Marfan's syndrome
• Carotid-cavernous fistula (both)
  • May follow minor head trauma
  • Spontaneous occurrence
  • May occur concomitantly with intracranial aneurysms
• Arterial Dissections (both)
  • Arteries fail to hold sutures
  • Dissection of both intra and external arteries
  • Carotid and basilar arteries are thin walled, enlarged and tortuous
  • Arteriograms are dangerous

Moyamoya Syndrome

• General Characteristics
  • Defined by the angiographic appearance of the collateral circulation following carotid occlusion
  • Obstruction of the carotid arteries occurs at the siphon (T Portion). Proximal portion of the MCA and ACA
  • Enlargement and tortuosity of basal penetrating collaterals of the ICA, MCA, and ACA cause:
    • Hazy appearance of the area like "cigarette smoke" on angiograms
    • Exuberant basilar collateral networks
      • Ethmoidal moyamoya if collaterals are restricted to frontobasal territory
      • Vault moyamoya if there are generalized collaterals
    • Rare involvement of branches of the external carotid artery
  • Epidemiology
    • Prominent genetic predominance in Japan
    • Sporadic cases are noted world wide
  • Differential diagnosis:
    • Sickle-cell disease
    • Basal meningitis (particularly tbc)
  • Usually present in children >15 years
    • Late neurological presentations occur
    • Girls > boys 50:1
    • Adult present 3–5th decade
• Pathology
  • Endothelial fibrosis and hyperplasia
  • Abnormalities of the internal elastic membrane
  • No inflammatory changes
• Neurological features:
  • Childhood presentation:
    • Transient hemiparesis precipitated by exercise or hyperventilation
    • Cognitive decline
    • Rare intermittent choreoathetosis
    • Headaches
    • Seizures
  • Adult presentation:
    • Brain hemorrhages
      • Thalamus, basal ganglion, deep white matter
      • Aneurysmal dilations of the collateral vessels with rupture
    • SAH and intraventricular hemorrhage
    • Aneurysms of the circle of Willis develop. Predilection for:
      • Anterior communicating artery
      • Basilar artery
    • Unusual prominent collaterals:
      • Ethmoidal arteries (from carotid)
      • Superficial temporal and middle meningeal arteries to transdural arteries
    • Process may stabilize with age

• MRI/MRA Evaluation
  • Collateral flow voids are prominent
  • Multiple bilateral infarctions of:
    • Basal ganglia
  • Subcortical white matter infarctions
  • Cortical atrophy and hydrocephalus ex vacuo
• Conventional arteriography
  • Demonstrates typical lenticulostriate collaterals ("puff of smoke")
  • Terminal carotid proximal ACA and MCA occlusions
  • Dilated collateral vessels

Sneddon's Syndrome

• General Characteristics
  • Young patients; pial artery strokes
  • Livedo reticularis of the skin
    • Reticulated skin pattern
    • Involves trunk and all extremities
  • Cold extremities
  • Diminished pulses
  • Differential diagnosis
    • Sympathically maintained pain patients:
      • Usually have concomitant allodynia, hyperalgesia, autonomic dysregulation

Differential Diagnosis between Sneddon's Syndrome and APL (antiphospholipid syndrome)

• Antiphospholipid antibody titers (APL) approximately equal in both
• APL Sneddon's patients are older than APL patients
• Miscarriages more frequent in APL patients
• Cardiac valve abnormalities APL > APL patients (marantic endocarditis)
• Venous thrombosis more common in APL than APL patients

Differential Diagnostic Points between Sneddon's vs. APL Patients

• Digital artery narrowing and dilation demonstrated angiographically; acrocyanosis (Sneddon's)
• Early inflammatory skin lesions (Sneddon's)
  • Medium-sized arteries between the dermis and subcutis affected
• May be familial (Sneddon's)
• May have antiphospholipid antibodies (Sneddon's)
• Valvular cardiac defects less common than APL⁺
• Neurological manifestations of Sneddon's
  • Multifocal cortical infarcts
  • Lesions in the cerebral white matter
  • Intranuclear ophthalmoplegia
• Arteriography
  • Branch occlusions of intracranial arteries

Differential Diagnosis of Livedo Reticularis

• Collagen vascular disease
  • SLE
  • Rheumatoid arthritis
  • PAN
• Tuberculosis
• Syphilis
• RSD (usually allodynia/hyperalgesia associated)
• APL syndrome
• TTP
• Thrombocythemia
• DIC
• Oral contraceptives
• Neoplasm
• Cryoglobulinemia (legs)
• Cholesterol emboli syndrome (legs and toes are blue)
• Divry Von Bogaert Syndrome

Susac's Syndrome (Retinocochleocerebral Syndrome)

• General characteristics
  • Obliteration of large retinal arteries
  • Gradual bilateral visual loss
  • Effects young women in second to fourth decade
• Neurological manifestations
  • Tinnitus and hearing loss
  • Bilateral pyramidal tracts signs
  • Cerebellar dysfunction
  • Dementia (paranoid, bizarre behavior)
  • Stepwise or gradual progression
  • Self-limiting 1–2 years
• CSF Evaluation
  • High protein; rarely >1 gram/dl
  • Minimal pleocytosis
• Pathology
  • Obliteration of small arteries
• Forme Frustes:
  • Branch retinal occlusions
  • Multifocal small infarctions
  • No VIIIth nerve deficits
  • Retinal and VIIIth nerve involvement
    • no other neurological deficit

