Journal of Neuro-Ophthalmology, December 1988, Volume 8, Issue 4

Paraneoplastic downbeating nystagmus. A sign of occult malignancy.

We report a case of primary position downbeating nystagmus due to an occult breast carcinoma in a 57-year-old woman with progressive oscillopsia and truncal ataxia. Acute nausea and vomiting precipitated hospitalization. Magnetic resonance imaging of the brain was normal, though a sterile mononuclear cerebrospinal fluid pleocytosis was present. Search for an occult malignancy disclosed an adenocarcinoma of the breast. Radical mastectomy and oral corticosteroid therapy did not alter the clinical course of the paraneoplastic syndrome in our patient. Primary position downbeating nystagmus is an uncommon manifestation of an occult malignancy. Our report and review of the literature suggests that investigations necessary for the diagnosis of occult malignancies of the lung, breast, uterus, and ovary be included in the search for cryptic causes of downbeating nystagmus.

Journal of Clinical Neuro-ophthalmology 8(4): 269-272, 1988. Paraneoplastic Downbeating Nystagmus A Sign of Occult Malignancy John R. Guy, M.D., and Norman J. Schatz, M.D. © 1988 Raven Press, Ltd., New York We report a case of primary position downbeating nystagmus due to an occult breast carcinoma in a 57­year- old woman with progressive oscillopsia and truncal ataxia. Acute nausea and vomiting precipitated hospi­talization. Magnetic resonance imaging of the brain was normal, though a sterile mononuclear cerebrospinal fluid pleocytosis was present. Search for an occult ma­lignancy disclosed an adenocarcinoma of the breast. Radical mastectomy and oral corticosteroid therapy did not alter the clinical course of the paraneoplastic syn­drome in our patient. Primary position downbeating nystagmus is an uncommon manifestation of an occult malignancy. Our report and review of the literature sug­gests that investigations necessary for the diagnosis of occult malignancies of the lung, breast, uterus, and ovary be included in the search for cryptic causes of downbeating nystagmus. Key words: Downbeating nystagmus-Occult malig­nancy. From the Departments of Ophthalmology and Neurology, UniverSity of Florida, Gainesville, Florida O.R.G.), and the De­!, artments of Ophthalmology and Neurology, University of Pennsylvania, Philadelphia, Pennsylvania (N.).S.). Address correspondence and reprint requests to Dr. J. R. Guy at the Neuro-Ophthalmology Service, Box )-284 )HMHC. University of Florida, School of Medicine, Gainesville, FL 32610, U.S.A. 269 The remote effects of cancer on the body are collectively known as the paraneoplastic syn­dromes. The visual system (I), the eNS (2-8), the peripheral nervous system (9), the neuromuscular junction (10), and the skeletal muscles (11) may be affected indirectly by malignancy. Moreover, the involvement of these organ systems may predate the discovery of a primary malignancy (12). The tumor's indirect effects may be due to the produc­tion of biologically active hormones or antigen­antibody interactions (13-19). The paraneoplastic syndrome of opsoclonus­myoclonus and ataxia in association with occult carcinomas of the lung, breast, and gynecologic organs in adults and neuroblastoma in children is well recognized (20-22). However, primary posi­tion downbeating nystagmus is an uncommon manifestation of an occult malignancy (24,25). We describe a case of paraneoplastic downbeating nystagmus and review its description in the liter­ature. CASE REPORT A 57-year-old woman complained of 2 months of progressive oscillopsia and difficulty with gait. She was no longer able to read or walk and due to persistent nausea and vomiting was unable to eat for 2 weeks before admission. Neuro-ophthalmic examination revealed visual acuity to be 20/40 in each eye. Downbeating nystagmus was present in primary position and increased in amplitude on upgaze and lateral gaze, but dampened on downgaze. Smooth pursuits were saccadic, and ocular dysmetria was easily elicited. There was neither ocular misalignment nor limitation in vertical or horizontal excursion of eye movements. Pupillary size and reactivity, Goldmann visual fields, and ophthalmoscopic ex­amination of the optic nerves were normal. Neu- 270 ]. R. GUY AND N. ]. SCHATZ rologic examination disclosed bilateral and sym­metric difficulty with performance of heel-to-shin and finger-to-nose testing. Severe truncal ataxia prevented ambulation without assistance. During hospitalization, nausea and vomiting were re-· lieved with a scopolamine skin patch. Oscillopsia was diminished by inducing convergence with 4 diopters of baseout Fresnel prism (26), making television viewing more comfortable. Neurodiagnostic imaging included normal mag­netic resonance imaging (MRI) of the brain and cervicomedullary junction. A sterile mononuclear cerebrospinal fluid (CSF) pleocytosis of 20 white blood cells per cubic millimeter was present, though a CSF glucose level of 65 mg/dl and CSF protein level of 43 mg/dl were normal. Cytologic examination of the CSF was negative for malig­nancy. The CSF IgG level was elevated to 6.5 mg/ dl. However, brainstem auditory evoked poten­tials and visual evoked potentials were normal. A 24-h urine screen for the presence of heavy metals was negative. A high CSF Purkinje cell antibody titer was detected at a dilution of 1:128,000. Search for an occult malignancy disclosed a pal­pable left-sided axillary lymph node. Mammogra­phy detected a small left-sided breast mass. Histo­pathologic findings obtained at the time of surgical biopsy confirmed the breast mass to be an infiltrat­ing ductal adenocarcinoma. A left radical mastec­tomy and postoperative oral corticosteroid treat­ment did not alter the clinical course of this