Leptomeningeal Dissemination of Optic Pathway Gliomas in Three Children
Carol S. Bruggers, M . D . , Henry S, Friedman, M . D . , Peter C. Phillips, M . D . , M. David Wiener, M . D . , Beverly Hockenberger, B.H.S., W. Jerry Oakes, M . D . , and Edward G. Buckley, M . D .
We t r e a t e d t h r e e c h i l d r e n w i t h o p t i c p a t h way g l i o m a s w h o h a d p r o g r e s s i v e d i s e a s e a s sociated with metastatic spread to the leptomeninges. One patient had radiographic resolution of l e p t o m e n i n g e a l disease after treatment with intravenous carmustine and oral m e r c a p t o p u r i n e but died of progressive p u l m o n a r y fibrosis. T h e s e c o n d p a t i e n t w a s treated with intravenous thiotepa, and the leptomeningeal disease remained stable. T h e third patient was treated with intravenous vincristine sulfate, cyclophosphamide, cisplatin, and etoposide and h a d a significant s i z e r e d u c t i o n of t h e l e p t o m e n i n g e a l l e s i o n . A l t h o u g h l e p t o m e n i n g e a l d i s s e m i n a t i o n is a s e e m i n g l y r a r e e v e n t , it is i m p o r t a n t t h a t a l l children with optic pathway gliomas be con s i d e r e d for t h i s p o s s i b i l i t y , p a r t i c u l a r l y a f t e r the o n s e t o f n e w , a t y p i c a l n e u r o l o g i c s y m p toms.
O P T I C PATHWAY GLIOMAS, rare tumors compris i n g 1 % to 5 % o f c h i l d h o o d i n t r a c r a n i a l n e o p l a s m s , o c c u r p r i m a r i l y in t h e first t w o d e c a d e s of life.''^ T h e c l i n i c a l c o u r s e c a n b e v a r i a b l e a n d often u n p r e d i c t a b l e , r a n g i n g from s t a b i l i t y o f b o t h v i s i o n a n d t u m o r for l o n g p e r i o d s o f t i m e to total b l i n d n e s s a n d d e a t h r e s u l t i n g f r o m local tumor invasion. Because of this, contro-
Accepted for publication March 15, 1991. From the Division of Hematology/Oncology, Depart ment of Pediatrics (Drs. Bruggers and Friedman and Ms. Hockenberger), Department of Radiology (Dr. Wiener), Division of Neurosurgery (Dr. Oakes), and Department of Ophthalmology (Dr. Buckley), Duke University Medi cal Center, Durham, North Carolina; and Department of Pediatric Neuro-oncology, Johns Hopkins Hospital, Bal timore, Maryland (Dr. Phillips). Reprint requests to Carol S. Bruggers, M.D., P.O. Box 2916, Pediatric Hematology-Oncology, Duke University Medical Center, Durham, NC 27710.
©AMERICAN JOURNAL OF OPHTHALMOLOGY 111:719-723, JUNE,
v e r s y e x i s t s r e g a r d i n g t h e o p t i m a l t h e r a p y for optic pathway gliomas. Proposed therapeutic options include observation alone, surgery, ra d i a t i o n t h e r a p y , or c h e m o t h e r a p y . C l i n i c a l f e a tures influencing the c h o i c e of therapy include the severity of s y m p t o m s , precise location and extent of tumor, functional impairment, and age of the patient. Although most optic pathway gliomas follow an indolent course, a c c e l e r a t e d local progres sion and, rarely, metastatic spread may occur. We t r e a t e d t h r e e c h i l d r e n w i t h o p t i c p a t h w a y gliomas who had progressive disease associat e d w i t h m e t a s t a t i c s p r e a d to t h e l e p t o m e n i n g e s .
Case Reports Case 1 In October 1 9 8 6 , an 8-year-old boy had visu al l o s s in h i s r i g h t e y e , a n d a m b l y o p i a w a s diagnosed. Progressive visual deterioration o c c u r r e d d e s p i t e p a t c h i n g o f h i s left e y e . In M a r c h 1987, a cranial computed tomographic scan disclosed a 3-cm enhancing, multiloculated, cystic mass o f the posterior optic chiasm, which e x t e n d e d to t h e a n t e r i o r b a s e o f t h e b r a i n . A n exploratory right frontoparietal craniotomy was performed, and biopsy of the mass dis closed a pilocytic astrocytoma. The child was t r e a t e d w i t h r a d i o t h e r a p y to t h e r e s i d u a l m a s s , receiving 5 , 0 7 5 cGy (in daily fractions of 1 7 5 cGy). In A u g u s t 1 9 8 7 , t h e p a t i e n t h a d e p i s o d i c visual disturbance and cognitive disorienta tion. Cranial c o m p u t e d tomography again dis c l o s e d the e n h a n c i n g s u p r a s e l l a r m a s s , v e n t r i c ular enlargement, and n e w subarachnoid tumor dissemination (Fig. 1 ) . Cerebrospinal fluid analysis d e m o n s t r a t e d a protein level of 3 6 4 m g / d l and clusters of cytologically benign as trocytes, consistent with dissemination of a
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Fig. 1 (Bruggers and associates). Case 1. Noncontiguous images from contrast-enlianced cranial computed tomographic scan show enhancing cystic suprasellar mass (large arrow) with contiguous extension into the right sylvian cistern (small arrow) and throughout the right hemispheric sulci (arrowheads). mature glioma. A ventriculoperitoneal shunt was placed. T h e p a t i e n t was t h e n t r e a t e d w i t h oral 6 m e r c a p t o p u r i n e ( 2 0 0 m g / m ^ on Days 1, 2 , a n d 3) and a single dose of intravenous carmustine ( 2 0 0 m g / m ^ ) g i v e n at s i x - w e e k i n t e r v a l s . A cranial computed tomographic scan performed after two c o u r s e s o f m e d i c a t i o n d i s c l o s e d a d e c r e a s e in b o t h t u m o r s i z e a n d s u b a r a c h n o i d d i s s e m i n a t i o n . After f o u r c o u r s e s o f m e d i c a tion, a cranial computed tomographic scan dis c l o s e d further d e c r e a s e in t h e t u m o r s i z e a n d r e s o l u t i o n of l e p t o m e n i n g e a l d i s e a s e . T h e p a t i e n t d e v e l o p e d p r o g r e s s i v e p u l m o n a r y fibrosis a n d cor p u l m o n a l e , h o w e v e r , w h i c h r e q u i r e d continued intervention with furosemide and oxygen and discontinuation of systemic c h e m o t h e r a p y . In M a r c h 1 9 8 8 , a c r a n i a l c o m p u t e d t o m o g r a p h i c s c a n d i s c l o s e d a s l i g h t d e c r e a s e in the tumor mass size and no evidence of sub arachnoid dissemination. Unfortunately, the patient died of progressive pulmonary fibrosis and severe cor pulmonale. Case 2 A 1 4 - w e e k - o l d girl was a d m i t t e d to h e r l o c a l h o s p i t a l for e x a m i n a t i o n b e c a u s e of failure to
