Ocular Oscillations in the Neuromyelitis Optica Spectrum

Four French West Indian women complained of oscillopsia and were found to have an acquired eye movement disorder. In 3 of them, different types of nystagmus were found, including upbeat, downbeat, and central form of vestibular nystagmus. One developed opsoclonus-myoclonus syndrome. Three patients had neuromyelitis optica antibodies, and 3 had brainstem abnormalities detected on MRI. Two patients had definite NMO, while the other 2 were considered to be at high risk for developing NMO. Treatment with high-dose systemic corticosteroids, with plasma exchanges, or in combination led to resolution of oscillopsia. We propose that eye movement disorders be added to the neurological manifestations of NMO.

Ocular Oscillations in the Neuromyelitis Optica Spectrum Rabih Hage, Jr, MD, Harold Merle, MD, Se´verine Jeannin, MD, Philippe Cabre, MD Abstract: Four French West Indian women complained of oscillopsia and were found to have an acquired eye move-ment disorder. In 3 of them, different types of nystagmus were found, including upbeat, downbeat, and central form of vestibular nystagmus. One developed opsoclonus-myoclonus syndrome. Three patients had neuromyelitis optica anti-bodies, and 3 had brainstem abnormalities detected onMRI. Two patients had definite NMO, while the other 2 were considered to be at high risk for developing NMO. Treatment with high-dose systemic corticosteroids, with plasma ex-changes, or in combination led to resolution of oscillopsia. We propose that eye movement disorders be added to the neurological manifestations of NMO. Journal of Neuro-Ophthalmology 2011;31:255-259 doi: 10.1097/WNO.0b013e31821d549b 2011 by North American Neuro-Ophthalmology Society Severe visual loss due to optic neuritis (ON) is the most common ophthalmologic manifestation of neuro-myelitis optica (NMO). In contrast, oscillopsia has not been reported in this disorder. Oscillopsia may be the conse-quence of 2 different types of eye movement abnormalities: nystagmus and involuntary saccadic intrusions. We report 4 patients, 2 with NMO and 2 at high risk for NMO, who presented with symptomatic abnormal eye movements, including upbeat nystagmus (UBN), downbeat nystagmus (DBN), central form of vestibular nystagmus, and op-soclonus- myoclonus syndrome (OMS). Including eye movement disturbances as another manifestation of NMO supports the concept of NMO spectrum disorders (1). CASE REPORTS Case 1 A 46-year-old Chinese woman who was previously healthy presented with acute bilateral visual loss. The patient could only see hand movements in each eye; pupils were sluggishly reactive to light, and the left optic disc was swollen. Visual evoked responses showed delayed latencies and amplitudes bilaterally. Cerebrospinal fluid (CSF) analysis showed 15 cells per cubic millimeter and a protein level of 53 mg/dL (normal, 20-40 mg/dL) without oligoclonal bands. Serum NMO antibodies were not detected. Brain MRI revealed areas of increased signal in the hypothalamus and both the optic tracts (Fig. 1). MRI of the spinal cord was normal. The patient partially improved following a 5-day course of in-travenous (IV) high-dose corticosteroids. Fifteen months later, she developed gait disturbance and oscillopsia. Neurological examination revealed tetraparesis, dysarthria, dysphagia, and tongue deviation to the right. Sensitivity to light touch on the left side of the face was decreased. Visual acuity was 20/200 in each eye. The patient had UBN in both eyes in primary position, which became more marked on upward gaze (see Video, Supplemental Digital Content 1, http://links.lww.com/WNO/A18). Range of eye movements was full. Fundus examination showed left optic atrophy. BrainMRI now demonstrated a lesion in the dorsal area of the caudal medulla (Fig. 2), while MRI of the spine showed a gadolinium ring-enhancing lesion in the upper cervical cord. Despite high-dose IV corticosteroids, UBN persisted. Amplitude increased in upgaze and decreased in downgaze and with convergence. Neither ocular fixation nor head position modified the direction or amplitude of UBN. On videooculography, the nystagmus had an exponentially de-creasing slow phase. Five treatments of plasma exchange led to complete resolution of oscillopsia within 2 weeks. Departments of Ophthalmology (RH, HM) and Neurology (SJ, PC), University Hospital of Fort-de-France, Martinique, French West Indies. The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.jneuro-ophthalmology.com). Address correspondence to Philippe Cabre, MD, Service de Neu-rologie, Centre Hospitalier Universitaire de Fort-de-France, Hoˆpital Pierre Zobda-Quitman, BP 632, Fort-de-France 97261, Martinique, French West Indies; E-mail: [e-mail]; and Rabih Hage, Jr, MD, BP 632 La Meynard, Fort-de-France 97200, Martinique, France; E-mail: [e-mail] Hage et al: J Neuro-Ophthalmol 2011; 31: 255-259 255 Clinical Observation Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. The patient was felt to have NMO. Following plasma exchange, the patient was given 4 infusions of IV rituximab (dose, 375 mg/m2), administered once per week. She has not experienced new neurological symptoms during 1 year of follow-up. Case 2 A 37-year-old Afro-Caribbean woman had a 10-year history of NMO. During the course