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Unconfirmed DRAFT COPY

Yoko Ozawa, New York Medical College; Oya Tugal MD, Martin L. Kutscher MD, Depts. of Pediatrics and Neurology, New York Medical College, Valhalla, NY.

Stroke is a relatively rare disorder in children with an incidence of 3-8/100,000. While atherosclerotic disease, hypertension, and diabetes are the most common causes of stroke in adults, the causes in children are quite different.

Three pathophysiologic variants underlie cerebrovascular accidents: thrombosis of a cerebral artery or vein, embolic disease, and intracranial hemorrhage. Classically, each variant has a characteristic clinical picture. A thrombotic stroke typically progresses in a crescendo manner, in which a mild deficit may progress to a maximum deficit over time as the thrombus propagates. Headaches, seizures, or loss of consciousness typically are absent. An embolic event typically presents with a sudden deficit of maximal loss of function at the onset. Intracranial hemorrhages are typically associated with a severe headache and altered mental state.

As shown below, the etiological differential diagnosis of a stroke in a child basically falls into problems with emboli, problems with the blood elements, or problems with the vessels. Non-vascular causes of acute hemiparesis must also be considered.

1. Cardiac/Carotid (leading to throwing an embolic clot -- sterile or infected)

• Congenital heart disease (VSD, AS, MS, patent foramen ovale, etc.)
• Acquired heart disease (rheumatic fever, prosthetic heart valve, arrhythmia, BACT. ENDOCARDITIS)
• Carotid vascular disease: carotid artery or basilar artery dissection at any age; atherosclerotic disease in adults

 

2. Hematologic (factors in the blood stream leading to increased or decreased clotting tendancy)

Typically Ischemic Stroke

• deficiency of factors that are supposed to limit clotting: Prot S or C or antithrombin III def., factor V Leiden. May account for increased stroke with pregnancy and birth control pills.
• presence of abnormal antibodies interfering with regulation of clot: Antiphospholipid Abs (which include the subclasses of Anticardiolipin Ab and lupus anticoagulant). Only IgG has a strong link.
• increase or abnormal blood elements: increased platelets, or increased amount or abnormal RBC (such as sickle cell or polycythemia)
• dehydration or infection with thrombosis of major cerebral veins or dural sinuses.

Typically Hemorrhagic Stroke

• hemorrhagic tendancies such as hemophilia A and B and other clotting factor abnormaities
• vitamin K defiiciency
• thromobocytopenia
• sometimes sickle cell
• hemorrhage into a (typically embolic) infarction,  area of venous infarction, tumor, or area of radiation
• hypernatremic dehydration (hyperosmolar endothelial damage with rupture of vessel as surrounding brain shrinks.
• hypertension

a. Inflammation of vessel (leading to closing off)

• mycotic aneurism
• non-infectious vasculitis: SLE, primary CNS vasculitis, polyarteritis nodosa, Wegener's arteritis
• infectious vasculitis: meningitis: TB, bacterial, HIV, Lyme, mycoplasma, varicella zoster
• inflammatory bowel disease (probably other causes for stroke as well.)

b. Abnormal vessels

• moya-moya (puff of telangiectatic vessels distal to carotid occlusion.
• aneurysm
• AVM
• fibromuscular dysplasia
• hypertension
• dissection

c. Vessel spasm

• migraine
• spasm due to SAH

d. Metabolic

• MELAS
• Homocysteinuria

Always broaden the diagnosis to include nonvascular causes of sudden hemiparesis:

B. Non Vascular causes of sudden hemiparesis

• encephalitis (from virus)
• encephalitis (postinfectious from virus)
• abscess
• meningitis
• transient paralysis after seizure
• trauma
• [hemorrhage into a tumor]

Following are comments about selected etiologies:

Infection Acute bacterial meningitis may produce an infectious arteritis, while a purulent meningitis that originates from an otitis media, mastoiditis, or sinusitis may occlude veins or dural sinuses.

Dehydration Fever and dehydration in infants may cause venous or sinus thrombosis. Clinically, patients present with multiple seizures, changing neurological signs, coma and increased ICP. Children with hypernatremic dehydration may have seizures, and depressed consciousness.

