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Show Literature Commentary Apiwattanakul M, Popescu BF, Matiello M, Weinshenker BG, Lucchinetti CF, Lennon VA, McKeon A, Carpenter AF, Miller GM, Pittock SJ. Intractable vomiting as the initial presentation of neuromyelitis optica. Ann Neurol. 2010;68: 757-761. We report 12 aquaporin 4 antibody-positive patients (12% of seropositive Mayo Clinic patients identified since 2005) whose initial presenting symptom of neuromyelitis optica was intractable vomiting. The initial evaluation in 75% was gastroenterologic. Vomiting lasted a median of 4 weeks (range, 2 days to 80 weeks). Optic neuritis or transverse myelitis developed after vomiting onset in 11 patients (median interval, 11 weeks; range, 1-156 weeks). At last evaluation (median, 48 months after vomiting onset), 7 patients fulfilled neuromyelitis optica diagnostic criteria. Our clinical, pathologic and neuro-imaging observations suggest the aquaporin 4-rich area postrema may be a first point of attack in neuromyelitis optica. This is a very interesting description of 12 NMO-IgG- positive patients who presented with severe intractable vomiting at a median of 3 months prior to a first episode of optic neuritis or transverse myelitis. Extensive GI workups were negative. The authors postulate that this is caused by the involvement of the chemosensitive vomiting center in the area postrema since capillaries in this region lack tight endothelial junctions. It might serve as the portal for cir-culating NMO-IgG entry into the CNS. Although this is a retrospective case series, it provides an important clinical observation that has not been described in typical demyelinating optic neuritis. In future, neuro-ophthalmologists who see patients presenting with severe vomiting prior to optic neuritis may have an insight into those who have NMO-prior to the lack of recovery or the frequent recurrence. This should allow earlier decision making for the appropriate treatment for an NMO spec-trum disorder, which requires more aggressive immuno-suppression than demyelinating disease. -Mark L. Moster, MD The authors make a compelling point with an autopsy showing loss of aquaporin 4 channels in the area postrema and another 4 MRIs showing abnormal signal there too. Interestingly, 8 of the 12 enjoyed spontaneous recovery of their intractable vomiting, which is very different than the recovery of optic neuritis and transverse myelitis with or without treatment. I have not observed intractable vomiting in patients with optic neuritis from NMO, but it is also something that I would not typically ask about especially since the median delay from vomiting to visual loss in this study was 3 months and in 1 case, more than 6 months. I will have a lower threshold to consider serologic testing if I get a hit on this historical clue. -Michael S. Lee, MD Green AJ, McQuaid S, Hauser SL, Allen IV, Lyness R. Ocular pathology in multiple sclerosis: retinal atrophy and inflammation irrespective of disease duration. Brain. 2010;133(pt 6):1591-1601. There has been growing interest in the use of retinal im-aging for tracking disease progression in multiple scle-rosis. However, systematic and detailed pathological descriptions of retinal tissue in multiple sclerosis are lacking. Graded histological evaluations on eyes of 82 patients with multiple sclerosis and 10 subjects with other neurological diseases, with immunohistochemistry on a subset, were performed and correlated with clinical and pathological findings. Multiple sclerosis cases dem-onstrated evidence of retinal atrophy and inflammation even in late-stage disease. Retinal ganglion cell loss was significant, and the remaining neurons appeared shrunken and were partially engulfed by human leukocyte antigen-DR-positive cells with the phenotype of microglia in samples subjected to immunohistochemistry. Neuro-filament staining revealed variable but prominent degrees of axonal loss and injury. Neuronal loss was noted in the inner nuclear layer with focal reduction in cell density. Foamy-appearing human leukocyte antigen-DR-positive cells were evident near vessels, and periphlebitis was found in a small but significant number of multiple scle-rosis cases. Glial fibrillary acidic protein staining showed extensive astrocytic hypertrophy and proliferation with prominent gliosis in multiple sclerosis cases. Frequent but previously unreported abnormalities in the iris were documented in the majority of chronic multiple sclerosis cases. The injury to both iris and retina could be seen at all stages of disease. Severity of retinal atrophy corre-lated with the overall brain weight at time of autopsy (P = 0.04), and a trend for increased atrophy was seen with longer disease duration (P = 0.13). This