| Identifier |
939-8 |
| Title |
Bilateral Sixth Nerve Palsy |
| Creator |
Shirley H. Wray, MD, PhD, FRCP |
| Contributors |
Steve Smith, Videographer |
| Affiliation |
(SHW) Professor of Neurology, Harvard Medical School; Director, Unit for Neurovisual Disorders, Massachusetts General Hospital, Boston, Massachusetts |
| Subject |
Bilateral Sixth Nerve Palsy; Bilateral Esotropia; Paraneoplastic Opsoclonus/Flutter; Paraneoplastic Cerebellar Syndrome; Carcinoma of the Breast; Paraneoplastic Opsoclonus |
| History |
This patient is a 62 year old woman with a six month history of double vision and difficulty walking. In August 1996, she first noted her right upper eyelid twitching followed by dizziness, nausea and vomiting. Soon after her voice became "shaky" and she experienced mild difficulty walking. She consulted her primary care physician and was prescribed Zoloft for depression. In November 1996, she developed double vision, and increasing unsteadiness walking. In December 1996, she consulted a neurologist. Brain MRI at an outside hospital reported to be normal In January 1997, she was admitted to Massachusetts General Hospital. Past History: Significant for right breast cancer in 1986, status post lumpectomy and radiation therapy. Family History: Negative for neurologic disease Neurological examination: Normal cognitive function Mild dysarthria and tremulous voice Spontaneous myoclonus and bilateral hand tremors Mild left hemiparesis with hyperreflexia and extensor plantar response Right flexor plantar response Bilateral limb ataxia and gait ataxia Neuro-ophthalmological examination: Visual acuity 20/20 OU Visual fields, pupils and fundus examination no abnormality Ocular Motility: • Intermittent opsoclonus with multivectorial conjugate saccades without an intersaccadic interval and • Ocular flutter with horizontal back to back saccades in central gaze • Esotropia OS > OD • Weakness of abduction OS - left sixth nerve palsy • Weakness of adduction OS • Weakness of abduction OD - right sixth nerve palsy • Full upgaze with upbeat nystagmus • Full downgaze with no nystagmus • Pursuit movements normal. Testing for ocular dysmetria show slow refixation saccades. No dysmetria. Diagnosis: Paraneoplastic cerebellar syndrome with opsoclonus/flutter. 1/27/97 Brain MRI: The following sequences were obtained: Axial FLAIR, T1, FSE T2, Diffusion weighted images and post gadolinium. The study showed areas of T2 and FLAIR hyperintensity involving the tegmen and extending cranially to the midbrain adjacent to the midline and just inferior to the cerebellar peduncle. Also noted were areas of FLAIR and T2 hyperintensity within the corona radiata and centrum semiovale bilaterally, left greater than right. Similar signal abnormalities were seen within the right putamen and globus pallidus. Impression: Diffuse demyelinating process consistent with a paraneoplastic syndrome. Lumbar Puncture: Cerebrospinal fluid protein 36 mg/dl Sugar 68 mg/dl 136 RBC 12 WBC 95% lymphs 4% monocytes Positive for oligoclonal bands Cytology was negative for malignant cells twice Chest/abdomen/pelvic CT Normal Bone scan and bone marrow biopsy: Normal Mammogram: Bilateral mammogram Cluster of microcalcifications in the subareolar region of the lateral aspect of the left breast suspicious for intraductal carcinoma. Procedure: A needle guided left breast biopsy Pathology: Intraductal adenocarcinoma in situ in the left breast. The primary breast cancer being in the right breast. Paraneoplastic Markers: CSF and serum were sent to Dr. Posner at the Memorial Sloane Kettering Cancer Center for antibody studies (Anti-Ri, Anti-Yo). No antibodies were detected. Ri Autoantibody Test - Negative Anti-Ri is a highly specific antineuronal antibody that reacts with nuclei of neurons in the central nervous system. The presence of anti-Ri antibody identifies the subset of patients with paraneoplastic ataxia and opsoclonus who suffer from breast or other gynecological cancer. The antibody when present is a useful marker for this type of underlying malignancy. The relative amount of anti-Ri was found to be always higher in CSF than in serum. 