Multiple Sclerosis

Upbeat Nystagmus; Lid Nystagmus; Square Wave Oscillations; Jerk Oscillations; Rotary Nystagmus; Saccadic Pursuit; Saccadic DysmetriaDifficulty focusingThe patient is a 56 year old woman who presented in 1982, at the age of 48, with a one week history of painless loss of vision in the left eye. Past History: Negative for a previous attack of optic neuritis or transient neurological symptoms. Family History: Negative for CNS disease Neuro-ophthalmological examination: Visual acuity (VA) 20/25 OD, 20/200 OS Afferent pupil defect OS. Automated perimetry OS central scotoma breaking out into the superior altitudinal field. OD visual field normal. Fundus examination normal optic discs. Ocular motility: Full eye movements Normal convergence No nystagmus Neurological examination: No abnormality Visual Evoked Potential: Normal response OD Absent response OS. CT brain and orbits: Minimal thickening of the left optic nerve Normal brain images. Plain x-rays of the optic foramen: Normal asymmetry of the foramena. The left optic foramen measured 4 mm and the right 5 mm. in diameter. Both were round, well corticated with no destructive bone changes. Diagnosis: Retrobulbar optic neuritis OS Treatment: Prednisone was started with a loading dose of 100 mg daily, quickly tapered down to 40 mg daily. After one week VA 20/40 OS. She remained on Prednisone 40 mg daily for six weeks. On follow-up at that time VA OS 20/25, a left afferent pupil defect, normal visual field and optic discs. Eight years later, in 1990, she developed diffuclty focusing, unsteadiness walking, and numbness of the left side of her face from the bridge of the nose to the middle of the chin and the left side of her tongue and cheek. Taste was impaired. She was admitted to Massachusetts General Hospital for evaluation. Neuro-ophthalmological examination: VA 20/25, J1+ OU corrected. Visual fields, pupils, and fundus examination normal Corneal reflexes intact OU Ocular motility: • Transient spontaneous primary position upbeat nystagmus with lid nystagmus. • Rapid bursts of horizontal square wave oscillations opening her eyes to fix on a target. • Rotary nystagmus in both eyes on gaze right and left. Rotation of the globe was best seen by observing the conjunctival blood vessels. • Full upgaze with unsustained upbeat nystagmus. • Saccadic pursuit on horizontal and upgaze • Smooth pursuit down • Saccadic Dysmetria Hypermetria left gaze to center Neurological examination: • Sensation on the left side of the face (2nd and 3rd division left trigeminal nerve) decreased to light touch and pinprick • Decreased taste to salt and sugar, left anterior aspect of the tongue • Muscle strength normal • Generalized hyperreflexia • Flexor plantar responses • Ataxia heel-knee-shin • Ataxic gait • Sensation intact all modalities Brainstem auditory evoked potentials: Normal on the right side Mildly abnormal on the left side with an increased latency in waves 1-5. Visual evoked potentials: Normal P100 latency OD, 115 msec, amplitude 15.3 Delayed P100 latency OS, 125 msec, amplitude 4.5. Impression: Unilateral lesion in the left visual pathway anterior to the optic chiasm (consistent with a previous attack of optic neuritis OS). Lumbar puncture: Normal cerebrospinal fluid. Electronystagmogram: 1. Spontaneous and gaze nystagmus - right beating nystagmus 30 degrees right lateral gaze with eyes open in the light. Right beating nystagmus stopped on eye closure. Upbeating nystagmus on upgaze with a rotary component. 2. Optokinetic nystagmus - symmetrical and appropriate 3. Positional testing: a. Hallpikes/Eyes open in the light In the right ear down position transient well formed left beating nystagmus in the right eye. In the left eye a small poorly formed right beating nystagmus. Similar but persistent nystagmus seen on sitting up from the right ear down position. In the left ear down position, well formed right beating nystagmus in the left eye and no definite nystagmus in the right eye. The nystagmus persisted and was present on sitting up from the left ear down position. No associated dizziness with the above maneuvers. Impression: Abnormal electronystagmogram • Positional nystagmus without dizziness • Gaze evoked nystagmus with eyes open in the light that stopped with eye closure • A reduced left caloric response of 37% on caloric testing. Brain