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Show Literature Commentary Khan O, Filippi M, Freedman MS, Barkhof F, Dore-Duffy P, Lassmann H, Trapp B, Bar-Or A, Zak I, Siegel MJ, Lisak R. Chronic cerebrospinal venous insufficiency and multiple sclerosis. Ann Neurol. 2010;67:286-290. A chronic state of impaired venous drainage from the central nervous system, termed chronic cerebrospinal venous insufficiency (CCSVI), is claimed to be a patho-logic phenomenon exclusively seen in multiple sclerosis (MS). This has invigorated the causal debate of MS and generated immense interest in the patient and scientific communities. A potential shift in the treatment paradigm of MS involving endovascular balloon angioplasty or venous stent placement has been proposed as well as conducted in small patient series. In some cases, it may have resulted in serious injury. In this point of view, we discuss the recent investigations that led to the de-scription of CCSVI as well as the conceptual and technical shortcomings that challenge the potential relationship of this phenomenon to MS. The need for conducting carefully designed and rigorously controlled studies to investigate CCSVI has been recognized by the scientific bodies engaged in MS research. Several scientific endeavors examining the presence of CCSVI in MS are being undertaken. At present, invasive and potentially danger-ous endovascular procedures as therapy for patients with MS should be discouraged until such studies have been completed, analyzed, and debated in the scientific arena. Poor drainage from the internal jugular vein (IJV) and azygos vein (AV) cause multiple sclerosis? Studies from Italy and Buffalo, NY have suggested a strong association between CCSVI and MS. To support this association, selective catheterization has shown that approximately 90% of patients with MS have IJV and AV stenosis. An unmasked, uncontrolled study of IJV and AV angioplasty in 65 MS patients showed improved clinical and MRI outcomes (1). However, there was a high rate of restenosis leading the investigators to suggest stent placement into the IJV or AV. The proposed theory is that poor venous drainage leads to iron accumulation in the brain, which causes an inflammatory response. MR spectroscopy studies have shown increased iron in MS brains compared to controls. This point-of-view article argues strongly against the idea that CCSVI causes MS. I would have to agree. It certainly appears that CCSVI occurs in MS, but I have trouble believing that CCSVI causes MS for many of the reasons outlined in this article. I wonder if, instead, MS causes CCSVI, and this may be another chicken vs. egg issue like transverse venous sinus stenosis and idiopathic intracranial hypertension (2). It appears that the excitement over this is likely to lead to a clinical trial of angioplasty or stenting. If a rigorous study is performed, I will be amazed if it turns out to be beneficial. -Michael S. Lee, MD CCSVI is currently a very hot topic in MS. The person at the forefront of this is Dr. Paolo Zamboni, an Italian vascular surgeon who began studying the venous drainage issue in an attempt to find a cure for his wife's MS. His findings have not been replicated by others (3) and venous anomalies are frequently found in people without MS. Perhaps, venous drainage issues do play some role. For instance increased iron deposition, which may be related to MS disability, has been correlated with venous drainage abnormalities (4). CCSVI may also be an epiphenomenon or actually secondary to the MS. The so-called ‘‘liberation procedure,'' with angioplasty and stenting, is not without risk. In fact, the procedure has been abandoned at Stanford University after a fatal intracranial hemorrhage and a complication requiring open heart surgery from stent movement into the right ventricle (5). I agree with Michael, and am ‘‘cautiously pessimistic'' that CCSVI really plays a role in the pathogenesis of MS. -Mark L. Moster, MD 1. Zamboni P, Galeotti R,Menegatti E,Malagoni AM, Gianesini S, Bartolomei I, Mascoli F, Salvi F. A prospective open-label study of endovascular treatment of chronic cerebrospinal venous insufficiency. J Vasc Surg. 2009;50:1348-1358, e1-e3. 2. Corbett JJ, Digre K. Idiopathic intracranial hypertension: an answer to, ‘‘the chicken or the egg?'' Neurology. 2002; 58:5-6. 3. Krogias C, Schroder A, Wiend IH, Hohlfeld R, Gold R. Chronic cerebrospinal venous insufficiency and multiple sclerosis: critical analysis and first observation in an unselected cohort of MS patients. Nervenarzt. 