Acute Posterior Multifocal Placoid Endoheliopathy

• General characteristics
  • Preceding "flu-like" illness
  • Disease of young adults
  • Eyes may be affected singularly or sequentially
  • Ophthalmological findings
    • Scotomata
    • Lesions of the retinal pigment epithelium
    • Vision recovers within weeks. An occasional patient has permanent visual loss
    • Choroidal vasculitis
• Neurological manifestations
  • Headache
  • Optic neuritis
  • Stroke
  • Visual blurring, distortion and scotomata
• Arteriogram
  • Endarteritis

Mencke's Disease

• General characteristics:
  • X-linked recessive
  • Mitochondrial dysfunction (lack of copper)
    • Impaired intestinal copper absorption
      • Low copper in serum; high excretion in feces
    • Mutation in gene encoding metal transporter (MNK ATP 7A^p)
  • Occipital horn syndrome (OHS)
    • Milder phenotype
    • Caused by ATP7A P-type gene mutation
• General Clinical Features
  • Coarse, stiff hair (triangular)
  • Hypothermia
  • Onset and death usually early childhood
• Neurologic Features
  • Hypotonia
  • Seizures
  • Failure to thrive
• Diagnostic Features
  • Muscle COX deficit; RRF (ragged red fibers)
  • EM: abnormal mitochondria
• Pathology
  • Microinfarcts
  • Occlusion of branch arteries
  • Cerebral atrophy

Vogt–Koyanagi Harada Syndrome

• General characteristics:
  • Uveomeningeal process
  • White forelock and eyelashes
  • Alopecia
  • Iridocyclitis
  • Choroiditis
• Neurological manifestations
  • Meningeal signs (cause of recurrent meningitis)
  • Adhesive arachnoiditis
  • Papilledema
  • Increased intracranial pressure
  • Dementia
  • Cerebellar signs
  • May remit after 6–12 months
• Laboratory Evaluation
  • CSF lymphocytic pleocytosis

Divry Von Bogaert Syndrome (DVBS)

• General characteristics:
  • Presents in adults between 18–40
  • May be familial or sporadic in the adult form
  • Affects males in the adult form
  • Juvenile form may follow vaccination or viral illness
  • Livedo reticularis is present
  • Death usually occurs in 20 years
• Neurological manifestations
  • Presenting symptoms:
    • Seizure
    • Dementia
    • Rigidity
    • Hyperreflexia
    • Ataxia
    • Multiple deep and superficial infarction that leads to:
      • Pseudo bulbar palsy
      • Corticomeningeal non-calcifying angiomatosis of vessels; arteries develop fibrous thickening

Sanguinay Lac St. Jean

• General characteristics
  • AR
  • Decreased COX (cytochrome oxidase) in tissues
• Neurological manifestations
  • Frontal cortical lesions
  • Stroke-like episodes
• Differential point:
  • MELAS affects parietoccipital areas primarily

Disseminated Intravascular Coagulation (DIC)

• General characteristics
  • Occurs in a setting of:
    • Septicemia
    • Cancer
    • Obstetrical procedures with release of amniotic fluid into the circulation
    • Neurosurgical procedures (release thromboplastin)
    • Chemotherapy
    • Viremia:
      • HIV
      • Hepatitis
      • Varicella
    • Intravascular hemolysis
    • Heat stroke
    • Burn patients
    • Liver disease
    • Prosthetic devices
    • Collagen vascular disease
  • Clotting and fibrinolytic system are activated simultaneously
  • Usually systemic hemorrhage and thrombosis:
    • Hypotension
    • Fever
    • Hypoxia
    • Acidosis
    • Shock
    • Acrocyanosis
    • Bleeding from all punctures sites
• Neurological manifestations
  • May present in coma with a nonfocal neurological exam
  • Large vessel occlusion
  • Lethargy; stupor
  • Cranial nerve palsies
  • Seizure
  • SAH
  • Emboli from NBTE
  • Multifocal hemorrhage and infarction
• Laboratory evaluation
  • Peripheral blood smear:
    • Schistocytes (fragmented RBC's) in 50% of patients
    • Thrombocytopenia <50,000 platelets mm³
    • Reticulocytosis
    • Slight shift to immature leukocytes
  • Clotting abnormalities:
    • Prothrombin time decreased
    • Activated partial thromboplastin time (aPTT) decreased
    • Exception:
      • 25% of DIC patients have a normal PT or fast time due to circulating activated clotting factors or early degradation products
      • 40–50% of patients may have normal or fast aPTT for similar reasons
    • Decreased factors II, V, VIII
    • Decreased antithrombin III
    • Elevated levels of B-peptides 15–42
    • D-dimer neoantigen DD-3B6/22 is noted
    • Elevated levels of platelet factor IV
  • Differential diagnosis of DIC from multiorgan thrombotic illness:
    • SLE with or without antiphospholipid syndrome
    • Thrombotic thrombocytopenic purpura hemolytic uremia syndrome (TTP-HUS)

Sturge Weber

• General characteristics
  • Port wine nevus that covers the upper eyelid (V₁)
  • Probable dural malformation of the parietal and occipital lobes
  • Hemiatrophy of the side opposite the malformation
  • Tram track cortical calcifications of the malformation
  • Malformation may be bihemispheric
• Neurological manifestations
  • Mental retardation
  • Intractable focal seizures
  • Stroke (ischemic)
  • Seizures and hemiparesis
    • Onset 2–3 years of life
    • During febrile illnesses
    • Focal motor tonic clonic or partial complex in adult
  • Intracranial hemorrhage
    • Rare
  • Repeated venous occlusions occur
    • Cause of stepwise deterioration
  • Ophthalmological manifestation
    • Buphthalmos
    • Amblyopia
    • Anomalous angle of the anterior chamber
      • Glaucoma