1. Anderson NE et al. Ann Neurol 1988;24:559-567 2. Budde-Steffen C. et al. Ann Neurol 1988;23:528-531. 3. Luque A. et al. Ann Neurol 1989;26:178 (Abstract) All diagnostic antibody tests should be considered within the context of clinical findings. 1. Dalmau et al. 1992 Medicine 71:2;59-72. Diagnosis: 1. Paraneoplastic opsoclonus/ocular flutter 2. Paraneoplastic cerebellar syndrome 3. Paraneoplastic brainstem encephalitis 4. Bilateral sixth nerve palsy 5. Intraductal adenocarcinoma in situ left breast Surgical resection of the intraductal adenocarcinoma in situ was done. Therapy: Ten days of IV solumedrol 1 gm per day Five day course of IV IgG For an overview of paraneoplastic opsoclonus/flutter review: ID931-1 Paraneoplastic opsoclonus/CA breast, ID936-7 Paraneoplastic ocular flutter/CA lung. Hospital Course: Over a period of ten days the opsoclonus and flutter completely resolved and there was significant improvement in her ophthalmoplegia. The left eye regained almost full abduction and the right eye was able to cross the midline looking right. The spontaneous myoclonus stopped, hand tremors waxed and waned but overall improved, and the gait instability was markedly improved. She was able to walk in her room without a walker and in the hallway with a wheeled walker. She was hospitalized for three weeks and then discharged to a rehabilitation hospital. Discharge medication: Prednisone 10 mg daily, three times a day and on a tapering dose to stop after two weeks. The patient was followed by the neuro-oncology team. |
| Pathology |
Paraneoplastic opsoclonus/ocular flutter is thought to be humorally mediated, and antibodies to diverse auto-antigens have been reported, but most patients are seronegative as in this case. The antineural antibodies associated with opsoclonus include Anti-Ri, Anti-Hu, Anti-Yo, Anti-Mal, and Anti-amphyphisin antibodies. With regard to opsoclonus (OC), it is not known whether OC is a cerebellar or brainstem disorder. (Review case ID931-1 the index case for the Anti-Ri antibody and ID936-7 Paraneoplastic ocular flutter). Cerebellum: Wong et al have suggested, on theoretical grounds, that the deep cerebellar nuclei should be activated in patients with opsoclonus. (9) Helmchen et al (7) 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. 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 cerebellar vermal nor brainstem activation but showed, for the first time, bilateral functional activation of the deep cerebellar fastigial nuclei. This result supports Wong et al's recent hypothesis that OC results from a disinhibition of the fastigial ocular motor region (FOR). 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 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 that it may be possible that membrane-stabilizing drugs may have a therapeutic role for flutter and opsoclonus in the future. (Personal communication, 2007) (For further discussion see ref 8). |
| Disease/Diagnosis |
Paraneoplastic opsoclonus/flutter; Paraneoplastic cerebellar syndrome; Paraneoplastic brainstem encephalitis; Bilateral sixth nerve palsy; Intraductal adenocarcinoma of the breast |
| Clinical |