thrive, developmental delay, emesis, and dehy d r a t i o n . O n t h e t h i r d day in t h e h o s p i t a l , s h e d e v e l o p e d a full, n o n t e n s e a n t e r i o r f o n t a n e l l e and rotatory nystagmus. A cranial ultrasound disclosed a solid suprasellar mass with mild ventriculomegaly. Contrast-enhanced magnet ic r e s o n a n c e i m a g i n g d i s c l o s e d a 5 x 4 x 3 - c m e n h a n c i n g t u m o r in t h e s u p r a s e l l a r c i s t e r n , multiple punctate areas of e n h a n c e m e n t on the surface o f the pons, and spinal subarachnoid drop metastases (Fig. 2 ) . Results of b o n e mar row aspirate, b o n e marrow biopsy, and a b d o m inal ultrasound showed no evidence of tumor. C e r e b r o s p i n a l fluid a n a l y s i s d i s c l o s e d t h e fol lowing values: protein, 1 4 2 m g / d l ; glucose, 51 m g / d l ; red b l o o d c e l l c o u n t , 3 0 c e l l s / μ ΐ ; w h i t e b l o o d cell count, 1 c e l l / μ ΐ and a differential of 1 0 0 % lymphocytes. Isolated atypical cells were a l s o p r e s e n t . T h e p a t i e n t w a s t r a n s f e r r e d to D u k e U n i v e r s i t y M e d i c a l C e n t e r for further examination and treatment. U p o n arrival at D u k e U n i v e r s i t y M e d i c a l Center, the patient was alert with the following vital signs and growth variables: heart rate, 1 4 0 beats per minute; b l o o d pressure, 1 1 0 / 6 8 m m H g ; r e s p i r a t i o n s , 3 2 p e r m i n u t e ; w e i g h t , 4 . 6 7 kg (tenth percentile); height, 6 1 . 5 cm (60th per-
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placement, and subsequent development of s u b d u r a l fluid c o l l e c t i o n s r e q u i r i n g p l a c e m e n t of a shunt. A regimen of intravenous thiotepa, 3.25 m g / kg o f b o d y w e i g h t , at t h r e e - w e e k i n t e r v a l s w a s begun. Six weeks later a cranial computed to m o g r a p h i c s c a n d i s c l o s e d n o c h a n g e in t h e suprasellar mass when compared with postop erative scans. Myelography disclosed persistent s u b a r a c h n o i d drop m e t a s t a s e s . After careful consideration of the multiple aspects of the infant's problem, her parents decided against further therapeutic intervention. As of N o v e m ber 1 9 9 0 , the patient r e m a i n e d alive, although she was severely developmentally and neurologically compromised.
Fig. 2 (Bruggers and associates). Case 2. Composite TI-weighted (TR = 5 0 0 msec, TE = 20 msec) midsagittal magnetic resonance images of the cervicothoracic spine with (right) and without (left) gadopentetate dimeglumine contrast enhancement. The spinal cord is irregularly widened on the noncontrast image (left) with multiple abnormal enhancing le sions in the cranial (arrowhead) and spinal (arrows) subarachnoid space consistent with metastases. centile); and head circumference, 41 cm (75th percentile). The head and neck examination s h o w e d a full, n o n b u l g i n g a n t e r i o r f o n t a n e l l e , mild paralysis of vertical gaze, and diminished extraocular movements with pendular nystag mus. Cardiovascular examination disclosed an i r r e g u l a r h e a r t rate a n d p e r i o d i c h y p o t e n s i o n . Neurologic abnormalities included weakness of t h e o c u l o m o t o r , t r o c h l e a r , a n d a b d u c e n t nerves, and pendular nystagmus. O p h t h a l m i c examination disclosed complete clinical blind ness. S h e w a s a d m i t t e d to t h e p e d i a t r i c i n t e n s i v e care unit b e c a u s e o f cardiac instability and treated with d e x a m e t h a s o n e , 0 . 3 5 m g / k g of b o d y w e i g h t p e r day, a n d fluid r e s t r i c t i o n . S u b total resection of the huge suprasellar m a s s w a s p e r f o r m e d . T h e m a s s o r i g i n a t e d at t h e o p t i c chiasm, encased the vessels of the circle of W i l l i s , a n d i m p i n g e d b i l a t e r a l l y on t h e m e d i a l aspects of the temporal l o b e s . T h e right optic nerve was enlarged. T h e r e were no apparent metastatic lesions on the surface of the brain. Final pathologic e x a m i n a t i o n d i s c l o s e d pilocytic astrocytoma. Postoperative c o m p l i c a t i o n s included diabetes insipidus responsive to des mopressin acetate, periodic hypothalamic auto nomic instability, panhypopituitarism treated with corticosteroid and thyroid h o r m o n e re
Case 3 A 2 - y e a r - o l d b o y w a s e x a m i n e d at J o h n s H o p kins University M e d i c a l C e n t e r in S e p t e m b e r 1 9 8 8 for a t w o - m o n t h h i s t o r y o f r o v i n g c o n j u gate ocular m o v e m e n t s and a o n e - m o n t h histo ry o f b u m p i n g i n t o o b j e c t s . A c r a n i a l c o m p u t e d t o m o g r a p h i c scan disclosed an e x t r e m e l y large hypothalamic, retrochiasmal multicystic tumor with extensions along the optic radiations. He had no other symptoms. Physical examination showed bilateral optic a t r o p h y , d i m i n i s h e d v i s u a l a c u i t y , a left v i s u a l field d e f e c t , r i g h t l a t e r a l g a z e p r e f e r e n c e , r o v ing n y s t a g m o i d p a t t e r n o f c o n j u g a t e o c u l a r m o v e m e n t that was most p r o m i n e n t on right lateral gaze, upbeat nystagmus, and counter clockwise rotatory nystagmus. Plantar stimula t i o n e v o k e d a flexor r e s p o n s e o n t h e left a n d withdrawal on the right. On Sept. 2 6 , 1 9 8 8 , the patient underwent n e e d l e aspiration b i o p s y a n d d e c o m p r e s s i o n of the cysts. Pathologic examination disclosed a m a t u r e a s t r o c y t o m a . C e r e b r o s p i n a l fluid o b t a i n e d at t h a t t i m e w a s s u g g e s t i v e o f t u m o r cells, and subsequent myelography demon strated an extensive intradural extrameduUary lesion extending dorsally from the lower cervi cal region to the lower thoracic region. The patient was given chemotherapy with intravenous vincristine sulfate and c y c l o p h o s phamide alternating with cisplatin and etoposide. There was a greater than 5 0 % reduction in t h e s i z e o f t h e l e p t o m e n i n g e a l t u m o r in r e s p o n s e to t h i s c h e m o t h e r a p y .
Discussion O p t i c pathway g l i o m a s are most frequently d i a g n o s e d d u r i n g t h e first 2 0 y e a r s o f life.