Osler Weber Rendu

• General characteristics
  • AD
  • Telangiectasias are found:
    • Face
    • Nasal mucosa (nose bleeds)
    • Conjunctiva (30%)
    • Hands > legs and trunk
    • Anterior tongue
    • Retina (10%)
  • Telangiectasia
    • Enlarge and multiply
  • Telangiectasia occur in internal organs
    • Lungs
    • GI tract
    • Genitourinary tract
• Neurological manifestations:
  • CNS affected in 8–12% of patients
  • Increased incidence of migraine
  • <1% develop cerebral abscess
    • Septic emboli access the brain through pulmonary A-V shunt
  • Large pulmonary AV shunts produce:
    • Polycythemia
    • Paradoxical embolus
      • MCA most affected
      • Transient neurologic symptoms in conjunction with:
        • Hemoptysis
        • Air in the arterial circulation through bleeding arteriovenous fistula
• Associated Intracranial Vascular Anomalies:
  • Angioma
  • Arteriovenous malformation
  • Carotid cavernous fistula
• Telangiectasias located:
  • Brain
  • Meninges
  • Spinal cord lesions:
    • Occur most commonly in the lumbar and lower thoracic areas
    • Posteriorly within the cord
    • Neurologic consequence:
      • SAH
      • Cord compression
      • Lesions within the cord

Bing Neel Syndrome

• General characteristics
  • Increased blood viscosity with decreased or slowed cerebral laminar flow
  • Hematocrit >67
  • Hemoglobin at 18–22 grams/ml
  • Bleeding from the gums
  • Dilated tortuous retinal veins
    • Box car phenomena (pressure on the globe with clumping of RBC's in the central retinal veins)
  • Petechiae of the lower extremities
  • Associated with:
    • IgM > IgG monoclonal gammopathy
    • Waldenström's macroglobulinemia
• Neurological manifestations
  • Encephalopathy
    • Poor cerebral perfusion
    • Cerebral small vessel ischemia

Grönblad–Strandberg Disease (Pseudoxanthoma Elasticum) PXE

• General characteristics
  • Angioid streaks in the retina
    • Grey streaks radiating from the disk
    • Break in Bruch's membrane
  • Thickened soft skin in general and particularly in the lower abdominal area
  • Angioid streaks are present in 85% of patients
  • Chorioretinal scarring
  • Macular degeneration
  • Leukoencephalopathy
  • Genetics
    • AR most common
    • AD
    • Sporadic forms
  • Female > male predominance
  • Progressive disease
  • Systems involved prematurely:
    • Cardiovascular
    • Ocular
    • Skin
  • Arterial disease:
    • Accelerated atherosclerosis
    • Calcification
    • Large and medium size vessels affected
  • Hypertension
  • Gastrointestinal hemorrhage
    • Intestinal and gastric mucosal vessel involvement
• Neurological manifestations
  • Stroke
    • Large artery infarction
  • Hemorrhage
    • Hypertension
    • Microaneurysm
    • Saccular aneurysm
    • SAH
  • Cavernous artery aneurysm.

Köhlmeier Degos Disease (Malignant Atrophic Papulosis)

• General characteristics
  • An occlusive endarteropathy
    • Involves small and middle size arteries and veins
    • Proliferative vasculopathy
  • Affects young adults
    • May be a more benign childhood form
  • Skin manifestations are pathognomic
    • May be absent early
    • Whitish or erythematous papules
    • Involve the trunk and limbs
    • Central part of the lesion is atrophic
      • Porcelain white
  • Gastrointestinal lesions
    • Early stages associated with abdominal pain and diarrhea
    • Intestinal obstruction
    • Perforation (often the cause of death)
  • May affect all organ systems
• Neurological manifestations
  • Stroke may precede other systemic manifestations
  • CNS dysfunction
    • Cranial nerve involvement
    • Cognitive decline
    • Ophthalmoplegia
    • Focal motor or sensory deficit
    • Multifocal infarction and hemorrhage
    • SAH (rare)
    • Dural sinus thrombosis
  • Peripheral nerve involvement
    • Demyelinative peripheral neuropathy
    • Rare polyradiculopathy
• Ophthalmological involvement of:
  • Conjunctiva
  • Sclera
  • Retina
  • Choroid
  • Urea
  • Pupils
  • Optic nerve
  • Optic tracts
• Angiography
  • Occlusions and beading
    • Distal branches of intracranial vessels

Cogan's Syndrome

• General characteristics
  • Affects young adults
  • Autoimmune vasculitis (putative)
  • Presents with visual symptoms:
    • Red eyes
    • Photophobia
    • Reduced vision
    • Interstitial keratitis
    • Uveitis (rare)
  • Vasculitis of small and medium sized blood vessels
  • Fever
  • Aortitis and bowel disease
  • Aortic aneurysm
• Neurological manifestations
  • Blindness (corneal opacification)
  • Hearing loss
  • Vertigo
  • Ataxia

Erdheim–Gesell Disease (medial cystic necrosis)

• General characteristics
  • Medial cystic necrosis
• Neurological manifestations
  • Spontaneous arterial dissection
  • Pathology
    • Necrosis of smooth muscle of the lamina media

May Turner Disease

• General characteristics
  • Iliac vein/artery compression
  • Iliofemoral deep vein thrombosis
• Neurological manifestations
  • Embolus to basilar apex

Vasculopathy

The term vasculopathy as used for this section denotes an abnormality of the vascular wall that predisposes to occlusion, emboli, hemorrhage or compression of neighboring structures. They most frequently occur in younger patients and are a significant component of the differential diagnosis of stroke in the young. The following is a description of the major vasculopathies and their differential diagnosis.