Trauma/Carotid or vertebral dissection

Pathology Trauma is a common cause of arterial thrombosis in children. Commonly, a penetrating injury (via pen or stick) to the child’s mouth may cause a dissecting aneurysm, followed later by thrombosis of the internal carotid artery. Carotid or basilar artery dissections due to insignificant head and neck trauma may also occur, especially if there is an underlying defect in the artery. Fibromusclular dysplasia is a common underlying pre-existin problem.Usually, the damage is bleeding within the wall of the vessel, although sometimes emboli can be released.  Dissections of the verterbro-basilar arteries tend to occur between the media and adventitia, leading to subarachnoid hemorrhae.  Thus, ischemia, thrombosis, subarachnoid bleed, or artery-to-distant-artery emboli can all occur.Symptoms can be immediate or delayed for days.  The classic adult symptoms of acute neurological defect with ipsilateral oculosympathetic paresis and headache are rare in children, who require a high index of suspicion.

External Carotid Sx 

• Headache which may proceed symptoms by hours or days; may be severe or mild; may radiate to ear or scalp
• Anterior neck pain
• Ischemic symptoms including TIAs may lag by >a week
• Monocular visual impaiment
• Cervical bruit, Horner's syndrome, or lower cranial neuropathies.
• Seizures in some patients.
  

Internal Carotid Sx

• Headache may preceed stroke by minutes to weeks.
• Less common, younger patients, more catastrophic
• Supraclinoid portion of the ICA, or MCA or ACA
• Anterior circulation in young adults; posterior circulation (Vertebral artery) in adults

Vertebral Artery Dissection

• Basilar artery dissection is less common than verterbral artery.
• May also occur with carotid dissection
• Abrupt vertigo, ataxia, dysarthria, and headache
• Alternating hemiparesis, ataxia, and head tilt in children.
• Lateral medullary syndrome in adults.
• Occipital headache may preceed or follow symptoms by days
• Distal basilar artery involvement may come from thrombotic extension or emboli.
• May have C1-C2 vertebral anomalies or fibromuscular dysplasia.
• Confusion and prostration if associated basilar artery of SAH.
• May also have subarachnoid bleed.

Radiographic Diagnosis of Vascular Dissections

• First test done is often whatever is available.
• Doppler Carotid Flow Studies seek indirect evidence and 68% sensitivity.
• Conventional Angiography usually reserved for unclear cases and pre-op.
• MRI with MRA considered by many to be best diagnostic test. 84% sensitive; 99% specific, although may miss intimal flap.
• CTAngio may be easier for children.
• [Intracranial dissection and vertebral dissection best detected with angio or MRA. Some feel that CTAngio is helpful for vertebral studies.

Treament of Dissection

• No concensus amongst the following choices:
• Heparin/warfarin to prevent embolic complications is the most widely used treatment, but has risks (esp if intracranial) and is unproven to help.
• Endovascular treatment (angioplasty, stents, occlusion) is too limited in children to make recommendations.Consider if persistant or worsening symptoms. Otherwise medical therapy and radiographic follow-up. Catheterization may cause complete occlusion while placing stent. Angioplasty is to too risky acutely.Occlusion (if demonstrated safe by balloon) may be needed to stop spread of thromboembolus. Surgery is considered for life-threatening hematomas or thrombi or expanding aneurism in accessible areas. Consider bypass or clipping.

 

Hematologic: Thrombotic Sickle cell disease is the most common hemoglobinopathy associated with CVD. Approximately 25% of sickle cell patients will develop cerebrovascular complications. The primary mechanism of a sickle cell crisis is an occlusion of small blood vessels by sickled erythrocytes. This forms an area of local anoxia that leads to further sickling and progression of the occlusion A normal CBC makes less likely other hyperviscosity conditions such as polycythemia vera, thrombocytosis and leukemic blastic crisis. Sometimes, the viscosity of the blood needs to be directly measured.

Deficiencies of inhibitors of coagulation, such as protein C, protein S, antithrombin III, factor V Leiden, heparin cofactor II, and dysfunctional plasminogen or fibrinogen, are prominent causes of venous thrombosis.

