Pediatrics

Cerebral venous thrombosis/ischemia

OVERVIEW: What every practitioner needs to know

Are you sure your patient has cerebral venous thrombosis? What are the typical findings for this disease?

Signs and symptoms of cerebral venous thrombosis (CVT) are variable depending on patient age, thrombosis location, and associated infarction or hemorrhage. In newborns, symptoms resemble those of many other acute neonatal encephalopathies:

Seizures

Depressed mental status

Poor feeding

Abnormal tone and reflexes

Among nonneonates, signs and symptoms are nonspecific, and most commonly include the following:

Headache—unremitting, progressive

Lethargy

Vomiting

In a minority there may be seizures, papilledema, sixth nerve palsy, or other focal deficits corresponding to focal venous infarction or hemorrahage. In the most severe cases, lethargy progresses to coma, herniation, and death.

Associated imaging abnormalities range from least to more severe as follows:

Focal or unilateral superficial dural sinus thrombosis without ischemic or hemorrhagic changes

Bilateral or widespread superficial dural sinus thrombosis with focal cortical or subcortical white matter infarction, often hemorrhagic

Deep sinus thrombosis with thalamic infarction, often hemorrhagic and bilateral

Deep sinus thrombosis with isolated intraventricular hemorrhage, usually seen only in newborns

Extensive superficial and deep sinus thrombosis with bilateral extensive confluent subcortical white matter hemorrhagic infarction, also more commonly seen in newborns than in older children

Widespread bilateral superficial and deep sinus thrombosis with extensive cerebral edema (supra- and infratentorial), hemorrhagic infarction, and transtentorial herniation

What other disease/condition shares some of these symptoms?

Because symptoms are nonspecific, many acute brain disorders mimic CVT. Diseases causing acute onset of raised intracranial pressure or diffuse/multifocal cerebral dysfunction resemble CVT. These include intracranial or parameningeal infection (meningitis, encephalitis, brain abscess); malignancy; intracranial hemorrhage such as subdural hemorrhage (SDH), intraventricular hemorrhage (IVH), and subarachnoid hemorrhage (SAH); hypertensive encephalopathy; metabolic derangement such as hyperammonemia or diabetic ketoacidosis; intoxication such as carbon monoxide poisoning; status migrainosus; pseudotumor cerebri; autoimmune cerebritis such as in lupus; acute demyelinating encephalomyelitis (ADEM); and trauma, including inflicted traumatic brain injury.

What caused this disease to develop at this time?

History and physical examination provide essential clues to possible risk factors and causes. The occurrence of any one or more of the following predisposing factors or diseases should raise suspicion for CVT as the cause of acute neurologic symptoms. Often multiple risk factors coexist, and the disease is precipitated by an acute intercurrent illness or event.

Infections: bacterial meningitis, sinusitis, mastoiditis, Lemierre syndrome (jugular vein septic phlebitis)

Genetic prothrombotic disorders: factor V Leiden mutation, prothrombin mutation, and genetic mutations causing protein C or protein S deficiency; hyperhomocysteinemia from methyl-tetrahydrofolate reductase (MTHFR) mutations; antithrombin III deficiency

Acquired autoimmune prothrombotic disorders: antiphospholipid antibody syndrome, Behçet's disease, inflammatory bowel disease, lupus erythematosus

Hematologic disorders: iron deficiency anemia, hemoglobinopathies, autoimmune hemolytic anemia

Cyanotic congenital heart disease

Treatment with prothrombotic drugs: L-asparaginase for leukemia; intravenous immune globulin

Chronic protein-losing diseases: nephrotic syndrome, protein-losing enteropathy, malabsorption syndromes

Cranial trauma involving the dural sinuses

Cranial surgery involving dural sinus manipulation, such as cranial reconstruction procedures

Nutritional disorders resulting in chronic dehydration, iron deficiency, malabsorption, or protein-deficient states

Acute systemic illness causing dehydration, circulatory failure, or consumptive coagulopathy

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Choice of laboratory studies is guided by severity of the patient's presenting symptoms and whether definitive radiologic confirmation of the diagnosis has been reached.

