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Spastic diplegia as a complication of interferon Alfa-2a treatment of hemangiomas of infancy
S
Spastic diplegia as a complication of interferon Alfa-2a treatment of hemangiomas of infancy
Charles F. Barlow, MD, Cedric J. Priebe, MD, John B. Mulliken, MD, Patrick D. Barnes, MD, Dorothy Mac Donald, RN, Judah Folkman, MD, and R. Alan B. Ezekowitz, MB, ChB, DPhil
We report the development of spastic diplegia in infants during the course of interferon Alfa-2a (IFN) therapy for potentially life-endangering hemangiomas. Five infants who displayed diplegia were selected from a group of 26 infants treated with IFN. Diplegia persisted in three infants, and in the remaining two significant recovery occurred after IFN was discontinued. Magnetic resonance imaging showed no significant brain or spinal abnormalities except minor to moderate delayed myelination in two patients. Myelination was normal on subsequent radiographic examination in all five patients. We conclude that IFN can adversely affect the immature central nervous system and produce spastic diplegia, which is potentially reversible. We recommend careful clinical assessment of neurodevelopmental status during IFN therapy. (J Pediatr 1998;132:527-30)
threatening complications such as obstruction to vision; distortion of a vital structure, eye, or lip; or extensive loss of tissue. Lesions were considered to be life-threatening if we believed that the patient would not survive long enough for the hemangioma to reach a natural stage of regression (hemangiomas of the liver, heart, and brain and those accompanied by thrombocytopenic coagulopathy and/or heart failure). IFN MRI
Adult patients treated with interferon-α have shown reversible changes in higher level cortical function and lesser adverse effects on the motor system; several have had Parkinsonian extrapyramidal signs.1,2 One reported patient had an “upper motor neuron” syndrome involving the legs.3 Neuropathy has also been recorded,2,4 indicating that several levels of neurologic function can be affected. There is, in addition, a well-documented case of a 2-year-old patient treated with “human leukocyte interferon” for laryngeal papilloma who had diplegia during therapy.5 In an ongoing study we have monitored a large number of infants treated with interferon Alfa-2a for hemangiomas of infancy. We have found that
periodic behavioral observations are not sufficiently discriminatory to reveal any leg-related handicaps in young children. In one child who was first seen with an unrelated neurologic complaint, the signs and symptoms of diplegia were identified; we then suspected that diplegia may be an IFN-related toxicity.
METHODS Our study population consisted of infants referred for management of endangering and life-threatening hemangiomas; most of these infants had not responded to corticosteroid therapy. We defined endangering tumors as those causing severe but not necessarily life-
From the Departments of Neurology, Medicine, Surgery, Radiology, Division of Plastic Surgery, Children’s Hospital, Boston, Massachusetts; the Pediatric Service, Massachusetts General Hospital, Boston; and the Departments of Neurology, Pediatrics, and Surgery, Harvard Medical School, Boston, Massachusetts. Supported by National Institutes of Health grant M01 RR02172. Submitted for publication July 30, 1996; accepted June 4, 1997. Reprint requests: Alan Ezekowitz, MB, ChB, DPhil, Pediatric Service, Massachusetts General Hospital, Boston, MA 02114. Copyright © 1998 by Mosby, Inc. 0022-3476/98/$5.00 + 0 9/22/83754
Interferon Alfa-2a Magnetic resonance imaging
The data consist of standard clinical history and results of examination presented as brief case reports. Patients with other potential causes of neurologic lesions of the brain or spinal cord were excluded. Two premature infants who had unexplained diplegia and one infant with intraspinal extension of a hemangioma that displaced but did not compress the spinal cord were excluded. We also excluded patients if there was little ambiguity that factors other than IFN were responsible; one child suddenly had diplegia 12 hours after undergoing therapeutic embolization of a paravertebral abdominal hemangioma, presumably caused by spinal cord embolus. Another child had demonstrable quadriparesis before being treated with IFN; computed tomography showed significant cerebral atrophy, and although the patient was thrombocytopenic, he had a large subdural hematoma. All patients in the series had periodic behavioral evaluations; 26 had careful neurologic examination, and of those, 5 were documented to have diplegia (Table). Neurologic examination (C. F. 527
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ET AL.