2010;81:740-746. 4. Zivadinov R, Schirda C, Dwyer MG, Haacke ME, Weinstock- Guttman B, Menegatti E, Heininen-Brown M, Magnano C, Malagoni AM, Wack DS, Hojnacki D, Kennedy C, Carl E, Bergsland N, Hussein S, Poloni G, Bartolomei I, Salvi F, Zamboni P. Chronic cerebrospinal venous insufficiency and iron deposition on susceptibility-weighted imaging in Section Editors: Mark L. Moster, MD Michael S. Lee, MD Moster and Lee: J Neuro-Ophthalmol 2010; 30: 295-298 295 Literature Commentary Copyright © North American Neuro-ophthalmology Society.Unauthorized reproduction of this article is prohibited. patients with multiple sclerosis: a pilot case-control study. Int Angiol. 2010;29:158-175. 5. Experimental multiple sclerosis vascular shunting procedure halted at Stanford. Ann Neurol. 2010;67:A13-A15. Ballanger B, Strafella AP, van Eimeren T, Zurowski M, Rusjan PM, Houle S, Fox SH. Serotonin 2A receptors and visual hallucinations in Parkinson disease. Arch Neurol. 2010;67:416-421. Background: Complex visual hallucinations (VHs) occur in several pathologic conditions; however, the neural mechanisms underlying these symptoms remain unclear. Although dopamine may have a role, indirect evidence indicates that serotonin may also contribute to the pathogenesis of complex VHs, probably via involvement of the serotonin 2 receptor. Objective: To examine for the first time in vivo changes in serotonin 2A receptor neurotransmission among patients having Parkinson disease (PD) with VHs. Design: Case-control study. Setting: Academic research. Patients: Seven patients having PD with VHs and 7 age-matched patients having PD without VHs were recruited. Main Outcome Measures: We used the selective seroto-nin 2A receptor ligand setoperone F18 during positron emission tomography among nondemented patients hav-ing PD with VHs. Results: Patients having PD with VHs demonstrate increased serotonin 2A receptor binding in the ventral visual pathway (including the bilateral inferooccipital gyrus, right fusiform gyrus, and inferotemporal cortex) as well as the bilateral dorsolateral prefrontal cortex, medial orbitofrontal cortex, and insula. Conclusions: This pilot study provides the first in vivo evidence suggesting a role for serotonin 2A receptors in mediating VHs via the ventral visual pathway in PD. Treatment studies should be performed using selective serotonin 2A receptor antagonists, which have important implications for the clinical management of VHs and psychosis in PD. It is very likely that various mechanisms underlie the different situations in which we see VHs (Bonnet syndrome, dementia with Lewy bodies, schizophrenia, seizures, PD, posterior cortical atrophy, etc.). This article demonstrates increased serotonin 2A binding in patients with PD who have VHs and would therefore suggest the possibility of benefit of serotonin 2A antagonists, such as clozapine. Elucidating mechanisms of VH in the above conditions will benefit a large population of patients suffering from VH. The assur-ance of ‘‘not being crazy,'' not going blind, and that the condition is not medically important helps patients but not nearly as much as eliminating the symptoms altogether. -Mark L. Moster, MD Pretty cool article. It would have been cooler if the in-vestigators had given the patients a selective serotonin 2A receptor antagonist, made the VHs go away, and showed reduced binding on a subsequent PET scan. This would convince me of a likely pathogenic basis and effective treat-ment instead of ‘‘important implications'' in the conclusion. -Michael S. Lee, MD Palmer S, Logan D, Nabili S, Dutton GN. Effective rehabilitation of reading by training in the technique of eccentric viewing: evaluation of a 4-year programme of service delivery. Br J Ophthalmol. 2010;94:494-497. Background/Aims: Central visual loss caused by con-ditions such as age-related macular degeneration (ARMD) is the commonest cause of blindness in the UK. Eccentric viewing training aims to teach patients how to utilize the functioning areas of macula or adjacent retina and es-tablish a ‘‘pseudofovea.'' This technique has yet to gain acceptance in the UK despite evidence of success. Sub-jects with ARMD in Glasgow, UK, have received such training, and the outcome of training for this group is de-scribed. Methods: Retrospective analysis auditing the outcome of eccentric viewing training to read was carried out in 300 subjects with ARMD. Results: The data for 300 patients were reviewed. Fifty-eight subjects were excluded due to incomplete