pa­tient's downbeating nystagmus and ataxia. DISCUSSION Downbeating nystagmus is a less frequently rec­ognized manifestation of a paraneoplastic syn­drome than the opsoclonus-myoclonus ataxia syn­drome (20-23). The association of downbeating nystagmus and the paraneoplastic cerebellar syn­drome has received mention in seven publications describing 14 patients. The first was in a report by Zee et al. (27), who had described downbeating nystagmus in a woman with an occult ovarian car­cinoma. The second was by Halmagyi et al. (24), who described four of 62 patients with downbeat­ing nystagmus as having a paraneoplastic syn­drome in association with carcinomas of the lung, ovary, and breast, two of whom had occult malig­nancies. The third case report, by Kearsley et al. (28), described downbeating nystagmus and ocu­lar flutter in a patient with adenocarcinoma of the breast. In a fourth case report, Tsukamoto et al. (15) described two cases with downbeating nystag­mus and paraneoplastic involvement of the cere- , " .•.. 1 \/,,1 S. No.4. 1988 bellum associated with uterine and ovarian adeno­carcinomas. The fifth report, by Saul and Towfighi (29), described one of three patients with parane­oplastic primary position vertical ny~tagmus as having downbeating nystagmus. The SIXth report, by Anderson et al. (30), revealed four patients with paraneoplastic downbeating nystagmus. T~o had carcinomas of the breast and ovary, while the other two had unknown primary cancers. Lastly, Miller (31) described a woman with paraneoplastic downbeating nystagmus and an occult ovarian car­cinoma. In our case, and in those of Halmagyi et al. (24), downbeating nystagmus did not obey Alexander's rule. However, further description of amplitude changes with upward or downward gazes in most case reports precluded any definitive statement of whether the changes in amplitude of downbeating nystagmus with vertical gaze may distinguish paraneoplastic downbeating nystagmus from other causes of downbeating nystagmus that obey Alexander's rule. Common to all reported cases of paraneoplastic downbeating nystagmus was a paraneoplastic de­generation of the cerebellum in association with truncal ataxia as a prominent clinical feature (15,24,27-31). While computerized axial tomogra­phy and MRI may confirm paraneoplastic atrophy of the cerebellum (15,24,32,33), neuroimaging studies may be normal (28,30,31,34). Pleocytosis of the CSF was present in our case and that of Kears­ley et al (28). The acute onset of neurologic signs associated with nausea and vomiting may also suggest a paraneoplastic syndrome. However, the latter signs were present in only three of the 11 patients reported to have paraneoplastic down­beating nystagmus. Moreover, these signs were not present at the onset of neuro-ophthalmic signs in our patient (Table 1). Marked loss of Purkinje cells in the absence of cerebellar inflammation has been a characteristic histopathologic finding in the syndrome of para­neoplastic cerebellar degeneration (35-37). Au­toantibodies directed against Purkinje cells are also a feature of this disorder. Our patient had a high antibody titer to Purkinje cells, as did the two pa­tients of Tsukamoto et al (15). The presence of these autoantibodies may suggest a tumor­induced immune-mediated origin of paraneoplas­tic downbeating nystagmus and paraneoplastic cerebellar degeneration (15). The differential diagnosis of downbeating ny~tagmus includes structural lesions of the pos­tenor fossa and craniocervical junction, medication toxicity, infection, and metabolic and degenerative PARANEOPLASTIC DOWNBEATING NYSTAGMUS 271 TABLE 1. Summary of cases of paraneoplastic downbeating nystagmus Acute Cerebrosinal nausea Occult fluid Neurologic Type of and Authors Malignancy Cases, n/sex malignancy pleocytosis imaging downbeat" vomiting Guy and Schatz Breast 1/F Yes Present MRI: nl 2 Yes Halmagyi et al. (24) Lung, breast, and ovary 4/M Yes (2) NO CT: cerebellar 2 No F (3) No (2) NO atrophy Kearsley et al. (28) Breast 1/F No Present CT: nl NO Yes Saul and Towfighi (29) Ovary 1/F Yes NO NO NO NO Miller (31) Ovary 1/F Yes Absent MRI: nl NO No Tsukamoto et al. (15) Uterus and ovary 21F Yes Absent CT: cerebellar NO Yes atrophy (2) Zee et al. (27) Ovary 1/F Yes Present CT: nl NO No Anderson et al. (30) Ovary, breast and 4/F (4) Yes NO CT/MRI: nl NO No unknown primary (2) CT, computerized axial tomography; MRI, magnetic resonance imaging; nl, normal; NO, not described. Numbers in parentheses reflect the numbers of patients associated with a particular category, if more than one. S Type of downbeat is 2 if amplitude increases in upgaze and 1 if its amplitude increases in downgaze. disorders (24,25,39). Investigation of structural le­sions associated with downbeating nystagmus may reveal a Chiari malformation (24,25), Klippel­Feil anomaly (25), platybasia (25), basilar impres­sion (25), or tumors and hemorrhage of the cere­bellum (24,25). Magnetic resonance imaging is the neuroimaging procedure of choice now recom­mended for investigation of lesions of the cranio­cervical junction and posterior fossa (39), Medica­tions and toxins that may induce downbeating nystagmus include carbamazepine (40), phenytoin (41), amiodarone hydrochloride (42), ethanol (43,44), and lithium carbonate (45). Infectious ori­gins of downbeating nystagmus may include herpes simplex encephalitis (46), Legionnaire's disease (47), and encephalomyelitis (48), Metabolic disorders associated with downbeating nystagmus include hypomagnesemia (49), vitamin B12 defi­ciency (50), and sudanophilic leukodystrophy (51), Neurodegenerative disorders may include the olivopontocerebellar atrophies (24,25) and familial periodic ataxia (52,53). 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