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PEDIATRICS MARCH 1998
OF
Table. Summary of interferon dosage
Birth weight
Duration of therapy
Cumulative dose (million units)
Maximum daily dose (million/units/day)
Diplegia status (age)
Case 1 (female, twin A)
7 lbs, 15 oz
5 wk to 10 mo
279.66
1.02
No recovery (10 mo)
Case 2 (female)
8 lbs, 6 oz
3 mo to 10 mo
322.20
2.10
No recovery (2 yr)
Case 3 (female)
7 lbs, 2 oz
2.5 mo to 33 mo
1946.04
3.60
No recovery (3 yr)
Case 4 (female)
8 lbs, 12 oz
3.5 mo to 15 mo
321.30
1.80
Recovery (15 mo)
Case 5 (female)
6 lbs, 0 oz
4 mo to 8 mo
253.86
2.70
Recovery (8 mo)
B.) was incorporated into the follow-up evaluation of two cases; both had come to neurologic attention for reasons other than diplegia at 9 months (case 4) and 7 months (case 5), respectively. Neurologic follow-up examination of these patients brought our attention to the possibility of diplegia as a complication of IFN therapy. Cases 1 (12 months), 2 (27 months), and 3 (15 months) were evaluated retrospectively. We have found that observation of the suspended posture of these infants has been most useful in detecting early diplegia. The normal posture in suspension is flexion at the knee with moderate flexion and external rotation at the hip. Toes are neutral. The infant must be relaxed, and this is often achieved by asking the mother to lift the child at the axilla. Abnormal posture consists of adduction at the hip; the knees become extended with legs parallel. Scissoring is a sign of advanced diplegia.6 The great toe is usually extended, and the other toes fan out.
IFN Administration of IFN was initiated according to our standard protocol.7 Treatment, which ranged from 6 to 29 months, was discontinued when indica528
tions for therapy had resolved and further hemangiomatous proliferation was regarded as unlikely or significant adverse reaction to therapy became apparent.
Informed Consent As soon as we became aware that IFN therapy might be associated with spastic diplegia, we amended the informed consent document. We also reported this adverse event to the Food and Drug Administration and to Hoffmann La Roche. The study was approved by the Institutional Review Board of the Children’s Hospital in Boston, Massachusetts.
Coronal T2-weighted fast spin-echo images were obtained. Brain maturation was evaluated on both T1-weighted and T2-weighted images to compare the degree and extent of myelination by using age-appropriate MRI criteria.8-11 The following marker sites were used: cerebellar peduncles, posterior limbs of the internal capsule, central corona radiata (term), optic radiations (6 months), genu splenium of the corpus callosum (1 year), anterior limb of the internal capsule (1 year), and deep white matter of the cerebral hemispheres (2 years). Myelinated white matter is T1 hyperintense and T2 hypointense on MRI.
Assessment of Myelination Magnetic resonance imaging of the brain was performed in all infants by using a 1.5 Tesla System (General Electric Medical Systems, Milwaukee, Wis.). Parameters of which images were obtained included 5 mm section-thickness, 256 × 192 matrix, and 24 cm field of views for sagittal T1-weighted conventional spin-echo images (TR 600 msec, TE 20 msec, NEX 2.0), fast spinecho axial proton density (TR 2000 msec, TE 20 msec, echo train length 4.0), and T2 (TR 3200 msec, TE 85 msec, echo train length 8.0) images.
RESULTS Case Reports CASE 1. This girl was born after a normal pregnancy and weighed 7 lbs, 15 oz. Multiple hemangiomas of the liver were documented shortly after birth. She was initially treated with prednisone for several weeks, followed by IFN therapy from 5 weeks to 10 months. She had cardiac decompensation (caused by liver hemangiomas) at age 4 months and had
THE JOURNAL OF PEDIATRICS Volume 132, Number 3, Part 1 a brief cardiorespiratory arrest without observable change in neurologic function after the incident. By age 12 months the intrahepatic hemangiomas were reduced in size, and by age 2 years MRI showed few residual liver tumors. She had good head control at 1 month, was transferring hand to hand at 6 months, and had pincer grasp at 11 months. At age 10 months her family and the physiotherapist noted increased tone in the legs, at which time IFN was discontinued. She sat alone and was able to stand at 11 to 12 months. Neurologic examination at 12 months found her to be alert with good upper extremity function. There was increased muscle tone in the legs with bilateral well-developed extensor plantar responses. With vertical suspension legs and toes showed abnormal extension, indicating spastic diplegia of moderate degree. MRI at 12 months showed a normal spinal cord; however, brain myelination was estimated at the 6-month level. By 17 months she was walking with a walker and was using a number of words and two-word phrases. At age 2 years she had normal verbal development for age, but she continued to require a walker to ambulate. Repeat MRI at age 17 months showed normal myelination for age.
