Blindness in Children with Neuroblastoma

1997 Blindness in Children with Neuroblastoma Asim F. Belgaumi, M.D. William M. Kauffman, M.D.1 Jesse J. Jenkins, M.D.2,3 Jose Cordoba, M.D.4 Laura C...
Author: Roger Porter
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1997

Blindness in Children with Neuroblastoma Asim F. Belgaumi, M.D. William M. Kauffman, M.D.1 Jesse J. Jenkins, M.D.2,3 Jose Cordoba, M.D.4 Laura C. Bowman, M.D.5 Victor M. Santana, M.D.5 Wayne L. Furman, M.D.5

BACKGROUND. Neuroblastoma is the most common extracranial solid tumor among pediatric patients, and orbital metastatic disease is not uncommon in these children. Physical signs as a consequence of orbital metastases, such as proptosis and periorbital ecchymosis, frequently are encountered. However, subsequent blindness is rare.

METHODS. A retrospective study was conducted to determine the incidence, related physical findings, treatment, and outcome of children who developed visual loss

1

Department of Diagnostic Imaging, St. Jude Children’s Research Hospital, Memphis, Tennessee. 2

Department of Pathology and Laboratory Medicine, St. Jude Children’s Research Hospital, Memphis, Tennessee. 3

Department of Pathology, University of Tennessee, Memphis, Tennessee. 4

Fundacao Hospitalar do Distrito Federal Hospital de Base de Brasilia Unidade de Pediatria, Brasilia, Brazil. 5

Department of Pediatrics, University of Tennessee, Memphis, Tennessee.

during treatment for neuroblastoma. Medical records for a 24-year period (1971– 1994) were reviewed to identify these patients. The charts, diagnostic imaging studies, and autopsy material of these patients were reviewed. RESULTS. Of the 450 patients treated for neuroblastoma at the study institution during this period, 47 presented with abnormalities in physical examination of the eye. Eight of these 47 patients and 7 others developed visual loss in at least 1 eye during the first week after diagnosis (n Å 5), during primary therapy (n Å 6), at recurrence (n Å 2), or after completion of therapy (n Å 2). In ten patients the visual loss was a direct consequence of the primary disease process, whereas a direct relationship between loss of vision and neuroblastoma could not be identified in the remaining five patients. Proptosis and periorbital ecchymosis were the most common associated physical findings. Although ten patients received steroids and eight received radiation, visual loss could not be prevented or reversed in these patients. CONCLUSIONS. Early initiation of effective, multiagent chemotherapy remains the primary approach for the treatment of neuroblastoma and its ophthalmologic complications. Radiation therapy and steroids may have benefit but failed to show good effect in this series. The prevention and treatment of blindness is probably most relevant in infants and children age õ 2 years because they have the best chance for cure. Cancer 1997;80:1997–2004. q 1997 American Cancer Society.

Dr. Belgaumi’s current address: P.O. Box 3354, MBC 64ONC, Riyadh 11211 Saudi Arabia.

KEYWORDS: neuroblastoma, blindness, orbital metastasis, ophthalmologic findings, proptosis, periorbital ecchymosis.

Supported in part by P30 CA-21765, CA-23099, and the American Lebanese Syrian Associated Charities (ALSAC).

N

The authors thank Dr. Judith Wilimas for her critical appraisal of the article and numerous invaluable comments and suggestions, Amy Frazier for editorial assistance, and Imella Herrington for preparation of the article. Address for reprints: Wayne L. Furman, M.D., Department of Hematology/Oncology, St. Jude Children’s Research Hospital, 332 North Lauderdale, Memphis, TN 38105-2794. Received February 6, 1997; revision received May 30, 1997; accepted May 30, 1997.

euroblastoma is the most common extracranial solid tumor of childhood, accounting for 8 – 10% of all childhood cancers. It may originate in the adrenal gland or at any site along the sympathetic nervous system chain.1 Most patients present with widely disseminated disease,2 and the presenting signs and symptoms depend on the anatomic site(s) involved. Ophthalmic manifestations are common and frequently are a result of periorbital soft tissue infiltration of tumor, producing proptosis and periorbital hematoma or ecchymosis (panda bear eyes or raccoon eyes).3 – 8 Other ocular manifestations include Horner’s syndrome, anisocoria, heterochromia iridis,9 displacement of the globe, convergent strabismus, fixed and dilated pupils, edema, atrophy of the optic nerve heads, retinal edema,3 and opsoclonus/myoclonus (dancing eyes, dancing feet).10,11 Despite ocular involvement, blindness in patients

q 1997 American Cancer Society

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TABLE 1 Clinical Characteristics, Treatment, and Outcome of Patients with Neuroblastoma and Blindness Blindnessa

