Journal of Neuro-Ophthalmology, June 2004, Volume 24, Issue 2

Bilateral Horizontal Gaze Palsy in Presumed Paraneoplastic Brainstem Encephalitis Associated with a Benign Ovarian Teratoma

A 28-year-old woman with a previous history of recurrent benign ovarian teratoma developed a bilateral horizontal gaze palsy, a right facial paresis, and bilateral trigeminal hypesthesia. Magnetic resonance imaging disclosed high signal in the rostral pons. Results of all other laboratory studies, including those for antineuronal antibodies (anti-Hu, anti-Yo, anti-Ri, anti-Tr, anti-Ma1, anti-Ma2, and anti-CV2/CRMP5), were negative. Pelvic ultrasound revealed a residual mass in the left ovary, which was confirmed as teratoma on surgical pathological examination. Complete neurologic recovery occurred within two weeks of surgical removal of the teratoma and treatment with intravenous corticosteroids and immunoglobulin. This case demonstrates that a search for an occult neoplasm is extremely important in the diagnosis of presumed paraneoplastic encephalitis even if antineuronal antibodies are not found.

ORIGINAL CONTRIBUTION Bilateral Horizontal Gaze Palsy in Presumed Paraneoplastic Brainstem Encephalitis Associated With a Benign Ovarian Teratoma RajeevH. Muni, MD, Richard Wennberg, MD, FRCPC, David J. Mikulis, MD, FRCPC, and Agnes M. F. Wong MD, PhD, FRCSC Abstract: A 28- year- old woman with a previous history of recurrent benign ovarian teratoma developed a bilateral horizontal gaze palsy, a right facial paresis, and bilateral trigeminal hypesthesia. Magnetic resonance imaging dis­closed high signal in the rostral pons. Results of all other laboratory studies, including those for antineuronal anti­bodies ( anti- Hu, anti- Yo, anti- Ri, anti- Tr, anti- Mai, anti- Ma2, and anti- CV2/ CRMP5), were negative. Pelvic ultra­sound revealed a residual mass in the left ovary, which was confirmed as teratoma on surgical pathological examina­tion. Complete neurologic recovery occurred within two weeks of surgical removal of the teratoma and treatment with intravenous corticosteroids and immunoglobulin. This case demonstrates that a search for an occult neoplasm is extremely important in the diagnosis of presumed paraneo­plastic encephalitis even if antineuronal antibodies are not found. ( JNeuvo- Ophthalmol 2004; 24: 114- 118) Paraneoplastic syndromes are remote effects of cancer that are not directly related to tumor growth, metastases, metabolic or nutritional derangements, or side effects of therapy. The clinical manifestations of a paraneoplastic From the Department of Ophthalmology and Vision Sciences ( RHM, AMFW), Division of Neurology ( RW, AMFW), and the Department of Medical Imaging ( DJM), Division of Neuroradiology, University of To­ronto and University Health Network, Toronto Western Hospital, Toronto, Ontario, Canada. Presented at the 35th Frank B. Walsh Session of the North American Neuro- Ophfhalmology Society Annual Meeting, Salt Lake City, Utah, February 9, 2003. Supported by the E. A. Baker Foundation of the Canadian National Institute for the Blind, the Canadian Institutes of Health Research ( New Investigator Award 55058 and grant MOP 57853), and the Toronto West­ern Hospital Department of Ophthalmology Practice Plan. Address correspondence to Agnes M. F. Wong, MD, PhD, FRCSC, WW5- 437, University Health Network, Toronto Western Hospital, 399 Bathurst Street, Toronto, Ontario M5T 2S8, Canada. E- mail: agnes. wong@ utoronto. ca process are often the first presentation of an underlying tu­mor ( 1). Paraneoplastic encephalomyelitis- sensory neu-ronopathy ( PEM- SN) is a well- characterized syndrome that is typically irreversible and most commonly associated with small- cell lung cancer and anti- Hu antibodies ( 2). The clinical manifestations are variable, including multifocal involvement of the central or peripheral nervous system or both, and brainstem or limbic encephalitis. There are a few case reports of supranuclear, nuclear, or internuclear ocular motor abnormalities affecting horizontal or vertical eye movements or both in patients with PEM- SN ( 3- 8). We re­port a case of complete bilateral horizontal gaze palsy in a patient with a presumed paraneoplastic brainstem encepha­litis associated with a benign ovarian teratoma. Surgical re­moval of the tumor, combined with intravenous corticoste­roid and immunoglobulin treatment, rapidly reversed all neuro- ophthalmic manifestations. CASE REPORT In 