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Research Article *Corresponding author Carla Fernandes, Department of Ophthalmology, Egas Moniz Hospital, Rua Da Junqueira 126, 1349- 019 Lisbon, Portugal, Tel: 00351910230955; E-mail: Sixteen-and-a-Half Syndrome: [email protected] Submitted: 30 October 2020 Accepted: 17 November 2020 An Unusual Cause of Published: 19 November 2020 Carla Fernandes1*, José Marona2,3, Pedro Arede1, Carolina ISSN: 2333-6447 Copyright 1 1 1 1 Bruxelas , Maria Sara Patrício , Marta Guedes , and João Costa © 2020 Fernandes C, et al. 1Department of Ophthalmology, Egas Moniz Hospital, Portugal OPEN ACCESS 2Department of Reumathology, Egas Moniz Hospital, Portugal 3 CEDOC - NOVA Medical School, Universidade Nova de Lisboa, Portugal Keywords • Behçet disease Abstract • Pontine neuro-ophthalmological syndromes • Diplopia Eight-and-a-half syndrome is a neuro-ophthalmological disorder of eye movements. It consists of an association between paralysis of the horizontal conjugated gaze in one direction (1), internuclear ophthalmoplegia in the opposite direction (1/2) and facial paralysis (7). It results from the lesion of the Paramedian Pontine Reticular Formation, Medial Longitudinal Fasciculus and facial colliculus/facial nerve fascicle. Sixteen-and-a-half syndrome is a combination of the eight-and- a-half syndrome with additional VIII cranial nerve palsy. The authors present a clinical case of a “sixteen-and-a-half syndrome” as an unusual cause of horizontal binocular diplopia that led to the diagnosis of Neuro-Behçet disease.

ABBREVIATIONS PPRF: Paramedian Pontine Reticular Formation; MLF: revealed a “sixteen-and-a-half syndrome” with subsequent Medial Longitudinal Fasciculus; NBD: Neuro-Behçet disease; diagnosisMATERIALS of a NBD. AND METHODS ESR: Erythrocyte Sedimentation Rate; MRI: Magnetic Resonance or current medication, presented at the emergency department A 26-year-old man, with no relevant past medical history Imaging; CSF: Cerebrospinal fluid; ANA: Antinuclear Antibody; ENA: Extractable Nuclear Antigens; RF: Rheumatoid Factor; Behçet Disease; GC: Glucocorticoids; IS: Immunosuppressants; complaining of binocular horizontal diplopia and severe HLA: Human Leukocyte Antigen; RE: Right Eye; LE: Left Eye; BD: holocranial headache for the last three days. Clinical examination showed a 38,3 Celsius tympanic temperature, left eye TNFi:INTRODUCTION Tumor Necrosis Factor Alpha Inhibitor in primary gaze position, complete limitation of the right conjugated gaze, dissociation of the conjugated gaze to the left syndromes allows the clinician to localize neurologic lesions (Figure 1), and dissociated horizontal . Peripheral The recognition of pontine neuro-ophthalmological facial palsy (Figure 2), sensorineural hearing loss (confirmed by Weber and Rinne testing), and leg ataxia were observed on the oneand direction act accordingly. with internuclear Freeman etophthalmoplegia al, first described in the the opposite clinical right side. Pupillary examination, vertical eye movements and association of paralysis of the horizontal conjugated gaze (1) in convergenceRESULTS AND assessment DISCUSSION were unremarkable.

direction (1/2) [1]. Later, Fischer named that association as “one-and-a-half syndrome” [2]. After that, and following this Blood test showed raised inflammatory markers: concept, Eggenberg described the “eight-and-a-half syndrome” leukocytosis (12,4x109/L), with neutrophilia (8,41 x109/L), as the “one-and-a-half syndrome” plus facial palsy (7) [3]. Given elevated ESR (47mm/h), and a c-reactive protein of 100mg/L, the close anatomical location, the sixth and the seventh cranial without other relevant findings. Blood cultures were done. nerves can be injured together and, in less frequent cases, the MRI revealed a tumefactive right bulbar-point hyperintense eighth cranial nerve is also affected. In 2011, Cummins et. Al., T2 FSE/T2 FLAIR (Figure 3), lesion, with subtle gadolinium proposed the “sixteen-and-a-half syndrome” as the “eight-and-a- enhancement. Cerebrospinal fluid was clear and colorless with half syndrome” with additional ipsilateral sensorineural hearing normal opening pressure and the cytochemical exam revealed a loss (8) [4]. polymorphonuclear pleocytosis (400 cells/μL), with a 0.59 g/L The authors describe a clinical case of a 26-year-old man who protein level and a normal glucose. presented to the emergency department complaining of diplopia Given the clinical findings in association with fever, raised and headache for the last three days. Careful examination inflammatory markers, CSF polymorphonuclear pleocytosis and Cite this article: Fernandes C, Marona J, Arede P, Bruxelas C, Patrício MS, et al. (2020) Sixteen-and-a-Half Syndrome: An Unusual Cause of Diplopia. JSM Ophthalmol 7(2): 1076. Fernandes C, et al. (2020)

