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Show ]. CJjn. Neuro-ophthalmol. 3: 245-249, 1983. Downbeat Nystagmus A Case Report of Herpetic Brain Stem Encephalitis LAWRENCE W. HIRST, M.D. ARTHUR W. CLARK M.D. JERRY S. WOLINSKY, M.D. DAVIO S. ZEE, M.D. HERBERT KAIZER, M.D. NEIL R. MILLER, M.D. PETER J. TUTSCHKA, M.D. GEORGE W. SANTOS, M.D. Abstract A 35-year-old man with aplastic anemia developed prominent downbeat nystagmus 80 days after receiving an allogeneic bone marrow transplant. A diagnosis of herpes simplex encephalitis was made which was confirmed by positive virus cultures at autopsy 1 week later. Routine pathologic examination of the brain stem revealed no lesions which would explain the downbeat nystagmus. Immunoperoxidase studies, however, revealed virus-infected neurones throughout the brain stem including the nuclei of the basis pontis, the superior olive, and nuclei of the spinal tracts of 5 and 10. The significance of "negative" pathologic brain stem findings in cases of downbeat nystagmus is discussed. Introduction Downbeat nystagmus in the primary position of gaze is usually related to abnormalities at the craniocervical junction that affect the inferior portion of the cerebellum l or the caudal brain stem. Experimentally, downbeat nystagmus can be produced by lesions in several locations including the cerebellar f1occulus/ or cerebellar nodulus,a the dorsal medulla,4 or pretectum.5 A number of mechanisms have been invoked to explain the appearance of the nystagmus. They include imbalance in vestibular tone,6 imbalance or "pursuit tone,"? and disorders of neural gaze-holding mechanismsH We report herein a patient with proven herpes simplex encephalitis in whom downbeat nystagmus in the primary position was a prominent neurologic abnormality. From the Wilmer Ophthalmological Institute (LWH, NRM); and the Departments of Neurology and Pathology (A WCj, Neurology (J5W, 052). and Oncology (PJT). (GW5, HK). Johns Hopkins University, Baltimore, Maryland. Case Report A 35-year-old man developed signs and symptoms which fulfilled the criteria for severe aplastic anemi.a9.10·10 December 1979. He fa1'1ed to respond to a brief trial of oxymethalone and required multiple blood and platelet tranfusions. In January 1980, he was transferred to the Johns Hopkins Hospital where he received a bone marrow transplant from an HLA identical sister. His pretransplant therapy consisted of cyclophosphamide and total body irradiation as described previously. 11 Despite rapid posttransplant hematologic recovery, the patient developed multiple complications. These included; herpes simplex mucositis, candidal esophagitis, salmonellosis with positive blood cultures, interstitial pneumonitis, hepatitis, and acute and chronic graft-versus-host disease (GVHD). Post-transplant medications included gentamicin, ticarcillin, amphothericin B, amikacin, and prednisolone, and azothioprin for treatment of GVHD. Eleven weeks after transplantation the patient developed unsteadiness of gait, dizziness, and disorientation. An electroencephalogram, brain scan, and lumbar puncture were all consistent with herpes encephalitis and he was begun on adenine arabinoside. Among the most prominent features of the patient's encephalopathy were the eye findings. Initially a unidirectional, right-beating nystagmus appeared. This was most marked on right gaze, but was also present on straight ahead and leftward gaze (Alexander Grade III). The range of extraocular motility was full and pupillary reactions were normal. His sacca des were accurate, but his pursuit was broken in all directions particularly on tracking to the right. Two days later his neuro-ophthalmologic examination changed. He showed marked blepharospasm with a prominent Bell's phenomenon. When he opened his eyes and relaxed his lids a prominent Downbeat Nystagmus Figure 1. Photomicrograph of a region of the subcortical white matter from the left temporal cortex shows several oligodendroglial cells with intranuclear inclusions. Some of the inclusions are classic Cowdry type A bodies (open arrow). Hematoxylin and eosin stain. downbeating nystagmus was observed in all positions of gaze. In the primary position its amplitude was 20-30° and its frequency at least 3 hertz. The downbeating nystagmus was exaggerated on right lateral gaze with a slight horizontal component (quick phase to the right) which gave an overall oblique direction to the nystagmus. The next day he became comatose with disconjugate upward tonic deviation of the eyes. Unilateral cold water irrigations generated appropriately directed slow phases. There was some doll's head response in all directions. His downbeating nystagmus then became less marked and he died 24 hours later. Pathological Findings At postmortem examination, particularly severe pathologic changes were found in the patient's gastrointestinal tract, lungs, and brain. The gastrointestinal tract showed herpetic (HSV) lesions of the esophagus and stomach, and hemorrhagic enterocolitis with cytomegalic (CMV) inclusions in the bowel. The lungs were consolidated with evidence