Literature Commentary

Literature Commentary Section Editors: Mark L. Moster, MD M. Tariq Bhatti, MD Literature Commentary In this issue of Journal of Neuro-Ophthalmology, Tariq Bhatti, MD and Mark Moster, MD, will discuss the following 6 articles: 1. Granet DB, Hodgson N, Godfrey KJ, Ventura R, Kikkawa DO, Levi L, Kinori M. Chemodenervation of extraocular muscles with botulinum toxin in thyroid eye disease. Graefes Arch Clin Exp Ophthalmol. 2016;254:999-1003. 2. Sanders DB, Wolfe GI, Benatar M, Evoli A, Gilhus NE, Illa I, Kuntz N, Massey JM, Melms A, Murai H, Nicolle M, Palace J, Richman DP, Verschuuren J, Narayanaswami P. International consensus guidance for management of myasthenia gravis: executive summary. Neurology. 2016;87:419-425. 3. Vodopivec I, Oakley DH, Perugino CA, Venna N, Hedley-Whyte ET, Stone JH. A 44-year-old man with eye, kidney, and brain dysfunction. Ann Neurol. 2016;79:507-519. 4. Martens C, Goplen FK, Nordfalk KF, Aasen T, Nordahl SH. Prevalence and characteristics of positional nystagmus in normal subjects. Otolaryngol Head Neck Surg. 2016;154:861-867. 5. Tur C, Goodkin O, Altmann DR, Jenkins TM, Miszkiel K, Mirigliani A, Fini C, Gandini Wheeler-Kingshott CA, Thompson AJ, Ciccarelli O, Toosy AT. Longitudinal evidence for anterograde trans-synaptic degeneration after optic neuritis. Brain. 2016;139:816-828. 6. Zhang Z, Wu S, Jonas JB, Zhang J, Liu K, Lu Q, Wang N. Dynein, kinesin and morphological changes in optic nerve axons in a rat model with cerebrospinal fluid pressure reduction: the Beijing Intracranial and Intraocular Pressure (iCOP) study. Acta Opthalmologica. 2016;94:266-275. Granet DB, Hodgson N, Godfrey KJ, Ventura R, Kikkawa DO, Levi L, Kinori M. Chemodenervation of extraocular muscles with botulinum toxin in thyroid eye disease. Graefes Arch Clin Exp Ophthalmol. 2016;254:999-1003. Background: Thyroid eye disease (TED) presents a management dilemma for strabismologists due to the variability of its clinical course. Prisms may be prescribed to relieve diplopia in small deviations. Surgical intervention, on the other hand, should not be done until the active phase of the disease has subsided. We report our experience with chemodenervation utilizing botulinum toxin (BT) injection in the management of TED-related strabismus. Methods: A retrospective chart review was done on 22 consecutive patients receiving BT injections at the University of California, San Diego (UCSD) Thyroid Eye Center. All BT injections were administered by a single physician under electromyographic guidance. Results: The clinical records of 22 patients (18 women) were reviewed. Seven patients (32%) had a reduction of their deviation to a point where surgery was not required. In 6 patients (27%), surgery was required but an improvement in ocular deviation was found, altering the original surgical plan. In 4 patients (18%), the deviation continued to progress after BT injection. Success rates were higher if pretreatment deviation was less than 20 prism diopters (Δ). Conclusion: One-third of the chemodenervation-treated patients avoided surgical intervention, with an additional 27% (total of 40% of those who needed surgery) having a reduced deviation before surgery. Using BT injection to extraocular 474 muscles to treat diplopia in TED patients is most effective in preventing surgery in those patients with 20 (Δ) or less of deviation. There are a multitude of clinical manifestations of thyroid eye disease (TED) including eyelid retraction, proptosis, orbital congestion, corneal exposure, optic neuropathy, and ocular motility dysfunction. Despite "successful" treatment during the active phase of the disease, many patients are often left with residual disease, in particular double vision due to a restrictive strabismus. If the ocular misalignment is small (,10 prism diopters [PD]), prisms often are very effective. However, for those patients with a large angle strabismus, either monocular occlusion or strabismus surgery is often the only 2 options available. However, this retrospective study adds injection of botulinum toxin (BT) to the extraocular ocular muscles to this short list of options. Although the results were modest at best (68% of the patients still needed surgery), the authors found that if the deviation was less than 20 PD, surgery could be prevented with BT injections. The bottom of Figure 2 showed 50% of the extraocular muscles