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(Ishihara’s plate test) was normal. Mydriatic fundus examination revealed a RE vitritis along peripheral retinal phlebitis (Figure 4).

contrast exudation secondary to inferior nasal sectoral vasculitis, withFluorescein scattered angiography dot and showed blot hemorrhages late hyperfluorescence and inferonasal due to ischemia (Figure 5). Therefore, the (multidisciplinary), diagnosis of Behçet disease was made, supported by the International Criteria for Behçet’s Disease [5]. Urogenital aphthosis, neurologic disorder and posterior with retinal vasculitis presented with diplopia and headache in the context of a “sixteen-and-a-half syndrome”. The patient started treatment with methylprednisolone pulses (1000mg/day during 5 days) and cyclophosphamide Figure 1 Ocular movements assessment. Complete limitation of the induction therapy (750mg/m2) with prompt favorable clinical conjugated gaze to the right, dissociation of the conjugated gaze to the outcome. Brain MRI showed signs of improvement three weeks left, normal vertical eye movements. later (Figure 6). Additionally, retinal focal laser photocoagulation was performed in ischemic areas.

BD is a multisystem relapsing inflammatory disorder of 5unknown years of cause.disease Neurologic (neurologic features onset is are unlikely) seen in [6]. 5-10% It is either of all causedpatients, by mostly primary in neural men, andparenchymal usually occurring lesions or after secondary the first to major vascular involvement [5]. Primary neural parenchymal involvement is more common and is predominantly localized at , thalamic, and regions. The two most Figure 2 Right peripheral facial palsy presenting Bell’s sign. common neural parenchymal involved structures are the junction of the and and the pontobulbar region [7]. Horizontal conjugate gaze is controlled by pontine structures, A B namely the PPRF. The signal from the PPRF is transmitted to the abducens nucleus and then projects via its nerve and simultaneously to the contralateral oculomotor nucleus via the

A B

Figure 3 A - Axial T2 FSE and B - Axial T2 FLAIR, showing right sided bulbar-point hyperintense lesion. Figure 4 A - Right eye B - Left eye: Ocular Fundus presenting peripheral retinal vasculitis.

ar-pontine lesion, the patient started empirical viral encephalitis treatment with ceftriaxone (2g A 12/12h),the non-specific ampicillin right (2g bulb 4/4h) and acyclovir (15mg/kg 8/8h). B Patient failed to improve with treatment. Persistent fever were appreciated in the following days. As CSF microbiology and bloodand additional cultures were urogenital negative, ulcers a Rheumatology and inflammatory consultation gonalgia was the HLA-B51 were negative and septic arthritis was excluded. Atrequested. the same The time, immunological the patient wasprofile evaluated (ANA, ENA, by Ophthalmology. ANCA, RF), and He’s best corrected visual acuity was 20/29 in the right eye Figure 5 and 20/22 in the left eye. Anterior segment biomicroscopy was scattered dot A and + B blot - Right hemorrhages eye fluorescein and inferonasal angiography ischemia. with late unremarkable in both eyes and chromatic vision evaluation hyperfluorescence due to inferonasal sectoral vasculitis, with

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brainstem parenchymal syndrome can be localized to the pontine presentation of an inflammatory multisystemic disease. This

tegmentumGiven the through clinical clinical diagnosis findings. of BD with neurologic and ocular involvement, the patient was treated with immunosuppressants, with resultant improvement in both and visual acuity. A multidisciplinary approach is essential in such a complex patient. In this clinical setting, early immunosuppressive therapy and high-dose glucocorticoids can be life and sight-saving. ACKNOWLEDGEMENTS The authors gratefully acknowledge Egas Moniz

