A 7-month-old male with severe hemophilia A (less than 1% factor VIII [FVIII] activity) presented to his pediatrician with fussiness and inability to sleep for 3 days. He had received his influenza vaccine 3 days earlier. What's the diagnosis?
A 7-month-old male with severe hemophilia A (less than 1% factor VIII [FVIII] activity) presented to his pediatrician with fussiness and inability to sleep for 3 days. He had received his influenza vaccine 3 days earlier. His mother attributed the fussiness to introducing lentils into his diet.
The infant was born to a 32-year-old primigravida mother via cesarean delivery after a normal pregnancy. Severe hemophilia A was diagnosed due to bleeding after a circumcision done at birth. There were no subsequent bleeding episodes and he was not on FVIII replacement therapy.
The infant’s review of systems was positive for atopic dermatitis, intermittent constipation, mild gastroesophageal reflux, and co-sleeping. His growth and development were normal. He was not on medications and his immunizations were up-to-date, including his influenza vaccine 3 days prior to this presentation. There was no history of fever, cough, cold, vomiting, diarrhea, or trauma. The child was treated initially with reflux precautions, dietary advice, and observation but the fussiness worsened. He continued to feed well and smiled when held but started crying when laid down. He slept only in his mother’s arms and awakened screaming at night.
Clinical course and evaluation
The mother called the hematologist for worsening fussiness and was advised to take the patient to the emergency department (ED). The Hematology service was consulted in the ED. The patient’s vital signs and physical exam were normal. Abdominal imaging (X-ray and abdominal ultrasound [US]) showed no evidence of constipation or intussusception.
The patient saw the pediatrician for a follow-up visit. He was afebrile, fussy, and tired appearing with normal vital signs and a normal physical exam other than crying when laid on the examination table that stopped when he was picked up. Rapid tests for respiratory syncytial virus (RSV) and influenza were negative. He was evaluated at the Hemophilia Clinic the next day when he had a complete blood count (CBC) and a head computed tomography (CT), which were normal.
He followed up again with the pediatrician. His mother reported continuing fussiness, increased flatulence, and pasty stools with straining and crying. On examination, the patient appeared uncomfortable and curled up when laid down. A repeat abdominal X-ray was normal. He was put on an elemental formula and advised polyethylene glycol 1 teaspoon per day in water. The family was advised to return to the ED if the fussiness continued.
The patient returned to the pediatrician the next day for worsening fussiness with a preference to curl up and turn to his left. Hospital admission with hematologic consultation was requested due to the concern for a hematologic, possibly intra-abdominal cause of his fussiness. During the hospital stay, a second abdominal US, a CT scan of his abdomen and pelvis, urinalysis, and blood tests including CBC, lipase, amylase, comprehensive metabolic panel, and C-reactive protein (CRP) were normal.
The patient was noted to be intermittently fussy but had normal vital signs and continued to feed well. He was noted to arch his back during episodes of fussiness. He showed a preference to turn his head to the left. Neck exam showed no asymmetry or evidence of muscle bleed. He did not awaken to an abdominal exam when asleep. The occupational therapist recommended gentle neck exercises for his neck stiffness that was thought to be related to his preferred sleep position in the parents’ arms for several days. His arching was attributed to gastroesophageal reflux. After 2 days, he was discharged.
Differential diagnosis for fussiness
Fussiness in infants is a common pediatric outpatient complaint and has many causes that range from trivial to life threatening.1 Both hematologic and nonhematologic causes of fussiness were considered in the differential diagnosis for this infant with hemophilia (Table 1). At the onset of fussiness, the patient appeared well, and nonorganic causes were considered such as his recent influenza vaccination, recent introduction of a new food, co-sleeping with parents, frequent awakening at night, and the onset of teething. His exam was negative for thrush, corneal abrasion, or musculoskeletal trauma. Infections appeared unlikely due to the lack of fever, cold symptoms, ear pain, or rash. Because of his history of mild gastrointestinal reflux, intermittent constipation, and fussiness, he was treated with reflux precautions, polyethylene glycol, and a trial of elemental formula.
The patient was simultaneously evaluated for signs and symptoms of hemophilia (Table 2). He demonstrated no obvious bruising, tenderness, swelling, or deformity. Additionally, he had no hemarthroses. He did exhibit worrisome signs such as refusal to lay on his back, turning to 1 side, and curving forward. Hence the child was evaluated for intracranial and intra-abdominal hemorrhage, which were ruled out based on clinical exam, laboratory evaluation, and imaging studies.
A worsening exam
During the follow-up with his pediatrician on the day after discharge from the hospital, the patient’s mother reported worsening fussiness with “his hands numb from pain.” On examination, he had torticollis with a head tilt to the left and a partial ptosis of his left eyelid. Tone and spontaneous movements of his trunk and upper extremities were decreased and he reached for a toy with his feet.
Unable to sit, he curved his spine forward when placed in a seated position. He was unable to lift himself up from the prone position. Grasp reflex was absent, and he appeared to have no sensation in his palms. The pediatrician advised the parent to return to the ED and called the hematologist about the new neurologic findings. The child was intubated in the ED and an imaging study confirmed the diagnosis.
The patient was diagnosed with spinal epidural hematoma (SEH) with cord compression presenting with Horner syndrome.
Magnetic resonance imaging (MRI) of the patient’s spine showed multiple epidural hematomas extending from C2 down to S1 with significant cord compression. This was especially pronounced from C6 to T4 where the spinal cord was severely compressed and displaced anteriorly and to the left. Multiple septations suggested that the hematomas could be subacute or chronic. (Figures 1 and 2 present preoperative T1- and T2-weighted sagittal and axial images of the spine.)