1998, a 28- year- old woman of Chinese descent de­veloped impaired memory, personality change, auditory hallucinations, inappropriate behavior, and hypersomno-lence followed by acute central respiratory failure that re­quired mechanical ventilation. Findings on magnetic reso­nance imaging ( MRI) scans and extensive laboratory work­ups were normal, except for a mild cerebrospinal fluid ( CSF) pleocytosis and minimal electroencephalographic bilateral background irregularities. A palpable pelvic mass was confirmed on ultrasound and computed tomography as a 14 x 10 x 10- cm complex cystic lesion in the right ovary. Neurologic symptoms resolved eight weeks after a com­plete right salpingo- oophorectomy and removal of a mature cystic ovarian teratoma, in conjunction with 400 mg/ kg in­travenous immunoglobulin ( IVIG) per day for five days and 1 g intravenous methylprednisolone daily for five days, fol­lowed by a gradual taper of oral prednisone starting at a daily dose of 60 mg. Nearly three years later, she developed slurred speech. An MRI scan showed a small, hyperintense T2- 114 JNeuro- Ophthalmol, Vol. 24, No. 2, 2004 Bilateral Horizontal Gaze Palsy JNeuro- Ophthalmol, Vol. 24, No. 2, 2004 weighted signal in the dorsal posterior aspect of the medulla just anterior to the fourth ventricle. Again, findings on ex­tensive laboratory testing, including CSF oligoclonal bands and evoked potentials, were normal. Ultrasonography re­vealed the presence of two small, 2- cm cystic masses in the left ovary that were not present at the time of her first ill­ness. Six weeks after partial left salpingo- oophorectomy with resection of a benign ovarian teratoma and IVIG and corticosteroid therapy, her neurologic manifestations resolved ( 9). Seven months later, she developed a one- week his­tory of progressive diplopia, numbness of both sides of the face ( including the anterior half of the tongue), and ataxia. Visual acuity was 20/ 20 in each eye. Pupils, visual field, color vision, and findings on slit- lamp and funduscopic ex­aminations were normal. She had a complete bilateral hori­zontal gaze palsy affecting saccades, smooth pursuit, and the vestibulo- ocular reflex ( VOR). Vertical eye movements and convergence were normal. She had reduced sensation to pinprick over the face and anterior scalp bilaterally. A mild right facial weakness was present. Corneal sensation FIG. 1. A. Axial T2- weighted magnetic resonance imaging periaqueductal region. B. Axial FLAIR at the same level accer was mildly reduced OD. She had moderate difficulty with tandem gait. Mental status examination was normal. Re­sults of cardiovascular, respiratory, and abdominal exami­nations were normal. Findings on investigation of the following were all normal: complete blood cell count; electrolytes, creatinine, blood urea nitrogen, glucose, calcium, magnesium, and phosphate; INR, partial thromboplastin time, AST, ALP, bilirubin, lactate dehydrogenase, creatine kinase, and C-reactive protein; CSF studies ( cell count, oligoclonal bands, glucose, protein, albumin, Venereal Disease Research Laboratories test, immunoglobulin G [ IgG], polymerase chain reaction for cytomegalovirus, herpes simplex virus, and Epstein- Barr virus, immunofluorescent assay for cyto­megalovirus, cryptococcal antigen, bacterial, viral and fun­gal cultures); anti- dsDNA, anti- Sm, anti- RNP, anti- Ro, anti- La, ANCA, rheumatoid factor, anti- centromere, anti-mitochondrial, and smooth muscle antibodies; cryoglobu­lin, C3, C4, human immunodeficiency virus ( HIV), hepati­tis B and C serological testing; alpha feto- protein and Cal25 tumor markers; antineuronal antibodies ( anti- Hu, scan at the level of the mid pons shows high signal in the tuates the high signal area noted on the T2- weighted study. 115 JNeuro- Ophthalmol, Vol. 24, No. 2, 2004 Muni et al anti- Yo, anti- Ri, anti- Tr, anti- Mai, anti- Ma2, and anti- CV2/ CRMP5); visual, somatosensory, and brainstem audi­tory evoked potentials; chest x- ray; urinalysis; and beta- HCG. Serum immunoglobulin quantification revealed an elevated IgG level ( 31.9g/ L) and normal immunoglobulin A and immunoglobulin M levels, with no M- spike. Pelvic ultrasound revealed a 1.7 x 1.5 x 1.1- cm mass in the left ovary, consistent with a residual or recurrent ter­atoma. Brain MRI scan demonstrated a region of hyperin-tense signal on T2- weighted scan and FLAIR in the midline dorsal pons involving the facial colliculus extending to