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A l t h o u g h t h e t u m o r may d e v e l o p a n y w h e r e w i t h i n the o p t i c p a t h w a y , m o s t i n v o l v e t h e o p t i c n e r v e or the o p t i c chiasm.''^ F u r t h e r m o r e , 2 0 % to 6 0 % of p a t i e n t s w i t h o p t i c p a t h w a y g l i o m a s a l s o have n e u r o f i b r o m a t o s i s . ' ° T h e c l i n i c a l s i g n s a n d s y m p t o m s at d i a g n o s i s in clude visual i m p a i r m e n t , s t r a b i s m u s , p r o p t o s i s , o p t i c a t r o p h y w i t h or w i t h o u t s w e l l i n g o f t h e o p t i c disk, a n d an afferent p u p i l l a r y d e f e c t . I n c r e a s e d i n t r a c r a n i a l p r e s s u r e m a y a l s o be p r e s e n t a n d result in h e a d a c h e , n a u s e a , e m e s i s , a n d p a r a l y s i s of v e r t i c a l g a z e . H y p o t h a l a m i c i n v o l v e m e n t may b e i n d i c a t e d b y d i a b e t e s in s i p i d u s or p r e c o c i o u s p u b e r t y . E x t e n s i v e tu m o r s may a l s o b e n o t e d w i t h d i e n c e p h a l i c s y n d r o m e m a n i f e s t e d as h y p e r a c t i v i t y , i n c r e a s e d alertness, pallor, and emaciation despite s e e m ingly adequate caloric intake. W h e n r e v i e w i n g t h e l o n g - t e r m s u r v i v a l data from s e v e r a l different s t u d i e s c o n c e r n i n g o p t i c p a t h w a y g l i o m a s , it b e c o m e s c l e a r t h a t c o n s i d e r a b l e v a r i a t i o n in c l i n i c a l o u t c o m e exists.'''*'"* Involvement of the optic chiasm, hydrocepha l u s , a n d i n c r e a s e d age at d i a g n o s i s are a m o n g the factors associated with a less favorable o u t c o m e . * ' F l i c k e n g e r , Torres, and Deutsch^ de scribed 3 6 pediatric patients with optic path way g l i o m a s t r e a t e d b e t w e e n 1 9 6 5 a n d 1 9 8 3 . A c t u a r i a l survival of p a t i e n t s w i t h g l i o m a s c o n fined to t h e o p t i c n e r v e w a s 1 0 0 % ( s e v e n p a t i e n t s ) at five, t e n , a n d 15 y e a r s after d i a g n o s i s . A c t u a r i a l s u r v i v a l of p a t i e n t s w i t h t u m o r s in volving the optic chiasm was 9 3 % (28 o f 3 0 patients), 9 0 % (27 of 30 patients), and 9 0 % (27 of 3 0 p a t i e n t s ) at five, t e n , a n d 15 y e a r s , r e s p e c tively. I m e s a n d H o y t ' r e p o r t e d an 8 2 % ( 2 3 o f 2 8 p a t i e n t s ) 1 5 - y e a r s u r v i v a l rate from o p t i c c h i a s m a l t u m o r s . Bilgic a n d a s s o c i a t e s * r e p o r t ed that six of 1 6 p a t i e n t s ( 3 7 . 5 % ) w i t h i n t r a c r a nial o p t i c p a t h w a y g l i o m a s w e r e a l i v e e i g h t y e a r s after d i a g n o s i s . A l t h o u g h v i s u a l a c u i t y r e m a i n e d s t a b l e in the s u r v i v o r s , o n l y o n e p a tient, who underwent biopsy followed by radia t i o n t h e r a p y , h a d full v i s i o n . H y p o t h a l a m i c i n v o l v e m e n t is a l s o a s s o c i a t e d w i t h a p o o r e r o u t c o m e . In a r e v i e w o f p u b l i s h e d r e p o r t s w i t h a 2 0 - y e a r f o l l o w - u p , A l v o r d a n d Lofton* r e p o r t ed that the m o r t a l i t y o f p a t i e n t s w i t h u n t r e a t e d , uncomplicated optic chiasmal tumors was 4 7 % ( 2 0 of 4 3 p a t i e n t s d i e d ) as c o m p a r e d w i t h 9 1 % (31 o f 3 4 p a t i e n t s d i e d ) i f t h e h y p o t h a l a m u s was also involved. O t h e r r e p o r t s have d e s c r i b e d c h i l d r e n w i t h clinically aggressive optic pathway gliomas de spite d i s p l a y i n g h i s t o l o g i c f e a t u r e s c o n s i s t e n t with low-grade lesions. De Keizer and associ ates' described a 3-year-old boy with neurofi b r o m a t o s i s w h o h a d a large j u v e n i l e p i l o c y t i c
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astrocytoma involving the optic nerve and the globe with intraocular seeding of the vitreous. A l t h o u g h t h e o c u l a r p o r t i o n of t h e t u m o r w a s composed of a mature astrocytoma, there were s m a l l i s l a n d s o f g r a d e t h r e e a s t r o c y t o m a in t h e optic canal. Civitello and associates'" described 1 6 2 p a t i e n t s w i t h l o w - g r a d e g l i o m a s ; six p a t i e n t s (3.7%) h a d l e p t o m e n i n g e a l t u m o r s p r e a d . O n l y o n e o f t h e s e p a t i e n t s h a d an o p t i c pathway glioma, which involved the optic chi a s m . T h i s p a t i e n t h a d d i s s e m i n a t i o n after l o c a l r a d i a t i o n t h e r a p y a n d d i e d w i t h i n two y e a r s o f leptomeningeal dissemination. Kocks and asso c i a t e s " d e s c r i b e d a 1 0 - y e a r - o l d girl w i t h a j u v e nile pilocytic astrocytoma of the optic chiasm, initially treated with radiation therapy. Six years later e n l a r g e m e n t of the primary tumor produced further visual deterioration. Within three years she had lumbar metastases, with the histologic characteristics of the tumor identical to t h o s e o f t h e p r i m a r y t u m o r . Trigg, S w a n s o n , a n d Letellier'^ d e s c r i b e d a 3y2-year-old b o y with a glioma involving the optic chiasm and left o p t i c n e r v e w h o w a s t r e a t e d w i t h p r i m a r y r a d i a t i o n t h e r a p y after p l a c e m e n t o f a v e n t r i c u l o p e r i t o n e a l s h u n t . After six m o n t h s t h e t u m o r progressed, and he was treated with intra venous vincristine and dactinomycin. Four m o n t h s l a t e r , h e h a d a s c i t e s after t h e d e v e l o p m e n t o f c e r e b r o s p i n a l fluid a n d p e r i t o n e a l seeding with malignant cells. No obvious features of a low-grade optic p a t h w a y a s t r o c y t o m a are t o t a l l y p r e d i c t i v e o f biologically aggressive behavior. A worse prog n o s i s h a s b e e n d e s c r i b e d in i n f a n t s w i t h o p t i c pathway gliomas as c o m p a r e d with older chil dren. Kanamori and a s s o c i a t e s " described sev en p e d i a t r i c p a t i e n t s w i t h o p t i c p a t h w a y g l i o m a s a n d n o t e d t h a t after a f o l l o w - u p p e r i o d e x c e e d i n g e i g h t y e a r s , five o f s e v e n c h i l d r e n with childhood gliomas were alive, compared w i t h o n l y o n e o f four p a t i e n t s w i t h i n f a n t i l e gliomas. O n e of the patients with infantile gliomas died of progressive tumor, one of infec tion, and one of hypothalamic crises. A l v o r d a n d Lofton" d e v i s e d a m a t h e m a t i c model describing the growth kinetics of optic pathway gliomas b a s e d on time to recurrence of disease. They concluded that these histological ly b e n i g n g l i o m a s o f t h e o p t i c p a t h w a y h a d a variable growth rate ranging along a continuum from a s i m p l e l o g a r i t h m i c r a t e to a d e c e l e r a t i n g growth rate. Upon microscopic examination, l o c a l infiltration o f t h e l e p t o m e n i n g e s b y t u m o r c e l l s , w i t h s p a r i n g o f t h e dura m a t e r , h a s b e e n well d e s c r i b e d in a s t r o c y t o m a s i n v o l v i n g t h e g l o b e a n d o p t i c n e r v e s , as w e l l as t h e c h i a s m and adjacent structures, although the clinical