Factor VIII replacement was given immediately after the MRI and perioperatively per standard guidelines for hemophilia.2 He underwent multiple partial hemilaminectomies for decompression of epidural hematomas. His neurologic exam improved the next day with increased spontaneous movements of his upper extremities.
One week postoperatively, another spinal MRI showed significant improvement (Figure 3). The patient was found to have a low titer inhibitor (0.8 BU) during the admission that self-resolved on follow-up testing. Postoperatively, further bleeding complications were successfully prevented with recombinant FVIII product, 200 units/kg/dose given every 6 hours that was gradually spaced out. He was discharged after 3 weeks with residual right-sided hemiparesis and left-sided ptosis.
Three months later, a central line was placed to facilitate the administration of the recombinant FVIII product every other day. Six months later, he transitioned to an extended half-life (EHL) FVIII product (50 units/kg/day every 4 days). He received physical and occupational therapy with steady improvement and was enrolled in Early Intervention services for children.
Hemophilia, an X-linked bleeding disorder, is the most common hereditary bleeding disorder in the United States. Its incidence is estimated to be approximately 1 in 5000 live male births.3 Hemophilia A, the condition affecting this patient, results from deficiency in FVIII. Central nervous system bleeding in patients with hemophilia is a rare complication with an incidence between 2% and 8%.4,5 Fewer than 10% of these hemorrhages occur within the spinal canal.4
This case highlights the importance of recognizing infancy as a high-risk age group for the occurrence of SEH. Infants may be predisposed to epidural bleeding as their cervical musculature begins to develop between ages 4 and 6 months.6 Increased cervical motion in the developing muscle body (due to acceleration and deceleration of the head mass in babies with poor head control) leads to cervical spine injury6,7 and the potential for hemorrhage.
Spontaneous SEH can be either venous or arterial in origin. In venous SEH, absence of valves in the venous plexus allows for venous backflow and sudden increases in pressure (from an infant’s crying, straining, coughing, or sneezing), inducing spontaneous rupture of these fragile vessels.8,9 In arterial SEH, it is hypothesized that the higher pressure of arterial bleeding could result in cord compression with a rapid onset in patients who previously performed strenuous activities without incident.10 Young infants with hemophilia also are at higher risk for hemorrhage because they typically do not begin prophylactic factor replacement until after age 1 year or following their first joint or muscle bleed once ambulatory.
Babies with SEH have nonspecific symptoms such as unexplained irritability, inconsolable crying, poor feeding, or refusal to bear weight11 The classic clinical triad without history of trauma, making it difficult to recognize.11 The classic clinical triad of SEH—radicular pain, severe localized spinal pain, and sensorimotor deficits—may initially be difficult to perceive in a nonverbal infant. However, a diligent physical exam demonstrating specific neurologic signs such as decreased neck range of motion, diminished arm reflexes, or decreased strength, tone, and sensation in the upper extremities11 should prompt diagnostic imaging.
Review of literature revealed 2 previous cases describing torticollis as a presentation of SEH in hemophilia A.11,12 Similar to this case, a 10-month-old infant with a cervicothoracic epidural hematoma presented initially with irritability and a normal neurologic exam but developed torticollis approximately 48 hours later that progressed to diffuse hypotonia, flaccid upper extremity paralysis, and respiratory distress requiring emergent decompressive laminectomy.11 Another 10-month-old boy developed torticollis 48 hours after an incident of repeated neck overextension and went on to develop flaccid upper extremity paralysis.12 There are no previous cases of SEH in hemophilia presenting with Horner syndrome. However, a similar presentation was found in a 72-year-old woman receiving anticoagulant therapy for atrial fibrillation.13
Early diagnosis and treatment of SEH in hemophilia patients is necessary to prevent progression of neurologic deficits leading to long-term sequelae. Magnetic resonance imaging is the diagnostic modality of choice for SEH. However, spinal ultrasonography is a reasonable screening tool should MRI not be readily available.14 Empirical factor replacement, even prior to imaging, is the initial therapy in cases of suspected central nervous system bleeding and is dosed to achieve factor levels of 100%. The role of surgical intervention is less clear. Prompt surgical decompression with or without laminectomy should be considered.11,15 However, surgery may be deferred in the presence of a stable neurologic exam with successful correction of the underlying coagulopathy.6,16
Kiehna and colleagues reviewed 24 cases of spontaneous epidural hemorrhage in children with hemophilia and found that prompt conservative treatment with FVIII and correction of coagulopathies was critical in patient outcomes. Aggressive medical management without surgery provided for full neurologic recovery in hemodynamically and neurologically stable patients.6 Importantly, these authors and other proponents of conservative management (under the appropriate circumstances) recommend a multidisciplinary approach to the treatment of these patients with a team consisting of a pediatric hematologist, neurosurgeon, and pediatric intensivist.6,16
A high index of suspicion for spinal hemorrhage and recognition of subtle neurologic signs of cord compression, which can be difficult in a nonverbal and nonambulatory child, are essential in order to obtain the correct imaging and make the diagnosis in a timely way.
Horner syndrome or oculosympathetic paresis is a classic neurologic syndrome whose signs include ptosis, miosis, and anhydrosis due to a lesion along the sympathetic pathway that supplies the head, eye, and neck. Children with new onset Horner syndrome must be evaluated for an underlying disorder and paraspinal masses must be considered as an etiology.17 The history of severe hemophilia with new onset torticollis, Horner syndrome, and upper extremity weakness suggested cord compression from cervical spinal hemorrhage in this patient.
The patient at age 6 years has no neurologic deficits and his general health is very good. His cognition and speech are excellent. He has had no further bleeding episodes. He recently transitioned from EHL FVIII product to a new prophylactic agent called emicizumab given subcutaneously once a week.
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