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Show Journal of Neuro- Ophthalmology 16( 1): 44- 48, 1996. < 1996 Lippincott- Raven Publishers, Philadelphia Clinicopathologic Study of Paraneoplastic Brainstem Encephalitis and Ophthalmoparesis P. B. Crino, M. D., Ph. D., S. L. Galetta, M. D., R. A. Sater, M. D., Ph. D., E. C. Raps, M. D., A. Witte, M. D., D. Roby, M. D., and A. C. Rosenquist, Ph. D. We report three patients who exhibited ophthalmoparesis as an early manifestation of progressive paraneoplastic brainstem encephalitis. In two patients, anti- Hu antibodies were detected, whereas in a third, found at postmortem to have thyroid cancer, no antibodies were identified. Postmortem examination of two patients disclosed extensive gliosis, perivascular inflammation, and cell loss in the midbrain and pontine tegmentum. In one of these patients, there was selective neuronal loss within the third, fourth, and sixth nerve nuclei. We conclude that supranuclear or nuclear ophthalmoparesis may be the initial manifestation of paraneoplastic brainstem encephalitis. Our pathologic data suggest that the ophthalmoparesis may result from selective neuronal death within the brainstem tegmentum and ocular motor nuclei. Key Words: Ophthalmoparesis- Paraneoplastic- Brainstem encephalitis- anti- Hu antibodies- Cancer. From the Departments of Neurology and Neuroscience ( A. C. R.), University of Pennsylvania Medical Center and University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, U. S. A. Address correspondence and reprint requests to Dr. S. Galetta, Department of Neurology, University of Pennsylvania Medical Center, 3400 Spruce St., Philadelphia, PA 19104, U. S. A. The anti- Hu paraneoplastic syndrome is most often characterized by encephalomyelitis ( limbic encephalitis) and sensory neuronopathy in association with small- cell lung cancer ( 1,2). However, brainstem dysfunction ( encephalitis), including facial weakness, dysarthria, dysphagia, hearing loss, and ocular motor impairment, may also occur as a result of widespread gliosis, perivascular inflammation ( without vasculitis), and neuronal loss throughout the brainstem ( 1,2). Neuronal death may result from complement- or antibody- dependent, cell- mediated neurotoxicity of anti- Hu immunoglobulin G ( IgG) isotypes that target neurons in specific brainstem regions ( 3- 5). However, there is not always a direct correlation between neurologic symptoms and deposition of IgG in regions of cell death. Furthermore, although brainstem encephalitis may be a manifestation of the anti- Hu syndrome, brainstem dysfunction may also occur in the absence of detectable Hu or other paraneoplastic antibodies. For example, horizontal ophthalmoparesis and laryngeal spasm in two patients with prostate cancer suggested a paraneoplastic brainstem syndrome, yet onconeural antibodies were not identified ( 6). At necropsy, cell loss and gliosis were detected in the brainstem, especially in the paramedian pontine reticular formation. We report three patients who developed progressive ocular motor abnormalities, including complete external ophthalmoparesis and supranuclear ophthalmoparesis, as a part of a paraneoplastic brainstem encephalitis. Anti- Hu antibodies were detected in two patients, one without evidence of systemic malignancy. In a third patient without anti- Hu antibodies, a thyroid malignancy was found at autopsy. In one patient, an extensive pathoanatomic study was performed to delineate regions of cell loss that accounted for the neuro-ophthalmological findings. 44 PARANEOPLASTIC BRAINSTEM SYNDROMES 45 CASE REPORTS Patient 1 A 63- year- old woman developed headache, horizontal diplopia, and gait ataxia. Initial examination revealed mild limitation of upgaze, horizontal endgaze nystagmus, and mild ataxia. Over the next 2 months, worsening gait ataxia, slowed horizontal saccades, upgaze paresis, dysphagia, and dysarthria evolved. Brain magnetic resonance imaging ( MRI) was unremarkable. Cerebrospinal fluid ( CSF) analysis revealed oligoclonal bands without a pleocytosis. Antinuclear antigen ( ANA), acetylcholine receptor antibodies, and human immunodeficiency virus ( HIV) serology were negative. Duodenal biopsy showed no evidence of Whipple's bacillus. Muscle, leptomeningeal, and brain biopsies were nondiagnostic. She was transferred