Figure 6 Axial T2- FLAIR three weeks after inductive treatment patientHospital diagnosis colleagues and frommanagement. the Neurology, Rheumatology and beginning showing lesion reduction. Neuroradiology departments, for their crucial support on this REFERENCES MLF. Any disruption involving the PPRF or abducens nucleus 1. Freeman W, Ammerman H, Stanley M. Syndromes of the pontile leads to lesion-sided horizontal gaze palsy. When the ipsilateral MLF is involved, the signal from the contralateral abducens 2. tegmentum. Arch. Neurol. & Psychiat. 1941; 46: 462-471. nucleus will not be transmitted to the sub nucleus of the III nerve nucleus, resulting in ipsilateral internuclear ophthalmoplegia Fisher CM. Some neuro-ophthalmological observations. J Neurol NeurosurgEggenberger, Psychiat. E. Eight-and-a-half 1967; 30: 383-392. syndrome: one-and-a-half syndrome 3. A spectrum of pontine affecting diseases that cause the “one- characterized by adduction deficit [8]. 4. plusCummins cranial G, nerve O’Hare VII palsy. A, Dunne J Neuroophthalmol. R, Connolly S, 1998; O’Rouke 18: 114-116. K, Lynch and-a-half syndrome” have been described in literature the most T. “Sixteen and a half”: a novel pontine neuroophthalmological common being cerebrovascular pathologies or demyelinating diseases. Other rare causes are head trauma, metastatic tumors 5. syndrome.The International J Neurol. Criteria 2011; for258: Behçet’s 1347-1348. Disease (ICBD): a collaborative of BD as the presentation cause of “sixteen-and-a-half syndrome”. criteria. Davatchi F, Assaad-Khalil S, Calamia KT, Crook JE, Sadeghi- or tuberculomas [8]. As far as we know this is the first description study of 27 countries on the sensitivity and specificity of the new The most frequent ocular manifestations in BD are bilateral non-granulomatous panuveitis, with or without , with 6. AbdollahiKalra S, Silman B, Schirmer A, Akman-Demir M, et al. JEADV. G, Bohlega2013; 28: S, 338-3347. Borhani-Haghighi A, obliterating and necrotizing retinal vasculitis, which has the distinctiveness of affecting both arteries and veins. If untreated, 261:Constantinescu 1662-1676. C. et al. Diagnosis and management of Neuro-Behçet’s vascular complications may lead to blindness [9]. disease: international consensus recommendations. J Neurol. 2014; 7. Current BD guidelines [10], advocate the use of high-dose glucocorticoids and immunosuppressants such as azathioprine Shahien R, Bowirrat A. Neuro-Behçet’s disease: A report of sixteen 8. patients.Choi S, Kim Neuropsychiatric T, Chung J, Joo DiseaseJ, Park I,and Moon Treatment. S, et al. Sixteen-and-a-half2010; 6: 219-225. In refractory cases, either tumor necrosis factor alpha inhibitor oras first-linecyclophosphamide therapy when may neurologicbe used. Despite involvement fertility is concerns present. 9. syndrome with metastatic tumor. Medicine. 2019; 98: 1-5. in young individuals, the multidisciplinary team agreed on nomenclatureJabs DA, Nussenblatt for reporting RB, Rosenbaum clinical JT. data. Standardization Results of ofthe Uveitis First Nomenclature (SUN) Working Group. Standardization of uveitis considering the high-risk parenchymal involvement according tocyclophosphamide some criteria previouslyas inductive described treatment, in instead literature of7 TNFi, thus 10. InternationalHatemi G, Christensen Workshop. R, AmBang J Ophthalmol. D, Bodaghi B,2005; Celik 140: A, Fortune 509-516. F, et al. 2018 update of the EULAR recommendations for the management of requiring a more “aggressive” treatment [11]. Additionally, cyclophosphamide has a theoretical faster onset of action (in 11. Behçet’sHatemi G, syndrome. Silman A, AnnBang Rheum D, Bodaghi Dis. 2018; B, Chamberlain 77: 808-818. AM, Gul A, et al. EULAR recommendations for the management of Behçet disease. Ann comparisonCONCLUSION to TNFi). This case portrays a “sixteen-and-a-half syndrome” as a Rheum Dis. 2008; 67: 1656-1662.

Cite this article Fernandes C, Marona J, Arede P, Bruxelas C, Patrício MS, et al. (2020) Sixteen-and-a-Half Syndrome: An Unusual Cause of Diplopia. JSM Ophthalmol 7(2): 1076.

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