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Show J. Clill. Neuro-ophthalmol. 4: 109-113, 1984. Opsoclonus Update on Clinical and Pathologic Associations GARY R. KILGO, M.D. GEORGE MARK SCHWARTZE, M.D. Abstract Opsoclonus is a bizarre oculomotor disturbance consisting of rapid, involuntary, repetitive conjugate eye movements in all directions. Clinically, it has been associated with infections, neoplasms, toxins, and drugs. Pathologically, there is no apparent consistently defined structural lesion. A case of opsoclonus with postmortem results is reported. Opsoclonus in adults and available autopsy data are reviewed. Opsoclonus is a bizarre oculomotor disturbance consisting of repetitive, involuntary saccades in all directions which persist during sleep. I These movements seem to be particularly intense during attempts to redirect gaze." Lesions in the brain stem or cerebellum have usually been felt to be responsible. Six cases of opsoclonus with autopsy results have been reported in the English language literature. We present another case with postmortem results. The diverse nature of the lesions in this and other cases make the neuroanatomic substrate uncertain. In spite of this uncertainty, however, opsoclonus has definite clinical implications which should be appreciated. Case Report A 71-year-old female experienced the sudden onset of vertigo with nausea and vomiting. She was treated initially with meclizine and promethazine without benefit. Wildly irregular eye movements and a jaw tremor were noted several days later. There was no history of viral prodrome, fever, headache, or previous disturbance of equilibrium. She had undergone a hysterectomy 7 years earlier for uterine cancer. There was no clinical evidence of recurrence. Neurologic examination revealed random, irregular, conjugate, and at times dysconjugate eye movements which occurred in all directions of gaze and at times had From the Department of Neurology. Bowman Gray School of Medicine of Wake Forest University, Winston-Salem. North Carolina. June 1984 a rotary (torsional) component. These movements were of wide amplitude. The patient was able to look voluntarily in all directions, but the involuntary movements prevented sustained fixation. A coarse, irregular tremor of the tongue and lips was also present, but there was no palatal myoclonus. An ataxic tremor on finger to nose testing was evident. Admission laboratory studies were unremarkable. A spinal fluid examination showed a protein of 64 mg% with a normal glucose, one red blood cell, and one white blood cell. A CT scan of the head and a posterior fossa arteriogram were both normal. An electroencephalogram showed diffuse slowing. Acute viral titers and a urine heavy metal screen were unrevealing. During a protracted hospitalization the patient steadily worsened and became stuporous. She was treated in sequence with thiamine, haloperidol, diazepam, levodopa, bromocriptine, and steroids. Despite such therapeutic attempts, the eye movements continued unabated until death from respiratory arrest 6 weeks after the onset of the illness. Postmortem examination limited to the cranial contents revealed only minimal round cell infiltration in the subarachnoid and VirchowRobins spaces of the brain stem (Fig. 1). The infiltrate was felt to be nonspecific. No parenchymal cell loss, neuronophagia, gliosis, or demyelination was seen in either the cerebrum, cerebellum, or brain stem. Discussion In 1913, the Polish physician Orzechowski described an unusual ocular movement disorder seen after nonepidemic encephalitis.3 He termed this disorder opsoclonus. The original paper was lost through a referencing error, but in a 1927 follow-up paper, he restated his original work. 2 According to Orzechowski, opsoclonus consisted of a continual state of ocular agitation with rapid, unequal movements which were generally horizontal, but also occurred in other directions. The activity seemed to be increased by emotion. During remission, the difficulty seemed to appear principally when trying to change direction of gaze. Myoclonic jerks of the face, body, or limbs 109 Opsoclonus figure 1. Perivascular round cell infiltrate in the brain stem. were frequent associations. Opsochoria which is similar to opsoclonus, but characterized by dysconjugate eye movements was also described. 