If the patient is comatose or obtunded, and CVT is suspected but not confirmed, initial laboratory studies should address any potential life-threatening cause for coma: comprehensive metabolic panel (electrolyte, glucose, blood urea nitrogen/creatinine levels; liver panel; calcium levels, and serum protein levels), ammonia level, blood gas determinations, toxicology profile, complete blood count, and platelet count.

Once the patient is hemodynamically stable and has airway and ventilatory status secured, imaging should proceed urgently to define the nature of the intracranial process (see below).

After CVT is confirmed radiologically, additional laboratory studies should be performed to identify the underlying cause and to provide pretreatment baseline data. These are further guided by known acute or chronic conditions such as leukemia, congenital heart disease, or hemoglobinopathy detailed as follows:

Prothrombin time/international normalized ratio, partial thromboplastin time in all patients before treatment with heparinoids

Antithrombin III level in all patients before treatment with heparinoids

Protein C, protein S levels

Lipoprotein a

Factor V Leiden and prothrombin gene mutations

Anticardiolipin and anti-glycoprotein B antibody levels

Blood homocysteine level; if elevated assess for MTHFR mutation

Expanded panel for rheumatologic diseases if lupus erythematosus or other primary autoimmune disease is suspected

Lumbar puncture if meningitis or encephalitis is suspected, but only if there is no risk of herniation from intracranial mass effect or cerebral edema

Iron profile if microcytic anemia is present

Would imaging studies be helpful? If so, which ones?

Adequate imaging is essential for timely and accurate diagnosis before starting anticoagulation (AC) therapy. Modalities to consider include computed tomography (CT), magnetic resonance imaging (MRI), and cerebral angiography. See Figure 1 for examples of findings on CT and MRI typical of this condition.

Figure 1.

(A) Head CT showing hyperdensity of the straight sinus (arrow) corresponding to acute thrombus. (B) Magnetic resoance imaging of the brain showing large hemorrhagic infarction (arrow) in patient with transverse sinus thrombosis. (C) Magnetic resonance venogram of the brain showing extensive absence of flow-related signal in all dural sinuses except for residual flow in the left transverse sinus.

Head CT is an appropriate first study in all children with suspected CVT. It is almost universally available, and performed quickly with a minimum of sedation. Sensitivity of CT for CVT is high, although specificity is suboptimal, especially in newborns in whom a high hematocrit often causes a hyperdense appearance of venous structures. It is also sensitive and specific in identifying complications of CVT such as hemorrhage, or alternative diagnoses such as hydrocephalus, cranial trauma, IVH, SAH, or SDH, which then have very different and immediate management implications.

If initial head CT supports a diagnosis of CVT, definitive venography is necessary to confirm the presence, location, and extent of thrombosis. MRI has many advantages (see below), but CT venography can also be performed. It may be performed more quickly than MR venography, but it adds radiation exposure.

Brain MRI with MRV is preferable and superior in most cases for multiple reasons:

MRI with MRV identifies, with high sensitivity and specificity, the presence and location of thrombosis in any part of the venous system (superficial or deep dural sinuses). MRV without MRI is inadequate, as hypoplastic dural sinuses or turbulent flow artifacts on MRV can be mistaken for thrombotic occlusion.

MRI identifies sequelae of CVT, including infarction, hemorrhagic infarction, and edema

MRI specifically and sensitively identifies conditions that mimic CVT, including encephalitis, ADEM, tumor, and trauma

The disadvantages of MRI are higher cost, need for sedation, lesser availability than CT, necessity to remove dental hardware for optimal images, incompatibility with implanted devices or life support

Cerebral catheter angiography is rarely useful for CVT because of the high sensitivity/specificity of noninvasive imaging. It may be performed in rare circumstances in which endovascular thrombolysis is performed because of failure of conventional anticoagulation treatment (see below).

