Paraneoplastic Opsoclonus

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Identifier 931-1
Title Paraneoplastic Opsoclonus
Ocular Movements Opsoclonus; Ocular Flutter
Creator Shirley H. Wray, M.D., Ph.D., FRCP, Professor of Neurology Harvard Medical School, Director, Unit for Neurovisual Disorders, Massachusetts General Hospital
Contributor Primary Shirley H. Wray, MD, PhD, FRCP, Professor of Neurology, Harvard Medical School; Director, Unit for Neurovisual Disorders, Massachusetts General Hospital
Subject Opsoclonus; Ocular Flutter; Oscillopsia; Saccadic Oscillations; Paraneoplastic Cerebellar Syndrome; Adenocarcinoma of the Breast; Anti-Ri Antibody; Paraneoplastic Opsoclonus; Paraneoplastic Ocular Flutter; Saccadomania
Supplementary Materials PowerPoint Presentation: Paraneoplastic Opsocolonus: Shirley H. Wray, M.D., Ph.D., FRCP, Harvard Medical School
Presenting Symptom Dizziness
History This patient is the index case of the Anti-Ri antibody, published in Annals of Neurology in 1988 (4). The Anti-Ri antibody is recognized to be a paraneoplastic marker in patients with breast and gynecological malignancies (10). The history of this case is particularly important because she was initially misdiagnosed as a case of acute labyrinthitis. In 1986, at age 56, she presented with the acute onset of dizziness, nausea and her eyes "going out of focus". Her symptoms began one month prior to admission, when she awoke one morning with a vague feeling of nausea and motion sickness. Because the symptoms were similar to those she had experienced during an episode of dizziness six years previously, her doctor attributed them to labyrinthitis. Five days later, she had difficulty focusing her eyes. When she attempted to read the newspaper the print appeared blurred and "moving in all directions". (oscillopsia). The next day she saw her ophthalmologist who commented on the presence of "marked nystagmus" . She complained of severe persistent dizziness with eyes open and closed and felt that the environment was spinning around her. She was admitted to the Infirmary at Massachusetts Institute of Technology Diagnosis: Acute labyrinthitis Four days later, she was unable to sit up in bed without falling over or stand. She was transferred and admitted to the Massachusetts General Hospital (MGH). Neurological examination showed: A constellation of cerebellar signs: • Titubation • Marked trunkal ataxia sitting and standing • Gait ataxia • Full horizontal eye movements disturbed by continuous bursts of rapid back-to-back saccades in all directions characteristic of opsoclonus. • Clockwise rotary nystagmus OU on gaze left • Right beating horizontal nystagmus OU on gaze right • Full vertical eye movements without nystagmus • Smooth pursuit eye movements when tested between attacks of opsoclonus to a slow moving target Motor system and sensory system intact. Reflexes 1+ throughout with flexor plantar responses. Coordination normal in the limbs. Diagnosis: Paraneoplastic Cerebellar Syndrome with Opsoclonus Investigations: The patient underwent intensive investigations to search for a primary occult neoplasm -- breast, ovary or lung. Lumbar puncture under fluoroscopy: Cerebrospinal fluid (CSF) protein 70 mg/dl Glucose 73 mg% RBC 0/cubic mm, WBC 8/cubic mm, 93% lymphocytes Cytology negative IgG 6.4 Albumin 4.1 and multiple oligoclonal bands. Chest x-ray: A tiny nodular density in the right middle lobe adjacent to the major fissure which was thought to represent a granuloma. A neoplasm could not be ruled out. (Figure 1) Bone Scan: Normal. Abdominal and Pelvic CT: normal. Brain MRI: Four MRI studies were done during her admission. The initial study in July 1986, and a study in October 1986 showed a lesion at the level of the tectum and inferior colliculus bilaterally, more obvious on the right. (Figure 2) This lesion was not seen in two MRI studies done in September, 1986, suggesting a transient waxing and waning of an inflammatory process. Mammogram: Mammography was delayed because of the patient's inability to stand for the examination due to severe vertigo. It revealed a small suspicious lesion in the upper outer quadrant of the right breast. Breast biopsy under fluoroscopy performed. (Figure 3) Pathology: Intraductal adenocarcinoma of the breast. (Figures 4-6). Surgery: The patient chose to have a segmental mastectomy followed by radiation. 