Differential Diagnosis of Vasculopathy

• Antiphospholipid syndrome
• Recanalization of atherosclerotic emboli
• Fibromuscular dysplasia
• Thrombotic thrombocytopenia purpura
• Sarcoid
• Neurofibromatosis 1
• Tuberous sclerosis
• SLE
• X-RT (irradiation treatment)
• Pseudoxanthomata elastica (PXE)
• Marfan's Disease
• Medial cystic necrosis
• Cerebral arterial ectasia and dolichoectasia
• Congophilic amyloid angiography

Recanalization of Embolus with Thrombus

• Embolus:
  • Fragments and moves distally
  • Movement occurs most often in the first 48 hours
• Recanalization of a thrombosed intracranial artery:
  • Evident by 14–21 days
  • Irregular vascular wall of the affected vessel

Fibromuscular Dysplasia (FMD)

• General characteristics:
  • Affects systemic arteries:
    • Renal arteries with consequent hypertension
  • May involve the entire arterial wall
  • Incidence of 6% in selected arteriogram
  • Most common in middle aged women
  • Bilateral ICA involved in 86% of patients
  • Spares the carotid bifurcation:
    • Most common in the pharyngeal carotid artery
    • Spares the in the intracranial carotid artery
  • 20% of patients have concomitant extracranial vertebral artery involvement (ECVA)
  • The media most often involved
    • Constricting bands (MRA; arteriogram)
    • Proliferation of smooth muscle cells that alternate with media thinning and disruption of the elastic membrane
    • Hypertrophy of fibrous tissue leads to focal stenosis
    • Band-like diaphragms within enlarged carotid bulbs (mega bulbs)
      • Embolic source
    • Affects medium sized muscular intracranial arteries
• Associations:
  • Aneurysms of intracranial arteries
  • Arterial dissections

Neurological Manifestations of FMD

• TIA
• Stroke
• Dissection
• Horner's syndrome
• Headache
• Syncope
• Intracranial hemorrhage
  • Renal hypertension
• Neurological complications of dissection
• Stroke recurrence is rare
• Internal carotid involvement
  • Periorbital pain

Neurofibromatosis Type I

• General characteristics:
  • vasculopathy in the setting of other general manifestations of the disease
  • may also overlap with tuberous sclerosis that also demonstrates arteriopathy
• Dilated vascular wall
• Rarely causes stroke

X-RT

• General characteristics:
  • Occurs following >3000 rads delivered to the arterial wall
  • Carotid artery involvement most frequent after the irradiation of:
    • Pharyngeal tumors
    • Hodgkin's and other lymphomas
    • Little soft tissue mass to protect the artery in the neck
  • Characteristics of bifurcation atherosclerosis
  • Arterial calcification
• Neurological manifestations:
  • TIA in the carotid and MCA territory
  • Stroke in similar distributions
    • Embolic
    • Thrombotic
    • Distal field ischemia

Tuberous Sclerosis

• Overlaps syndromically with NF-I
• Arteriopathy is usually asymptomatic

Cerebral Arterial Ectasia

• General characteristics
  • May be seen in children
  • Often involves several arteries
  • Familial tendencies noted:
    • One family with alpha-glucosidase deficiency
  • If severe the condition is known as dolichoectasia
• Most frequent location:
  • Posterior fossa
  • Basilar and vertebral artery
  • Middle cerebral artery
  • Both anterior and posterior circulations may be involved concomitantly
• Pathology:
  • Gaps in the internal elastic lamina
  • Decrease in the muscularis layer
  • Fibrotic arterial segments
  • Elastic tissue degeneration and increase in the vasa vasorum
• Neurological manifestations:
  • Spasticity (ventral pontine compression)
  • Dysarthria (XIIth nerve compression)
  • Hydrocephalus (pressure on the IIIrd ventricle); obliterates the prepontine cistern
  • Ischemia in the distribution of the affected arteries:
    • Emboli from thrombi in ectatic aneurysms
    • Plaque or clot obstruction in penetrating arteries
    • Rare rupture of aneurysms with SAH
    • Distortion and elongation of arteries cause reduced blood flow
• Transcranial Doppler Evaluation:
  • Reduced mean-flow velocities
  • Preserved peak-flow velocities
  • Reduced antegrade flow
    • To and fro movement within the dilated vessel
• Imaging Evaluation
  • CT, MRA > MRI are diagnostic
    • Reveal dilated, enlarged tortuous vessels

Occulo Meningeal Amyloid

• Primary uveal veil (vitreous)
• SAH with secondary vasospasm and stroke
• Thickened dura
• Acquired factor V deficiency

Cerebral Amyloid Angiopathy (congophilic angiopathy)

• General characteristics:
  • Increase of E2/E4 alleles
  • Amyloid AB 39–43 amino acids
    • Usual vascular amyloid 39–40 aa
  • Younger at first hemorrhage
  • Rare association with isolated cerebral angiitis
• Genetic groups affected:
  • Hereditary cerebral amyloidosis (Dutch); Icelandic
  • chromosome 21 p11
  • APP gene (amyloid precursor protein) gene
  • Clinical manifestations:
    • Ocular vessels involved
    • Leptomeningeal deposits of amyloid
    • Lobar hemorrhages
  • Icelandic
    • Cystatin C gene (chromosome 21 p11)
• Clinical manifestations:
  • Cerebral hemorrhages
    • Multiple
    • Superficial
    • Subcortical lobar
    • Recurrent
  • Rare TIA
  • Multiple infarcts
  • SAH
  • Leukoencephalopathy
    • Concomitant multiple infarcts
    • Clinically similar to Binswanger microangiopathy
  • Dementing illness from:
    • Concomitant multiple infarcts
    • Alzheimer's pathology
• Imaging studies
  • Gradient ECHO MRI
    • Demonstrates old hemorrhages (residual hemosiderin)