Cranial ultrasonography is sometimes considered in newborns who are too unstable to transport for conventional CT or MRI. It is useful only in demonstrating absence of flow in the superior sagittal sinus and for identifying intracranial hemorrhage. It is inadequate for evaluating the other dural sinuses and may miss partial nonocclusive thrombosis. It should not be used alone to confirm a diagnosis of CVT for purposes of initiating anticoagulation therapy.

If you are able to confirm that the patient has cerebral venous thombosis, what treatment should be initiated?

Acute supportive treatment is reasonable in all patients and is aimed at restoring and maintaining normal circulating blood volume, perfusion, and oxygen and glucose delivery to the brain. These measures include:

Administer intravenous (IV) fluid at more than maintenance levels using isotonic fluids

Maintain airway, ventilation, and adequate oxygenation

Correct anemia

Monitor and maintain normal levels of blood glucose and sodium

Correct acid-base and electrolyte abnormalities

Elevate head of bed to 30 degrees

Consult hematologist about providing factor replacement or plasma products if there is consumptive coagulopathy or deficient levels of serum protein or fibrinolytic protein levels (protein C or S)

AC therapy: systemic AC with heparin infusion or low-molecular weight heparin (LMWH) should be considered as urgent and first-line therapy for all children with acute CVT. The importance of starting therapy urgently with a minimum of delay should not be underestimated because clot propagation may be very rapid and unpredictable, resulting in irreversible brain injury or death. The following factors need to be considered in the risk-versus-benefit consideration of starting treatment:

Recent major surgery, such as cardiac surgery or craniotomy for tumor resection or cranial reconstruction, increase the risk of bleeding and may require postponing AC in accordance with the surgeon's recommendation.

Presence of extraaxial intracranial hemorrhage or chronic SDH increases the risk of AC and requires neurosurgical consultation before and during treatment with AC.

Major cranial trauma with skull fracture and/or hemorrhagic traumatic brain injury usually precludes treatment with AC

Treatment with AC in the presence of hemorrhagic venous infarction is controversial, especially in neonates (see below). In most children or adolescents who have hemorrhagic venous infarction from CVT, the risk of death from uncontrolled or progressive untreated CVT is significant. It is reasonable to proceed with AC in these patients.

Consultation with a hematologist/thrombosis expert to help counsel families on the risk-versus-benefit of AC and to assist with choice of drug and dosing is advisable.

Causes of on-going or recurrent thrombosis should be identified and treated aggressively, such as iron deficiency anemia, parameningeal infection (mastoiditis), inflammatory bowel disease, nephrotic syndrome, and antiphospholipid antibody syndrome.

Is there a role for endovascular treatment with thrombolytic agents? In rare circumstances, clot progression and extension of infarction occur in the face of aggressive supportive and AC treatment. In cases in which the patient's neurologic condition deteriorates from clot propagation after a trial of maximal medical therapy, endovascular therapy with thrombolysis may be considered as a life-saving measure. Consultation with the interventional radiology team early during the course of the obtunded or comatose patient is advisable. Patients with intact mental status and no infarction at the onset of treatment with AC usually respond to medical therapy and do not need the more invasive and high-risk endovascular therapy.

What about duration of treatment? Duration of AC depends on the underlying cause, the response to early treatment, and existence and nature of prothrombotic risk factors. AC can reasonably be discontinued when several conditions are satisfied:

The underlying cause of the thrombosis resolves

Recanalization of thrombosis is demonstrated radiologically

Signs and symptoms referable to venous outflow obstruction resolve

Options for AC therapy in children include heparin or LMWH for acute (first week) therapy, and coumadin or LMWH for long-term maintenance therapy.

Conditions for stopping AC are typically achieved after a minimum of 6 weeks to 3 months in most cases of reversible causes of CVT, such as with dehydration and acute infectious illness, iron deficiency anemia, mastoiditis, after IV immunoglobulin administration, or after L-asparaginase treatment. Conditions in which a longer duration of AC may be necessary while an underlying disease is treated to remission may include nephrotic syndrome, inflammatory bowel disease, and Behçet's disease. Conditions in which lifelong treatment with AC might be considered include genetically determined severe protein C or S deficiency, catastrophic antiphospholipid antibody syndrome, and recurrent life-threatening CVT on discontinuing AC.