5/9 lymph nodes were positive for CA. Chemotherapy was recommended. Paraneoplastic Markers: At the time the patient was in the MGH, the American Academy of Neurology met in Boston. I took the opportunity to meet Dr. Jerome Posner (for the first time) following his talk on Paraneoplastic Syndromes and Marker Antibodies. I asked Dr. Posner if he would be willing to study my patient and he agreed to do so. We sent tumor tissue, CSF and serum samples to him at the Sloan Kettering Cancer Center for assay for anti-Purkinje cell antibodies and other markers. Anti-Ri antibody: Dr. Posner discovered a new antibody. A highly specific anti-CNS nuclear neuronal antibody in the serum in a dilution of 1:800 and in the CSF in a dilution of 1:50. This observation was very significant. The antibody was named anti-Ri (Ri being the first two initials of the patient's last name) (Figures7-9). The Anti-Ri antibody is well recognized now to be a marker for occult malignancy of the breast and gynecological tumors. Plasmapheresis: The presence of anti-CNS neuronal antibodies in this patient raised the possibility that treatment with plasmapheresis might be beneficial. She was, however, turned down for this therapy. Chemotherapy and Radiation: In October 1986 she received a chemotherapeutic cocktail of Cytoxin, Adriamycin and 5 FUs weekly for a period of six months followed by local radiation therapy. Medications: The patient's vertigo, opsoclonus, titubation, trunkal ataxia and anxiety were variable throughout her hospital course. Multiple combinations of medications were tried to relieve vertigo and the most effective were Baclofen and Meclizine. She received Xanax for anxiety. Prednisone (20 mg p.o., t.i.d.) and Ranitidine were prescribed and taken for a period of six to eight weeks. Progress: Over the next two months she slowly improved and on completion of her chemotherapy she reported that she was "back in the land of the living", able to walk with a cane, climb one flight of stairs, go riding in a car out for lunch and generally doing much better. Visual blurring was less marked and she was able to read. She was considerably encouraged and cheerful at that time even though she was still experiencing occasional bursts of opsoclonus. Full recovery is excellent in these cases because the immune-mediated process affects the brainstem sparing the cerebellar Purkinje cells. Follow-up: By January 1987, she had made a complete recovery. She then remained well until 1993 when she was diagnosed with cancer of the bladder. She again made a complete recovery. I continued to follow this patient on an annual basis until Sept 2002 when she transferred her care to the University of Massachusetts to be close to her home.
Clinical This 58 year old woman with paraneoplastic opsoclonus gives an excellent description of oscillopsia - the illusion of the visual world moving. She also vividly describes episodic "vertigo" - an erroneous perception of movement. The first video clip, made shortly after her admission when she was very vertiginous, shows large amplitude conjugate constant rapid multidirectional saccades. Weeks later when the second video was made she was able to sit and stand. The opsoclonus had improved and she had then: • Horizontal ocular flutter in primary gaze • Eyelid flutter on gaze right and left • Bursts of opsoclonus i.e. multidirectional saccades of small amplitude prominent on looking up and on pursuit of an upward moving target • Opsoclonus under closed eyelids associated with eyelid flutter • Suppression of opsoclonus by fixation. Prognosis: Full recovery is excellent in these cases because the immune-mediated process affects the brainstem sparing the cerebellar Purkinje cells.
Neuroimaging Review fMRI (8)
Pathology Opsoclonus (OC) is characterized by omnidirectional saccadic oscillations. It is not known however whether OC is a cerebellar or brainstem disorder. Cerebellum: Wong et al have suggested, on theoretical grounds, that the deep cerebellar nuclei should be activated in patients with opsoclonus. (12) Helmchen et al (8) assessed this hypothesis with fMRI in two patients with opsoclonus and compared them with healthy subjects. They used three-dimensional (3D) scleral search coil recordings to characterize the pathologic eye oscillations. (Figure 10) Fortuitously, both patients showed a decrease of or no OC with the eyes closed, so fMRI signals under two conditions (open eyes with OC vs closed eyes without OC) could be compared. A comparison of these two states revealed neither vermal nor brainstem activation but showed, for the first time, bilateral functional activation of the deep cerebellar nuclei. (Figure 11 (8)) This result supports Wong et al's recent hypothesis that OC results from a disinhibition of the fastigial ocular motor region (FOR). The FOR contains saccade-related neurons that augment the ongoing discharge of pontine excitory and inhibitory burst neurons. Because the cerebellar ocular motor vermis physiologically inhibits the FOR, the authors concluded that the absence of vermal activation during OC may reflect a cause of OC. Brainstem: Glycine has been identified as the neurotransmitter of omnipause neurons and poisoning with a glycine antagonist, strychnine, is reported to produce opsoclonus and myoclonus. Zee postulates that an immune-mediated Glycine Channelopathy affecting the membrane of omnipause cells may be the underlying mechanism for ocular flutter and opsoclonus and suggests that it may be possible that membrane-stabilizing drugs may find a therapeutic role for flutter and opsoclonus in the future. (Personal communication, 2007 (13)) (For further discussion (9)).