Rare Causes of Vasculopathy

• Familial occipital calcification:
  • Optic atrophy
  • Dementia by age 33
  • VIII nerve involvement
  • Hemorrhagic stroke

Vasoconstriction and Stroke

Migraine headache and vasoconstriction following subarachnoid hemorrhage are the two most common causes of cerebral artery vasoconstriction and consequent stroke. During migraine headache there is frequently demonstrated arteriographic vasoconstriction; a reduced cerebral blood flow and increase velocity measurement by TCD. F18-2DG PET studies have also demonstrated a spreading posterior to anterior Oligemia often preceding change in blood vessel diameter. This spreading cortical depression of metabolic activity with consequent lessened production of H⁺ from decreased production of lactic acid may also cause vasoconstriction. The DRASC receptor on cerebral blood vessels interacts with H⁺ to dilate the vessel. This autoregulation with a match between lCMR glu (and production of H⁺) and ICBF may determine the caliber of cerebral blood vessels during migraine attacks. The locus ceruleus (norepinephrine) may contract proximal cerebral blood vessels whereas out flow from the superior nucleus salivatorius may dilate cerebral blood vessels during a migrainous attack. The relationship between spreading depression and cerebral blood flow has not been fully elucidated. Migraine has been associated with severe intense vasoconstriction with infarction. Vasoconstriction in migraine may cause ICH and arterial dissection.

Reversible cerebral segmental vasoconstriction usually affects young women following delivery, but may occur during their menopause. It may occur after carotid endarterectomy and involves large, medium and small vessels. There are focal regions of vasodilation and vasoconstriction.

Vasoconstriction following subarachnoid hemorrhage is a major cause of death and morbidity from this event. It is most often seen at 4–7 days following the bleed and is correlated with the amount of blood surrounding the affected vessels. Mechanisms and characteristics will be discussed in the section on subarachnoid hemorrhage from aneurysms.

Migraine

• General characteristics:
  • Affects all age groups
  • During attacks:
    • Vasoconstriction of intracranial blood vessels does occur
    • Spreading depression
      • Occipital to frontal
      • More important as basic mechanism than vasoconstriction for auras
• Clinical manifestations
  • Ischemic symptoms
    • Precede, are concomitant with or follow attacks
    • Usually occur 10–20 minutes prior to the headache
  • Small vessel infarction
    • Intense vasoconstriction with thrombosis
    • Activation of platelets
    • Vasoconstriction per se:
      • Stimulates endothelium to promote thrombosis
  • Migraine and possible association with reversible cerebral segmental vasoconstrictions
  • intracranial hemorrhage
    • Reported during migraine attack
    • Possible reperfusion etiology
  • Associated with carotid dissection

Differential Points of Migraine versus Ischemia Stroke

• Sensory modalities involved sequentially
  • Vision, sensory, speech
    • Several modalities involved concomitantly in stroke
    • Negative symptoms predominate in stroke
• Symptoms are positive in migraine:
  • Scintillating scotomata
  • Paresthesi
  • Teichopsia
  • Brightness in a VF
• Positive symptoms followed by negative symptoms in migraine
  • Brightness followed by scotomata
• Headache follows neuralgic symptoms by 10–15 minutes in migraine
  • Sometimes headaches precede symptoms
  • Rarely headache and symptoms are concomitant
• Average attack lasts 20 minutes in migraine
• Women > men in migraine
• Attacks lasts over life time of the patient
  • Acephalgic form of migraine occurs more frequently in older patients
• No atheromatous risk factors in migraine

Ischemic Symptoms in Stroke

• Several modalities involved concomitantly
• Negative symptoms predominate
• Deficits in two modalities occur simultaneously
• Headache often concomitant with deficits
• Small white platelet fibrin emboli cause deficits of <2 minutes; clots (red emboli) >5 minutes
• Distal field ischemia-same territory involved with each attack
• men > women
• Attacks <1 year duration
• Clear risk factors

Reversible Cerebral Segmental Vasoconstriction

• General characteristics:
  • Affects young women; during puerperium
  • May occur at menopause
  • Occurs at all ages
  • Rarely after carotid endarterectomy
  • Brain and coronary circulation after subarachnoid hemorrhage
  • Involves large, medium, and small cerebral arteries
• Neurological manifestations
  • Severe headache
  • Seizures
  • Spectrum of altered mental status to coma
  • Multifocal neurologic signs
  • Edema
• Imaging evaluation
  • Angiography
    • Multifocal vasodilatation and narrowing
  • MRI/CT
    • Brain edema
    • Areas of infarction and hemorrhage

Differential Diagnosis of Reversible Vasculopathy

• Cocaine
• Sympathomimetic drugs
• Pheochromocytoma
• Benign cerebral vasculitis
• Migraine
• Birth control pills with angiopathy
• Post partum angiopathy
• Subarachnoid hemorrhage from aneurysmal rupture

Collagen Defects and Stroke

Hereditary diseases of connective tissue involve the skin, all aspects of the vascular system, the eye and the gastrointestinal tract. PXE is characterized by tortuosity of cerebral vessels, vascular calcification, microaneurysms, fusiform aneurysms and initial hemorrhage. Gastrointestinal hemorrhage and retinal angioid streaks are seminal differential features.

Ehlers–Danlos syndrome, primarily type I and IV affect the cerebral circulation. Elongation and degeneration of the chordae tendinea lead to mitral and tricuspid valve prolapse, septal defects and pulmonary and aortic dilatation. Carotid cavernous fistulae as well as rupture of cerebral vessels are seminal features.

Marfan's syndrome is recognized by clinical dysmorphisms. There is a defect of collagen and elastin. Subluxation of the lens, aortic insufficiency and aneurysms are seminal.