Gender

Ophthalmic signs with blindness

Site

Dayb

Chemotherapy protocol

Stage POG INSS

R adrenal

M

P, Hem

R

0

NB77

D

IV

67

L adrenal

F



D

IV

28 22 4

Thorax L adrenal L adrenal

F M F

P, PE P, CNVI PE

0 0 0 0 3



3 4 5

R L R L R

NB79 NB84 POG9243

D D D

IV IV IV

Orbits Skull base Sphenoid wings

6

25

R adrenal

M

Hem

D

IV



5 6

R neck L adrenal

M F

P, CNVI, H CNVI, Hem

3 140 140 418 21

NB68

7 8

L R L R L

NB74 NB74

D D

IV IV

9

63

Unknown

F

PE

R L

272c 277

NB77

D

IV

10 11 12

15 11 54

L adrenal Thorax L adrenal

M M F

P, PE P, PE, CNVI PE

D D D

IV IV IV

13

R adrenal

M

P

NB79

D

IV



14

14

R adrenal

M

P, Pup n.

485 221 68 68 188 188 23

NB79 NB79 —

13

R R R L R L R

— Skull Left orbit Skull Midplain chiasm — — —

NB79

D

IV

15

32

L adrenal

F

P, PE, CNVI

R

386c

NB79

D

IV

Skull Right orbit Skull

Patient no.

Age (mos)

Primary site

1

47

2

Site

Radiation to orbits/ skull Dose (cGy)

Midplain skull —

1400 600

1800 800 2100 800

2000 800 2000

Steroid therapy

Outcome

No

DOD, 5 mos

No

DOD, 0.5 mos

Yes Yes Yes

DOD, 8 mos DOD, 2.4 yrs NED, 2.5/ yrs

Yes

DOD, 8 mos

No Yes

NED, 20/ yrs DOD, 2.8 yrs

Yes

DOD, 10 mos

No No No

NED, 15/ yrs NED, 13/ yrs DOD, 3 mos

Yes

DOD, 7 mos

Yes

DOD, 8 mos

Yes

DOD, 2 yrs

F: female; M: male; L: left eye; R: right eye; DOD: died of disease; NED: no evidence of disease; P: proptosis; PE: periorbital ecchymosis; CNVI: cranial nerve VI paralysis; Hem: Vitreous or retinal hemorrhage; Pup n: pupilary nerve paralysis; H: Horner’s syndrome; POG: Pediatric Oncology Group; INSS: International Neuroblastoma Staging System; cGy: centigrays. a Due to vitreous hemorrhage in Patient 10 and cytomegalovirus retinitis in Patient 11; due to direct or indirect effect of neuroblastoma on ophthalmic or orbital structures in other patients. b After presentation; Day 0 indicates patient presented with blindness. c Patients presented at time of recurrence after completing initial therapy.

with neuroblastoma is very unusual.3,6,7,12 – 14 An infant who became blind at presentation despite intervention with high dose steroids, local radiation therapy, and systemic chemotherapy prompted the authors to examine their hospital records to determine the clinical presentation, frequency, natural history, and outcome of this unusual complication of neuroblastoma.

PATIENTS AND METHODS Between January 1971 and December 1994, 450 patients with neuroblastoma were seen and treated at St. Jude Children’s Research Hospital. The medical records were reviewed to determine the frequency of signs or symptoms related to the eye at initial presentation as well as the frequency of blindness developing at any time during the course of their disease. The clinical staging procedures at diagnosis differed over the years, but were standard for the particular era. The diagnosis was confirmed in all patients by

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histopathologic examination of the primary tumor or by its bone marrow metastasis. Chemotherapy for these 15 children who became blind varied over the 24 years of the study period. The patients were treated on five consecutive institutional protocols (NB68, NB74, NB77, NB79, and NB84) and one Pediatric Oncology Group (POG) protocol (POG9243); specifics of the therapy provided in the institutional protocols have been published.2 Patients received between 2 and 4 chemotherapeutic agents, which were administered over 3 – 10 months. The families of two patients declined any antineoplastic therapy for their children.