What are the adverse effects associated with each treatment option?

What is the risk of treatment with AC? Systemic or intracranial hemorrhage are the main risks of AC. Treatment with heparinoids is rarely associated with heparin-induced thrombocytopenia. Long-term treatment with LMWH adversely impacts bone health and is poorly tolerated by some patients because of the need for twice-daily injections.

What is the risk of supportive treatment alone without the use of AC? The main risk is clot propagation, and with that comes the a risk of new or progressive venous infarction, hemorrhage, and ultimately death from cerebral edema and herniation. The magnitude of the risk of clot propagation depends on the underlying cause for thrombosis—the greater the extent of thrombus at the start of treatment, the greater the risk of clot propagation without AC treatment. The risk of death from progressive infarction is greater in children and adolescents than in newborns because of the expansile cranium of the newborn.

What are the possible outcomes of cerebral venous thrombosis?

What is the outcome in CVT? The spectrum of adverse outcomes in CVT includes the following:

Death

Temporary or permanent neurologic impairment and disability

Epilepsy

Hydrocephalus

Chronic venous outflow obstruction resulting in chronic headache and/or pseudotumor cerebri

Vision impairment from intracranial hypertension-induced optic nerve injury

Recurrent CVT

Outcome depends on several factors, including occurence, location, and extent of infarction; nature and reversibility of the underlying cause of CVT; and the extent of recanalization of the thrombosed veins. When CVT causes no infarction or hemorrhage and recanalization is complete, the outcome is usually normal with no neurologic sequelae. When there is infarction, the location and extent of infarction contribute to long-term outcome. For example, in newborns with infarction due to CVT, the most vulnerable regions are the subcortical white matter (SWM). If infarction is extensive and involves SWM of both hemispheres bilaterally, there is a high probability of permanent motor and cognitive disability. If foci of infarction are small, unilateral, or unifocal, the outlook may be very good.

Predicting outcome in CVT based on very early MRI findings of infarction and early clinical neurologic status is highly uncertain. Compared with other forms of acute brain injury such as encephalopathy after cardiac arrest or traumatic brain injury, the acute encephalopathy from venous thrombosis may appear very severe, including deep coma, and yet may be entirely reversible if venous outflow can be restored as late as several days after onset of symptoms. Infants and children with infarction who are treated aggressively with antithrombotic therapy, and who receive aggressive rehabilitation in the postacute phase, may make a much better long-term functional recovery than would be predicted from the initial clinical picture and MRI findings.

What will you tell the family about prognosis? Overall prevalence data on adverse outcomes in CVT has been reported in recent cohort studies as follows:

Mortality: 5%-19%, higher if comatose or obtunded at initial diagnosis, and higher in neonates than in nonneonates

Motor or cognitive impairment: 2%5-40%

Pseudotumor cerebri: 20%-30%

Epilepsy: 10%-20%

Recurrent CVT: 4%-6% at median time of 6 months after the initial illness; mostly in children older than age 2 years at initial illness

What causes this disease and how frequent is it?

Epidemiology: minimal estimates of incidence range from 0.4-0.7/100,000/year in children, up to 2.6/100,000/year in neonates, and is greater in boys than in girls, with a ratio of 60:40. There is no specific prediliction by race, ethnicity, or geographic factors.

Causes are as described above and vary by age. In newborns, the cause is usually volume depletion and/or acute systemic illness.

Genetics: CVT is muiltifactorial, with no disease-causing single-gene defects. Genetically determined thrombophilias (detailed above) may contribute as comorbid defects.

How do these pathogens/genes/exposures cause the disease?

Pathogenesis of venous thrombosis involves three factors (Virchow triad): venous stasis due to obstruction or slow flow, injury or inflammation of vessel wall or endothelium, and prothrombotic state. Any or all these factors are at play in virtually all the risk factors or underlying conditions listed above.