Erdheim–Gesell Disease (Cystic medial necrosis) is caused by focal fragmentation of elastic fibers and loss of smooth muscle cells of the media. Deposition of mucopolysaccharides leads to thickening of the vessel wall which may be appreciated in the radial artery at the wrist. Huge dilated aortic arch aneurysm is a seminal feature.

Pseudoxanthoma elasticum

• General characteristics
  • Prevalence of 1/160,000 people
  • AD and AR inheritance
  • Mutation of the ABC 6 (MRP6) gene
    • Transporter for organic ions
  • Concomitant rheumatoid arteritis
• Eye and systemic manifestation
  • Retinal signs:
    • Angioid retinal streaks occur in 85% of patients
    • Grey in color
    • Radiate outwardly from the optic disc
    • Associated chorioretinitis
    • Macular scarring; retinal hemorrhages
    • Decreased visual acuity
    • Due to a disruption of Bruch's membrane
  • Gastrointestinal bleeding
  • HCVD (renal artery involvement)
  • Arterial calcification
  • Premature atherosclerosis of vessels:
    • Coronary
    • Peripheral
    • Retinal
    • Cerebral
  • Blood vessel pathology
    • Fragmentation and calcification of the internal elastic lamina
    • Internal and medial vessel wall calcification
    • Topography of lesions:
      • Aortic arch
      • Intracranial arteries
  • Skin manifestation
    • Skin of the neck and axilla prominently involved
      • Tan-yellow papules
      • Thickened and redundant skin particularly of the axilla, groin and flexor surfaces

• Neurologic Manifestation
  • Rare aneurysms with SAH
  • Thrombosis of cerebral vessels:
    • Rarely pial vessels
    • Lacunar strokes
    • Binswanger's microangiopathy

Ehlers Danlos Syndrome

• Type I (gravis): hyperextensibility of joints, fragile skin; prematurity, AD
• Type II (mitis): joint hyperextensibility limited to hands and feet; AD
• Type III (benign hypermobile): AD; hypermobility of joints
• 80% of patients have type I–III
  • Diminished collagen fiber diameters
  • Type IV decreased type III collagen which is most prevalent in blood vessels and GI tract
  • Type V; absence of Lysol oxidase (necessary for collagen and elastin cross-linking; x-linked)
  • Type VI (Kyphoscoliotic form)
    • Hydroxylysine deficient collagen
    • AR
    • Mutation in Lysol hydroxylase 1 gene (PLOD 1)
  • Type VII: procollagen peptidase; enlarged form of collagen accumulates
  • Stroke syndromes
    • Carotid cavernous fistula
    • Intracranial aneurysm
    • Arterial dissection
  • Patients with cerebrovascular lesions have type IV
    • Decreased synthesis of type III collagen
    • Major collagen of blood vessels

• Clinical Features
  • Skin unusually soft; poor wound healing: molluscoid pseudotumors; freely moveable calcified areas; easy bruisability; excessive scarring
  • Hyperextensible joints; dislocations of patella; shoulder
  • Kyphoscoliosis; carious teeth
  • Blue sclerae, microcornea myopia, keratoconus, dislocated lens; retinal detachment
  • Cardiac lesions
    • MVP, tricuspid valve prolapse, septal defects (rare cause of emboli)
    • Dilatation of the aortic and pulmonary roots

Aneurysms with Ehlers Danlos Syndrome

• Clinical features:
  • May involve both intra and extracranial blood vessels
  • Multiple intracranial aneurysms occur
    • Most common vessel is the internal carotid
      • In the cavernous sinus
      • As it emerges from the sinus
• SAH from aneurysmal rupture
  • Spontaneously
  • During exercise

Carotid Cavernous Fistula with Ehlers Danlos

• May occur with minor head trauma
• Clinical manifestations:
  • Proptosis
  • Chemosis (conjunctival edema)
  • Conjunctival arterialized venous blood
    • Small vessels reach the iris; with infection they don't
  • Proptosis
  • Visual loss
  • Diplopias
  • Pulsatile tinnitus
  • CCF may occur concomitantly with intracranial aneurysms of ICA

Arterial Dissection with Ehlers Danlos

• Clinical signs and symptoms depend on the artery affected
  • Carotid artery
    • Oculosympathetic paralysis
    • Emboli rather than flow limiting signs and symptoms
    • Lateral face pain
    • Painless monocular blindness
    • Carotid occlusion is rare
    • Neck pain
    • Carotid territory stroke
  • Vertebral artery
    • Pulsatile lateral neck mass
    • Pain in the neck
    • Embolic signs and symptoms
• Enlarged and tortuous carotid and basilar arteries
• Mortality for any type of vascular surgery is 40%
• Post operative complication
  • Vertebral artery dissection
  • Pneumothorax

Marfan's Syndrome

• General characteristics:
  • AD
  • Pevalence 4–6/100,000 individuals
  • Fbrillin gene defect
  • Cromosome 15
• General features:
  • • Arachnodactyly
    • Am spread > height
    • Lateral lens dislocation (50% of patients)
    • Pectus incurvatum
    • Hyperextensible joints
  • Enlarged aortic root
  • MVP associated
  • Aortic insufficiency
• Neurological manifestations
  • Giant intracranial aneurysm (internal carotid)
  • bBerry aneurysms occur with higher frequency than expected
  • Rare vascular thrombotic or embolic stroke (MVP); emboli also from giant aneurysms
  • Increased incidence of dissection

Cystic Medial Necrosis (Erdheim–Gesell Disease)

• General Characteristics
  • Focal fragmentation of elastic fibers
  • Loss of smooth muscle cells of the media
  • Deposits of mucopolysaccharides
  • Similar lesions also noted in:
    • Ascending aorta of Marfan's patients
    • Advancing age
    • Possible relationship to hypertension
• Clinical Features:
  • Coronary artery dissection
  • Carotid artery aneurysm
  • Giant aneurysm of the ascending aorta

Fibromuscular Dysplasia

Fibromuscular dysplasia affects the media of the vessel wall with constricting bands that are composed of virous dysplastic tissue and proliferating smooth muscle cells. There are alternating areas of vessel wall dilatation related to medial thinning and disruption of the internal elastic membrane. The process affects renal vessels with consequent arterial hypertension. The entity will be discussed more completely under arterial dissection.