RESULTS Of the 450 patients diagnosed with neuroblastoma at St. Jude Children’s Research Hospital from January 1971 to December 1994, 47 presented with symptoms or signs related to the eye. Eight of these 47 patients

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Blindness in Neuroblastoma/Belgaumi et al. TABLE 2 Comparison of Eye Signs in Children with Neuroblastoma at Presentation and Eye Signs during their Disease Course in Children Who Developed Visual Loss

Proptosis Periorbital ecchymosis Horner’s syndrome Anisocoria Nystagmus Hemorrhage CNVI paralysis

Eye signs at presentation n Å 47 (%)

Eye signs in children with visual loss n Å 15 (%)

28 (59.6) 19 (40.4) 8 (17.0) 2 (4.3) 1 (2.1) 1 (2.1) 3 (6.4)

9 (60.0) 7 (46.7) 1 (6.7) 1 (6.7) 0 3 (20.0) 5 (33.3)

CNVI: cranial nerve VI.

and an additional 7 patients developed blindness in at least 1 eye at some point during their disease course. The clinical characteristics of the patients who had visual loss are summarized in Table 1. Presenting ophthalmologic signs in children with neuroblastoma and ophthalmologic signs that developed during the course of treatment in the children with a loss of vision are detailed in Table 2. Eight of the 35 children (22.9%) who presented with proptosis and/or periorbital ecchymosis eventually developed blindness, 4 within the first week of presentation. One patient developed right-sided blindness at the time of recurrence. He had recurrence of proptosis and periorbital ecchymosis at the time of his disease recurrence. The remaining three patients had loss of vision late in their course, and were still alive at last follow-up. Two of the three children who presented with sixth cranial nerve palsy developed blindness, whereas there was no visual loss observed among the six patients who had Horner’s syndrome as the only presenting orbital manifestation. There were no apparent differences between those patients who lost their eyesight and those who presented with ophthalmologic signs or symptoms in relation to age (mean age [range]: 27.1 months [range, 5 – 67 months] vs. 28.8 months [range, 0 – 189 months]) or primary site of tumor (adrenal primary in 11 of 15 patients vs. 30 of 47 patients). All 15 patients who developed visual loss had disseminated disease (International Neuroblastoma Staging System [INSS] Stage 4), whereas 4 of the 47 children who presented with abnormalities on physical examination of their eyes had INSS Stage 3 disease. All four of these patients had Horner’s syndrome as their only ophthalmologic manifestation of neuroblastoma. Four patients were blind at presentation, and another became blind 3 days after presentation. In one

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of these five patients no orbital/ophthalmic signs or symptoms accompanied the sudden onset of visual loss. Four of these patients received radiation therapy to the orbital metastases. Three of the patients who received radiation also were treated with steroids, whereas another patient received only steroids in an attempt at reversing the ophthalmic complications (Table 3). Transient, partial recovery of vision was observed only in one patient (Patient 4), who received both steroids and radiation but subsequently became blind due to disease progression. At last follow-up, one of these five patients was alive with no evidence of disease, at ú3 years from diagnosis. Ten patients developed blindness later in their disease course. Median time to visual loss in this group of patients was 204.5 days (range, 21 – 485 days). In five patients, the visual loss was related to disease progression (three patients) or recurrence (two patients). The two patients with a recurrence completed their chemotherapeutic regimens and had been off therapy with no active disease when they presented with orbital/ophthalmologic signs and blindness as a manifestation of their recurrence. Subsequent chemotherapy, radiation, and/or high dose steroids failed to restore vision in either of these patients. A sixth patient (Patient 8) developed a vitreous hemorrhage at Day 21 of therapy and subsequently became blind as this hemorrhage organized. The hemorrhage was associated with subarachnoid and intraventricular bleeding and was believed to be secondary to coagulopathy due to hepatic dysfunction. One other patient (Patient 6) lost his vision at Day 140, with disease progression refractory to therapy. However, at autopsy he was noted to have exudative, hemorrhagic retinitis, with retrobulbar optic neuritis suggestive of cytomegalovirus-induced retinitis. No evidence of neuroblastoma was observed within or in proximity to the orbits. Two patients had progressive loss of vision after completion of therapy for neuroblastoma. Fundoscopic examination of these patients showed optic atrophy with progressive pallor of the optic discs until vision was completely lost. Both of these patients (Patients 7 and 10) were alive with no evidence of disease at ú20 and 15 years after presentation, respectively. Patient 11 also developed a progressive decline in vision with similar ophthalmic findings. However, this occurred at Day 221, while he was still undergoing chemotherapy. He was alive at ú12 years after therapy, was blind in 1 eye, and had diminished vision in the other. Of these ten patients who developed blindness later in their disease course, six received steroids and four received radiation therapy, without any transient or permanent benefits in visual outcome (Table 3). In fact, two patients developed blindness while receiving