Once thrombus forms, the Virchow triad self-perpetuates. Venous outflow obstruction leads to ischemia when venous pressure equals or exceeds arterial pressure. Injured endothelium serves as a conduit for hemorrhagic transformation in regions of ischemia. Increased venous pressure and venous obstruction directly increase intracranial pressure, which is additionally made worse by impeding cerebrospinal resorption. Diffusely raised intracranial pressure is a hallmark of CVT and contributes to the symptoms of headache, vomiting, depressed mental status, papilledema, and abducens palsy.

Other clinical manifestations that might help with diagnosis and management

Acute symptomatic seizures may be subclinical, especially in young infants and in children with depressed mental status. In such cases, video electroencephalographic monitoring may be helpful.

What complications might you expect from the disease or treatment of the disease?

Complications during the acute phase include herniation and death, hydrocephalus, or pseudotumor cerebri; during the chronic phase, there may be chronic neurologic or functional impairment such as hemiparesis, quadriparesis, speech/language impairment, neurocognitive or neurobehavioral disorders, epilepsy, cranial nerve deficits, or chronic headache.

How can cerebral venous thrombosis be prevented?

Prevention rests on maintaining general good health status, avoiding dehydration, and preventing iron deficiency.

What is the evidence?

Chalmers, E, Ganesen, V, Liesner, R. "British Committee for Standards in Haematology. Guideline on the investigation, management and prevention of venous thrombosis in children". Br J Haematol. vol. 154. 2011. pp. 196-207.

Yang, JY, Chan, AK, Callen, DJ. "Neonatal cerebral sinovenous thrombosis: sifting the evidence for a diagnostic plan and treatment strategy". Pediatrics. vol. 26. 2010. pp. e693-700.

Dlamini, N, Billinghurst, L, Kirkham, FJ. "Cerebral venous sinus (sinovenous) thrombosis in children". Neurosurg Clin North Am. vol. 21. 2010. pp. 511-27.

Sebire, G, Tabarki, B, Saunders, DE. "Cerebral venous sinus thrombosis in children: risk factors, presentation, diagnosis and outcome". Brain. vol. 128. 2005. pp. 477-89.

Berfelo, FJ, Kersbergen, KJ, van Ommen, CH. "Neonatal cerebral sinovenous thrombosis from symptom to outcome". Stroke. vol. 41. 2010. pp. 1382-8.

Sebire, G, Tabarki, B, Saunders, DE. "Cerebral venous sinus thrombosis in children: risk factors, presentation, diagnosis and outcome". Brain. vol. 128. 2005. pp. 477-89.

Grunt, S, Wingeier, K, Wehrli, E. "Cerebral sinus venous thrombosis in Swiss children. Swiss Neuropaediatric Stroke Registry". Dev Med Child Neurol. vol. 52. 2010. pp. 1145-50.

Moharir, MD, Shroff, M, Stephens, D. "Anticoagulants in pediatric cerebral sinovenous thrombosis: a safety and outcome study". Ann Neurol. vol. 67. 2010. pp. 590-9.

Jordan, LC, Rafay, MF, Smith, SE. "International Pediatric Stroke Study Group. Antithrombotic treatment in neonatal cerebral sinovenous thrombosis: results of the International Pediatric Stroke Study". J Pediatr. vol. 156. 2010. pp. 704-10, 710.

Monagle, P, Chalmers, E, Chan, A. "Antithrombotic therapy in neonates and children: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)". Chest. vol. 133. 2008. pp. 887S-968S.

Roach, ES, Golomb, MR, Adams, R. "Council on Cardiovascular Disease in the Young. Management of stroke in infants and children: a scientific statement from a Special Writing Group of the American Heart Association Stroke Council and the Council on Cardiovascular Disease in the Young". Stroke. vol. 39. 2008. pp. 2644-91.

Ongoing controversies regarding etiology, diagnosis, treatment

Treatment of neonates with AC is controversial. Although existing single-center cohort studies suggest AC with lovenox is safe in newborns, it is common practice to refrain from using AC in neonates who have intracranial hemorrhage. Conversely, clot propagation with new/progressive infarction is common when AC is witheld. A controlled clinical trial of AC for neonatal CVT is greatly needed.

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