of her disease, she experienced bilateral ON twice, each time treated with corticosteroid therapy. Her visual acuity was counting fingers in the right eye and no light perception in the left eye. Several forms of therapy, including mitoxantrone, cyclophosphamide, and rituximab, had failed to prevent relapses. NMO antibody was found in her serum on several determinations. Weekly plasma exchange had been instituted but was suspended due to a presumed infectious spondylitis. Two months later, she complained of acute vertigo, unsteadiness of gait, and bi-lateral upper limb weakness. Neurological examination revealed DBN in primary position. Electronystagmography showed that the nystagmus increased in amplitude in lateral gaze and remained unchanged during convergence. Eye movements were full. Following plasma exchange, vertigo disappeared but the DBN persisted. Brain MRI performed 2 years later was unremarkable. Case 3 A 49-year-old Afro-Caribbean woman without significant medical history noticed decreased sensation in her left arm, leg, and left side of her face. Within a few days, she ex-perienced urinary hesitancy and she complained of oscil-lopsia in right gaze. Examination showed a right-beating horizontal-rotatory nystagmus in right gaze, which did not change with head position or convergence. Brain MRI disclosed a presumed inflammatory lesion in the left pons (Fig. 3). MRI of the spinal cord demonstrated extensive longitudinal myelitis. NMO antibodies were found in her serum. The nystagmus was considered to be a central ves-tibular form of vestibular nystagmus since it was not as-sociated with symptoms such as tinnitus, hyperacusis, or vertigo. High-dose IV corticosteroids led to disappearance of nystagmus. The patient was felt to be at high risk for NMO, and treatment was begun with mitoxantrone at a dose of 12 mg/m2 administrated once per month. Case 4 A 22-year-old Afro-Caribbean woman with a history of systemic lupus erythematosus was referred for quad-raparesis, slowly worsening for more than 1 week. Symp-toms then rapidly progressed over a few hours to flaccid paraplegia associated with severe multimodal hypoesthesia of lower limbs, sphincter disturbances, hypovigilance, and oscillopsia. Examination revealed opsoclonus consisting of multidirectional rapid involuntary eye movements. She also had myoclonus of right arms during voluntary movements. CSF contained 300 cells per cubic millimeter and a protein level of 155 mg/dL (normal, 20-40 mg/dL). There were no oligoclonal bands. Brain MRI showed involvement of the hypothalamus and increased signal in the medulla, pons, and cerebral peduncles in the periaqueductal area (Fig. 4A). MRI of the spine showed longitudinally extensive myelitis involving the entire spinal cord (Fig. 4B). The patient received pulse IV methylprednisolone (2 g/ day for 5 days), followed by a series of plasma exchange treatments with resolution of OMS, upper limb weakness, FIG. 1. Case 1. Axial FLAIR MRI shows high-signal lesions in the hypothalamus (A) and optic tracts (B). 256 Hage et al: J Neuro-Ophthalmol 2011; 31: 255-259 Clinical Observation Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. and somnolence. She remained paraplegic, and neurological examination showed that pinprick, vibratory, and touch sensation were still abolished below T10 level bilaterally. Since she had NMO antibodies, the patient was felt to be at high risk for NMO. Mitoxantrone given at 12 mg/m2, administrated once per month, was begun. Two months after the onset of symptoms, brain MRI showed disap-pearance of all brain lesions. Spinal cord MRI showed a significant reduction in high-signal lesions on T2 se-quences, with a moderate decrease in edema of the thor-acolumbar cord. The patient remained unchanged during the subsequent 4 months. DISCUSSION With established diagnostic criteria (2) and a specific serum biomarker (3), recognition of the clinical manifestations of NMO continues to expand. This has given rise to the concept of NMO spectrum disorders (Table 1). It is the brainstem involvement that led to our patients' eye movement abnormalities and symptom of oscillopsia. Although these involuntary eye movements have not been previously described in the NMO spectrum, they do not appear to be exceptional in our French West Indian cohort of 50 NMO patients. Our first patient experienced bilateral ON and sub-sequently developed UBN. While the amplitude of nys-tagmus increased in upgaze, it resolved in lateral gaze and with ocular fixation. Videooculography showed an expo-nential decreasing slow-phase velocity suggestive of neural integrator dysfunction. UBN may be due to lesions of the ventral tegmental tract (VTT) of the pons as well as the medulla. In our patient, MRI demonstrated a lesion in-volving part of the perihypoglossal nuclei, including the nucleus of Roller and nucleus intercalatus, 2 areas felt to be involved in the pathophysiology of UBN. A lesion of these nuclei results in loss of inhibition of flocculovestibular neurons leading to overinhibition of the VTT. This creates a slow downward drift of the eyes and corrective upward saccades (4). Our second patient developed DBN without any other ocular motor abnormalities. Unlike cerebellar degeneration, inflammatory diseases of the central nervous system are seldom