2 Although not immediately recognized as such, other probable cases of opsoclonus were also reported in the European literature. In 1925 in Germany, Shou reported a patient with progressive myoclonic epilepsy. The patient also had what was probably opsoclonus. In the 1940 Italian literature, Alessi reported a case of "ocular myoclonus" which had the characteristics of opsoclonus. This case was associated with carcinoma of the uterus. At autopsy there was peridentatal demyelination, mild loss of Purkinje cells, and cerebral and cerebellar glosis. J In 1947, reports of opsoclonus began to appear in the English literature, as Marmion and Sandilands described a young boy with "opsochoria"; and Walsh described several children with "ataxic conjugate movements of the eyes"." 0 In 1960, Smith and Walsh reviewed these earlier reports and concluded that "ataxic conjugate eye movements" and opsoclonus were identical. 2 Although opsoclonus is perhaps best recognized for its association with neuroblastoma in children, the in-tent of this communication is to review its significance as an acquired disorder in the adult as found in the literature over the last 30 years. Fourteen cases of opsoclonus reported between 1954 and 1972 were associated with a mild viral or postinfectious encephalitis. 2 h-~ A respiratory or gastrointestinal illness was usually followed by opsoclonus plus truncal ataxia or myoclonus. The course was limited to (at most) 12 weeks and there was complete recovery with no late sequelae. Viral titers were done in six cases and were negative. Cerebrospinal fluid analysis revealed mild protein elevation and mild to moderate pleocytosis. No pathologic specimens were obtained because of the benign course, but speculation was that the disorder was cerebellar in origin.? In 1954, Cogan reported opsoclonus in a patient with encephalitis who died 9 days into the illness (Table 1).4 10 The patient had manifested horizontal, rotary, and vertical eye movements up to the time of death. At autopsy, a marked perivascular and subarachnoid round cell infiltration was present. The cerebellar cortex was spared, but there was spotty cell loss in the thalamus and hypothalamus. Lesser degrees of cell loss were seen in Journal of Clinical Neuro-ophthalmology Kilgo, Schwartze TABLE 1. Autopsy Findings in Opsoclonus Case 2 3 4 5 6 7 Author Cogan' Ross and Zeman17 Ellenberger, Campa, and Netsky3 Keane and Devereaux") Keane" Wertenbaker et al.'l Present case Clinical Association Encephalitis Undifferentiated adenocarcinoma of the lung Adenocarcinoma of the breast Glioblastoma Hypertensive hemorrhage Encephalitis History of uterine carcinoma Postmortem Results Perivascular and subarachnoid round cells infiltrate, Spotty cell loss in thalamus, Cerebellar involvement minimal Cerebellar degeneration with 20% empty baskets in Purkinje cell layers, No demyelination, Histoenzymatic changes in dentate, Mild diffuse perivascular round cell infiltration Complete loss of Purkinje cells, Peridentatal demyelination, Focal gliosis with neuronophagia and neuronal loss in dentate Tumor involved corpus callosum and thalamus, and extended down into both sides of mesencephalic tegmentum, Purkinje cells were normal as was dentate, No peridentatal demyelination present Hemorrhage into right thalamus with dissection into upper midbrain adjacent to aqueduct Perivascular lymphocytic infiltrates, Slightly increased subarachnoid lymphocytes, Reactive astrocytes, A single glial nodule, Patchy loss of Purkinje cells, No peridental demyelination Diffuse mild perivascular round cell infiltration involving brain stem the brain stem and cerebellum, The cause of the encephalitis was not determined. Cogan felt there was no