study provides the first large-scale pathological description of retinas in multiple sclerosis, including patients with different sub-types of disease at all stages and with variable clinical Section Editors: Mark L. Moster, MD Michael S. Lee, MD Moster and Lee: J Neuro-Ophthalmol 2011; 31: 89-93 89 Literature Commentary Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. severity. Changes were seen not only in the retinal nerve fiber layer and ganglion cell layer but also in the inner nuclear layer, suggesting that retinal injury is more widespread than previously appreciated. Furthermore, the human retina is devoid of myelin, but inflammation was demonstrated to be prominent in multiple sclerosis and to persist in the retina at late stages of disease. The prominent gliosis and inflammation surrounding vessels of the inner retina could potentially impact optical co-herence tomography evaluations in multiple sclerosis as standard techniques exploit presumed differences in tis-sue reflectivity and utilize automated edge detection al-gorithms to judge axon loss in the nerve fiber layer. Deciphering the relationships between the different types of retinal pathology may aid us in understanding the factors that drive both inflammation and tissue atrophy in multiple sclerosis. This is the largest description of ocular pathology in MS to date. As expected, retinal nerve fiber layer (RNFL) and retinal ganglion cell layer (RGC) atrophy and decreased RGC density were common and prominent. However, inner nuclear layer (INL, horizontal and bipolar cells) at-rophy was seen in 40% of cases, most common in long-standing and progressive disease. The authors offer 3 pos-sible explanations including that the INL may be a target of the immune process and may share a susceptibility to the neurodegenerative process, or that it represents retrograde transneuronal degeneration. The latter makes the most sense, since RGC loss was more pronounced than INL, no acute MS cases had INL loss, and no inflammatory cells were found in the INL. Inflammatory retinal periphlebitis was seen in 29%, independent of disease duration, including secondary pro-gressive MS. Scattered mononuclear inflammatory cells were also seen in the RNFL and RGCL in 12%. A surprise was prominent iris involvement in 72% of MS patients-findings included rubeosis iridis, eversion of pigmented layer, and stromal inflammation, sometimes with anterior uveitis. The authors postulate either a direct inflammatory response or a response to a ‘‘distressed retina.'' Limitations of the study include a control group con-sisting of only 10 cases, mainly with peripheral neuropathy. Perhaps, evaluation of other CNS diseases as controls would show that some of these retinal changes are nonspecific correlates of CNS disease. The lack of exhaustive clinical information (eg, coexisting glaucoma or other diseases) also may create bias in this study. The strength of the study is that almost all cases were obtained prior to availability of immunomodulatory ther-apies and therefore reflect the natural course of the disease. Additionally, 2 pathologists reviewed the slides in a masked fashion, not knowing the small size of the control group. The findings of inflammatory and degenerative features in RRMS and SPMS at all stages of disease suggest that both of these processes may play a role during the entire course of MS. -Mark L. Moster, MD I wish the authors had divided up the iris findings instead of lumping rubeosis, pigment eversion, and stromal in-flammation together. To me, these are very different. I agree with Dr. Moster that it is very surprising how uncommon it is to see these anterior segment findings clinically given the high proportion seen histopathologically. I think it would be fascinating to repeat this study on a group of MS patients treated in the immunomodulatory era and determine if the frequency or severity of pathologic findings improves. --Michael S. Lee, MD Echaniz-Laguna A, Chassagne M, de Se`ze J, Mohr M, Clerc-Renaud P, Tranchant C, Mousson de Camaret B. POLG1 Variations Presenting as Multiple Sclerosis. Arch Neurol. 