Journal of Neuro-Ophthalmology, December 1990, Volume 10, Issue 4

Internuclear ophthalmoplegia from intracranial tumor.

Bilateral internuclear ophthalmoplegia (INO) is most often demyelinative in origin. Rarely, structural lesions may present with this finding, but in these cases the age at onset and the associated signs of increased intracranial pressure and widespread brainstem dysfunction usually make the distinction. This report describes the 13th published case of tumor-induced INO, produced by an atypical adult medulloblastoma. Potential pathophysiologic mechanisms are discussed.

Journal of CliniCJ11 NeuTo- ophtlullmology 10( 4): 278- 286, 1990. Internuclear Ophthalmoplegia from Intracranial Tumor Anthony C. Arnold, M. D. ' 0 1990 Raven Press, Ltd., New York Bilateral internuclear ophthalmoplegia ( lNO) is most of­ten demyelinative in origin. Rarely, structural lesions may present with this finding, but in these cases the age at onset and the associated signs of increased intracra­nial pressure and widespread brainstem dysfunction usually make the distinction. This report describes the 13th published case of tumor- induced INO, produced by an atypical adult medulloblastoma. Potential pathophys­iologic mechanisms are discussed. Key Words: Internuclear ophthalmoplegia- Intracranial tumor- Medulloblastoma- Hydrocephalus. From the Department of Ophthalmology, Jules Stein Eye In­stitute, University of California, Los Angeles, California, U. S. A. Address correspondence and reprint requests to Anthony C. Arnold, M. D., Jules Stein Eye Institute. 800 Westwood Plaza, Los Angeles, CA 90024, USA. Presented to the 18th Annual I'vleeting 01 the Frank Walsh Society, Seattle, Washingtl11i. ['", bru" rv 21, 198,: 278 Internuclear ophthalmoplegia ( INO) indicates localized damage within the median longitudinal fasciculus ( MLF) and may be seen in a number of disease entities. Bilateral INO, particularly in a young adult, has long been considered the hall­mark of brainstem involvement in multiple sclero­sis ( MS); indeed, Cogan's early monograph stated that " when it is present alone or when it is the most conspicuous abnormality, the underlying condition is almost invariably MS" ( 1). Rarely, however, it is the presenting sign of a structural abnormality within the posterior fossa. This report documents the 13th published case of intracranial tumor manifesting this feature. CASE REPORT A 31- year- old white woman suffered an episode of horizontal diplopia lasting several hours and re­solving spontaneously. Over the next several weeks, she noted a persistent " clumsiness" of her eyes. During that time, she became aware of in­constant, mild left eyelid droop along with tearing of the right eye. She also developed an intermit­tent unsteadiness of gait attributed to easy fatiga­bility of her lower extremities. There was no his­tory of headache, visual loss, Uhthoff's phenome­non, or other neurologic dysfunction. Medical history was negative. Initial evaluation revealed corrected acuity of 20/ 15 bilaterally. Pupils measured 5 mm and were normally reactive without afferent pupillary de­fect. There was variable mild bilateral blepharo­ptosis, the left upper lid consistently 1- 2 mm be­low the right. Right orbicularis oculi weakness was present, but neither a lid twitch sign nor fatigabil­ity was detectable. The prominent neuro­ophthalmologic abnormality was marked ~ lowing of adducting saccades bilaterally, worse ( In the right, with mild limitation of right adduction .. , nge INTERNUCLEAR OPHTHALMOPLEGIA FROM INTRACRANIAL TUMOR 279 and bilateral horizontal gaze- evoked nystagmus, worse in the abducting eye. There was a mild ab­duction deficit on the right. Convergence was nor­mal. Supraduction was mildly symmetrically im­paired, not improved by oculocephalic testing, and associated with prominent gaze- evoked upbeating nystagmus. The ophthalmologic and cranial nerve examinations were otherwise normal; there was no evidence of papilledema. General neurologic ex­amination revealed only impaired tandem walk. Tensilon testing was negative on two occasions. Cerebrospinal fluid ( CSF) protein was 38 mg/ ml, glucose 56 mg/ ml, with no leukocytes or malignant cells; and samples sent for IgG synthesis, oligo­clonal