substantial evidence to point to a cerebellar contribution, but he offered no other explanation. Wertenbaker et al. reported a similar case of presumed viral etiology in 1981.11 At autopsy, findings of a mild encephalitis involving predominantly the basal ganglia were reported. There were no definite cerebellar abnormalities. While most cases of opsoclonus in apparently infectious processes had not had a specific etiologic diagnosis made, confirmed reports of its occurrence in St. Louis encephalitis, psittacosis, and Salmonella paratyphi A infection have appeared.I~-I' In children, opsoclonus has occurred in the setting of infections due to Hemophilus il1fluel1zae and Coxsackie B3. 1; 1h Opsoclonus is also thought to be a remote effect of malignancy. Ellenberger et al. reported a case of opsoclonus with breast adenocarcinoma.' At autopsy, the cerebellum was almost completely devoid of Purkinje cells. There was proliferation June 1984 of the Bergman glia and demyelination was present in the peridentatal white matter. These and other changes of parenchymous cerebellar degeneration were thought to be the causative lesion. Two cases of undifferentiated adenocarcinoma and one case of squamous cell carcinoma of the lung have also been associated with opsoclonus. 17 - 1 " In a case of undifferentiated adenocarcinoma, autopsy again showed changes of cerebellar degeneration; however, unlike previous cases, no demyelination was detected. This case reported by Ross and Zeman did, however, demonstrate a histoenzymatic abnormality in the dentate nucleus of the cerebellum, Specifically, this involved a decrease in succinate dehydrogenase. A later case with a similar malignancy who survived was reported by Nausieda et al.; this patient received thiamine with subsequent improvement in the opsocionus. IH It was hypothesized that the previously reported enzymatic change was a result of a reversible remote effect of the malignancy on thiamine metabolism. 1H 111 Opsoclonus Keane reported four cases of opsoclonus associated with either brain tumor or hemorrhage. Autopsy results were reported in two of these. The first involved a glioblastoma with widespread involvement of the cerebral hemispheres and the brain stem. The cerebellum was relatively spared. The second case involved a thalamic hemorrhage with extension into the ventricular system and upper midbrain. In these cases, Keane postulated the release of pontine centers from higher controlling influences as the cause of opsoclonus and rejected the cerebellar influence as being important. 211 . 21 Various toxins and drugs have been associated with opsoclonus including amitriptyline, chlordecone, thallium, and a combination regimen of lithium-haldoI. 22 - 25 None of these however have helped clarify the pathophysiology. Unfortunately, autopsy cases reported thus far have not provided consistent information sufficient to define the anatomic systems responsible for opsoclonus. Part of the problem may be related to cellular dysfunction at the molecular level without attendant change anatomically. This may be particularly applicable to paraneoplastic and infectious cases. As suggested by Wertenbaker et aI., such changes could elude standard neuropathological techniques. I I Not excluded would be anatomic changes in areas not responsible for the opsoclonus. It is possible that certain cases may be reversible up to a point and thus resolve spontaneously or be helped by pharmacologic intervention. The studies by Ross and Zeman and Nausieda et al. suggest these ideas.17.1~ The steroid responsiveness of certain cases in childhood is similarly supportive. 