Anti Thrombin III (AT III) is a plasma inhibitor protein that blocks the activity of some serine protease coagulation factors. AT III activity is increased by heparin and is therefore necessary for heparin’s anticoagulant activity. Congenital AT III deficiency is an autosomal dominant trait that affects both sexes. Diagnosis is by detection of reduced AT III activity in plasma. There are two types: type I patients (most common) lack both AT III functional activity and protein, and type II patients have a dysfunctional protein but a normal amount of protein.

Protein C is a plasma inhibitor protein that, once activated, inhibits clot formation and enhances fibrinolysis. Congenital protein C deficiency is an autosomal dominant trait. Diagnosis is by detection of reduced protein C activity in plasma. Protein S is a vitamin-K-dependent plasma protein that functions as a cofactor for the anticoagulant affect of activated protein C. Congenital protein S deficiency is also an autosomal dominant trait. In Activated Protein C resistance (APC), there is a mutation in factor V molecule that makes it resistant to the inactivating effects of protein C. Diagnosis is by detection of factorV Leiden.

The antiphospholipid antibody syndrome (lupus anticoagulant) may be primary (idiopathic) or associated with systemic lupus erythematosus, infections, drug reactions, or other autoimmune diseases. Patients with circulating lupus anticoagulant are at increased risk of thrombus formation (despite the name). Associated features include livedo reticularis, recurrent fetal loss, thrombocytopenia, and thrombosis. Of note, the activated partial thromboplastin time (aPTT) may be prolonged. Diagnosis is by specific assays to detect the antiphospholipid antibody. Treatment includes warfarin with or without aspirin.

Other causes of thrombosis include: systemic malignancy, pregnancy, birth control pills, and inflammatory bowel disease.

Hematolgic: Hemorrhagic  Thrombocytopenia usually does not result in intracranial bleeding unless platelets are less than 20,000 or there is trauma. ITP and chemotherapy are the most common causes. Hemophilia A, hemophelia B, vitamin K deficiency, Factor VII and Factor VIII defiiciencies also lead to bleeds.   Hemorrhage into an area of infarction can also occur in ischemic and venous/dural sinus occlusions.Hemorrhage may also occur into a tumor, and may even be the presenting sign. Both hemorrhage in ischemic infarctions can occur after radiation therapy. Rarely, hypertension can be a cause in children.

Dural sinus/venous occlusion may be secondary to mastoiditis, otitis media, meningitis, dehydration, or underlying coagulapathy.

Cardiovascular Cyanotic congenital heart disease may cause both thrombotic and embolic strokes, although the latter is more common. Thrombotic strokes typically occur when the child is less than 2 years old; and present with sudden hemiparesis, increased intracranial pressure, seizure and decreased consciousness. The increased risk of thrombosis is related to polycythemia and hyperviscosity. Embolic strokes in children with cyanotic CHD may involve paradoxical emboli through a patent foramen ovali, or cardiac thrombus formation secondary to arrythmias or dilated cardiomyopathies. Rheumatic heart disease or prosthetic valves are often associated with bacterial endocarditis and therefore increase the risk of septic emboli. SBE should always be considered in the setting of acute stroke in a child.

Vasculitis/Collagen vascular disease Systemic arteritis, such as polyarteritis nodosa, causes a vascular disease in many organs in which the brain is just one target. Henoch-Schonlein purpura and Takayasu’s disease also may be complicated by cerebral infarcts, as can varicella zoster.

Systemic lupus erythematosus may cause a small vessel vasculitis that results in multiple microinfarctions. Patients may present with cerebral symptoms and signs, including hemiparesis due to arterial or venous thrombosis. On occasion, isolated primary CNS vasculitis can occur. An angiogram may be required for diagnosis.

Metabolic Patients with homocystinuria are deficient in crystathionine synthase. The pathophysiology appears to involve endothelial injury (from toxic amounts of sulphur containing amino acids)  and an increase in platelet consumption, with resultant arterial and venous occlusions. Elevated levels of homocysteine in the serum or urine would be diagnostic.Clinically, they may show skeletal and cutaneous findings along with dislocated ocular lenses and developmental delay.  MELAS (Myoclonic epilepsy with lactic acidosis and strokes) is a mitochondrial metabolic disorder.