bands, and myelin basic protein later re­turned negative. Visual evoked potentials ( VEP) and brainstem auditory evoked potentials ( BAEP) were normal. Serum VORL and fluorescent trepo­nemal antibody absorption ( FTA- Abs) were nega­tive. Anti- nuclear antibody ( ANA) was positive at 1: 100 ( speckled), but anti- DNA antibody was negative and the erythrocyte sedimentation rate was 5 mm/ hr. During the following week she developed gaze­evoked downbeat nystagmus and progressive lim­itation of left adduction range; neuroradiologic testing was performed. A double- dose contrast­enhanced computerized tomographic ( CT) scan was required to demonstrate a large posterior fossa mass with distortion and dilation of the third and fourth ventricles ( Figs. 1- 4). Tl- weighted views from the magnetic resonance ( MR) study more ef­fectively revealed a midline posterior fossa mass - 3 cm in diameter, arising from the cerebellar ver- FIG. 1. Double- dose contrast- enhanced axial CT scan displays a posterior fossa mass. FIG. 2. Higher axial view demonstrates distortion of the fourth ventricle by tumor ( arrow). mis, extending circumferentially around much of the fourth ventricle, and protruding forward to compress the region of the pontomedullary junc­tion. The Sylvian aqueduct and fourth ventricle were significantly dilated ( Figs. 5- 7). Right sagittal views showed infiltration of the brainstern ( Fig. 8). A suboccipital craniectomy was performed; the tumor was confirmed to arise from the vermis and to be infiltrating the floor of the fourth ventricle. There was no evidence of spread to the remaining neuroaxis. A subtotal excision was accomplished. Microscopic sections demonstrated a highly cel­lular small cell malignant neoplasm on a fibrillary background ( Fig. 9). Prominent within the tumor FIG. 3. The fourth ventricle is distended above level of tumor ( arrowhead). I Clill Neuro- ophlhalmol. Vol. 10. No. 4. 1990 280 A. C. ARNOLD FIG. 4. Axial view through third ventricle shows en­largement ( arrow). were rosettes surrounding fibrillary cores, typical for medulloblastoma ( Fig. 10). After radiation therapy, the patient was stable at 4 months after excision. Eye movements had im­proved significantly, but still demonstrated mild bilateral adduction range limitation. DISCUSSION INO is most commonly caused by demyelination or ischemia [ vertebrobasilar atherosclerosis, hy- FIG. 5. Axial T1- weighted MR scan view more clearly delineates the mass, 3 cm In diameter, arising from the cerebellum ( compare with Fig 1) I CIIII FIG. 6. Higher axial MR view, with circumferential ex­tension of the tumor around the fourth ventricle ( small arrow), abutting the brainstem ( large arrow). Compare with Fig. 2. pertensive or diabetic microvasculopathy, vasculi­tis, especially in lupus erythematosus ( 2) l, but has also been reported with hemorrhagic infarction from intrinsic brainstem vascular malformations, with syphilis, trauma, Wernicke's encephalopa­thy, encephalitis, drug intoxication, and syringo­bulbia ( 3,4). The demyelinative lesions of MS are most commonly bilateral ( 62- 71% in recent series) ( 5,6). Ischemic lesions are typically unilateral, re­flecting the paired, segmental distribution of the paramedian branches of the basilar artery in the brainstem. Although Gonyea ( 7) reported a signif­icant ( 29%) incidence of bilaterality in ischemic INO, mean age in the series was 57, with only one patient below 40, allowing a distinction from the demyelinative group. Clearly, the presence of prominent bilateral INO in a young adult without other significant neurologic dysfunction suggests MS; however, several important exceptions to this rule exist. The pseudo- INO of myasthenia described by Glaser ( 8) may resemble true INO very closely. In addition, the multiple ocular motor palsies, mus­cle- paretic nystagmus, and orbicularis weakness seen in this disorder may mimic the brainstem dys­function that can accompany true INO. A negative Tensilon test, which occurs in 10-- 20% of myas­thenics ( 9), particularly the ocular form, may n~ ake INTERNUCLEAR OPHTHALMOPLEGIA FROM INTRACRANIAL TUMOR 281 FIG. 7. Midline sagittal view illustrates the tumor's origin from the mid- inferior vermis, with anterior expansion into