This 62 year old woman with paraneoplastic opsoclonus/flutter and diplopia due to bilateral sixth nerve palsy describes the visual disturbance of oscillopsia. At the time the video was made she had no opsoclonus/flutter. The eyes show: • Esotropia OS > OD • Weakness of abduction OS - left sixth nerve palsy • Weakness of abduction OD - right sixth nerve palsy • Impaired adduction OS • Full upgaze with upbeat nystagmus • Full downgaze with no nystagmus • Pursuit movements normal. Testing for ocular dysmetria show slow refixation saccades. No dysmetria. In addition this patient had • Bilateral ataxia on finger/nose test and heel-knee-shin • Loss of rhythm hand tapping • Gait ataxia Ocular flutter and flutter dysmetria are the major diagnostic signs. • Intermittent epochs of ocular flutter - horizontal back-to-back saccadic oscillations without an intersaccadic interval. • Flutter dysmetria most evident when the eyes make voluntary saccadic movements to the left Occasionally the amplitude of flutter is very small - microflutter, and the oscillations only detected with an ophthalmoscope or eye movement recordings. (6). Ocular flutter is often associated with paraneoplastic opsoclonus. Comment Dr. Zee (DZ), March 2007 SHW: David, I neglected to test for ocular flutter under closed lids by asking the patient to look to the right and back to center and to the left and back to center. Would I expect to see flutter with eyes closed? DZ: Good question. This would seem to be very likely since eye closure shuts off the pause cells, and flutter itself can often be triggered by making a saccade, even in the light. |
| Presenting Symptom |
Double Vision and ataxia |
| Ocular Movements |
Bilateral Sixth Nerve Palsy; Bilateral Esotropia; Paraneoplastic Opsoclonus/Flutter |
| Neuroimaging |
Neuroimaging studies are unavailable in this case. Illustrative brain MRI scans in another patient with paraneoplastic opsoclonus/ocular flutter are shown here. Axial FLAIR shows hyperintensity in both cerebellar hemispheres. Axial FLAIR through the mid-pons shows striking signal abnormality in the dorsal pons and cerebellar hemispheres. Axial FLAIR scan through the upper pons shows paraneoplastic brainstem multifocal hyperintensities consistent with encephalitis. (Courtesy of Anne Osborn, M.D.) |
| Treatment |
Immune modulation - intravenous IgG |
| Etiology |
Intraductal adenocarcinoma of the breast |
| Date |
1997 |
| References |
1. Alderson LM. Neurologic complications of breast cancer. In: Office Practice of Neurology 2nd Edition. Eds. Samuels MA, Feske SK. Churchill Livingston, 2003; 184:1181-1186. 2. Anderson NE. Rosenblum MK, Posner JB. Paraneoplastic cerebellar degeneration: clinical-immunological correlations. Ann Neurol 1988;24:559-567. http://www.ncbi.nlm.nih.gov/pubmed/3239956 3. Bataller L, Dalmau J. Paraneoplastic Neurologic Syndromes: Approaches to Diagnosis and Treatment. Semin Neurol 2003;23:215-224. http://www.ncbi.nlm.nih.gov/pubmed/12894387 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. http://www.ncbi.nlm.nih.gov/pubmed/3389761 5. Cogan DG. Ocular dysmetria, flutter-like oscillations of the eyes and opsoclonus. Arch. Ophthalmol 1954;51:318. http://www.ncbi.nlm.nih.gov/pubmed/13123617 7. Helmchen C, Rambold H, Sprenger A, Erdmann C, Binkofski F. Cerebellar activation in opsoclonus: An fMRI study. Neurology 2003;61:412-415. http://www.ncbi.nlm.nih.gov/pubmed/12913213 8. Leigh RJ, Zee DS. Diagnosis of Pheripheral Ocular Motor Palsies and Strabismus Chp 9:385-474. In The Neurology of Eye Movements. 4th Ed. Oxford University Press, New York 2006. 9. 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. http://www.ncbi.nlm.nih.gov/pubmed/11535236 |
| Language |
eng |
| Format |
video/mp4 |
| Type |
Image/MovingImage |
| Source |
3/4" Umatic master videotape |
| Relation is Part of |
163-3, 169-34, 944-5, 946-2 |
| Collection |
Neuro-Ophthalmology Virtual Education Library: Shirley H. Wray Collection: https://novel.utah.edu/Wray/ |
| Publisher |
North American Neuro-Ophthalmology Society |
| Holding Institution |
Spencer S. Eccles Health Sciences Library, University of Utah |
| Rights Management |
Copyright 2002. For further information regarding the rights to this collection, please visit: https://NOVEL.utah.edu/about/copyright |
| ARK |
ark:/87278/s6ng7n6f |
| Setname |
ehsl_novel_shw |
| ID |
188525 |
| Reference URL |
https://collections.lib.utah.edu/ark:/87278/s6ng7n6f |