the floor of the fourth ventricle ( Fig. 1). No abnormality was found in the cerebral hemispheres. The patient was started on a daily regimen of 1 g in­travenous methylprednisolone and 24 g IVIG. Despite treatment, she continued to deteriorate with new onset of dysphagia after five days. She underwent a partial left sal-pingo- oophorectomy. Surgical pathological findings re­vealed a benign residual cystic teratoma characterized by a small, keratin- filled cyst of 1.4 cm in maximum dimension with an associated granulomatous reaction ( Fig. 2). Follow­ing surgery, she was treated with another three- day course of 24 g IVIG daily. Within two weeks after surgery, her bilateral horizontal gaze palsy, dysphagia, and bilateral fa­cial numbness had resolved. She was discharged on a taper­ing dose of oral prednisone and remained free of symptom at a 10- month follow- up. DISCUSSION Our patient, who had history of recurrent benign ovarian teratoma, manifested recurrent central nervous sys­tem ( CNS) symptoms and signs, starting with a limbic en­cephalopathy and later brainstem involvement. All neuro­logic manifestations disappeared promptly after surgical removal of the teratoma, in combination with corticosteroid and IVIG therapy. In the most recent episode, she presented with a brainstem encephalitis manifested by hypesthesia in the tri­geminal distribution, bilateral horizontal gaze palsy, and a right lower motor neuron facial paresis. The absence of horizontal saccades, smooth pursuit, and VOR, with spar­ing of convergence, was consistent with a lesion in the sixth nerve nuclei bilaterally, with or without involvement of the paramedian pontine reticular formation. It is conceivable that the tumor was a coincidental finding and that the neurologic manifestations were due to another disease process. However, results of our extensive investigations for an infectious, vasculitic, or other neoplas­tic condition were negative. A relapsing demyelinating dis­ease is unlikely, considering the prolonged psychiatric disturbance followed by acute central respiratory arrest, normal laboratory findings ( including the absence of oligo-clonal bands in the CSF), the absence of white matter FIG. 2. Histopathological appearance of the left ovary ( he­matoxylin and eosin stain). A. Low magnification ( original magnification X25) shows a keratin- filled cyst of 1.4 cm in maximum dimension. B. Higher magnification ( original magnification X50) shows a keratin- filled cyst { long arrow) and associated granulomatous reaction ( short arrows). abnormalities in either hemisphere on multiple MRI scans, and the dramatic recovery following surgical resection of the tumor in each episode. These phenomena support a di­agnosis of paraneoplastic encephalitis. PEM- SN, first described by Henson ( 10) in 1965, is a rare disorder with variable clinical manifestations depend­ing on the location of degeneration in the central or periph­eral nervous system, or both. Dalmau et al ( 11) found that 78% of patients with PEM- SN and anti- Hu antibodies in their serum had small- cell lung cancer, whereas 13 % had no detectable tumor. Other malignancies associated with PEM- SN include ovarian and breast carcinomas, Hodg-kin's disease, non- Hodgkin's lymphoma, other lung tu­mors, and cancers of the gastrointestinal tract, kidney, bladder, and prostate gland ( 1). Seventy- three percent of patients with PEM- SN present with multifocal involvement of the nervous system ( 11). Predominant findings include 116 © 2004 Lippincott Williams & Wilkins Bilateral Horizontal Gaze Palsy JNeuro- Ophthalmol, Vol. 24, No. 2, 2004 sensory neuronopathy ( 62%), motor neuron dysfunction ( 20%), limbic encephalopathy ( 20%), cerebellar involve­ment ( 15%), brainstem encephalopathy ( 14%), and auto­nomic nervous system dysfunction ( 10%) ( 11). A number of antibodies have been associated with PEM- SN ( 2,12). Because the sensitivity of available tests for these antibodies is only 50% to 60% ( 12), the diagnosis of PEM- SN should be entertained even without positive se­rological findings. Pathologically, PEM- SN is characterized by gliosis and glial nodule formation, neuronal loss and degeneration, and perivascular lymphocytic infiltration without concomi­tant vasculitis in small arterioles ( 13). Treatment consists of removal of the underlying tumor. Immunomodulatory therapy using corticosteroids, plasmapheresis, or IVIG is rarely effective ( 11,14), but improvement