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p r o g n o s i s is m o r e f a v o r a b l e in the g l o b e a n d optic nerves.'" T h e a b i l i t y to d e t e c t n e o p l a s t i c c e l l s i n c e r e b r o s p i n a l fluid in p a t i e n t s w i t h b e n i g n i n t r a c r a nial gliomas before surgery has b e e n demon strated. Wilkins and Odom'* reported a 2 5 % incidence (22 of 87 patients) of neoplastic cells from b e n i g n i n t r a c r a n i a l g l i o m a s in t h e c e r e b r o s p i n a l fluid b e f o r e s u r g e r y w i t h o u t a signifi c a n t i n c r e a s e after s u r g e r y . S u r g e r y did n o t s e e m to play a r o l e in t u m o r d i s s e m i n a t i o n in our t h r e e p a t i e n t s , b e c a u s e o n e o f the c h i l d r e n had widespread disease before surgery, one had a needle aspiration biopsy only, and the third p a t i e n t h a d an o p e n b i o p s y f o l l o w e d b y r a d i a t i o n t h e r a p y b e f o r e d i s s e m i n a t i o n . It r e m a i n s u n c l e a r w h y in a s m a l l p e r c e n t a g e o f patients, leptomeningeal dissemination of lowgrade astrocytomas occurs. M o s t o p t i c p a t h w a y g l i o m a s in c h i l d r e n h a v e an i n d o l e n t c l i n i c a l c o u r s e , w i t h r a d i o t h e r a p y ' ' ' * and more recently c h e m o t h e r a p y " im p r o v i n g the d u r a t i o n a n d q u a l i t y o f s u r v i v a l . Despite low-grade histologic features, however, o c c a s i o n a l l y o p t i c p a t h w a y g l i o m a s b e h a v e in a biologically aggressive fashion, with develop ment of leptomeningeal metastases and death. Although leptomeningeal dissemination of gli omas generally has a poor prognosis, three of t h e six p a t i e n t s d e s c r i b e d b y C i v i t e l l o a n d a s s o c i a t e s ' " w e r e alive after m u l t i a g e n t s y s t e m i c c h e m o t h e r a p y w i t h or w i t h o u t r a d i a t i o n t h e r a p y . O n e o f t h e s e p a t i e n t s w a s still a l i v e m o r e t h a n t h r e e y e a r s after t h e d i a g n o s i s o f l e p t o m e n i n g e a l d i s s e m i n a t i o n from t h e s p i n a l glioma. With improved radiologic diagnostic capa bilities, earlier detection of leptomeningeal s p r e a d m a y b e p o s s i b l e a n d m a y i m p a c t signifi cantly upon treatment planning and overall p r o g n o s i s . It is i m p o r t a n t that all c h i l d r e n w i t h o p t i c p a t h w a y t u m o r s b e c o n s i d e r e d for t h i s possibility, particularly patients who have l a r g e , infiltrating c h i a s m a l t u m o r s a n d p a t i e n t s with new, atypical neurologic s y m p t o m s . In c r e a s e d a w a r e n e s s of t h i s p o t e n t i a l p r o b l e m s h o u l d p r o m p t a m o r e e x t e n s i v e e x a m i n a t i o n in t h i s s u b g r o u p of p a t i e n t s w i t h o p t i c p a t h w a y gliomas, including cranial and spinal gadolini um-enhanced magnetic resonance imaging and c e r e b r o s p i n a l fluid e x a m i n a t i o n .
References 1. Wong, J. C. Y., Uhl, V., Wara, W. M., and Sheline, G. E.: Optic gliomas. A reanalysis of the
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University of California, San Francisco experience. Cancer 60:1847, 1987. 2. Flickenger, J. C , Torres, C , and Deutsch, Μ.: Management of low-grade gliomas of the optic nerve and chiasm. Cancer 6 1 : 6 3 5 , 1 9 8 8 . 3. Weiss, L., Sagerman, R. H., King, G. Α., Chung, C. T., and Dubowy, R. L.: Controversy in the man agement of optic nerve glioma. Cancer 5 9 : 1 0 0 0 , 1987. 4. Easley, J. D., Scharf, L., Chou, J. L., and Riccardi, V. M.: Controversy in the management of optic pathway gliomas. Neurofibromatosis 1:248, 1 9 8 8 . 5. Duffner, P. K., and Cohen, M. E.: Isolated optic nerve gliomas in children with and without neurofi bromatosis. Neurofibromatosis 1:201, 1 9 8 8 . 6. Alvord, E. C , and Lofton, S.: Gliomas of the optic nerve of chiasm. Outcome by patient's age, tumor site and treatment. J. Neurosurg. 68:85, 1988. 7. Imes, R. K., and Hoyt, W. F.: Childhood chias mal gliomas. Update on the fate of patients in the 1969 San Francisco study. Prog. Exp. Tumor Res. 30:108, 1987. 8. Bilgic, S., Erbengi, Α., Tinaztepe, B., and Onol, B.: Optic glioma of childhood. Clinical, histopatho logical, and histochemical observations. Br. J. Oph thalmol. 73:832, 1 9 8 9 . 9. de Keizer, R. J. W., de Wolff-RouendaaL D., Bots, G. T. A. M., Thomeer, R. T. W. M., Brouwer, O. F., and Vielvoye, G. J.: Optic glioma with intraoc ular tumor and seeding in a child with neurofibroma tosis. Am. J. Ophthalmol. 108:717, 1 9 8 9 . 10. Civitello, L. Α., Packer, R. J . , Rorke, L. B., Sie gel, P. Α., Sutton, L. N., and Schuf, L.: Leptomenin geal dissemination of low grade gliomas in child hood. Neurology 38:562, 1988. 11. Kocks, W., Kalff, R., Reinhardt, V., Grote, W., and Hilke, J.: Spinal metastasis of pilocytic astrocyto ma of the chiasma opticum. Child Nerv. Syst. 5:18, 1989. 12. Trigg, Μ. Ε., Swanson, J. D., and Letellier, M. Α.: Metastasis of an optic glioma through a ven triculoperitoneal shunt. Cancer 52:599, 1 9 8 3 . 13 Kanamori, M., Shibuya, M., Yoshida, J . , Takayasu, Μ., and Kageyama, N.: Long-term followup of patients with optic glioma. Child Nerv. Syst. 1:72, 1 9 8 5 . 14. Borit, Α., and Richardson, E. P., Jr.: The biolog ical and clinical behavior of pilocytic astrocytomas of the optic pathways. Brain 105:16, 1982. 15. Wilkins, R. H., and Odom, G. L.: Cytologicai changes in cerebrospinal fluid associated with resec tions of intracranial neoplasms. J. Neurosurg. 25:24, 1966. 16. Kovalic, J. J., Grigsby, P. W., Shepard, M. J . , Fineberg, Β. Β., and Thomas, P. R.: Radiation therapy for gliomas of the optic nerve and chiasm. Int. J. Radiat. Oncol. Biol. Phys. 18:927, 1 9 9 0 . 17. Packer, R. J . , Sutton, L. N., Bilaniuk, L. T., Radcliffe, J., Rosenstock, J. G., Seigel, K. R., Bunin, G. R., Savino, P. J . , Bruce, D. Α., and Schut, L.: Treatment of chiasmatic/hypothalamic gliomas of childhood with chemotherapy. An update. Ann. Neurol. 23:79, 1988.