of mixed viral (both HSV and CMV) and bacterial (pseudomonas and klebsiella) infection. The brain weighed 1,440 g. The dura was markedly icteric. The leptomeninges were somewhat thickened at the base of the brain. Small hemor-rhagic lesions were apparent on the surface of the left occipital lobe and the uncus of the left temporal lobe. Despite prominent uncal notching bilaterally, there was no definite evidence of uncal or cerebellar herniation. Coronal sections revealed a zone of softening, bilirubin staining, and hemorrhage involving the left insula and medial aspects of the left temporal lobe. The occipital hemorrhagic lesion measured 1 X 1 cm and extended into the white matter. Microscopically, the areas of softening in the left insular and temporal regions showed numerous intranuclear inclusions and perivascular cuffs (Fig. 1). There were widespread changes of hypoxiaischemia in neurons of the cerebral and cerebellar cortices and similar changes scattered in brainstem nuclei. Occasional clusters of "microglia" were apparent in the basis pontis, and rare neurons with atypical intranuclear inclusions were identified (superior olive, locus coeruleus, cerebellar cortex) (Fig. 2). Otherwise, there were no histologic abnormalities in routine preparations of the cerebral cortex, basal ganglia, brain stem, or cerebellum. Immunocytochemical studies were carried out on 6 micron-thick deparaffinized sections of routinely embedded autopsy specimens. A modification of previously detailed postembedding procedures was used. 12 For these studies, the primary antibody was a rabbit immunoglobulin fraction Journal of Clinical Neuro-ophthalmology Hirst et al. Figure 2. Photomicrograph of a portion of the dorsal accessory olivary nucleus of the medulla. Most of the neurons of this nucleus appear normal; however. a few show rather nonspecific cytolytic alterations (solid arrow). There is no evidence of an inflammatory infiltrate, and myelinated tracks which traverse the nuclear appear intact. Hematoxylin and eosin stain. with reactivity to herpes simplex virus type 1 (Accurate Chemical, Westbury, N.Y.), effectively used at dilutions of 1:1,000-1:10,000. Binding of the primary antibody to virus antigens in tissues was detected with a 1:200 dilution of biotinylated goat anti-rabbit immunoglobulin (Bethesda Research Laboratories, Inc., Gaithersburg, MD), followed by a 1:200 dilution of streptavidin-horseradish peroxidse complex (Bethesda Research Laboratories) and the reaction product developed with diaminobenzidine. Normal rabbit immunoglobulin was substituted as a control. The immunohistochemical studies disclosed foci of numerous, otherwise normal-appearing foci of cells containing herpes antigen in the following infratentorial locations: oculomotor nucleus, granule cells of the cerebellum, Purkinje cells of the cerebellum, scattered cells in the reticular formation and in the nuclei basis pontis, in the superior December 1983 olive (Fig. 3), in the reticular formation of the medulla, in the dorsomotor nucleus of the tenth cranial nerve, and in the spinal nucleus of the fifth cranial nerve. Viral antigen containing cells were widespread in affected regions of the cerebral hemispheres. Discussion The possible anatomic sites involved in causing downbeat nystagmus have been investigated extensively in animal models and in patients. I -'. Despite a general implication of the lower brain stem or cerebellum, specific areas of localization have never been confirmed in human patients. The etiologic basis of downbeat nystagmus includes a variety of conditions including ArnoldChiari malformation, platybasia, demyelinating disease, diabetes, syphilis, menigiomas and aneurysms. I Although brain stem encephalitis has been 247 Downbeat Nystagmus - I 3 , • OJ Figure 3. Immunocytochemical stain shows viral antigens (black deposits) in both nucleus and cytoplasm of involved neurons of the dorsal accessory olivary nucleus. The dendritic and axonal processes of these neurons also contain antigen. implicated as a cause of downbeat nystagmus in a few cases, I:l proven infectious etiology remains unreported. Herpes simplex encephalitis usually presents as an acute necrotizing inflammation of the frontal and temporal lobes.l~ Contiguous spread to the brain stem has been thought principally to occur in patients who are immunosuppressed15 When brain stem involvement becomes evident,16-23 ocular movement disorders have been recorded ranging from internuclear ophthalmoplegias to gaze palsies. Downbeat nystagmus has not been reported as a result of proven herpes simplex brain stem encephalitis. In our patient, the prominent neuro-ophthalmic abnormality 2 days before death was the marked downbeat nystagmus. The early unidirectional horizontal nystagmus is suggestive of an initial central vestibular nuclei or vestibulocerebellar dysfunction. The later development of prominent downbeat nystagmus hints at bilateral involvement of either of the above general anatomic areas. An antemortem diagnosis of herpes simplex encephalitis was confirmed at postmortem examination by positive