CASE 2. This girl was born weighing 8 lbs, 6 oz. Nascent hemangioma involving the left side of the face, pharynx, scalp, and posterior neck was apparent at birth, and at 2 weeks the hemangiomas began to grow rapidly with ulceration; laser therapy was unsuccessful. IFN was administered from age 3 months to age 10 months. The hemangioma responded well and has continued to fade over time. Verbal and cognitive development were normal, as were early gross motor milestones (sat at 7 to 8 months, stood with support at 9 to 10 months). However, walking alone was delayed to 17 months, and balance was poor to age 2 years. Her parents stated that she tended to drag her toes. She was seen for neurologic evaluation by a pediatric neurologist at 27 months, and spasticity involving the legs (diplegia) was noted. When examined at age 35 months, her cognition, speech, cranial
BARLOW
nerves, and upper extremities were normal; her legs demonstrated exaggerated reflexes, increased adductor tone, and bilateral extensor plantar responses. On walking, she toed-in with a tendency to walk on her toes. Results of MRI of the head were normal at 3 1/2 months, 14 months, and 28 months; ventricular size was normal. Magnetic resonance angiography showed a slightly smaller right carotid artery. Results of spinal MRI at age 28 months were normal.
CASE 3. This girl was delivered normally and weighed 7 lbs, 2 oz at birth; Macular facial hemangioma was apparent at birth, and later, tumors appeared on the chest wall, mediastinum, and small bowel. Initial treatment with prednisone was unsuccessful. IFN was discontinued at 2 years, 9 months.6 She was hypotonic and irritable during the first 6 months, at which time gross motor function was delayed. By 12 months she was able to sit alone, and tendon reflexes were normal with a flexor plantar response. Fine motor function was normal, and she had a pincer grasp at age 9 months. Her development was thought to be appropriate until the age of 2 years. She was able to stand at 18 months and was cruising at 2 years. By age 3 years expressive speech was clearly delayed, but receptive abilities were close to normal. By this time it was apparent that she had spastic diplegia involving the legs. At age 4 years she continued to require a walker and had evidence of significant motor speech delay. MRI at age 20 months showed slightly prominent subarachnoid spaces and ventricles but no abnormality of the brain parenchyma including myelination. At age 3 years MRI of the head and spinal cord showed no abnormality.
CASE 4. This girl was born after an uncomplicated term pregnancy and delivery with birth weight of 8 lbs, 12 oz. She had a large ecchymotic tumor in her right groin and perineum with complicating thrombocytopenia (KasabachMerritt phenomenon). She was treated at age 3 1/2 months with corticosteroids resulting in an increase in platelet count and softening of the mass. Rebound
ET AL.
growth occurred when the steroids were discontinued, at which point she was treated with IFN from 9 to 15 months, including a 4-day course of cytoxan at 11 months, resulting in gradual resolution of the tumor and correction of the coagulopathy. When seen for neurologic evaluation at 9 months, she had a right femoral compression neuropathy with absent knee jerk and quadriceps weakness accompanied by hip and leg pain. By 12 months the femoral neuropathy was much improved coincident with shrinkage of the tumor. She had begun to sit alone and to stand with support at 11 1/2 months. Reflexes and muscle tone in the legs were normal. At 15 months she showed no evidence of the femoral neuropathy, but reflexes in the legs were now overactive with increased tone in the adductors and quadriceps, bilateral unsustained ankle clonus, and extensor plantar responses. While suspended, her legs were stiffly extended, and her toes adopted an extensor posture. IFN was discontinued. When seen at age 18 months, she continued to demonstrate the signs of diplegia but had been crawling and cruising (up on toes) since the age of 17 months. She walked alone at 20 months. When seen at 31 months, she was walking and running with scarcely detectable abnormality of gait. Reflexes in the legs were brisk, and she had bilateral extensor plantar responses. She had a full vocabulary for her age and was speaking in sentences. MRI at 15 months showed slightly delayed myelination estimated to be less than 12 months but with normal brain parenchymas. Repeat MRI at 18 months, however, showed normal myelination.
CASE 5. This term girl was born after a normal pregnancy and delivery weighing 6 lbs. She had multiple cutaneous and liver hemangiomas and was first seen at 1 month with anemia and thrombocytopenia. She was treated with corticosteroids without success. Because of enlarging liver lesions and congestive heart failure, IFN was begun at age 4 months (Table). At 8 months the mother expressed concern that her child seemed to have lost certain motor abilities; that is, she had less effective pincer grasp and 529
BARLOW
ET AL.
increased fisting, although she was now able to sit with support. The only clearly abnormal neurologic sign was abnormal extension of the legs with extension of the toes on vertical suspension. Because her liver hemangioma had regressed, IFN was discontinued at 8 months. At 10 1/2 months her mother stated that she had “regained everything” and was able to sit without support, although she had strabismus. She had begun to walk alone at 13 months and was speaking in twoword phrases at 18 months. Results of MRI at ages 11 months and 23 months were entirely normal.