has been reported in single patients ( 15,16). Even with tumor removal, the majority of patients have progressive neurologic decline, often ending in death within weeks to months as a result of autonomic dysfunction or respiratory failure of central or neuromuscular origin ( 11). There are a few cases with an indolent ( 17) or fluctuating ( 18,19) natural course, as well as those with spontaneous improvement of neurologic symptoms ( 20) or tumor regression ( 21). Our patient is the first documented case of complete bilateral horizontal gaze palsy secondary to a reversible presumed paraneoplastic brainstem encephalitis associated with a benign ovarian teratoma. There have been two other reported cases of limbic encephalitis associated with imma­ture ovarian teratomas. In both cases, antineuronal antibod­ies were not detected and symptoms improved or stabilized after tumor removal ( 22,23). In fact, our patient's initial presentation was in many ways similar to these two re­ported cases, lending further support to a paraneoplas­tic origin. Ocular motor abnormalities have been associated with several different CNS paraneoplastic syndromes. In subacute paraneoplastic cerebellar degeneration, there have been descriptions of downbeat, upbeat, rotary, gaze-evoked, and rebound nystagmus, as well as opsoclonus, ocular flutter, saccadic dysmetria, saccadic pursuit, and skew deviation ( 1). In paraneoplastic opsoclonus syn­drome, involuntary, arrhythmic, multidirectional saccades in all three dimensions have been documented ( 24). Supranuclear, nuclear, and internuclear abnormali­ties of ocular motility have been described in PEM- SN, but not with a benign ovarian teratoma ( 3- 8). Baloh et al ( 4) reported two patients with prostate cancer who had selec­tive loss of horizontal saccades with sparing of horizontal slow eye movements. Postmortem examination revealed perivascular chronic inflammatory cells and microglial infiltration of the pons and medulla; neuronal loss in the pontine tegmentum, medulla, and cerebellum; but preser­vation of brainstem motor nuclei. Both patients had promi­nent inflammatory cell infiltrates and microglial nodules in the paramedian pontine reticular formation, accounting for the selective loss of horizontal saccades. Neither patient had antineuronal antibodies detected in the blood. Crino et al ( 13) reported three patients with ophthal-moparesis who had paraneoplastic brainstem encephalitis. One of them, who had a small- cell lung cancer and anti- Hu antibodies, had a bilateral horizontal gaze palsy affecting saccades, pursuit, and the VOR. Another patient had a com­plete external ophthalmoplegia and positive anti- Hu anti­bodies, but no evidence of systemic malignancy. On post­mortem examination, the oculomotor, abducens, and trochlear nuclei were devoid of normal neurons. A third patient ex­hibited supranuclear ophthalmoparesis with profoundly re­duced voluntary vertical and horizontal eye movements. Anti- Hu antibodies were negative. Following a course of methylprednisolone, the patient's neurologic status contin­ued to decline, and she subsequently died of pneumonia. On postmortem examination, a papillary follicular thyroid car­cinoma and an uterine leiomyoma were detected. Pillay et al ( 5) described internuclear ophthalmople­gia and " optic neuritis" in a patient with bronchial carci­noma. Pathological examination revealed secondary demy-elination of the medial longitudinal fasciculus and focal neuronal loss in the nuclei of the third, fourth, and sixth nerves. Reddy and Vakili ( 6) described a patient with mid­brain encephalitis and lung cancer who had a bilateral third nerve palsy. Pathological correlation revealed focal neuronal loss and gliosis involving the oculomotor nu­clear complex. Schiff et al ( 7) reported a patient with small- cell car­cinoma of the lung and anti- Hu- associated encephalopathy, with vertical gaze paresis, absent downgaze, poor fixation, and hypometric horizontal saccades. Bennett et al ( 8) re­ported two patients with testicular cancer who exhibited su­pranuclear gaze disorders as a manifestation of PEM- SN. The first patient had a vertical gaze palsy with oculogyric crisis, lid retraction, and ocular tilt reaction. The second pa­tient had a left hypertropic skew deviation, accompanied by a fluctuating, mixed pendular and jerk nystagmus. Both were positive for anti- Ta antibodies. 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