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TABLE 3 Relation of Radiation and Steroid Therapy with Onset of Blindness Radiation therapy

Early visual lossc Late visual loss

Steroid therapy

Early a

Lateb

Early a

Lateb

2 1

2 3

4 4

0 2

a

Before or within 48 hours of development of visual loss. Greater than 48 hours after development of visual loss. c Less than 7 days from initial presentation. b

steroids for worsening proptosis or for visual loss in the contralateral eye. The three patients who were long term survivors in this group received neither steroids nor radiation. Overall, 4 of these 15 patients were alive, with no evidence of disease, at a median of 13.5 years (range, 3 – 20 years) from presentation. Three of these four patients were infants (age õ 12 months) at diagnosis, whereas the remaining child was age 15 months. One patient was bilaterally blind, and the other three had unilateral blindness, with decreased visual acuity in the contralateral eye. The 11 patients who died of disease had a median survival time from diagnosis of 8 months (range, 0.5 – 34 months). Four of these patients were bilaterally blind at the time of death, and the other seven had unilateral blindness.

Autopsy Results Autopsies were performed on 5 of these 15 patients. Two patients (Patients 2 and 15) had bulky disease. Patient 2 had compression and replacement of both optic nerves and chiasm. In patient 15 the right optic nerve had been invaded by tumor, corresponding to visual loss in that eye. In addition, microscopic invasion by neuroblastoma was observed in the left optic nerve just proximal to the optic chiasm; no grossly visible disease or any visual deficit was detected on this side. Another patient (Patient 1) was found to have abnormal intrusion of the right optic nerve head into the vitreous body with tremendous choroidal ectasia occupying an estimated 50% of the choroid substance. This was associated with blindness in the ipsilateral eye. Retinal inflammatory changes with viral inclusions were noted in Patient 6, and a post-mortem diagnosis of cytomegalovirus retinitis was made. An additional patient (Patient 8) had no tumor observed within or in proximity to the orbits or optic structures. Dissection and examination of the globes was not conducted in this case.

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Diagnostic Imaging The radiographic studies used for the diagnosis of periorbital neuroblastoma evolved over the course of this retrospective study. Although 12 patients underwent plain roentgenograms of the skull and 5 patients underwent technetium 99m-methylene diphosphonate (99mTc-MDP) skeletal scintigraphy, the information derived from these studies was not found to be helpful in predicting visual loss or in identifying specific structures involved. Four patients underwent computed tomography (CT) scans and one patient underwent magnetic resonance imaging (MRI) of the head and brain. These studies provided much better anatomic distinction, and discernible abnormalities were observed in all five patients. Two patients (Patients 3 and 14) had massive disease arising from their lateral orbital walls, with encroachment on or proximity to the optic nerves. Both these patients had proptosis and became blind in the ipsilateral eye. One patient (Patient 10) (Fig. 1) had metastatic involvement of both orbits with soft tissue masses. This patient developed unilateral visual loss related to the smaller of the two masses. Another patient (Patient 4) had a soft tissue mass in only one of his orbits, but developed blindness in the contralateral eye. Proptosis and ecchymosis was documented on physical examination on the side of the radiographic lesion as well as the visually deficient eye. One patient (Patient 5) in this series underwent examination with an MRI, which identified metastatic involvement of the lesser wing of the sphenoid bone with compromise of the optic chiasm, optic tracts, and the optic nerves (Fig. 2). She had bilateral ecchymoses and proptosis and developed bilateral blindness consistent with her radiographic findings.