the floor of the fourth ventricle and com­pression of the pontomedullary junc­tion ( large arrowhead). The Sylvian aq­ueduct and fourth ventricle are signifi­cantly enlarged ( small arrowheads). the distinction clinically more difficult. Careful evaluation of fatigability, complemented by quan­titative eye movement recordings and supplemen­tal serologic and electromyographic testing, will nearly always establish this diagnosis. Structural lesions may rarely produce a picture in which INO is the prominent feature. Six cases of Chiari II malformation presenting with bilateral INO have been reported ( 3,10- 13); an additional three have recently been studied ( Arnold et al.). FIG. 8. Right sagittal view demon­strates infiltration into brainstem ( ar­rowhead). f Clin Nellro- ophthalmol. Vol. 10, No. 4, 1990 282 1( 1111 A. C. ARNOLD FIG. 9. Photomicrograph shows a highly cellular small cell malignant neoplasm on fibrillary background ( hematoxylin and eosin, x34). FIG. 10. Higher power shows typical Homer Wright rosettes ( hematoxylin and eosin, :> 212). \ ( I ] •• INTERNUCLEAR OPHTHALMOPLEGIA FROM INTRACRANIAL TUMOR 283 All nine had other evidence of significant brain­stem dysfunction; all but two were below age 21 and had signs or symptoms of elevated intracranial pressure. Madonick ( 14) published a case of INO attributed to brainstern compression by a cerebel­lar tuberculoma. Inocencio and Ballacer docu­mented bilateral INO in a patient with a midbrain tuberculous granuloma ( 15). Subdural hematoma has also been reported as a cause ( 16). Table 1 summarizes the reported cases of CNS tumor in which INO was a conspicuous initial finding ( 17- 22); in five, involvement was bilateral. Superimposed ipsilateral or contralateral horizon­tal gaze paresis, suggesting additional involve­ment of pontine paramedian reticular formation ( PPRF), abducens nucleus, fascicle, or peripheral nerve, was present in eight ( cases 3- 6, 10- 13). Two demonstrated complete " one and a half" syn­dromes ( cases 11, 12). Undoubtedly, additional cases with MLF involvement have been masked by more severe coincident dysfunction of the brain­stem oculomotor pathways. The majority of cases were infiltrating brainstem gliomas ( six patients), with two definite cerebellar medulloblastomas, one cerebellar astrocytoma, one epidermoid tumor of the fourth ventricle, and one metastatic malignant melanoma. Eight were under 18 years of age; Cogan and Wray stated in their report ( 18) that this was the most important factor in differentiating tumor from MS initially. In six of the cases, headache and/ or papilledema was present, while four additional patients had only neuroradiologic documentation of hydrocephalus as evidence of increased intracranial pressure. All had superimposed signs of more extensive brain­stem dysfunction, typically nystagmus, cranial nerve palsy, or ataxia. Thus, the key features that suggest a structural lesion rather than a demy­elinating focus causing INO are ( a) young age, ( b) signs and symptoms of elevated intracranial pres­sure, and ( c) Widespread brainstem abnormality, especially subtle superimposed gaze palsy. Gaze­evoked upbeat nystagmus as an isolated additional finding, however, is not necessarily indicative of a mass lesion, as it is not uncommonly associated with INO in MS. There is evidence that pathways for vertical gaze maintenance, vertical pursuit, and the vestibular input to the midbrain vertical gaze centers all pass through the MLF ( 4); an isolated plaque could account for both signs. Medulloblastoma is a highly malignant midline cerebellar tumor of childhood. The majority of cases present before the age of 10 ( 23), although a small number ( 20%) occur in patients over 16 ( 24); they have rarely been reported after age 20 ( 24). /---------- The adult forms are more often located in the cer­ebellar hemispheres, display corresponding signs of extremity ataxia without ocular findings, and have a better prognosis for survival, particularly the so- called " desmoplastic" variety ( 23). The typ­ical childhood midline tumor, however, originates from the roof of the fourth ventricle and invades the vermis, later growing into the ventricle and up the Sylvian aqueduct; rarely, late in the course, it