that were injected with BT with a deviation less than 20 PD did not need surgery. However, I could not find the percentage of patients with less than 20 PD deviation that did not need surgery. There are several limitations of this study including the retrospective design, small number of patients (22 patients, 29 extraocular muscles), and no control group. Moster and Bhatti: J Neuro-Ophthalmol 2016; 36: 474-478 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary Important information that was not provided in the article included how patients were treated during the active phase of the disease, the duration of the disease and how long the ocular motility was stable before undergoing BT injection. It is important to keep in mind that strabismus surgery for TED should be done during the chronic or inactive phase of the disease with documented ocular motility stability for at least 9-12 months. -M. Tariq Bhatti, MD Hey Tariq, I agree with all your comments and the limitations, which the authors do acknowledge in the discussion. However, I welcome BT injections as another option for early treatment in patients with diplopia with TED, which is one of the more frustrating conditions we deal with in daily neuro-ophthalmologic practice. -Mark L. Moster, MD Sanders DB, Wolfe GI, Benatar M, Evoli A, Gilhus NE, Illa I, Kuntz N, Massey JM, Melms A, Murai H, Nicolle M, Palace J, Richman DP, Verschuuren J, Narayanaswami P. International consensus guidance for management of myasthenia gravis: executive summary. Neurology. 2016;87:419-425. Objective: To develop formal consensus-based guidance for the management of myasthenia gravis (MG). Methods: In October 2013, the Myasthenia Gravis Foundation of America appointed a Task Force to develop treatment guidance for MG, and a panel of 15 international experts was convened. The RAND/UCLA appropriateness methodology was used to develop consensus guidance statements. Definitions were developed for goals of treatment, minimal manifestations, remission, ocular MG, impending crisis, crisis, and refractory MG. An in-person panel meeting then determined 7 treatment topics to be addressed. Initial guidance statements were developed from literature summaries. Three rounds of anonymous e-mail votes were used to attain consensus on guidance statements modified on the basis of panel input. Results: Guidance statements were developed for symptomatic and immunosuppressive treatments, IV immunoglobulin and plasma exchange, management of impending and manifest myasthenic crisis, thymectomy, juvenile MG, MG associated with antibodies to muscle-specific tyrosine kinase, and MG in pregnancy. Conclusion: This is an international formal consensus of MG experts intended to be a guide for clinicians caring for patients with MG worldwide. This group of international experts on myasthenia gravis (MG) was convened to provide guidance for the management of MG. The authors state that there is no internationally accepted "standard of care" for patients with MG and of the few randomized controlled trials Moster and Bhatti: J Neuro-Ophthalmol 2016; 36: 474-478 (RCTs) that have been performed, it is difficult to implement them into practice because of the lack of generalizability of the results. However, the value of this report is that it is generated by some of the world's experts in MG who are not only proficient in understanding the published MG literature but have years of clinical experience and expertise. Some of the highlights are: 1. Use of cholinesterase inhibitors (i.e., pyridostigmine) is the first line of treatment for most patients with MG. 2. Corticosteroids (CS) or immunosuppressive (IS) therapy should be used if pyridostigmine is not effective. 3. IS medications (e.g., azathioprine, cyclosporine, myocophenolate mofetil, methotrexate and tacrolimus) should be used either in combination with CS or if CS are contraindicated or refused by the patient. Azathioprine seems to be the IS agent of choice but in the context of limited RCT data. 4. Intravenous immunoglobulin (IVIg), plasma exchange (PLEX), cyclophosphamide and rituximab should be considered in refractory MG. 5. IVIg or PLEX should be considered in patients with lifethreatening generalized MG or MG patients in crisis. 6. PLEX may be better in muscle-specific tyrosine kinase MG and MG crisis. 