final data. Reading speed, font size, degree of comprehension, duration of reading, age, and number of lessons were recorded before and after training. The mean age was 75.4 (SD 12) years. The mean number of 1-h lessons required was 3.8 (SD 1.6). The starting mean number of corrected words per min (WPM) reading speed was 48 (SD 35) and this increased to 71.9 (SD 30.5) (P = 0.000). The starting Arial font size that could be read fluently was 14.3 (SD 7.6) and this improved to 11.5 (SD 2.4). The starting mean duration of comfortable reading was 1.7 (SD 2.0) min. This increased to 15.8 (SD 14.6) min. The mean percentage of material read that was understood by the patients was 73.7 (SD 36.9)%. This improved to 92.7 (SD 16.2)% (P = 0.000). Overall, the majority of patients exhibited improvement in one or more of the vision-related tasks measured. Conclusion: Eccentric viewing training is successful in improving the reading ability of individuals with a central scotoma. This article shows evidence of the success of training provided by the voluntary sector and funded by adult literacy funding. The results are comparable with those reported in the literature. It is pretty intuitive that a patient with a central scotoma needs to use eccentric vision in order to read. However, what is not intuitive is the manner described in this paper. First, the authors identified the preferred reading eye and the preferred retinal locus among patients with macular degeneration. After optimum refraction and magnification, instead of having the patients move their eye or their head back and forth over the text, the patients were trained to keep their eye steady while moving the text back and forth. The reading speed improved dramatically and so did the number of folks who could read normal size print (2.5% to 36%). There was no added benefit for more than 5 training sessions. There was no control group, so it is not completely Literature Commentary 296 Moster and Lee: J Neuro-Ophthalmol 2010; 30: 295-298 Copyright © North American Neuro-ophthalmology Society.Unauthorized reproduction of this article is prohibited. clear that this is better than the patient moving his/her eye, but the outcomes are extremely positive. I have already talked to my low vision provider about starting this, and we'll see how they do. If a patient cannot see a low vision provider, it is a nice tip for a patient to try to improve their reading proficiency. -Michael S. Lee, MD One of the most important features that contributed to the success of this program was the choice of trainer. The trainer was a seasoned adult literacy tutor with experience in motivating students, who acted as a ‘‘coach.'' Patients were elderly and the training was non-threatening. In fact, a major reason for exclusion (58 patients) was that these were anxious or reluctant patients, who felt threatened by formal testing. Additionally, because of the individual personal atten-tion and the lack of a control group, this study may lend more support to the way a visual rehabilitation program is administered than to the actual visual technique employed. -Mark L. Moster, MD Thurtell MJ, Joshi AC, Leone AC, Tomsak RL, Kosmorsky GS, Stahl JS, Leigh RJ. Crossover trial of gabapentin and memantine as treatment for acquired nystagmus. Ann Neurol. 2010;67:676- 680. We conducted a masked, crossover, therapeutic trial of gabapentin (1,200 mg/day) vs memantine (40 mg/day) for acquired nystagmus in 10 patients (aged 28-61 years; 7 female; 3 multiple sclerosis [MS]; 6 post-stroke; and 1 post-traumatic). Nystagmus was pendular in 6 patients (4 oculopalatal tremor; 2 MS) and jerk upbeat, hemi-seesaw, torsional, or upbeat-diagonal in each of the others. For the group, both drugs reduced median eye speed (P , 0.001), gabapentin by 32.8% and memantine by 27.8%, and im-proved visual acuity (P , 0.05). Each patient improved with 1 or both drugs. Side effects included unsteadiness with gabapentin and lethargy with memantine. Both drugs should be considered as treatment for acquired forms of nystagmus. This is a small study of patients with acquired symp-tomatic (oscillopsia or blurred vision) nystagmus. It re-inforces the benefits of both gabapentin and memantine for pendular nystagmus. Six patients had pendular and the other 4 had different types of jerk nystagmus. Patients with jerk nystagmus had variable responses from no improve-ment to improvement but symptomatic side effects. The benefits reported for jerk nystagmus are more encouraging than I have seen in my