DISCUSSION These five children all demonstrated signs of spastic diplegia during the course of treatment with IFN. Other risk factors were not convincing as a possible cause for diplegia; however, all were young infants at the time IFN was begun with the attendant ambiguity regarding neurologic status. A well-known consequence of several significant systemic illnesses, nonspecific motor delay does not account for the observed diplegia. Specific risk factors such as maternal toxemia were present in two of our patients; in both instances the risk factors were mild and regarded to be of minor significance. Case 3 had airway compromise and cardiac decompensation, cases 4 and 5 also had high output cardiac failure, and case 1 had a brief period of cardiac arrest. However, we believe that none of these risk factors was sufficient to account for their neurologic disability. Moreover, none of the MRIs showed increased T2 signal or small cysts suggestive of periventricular leucomalacia or other anoxic ischemic lesions in the brain parenchyma. In three infants (cases 1, 2, and 3) diplegia was persistent and functionally significant. In two infants (cases 4 and 5) diplegia improved after IFN was discontinued. Other more subtle neurologic abnormalities may become apparent during later follow-up of these patients. MRI showed structurally normal brain and spinal cord in all patients. In two patients (cases 1 and 4) early stud530
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ies demonstrated delayed myelination. Later studies, after discontinuance of IFN, showed normally developed myelin. These findings suggest that an adverse effect of IFN may be delayed myelination, although this finding was not noted in all patients. The MRI may not have been done at the critical stage to be most revealing. Furthermore, the range of normal myelination is not fully established, and the observed delay may not be significant or may represent nonspecific changes in chronically ill infants. Our findings take on added significance in light of the single previous case report.5 This child was treated with “human leukocyte interferon.” The initial dose was 3 million units daily (intramuscularly), which produced a febrile reaction and granulocytopenia. After 12 days the dose was reduced to 2 million units for 18 days, followed by 2 million units every other day. At age 2 years, 7 months the patient ceased walking upright and began to “move on all fours.” IFN was reduced further to 1 million units every 2 days, and walking improved. Interferon was discontinued after a total treatment period of 11 months. There was no progression after discontinuing IFN, but signs of diplegia remained for the 1 year of reported follow-up. Cerebrospinal fluid and results of electroencephalography, brain and spinal cord computed axial tomography, and myelography were all normal. The authors suggested a causal relationship between IFN administration and spastic diplegia and the need for caution in prolonged IFN therapy in young children.5 Careful clinical assessment of neurodevelopmental status, especially motor development, is necessary in IFN treated infants. Any abnormality should be assessed for etiologic factors by MRI of the brain and spinal cord. If no abnormality is found, whether or not delayed myelination is present, serious consideration should be given to discontinuing IFN therapy. This decision should be balanced against the risk of morbidity or death associated with the hemangioma. This poses a very difficult dilemma, occasionally resolved in favor of continuing therapy, but at a lower dose, if possible.
PEDIATRICS MARCH 1998
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There is no indication that the dose of IFN in the range we have used is a key factor in the pathogenesis of diplegia. It is apparent that there is the potential for reversibility, as exemplified by cases 4 and 5. In both, the diplegia was minor and resolved within several months after IFN was discontinued. We appreciate the assistance of our colleagues, house officers, and nurses of the General Clinical Research Center at Children’s Hospital, Boston, Massachusetts.