DISCUSSION Blindness in children with neuroblastoma usually is associated with widely disseminated disease. Because children age õ 1 year at diagnosis of neuroblastoma

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FIGURE 1.

An axial, uncontrasted computed tomography scan shows an epidural mass arising from the lateral wall of the left orbit (large black arrows). The mass abuts the left optic nerve, which is only observed faintly (small black arrows). There is also anterior displacement of the left globe. A similar, but smaller, mass arises from the right lateral orbital wall. However, it is not as near the optic nerve as the left orbital mass.

have a 4-year survival rate ú 80%,2 early recognition of impending visual problems in this group of patients and the initiation of effective therapy is important to prevent neuroblastoma-related blindness. Once blindness develops, it is irreversible, even in the face of responsive primary disease. Orbital metastatic involvement with neuroblastoma, presenting as proptosis and periorbital ecchymosis, is considered one of the classic signs of this disease.1 Large series examining orbital metastatic disease in children with neuroblastoma and other solid tumors have reported an incidence of between 20–40% for this complication in patients with neuroblastoma4,5; however, blindness has been described very rarely and only in reports of isolated cases.3,6,7,12–14 Any evidence of orbital metastatic disease places the patient at risk for developing blindness. Although proptosis was the most common associated ophthalmologic physical sign in the patients in the current study with visual loss (n Å 9), it was not significantly higher than the published incidence of this finding in neuroblastoma patients in general (21 – 53%).3,5 Proptosis is a result of an enlarging intraorbital mass lesion and an indication of mass effect on the optic nerves. Blindness in such a situation arises from physical compression and attenuation of the optic nerve(s)

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FIGURE 2.

(a) This gadolinium-contrasted, sagittal, T1-weighted magnetic resonance image of the brain shows a large enhancing mass arising from the lesser wing of the sphenoid bone (black arrow). The mass compromises the optic chiasm and proximal optic nerves. (b) In this axial T1-weighted, fat-saturated image with gadolinium contrast, the optic tract can be observed adjacent to the mass. The mass is observed encasing the more anterior component of the optic tract (white arrows in both figures).

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FIGURE 3.

(a) This figure shows the anterior surface of a coronal section of brain through the level of the anterior commissure and the optic tracts. The right optic tract is expanded and destroyed by metastatic neuroblastoma. (b) A higher power magnification of a section through the right optic nerve showing metastatic neuroblastoma adjacent to the nerve (open arrow). Also observed is hemorrhagic, metastatic neuroblastoma within the nerve, splaying the neural fibers (black arrow).

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and chiasm. However, this may not be the only mechanism, because loss of vision contralateral to the proptotic eye was observed in one of the patients in the current study. Direct microscopic invasion of the optic nerve was found at autopsy in another of the patients in the current study (Fig. 3). To the authors’ knowledge, this manifestation has been described in only one prior report.15 Although metastases to the anterior and posterior chambers of the globe have been reported on rare occasions,16,17 they were not identified in any of the patients in the current study. It is important to note that not all ophthalmic signs are a result of metastatic disease. For example, Horner’s syndrome is a result of disruption of the sympathetic nerve chain anywhere in the neck or the thorax, and can be related to localized disease. One of the current study patients had loss of vision in the eye that manifested Horner’s syndrome. This loss of vision was not a direct consequence of the syndrome; however, these two entities can coexist. Opsoclonus/myoclonus, a distinctly unusual presenting sign, was not noted in any of the patients in the current study who developed visual loss. It is reported to be associated with a better prognosis and is believed to be due to some as yet unclassified tumor product.18 Other causes not directly related to the underlying disease process, should always be kept in mind. Infection, in the face of an immunocompromised state, is a likely etiology, as was observed in another one of the patients in the current study. At autopsy, that patient was found to have retinitis caused by cytomegalovirus; before that, his loss of vision had been believed due to metastatic neuroblastoma. Diagnostic imaging techniques are useful for the diagnosis of metastatic disease in general but may not reveal orbital disease. Skull roentgenograms and 99m Tc-MDP bone scans are too insensitive to delineate small anatomic structures that are involved by neuroblastoma. In this series, CT also was fairly insensitive. MRI may prove to be more sensitive than CT; however, its utility in distinguishing involved structures and predicting subsequent blindness needs further study. Until more data are available, all patients with ophthalmic/orbital signs on physical examination, especially proptosis, should be considered at risk for developing blindness. Systemic antineoplastic therapy should be rapidly initiated in these patients. Those patients who developed blindness early in the course of their disease (five patients), or at the time of recurrence (two patients) had visual loss as a direct result of progressive involvement of the optic nerves and chiasm by the growing tumor. This correlation was corroborated by diagnostic imaging studies and by findings at autopsy. If blindness is to be pre-