7. Thymectomy should be considered in all patients with a thymoma, nonthymomatous patients who wish to avoid/minimize use of IS, are intolerant to IS, or refractory to treatment. 8. Additional recommendations were offered for MG in the setting of pregnancy or children. From a neuro-ophthalmologist's perspective, I was a bit disappointed in the lack of guidance on patients with ocular MG. The only statement I could find on ocular MG was, "The efficacy of IVIg is less certain in milder MG or in ocular MG." As you know Mark, there remains controversy on the initial treatment of ocular MG in terms of use of pyridostigmine or CS (1). I would have enjoyed very much reading the consensus from this group on the management of ocular MG. -M. Tariq Bhatti, MD REFERENCE 1. Wong SH, Plant GT, Cornblath W. Does treatment of ocular myasthenia gravis with early immunosuppressive therapy prevent secondarily generalization and should it be offered to all such patients? J Neuroophthalmol. 2016;36:98-102. Although the approach to treating myasthenia varies, this consensus goes along with what many of us do in practice. Little new information is given in this consensus and it reminds me of a casual conversation you and I might have over a drink on how to work up a sixth nerve 475 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary palsy!! I also was quite disappointed with little mention of ocular MG. -Mark L. Moster, MD type discussion on an unusually constellation of clinical findings. The fact that it came up as the number one hit on a PubMed search combining 4 of the clinical findings is really encouraging. -Mark L. Moster, MD Vodopivec I, Oakley DH, Perugino CA, Venna N, Hedley-Whyte ET, Stone JH. A 44-year-old man with eye, kidney, and brain dysfunction. Ann Neurol. 2016;79:507-519. Abstract: Retinal vasculopathy with cerebral leukodystrophy (RVCL) is a rare, autosomal-dominant condition caused by mutations of TREX1 (3-prime repair exonuclease-1). The phenotypic expressions range from isolated retinal involvement to varying degrees of retinopathy, cerebral infarction with calcium depositions, nephropathy, and hepatopathy. We report a case of RVCL caused by a novel TREX1 mutation. This patient's multisystem presentation, retinal involvement interpreted as "retinal vasculitis," and improvement of neuroimaging abnormalities with dexamethasone led to the accepted diagnosis of a rheumatologic disorder resembling Behçet disease. Clinicians should consider RVCL in any patient with retinal capillary obliterations associated with tumefactive brain lesions or nephropathy. I have always enjoyed reading case reports, participating in grand round presentations, and most of all attending the great Frank B. Walsh meeting! Although case reports are categorized as Level IV clinical evidence, that should not diminish the importance of their educational value. In fact, case reports are in many ways the cornerstone of not only neuro-ophthalmology but the entire field of medicine. I decided to choose this case report of a young man with retinal vasculopathy with cerebral leukodystrophy (RVCL) not just because of the unique diagnosis but also because of the excellent differential diagnosis it generated (e.g., Bechet disease, thrombotic microangiopathy purpura, sarcoidosis, tubulointerstitial nephropathy and uveitis, granulomatosis with polyangiitis, Eales disease, progressive multifocal leukoencephalopathy, toxoplasmosis, and Susac syndrome) and the genetic explanation of the disease (TREX1 mutation resulting in dysfunction of a DNA exonuclease resulting in upregulation of interferon signaling). The brief mention on the use of tofactinib (a small molecule kinase inhibitor) was interesting and the use of PubMed to arrive at the diagnosis was brilliant! If this case report seems familiar to you Mark, that's because a similar case was presented at the recent (February 28, 2016) Frank B. Walsh meeting in Tucson, Arizona titled "It is, is it not?". I think you were sitting next to me at the meeting when the case was presented and I am not ashamed to say that I did not get the correct diagnosis. -M. Tariq Bhatti, MD I can't confirm or deny sitting next to you at the Walsh, because the case does not seem familiar to me. Nonetheless, it is a nice clinical-pathological-correlation 476 Martens C, Goplen FK, Nordfalk KF, Aasen T, Nordahl SH. Prevalence and characteristics of positional nystagmus in normal subjects. Otolaryngol Head Neck Surg. 2016;154:861-867. Objective: In clinical practice, patients are often referred due to a finding of positional nystagmus that does not always appear to correlate with clinical symptoms of benign paroxysmal positional vertigo. To know when to consider nystagmus to be of clinical relevance, it is necessary to know the prevalence and characteristics of positional nystagmus in a healthy population. Study Design: Case series of 75 healthy subjects. Setting: Two tertiary referral centers in Norway. Subjects and Methods: Seventy-five adult subjects aged 40 ± 13 years (mean ± SD; range, 21-87) without a history of vertigo or balance disorder were included from 2013 to 2015. The subjects underwent 6 different standardized positional tests in a repositioning chair. Videonystagmography was used to record eye movements. Of 1350 recordings, 1329 were included and analyzed. Results: Positional nystagmus was detected in 88% of the subjects. The most common finding was nystagmus in the Dix-Hallpike position, which occurred in 55% of the subjects. The 95th percentile of the maximum slow-phase velocity for each subject was found to be 5.06° per second (n = 54) in the horizontal plane and 6.48° per second (n = 48) in the vertical plane. Conclusion: Positional nystagmus is a common finding in normal subjects and occurred in 88% of the healthy subjects in the present study. Horizontal direction-changing apogeotropic or geotropic nystagmus may occur in asymptomatic subjects. However, nystagmus that is of the paroxysmal type or has a slow-phase velocity greater than approximately 5° per second in the horizontal plane or 6.5° per second in the vertical plane should be considered outside the 95th percentile. Many of us use formal vestibular testing to come to a diagnosis in patients with vertigo. This study demonstrating that 88% of normal subjects have asymptomatic positional nystagmus should give us concern about accepting balance test results without proper clinical context. The findings may be more prominent in this study than we would see clinically, since the patients were in a biaxial rotational chair, which likely caused more of a stimulus than the clinical Dix-Hallpike maneuver. There were some criteria that help distinguish the positional nystagmus from true BPPV. First, the normal subjects had the nystagmus for the duration of the stimulus without a latency-so it is not paroxysmal. Second, if the slowMoster and Bhatti: J Neuro-Ophthalmol 2016; 36: 474-478 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary phase velocity is greater than 5° in the horizontal plane or 6.5° in the vertical plane, it is likely significant. Studies such as this should help us in continuing to fine-tune our diagnostic capabilities. -Mark L. Moster, MD I want to thank you Mark for bringing this article to my attention because I normally would not have read it. Given my training background and practice focus, I often defer the evaluation and management of patients with dizziness to my neurology and neuro-otology colleagues. This study is an excellent example that diagnoses should not be made solely on a test result but within the context of the clinical situation. -M. Tariq Bhatti, MD Tur C, Goodkin O, Altmann DR, Jenkins TM, Miszkiel K, Mirigliani A, Fini C, Gandini Wheeler-Kingshott CA, Thompson AJ, Ciccarelli O, Toosy AT. Longitudinal evidence for anterograde trans-synaptic degeneration after optic neuritis. Brain. 2016;139:816-828. Abstract: In multiple sclerosis, microstructural damage of normal-appearing brain tissue is an important feature of its pathology. Understanding these mechanisms is vital to help develop neuroprotective strategies. The visual pathway is a key model to study mechanisms of damage and recovery in demyelination. Anterograde trans-synaptic degeneration across the lateral geniculate nuclei has been suggested as a mechanism of tissue damage to explain optic radiation abnormalities seen in association with demyelinating disease and optic neuritis, although evidence for this has relied solely on cross-sectional studies. We therefore aimed to assess: 1) longitudinal changes in the diffusion properties of optic radiations after optic neuritis suggesting trans-synaptic degeneration; 2) the predictive value of early optic nerve magnetic resonance imaging measures for late optic radiations changes; and 3) the impact on visual outcome of both optic nerve and brain post-optic