REFERENCES 1. Adams F, Fernandez F, Maviligit G. Interferon-induced organic mental disorders associated with unsuspected preexisting neurologic abnormalities. J Neuro Onc 1988;6:355-9. 2. Meyers CA, Scheibel MA, Forman AD. Persistent toxicity of systemically administered interferon-alpha. Neurology 1991;41:672-6. 3. Smedley H, Katrak M, Sikora K, Sheeler T. Neurological effects of recombinant human interferon. BMJ 1983;286:262-4. 4. Bernson PLJA, Chung EW, Vingerhoets HM, Janssen JTP. Bilateral neuralgic amyotrophy induced by interferon treatment. Arch Neurol 1988;45:449-51. 5. Vesikari T, Nuutila A, Cantell K. Neurologic sequellae following interferon therapy of juvenile laryngeal papilloma. Acta Paediatr Scand 1988;77:61922. 6. Ezekowitz RAB, Mulliken JB, Folkman J. Inteferon alfa-2a therapy for lifethreatening hemangiomas of infancy. N Engl J Med 1992;326:1456-63; Ibid Corrections. 1994;330:300; Ibid additional corrections. 1995;333:395-6. 7. Paine RS. Neurologic examination of infants and children. In: Pediatric clinics of North America. Philadelphia: WB Saunders Company; 1960. p. 471-88. 8. Vander Knapp MS, Valk J. MR imaging of the various stages of normal myelination during the first year of life. Neuroradiol 1990;31:459-70. 9. Barkovich AJ, Kjos BO, Jackson De, Jr, Norman D. Normal maturation of the neonatal and infant brain imaging at 1.5 Tesla. Radiology 1988;166:173-80. 10. Bird CR, Hedberg M, Drayer BP, Keller PJ, Flom RA, Hodak JA, et al. MR assessment of myleination in infants and children: usefulness of marker sites. AJNR 1989;11:731-40. 11. Squires LA, Krishnamoorthy KS, Natowicz MR. Delayed myelination in infants and young children: radiographic and clinical correlates. J Child Neurol 1955;10:100-10.
Spastic diplegia as a complication of interferon Alfa-2a treatment of hemangiomas of infancy
Charles F. Barlow, MD, Cedric J. Priebe, MD, John B. Mulliken, MD, Patrick D. Barnes, MD, Dorothy Mac Donald, RN, Judah Folkman, MD, and R. Alan B. Ezekowitz, MB, ChB, DPhil
We report the development of spastic diplegia in infants during the course of interferon Alfa-2a (IFN) therapy for potentially life-endangering hemangiomas. Five infants who displayed diplegia were selected from a group of 26 infants treated with IFN. Diplegia persisted in three infants, and in the remaining two significant recovery occurred after IFN was discontinued. Magnetic resonance imaging showed no significant brain or spinal abnormalities except minor to moderate delayed myelination in two patients. Myelination was normal on subsequent radiographic examination in all five patients. We conclude that IFN can adversely affect the immature central nervous system and produce spastic diplegia, which is potentially reversible. We recommend careful clinical assessment of neurodevelopmental status during IFN therapy. (J Pediatr 1998;132:527-30)
threatening complications such as obstruction to vision; distortion of a vital structure, eye, or lip; or extensive loss of tissue. Lesions were considered to be life-threatening if we believed that the patient would not survive long enough for the hemangioma to reach a natural stage of regression (hemangiomas of the liver, heart, and brain and those accompanied by thrombocytopenic coagulopathy and/or heart failure). IFN MRI
Adult patients treated with interferon-α have shown reversible changes in higher level cortical function and lesser adverse effects on the motor system; several have had Parkinsonian extrapyramidal signs.1,2 One reported patient had an “upper motor neuron” syndrome involving the legs.3 Neuropathy has also been recorded,2,4 indicating that several levels of neurologic function can be affected. There is, in addition, a well-documented case of a 2-year-old patient treated with “human leukocyte interferon” for laryngeal papilloma who had diplegia during therapy.5 In an ongoing study we have monitored a large number of infants treated with interferon Alfa-2a for hemangiomas of infancy. We have found that
periodic behavioral observations are not sufficiently discriminatory to reveal any leg-related handicaps in young children. In one child who was first seen with an unrelated neurologic complaint, the signs and symptoms of diplegia were identified; we then suspected that diplegia may be an IFN-related toxicity.
METHODS Our study population consisted of infants referred for management of endangering and life-threatening hemangiomas; most of these infants had not responded to corticosteroid therapy. We defined endangering tumors as those causing severe but not necessarily life-
From the Departments of Neurology, Medicine, Surgery, Radiology, Division of Plastic Surgery, Children’s Hospital, Boston, Massachusetts; the Pediatric Service, Massachusetts General Hospital, Boston; and the Departments of Neurology, Pediatrics, and Surgery, Harvard Medical School, Boston, Massachusetts. Supported by National Institutes of Health grant M01 RR02172. Submitted for publication July 30, 1996; accepted June 4, 1997. Reprint requests: Alan Ezekowitz, MB, ChB, DPhil, Pediatric Service, Massachusetts General Hospital, Boston, MA 02114. Copyright © 1998 by Mosby, Inc. 0022-3476/98/$5.00 + 0 9/22/83754
Interferon Alfa-2a Magnetic resonance imaging
The data consist of standard clinical history and results of examination presented as brief case reports. Patients with other potential causes of neurologic lesions of the brain or spinal cord were excluded. Two premature infants who had unexplained diplegia and one infant with intraspinal extension of a hemangioma that displaced but did not compress the spinal cord were excluded. We also excluded patients if there was little ambiguity that factors other than IFN were responsible; one child suddenly had diplegia 12 hours after undergoing therapeutic embolization of a paravertebral abdominal hemangioma, presumably caused by spinal cord embolus. Another child had demonstrable quadriparesis before being treated with IFN; computed tomography showed significant cerebral atrophy, and although the patient was thrombocytopenic, he had a large subdural hematoma. All patients in the series had periodic behavioral evaluations; 26 had careful neurologic examination, and of those, 5 were documented to have diplegia (Table). Neurologic examination (C. F. 527
BARLOW
ET AL.