to our hospital. On neurologic examination, she perseverated when responding to questions and exhibited repetitive compulsive counting when agitated. Bilateral ptosis, complete external ophthalmoplegia, and facial myokymia were observed. There was no ocular response to optokinetic, vestibulo- ocular, or caloric stimuli. Forced ductions showed no restriction. Pupils were 3 mm and briskly reactive to light. Visual fields were full, and the fundi were normal. Strength was diminished in the upper and lower extremities ( 4/ 5 arms, 2/ 5 legs) with clasp-knife rigidity. Occasional myoclonus and an intention tremor were noted. Reflexes were 3 + except for absent ankle jerks. The left plantar response was extensor. A repeat MRI showed only postoperative changes in the right frontal lobe. A hexamethyl-propyleneamine- oxime- single photon emission computed tomography ( HmPAO- SPECT) scan revealed decreased activity in the left anterior temporal lobe and the brainstem. Electroencephalogram ( EEG) revealed generalized disorganization of background with bursts of rhythmic high-amplitude delta. Computed tomography of the abdomen and chest, mammography, purified protein derivative ( PPD) rapid plasma reagin/ micro-hemagglutination- Treponemfl pallidum ( RPR/ MHA-TP), B12/ folate, erythrocyte sedimentation rate ( ESR), Lyme titer, blood cultures, serum lactate and pyruvate, thyroid and liver function studies, serum protein electrophoresis ( SPEP), serum car-cinoembryonic antigen ( CEA) and CA125 were either negative or normal. A Tensilon test was negative. Lumbar puncture showed a protein of 60 mg/ dl and two white blood cells ( WBC) per mm3. CSF cytology was negative for malignancy. Cryp-tococcal and fungal studies were negative. In light of the SPECT scan abnormality, biopsy of the temporal lobe was performed and was negative for herpes, cytomegalovirus, fungus, or bacteria. There was no evidence of spongiform degeneration. No abnormal periodic- acid- Schiff ( PAS) staining was observed. Her neurologic status continued to deteriorate, and she subsequently died of aspiration pneumonia. After her death, anti- Hu IgG level was found to be positive at > 80 units, whereas anti- Yo antibodies were not detected. Postmortem examination revealed coronary atherosclerosis and a solitary uterine leiomyoma without evidence of systemic cancer despite an extensive search. Chronic perivascular inflammation ( Fig. 1), gliosis, and glial nodules were evident, extending from the caudal thalamus to the rostral medulla. Neuronal loss was prominent in the midbrain and pons, especially within the ocular motor nuclei. Spongiform changes were not observed, and there was no Purkinje cell loss within the cerebellum. No other abnormal regions were identified including examination of the basal ganglia and cerebral cortex. To more completely characterize the pathoana-tomic lesion in this patient, blocks of brainstem tissue extending from the midbrain to medulla were embedded in celloidin and then cut into 48- | xm serial sections. Sections through the Edinger- Westphal nucleus were not available. These sections were alternately stained for myelin ( Woelke stain) or Nissl substance ( cresyl violet) to define more clearly the regions of cell body and myelin loss. The oculomotor and abducens nuclei were nearly devoid of normal neurons ( Fig. 2). The few remaining cells in each nucleus were undergoing chromatolysis, as evidenced by perikaryal swelling, displacement of the nucleus, dispersion of the Nissl substance, and pallor of the cytoplasm. No neurons within the trochlear nuclei could be identified because of extensive gliosis. In contrast, the cell bodies in cranial nerve nuclei V, VII, and XII appeared normal without evidence of chromatolysis. Similarly, there was no neuronal loss within the closely adjacent red nucleus, locus coeruleus, raphe nuclei, or substantia nigra. In sections stained for myelin, the sixth nerve fascicles were barely labeled as they traversed the pontine tegmentum ( Fig. 3), reflecting the extensive neuronal loss within the abducens nuclei. In contrast, the fascicles of cranial nerves V, VII, and XII were normal. The medial longitudinal fasciculus, pyramidal tracts, and superior, middle, and inferior J Neuro- Ophthalmol, Vol 16, No. 1, 19% 46 P. B. CRINO ET AL. FIG. 1. Perivascular lymphocytic