neuritis changes. Twenty-eight consecutive patients with acute optic neuritis and 8 healthy controls were assessed visually (logMAR, colour vision, and Sloan 1.25%, 5%, 25%) and by magnetic resonance imaging, at baseline, 3, 6, and 12 months. Magnetic resonance imaging sequences performed (and metrics obtained) were: 1) optic nerve fluid-attenuated inversion-recovery (optic nerve cross-sectional area); 2) optic nerve proton density fast spin-echo (optic nerve proton density-lesion length); 3) optic nerve post-gadolinium T1-weighted (Gd-enhanced lesion length); and 4) brain diffusion-weighted imaging (to derive optic radiation fractional anisotropy, radial diffusivity, and axial diffusivity). Mixed-effects and multivariate regression models were performed, adjusting for age, gender, and optic radiation lesion load. These identified changes over time and associations between early optic nerve measures and 1-year global optic radiation/clinical measures. The fractional anisotropy in patients' optic radiations decreased (P = 0.018) and radial diffusivity increased (P = 0.002) over 1 year following optic neuritis, Moster and Bhatti: J Neuro-Ophthalmol 2016; 36: 474-478 whereas optic radiation measures were unchanged in controls. Also, smaller cross-sectional areas of affected optic nerves at 3 months post-optic neuritis predicted lower fractional anisotropy and higher radial diffusivity at 1 year (P = 0.007) in the optic radiations, whereas none of the inflammatory measures of the optic nerve predicted changes in optic radiations. Finally, greater Gd-enhanced lesion length at baseline and greater optic nerve proton density-lesion length at 1 year were associated with worse visual function at 1 year (P = 0.034 for both). Neither the cross-sectional area of the affected optic nerve after optic neuritis nor the damage in optic radiations was associated with 1-year visual outcome. Our longitudinal study shows that, after optic neuritis, there is progressive damage to the optic radiations, greater in patients with early residual optic nerve atrophy, even after adjusting for optic radiation lesions. These findings provide evidence for trans-synaptic degeneration. Trans-synaptic degeneration has long been known to occur. As neuro-ophthalmologists, we are used to seeing this in optic nerve changes from postgeniculate lesions that are longstanding. To better assess trans-synaptic degeneration in the other direction, the authors undertook a prospective longitudinal analysis of optic radiation changes over 1 year following an episode of optic neuritis. The findings were that optic neuritis patients had progressive changes in the optic radiations for 1 year after the episode as measured by fractional anisotropy and radial diffusivity on MRI. More prominent optic atrophy at 3 months predicted more prominent subsequent optic radiation changes. Additionally, longer gadolinium enhancing lesions were associated with poorer visual outcome. Finally, there was no association of visual outcome with degree of optic radiation changes. This study provides further evidence of trans-synaptic degeneration, which in this study did not correlate with visual function. However, I suspect that the changes leave less reserve for future episodes of demyelination. -Mark L. Moster, MD I would like to make 2 points regarding this study. First, I want to emphasize what the authors stated in the last paragraph of the discussion, "Future studies could investigate the clinical consequence of the post-synaptic changes that occur after optic neuritis, and whether they are due to the accumulation of structural brain damage or whether they are better explained by a disruption of brain structural connectivity secondary to axonal damage." Second, there are other studies that have shown both anterograde as well as retrograde trans-synaptic degeneration in the context of demyelinating disease (1). -M. Tariq Bhatti, MD REFERENCE 1. Balk LJ, Steenwijk MD, Tewarie P, Daams M, Killestein J, Wattjes MP, Vrenken H, Barkhof F, Polman CH, Uitdehaag BM, 477 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Literature Commentary Petzold A. Bidirectional trans-synaptic axonal degeneration in the visual pathway in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2015;86:419-424. Zhang Z, Wu S, Jonas JB; Zhang J, Liu K, Lu Q, Wang N. Dynein, kinesin and morphological changes in optic nerve axons in a rat model with cerebrospinal fluid pressure reduction: the Beijing Intracranial and Intraocular Pressure (iCOP) study. Acta Opthalmologica. 