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PEDIATRICS MARCH 1998
OF
Table. Summary of interferon dosage
Birth weight
Duration of therapy
Cumulative dose (million units)
Maximum daily dose (million/units/day)
Diplegia status (age)
Case 1 (female, twin A)
7 lbs, 15 oz
5 wk to 10 mo
279.66
1.02
No recovery (10 mo)
Case 2 (female)
8 lbs, 6 oz
3 mo to 10 mo
322.20
2.10
No recovery (2 yr)
Case 3 (female)
7 lbs, 2 oz
2.5 mo to 33 mo
1946.04
3.60
No recovery (3 yr)
Case 4 (female)
8 lbs, 12 oz
3.5 mo to 15 mo
321.30
1.80
Recovery (15 mo)
Case 5 (female)
6 lbs, 0 oz
4 mo to 8 mo
253.86
2.70
Recovery (8 mo)
B.) was incorporated into the follow-up evaluation of two cases; both had come to neurologic attention for reasons other than diplegia at 9 months (case 4) and 7 months (case 5), respectively. Neurologic follow-up examination of these patients brought our attention to the possibility of diplegia as a complication of IFN therapy. Cases 1 (12 months), 2 (27 months), and 3 (15 months) were evaluated retrospectively. We have found that observation of the suspended posture of these infants has been most useful in detecting early diplegia. The normal posture in suspension is flexion at the knee with moderate flexion and external rotation at the hip. Toes are neutral. The infant must be relaxed, and this is often achieved by asking the mother to lift the child at the axilla. Abnormal posture consists of adduction at the hip; the knees become extended with legs parallel. Scissoring is a sign of advanced diplegia.6 The great toe is usually extended, and the other toes fan out.
IFN Administration of IFN was initiated according to our standard protocol.7 Treatment, which ranged from 6 to 29 months, was discontinued when indica528
tions for therapy had resolved and further hemangiomatous proliferation was regarded as unlikely or significant adverse reaction to therapy became apparent.
Informed Consent As soon as we became aware that IFN therapy might be associated with spastic diplegia, we amended the informed consent document. We also reported this adverse event to the Food and Drug Administration and to Hoffmann La Roche. The study was approved by the Institutional Review Board of the Children’s Hospital in Boston, Massachusetts.
Coronal T2-weighted fast spin-echo images were obtained. Brain maturation was evaluated on both T1-weighted and T2-weighted images to compare the degree and extent of myelination by using age-appropriate MRI criteria.8-11 The following marker sites were used: cerebellar peduncles, posterior limbs of the internal capsule, central corona radiata (term), optic radiations (6 months), genu splenium of the corpus callosum (1 year), anterior limb of the internal capsule (1 year), and deep white matter of the cerebral hemispheres (2 years). Myelinated white matter is T1 hyperintense and T2 hypointense on MRI.
Assessment of Myelination Magnetic resonance imaging of the brain was performed in all infants by using a 1.5 Tesla System (General Electric Medical Systems, Milwaukee, Wis.). Parameters of which images were obtained included 5 mm section-thickness, 256 × 192 matrix, and 24 cm field of views for sagittal T1-weighted conventional spin-echo images (TR 600 msec, TE 20 msec, NEX 2.0), fast spinecho axial proton density (TR 2000 msec, TE 20 msec, echo train length 4.0), and T2 (TR 3200 msec, TE 85 msec, echo train length 8.0) images.