virus cultures and a necrotizing inclusion cell encephalitis of the temporal lobes. Despite the prominent neuro-ophthalmic signs, the brain stem to gross external and regular microscopic examination revealed no obvious herpetic involvement. Using immunoperoxidase staining techniques, numerous virus-infected neurons were found within selected neuroanatomic regions throughout the brain stem. 12 Most anatomic areas implicated previously in downbeat nystagmus were involved, but there was no particularly prominent area of involvement which could suggest a single anatomical localizing site. No other factors could clearly be implicated in the production of the downbeat nystagmus, and it must be presumed that abnormalities of the "luxury" or "higher level" functions of the virus-infected neurons were responsible for the prominent downbeat nystagmus. 13 It would appear that patients with herpes simplex encephalitis may develop brain stem neurologic signs for which Journal of Clinical Neuro-ophthalmology there is no apparent gross or microscopic pathological cause. Careful examination with specific immunocytochemical staining techniques may be required to reveal the underlying neuronal involvement. References 1. Cogan, D.G.: Down-beat nystagmus. Arch. Ophthalmol. 80: 757-768, 1968. 2. Zee, D.S., Yamazaki, A., Butler, P.H., and Gucer, G.: Effects of ablation of flocculus and paraflocculus on eye movements in primate. f. Neurophysiol. 46: 878899, 1981. 3. Takemori, 5., and Suzuki, M.: Cerebellar contribution to oculomotor function. Oto. Rhino. laryngol. 39: 209-217, 1977. 4. Jong, ].M.B., Vianney De, CB., Matsuo, V., and Uemura, T: Midsagittal pontomedulJary brain stem section: Effects on ocular adduction and nystagmus. Exp. Neurol. 68: 420-442, 1980. 5. Pasik, T, Pasik, P., and Bonder, M.B.: The pretectoral syndrome in monkeys. II. Spontaneous nystagmus and induced nystagmus and lightening eye movements. Brain 92: 871-884,1969. 6. Baloh, R., and Spooner, ]. W.: Downbeat nystagmus: A type of central vestibular nystagmus. Neurology 31: 304,1981. 7. Zee, OS, Friendlich, A.R., and Robinson, D.A.: Mechanism of downbeat nystagmus. Arch. Neurol. 30: 227-237, 1974. 8. leigh, J., and Zee, 0.5.: Neurology of Eye Movement. F.A. Davis, Philadephia, 1983. 9. Hanley, D.F., Sara!, R., and Wolinsky, ].5.: Herpes virus encephalitis in the severely immunocompromised patient. Trans. Am. Neurol. Assoc. 106: 1-3, 1981. 10. Camitta, B.M., Thomas, ED., Nathan, B.G., et a!.: A prospective study of androgens in bone marrow transplantation for treatment of severe aplastic anemia. Blood 53: 504-514,1979. 11. Elfenbein, G., Kallman, C, Braine, H., et al.: Analysis of factors related to bone marrow graft rejection in aplastic anemia. Usefulness of measures of broad alloimmunity as predictors. Transplant. Proceed. 1983. (In press.) 12. Schwendemann, G., Wolinsky, J.5., Hatzidimitriou, G., Merz, D.C, and Waxham, M.N.: Postembedding immunocytochemical localization of paramyxovirus December 1983 Hirst et "I. antigens by light and electron microscopy. f. Histochern. Cytochem. 30:(12) 1313-1319, 1982. 13. Shimizu, N.. Weinberger, J., and Yahr, MD.: Downbeat nystagmus as a sign of brainstem involvement in acute meningoencephalitis. Neurology 25: 267270, 1975. 14. Baringer, j.R.: Human herpes-simplex virus infections. Adv. Neurol. 6: 41-51,1974. 15. Davis, LE., and Johnson, R.T: An explanation for the localization of herpes simplex encephalitis? Ann. Neurol. 5: 2-5, 1979. 16. Roman-Campos, G., and Toro, G: Herpetic brainstem encephalitis. Neurology 30: 981-986, 1980. 17. Bickerstaff, E.R.: Brain-stem encephalitis. Further observations on a Grave syndrome with benign prognosis. Br. Med. f. 1: 1384-1387, 1957. 18. Dayan, AD., Gooddy, W., Harrison, M.j.G., and Rudge, P.: Brain stem encephalitis caused by herpesvirus hominis. Br. Med. f. 4: 405-406, 1972. 19. Ellison, Ph., and Hanson, P.A.: Herpes simplex: A possible cause of brainstem encephalitis. Pediatrics 59: 240-243, 1977. 20. Fenton, TR., Marshall, P.C, Cavanagh, N., et al.: Herpes-simplex infection presenting as brainstem encephalitis. lancet 2: 977-978, 1977. 21. Kindley, AD., Harris, F., and Bush, G.H.: Herpessimplex infection presenting as brainstem encephalitis. lancet 1: 212-213,1978. 22. Iannetti, P., Balducci, L, Businco, L, et a!.: Herpetic encephalitis with associated cytomegalovirus infection and nyoclonus. lancet 2: 1227-1228, 1978. 23. Oldstone, M.B.A., Holmstoen, J., and Welsh, R.M., Jr.: Alterations of acetylcholine enzymes in neuroblastoma cells persistently infected with lymphocytic choriomeningitis virus. f. Cel1. Physiol. 91: 459472,1977. Acknowledgments This study was supported in part by NEI grants EY 02476 (LWH), EY 01849 (DSZ), Computer Core grant 2P30 EY 01765 (Wilmer Institute), and a Program Project grant NS 115721. JSW is the recipient of a Career Research Development Award (NS 00443). DSZ is the recipient of a Career Research Development Award (EY 00158). Write for reprints to: L W. Hirst, M.D., The Bethesda Eye Institute, St. Louis University, 3655 Vista Avenue, St. louis, Missouri 63110. 249 |