infiltrates the ventricular floor. The usual presentation is thus commonly the re­sult of CSF flow obstruction, with headache, nau­sea, vomiting, and papilledema. Truncal or gait ataxia is commonly associated, but other signs of brainstem abnormality develop only in late stages of tumor growth. Eye movement disorders have rarely been described in detail. Most reports indi­cate only gaze- evoked or unspecified forms of nystagmus; the specific signs of midline cerebellar disease, such as ocular dysmetria, flutter, and re­bound nystagmus, have not been recorded. Cogan's earlier noted case of INO associated with medulloblastoma ( case 4) was a 10- year- old girl who initially demonstrated prominent elevated in­tracranial pressure and ataxia, only later develop­ing the eye movement abnormalities characteristic of brainstem dysfunction. This more classic pre­sentation is the only prior reported case of medul­loblastoma with INO. The present case is thus unusual in regard to age at onset, tumor type for age, early brainstem inva­sion in relation to other CNS signs, and the relative isolation of the INO ( including lack of the usual evidence of elevated intracranial pressure), caus­ing distinct diagnostic confusion with the more fre­quent causes of INO. It underscores the basic tenet that in the presence of neurologic signs and/ or symptoms, even those classic for nonstructuralle­sions, neuroimaging is essential before lumbar puncture. There are several possible mechanisms for the development of INO in patients with intracranial tumor: 1. Intra- axial involvement ( direct infiltration) of the MLF. Most prior reports have presumed this to be the cause of damage. 2. Extra- axial involvement ( external compres­sion) of the MLF by tumor. 3. Hydrocephalus- induced compression of the MLF within the floor of the distended fourth ventricle. This mechanism may also playa role in the rare cases of INO reported in the Arnold- Chiari malformation. 4. Ischemic or hemorrhagic infarcts of the MLF J elin Neuro- ophthalmol. Vol. 10. No. 4. 1990 INTERNUCLEAR OPHTHALMOPLEGIA FROM INTRACRANIAL TUMOR 285 caused by brainstem vascular distortion as a result of increased intracranial pressure and herniation ( 25). This has been proposed as a mechanism to explain the INO seen in trauma as well ( 16,26). The ischemic process probably was not a signifi­cant factor in these cases in which herniation was not present. The other three potentially treatable mechanisms all most likely contributed in varying degrees to the damage ( Table 2). Brainstem infiltration was prominent in 11 pa­tients, four of which ( cases 3- 5, 7) suffered relent­less clinical deterioration. In four, no follow- up was reported. The remaining three, all of which had superimposed dilation of the fourth ventricle, demonstrated improvement of eye movement ab­normalities after treatment: 1. Case 2 ( infiltrative glioma vs. medulloblas­toma) underwent tumor excision, shunt, and irradiation, with partial resolution of INO 11 months after treatment. 2. Case 9 ( infiltrative malignant glioma) showed mild clinical improvement after surgical de­compression, irradiation, and chemotherapy. 3. Case 13 ( medulloblastoma) improved signifi­cantly and was stabilized at 4 months after surgical decompression and irradiation. Three cases showed brainstem compression along with fourth ventricle dilation: 1. Case 8 ( extra- axial compression by epider­moid tumor) improved somewhat after tumor excision; it was not until shunt procedure that there was complete resolution of eye move­ment abnormalities. It is of interest that one TABLE 2. Presumed mechanisms of INO and response to therapy Case Mechanism Treatment Course 1 I 2 I, H S, D, R I 3 I S, D, R D 4 I R D 5 I S( late), D, R D 6 I, H S, R 7 I S( late), R D 8 C, H S, D I( resolved) 9 I, H D, R, C I 10 I S, D 11 C, H D N 12 I 13 I, C, H D, R Mechanism: I, infiltrative; H, 4th ventricle dilation; C, com­pression. Treatment: S, shunt; D, surgical decompression; R. radiation; C, chemotherapy. Course: I, improved: D, deterio­rated; N, no change. (-, No data available.) of Cogan's reported cases of Amold- Chiari malformation showed resolution of INO with shunt and recurrence after return of hydro­cephalus ( 3). 