infiltration in the brainstem of patient 1 ( hematoxylin and eosin). cerebellar peduncles also exhibited normal myelin staining. Patient 2 A 45- year- old woman developed headache, diplopia, and paranoid ideation. Evaluation at an outside institution included brain MRI, electrolytes, CBC, Lyme serology, RPR, thyroid function studies, HIV serology, ESR, SPEP, ceruloplasmin, and B12/ folate, which were normal or negative. Lumbar puncture was normal ( WBC, 1/ mm3; RBC, 1/ mm3; glucose, 65 mg/ dl; protein, 45 mg/ dl), and a cerebral angiogram was unremarkable. Over the next 5 months, her symptoms progressed. At the time of admission to our hospital, she suffered ongoing paranoid delusions but was oriented to person and date. Pupillary light reflexes were intact, visual fields were full, and the fundi were normal. She exhibited supranuclear ophthalmoparesis with profoundly reduced voluntary vertical and horizontal eye movements. Ocu-locephalic maneuvers produced full ocular movements except for superimposed bilateral adduction limitation. A repeat lumbar puncture was normal. Cerebrospinal fluid cytology was negative for malignancy. Serum assay and CSF viral enzyme- linked immunosorbent assay ( ELISA) ( Division of Vector Borne Diseases, Centers for Disease Control, Fort Collins, CO, U. S. A.) did not detect arboviral infection. EEG showed only generalized slowing, and FIG. 2. Focal cell loss ( arrows) in the region of the abducens nucleus ( cresyl violet). / Neuro- Ophthalmoi, Vol. 16, No. 1, 19% PARANEOPLASTIC BRAINSTEM SYNDROMES 47 FIG. 3. Loss of myelin staining within the sixth- nerve fascicles as they travel ventrally through the pons ( arrows). In contrast, note the abundant myelin staining of the adjacent seventh- nerve fascicles ( open arrowhead, Woelke stain). H HK^ SSES fe^^^ j v ^ l w? a| ££^ j| I ff^/'^ l brain MRI now revealed generalized atrophy. Duodenal biopsy was negative for Whipple's disease. Serum anti- Hu and anti- Yo antibodies were not detected. Brain biopsy was negative. Her neurologic status declined, and she developed cog-wheeling, tremor, unsteady gait, and frontal release signs. An empiric course of methylpredniso-lone was without benefit. She subsequently died of pneumonia. At postmortem examination, she was noted to have bilateral aspiration pneumonias, a small uterine leiomyoma, and a 4- mm papillary follicular thyroid carcinoma. Biotin- labeled IgG obtained from the patient's serum did not react with the tumor cells ( courtesy J. Dalmau, MSKCC). In the brain, diffuse and dense gliosis was noted throughout the caudal thalamus, hypothalamus, amygdala, and brainstem, especially within the midbrain and rostral pons. In addition, cell loss, glial nodules, and perivascular inflammation were observed. Gliosis was also noted within the substantia innominata, caudate, and globus pallidus. The cerebellum and cerebral cortex were normal. Patient 3 A 53- year- old right- handed woman with a history of small- cell lung cancer developed rapidly progressive memory loss, personality change, and complex partial seizures after hyperfractionated radiation therapy ( 4,500 rads total to the chest) and chemotherapy [ etoposide ( VP- 16) and cis- platinum followed by cyclophosphamide ( Cytoxan), doxorubicin ( Adriamycin), and Vincristine]. Brain MR showed only a small incidental arachnoid cyst. Lumbar puncture was unrevealing ( WBC, 4 mm3; glucose, 74 mg/ dl; protein, 44 mg/ dl) with negative cytology and cultures. Anti- Hu antibodies were detected in the serum (> 1: 1000) and CSF, confirming the diagnosis of anti- Hu paraneoplastic encephalomyelitis . Several months later, she developed horizontal diplopia. Neurologic examination revealed a mild memory deficit with normal visual acuity, pupillary light reflexes, full visual fields, and normal fundi. A horizontal gaze palsy to saccadic and pursuit eye movements was present. Attempts at horizontal gaze often produced convergence substitution, whereas oculocephalic maneuvers elicited only partial horizontal movement. Vertical eye movements were normal. One year later, the patient's mental status remained stable. On examination, bilateral horizontal gaze palsies were present. With oculocephalic testing, her right eye abducted only minimally, and the left eye did not move. Vertical eye movements were preserved. The