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vented, clinicians need to be aware of the problem, and intervention needs to occur early in the course of the disease, prior to permanent neuronal injury. The optimal timing for intervention is not known. However, irreversible neurologic deficit has been reported in children with neuroblastoma-related nerve root compression when symptoms or signs have been present for as little as 48 hours.19,20 Traditionally, therapy for impending neuroblastoma-associated visual loss includes radiation and/or high dose steroids to decompress the optic nerve(s), thereby preventing any further damage. Eight of the 15 patients in the current study received radiation therapy directed at the orbital/cranial metastatic disease without prevention or correction of blindness. High dose steroids have been used empirically to decrease inflammation, lower the perineural pressure, and prevent neuronal injury. In the current series, there was little success in correcting blindness with steroid use, although most patients were started on steroids after becoming blind (seven patients). Steroids may be more beneficial if initiated prior to visual loss, although this also is not necessarily true, because some of the patients in the current study developed blindness while receiving steroids. Without early initiation of effective treatment of the primary tumor, radiation therapy or steroids have a restricted role at best. In chemotherapy-naive children with spinal cord compression, early initiation of effective chemotherapy has prevented progression of neurologic compromise.21,22 Most patients in the current series were newly diagnosed. Certainly, chemotherapy should be initiated as soon as possible in any patient with orbital/ophthalmic signs if blindness is to be averted. This is probably most pertinent in infants and young children (age õ 2 years), who have a better chance of long term cure.2,23 – 25 In the authors’ own series, 3 of the 4 survivors were infants at the time of diagnosis; the remaining patient was only age 15 months when diagnosed. Two patients lost their vision due to progressive disease while receiving therapy. One of these patients (Patient 13) received radiation treatment to his orbital and cranial metastases, without any additional benefit. In such patients whose disease is treatment-resistant, radiation therapy may be useful in providing palliation. Two of the surviving patients in the current study developed visual loss after completing therapy, and another became blind ú 7 months after starting clearly effective therapy. Although the exact etiology of this progressive visual loss remains elusive, it may have resulted from progressive deposition of scar tissue within or around the optic nerve as inflammation and

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healing took place. All three of these patients had proptosis or periorbital ecchymosis at presentation. This progressive loss of vision also could have resulted from an as yet undetermined toxic effect of therapy. None of these three patients received any radiation therapy; however, two of these patients (Patients 14 and 15) received cisplatin as part of their therapy. Cortical blindness, retinopathy, and peripheral neuropathy resulting in visual deficits have been reported as toxic complications of cisplatin therapy.26 – 31 It is interesting to note that in these reports, patients who developed optic neuritis, rather than retinopathy, with subsequent blindness, had a much more chronic course, similar to what the authors observed in the patients in the current study. In one series, visual symptoms started 1 – 5 months after the administration of cisplatin, with stabilization of ophthalmic findings taking a additional 2 – 4 months.31 The exact etiology of this delayed blindness remains unknown. Children, especially infants, with periorbital neuroblastoma should receive close ophthalmologic follow-up, because even temporary correction of visual acuity can have tremendous impact on normal development. This becomes even more important when one notes that most neuroblastoma survivors are infants and very young children. In summary, ophthalmic/orbital metastatic disease is not uncommon in patients with neuroblastoma. These patients are at risk for losing their vision, and effective therapy should be initiated as quickly as possible. The form of therapy optimal for preventing blindness remains controversial; however, systemic treatment using multiagent chemotherapy, with or without steroids and/or radiation, may be of most benefit. Early initiation of therapy may be especially advantageous in infants and children age õ 2 years, because they have the best prognosis for long term cure.

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