Enzyme Deficiencies and Stroke

Enzyme deficiencies cause stroke by:

• All acclerating atherosclerosis
• Deposition subendothelial or the surface of vascular tissue
• Clotting factor and platelet abnormalities

Rarely, defects that cause hypertension (adrenal steroid enzymes) cause stroke by the induction of hypertension.

The major enzyme deficiencies that cause stroke are:

• Fabry's disease
• Homocystinuria
• Paroxysmal nocturnal hemoglobinuria
• Ehlers–Danlos syndrome

Fabry's Disease

• General Characteristics
  • X-linked
  • Deficiency of alpha-galactosidase A
    • Deficiency of alpha activator protein
  • Primarily a small vessel disease
  • Larger vessel ectasia in posterior vessels of the posterior circulation
    • TCD demonstrates elevated CBF velocities
  • Ceramide trihexoside accumulates in cerebral and somatic arteries
• Systemic Clinical Features
  • Decreased ability to sweat
  • Severe acroparesthesias
  • Cutaneous angiokeratomas
    • Predilection for perineal areas
  • Renal failure
  • Severe heat intolerance (failure to sweat normally)
    • Coma with increased temperature
  • Facial swelling (during heat stress)
  • Lumbosacral bone and disc disease in carriers
  • Exercise intolerance
  • Cardiomyopathy (percentage of patients)
• Neurologic Features
  • Large vessel strokes
  • Vertebrobasilar insufficiency (rare)
  • Autonomic nerve dysfunction (small fiber neuropathy
    • Decreased sweating (hypotension)
    • Syncope
  • Retinal angioid streaks
  • Aneurysmal dilatation of posterior circulation

Homocystinuria

• General Characteristics:
  • Definition: homocysteine is found in the urine
  • Seven biochemically different entities have been identified
  • Major categories of entities causing deficit:
    • Enzymopathies
    • Deficiencies of:
      • B6
      • Tetrahydrofolic acid
• Pathology of Elevated Homocysteine Levels
  • Related to:
    • Stroke
    • Premature atherosclerosis
    • Myocardial infarction
    • Venous thromboembolism
    • More severe carotid disease
  • Injury to the vascular endothelium
    • Platelet activation
    • Formation of thrombi
  • Vascular smooth muscle proliferation

Cystathionine Beta-Synthetase Deficiency

• General Characteristics
  • Common in Ireland
  • AR; chromosome 21q
  • Homocysteine interferes with the cross-linking of collagen
• Systemic manifestations
  • Mental retardation
  • Osteoporosis
  • Dislocation of the lens
  • Occlusion of coronary and renal arteries
  • Marfan habitus
  • Premature atherosclerosis
• Neurological manifestations:
  • Thrombotic strokes may occur in the first decade; usually <30 years of age

Methylene Tetrahydrofolate Reductase Deficiency

• General Characteristics
  • Affects:
    • Methionine synthesis
    • Tetrahydrofolate generation
      • RNA/DNA synthesis
  • AR (very rare)

Deficiency of Vitamin B12 Coenzyme Synthesis

• General Characteristics
  • 5 different defects in the activation of the vitamin precursor have been described
    • Cobalamine C,D,E,F,G
  • AR

Methylmalonic Aciduria

• General Characteristics
  • Effect of activated B12 deficiency
  • Megaloblastic anemia
  • Clinical picture of homocystinuric
  • Childhood onset

Pernicious Anemia

• General Characteristics
  • Adult onset
  • Hemocystinuria secondary to PA has been associated with recurrent stroke
• Low B12 levels in PA

Enzyme Defects causing Mineral Corticoid Excess with Hypertension (Possible Stroke)

• I7 – alpha-hydroxylase deficiency
• II – beta-hydroxylase deficiency
• II – beta-ketoreductase deficiency

Paroxysmal Nocturnal Hemoglobinuria

• General Characteristics
  • Requires two coincident factors
    • Somatic mutation of the PIG-A gene (short arm of X-chromosome)
    • Hypoplastic bone marrow
  • Failure of synthesis of glycosyl phosphatidyl inositol (GPI) anchor
    • Causes inability of proteins to attach to cell surfaces
    • RBC's lose complement defense proteins
      • Causes intravascular complement mediated hemolysis
    • Platelet activation by similar mechanism
  • Associated with marrow aplasia and myelodysplasia
  • Hemolytic and thrombotic features of PNH
    • Mediated by complement sensitivity
      • CD59 (inhibitor of the membrane attack complex) is deficient
  • Incidence 4/1 million people
  • Intermittent paroxysms of hemolysis
    • Rare spontaneous remission
  • Rare leukemic transformation <5%
  • Hemolysis is cardinal feature
  • Thrombosis
    • Hepatic vein propensity
  • Dark urine upon arising
  • Neutropenia and thrombocytopenic
• Neurological features
  • Thrombosis of large vessels
  • Patients with aplastic anemia and only lab evidence of PNH
    • Less likely to suffer thrombosis
  • Patients with active thrombosis and large proportion of PNH cells in the blood
    • Thrombosis in 50%
    • Death in 33 1/3%
  • Cerebral venous and dural sinus thrombosis
  • ICH secondary to thrombocytopenia

Dissection of Intra and External Cranial Arteries

Dissection is a major cause of stroke in young patients. Most often the dissection itself is not flow limiting but causes stroke by embolization that forms at the site of the tear. Carotid disease has the seminal features of oculosympathetic paresis and ipsilateral facial pain. It is seen in the context of trauma, migraine headache, fibromuscular dysplasia and hereditary disease of collagen all of which predispose to the disease. Bilateral dissection, and intracranial dissection of the middle cerebral artery all suggest an underlying disease of connective tissue. Intracranial dissections cause infarction, subarachnoid hemorrhage or mass effect. Dissection between the media and intima are often flow limiting and cause infarction. The supraclinoid ICA and the stem MCA are often affected.