RESULTS Case Reports CASE 1. This girl was born after a normal pregnancy and weighed 7 lbs, 15 oz. Multiple hemangiomas of the liver were documented shortly after birth. She was initially treated with prednisone for several weeks, followed by IFN therapy from 5 weeks to 10 months. She had cardiac decompensation (caused by liver hemangiomas) at age 4 months and had
THE JOURNAL OF PEDIATRICS Volume 132, Number 3, Part 1 a brief cardiorespiratory arrest without observable change in neurologic function after the incident. By age 12 months the intrahepatic hemangiomas were reduced in size, and by age 2 years MRI showed few residual liver tumors. She had good head control at 1 month, was transferring hand to hand at 6 months, and had pincer grasp at 11 months. At age 10 months her family and the physiotherapist noted increased tone in the legs, at which time IFN was discontinued. She sat alone and was able to stand at 11 to 12 months. Neurologic examination at 12 months found her to be alert with good upper extremity function. There was increased muscle tone in the legs with bilateral well-developed extensor plantar responses. With vertical suspension legs and toes showed abnormal extension, indicating spastic diplegia of moderate degree. MRI at 12 months showed a normal spinal cord; however, brain myelination was estimated at the 6-month level. By 17 months she was walking with a walker and was using a number of words and two-word phrases. At age 2 years she had normal verbal development for age, but she continued to require a walker to ambulate. Repeat MRI at age 17 months showed normal myelination for age.
CASE 2. This girl was born weighing 8 lbs, 6 oz. Nascent hemangioma involving the left side of the face, pharynx, scalp, and posterior neck was apparent at birth, and at 2 weeks the hemangiomas began to grow rapidly with ulceration; laser therapy was unsuccessful. IFN was administered from age 3 months to age 10 months. The hemangioma responded well and has continued to fade over time. Verbal and cognitive development were normal, as were early gross motor milestones (sat at 7 to 8 months, stood with support at 9 to 10 months). However, walking alone was delayed to 17 months, and balance was poor to age 2 years. Her parents stated that she tended to drag her toes. She was seen for neurologic evaluation by a pediatric neurologist at 27 months, and spasticity involving the legs (diplegia) was noted. When examined at age 35 months, her cognition, speech, cranial
BARLOW
nerves, and upper extremities were normal; her legs demonstrated exaggerated reflexes, increased adductor tone, and bilateral extensor plantar responses. On walking, she toed-in with a tendency to walk on her toes. Results of MRI of the head were normal at 3 1/2 months, 14 months, and 28 months; ventricular size was normal. Magnetic resonance angiography showed a slightly smaller right carotid artery. Results of spinal MRI at age 28 months were normal.
CASE 3. This girl was delivered normally and weighed 7 lbs, 2 oz at birth; Macular facial hemangioma was apparent at birth, and later, tumors appeared on the chest wall, mediastinum, and small bowel. Initial treatment with prednisone was unsuccessful. IFN was discontinued at 2 years, 9 months.6 She was hypotonic and irritable during the first 6 months, at which time gross motor function was delayed. By 12 months she was able to sit alone, and tendon reflexes were normal with a flexor plantar response. Fine motor function was normal, and she had a pincer grasp at age 9 months. Her development was thought to be appropriate until the age of 2 years. She was able to stand at 18 months and was cruising at 2 years. By age 3 years expressive speech was clearly delayed, but receptive abilities were close to normal. By this time it was apparent that she had spastic diplegia involving the legs. At age 4 years she continued to require a walker and had evidence of significant motor speech delay. MRI at age 20 months showed slightly prominent subarachnoid spaces and ventricles but no abnormality of the brain parenchyma including myelination. At age 3 years MRI of the head and spinal cord showed no abnormality.
CASE 4. This girl was born after an uncomplicated term pregnancy and delivery with birth weight of 8 lbs, 12 oz. She had a large ecchymotic tumor in her right groin and perineum with complicating thrombocytopenia (KasabachMerritt phenomenon). She was treated at age 3 1/2 months with corticosteroids resulting in an increase in platelet count and softening of the mass. Rebound
ET AL.
growth occurred when the steroids were discontinued, at which point she was treated with IFN from 9 to 15 months, including a 4-day course of cytoxan at 11 months, resulting in gradual resolution of the tumor and correction of the coagulopathy. When seen for neurologic evaluation at 9 months, she had a right femoral compression neuropathy with absent knee jerk and quadriceps weakness accompanied by hip and leg pain. By 12 months the femoral neuropathy was much improved coincident with shrinkage of the tumor. She had begun to sit alone and to stand with support at 11 1/2 months. Reflexes and muscle tone in the legs were normal. At 15 months she showed no evidence of the femoral neuropathy, but reflexes in the legs were now overactive with increased tone in the adductors and quadriceps, bilateral unsustained ankle clonus, and extensor plantar responses. While suspended, her legs were stiffly extended, and her toes adopted an extensor posture. IFN was discontinued. When seen at age 18 months, she continued to demonstrate the signs of diplegia but had been crawling and cruising (up on toes) since the age of 17 months. She walked alone at 20 months. When seen at 31 months, she was walking and running with scarcely detectable abnormality of gait. Reflexes in the legs were brisk, and she had bilateral extensor plantar responses. She had a full vocabulary for her age and was speaking in sentences. MRI at 15 months showed slightly delayed myelination estimated to be less than 12 months but with normal brain parenchymas. Repeat MRI at 18 months, however, showed normal myelination.