MRI: T2 WI showed extensive multifocal signal abnormalities involving the centrum semiovale, the posterior fossa and the left temporal lobe. Some foci showed Gadolinium enhancement and some tissue loss. There were no flow abnormalities within these areas and no hemorrhage. Impression: Multifocal white matter lesions consistent with demyelinating disease. Inspite of the prior history of retrobulbar neuritis and a positive brain MRI for multiple white matter lesions, her primary care physician had felt it was impossible to make a diagnosis of Multiple Sclerosis (MS). Diagnosis on discharge: Multiple SclerosisThis patient with MS had: • Transient spontaneous primary position upbeat nystagmus with lid nystagmus • Rapid bursts of horizontal square wave oscillations opening her eyes to fix on a target • Rotary nystagmus in both eyes on gaze right and left. Rotation of the globe was best seen by observing the conjunctival blood vessels. • Full upgaze with unsustained upbeat nystagmus • Saccadic pursuit on horizontal and upgaze • Smooth pursuit on downgaze. • Saccadic Dysmetria Hypermetria left gaze left to center. The constellation of eye signs localized to a Medial Medullary Brainstem Syndrome due to MS. Comment: Dr. Zee (DZ) on review of this case commented that the point of interest in this patient is that she had a period with upbeat nystagmus in primary position which resolved. We wondered about a possible localization in the medial medulla involving inferior olivary projections on their way to cross in the midline and run to the cerebellum and the inferior cerebellar peduncle and /or lesion(s) in the region of the nucleus intercalatus and the nucleus of Roller to account for the upbeat nystagmus. DZ thought that the abnormal horizontal eye movements in this case were somewhat similar clinically to patients with Wallenberg's Syndrome (due to vascular lesions in the same territory) that have been studied by Tilikete et al (10) In this particular MS patient, however, the saccadic dysmetria, or if you will, contrapulsion is subtle. There is some deviation of the eyes under closed lids and there may be a hint of hypermetria with saccades going to the right but it certainly is not striking and there did not seem to be any pulsion of saccades during attempted vertical refixations. However, the association of primary position upbeat nystagmus and saccadic lateropulsion is also very similar to one of Tilikete's patients with a medial caudal medullary brainstem syndrome (11). Box 10-3 Clinical Features of Upbeat Nystagmus Pg487 Box 10-4 Clinical Features of Torsional Nystagmus Pg488 Table 10-2 Etiology of Upbeat Nystagmus Pg 485 (5)Neuroimaging studies were not available in this patient. Illustrative images in another MS case are shown here. Figure 1 MRI Axial FLAIR scan showing white matter foci of increased signal intensity surrounding cavitating areas characteristic of long-standing MS. Figure 2 MRI axial FLAIR scan of deep periventricular foci of increased signal intensity surrounding cavitating areas. Figure 3 MRI sagittal FLAIR scan with classic calloseptal deep periventricular foci perpendicular to ventricle surface classic for Dawson fingers. Courtesy of Anne Osborn, M.D. Professor Ian McDonald at the Institute of Neurology, Queen Square, London, contributed his remarkable time-lapse MRI study of a single patient with MS over a period of one year. This study shows focal demyelinating lesions appearing and disappearing over time. View ID40-1- Time Lapse MRI of focal MS Lesions This time lapse video was assembled from serial T2- weighted MRI scans from a 25-year old woman with multiple sclerosis which had recently entered the secondary progressive phase. Scans were performed at 2-weekly intervals for three months then monthly intervals for a further six months. Gadolinium DTPA was injected on each occasion for the first 6 months and monthly thereafter. The areas of enhancement in T1- weighted scans have been superimposed in red on the T2 weighted scans. In the video one second represents approximately one week in the patient's life. Three successively deeper planes are shown covering the same period. New lesions almost always begin with enhancement, representing a breakdown in the blood- brain barrier. Enhancement usually lasts 2-4 weeks. The lesions increase in size over this period then shrink. The waxing and waning element represents oedema. Re-enhancement occurs in some lesions. There is a tendency to temporal clustering of lesion activity. During the period of observation there were 97 separate episodes of activity but only three clinical relapses. The patient was one of those included in an investigation undertaken to test the hypothesis that there are differences in the frequency of disease activity between primary and secondary progressive multiple sclerosis. This proved to be the case, enhancement being much more frequent in the latter.