Vertebral artery dissection is characterized by neck pain. Most symptoms are related to lateral medullary distribution ischemia and include dizziness, dysarthria, and lateral pulsion. Rarely patients suffer diplopia and cortical spinal tract involvement if the pons is involved by embolus or extension of the dissection. Extracranial vertebral artery dissection may be associated with cervical root pain. In general, TIA symptoms are less common with vertebral than carotid dissection. Rarely, vertebral artery dissection begins intracranially; patients may suffer chronic dissections with arteriographic evidence of recanalization. Patients with vertebral dissections may have only neck pain. Chiropractic manipulation in this setting may cause further dissection particularly of the C2 horizontal portion of the artery. Intracranial dissections may also present as mass lesions from aneurysmal dilation and compress adjacent cranial nerves and long tracts.

Carotid artery

• General features
  • Location
    • Pharyngeal portion
    • Above the bifurcation
    • Artery is mobile in this sectionInvolves redundant portions of the artery
    • Often associated with:
      • Minor trauma
      • Congential abnormalities of connective tissue as exemplified by:
        • Cystic medial sclerosis
        • Marfan's Syndrome
        • COLIA defects
        • Fibromuscular dysplasia
      • Migraine
        • edema of the vessel wall

    • Pathogenesis of clinical phenomena:

      • Arterial wall tear
        • Dissection of blood within the media longitudinally
      • Dissection of blood between the media and adenia
        • Aneurysmal pouching of the artery demonstrated by arteriography
      • Intimal tear
        • Reentry of blood into the intima at a distal site
      • Occlusion caused by:
        • Compression of the lumen from blood in the arterial wall
        • local thrombosis (endothelial procoagulant factors)
      • Emboli:
        • From luminal clot
        • Most common cause of clinical symptomatology
      • Clinical manifestation:
        • Ipsilateral throbbing headache
        • Face, jaw, neck, pharyngeal pain
        • Ipsilateral partial Horner's syndrome
          • Ischemia of the vasonervorum of the oculosympathetic fibers that course with the internal carotid:
            • Ptosis
            • Meiosis
            • Apparent enophthalmos
            • Facial sweating intact
              • Course with the external carotid artery
        • Pharyngeal carotid segment aneurysm:
          • Horner's syndrome (complete)
          • Dysgeusia
          • Tongue atrophy
            • Compression of the hypoglossal nerve by the carotid sheath
        • TIA affecting the ipsilateral eye and hemisphere
          • If extremely frequent, they may be termed carotid allegro
        • Scintillating scotomata
        • Pulsatile tinnitus
        • Ischemic optic neuropathy:
          • Dissection reaches the carotid sinus
          • Often followed by stroke; may be delayed for days to weeks
        • Persistent neck pain:
          • Suggests extension of dissection
        • Vertebral and carotid dissections may occur concomitantly
          • Suggests collagen defect
        • Patterns of dissection:
          • String sign (long dissection)
            • Distal to the carotid bifurcation with extensions to the skull base
          • Radiographic signs of occlusion:
            • >2 cm distal to ICA origin
            • Spares the siphon
            • Gradually tapering segment to area of occlusion
            • Localized aneurysmal out pouching
            • MRI/MRA demonstrate intramural bleeding and mural thickening

Extracranial Vertebral Dissection

General Features:

• Precipitating factors:
  • Neck trauma
  • Sustained posture
  • Chiropractic manipulation
    • Patients frequently go to the chiropractor because of neck pain
    • Further manipulation extends the dissection
  • Collagen defects
  • Maintenance of the neck in fixed posture
    • Prolonged surgical procedure
    • Following resuscitation
    • Involve the distal 1/3 of the vertebral artery

Clinical Manifestation

• Lateral neck pain
  • May precede neurological symptoms
  • May be the only symptom
• Posterior circulation TIA
  • Less common than from ICA dissection
• Infarcts
  • Most common in PICA territory
  • Embolic pathogenesis
  • Dissection may extend intracranially
  • Rarely infarctions of SCA, basilar artery, PCA
• Cervical root pain
  • Aneurysmal dilation of the artery compresses the root
    • Motor, sensory, reflux signs
• Hypoperfusion of the cervical spinal cord
  • May cause infarction

• Intracranial dissection causes:
  • Infarctions
  • SAH
  • Mass effect

• Anterior circulation:
  • Supraclinoid carotid and may dissect into the intracranial MCA

• Posterior Intracranial Extension Affects:
  • Intracranial vertebral artery
  • Basilar artery

• Media and adenia dissection are associated with:
  • SAH (may be recurrent)

• Aneurysmal mass from dissection may cause:
  • Compression of cranial nerves and brain substance

• Chronic dissections:
  • Lesions are of different ages
  • Multifocal sites
  • Abnormal arterial media and internal elastic membrane
  • Most frequent with fibromuscular dysplasia

• Recanalization:
  • Occurs if some lumina is patent