practice. When actually reading the individual clinical reports, the benefits seem mild, and the side effects concerning. I have not used memantine at 10 mg QID in these patients and will consider increasing the dose. -Mark L. Moster, MD The article does not mention how the acuity was mea-sured (e.g., Snellen vs. ETDRS). The mean improvement in visual acuity was logMAR 0.084. As a reminder, a visual acuity of 20/20 is logMAR 0.00 and 20/25 is logMAR 0.10. So, on average, these patients gained # 1 line of acuity, which could simply represent normal fluctuation especially in unmasked patients and examiners. I will continue to try gabapentin and memantine in patients with acquired nys-tagmus since the eye speed improved and the oscillopsia is often the worst symptom for patients. The authors note, and I think it is important to highlight here, the importance of avoiding memantine in patients with MS since it can lead to increased relapses (1). -Michael S. Lee, MD 1. Villoslada P, Arrondo G, Sepulcre J, Alegre M, Artieda J. Memantine induces reversible neurologic impairment in patients with MS. Neurology. 2009;72:1630-1633. Jenkins TM, Toosy AT, Ciccarelli O, Miszkiel KA, Wheeler-Kingshott CA, Henderson AP, Kallis C, Mancini L, Plant GT, Miller DH, Thompson AJ. Neuroplasticity predicts outcome of optic neuritis independent of tissue damage. Ann Neurol. 2010; 67:99-113. Objectives: To determine whether lateral occipital com-plex (LOC) activation with functional magnetic resonance imaging (fMRI) predicts visual outcome after clinically isolated optic neuritis (ON). To investigate the reasons behind good recovery following ON, despite residual optic nerve demyelination and neuroaxonal damage. Methods: Patients with acute ON and healthy volunteers were studied longitudinally over 12 months. Structural MRI, visual evoked potentials (VEPs), and optical co-herence tomography (OCT) were used to quantify acute inflammation, demyelination, conduction block, and later to estimate remyelination and neuroaxonal loss over the entire visual pathway. The role of neuroplasticity was investigated using fMRI. Multivariable linear regression analysis was used to study associations between vision, structure, and function. Results: Greater baseline fMRI responses in the LOCs were associated with better visual outcome at 12 months. This was evident on stimulation of either eye (P = 0.007 affected; P = 0.020 fellow eye) and was independent of measures of demyelination and neuroaxonal loss. A negative fMRI response in the LOCs at baseline was associated with a relatively worse visual outcome. No acute electrophysiological or structural measures, in the anterior or posterior visual pathways, were associated with visual outcome. Interpretation: Early neuroplasticity in higher visual areas appears to be an important determinant of recovery from ON, independent of tissue damage in the anterior or posterior visual pathway, including neuroaxonal loss (as measured by MRI, VEP, and OCT) and demyelination (as measured by VEP). One of the clinical challenges in neuro-ophthalmology is determining which patient with optic neuritis will have poor visual recovery. Although no current treatment has been Literature Commentary Moster and Lee: J Neuro-Ophthalmol 2010; 30: 295-298 297 Copyright © North American Neuro-ophthalmology Society.Unauthorized reproduction of this article is prohibited. shown to affect the ultimate outcome, identifying patients with poor visual prognosis is important in order to develop effective interventions. To date, the main predictor of poor outcome has been poor visual acuity at baseline (1). Thinning of RNFL on OCT or GDx has correlated with poor outcome, but this occurs after months, likely at a time too late for effective intervention. Prior reports have found fMRI evidence of adaptive neuroplasticity after a bout of ON. The current study tested the hypothesis that after accounting for markers of anterior and posterior visual pathway damage, early LOC activation would be associated with better visual outcome and found it to be the case. This provides another glimpse into the crystal ball of decreased recovery. Besides determining a poorer prognosis, it might eventually provide an avenue for treatment with CNS manipulations in addition to the approach of protecting the optic nerve and ganglion cells. -Mark L. Moster, MD It will be interesting to see if others find a similar association. There were only 7 patients in the ‘‘poor'' vision outcome, and the authors defined poor vision as worse than logMAR 0.2 (equivalent to Snellen 20/32). Personally, I would consider ‘‘less than desirable'' visual outcome as worse than 20/40 (logMAR 0.3). Using that cutoff, there were only 2 patients in that category and one of them had acuity of logMAR 0.32, which is approximately 20/42. Given the lack of moderate or severe vision loss in this study, it is hard to know how predictive fMRI of the LOC really is. -Michael S. Lee, MD 1. The optic neuritis study group. Visual function more than 10 years after optic neuritis: experience of the optic neuritis treatment trial. Am J Ophthalmol. 