2010;67:1140- 1143. doi:10.1001/archneurol.2010.219. Objective: To describe 2 unrelated patients with novel variations in the POLG1 gene and features undis-tinguishable from multiple sclerosis, that is, optic neuri-tis, brain white matter hyperintense areas, and unmatched cerebrospinal fluid oligoclonal bands. Design: Case report. Setting: University hospital. Patients: Both patients subsequently developed bilateral ophthalmoplegia, ptosis, myopathy, cardiomyopathy, ataxia, dysphagia, and hearing and cognitive impairment. Main Outcome Measures: Detailed clinical and laboratory examinations including brain MRI, morphological analysis of a muscle biopsy, characterization of mitochondrial DNA integrity, sequencing of the POLG1 gene, and screening of control subjects for POLG1 sequence variants. Results: Ragged red fibers and multiple deletions of mi-tochondrial DNA were detected in the skeletal muscle. Four compound heterozygous variations, including 3 previously unreported, were identified in POLG1. Conclusion: Clinicians should be aware of the existence of POLG1-related multiple sclerosis-like illness, as it has important implications on management, treatment, and genetic counseling. In an era of earlier and more aggressive treatment of MS and clinically isolated syndromes, this article raises a ‘‘red flag.'' It describes 2 patients with POLG1 mutations who presented with a clinical picture of optic neuritis, MRI with white matter lesions, and oligoclonal bands in the CSF, quite typical for MS. It was only after many years and a more typical clinical progression for a POLG1 mutation (ophthalmoplegia, ptosis, ataxia, myopathy, depression, hearing loss, dysphagia, cognitive impairment, and cardiomyopathy) that the correct diagnosis was pursued. Both were treated with steroids initially for MS. Had they presented today, they may have been given im-munomodulating agents for MS, likely not the correct treatment. This report adds to a growing list of MS mimickers, including other mitochondrial disorders, such as LHON. 90 Moster and Lee: J Neuro-Ophthalmol 2011; 31: 89-93 Literature Commentary Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Prior to prescribing immunomodulating agents, one must at least consider these other possibilities. -Mark L. Moster, MD The clinical description in the article notes only ‘‘blurred vision'' in 1 eye and ‘‘bilateral increased P100 latency'' on VEP testing for both patients. As we all know that story alone does not equal optic neuritis. There is also no com-ment on the MRI of the optic nerve. Likely, if we put the screws to them, these patients did not have a story or clinical findings consistent with optic neuritis. That being said, I can see how the white matter lesions on MRI could have led to a lumbar puncture, which led to oligoclonal banding and a misdiagnosis of MS. --Michael S. Lee, MD I agree there is not a lot of detail provided on the blurred vision in these patients-onset, course, duration, pain, and the like. However, one was a 30-year-old man and the second a 37-year-old woman and both had white matter abnormalities on MRI, oligoclonal bands in the CSF, and were diagnosed by university neurologists as optic neuritis. -Mark L. Moster, MD . . .Which may tell us something about university neurologists! =) --Michael S. Lee, MD Kranz G, Shamim EA, Lin PT, Kranz GS, Hallett M. Transcranial magnetic brain stimulation modulates blepharospasm: a randomized controlled study. Neurology. 2010;75:1465-1471. Background: Benign essential blepharospasm (BEB) is a common form of focal dystonia. Besides pathology in the basal ganglia, accumulating evidence suggests patho-logic changes in the anterior cingulate cortex (ACC). Methods: This is a randomized, sham-controlled, observer-blinded, prospective study. In 12 patients with BEB, we evaluated the effects of a 15-minute session of low-frequency (0.2 Hz) repetitive transcranial magnetic stimulation (rTMS) over the ACC with stimulation in-tensities at 100% active motor threshold with 3 stimu-lation coils: a conventional circular coil (C-coil), a sham coil (S-coil), and a Hesed coil (H-coil, which allows stim-ulation of deeper brain regions. Primary outcome was the clinical effects on BEB (blink rate, number of spasms rated by a blinded physician and patient rating before, immediately after, and 1 hour after stimulation); sec-ondary outcome was the blink reflex recovery curve. Results: Subjective stimulation comfort was similar for each coil with no stimulation-associated adverse events. Stimulation with the H- and C-coils resulted in a significant improvement in all the 3 outcome measures and was still detectable in physician rating and patient rating 1 hour after stimulation. S-coil stimulation had no effects. The active motor threshold was significantly lower for the H-coil compared to the other 2 coils. Conclusions: rTMS could be used as a therapeutic tool in BEB. Further studies will be necessary to show whether repeated stimulation applications result in lasting clinical effects. Classification of evidence: This study provides Class II evidence that for patients with BEB, H- and C-coil rTMS is safe and improves clinical symptoms of BEB immediately and 1 hour after stimulation. Functional imaging studies show increased excitability in the anterior cingulate cortex (ACC) among patients with benign essential blepharospasm (BEB). Each patient in this study underwent 3 