CASE 5. This term girl was born after a normal pregnancy and delivery weighing 6 lbs. She had multiple cutaneous and liver hemangiomas and was first seen at 1 month with anemia and thrombocytopenia. She was treated with corticosteroids without success. Because of enlarging liver lesions and congestive heart failure, IFN was begun at age 4 months (Table). At 8 months the mother expressed concern that her child seemed to have lost certain motor abilities; that is, she had less effective pincer grasp and 529
BARLOW
ET AL.
increased fisting, although she was now able to sit with support. The only clearly abnormal neurologic sign was abnormal extension of the legs with extension of the toes on vertical suspension. Because her liver hemangioma had regressed, IFN was discontinued at 8 months. At 10 1/2 months her mother stated that she had “regained everything” and was able to sit without support, although she had strabismus. She had begun to walk alone at 13 months and was speaking in twoword phrases at 18 months. Results of MRI at ages 11 months and 23 months were entirely normal.
DISCUSSION These five children all demonstrated signs of spastic diplegia during the course of treatment with IFN. Other risk factors were not convincing as a possible cause for diplegia; however, all were young infants at the time IFN was begun with the attendant ambiguity regarding neurologic status. A well-known consequence of several significant systemic illnesses, nonspecific motor delay does not account for the observed diplegia. Specific risk factors such as maternal toxemia were present in two of our patients; in both instances the risk factors were mild and regarded to be of minor significance. Case 3 had airway compromise and cardiac decompensation, cases 4 and 5 also had high output cardiac failure, and case 1 had a brief period of cardiac arrest. However, we believe that none of these risk factors was sufficient to account for their neurologic disability. Moreover, none of the MRIs showed increased T2 signal or small cysts suggestive of periventricular leucomalacia or other anoxic ischemic lesions in the brain parenchyma. In three infants (cases 1, 2, and 3) diplegia was persistent and functionally significant. In two infants (cases 4 and 5) diplegia improved after IFN was discontinued. Other more subtle neurologic abnormalities may become apparent during later follow-up of these patients. MRI showed structurally normal brain and spinal cord in all patients. In two patients (cases 1 and 4) early stud530
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ies demonstrated delayed myelination. Later studies, after discontinuance of IFN, showed normally developed myelin. These findings suggest that an adverse effect of IFN may be delayed myelination, although this finding was not noted in all patients. The MRI may not have been done at the critical stage to be most revealing. Furthermore, the range of normal myelination is not fully established, and the observed delay may not be significant or may represent nonspecific changes in chronically ill infants. Our findings take on added significance in light of the single previous case report.5 This child was treated with “human leukocyte interferon.” The initial dose was 3 million units daily (intramuscularly), which produced a febrile reaction and granulocytopenia. After 12 days the dose was reduced to 2 million units for 18 days, followed by 2 million units every other day. At age 2 years, 7 months the patient ceased walking upright and began to “move on all fours.” IFN was reduced further to 1 million units every 2 days, and walking improved. Interferon was discontinued after a total treatment period of 11 months. There was no progression after discontinuing IFN, but signs of diplegia remained for the 1 year of reported follow-up. Cerebrospinal fluid and results of electroencephalography, brain and spinal cord computed axial tomography, and myelography were all normal. The authors suggested a causal relationship between IFN administration and spastic diplegia and the need for caution in prolonged IFN therapy in young children.5 Careful clinical assessment of neurodevelopmental status, especially motor development, is necessary in IFN treated infants. Any abnormality should be assessed for etiologic factors by MRI of the brain and spinal cord. If no abnormality is found, whether or not delayed myelination is present, serious consideration should be given to discontinuing IFN therapy. This decision should be balanced against the risk of morbidity or death associated with the hemangioma. This poses a very difficult dilemma, occasionally resolved in favor of continuing therapy, but at a lower dose, if possible.
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There is no indication that the dose of IFN in the range we have used is a key factor in the pathogenesis of diplegia. It is apparent that there is the potential for reversibility, as exemplified by cases 4 and 5. In both, the diplegia was minor and resolved within several months after IFN was discontinued. We appreciate the assistance of our colleagues, house officers, and nurses of the General Clinical Research Center at Children’s Hospital, Boston, Massachusetts.
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