2016;94:266-275. Purpose: To examine the influence of experimentally reduced cerebrospinal fluid pressure (CSFP) as compared to elevated intraocular pressure (IOP) on axonal morphology and axonal motor proteins in retinal ganglion cells (RGCs). Methods: The experimental study included 39 rats which underwent cerebrospinal fluid drainage for 6 hours, 30 rats which unilaterally underwent IOP elevation for 6 hours and 30 rats in a control group. Six hours after baseline, the animals were killed and the eyes were histologically and immunohistochemically examined. Results: In experimental models in the high-IOP group and the low-CSFP group as compared to the control group, RGC axons became abnormally dilated and accumulated vesicles. Both groups as compared to the control group showed an accumulation of dynein IC (intermediate chain) at the optic nerve head and retina and a reduction in kinesin HC (heavy chain) immunoreactivity in the optic nerve fibre axons. As a corollary, Western blot analysis revealed an elevation of dynein IC protein levels in the optic nerve head and retina and a decrease in kinesin HC protein levels in the optic nerve. Conclusions: Experimental models with an acute IOP rise or with an acute CSFP reduction showed similar morphologic changes in the retinal ganglion cell axons and similar immunohistochemical changes in the axonal motor proteins kinesin HC and dynein IC. It supports the hypothesis that an experimental model with an acute reduction in CSFP as well as an experimental model with an acute rise in IOP may share similarities in the process of optic nerve damage. and a low or negative translaminar pressure is protective (often seen in intraocular hypertension without glaucoma). However these claims have been questioned by legitimate concerns, including the fact that not all pressures that are retrolaminar are related to cerebrospinal fluid (CSF), that one cannot equate a measured ICP in the lumbar space with an orbital ICP and that a single lumbar puncture ICP in humans gives no information about ongoing ICP. With that background comes one more study showing similar pathologic changes in rats treated by decreasing CSF pressure as by elevation of IOP. Markers of retrograde and orthograde transport were equally diminished and some but not all changes in retinal ganglion cells (RGCs) were equally seen. This simple 6-hour study in rats has many limitations and does not clear up any controversy that exists related to translaminar pressure. However, it contributes to the developing story. It may be bringing us closer to a day when we might treat glaucoma by increasing ICP and beyond that to a day when we might treat visual loss from elevated ICP by elevating IOP. -Mark L. Moster, MD Maybe I am a simpleton, but I continue to be baffled by CSF dynamics! David Pincus MD PhD, a pediatric neurosurgeon at the University of Florida, and I have had many conversations trying to understand conditions such as idiopathic intracranial hypertension, Chiari malformation, and hydrocephalus. As you mentioned, the role of ICP in the pathogenesis of glaucoma remains debated but I want to take this opportunity to acknowledge one of my very respected colleagues here at Duke-Dr. Rand Allingham- for being at the forefront of the discussion on the role of ICP and glaucoma following the publication of his case- control study coauthored by Drs. Berdahl and Johnson in 2008 (2). -M. Tariq Bhatti, MD In 1979, Yablonski et al (1) induced glaucoma in a cat by decreasing intracranial pressure (ICP). More recently, there is a developing literature suggesting that intraocular pressure (IOP) in isolation is not the only determinant of glaucomatous damage but that the translaminar pressure (IOP-ICP) is important. The claim is that a high translaminar pressure is associated with glaucoma (often normal tension glaucoma) 478 REFERENCE 1. Yablonski M, Ritch R, Pokorny KS. Effect of decreased intracranial pressure on optic disc. Invent Ophthalmol Vis Sci. 1979;18(suppl 1):165. 2. Berdahl JP, Allingham RR, Johnson DH. Cerebrospinal fluid pressure is decreased in primary open-angle glaucoma. Ophthalmology. 2008;115:763-768. Moster and Bhatti: J Neuro-Ophthalmol 2016; 36: 474-478 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.