sessions of repetitive transcranial mag-netic stimulation (rTMS) for 15 minutes using different coils: 1) Standard C-coil, 2) H-coil, which stimulates deeper brain structures, and 3) S-coil or sham therapy. Patients evaluated subjective improvement and a masked evaluator objectively graded videos before, immediately after, and 1 hour following rTMS. The S-coil showed no benefit, but both the H- and the C-coil showed a similar benefit sub-jectively and objectively. The authors anticipated a large difference between rTMS and sham TMS and calculated a small study sample. Bot-ulinum toxin injections can be painful, but they can last for 2-4 months. RTMS is not painful but it lasts approximately 1 hour. The authors comment that perhaps modifying the duration or frequency could improve treatment duration, but I don't see that happening with only an hour of im-provement. It seems to me that a constant portable stim-ulator would need to be developed. Deep brain stimulator implants placed in the globus pallidus internus in patients with Meige syndrome have shown improvement (1). So, I also talked to a neurosurgeon who does deep brain stim-ulator implants who said that these could be placed in the ACC. Obviously, it would have to be a pretty debilitated patient who has failed botulinum toxin and orbicularis myectomy to even consider going there. --Michael S. Lee, MD Alternative treatments to botulinum toxin injections for blepharospasm are very important, particularly for patients refractory to treatment. This preliminary study shows promising results and must be further investigated. I wouldn't take the 1-hour response as a negative as Dr. Lee does-patients with rTMS for other conditions (eg, dys-tonia, depression) have had a course of multiple treatments over days to weeks followed by up months to years of benefit on occasion (2,3). Presumably, there is some plasticity in the system that can be modified by this technique. I think these preliminary results are promising. -Mark L. Moster, MD Thanks for pointing out the rTMS article in movement disorders (2). I was not aware of this. I just read it and the Moster and Lee: J Neuro-Ophthalmol 2011; 31: 89-93 91 Literature Commentary Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. authors found that the rTMS effect can last up to a few months, but that the effect was subtherapeutic. Also, daily stimulation for weeks is a large burden on patients who can enjoy months of benefit using botulinum toxin A. Finally, the biggest benefit in the rTMS in movement disorders was observed with the highest stimulation intensities. These intensities come with scalp tingling and most likely the patients were not masked to the sham therapy. So, I am still a bit pessimistic for rTMS as an alternative to botulinum toxin A in the treatment of blepharospasm. --Michael S. Lee, MD 1. Ghang JY, Lee MK, Jun SM, Ghang CG. Outcome of pallidal deep brain stimulation in meige syndrome. J Korean Neurosurg Soc. 2010;48:134-138. 2. Edwards MJ, Talelli P, Rothwell JC. Clinical applications of transcranial magnetic stimulation in patients with movement disorders. Lancet Neurol. 2008;7:827-840. 3. Krisanaprakornkit T. Transcranial magnetic stimulation for treatment resistant depression: six case reports and review. J Med Assoc Thai. 2010;93:580-584. Avery RA, Shah SS, Licht DJ, Seiden JA, Huh JW, Boswinkel J, Ruppe MD, Chew A, Mistry RD, Liu GT. Reference range for cerebrospinal fluid opening pressure in children. N Engl J Med. 2010;363: 891-893. No abstract. The authors recorded opening pressures on pediatric patients over a 2-year period. None of the patients had papilledema, hydrocephalus, meningitis, or used diuretics. Opening pressures were obtained in the lateral decubitus position. A total of 197 patients were enrolled. The normal distribution of opening pressures based on the 10th to the 90th percentile was 11.5-28.0 cm H20. Sedatives and BMI increased the opening pressure slightly. A post hoc analysis of 52 nonobese patients who received minimal or no se-dation resulted in a 90th percentile of 25 cm H20. The authors conclude that a normal opening pressure in children is 28 cm H20 or less. This is a surprising outcome given the typical opening pressure in adults is thought to be less than 20 cm and a previous article had suggested 18 cm as the upper limit of normal in children younger than 8 years (1). Recently, I had a 13-year-old patient with optic disc drusen mistaken as papilledema. Her opening pressures were 27 cm and 29 cm. She had some mild arcuate defects bilaterally. This article supported the idea that this pressure may be normal for her. On the other hand, if I saw another child with obvious bilateral optic disc edema and an opening pressure of 25 cm, I would not have any trouble with the fact that the pressure is too high for her. --Michael S. Lee, MD I agree with Dr. Lee. This study is helpful in clinical practice and reassures us that an ICP in the 20s may be normal in children and allows a slightly higher reading for an increased BMI and sedation. Next, we need a study of normal ICP in the prone position, since increasingly our patients are having LPs under fluoroscopy by radiologists. -Mark L. Moster, MD 1. Rangwala LM, Liu GT. Pediatric idiopathic intracranial hypertension. Surv Ophthalmol. 