Neurocutaneous dermatologic signs suggestive of Neurofibromatosis, Sturge-Weber, or Tuberous sclerosis.

Vascular abnormalities  Arteriovenous malformations typically have intraparenchymal bleeds presenting with headache and symptoms of raised intracranial pressure. Aneurisms are less common in children, and usually involve the subarchnoid space (and sometimes intraparenchymal as well).

Work Up

In general, start with the studies with the highest yield and the lowest risk:

• ESR, CBC, PT, PTT, blood culture.
• MRI/MRA/MRV of the head
• MRA or preferably ctAngio of the neck vessels
• Lumbar Puncture routine, viral, tb, L/P
• Neurology, Hematology (see Appendix A), Rheumatology, Cardiology consults
• Consider true angiogram.

Treatment  (Recommendations based on limited data and are in flux. Adapted from Bodensteinter)

1. Identify and specifally treat any identifiable (disorders).

2. Treatment is often difficult due to delay in diagnosis in children.

3, Very limited data for treatment in children.

4. Aspirin

• Often used, apparently safely without Reye's syndrome seen in these doses, yet.
• 3-5mg/kg/day ASA is most common dose used to prevent recurrent arterial stroke. No clear data on its use in children.

5. Heparin

• Consider if 1) a high risk of recurrence of stroke and 2) low risk of complication.
• Limited data suggest effective with less than 5% chance of bleed. Value is unclear but consider when:
  • arterial dissection
  • dural sinus thrombosis
  • coagulation disorders
  • recurrent thrombosis or emboli
  • stroke in evolution
  • ? with a new stroke
  • Heparin Dose: 20 U/kg/hr for children over 1 year of age
  • Heparin Dose: 28 U/kg/hr for children <1 year of age
  • Typically avoid any loading dose to reduce risk of hemorragic conversion of recent infarct.
  • Target APTT is 60-85 seconds
  • Low molecular weight heparin (Lovenex): 1mg/kg/dose (or 1.5mg/kg/dose in neonates) q12hr SQ, and requires only weekly or less monitoring. Not clear that it helps arterial strokes vs. risks and ASA might be better.

6. Warfarin

• Limited experience in children.
• Additonal concerns over children's activity level, but probably OK if avoid contact sports.
• Consider indications like adults
  • Cogenital/acquired heart disease
  • hypercoagulable states
  • arterial dissection
  • dural sinus thrombosis
  • INR of 2.0-3.0; unless mechanical heart valves 2.5 to 3.5

7. Thrombolytic Agents

• tPA (tissue Plasminogen Activator) not currently recommened for patients with acute stroke becaue of rate of serious bleeding after systemic tP''a given for systemic cots in children and the lack of safety data in childhood stroke.
• Clinical trials for stroke < 3 hours old are being considered.
• Limited data suggests tPA dissolves the clot, but 25-50% had minor or major bleeding.
• Several cases of use of intrasinus urokinase or streptokinase were given without complications.
• Overall: Insufficient data to comment on effectiveness of any of the thrombolytic agents in children with ischemic stroke. If given more than 3-4 hours post event, unacceptable rates of bleeding.

8. Sickle Cell Transfusion

• Half of Sickle Cell patients with one stroke will have another.
• Repeat transfusions to suppress sickle hemoglobin to <30% will lower repeat risk, and must be continued.
• Transfusions can also help prevent first sickle stroke in patients at increased risk.
• TCD can help identify sicklers at highest risk for first stroke.
• Iron toxicity might be reduced if even 50% HgS is maintained. Needs further study.

Reference: Bodensteiner JB, Roach ES, and deVeber G; Seminars in Pediatric Neurology: Cerebrovascular Diseases in Childhood. WB Saunders. Vol.7 No.4. December 2000.

APPENDIX A: Standard work-up for prothrombotic disorder.

Section of Hematology/Oncology

Department of Pedicatrics

New York Medical College

APPENDIX I: Standard work-up for thrombophilia (prothrombotic disorders)

Note: Consider sucrose hemolysis test if there is a suspicion of PNH (call 493-1475 Special Hematology to arrange the test).

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