What is the management approach for a 45-day-old male baby presenting with lethargy, hypoglycemia, seizures, and cerebral venous thrombosis without hepatosplenomegaly, with normal prothrombin time (PT)/partial thromboplastin time (PTT) and platelet count?

Management of Neonatal Cerebral Venous Thrombosis with Hypoglycemia and Seizures

For this 45-day-old infant with cerebral venous thrombosis, lethargy, hypoglycemia, and seizures, initiate anticoagulation immediately with either unfractionated heparin or low-molecular-weight heparin, even though the PT/aPTT and platelet counts are normal, and continue for 6 weeks to 3 months. 1, 2, 3

Immediate Management Steps

Acute Stabilization

• Correct hypoglycemia immediately with IV dextrose bolus (2-4 mL/kg of D10W) followed by continuous glucose infusion to maintain normoglycemia, as hypoglycemia can worsen neurological outcomes 1
• Control seizures aggressively with antiepileptic medications (phenobarbital loading dose 20 mg/kg IV is first-line in neonates), as seizures occur in 40% of cerebral venous thrombosis cases and require immediate treatment 1, 2, 4
• Admit to neonatal intensive care unit for continuous cardiorespiratory monitoring and neurological assessment every 2-4 hours 3, 4

Anticoagulation Protocol

Start anticoagulation immediately upon diagnosis confirmation, as this is the cornerstone of treatment even in neonates 1, 2, 3:

• Unfractionated heparin (UFH): Initial bolus 75 units/kg IV over 10 minutes, then continuous infusion at 28 units/kg/hour for infants <1 year, adjusted to maintain anti-Xa levels 0.35-0.7 units/mL or aPTT 60-85 seconds 1
• OR Low-molecular-weight heparin (LMWH): Enoxaparin 1.5 mg/kg subcutaneously every 12 hours for infants <2 months, adjusted to maintain anti-Xa levels 0.5-1.0 units/mL 1

Critical point: The American College of Chest Physicians specifically recommends anticoagulation for neonates with cerebral sinovenous thrombosis without significant intracranial hemorrhage 1. Even with significant hemorrhage, consider either immediate anticoagulation or supportive care with repeat imaging at 5-7 days and anticoagulation if thrombus extends 1.

Duration of Anticoagulation

• Continue therapeutic anticoagulation for 6 weeks to 3 months total after transitioning from UFH/LMWH to LMWH for ongoing therapy 1
• If transient reversible risk factor identified (dehydration, infection): 6 weeks minimum 1
• If no clear risk factor (idiopathic): 3 months 1, 3

Diagnostic Workup While Initiating Treatment

Metabolic Investigation for Hypoglycemia

The combination of lethargy, hypoglycemia, and seizures in a neonate requires urgent metabolic evaluation 5:

• Measure plasma amino acids and urine organic acids to rule out nonketotic hyperglycinemia, which has been associated with neonatal cerebral venous thrombosis and presents with progressive lethargy, hypoglycemia, and seizures 5
• Check serum ammonia, lactate, and acylcarnitine profile to exclude other inborn errors of metabolism
• Obtain blood glucose, insulin, cortisol, and growth hormone levels during hypoglycemic episode to determine etiology

Thrombophilia Screening

Test for prothrombotic conditions as these directly affect anticoagulation duration 1, 4:

• Protein C, protein S, and antithrombin III levels (most common coagulopathies in neonatal cerebral venous thrombosis) 6
• Factor V Leiden and prothrombin G20210A mutation 4
• Lipoprotein(a) level (elevated levels associated with neonatal internal cerebral venous thrombosis) 7
• Homocysteine level 1

Important caveat: Obtain these tests before starting anticoagulation if possible, but do not delay anticoagulation to obtain them 1, 4. Protein C and S levels are physiologically low in neonates, so interpret with age-appropriate reference ranges 1.

Additional Risk Factor Assessment

• Evaluate for dehydration (common risk factor in neonates) 6
• Screen for infection including mastoiditis, meningitis, or sepsis 6
• Assess for cardiac malformations with echocardiography 6
• Review maternal and perinatal history for prothrombotic risk factors 1

Monitoring During Anticoagulation

Clinical Monitoring

• Neurological examination every 2-4 hours for signs of deterioration (worsening lethargy, new focal deficits, increased seizure activity) 3, 4
• Monitor for bleeding complications including serial hemoglobin/hematocrit, stool guaiac testing 1

Laboratory Monitoring

• Anti-Xa levels (for LMWH): Check 4 hours after third dose, then weekly once therapeutic 1
• aPTT (for UFH): Check 4 hours after initiation and 4 hours after each dose adjustment 1
• Platelet count every 2-3 days to monitor for heparin-induced thrombocytopenia 1

Imaging Follow-up

• Repeat MRI with MR venography at 5-7 days if clinical deterioration occurs or if initial management included observation rather than immediate anticoagulation 1, 4
• Follow-up imaging at 3-6 months to assess recanalization in stable patients 3, 4

Management of Complications

If Neurological Deterioration Despite Anticoagulation

• Consider endovascular thrombolysis for life-threatening thrombosis, though this is rarely used in neonates 1, 3
• Decompressive surgery may be life-saving if severe mass effect with impending herniation develops 3, 4

If Significant Intracranial Hemorrhage Present

The American College of Chest Physicians provides two options 1:

1. Proceed with anticoagulation (preferred if no active bleeding expansion)
2. Supportive care with radiologic monitoring at 5-7 days and anticoagulate if thrombus extends

Common Pitfalls to Avoid

• Do not withhold anticoagulation due to presence of hemorrhagic infarction, as hemorrhagic transformation is common in venous thrombosis and anticoagulation prevents propagation 1, 2, 3
• Do not assume normal PT/aPTT excludes thrombophilia, as many prothrombotic conditions (protein C/S deficiency, factor V Leiden) do not affect these screening tests 1, 6
• Do not delay treatment to complete thrombophilia workup, as anticoagulation should begin immediately upon diagnosis 1, 4
• Do not use adult heparin dosing, as neonates require higher weight-based doses due to different pharmacokinetics 1
• Do not overlook metabolic causes when hypoglycemia and seizures accompany cerebral venous thrombosis, as conditions like nonketotic hyperglycinemia can coexist 5
• Do not assume idiopathic neonatal cerebral venous thrombosis has benign prognosis without treatment, as outcomes are worse in neonates compared to older children, with 61% having residual deficits at discharge 6

Prognosis and Long-term Follow-up

• Neonatal cerebral venous thrombosis carries worse prognosis than in older children, with only 35% having normal outcomes at discharge and 41% having normal development at long-term follow-up 6
• Arrange developmental follow-up at 3,6, and 12 months to assess for developmental delay, which occurs in approximately 48% of survivors 6
• Consider indefinite anticoagulation only if recurrent thrombosis occurs or high-risk inherited thrombophilia is confirmed 3