2004;137:77-83. Shome D, Honavar SG, Raizada K, Raizada D. Implant and prosthesis movement after enucleation a randomized controlled trial. Ophthalmology. 2010 Apr 22 [epub ahead of print]. Objective: To evaluate implant and prosthesis movement after myoconjunctival enucleation and subsequent poly-methyl methacrylate (PMMA) implantation, compared with the traditional enucleation with muscle imbrication using a PMMA implant and with enucleation accompanied by porous polyethylene implantation. Design: Randomized, controlled, observer-masked, inter-ventional study. Participants: One hundred fifty patients, equally and randomly allocated to the 3 groups. Intervention: Group 1 consisted of patients in whom a PMMA implant was used after enucleation with muscle imbrication (traditional PMMA group). Group 2 consisted of patients in whom a PMMA implant was used after enucleation with a myoconjunctival technique (myoconjunctival PMMA group). Group 3 consisted of patients in whom a porous polyethylene implant was used after enucleation by the scleral cap technique (porous polyethylene group). Fifty patients were included in each group. Patients were allocated to 1 of the 3 groups using stratified randomization. Informed consent was obtained. Acrylic prostheses custom made by a trained ocularist were fitted 6 weeks after surgery in all patients. A masked observer measured implant and prosthesis movement 6 weeks after surgery using a slit-lamp device with real-time video and still photographic documentation. Analysis of implant and prosthesis movement was carried out using the Mann-Whitney U test, and a P value of #0.03 was considered significant. Complications including implant displacement and exposure also were noted. Main Outcome Measures: Implant and prosthesis move-ment. Results: Myoconjunctival PMMA implant movement was better than the traditional PMMA implant (P = 0.001), but was similar to that of the porous polyethylene implant. Prosthesis movement with the myoconjunctival PMMA implant was better than that of either the traditional PMMA (P = 0.001) or the porous polyethylene (P = 0.002) implants. Conclusions: Myoconjunctival enucleation technique with a PMMA implant provides statistically and clinically sig-nificantly better implant and prosthesis movement than the traditional PMMA implant and better prosthesis movement than the porous polyethylene implant. After enucleation, an implant is placed intraconally to provide orbital volume, and then, Tenon capsule and conjunctiva are sutured closed over the implant. Later, a cosmetic prosthestic shell is placed over the conjunctiva. When the patient moves his/her contralateral eye, the desired outcome is for the prosthesis to move as much as possible. There are essentially two kinds of implants: a porous implant that allows in-growth of tissue into the implant and a nonintegrated implant. Two of the most common implants are the nonintegrated PMMA implant (cost ;$2-10) and the porous polyethylene implant (cost ;$300). The authors randomized patients to one of 3 groups and used a masked observer to measure prosthesis movement. The traditional PMMA group sutured the extraocular mus-cles (EOM) to each other. The myoconjunctival PMMA group sutured the EOM to the closest fornix. The porous polyethylene group sewed a scleral cap to the implant and then sutured the EOM to the wrapping. Evaluators were masked to surgical technique. The authors show that the cheaper PMMA implant had better prosthesis movement with the myoconjunctival technique than the traditional surgical technique with PMMA and the more expensive porous implant. This is a great study that represents not only substantial cost savings but also better outcome. -Michael S. Lee, MD Ditto. -Mark L. Moster, MD Literature Commentary 298 Moster and Lee: J Neuro-Ophthalmol 2010; 30: 295-298 Copyright © North American Neuro-ophthalmology Society.Unauthorized reproduction of this article is prohibited. |