Carol S. Bruggers, M . D . , Henry S, Friedman, M . D . , Peter C. Phillips, M . D . , M. David Wiener, M . D . , Beverly Hockenberger, B.H.S., W. Jerry Oakes, M . D . , and Edward G. Buckley, M . D .
We t r e a t e d t h r e e c h i l d r e n w i t h o p t i c p a t h way g l i o m a s w h o h a d p r o g r e s s i v e d i s e a s e a s sociated with metastatic spread to the leptomeninges. One patient had radiographic resolution of l e p t o m e n i n g e a l disease after treatment with intravenous carmustine and oral m e r c a p t o p u r i n e but died of progressive p u l m o n a r y fibrosis. T h e s e c o n d p a t i e n t w a s treated with intravenous thiotepa, and the leptomeningeal disease remained stable. T h e third patient was treated with intravenous vincristine sulfate, cyclophosphamide, cisplatin, and etoposide and h a d a significant s i z e r e d u c t i o n of t h e l e p t o m e n i n g e a l l e s i o n . A l t h o u g h l e p t o m e n i n g e a l d i s s e m i n a t i o n is a s e e m i n g l y r a r e e v e n t , it is i m p o r t a n t t h a t a l l children with optic pathway gliomas be con s i d e r e d for t h i s p o s s i b i l i t y , p a r t i c u l a r l y a f t e r the o n s e t o f n e w , a t y p i c a l n e u r o l o g i c s y m p toms.
O P T I C PATHWAY GLIOMAS, rare tumors compris i n g 1 % to 5 % o f c h i l d h o o d i n t r a c r a n i a l n e o p l a s m s , o c c u r p r i m a r i l y in t h e first t w o d e c a d e s of life.''^ T h e c l i n i c a l c o u r s e c a n b e v a r i a b l e a n d often u n p r e d i c t a b l e , r a n g i n g from s t a b i l i t y o f b o t h v i s i o n a n d t u m o r for l o n g p e r i o d s o f t i m e to total b l i n d n e s s a n d d e a t h r e s u l t i n g f r o m local tumor invasion. Because of this, contro-
Accepted for publication March 15, 1991. From the Division of Hematology/Oncology, Depart ment of Pediatrics (Drs. Bruggers and Friedman and Ms. Hockenberger), Department of Radiology (Dr. Wiener), Division of Neurosurgery (Dr. Oakes), and Department of Ophthalmology (Dr. Buckley), Duke University Medi cal Center, Durham, North Carolina; and Department of Pediatric Neuro-oncology, Johns Hopkins Hospital, Bal timore, Maryland (Dr. Phillips). Reprint requests to Carol S. Bruggers, M.D., P.O. Box 2916, Pediatric Hematology-Oncology, Duke University Medical Center, Durham, NC 27710.
©AMERICAN JOURNAL OF OPHTHALMOLOGY 111:719-723, JUNE,
v e r s y e x i s t s r e g a r d i n g t h e o p t i m a l t h e r a p y for optic pathway gliomas. Proposed therapeutic options include observation alone, surgery, ra d i a t i o n t h e r a p y , or c h e m o t h e r a p y . C l i n i c a l f e a tures influencing the c h o i c e of therapy include the severity of s y m p t o m s , precise location and extent of tumor, functional impairment, and age of the patient. Although most optic pathway gliomas follow an indolent course, a c c e l e r a t e d local progres sion and, rarely, metastatic spread may occur. We t r e a t e d t h r e e c h i l d r e n w i t h o p t i c p a t h w a y gliomas who had progressive disease associat e d w i t h m e t a s t a t i c s p r e a d to t h e l e p t o m e n i n g e s .
Case Reports Case 1 In October 1 9 8 6 , an 8-year-old boy had visu al l o s s in h i s r i g h t e y e , a n d a m b l y o p i a w a s diagnosed. Progressive visual deterioration o c c u r r e d d e s p i t e p a t c h i n g o f h i s left e y e . In M a r c h 1987, a cranial computed tomographic scan disclosed a 3-cm enhancing, multiloculated, cystic mass o f the posterior optic chiasm, which e x t e n d e d to t h e a n t e r i o r b a s e o f t h e b r a i n . A n exploratory right frontoparietal craniotomy was performed, and biopsy of the mass dis closed a pilocytic astrocytoma. The child was t r e a t e d w i t h r a d i o t h e r a p y to t h e r e s i d u a l m a s s , receiving 5 , 0 7 5 cGy (in daily fractions of 1 7 5 cGy). In A u g u s t 1 9 8 7 , t h e p a t i e n t h a d e p i s o d i c visual disturbance and cognitive disorienta tion. Cranial c o m p u t e d tomography again dis c l o s e d the e n h a n c i n g s u p r a s e l l a r m a s s , v e n t r i c ular enlargement, and n e w subarachnoid tumor dissemination (Fig. 1 ) . Cerebrospinal fluid analysis d e m o n s t r a t e d a protein level of 3 6 4 m g / d l and clusters of cytologically benign as trocytes, consistent with dissemination of a
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Fig. 1 (Bruggers and associates). Case 1. Noncontiguous images from contrast-enlianced cranial computed tomographic scan show enhancing cystic suprasellar mass (large arrow) with contiguous extension into the right sylvian cistern (small arrow) and throughout the right hemispheric sulci (arrowheads). mature glioma. A ventriculoperitoneal shunt was placed. T h e p a t i e n t was t h e n t r e a t e d w i t h oral 6 m e r c a p t o p u r i n e ( 2 0 0 m g / m ^ on Days 1, 2 , a n d 3) and a single dose of intravenous carmustine ( 2 0 0 m g / m ^ ) g i v e n at s i x - w e e k i n t e r v a l s . A cranial computed tomographic scan performed after two c o u r s e s o f m e d i c a t i o n d i s c l o s e d a d e c r e a s e in b o t h t u m o r s i z e a n d s u b a r a c h n o i d d i s s e m i n a t i o n . After f o u r c o u r s e s o f m e d i c a tion, a cranial computed tomographic scan dis c l o s e d further d e c r e a s e in t h e t u m o r s i z e a n d r e s o l u t i o n of l e p t o m e n i n g e a l d i s e a s e . T h e p a t i e n t d e v e l o p e d p r o g r e s s i v e p u l m o n a r y fibrosis a n d cor p u l m o n a l e , h o w e v e r , w h i c h r e q u i r e d continued intervention with furosemide and oxygen and discontinuation of systemic c h e m o t h e r a p y . In M a r c h 1 9 8 8 , a c r a n i a l c o m p u t e d t o m o g r a p h i c s c a n d i s c l o s e d a s l i g h t d e c r e a s e in the tumor mass size and no evidence of sub arachnoid dissemination. Unfortunately, the patient died of progressive pulmonary fibrosis and severe cor pulmonale. Case 2 A 1 4 - w e e k - o l d girl was a d m i t t e d to h e r l o c a l h o s p i t a l for e x a m i n a t i o n b e c a u s e of failure to
thrive, developmental delay, emesis, and dehy d r a t i o n . O n t h e t h i r d day in t h e h o s p i t a l , s h e d e v e l o p e d a full, n o n t e n s e a n t e r i o r f o n t a n e l l e and rotatory nystagmus. A cranial ultrasound disclosed a solid suprasellar mass with mild ventriculomegaly. Contrast-enhanced magnet ic r e s o n a n c e i m a g i n g d i s c l o s e d a 5 x 4 x 3 - c m e n h a n c i n g t u m o r in t h e s u p r a s e l l a r c i s t e r n , multiple punctate areas of e n h a n c e m e n t on the surface o f the pons, and spinal subarachnoid drop metastases (Fig. 2 ) . Results of b o n e mar row aspirate, b o n e marrow biopsy, and a b d o m inal ultrasound showed no evidence of tumor. C e r e b r o s p i n a l fluid a n a l y s i s d i s c l o s e d t h e fol lowing values: protein, 1 4 2 m g / d l ; glucose, 51 m g / d l ; red b l o o d c e l l c o u n t , 3 0 c e l l s / μ ΐ ; w h i t e b l o o d cell count, 1 c e l l / μ ΐ and a differential of 1 0 0 % lymphocytes. Isolated atypical cells were a l s o p r e s e n t . T h e p a t i e n t w a s t r a n s f e r r e d to D u k e U n i v e r s i t y M e d i c a l C e n t e r for further examination and treatment. U p o n arrival at D u k e U n i v e r s i t y M e d i c a l Center, the patient was alert with the following vital signs and growth variables: heart rate, 1 4 0 beats per minute; b l o o d pressure, 1 1 0 / 6 8 m m H g ; r e s p i r a t i o n s , 3 2 p e r m i n u t e ; w e i g h t , 4 . 6 7 kg (tenth percentile); height, 6 1 . 5 cm (60th per-
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placement, and subsequent development of s u b d u r a l fluid c o l l e c t i o n s r e q u i r i n g p l a c e m e n t of a shunt. A regimen of intravenous thiotepa, 3.25 m g / kg o f b o d y w e i g h t , at t h r e e - w e e k i n t e r v a l s w a s begun. Six weeks later a cranial computed to m o g r a p h i c s c a n d i s c l o s e d n o c h a n g e in t h e suprasellar mass when compared with postop erative scans. Myelography disclosed persistent s u b a r a c h n o i d drop m e t a s t a s e s . After careful consideration of the multiple aspects of the infant's problem, her parents decided against further therapeutic intervention. As of N o v e m ber 1 9 9 0 , the patient r e m a i n e d alive, although she was severely developmentally and neurologically compromised.