remainder of her cranial nerves were intact, and her neurologic examination was otherwise unchanged. Orbital MRI and thyroid function studies were normal. Repeat examination several months later was remarkable for worsened memory and attentional deficits. Horizontal optokinetic responses were absent. Cold- water irrigation of the right ear produced incomplete adduction of the left eye. Irrigation of the left ear produced partial conjugate leftward deviation of both eyes. No corrective fast phases were observed. DISCUSSION Although the clinical manifestations of paraneoplastic syndromes are protean, a subgroup of pa- / Neuro- Ophthalmol, Vol. 16, No. 1, 1996 48 P. B. CRINO ET AL. tients in whom anti- Hu antibodies are detected may develop early focal brainstem dysfunction manifesting as diplopia ( 2). The three patients reported here demonstrate that ocular motor dysfunction in patients with paraneoplastic brainstem encephalitis may reflect supranuclear, internu-clear, or nuclear pathology because gliosis and neuronal loss can occur in nuclear and prenuclear ocular motor regions. Only a few reports have focused specifically on eye- movement abnormalities in paraneoplastic brainstem encephalitis or have attempted to correlate ocular motor dysfunction with anatomic lesions ( 7). For example, focal cell loss in the third-, fourth-, and sixth- nerve nuclei has been documented in a patient with lung carcinoma, optic neuritis, and internuclear ophthalmoplegia ( 8). Reddy and Vakili ( 9) also reported a patient with lung cancer and bilateral third- nerve palsies with focal neuron loss and gliosis encompassing the third- nerve complex. However, these reports were published before the association of the Hu antibody and encephalomyelitis was established. Our detailed pathoanatomic analysis of patient 1 with anti- Hu antibodies demonstrates that ocular motor dysfunction may result from selective and extensive neuronal loss within the oculomotor, trochlear, and abducens nuclei. We believe these findings reflect selective neuronal death because closely adjacent motor and sensory cranial nerve nuclei ( i. e., V, VII, and XII) were unaffected, as were several brainstem monoaminergic nuclei. The mechanism by which anti- Hu IgG induces several distinct neurologic syndromes associated with discrete anatomic lesions is unclear and has been reviewed elsewhere ( 2,4,5). Pathologically, paraneoplastic brainstem encephalitis is characterized by gliosis and glial nodule formation. Perivascular lymphocytic infiltration ( Fig. 1) without concomitant vasculitis may involve many small arterioles within the brainstem parenchyma ( 2). Although these changes resemble an infectious process, in no instance has a virus, fungus, or parasite been identified. In one of our patients, comprehensive screening of CSF and serum did not reveal evidence of arboviral infection. Moreover, on two brain biopsy specimens, there was no evidence to suggest Creutzfeldt- Jakob or Whipple's disease. In some patients, serum anti- Hu antibodies may be detected in the absence of systemic malignancy. This raises the issue as to whether antineuronal antibodies can be generated spontaneously in the absence of cancer or whether, in rare patients, antibodies mediate tumor regression or limit metastases ( 10). In one of our patients with anti- Hu antibodies, an extensive postmortem search for malignancy was unrevealing, and another patient has survived with small- cell lung cancer for several years with limited metastases. The clinical evaluation of patients with paraneoplastic brainstem encephalitis may be unrevealing because brain CT, MRI, and angiography are usually normal, and the CSF may show only nonspecific abnormalities ( 2,6). In one of our patients, Hm- PAO- SPECT correctly indicated focal brainstem dysfunction in corroboration of the patient's clinical symptoms. This imaging modality has not been widely used to evaluate paraneoplastic CNS disease and may be useful in future cases. Acknowledgment: This material was presented at the 26th Annual Frank Walsh Neuro- Ophthalmology Meeting, Chicago, Illinois, April 1994. P. B. C. is a Howard Hughes Medical Institute Physician Postdoctoral Fellow. Partial support for this work is from NIH EY02654 ( A. C. R.). REFERENCES 1. Posner J. 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