(9)Lesion(s) involving the nucleus intercalatus and the nucleus of Roller have been reported to cause primary position upbeat nystagmus, suggesting that either of these structures may relay vertical eye position signals to the cerebellum. Upbeat nystagmus is also reported with lesions involving the brachium conjunctivum in the rostral pons and midbrain. Upbeat nystagmus is a manifestation of central vestibular dysfunction. The coexistence of upbeat nystagmus and saccadic contrapulsion provide a clue about the pathogenesis of these two eye movement signs. Lateral pulsion of saccades can be attributed to interruption of either climbing fiber pathways running from the inferior olivary nucleus to the cerebellar vermis, or to disruption of outputs from the fastigial nucleus running in the superior cerebellar peduncle. Contrapulsion (accompanied by upbeat nystagmus) occurs with lesions affecting climbing fibers before they cross the midline, or projections from the fastigial nucleus running in the superior cerebellar peduncle. Unlike downbeat nystagmus, upbeat nystagmus does not seem to occur with cerebellar lesions, but is encountered with lesions throughout the brainstem that may also include cerebellar connections. Torsional nystagmus is seen in a wide range of lesions throughtout the brainstem, including lateral medulla infarction, syringobulbia, pontine tegmental venous angioma, and midbrain lesions involving the rostral interstitial nucleus of the MLF and interstitial nucleus of Cajal. For full discussion review (5).Review (4)Review Multiple Sclerosis in 2008 Courtesy of Stephen Hauser, M.D.Review Multiple Sclerosis and other demyelinating diseases. Courtesy of Stephen Hauser, M.D.1. Benjamin EE, Zimmerman CF, Troost BT. Lateropulsion and upbeat nystagmus are manifestations of central vestibular dysfunction. Arch Neurol 1986;43:962-964. http://www.ncbi.nlm.nih.gov/pubmed/3488729 2. Hauser SL, Goodin DE. Multiple Sclerosis and other demyelinating diseases in Harrison's Principals of Internal Medicine, 16th Edition, Kasper DL et al eds. McGraw-Hill, New York, 2005. 3. Kattah JC, Dagli TF. Compensatory head tilt in upbeating nystagmus. J Clin Neuroophthalmol 1990;10:27-31. http://www.ncbi.nlm.nih.gov/pubmed/2139045 4. Keane JR, Itabashi HH. Upbeat nystagmus: Clinicopathologic study of two patients. Neurology 1987; 37:491-494. http://www.ncbi.nlm.nih.gov/pubmed/3822146 5. Leigh JR and Zee DS. Diagnosis of Nystagmus and Saccadic Intrusion. Chp 10;475-558. In: The Neurology of Eye Movements, 4th Edition. Oxford University Press, New York 2006. 6. Munroe NA. The role of the nucleus intercalatus in vertical gaze holding. J Neurol Neurosurg Psychiatry 1999,66:552-553. http://www.ncbi.nlm.nih.gov/pubmed/10201443 7. Nakada T, Remler MP. Primary position upbeat nystagmus: another central vestibular nystagmus? J Clin Neuroophthalmol 1981;1:181-185. http://www.ncbi.nlm.nih.gov/pubmed/6213659 8. Pierrot-Desseilligny C, Milea D. Vertical nystagmus: clinical facts and hypotheses. Brain 2005,128;1237-1246. http://www.ncbi.nlm.nih.gov/pubmed/15872015 9. Thompson AJ, Kermode AG, Wicks D, MacManus DG, Kendall BE, Kingsley DP, McDonald WI. Major differences in the dynamics of primary and secondary progressive multiple sclerosis. Ann Neurol 1991,29: 53-62. http://www.ncbi.nlm.nih.gov/pubmed/1996879 10. Tilikete C, Koene A, Nighoghossian N., Vighetto A, Pélisson . Sacadic lateropulsion in Wallenberg syndrome: a window to access cerebellar control of saccades? Exp Brain Res 2006, 174(3);555-65. http://www.ncbi.nlm.nih.gov/pubmed/16680426 11. Tilikete C. Hermier M. Pelisson D, Vighetto A. Saccadic lateropulsion and primary position upbeat nystagmus: disorders of caudal medulla. Ann Neurol 2002, 52:658-662. http://www.ncbi.nlm.nih.gov/pubmed/1240226