Etiology Table 10-8 Etiology of Ocular Flutter and Opsoclonus (p.525 ref 9).
Disease/Diagnosis Intraductal adenocarcinoma of the breast
Treatment The approach to treatment in paraneoplastic opsoclonus syndromes is: 1. Appropriate therapy for the cancer • Surgery • Chemotherapy and/or Radiation 2. Immune modulation • Plasmapheresis • Immunoadsorption Therapy • Intravenous immunoglobulin • Steroids 3. Symptomatic treatment for vertigo etc.
References 1. Anderson NE. Rosenblum MK, Posner JB. Paraneoplastic cerebellar degeneration: clinical-immunological correlations. Ann Neurol 1988;24:559-567. 2. Averbuch-Heller L, Remler B. Opsoclonus. Semin Neurol 1996;16 (1):21-26. 3. Bataller L, Dalmau J. Paraneoplastic Neurologic Syndromes: Approaches to Diagnosis and Treatment. Semin Neurol 2003; 23:215-224. 4. Budde-Steffen C, Anderson NE, Rosenblum MK, Graus F., Ford, D, Synek, BJL, Wray, SH, Posner JB. An anti-neuronal autoantibody in paraneoplastic opsoclonus. Ann Neurol 1988;23:528-531. 5. Cogan DG. Ocular dysmetria, flutter-like oscillations of the eyes and opsoclonus. Arch. Ophthalmol 1954;51:318. 6. Dropcho E, Payne R. Paraneoplastic opsoclonus-myoclonus. Association with medullary thyroid carcinoma and review of the literature. Arch Neurol 1986;43:410-415. 7. Ellenberger C, Jr. Campa JF, Netsky MG. Opsoclonus and parenchymatous degeneration of the cerebellum. The cerebellar origin of an abnormal eye movement. Neurology 1968;18:1041-1046. 8. Helmchen C, Rambold H, Sprenger A, Erdmann C, Binkofski F. Cerebellar activation in opsoclonus: An fMRI study. Neurology 2003;61:412-415. 9. Leigh RJ, Zee DS. Diagnosis of Nystagmus and Saccadic Intrusion. Part 2: Chapter 10, 521-534. In The Neurology of Eye Movements. 4th Ed. Oxford University Press, New York 2006. 10. Luque AF. Furneaux HM, Ferziger R, Rosenblum MK, Wray SH, Schold SC Jr, Glantz MJ, Jaeckle KA, Biran H, Lesser MK, Paulsen WA, River ME, Posner JH. Anti-Ri: an antibody associated with paraneoplastic opsoclonus and breast cancer. Ann Neurol 1991;29:241-251. 11. Shams'ili S, Grefkens J, de Leeuw, B, van den Bent M, Hooijkaas H, van der Holt, Bronno, Vecht C, and Smitt, PS. Paraneoplastic cerebellar degeneration associated with antineuronal antibodies: analysis of 50 patients. Brain 2003; 126(6):1409-1418. 12. Wong AM, Musallam S, Tomlinson RD, Shannon P, Sharpe JA. Opsoclonus in three dimensions: oculographic, neuropathologic and modeling correlates. J Neurol Sci 2001;189:71-81. 13. Zee D. Personal communication, 2007.
Relation is Part of 166-1, 166-12, 936-7, 936-8
Publisher Spencer S. Eccles Health Sciences Library, University of Utah
Date 1986
Type Image/MovingImage
Format video/mp4
Source 3/4" Umatic master videotape
Rights Management Copyright 2002. For further information regarding the rights to this collection, please visit:
Holding Institution Spencer S. Eccles Health Sciences Library, University of Utah, 10 N 1900 E, SLC, UT 84112-5890
Collection Neuro-ophthalmology Virtual Education Library: NOVEL
Language eng
ARK ark:/87278/s6dv4ghw
Setname ehsl_novel_shw
Date Created 2005-08-22
Date Modified 2017-11-22
ID 188550
Reference URL
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