2007;52:597-617. Cohen JA, Barkhof F, Comi G, Hartung HP, Khatri BO, Montalban X, Pelletier J, Capra R, Gallo P, Izquierdo G, Tiel-Wilck K, de Vera A, Jin J, Stites T, Wu S, Aradhye S, Kappos L; TRANSFORMS Study Group. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010; 362:402-415. Background: Fingolimod (FTY720), a sphingosine-1- phosphate receptor modulator that prevents lymphocyte egress from lymph nodes, showed clinical efficacy and improvement on imaging in a phase 2 study involving patients with multiple sclerosis. Methods: In this 12-month, double-blind, double-dummy study, we randomly assigned 1,292 patients with re-lapsing- remitting multiple sclerosis who had a recent history of at least 1 relapse to receive either oral fingo-limod at a daily dose of either 1.25 or 0.5 mg or in-tramuscular interferon beta-1a (an established therapy for multiple sclerosis) at a weekly dose of 30 mg. The primary endpoint was the annualized relapse rate. Key secondary endpoints were the number of new or enlarged lesions on T(2)-weighted MRI scans at 12 months and progression of disability that was sustained for at least 3 months. Results: A total of 1,153 patients (89%) completed the study. The annualized relapse rate was significantly lower in both groups receiving fingolimod-0.20 (95% confidence interval [CI], 0.16-0.26) in the 1.25-mg group and 0.16 (95% CI, 0.12-0.21) in the 0.5-mg group-than in the interferon group (0.33; 95% CI, 0.26- 0.42; P , 0.001 for both comparisons). MRI findings supported the primary results. No significant differences were seen among the study groups with respect to progression of disability. Two fatal infections occurred in the group that received the 1.25-mg dose of fingolimod: disseminated primary varicella zoster and herpes sim-plex encephalitis. Other adverse events among patients receiving fingolimod were nonfatal herpes virus infections, bradycardia and atrioventricular block, hypertension, macular edema, skin cancer, and elevated liver-enzyme levels. Conclusions: This trial showed the superior efficacy of oral fingolimod with respect to relapse rates and MRI out-comes in patients with multiple sclerosis, as compared with intramuscular interferon beta-1a. Longer studies are needed to assess the safety and efficacy of treatment beyond 1 year. (ClinicalTrials.gov number, NCT00340834.) 92 Moster and Lee: J Neuro-Ophthalmol 2011; 31: 89-93 Literature Commentary Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. The FDA granted approval for oral fingolimod in the treatment of relapsing remitting MS in September 2010. In this study, known as TRANSFORMS (the Trial Assessing Injectable Interferon versus FTY720 Oral in Relapsing- Remitting Multiple Sclerosis), 1,153 RRMS patients were randomized to receive either oral fingolimod at 1.25 or 0.5 mg or intramuscular interferon beta-1a at a weekly dose of 30 mg for 12 months. There was a significantly lower relapse rate and significantly fewer new or enlarged white matter lesions in both fingolimod groups compared to the in-terferon group. The cost of fingolimod is almost twice that of interferon beta-1a, which isn't that cheap to begin with. However, fingolimod appears to be a better treatment and it is much easier to administer. I could envision a trial of optic neuritis patients (CIS) receiving oral fingolimod vs. oral placebo or injectable immunomodulating agents for the prevention of MS. I am hoping that the long-term safety data show good results. --Michael S. Lee, MD With the approval of the first oral immunomodulating agent, a new era in MS treatment begins: one that is more exciting and more complicated. Although this study showed better efficacy with fingolimod than with weekly interferon beta-1a, it was only 1 year in length, and therefore, longer studies will be necessary to demonstrate safety, particularly for the immune-related toxicities of infection and tumors. A special role neuro-ophthalmologists will play is in the as-sessment of patients for macular edema, which occurred in 1% of the high-dose group and 0.5% with the lower dose (FDA approved dose). -Mark L. Moster, MD Moster and Lee: J Neuro-Ophthalmol 2011; 31: 89-93 93 Literature Commentary Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. |