2. Case 11 ( benign cerebellar astrocytoma) had no change after tumor excision; a shunt pro­cedure was not described. 3. Case 13 ( medulloblastoma), described above, had additional evidence of infiltration, but improved with therapy. In total, a dilated fourth ventricle was present in six cases, four of which improved with treatment, one demonstrated no change, and one had no fol­low- up reported. Data available on long- term course is limited in these cases, but to the extent to which hydrocephalus and extra- axial compres­sion are involved, a significant reversible compo­nent of eye movement abnormalities may be present. Infiltration without other contributing mechanisms has a predictably poor response to therapy. REFERENCES 1. Cogan DG. Neurology of the Ocular Muscles. Springfield, lL: Charles C. Thomas, 1956: 87- 88. 2. jackson G, Miller M, Littlejohn G, et al. Bilateral internu­clear ophthalmoplegia in systemic lupus erythematosus. f RheumatoI1986; 13: 1161- 2. 3. Cogan DG. Internuclear ophthalmoplegia, typical and atypical. Arch Ophthalmol 1970; 84: 583- 9. 4. Miller NR. Topical diagnosis of neuropathic ocular motility disorders: internuclear ophthalmoplegia. In: Walsh and Hoyt's Clillical Nel/ yo- Ophthalmology. Baltimore: Williams and Wilkins, 1985: 707- 15. 5. Crane TB, Yee RD, Baloh RW, et al. Analysis of character­istic eye movement abnormalities in internuclear ophthal­moplegia. Arch Ophthalmol 1983; 101: 206- 10. 6. Ruelen jPH, Sanders EACM, Hogenhuis LAH. Eye move­ment disorders in multiple sclerosis and optic neuritis. Braill 1983; 106: 121-- 40. 7. Gonyea EF. Bilateral internuclear ophthalmoplegia. Arch Neurol 1974; 31: 16&- 73. 8. Glaser jS. Myasthenic pseudo- internuclear ophthalmople­gia. Arch Ophthalmol 1966; 75: 363- 6. 9. Wechsler AS, Olanow CWo Myasthenia gravis. Surg Clin N Am 1980; 60: 931-- 45. 10. Houtman WA, Meihuizen- De Regt MJ, Rutgers CH. Stra­bismus and meningimyelocele. Doc OphthalmoI1981; 50: 255­61. 11. Collard M, Strubel- Streicher 0, Eber AM, et al. Les troubles oculomoteurs dans les malformations d' Arnold- Chiari. Rt? ll Neural ( Paris) 1980; 136: 531- 8. 12. Nishizaki T, Tamaki N, Nishida Y, et al. Bilateral internu­clear ophthalmoplegia due to hydrocephalus: a case report. Neurosurgery 1985; 17: 822- 5. 13. Woody RC, Reynolds jD. Association of bilateral internu­clear ophthalmoplegia and myelomeningocele with Ar­nold- Chiari malformation, type II. f Cli'l Nellro- ophthalmol 1985; 5: 124-- Q. 14. Madonick Mj. Ophthalmoplegia internuclearis anterior without a lesion of the posterior longitudinal bundle. Arch Neural Psychiatry 1951; 66: 338-- 45. , Clill NeIlTo- ophthalmol, Vol. 10. No. 4. 1990 286 A. C. ARNOLD 15. Inocencio FP, Ballecer R. Tuberculosis granuloma in the midbrain causing wall- eyed bilateral internuclear ophthal­moplegia ( webino). JClin Neuro- ophthalmoI1985; 5: 31- 5. 16. Devereaux MW, Brust JCM, Keane JR. Internuclear oph­thalmoplegia caused by subdural hematoma. Neurology 1979; 29: 251- 5. 17. Smith Jl, Cogan DG. Internuclear ophthalmoplegia. Arch OphthalmoI1959; 61: 687- 94. 18. Cogan DG, Wray SH. Internuclear ophthalmoplegia as an early sign of brainstem tumors. Neurology 1970; 20: 629- 33. 19. Enoksson P. Internuclear ophthalmoplegia and paralysis of horizontal gaze. Acta OphthalmoI1965; 43: 697- 707. 20. Troost RI, Martinez 1. Abel lA, et al. Upbeat nystagrnus and internuclear ophthalmoplegia with brainstem glioma. Arch Neurol 1980; 37: 453- 6. 21. Schraeder Pl, Cohen MM, Goldman W. Bilateral internu-clear ophthalmoplegia associated with fourth ventricular epidermoid tumor. JNeurosurg 1981; 54: 403- 5. 22. Pierrot- Deseilligny CH, Chain F, Serdaru M, et al. The " one- and- a- half" syndrome. Electro- oculographic analyses of five cases with deductions about the phySIologIcal mech­anisms of lateral gaze. Brain 1981; 104: 665- 99. 23. Cohen ME, Duffner PK. Brain Tumors in Children. New York: Raven Press, 1984: 103- 21. 24. Hughes PG. Cerebellar medulloblastoma in adults. J Neu­rosurg 1984; 60: 994-- 7. 25. Wolman L. Ischaemic lesions in the brain- stem associated with raised supratentorial pressure. Brain 1953; 76: 364-- 77. 26. Rich JR, Gregorius FK Hepler RS. Bilateral internuclear ophthalmoplegia after trauma. Arch Ophthalmol 1974; 92: 66- 8.