Fig. 2 (Bruggers and associates). Case 2. Composite TI-weighted (TR = 5 0 0 msec, TE = 20 msec) midsagittal magnetic resonance images of the cervicothoracic spine with (right) and without (left) gadopentetate dimeglumine contrast enhancement. The spinal cord is irregularly widened on the noncontrast image (left) with multiple abnormal enhancing le sions in the cranial (arrowhead) and spinal (arrows) subarachnoid space consistent with metastases. centile); and head circumference, 41 cm (75th percentile). The head and neck examination s h o w e d a full, n o n b u l g i n g a n t e r i o r f o n t a n e l l e , mild paralysis of vertical gaze, and diminished extraocular movements with pendular nystag mus. Cardiovascular examination disclosed an i r r e g u l a r h e a r t rate a n d p e r i o d i c h y p o t e n s i o n . Neurologic abnormalities included weakness of t h e o c u l o m o t o r , t r o c h l e a r , a n d a b d u c e n t nerves, and pendular nystagmus. O p h t h a l m i c examination disclosed complete clinical blind ness. S h e w a s a d m i t t e d to t h e p e d i a t r i c i n t e n s i v e care unit b e c a u s e o f cardiac instability and treated with d e x a m e t h a s o n e , 0 . 3 5 m g / k g of b o d y w e i g h t p e r day, a n d fluid r e s t r i c t i o n . S u b total resection of the huge suprasellar m a s s w a s p e r f o r m e d . T h e m a s s o r i g i n a t e d at t h e o p t i c chiasm, encased the vessels of the circle of W i l l i s , a n d i m p i n g e d b i l a t e r a l l y on t h e m e d i a l aspects of the temporal l o b e s . T h e right optic nerve was enlarged. T h e r e were no apparent metastatic lesions on the surface of the brain. Final pathologic e x a m i n a t i o n d i s c l o s e d pilocytic astrocytoma. Postoperative c o m p l i c a t i o n s included diabetes insipidus responsive to des mopressin acetate, periodic hypothalamic auto nomic instability, panhypopituitarism treated with corticosteroid and thyroid h o r m o n e re
Case 3 A 2 - y e a r - o l d b o y w a s e x a m i n e d at J o h n s H o p kins University M e d i c a l C e n t e r in S e p t e m b e r 1 9 8 8 for a t w o - m o n t h h i s t o r y o f r o v i n g c o n j u gate ocular m o v e m e n t s and a o n e - m o n t h histo ry o f b u m p i n g i n t o o b j e c t s . A c r a n i a l c o m p u t e d t o m o g r a p h i c scan disclosed an e x t r e m e l y large hypothalamic, retrochiasmal multicystic tumor with extensions along the optic radiations. He had no other symptoms. Physical examination showed bilateral optic a t r o p h y , d i m i n i s h e d v i s u a l a c u i t y , a left v i s u a l field d e f e c t , r i g h t l a t e r a l g a z e p r e f e r e n c e , r o v ing n y s t a g m o i d p a t t e r n o f c o n j u g a t e o c u l a r m o v e m e n t that was most p r o m i n e n t on right lateral gaze, upbeat nystagmus, and counter clockwise rotatory nystagmus. Plantar stimula t i o n e v o k e d a flexor r e s p o n s e o n t h e left a n d withdrawal on the right. On Sept. 2 6 , 1 9 8 8 , the patient underwent n e e d l e aspiration b i o p s y a n d d e c o m p r e s s i o n of the cysts. Pathologic examination disclosed a m a t u r e a s t r o c y t o m a . C e r e b r o s p i n a l fluid o b t a i n e d at t h a t t i m e w a s s u g g e s t i v e o f t u m o r cells, and subsequent myelography demon strated an extensive intradural extrameduUary lesion extending dorsally from the lower cervi cal region to the lower thoracic region. The patient was given chemotherapy with intravenous vincristine sulfate and c y c l o p h o s phamide alternating with cisplatin and etoposide. There was a greater than 5 0 % reduction in t h e s i z e o f t h e l e p t o m e n i n g e a l t u m o r in r e s p o n s e to t h i s c h e m o t h e r a p y .
Discussion O p t i c pathway g l i o m a s are most frequently d i a g n o s e d d u r i n g t h e first 2 0 y e a r s o f life.