2h Unfortunately, our case did not respond to thiamine, steroids, or other agents, and had a steadily progressive course. Because of the nonspecific findings at autopsy, we are unable to define which systems may have been involved. It would seem apparent from the literature that most cases of opsoclonus in adults are associated with infectious diseases which are either selflimited or treatable. As a manifestation of malignancy, however, opsoclonus tends to be persistent. There is no evidence that treatment of the tumor affects the course of opsoclonus.3.17-14 Therefore, we would suggest that empiric trials of thiamine, steroids, or other pharmacologic agents be continued until a better understanding of the pathophysiology or a more exact therapy becomes known. References 1. Daroff R.B., Troost, B.T., and Delrosso, L.F. Nystagmus and related ocular oscillations. In Neuroophtha[ l11o[ogl/, J.5. Glaser, Ed., Harper and Row, Hagerstown, Maryland: 1978, pp. 219-240. 2. Smith, J.L., and Walsh, F.B. Opsoclonus-Ataxic conjugate movements of the eyes. Arch. aphthalmol. 64: 244-250, 1960. 3. Ellenberger, e, Campa, J.F., and Netsky, M.G. Opsoclonus and parenchymous degeneration of the cerebellum. Neurology 18: 1041-1046, 1968. 4. Marmion, D.E., and Sandilands, J. Opsoclonia-A rare ocular sign in polioencephalitis. Lancet 2: 508509,1960. 5. Walsh, E.B. Clinical Neuro-ophthalmology. Williams & Wilkins Co., Baltimore, 1947, p. 310. 6. Cogan, D.G. Opsoclonus, body tremulousness, and benign encephalitis. Arch. aphthalmol. 79: 545551, 1968. 7. Baringer, J.R., Sweeney, V.P., and Winkler, G.F. An acute syndrome of ocular oscillatious and truncal myoclonus. Brain 91: 473-480, 1958. 8. Ellenberger, e, Keltner, J.E., and Stroud, M.H. Ocular dyskinesia in cerebellar disease. Brain 95: 685-692, 1972. 9. Cogan, D.G. Ocular dysmetria; flutter-like oscillations of the eyes, and opsoclonus. Arch. aphthalmol. 51: 318-335,1954. 10. Case Records of the Massachusetts General Hospital. N. Engl. f. Med. 246: 266-269,1952. 11. Wertenbaker, e, Behrens, M.M., Hunter, S.B., and Plank, eR. Opsoclonus-a cerebellar disorder? Neuro-ophthalmology 2: 73-84, 1981. 12. Estrin, W.J. The serological diagnosis of St. Louis encephalitis in a patient with the syndrome of opsoclonia, body tremulousness and benign encephalitis. Ann. Neural. 1: 596-598, 1977. 13. Blue, S.K., Janeway, R., and Stanley, J.A Opsoclonus and body tremulousness. A case report with suggested cause. TrQ/lS. Am. Neural. Assaf. 96: 208210,1971. 14. Vejjajiva, A, and Lerdverasirikul, P. Opsoclonus in Salmonella infection. Br. Med. f. 2: 1260, 1977. 15. Rivner, M.H., Jay, W.M., Green, J.B., and Dyken, P.R. Opsoclonus in Hemophilus inf!uenzae meningitis. Neurology 32: 661-663,1982. 16. Kuban, K.e, Ephros, M.A, Freeman, R.L., Laffell, L.B., and Bresnan, M,J. Syndrome of opsoclonusmyoclonus caused by Coxsackie B3 infection. Ann. Neurol. 13: 69-71, 1983. 17. Ross, AT., and Zeman, W. Opsoclonus, occult carcinoma and chemical pathology in dentate nuclei. Arch. Neural. 17: 546-551, 1967. 18. Nausieda, P.A, Tunner, eM., and Weiner, W.J. Opsoclonic cerebellopathy-a paraneoplastic syndrome responsive to thiamine. Arch. Neural. 38: 780-781,1981. 19. Bellur, S.N. Opsoclonus: Its clinical value. Neurology 25: 502-507,1974. 20. Keane, J.R., and Devereaux, M.W. Opsoclonus associated with an intracranial tumor. Arch. aphthalmol. 92: 443-445, 1974. 21. Keane, J.R. Transient opsoclonus with thalamic hemorrhage. Arch. Neural. 37: 423-424, 1980. 22. Au, W.J., and Keltner, J.L. Opsoclonus with amitriptyline overdose. Ann. Neurol. 6: 87,1979. 23. Taylor, J.R., Selhoist, 1.B., Houff, SA, and Martinez, A,J. Chlordecone intoxication in man. Neurol- Journal of Clinical Neuro-ophthalmology ogy 28: 626-630, 1978. 24. Maccario, M., Seelinger, D., and Snyder, R. Thallotoxicosis with coma and abnormal eye movements (opsoclonus): Clinical and EEG correlations. Electroencephalogr. Clin. Neurophysiol. 38: 98, 1975 25. Cohen, W.]., and Cohen, N.H. Lithium carbonate, haloperidol, and irreversible brain damage. J.A.M.A. 230: 1283-1287, 1974. June 1984 Kilgo, Schwartze 26. Tal, Y., Jaffe, M., Sharf, B., and Amir, N. Steroiddependent state in a child with opsoclonus. J. Pediatr. 103: 420-421, 1983. Write for reprints to: Gary R. Kilgo, M.D., Department of Neurology, Bowman Gray School of Medicine, Wake Forest University, 300 South Hawthorne Road, Winston- Salem, North Carolina 27103. 113 |