implicated in DBN (5). While the pathophysiology of DBN is not well understood, it may be due to impair-ment of cerebellovestibular inhibitory pathways between the FIG. 2. Case 1. T2 sagittal (A) and T1 axial (B) MRI demonstrates an area of increased signal in the caudal medulla. Accompanying schematic diagrams show extent of involvement (hatched area). Line with arrows on sagittal schematic drawing indicates level of axial scan (B). Structures affected include the nucleus intercalatus (red) located between nucleus prepositus hypoglossi (green) and medial vestibular nucleus (yellow). The nucleus of Roller (blue) is also involved. Hage et al: J Neuro-Ophthalmol 2011; 31: 255-259 257 Clinical Observation Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. flocculus and superior vestibular nucleus. Such a lesion would lead to disinhibition of elevator motoneurons elic-iting an upward slow-phase deviation, followed by correc-tive downward saccades (4). Unfortunately, we were not able to document a lesion in the lower brainstem at the nadir of attack producing DBN. We speculate that the signal of the lesion gradually disappeared over time in the same manner to that is observed for some spinal cord lesions of NMO (6). Binocular horizontal nystagmus with a right-beating fast phase characterized the eye movement disorder in our third patient. The nystagmus persisted despite ocular fixation, and MRI demonstrated a left pontine lesion with an in-volvement of the vestibular nucleus. This nystagmus was considered to be a central form of vestibular nystagmus. Our fourth patient presented with OMS. The patho-genesis of opsoclonus is not completely understood, but it is believed to be either a cerebellar or brainstem disorder. Functional MRI studies suggest that fastigial nucleus acti-vation leads to inhibition of omnipause neurons (OPN) in turn causing disinhibition of saccadic burst neurons and opsoclonus (7). The extensive pontine lesions on MRI in our patient included involvement of the pontine para-median reticular formation where OPN are located. NMO is a severe demyelinating disease that was initially thought to affect only optic nerves and spinal cord. Other neurological symptoms attributable to lesions outside these locations do not exclude a diagnosis of NMO according to recently revised diagnostic criteria (2). The NMO antibody that was present in 3 of our patients targets the water channel FIG. 4. Case 4. A. Axial FLAIRMRI shows increased signal in the tegmentum and paramedian regions of themidbrain. B. T2 sagittal MRI demonstrates longitudinally extensive myelitis with high signal (arrows) involving the entire spinal cord. FIG. 3. Case 3. T1 axial MRI reveals a left pontine lesion (arrow) in the area of left vestibular nucleus. 258 Hage et al: J Neuro-Ophthalmol 2011; 31: 255-259 Clinical Observation Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. aquaporin-4 (AQP-4). In addition to the optic nerves and spinal cord regions that are enriched in AQP-4 include the hypothalamus, corpus callosum, periventricular region, and brainstem (8). Two of our patients had hypothalamic lesions, and 3 had an involvement of the brainstem. We propose that the eye movement abnormalities in our patients with NMO or at high risk for NMO are due to inflammatory lesions in the brainstem. Fortunately, treatment with corticosteroids and plasma exchange led to clinical improvement in all our patients. REFERENCES 1. Wingerchuk DM, Lennon VA, Lucchinetti CF, Pittock SJ, Weinshenker BG. The spectrum of neuromyelitis optica. Lancet Neurol. 2007;6:805-815. 2. Wingerchuk DM, Lennon VA, Pittock SJ, Lucchinetti CF, Weinshenker BG. Revised diagnostic criteria for neuromyelitis optica. Neurology. 2006;66:1485-1489. 3. Lennon VA, Wingerchuk DM, Kryzer TJ, Pittock SJ, Lucchinetti CF, Fujihara K, Nakashima I, Weinshenker BG. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet. 2004;364: 2106-2112. 4. Pierrot-Deseilligny C, Milea D. Vertical nystagmus: clinical facts and hypotheses. Brain. 2005;128:1237-1246. 5. Wagner JN, Glaser M, Brandt T, Strupp M. Downbeat nystagmus: aetiology and comorbidity in 117 patients. J Neurol Neurosurg Psychiatry. 2008;79:672-677. 6. Cassinotto C, Deramond H, Olindo S, Aveillan M, Smadja D, Cabre P. MRI of the spinal cord in neuromyelitis optica and recurrent longitudinal extensive myelitis. J Neuroradiol. 2009;36:199-205. 7. Wong A. An update on opsoclonus. Curr Opin Neurol. 2007; 20:25-31. 8. Pittock SJ, Weinshenker BG, Lucchinetti CF, Wingerchuk DM, Corboy JR, Lennon VA. Neuromyelitis optica brain lesions localized at sites of high aquaporin 4 expression. Arch Neurol. 2006;63:964-968. TABLE 1. NMO spectrum disorders NMO Limited forms of NMO Idiopathic single or recurrent longitudinally extensive myelitis ($3 vertebral segment spinal cord lesion on MRI) ON: recurrent or simultaneous bilateral Asian optic-spinal multiple sclerosis ON or longitudinally extensive myelitis associated with systemic autoimmune disease ON or myelitis associated with brain lesions typical of NMO (hypothalamus, corpus callosum, periventricular, brainstem) From Wingerchuk et al (1). NMO, neuromyelitis optica; ON, optic neuritis. Hage et al: J Neuro-Ophthalmol 2011; 31: 255-259 259 Clinical Observation Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.