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A l t h o u g h t h e t u m o r may d e v e l o p a n y w h e r e w i t h i n the o p t i c p a t h w a y , m o s t i n v o l v e t h e o p t i c n e r v e or the o p t i c chiasm.''^ F u r t h e r m o r e , 2 0 % to 6 0 % of p a t i e n t s w i t h o p t i c p a t h w a y g l i o m a s a l s o have n e u r o f i b r o m a t o s i s . ' ° T h e c l i n i c a l s i g n s a n d s y m p t o m s at d i a g n o s i s in clude visual i m p a i r m e n t , s t r a b i s m u s , p r o p t o s i s , o p t i c a t r o p h y w i t h or w i t h o u t s w e l l i n g o f t h e o p t i c disk, a n d an afferent p u p i l l a r y d e f e c t . I n c r e a s e d i n t r a c r a n i a l p r e s s u r e m a y a l s o be p r e s e n t a n d result in h e a d a c h e , n a u s e a , e m e s i s , a n d p a r a l y s i s of v e r t i c a l g a z e . H y p o t h a l a m i c i n v o l v e m e n t may b e i n d i c a t e d b y d i a b e t e s in s i p i d u s or p r e c o c i o u s p u b e r t y . E x t e n s i v e tu m o r s may a l s o b e n o t e d w i t h d i e n c e p h a l i c s y n d r o m e m a n i f e s t e d as h y p e r a c t i v i t y , i n c r e a s e d alertness, pallor, and emaciation despite s e e m ingly adequate caloric intake. W h e n r e v i e w i n g t h e l o n g - t e r m s u r v i v a l data from s e v e r a l different s t u d i e s c o n c e r n i n g o p t i c p a t h w a y g l i o m a s , it b e c o m e s c l e a r t h a t c o n s i d e r a b l e v a r i a t i o n in c l i n i c a l o u t c o m e exists.'''*'"* Involvement of the optic chiasm, hydrocepha l u s , a n d i n c r e a s e d age at d i a g n o s i s are a m o n g the factors associated with a less favorable o u t c o m e . * ' F l i c k e n g e r , Torres, and Deutsch^ de scribed 3 6 pediatric patients with optic path way g l i o m a s t r e a t e d b e t w e e n 1 9 6 5 a n d 1 9 8 3 . A c t u a r i a l survival of p a t i e n t s w i t h g l i o m a s c o n fined to t h e o p t i c n e r v e w a s 1 0 0 % ( s e v e n p a t i e n t s ) at five, t e n , a n d 15 y e a r s after d i a g n o s i s . A c t u a r i a l s u r v i v a l of p a t i e n t s w i t h t u m o r s in volving the optic chiasm was 9 3 % (28 o f 3 0 patients), 9 0 % (27 of 30 patients), and 9 0 % (27 of 3 0 p a t i e n t s ) at five, t e n , a n d 15 y e a r s , r e s p e c tively. I m e s a n d H o y t ' r e p o r t e d an 8 2 % ( 2 3 o f 2 8 p a t i e n t s ) 1 5 - y e a r s u r v i v a l rate from o p t i c c h i a s m a l t u m o r s . Bilgic a n d a s s o c i a t e s * r e p o r t ed that six of 1 6 p a t i e n t s ( 3 7 . 5 % ) w i t h i n t r a c r a nial o p t i c p a t h w a y g l i o m a s w e r e a l i v e e i g h t y e a r s after d i a g n o s i s . A l t h o u g h v i s u a l a c u i t y r e m a i n e d s t a b l e in the s u r v i v o r s , o n l y o n e p a tient, who underwent biopsy followed by radia t i o n t h e r a p y , h a d full v i s i o n . H y p o t h a l a m i c i n v o l v e m e n t is a l s o a s s o c i a t e d w i t h a p o o r e r o u t c o m e . In a r e v i e w o f p u b l i s h e d r e p o r t s w i t h a 2 0 - y e a r f o l l o w - u p , A l v o r d a n d Lofton* r e p o r t ed that the m o r t a l i t y o f p a t i e n t s w i t h u n t r e a t e d , uncomplicated optic chiasmal tumors was 4 7 % ( 2 0 of 4 3 p a t i e n t s d i e d ) as c o m p a r e d w i t h 9 1 % (31 o f 3 4 p a t i e n t s d i e d ) i f t h e h y p o t h a l a m u s was also involved. O t h e r r e p o r t s have d e s c r i b e d c h i l d r e n w i t h clinically aggressive optic pathway gliomas de spite d i s p l a y i n g h i s t o l o g i c f e a t u r e s c o n s i s t e n t with low-grade lesions. De Keizer and associ ates' described a 3-year-old boy with neurofi b r o m a t o s i s w h o h a d a large j u v e n i l e p i l o c y t i c
June, 1991
astrocytoma involving the optic nerve and the globe with intraocular seeding of the vitreous. A l t h o u g h t h e o c u l a r p o r t i o n of t h e t u m o r w a s composed of a mature astrocytoma, there were s m a l l i s l a n d s o f g r a d e t h r e e a s t r o c y t o m a in t h e optic canal. Civitello and associates'" described 1 6 2 p a t i e n t s w i t h l o w - g r a d e g l i o m a s ; six p a t i e n t s (3.7%) h a d l e p t o m e n i n g e a l t u m o r s p r e a d . O n l y o n e o f t h e s e p a t i e n t s h a d an o p t i c pathway glioma, which involved the optic chi a s m . T h i s p a t i e n t h a d d i s s e m i n a t i o n after l o c a l r a d i a t i o n t h e r a p y a n d d i e d w i t h i n two y e a r s o f leptomeningeal dissemination. Kocks and asso c i a t e s " d e s c r i b e d a 1 0 - y e a r - o l d girl w i t h a j u v e nile pilocytic astrocytoma of the optic chiasm, initially treated with radiation therapy. Six years later e n l a r g e m e n t of the primary tumor produced further visual deterioration. Within three years she had lumbar metastases, with the histologic characteristics of the tumor identical to t h o s e o f t h e p r i m a r y t u m o r . Trigg, S w a n s o n , a n d Letellier'^ d e s c r i b e d a 3y2-year-old b o y with a glioma involving the optic chiasm and left o p t i c n e r v e w h o w a s t r e a t e d w i t h p r i m a r y r a d i a t i o n t h e r a p y after p l a c e m e n t o f a v e n t r i c u l o p e r i t o n e a l s h u n t . After six m o n t h s t h e t u m o r progressed, and he was treated with intra venous vincristine and dactinomycin. Four m o n t h s l a t e r , h e h a d a s c i t e s after t h e d e v e l o p m e n t o f c e r e b r o s p i n a l fluid a n d p e r i t o n e a l seeding with malignant cells. No obvious features of a low-grade optic p a t h w a y a s t r o c y t o m a are t o t a l l y p r e d i c t i v e o f biologically aggressive behavior. A worse prog n o s i s h a s b e e n d e s c r i b e d in i n f a n t s w i t h o p t i c pathway gliomas as c o m p a r e d with older chil dren. Kanamori and a s s o c i a t e s " described sev en p e d i a t r i c p a t i e n t s w i t h o p t i c p a t h w a y g l i o m a s a n d n o t e d t h a t after a f o l l o w - u p p e r i o d e x c e e d i n g e i g h t y e a r s , five o f s e v e n c h i l d r e n with childhood gliomas were alive, compared w i t h o n l y o n e o f four p a t i e n t s w i t h i n f a n t i l e gliomas. O n e of the patients with infantile gliomas died of progressive tumor, one of infec tion, and one of hypothalamic crises. A l v o r d a n d Lofton" d e v i s e d a m a t h e m a t i c model describing the growth kinetics of optic pathway gliomas b a s e d on time to recurrence of disease. They concluded that these histological ly b e n i g n g l i o m a s o f t h e o p t i c p a t h w a y h a d a variable growth rate ranging along a continuum from a s i m p l e l o g a r i t h m i c r a t e to a d e c e l e r a t i n g growth rate. Upon microscopic examination, l o c a l infiltration o f t h e l e p t o m e n i n g e s b y t u m o r c e l l s , w i t h s p a r i n g o f t h e dura m a t e r , h a s b e e n well d e s c r i b e d in a s t r o c y t o m a s i n v o l v i n g t h e g l o b e a n d o p t i c n e r v e s , as w e l l as t h e c h i a s m and adjacent structures, although the clinical
Dissemination of Optic Pathway Gliomas
Vol. I l l , No. 6
p r o g n o s i s is m o r e f a v o r a b l e in the g l o b e a n d optic nerves.'" T h e a b i l i t y to d e t e c t n e o p l a s t i c c e l l s i n c e r e b r o s p i n a l fluid in p a t i e n t s w i t h b e n i g n i n t r a c r a nial gliomas before surgery has b e e n demon strated. Wilkins and Odom'* reported a 2 5 % incidence (22 of 87 patients) of neoplastic cells from b e n i g n i n t r a c r a n i a l g l i o m a s in t h e c e r e b r o s p i n a l fluid b e f o r e s u r g e r y w i t h o u t a signifi c a n t i n c r e a s e after s u r g e r y . S u r g e r y did n o t s e e m to play a r o l e in t u m o r d i s s e m i n a t i o n in our t h r e e p a t i e n t s , b e c a u s e o n e o f the c h i l d r e n had widespread disease before surgery, one had a needle aspiration biopsy only, and the third p a t i e n t h a d an o p e n b i o p s y f o l l o w e d b y r a d i a t i o n t h e r a p y b e f o r e d i s s e m i n a t i o n . It r e m a i n s u n c l e a r w h y in a s m a l l p e r c e n t a g e o f patients, leptomeningeal dissemination of lowgrade astrocytomas occurs. M o s t o p t i c p a t h w a y g l i o m a s in c h i l d r e n h a v e an i n d o l e n t c l i n i c a l c o u r s e , w i t h r a d i o t h e r a p y ' ' ' * and more recently c h e m o t h e r a p y " im p r o v i n g the d u r a t i o n a n d q u a l i t y o f s u r v i v a l . Despite low-grade histologic features, however, o c c a s i o n a l l y o p t i c p a t h w a y g l i o m a s b e h a v e in a biologically aggressive fashion, with develop ment of leptomeningeal metastases and death. Although leptomeningeal dissemination of gli omas generally has a poor prognosis, three of t h e six p a t i e n t s d e s c r i b e d b y C i v i t e l l o a n d a s s o c i a t e s ' " w e r e alive after m u l t i a g e n t s y s t e m i c c h e m o t h e r a p y w i t h or w i t h o u t r a d i a t i o n t h e r a p y . O n e o f t h e s e p a t i e n t s w a s still a l i v e m o r e t h a n t h r e e y e a r s after t h e d i a g n o s i s o f l e p t o m e n i n g e a l d i s s e m i n a t i o n from t h e s p i n a l glioma. With improved radiologic diagnostic capa bilities, earlier detection of leptomeningeal s p r e a d m a y b e p o s s i b l e a n d m a y i m p a c t signifi cantly upon treatment planning and overall p r o g n o s i s . It is i m p o r t a n t that all c h i l d r e n w i t h o p t i c p a t h w a y t u m o r s b e c o n s i d e r e d for t h i s possibility, particularly patients who have l a r g e , infiltrating c h i a s m a l t u m o r s a n d p a t i e n t s with new, atypical neurologic s y m p t o m s . In c r e a s e d a w a r e n e s s of t h i s p o t e n t i a l p r o b l e m s h o u l d p r o m p t a m o r e e x t e n s i v e e x a m i n a t i o n in t h i s s u b g r o u p of p a t i e n t s w i t h o p t i c p a t h w a y gliomas, including cranial and spinal gadolini um-enhanced magnetic resonance imaging and c e r e b r o s p i n a l fluid e x a m i n a t i o n .
References 1. Wong, J. C. Y., Uhl, V., Wara, W. M., and Sheline, G. E.: Optic gliomas. A reanalysis of the
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University of California, San Francisco experience. Cancer 60:1847, 1987. 2. Flickenger, J. C , Torres, C , and Deutsch, Μ.: Management of low-grade gliomas of the optic nerve and chiasm. Cancer 6 1 : 6 3 5 , 1 9 8 8 . 3. Weiss, L., Sagerman, R. H., King, G. Α., Chung, C. T., and Dubowy, R. L.: Controversy in the man agement of optic nerve glioma. Cancer 5 9 : 1 0 0 0 , 1987. 4. Easley, J. D., Scharf, L., Chou, J. L., and Riccardi, V. M.: Controversy in the management of optic pathway gliomas. Neurofibromatosis 1:248, 1 9 8 8 . 5. Duffner, P. K., and Cohen, M. E.: Isolated optic nerve gliomas in children with and without neurofi bromatosis. Neurofibromatosis 1:201, 1 9 8 8 . 6. Alvord, E. C , and Lofton, S.: Gliomas of the optic nerve of chiasm. Outcome by patient's age, tumor site and treatment. J. Neurosurg. 68:85, 1988. 7. Imes, R. K., and Hoyt, W. F.: Childhood chias mal gliomas. Update on the fate of patients in the 1969 San Francisco study. Prog. Exp. Tumor Res. 30:108, 1987. 8. Bilgic, S., Erbengi, Α., Tinaztepe, B., and Onol, B.: Optic glioma of childhood. Clinical, histopatho logical, and histochemical observations. Br. J. Oph thalmol. 73:832, 1 9 8 9 . 9. de Keizer, R. J. W., de Wolff-RouendaaL D., Bots, G. T. A. M., Thomeer, R. T. W. M., Brouwer, O. F., and Vielvoye, G. J.: Optic glioma with intraoc ular tumor and seeding in a child with neurofibroma tosis. Am. J. Ophthalmol. 108:717, 1 9 8 9 . 10. Civitello, L. Α., Packer, R. J . , Rorke, L. B., Sie gel, P. Α., Sutton, L. N., and Schuf, L.: Leptomenin geal dissemination of low grade gliomas in child hood. Neurology 38:562, 1988. 11. Kocks, W., Kalff, R., Reinhardt, V., Grote, W., and Hilke, J.: Spinal metastasis of pilocytic astrocyto ma of the chiasma opticum. Child Nerv. Syst. 5:18, 1989. 12. Trigg, Μ. Ε., Swanson, J. D., and Letellier, M. Α.: Metastasis of an optic glioma through a ven triculoperitoneal shunt. Cancer 52:599, 1 9 8 3 . 13 Kanamori, M., Shibuya, M., Yoshida, J . , Takayasu, Μ., and Kageyama, N.: Long-term followup of patients with optic glioma. Child Nerv. Syst. 1:72, 1 9 8 5 . 14. Borit, Α., and Richardson, E. P., Jr.: The biolog ical and clinical behavior of pilocytic astrocytomas of the optic pathways. Brain 105:16, 1982. 15. Wilkins, R. H., and Odom, G. L.: Cytologicai changes in cerebrospinal fluid associated with resec tions of intracranial neoplasms. J. Neurosurg. 25:24, 1966. 16. Kovalic, J. J., Grigsby, P. W., Shepard, M. J . , Fineberg, Β. Β., and Thomas, P. R.: Radiation therapy for gliomas of the optic nerve and chiasm. Int. J. Radiat. Oncol. Biol. Phys. 18:927, 1 9 9 0 . 17. Packer, R. J . , Sutton, L. N., Bilaniuk, L. T., Radcliffe, J., Rosenstock, J. G., Seigel, K. R., Bunin, G. R., Savino, P. J . , Bruce, D. Α., and Schut, L.: Treatment of chiasmatic/hypothalamic gliomas of childhood with chemotherapy. An update. Ann. Neurol. 23:79, 1988.
