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Show Literature Commentary Raz N, Dotan S, Benoliel T, Chokron S, Ben-Hur T, Levin N. Sustained motion perception deficit following optic neuritis: behavioral and cortical evidence. Neurology. 2011;76:2103-2111. Objective: To assess the recovery process in patients after an acute optic neuritis (ON) attack, comparing static and dynamic visual functions. Methods: In this prospective controlled study, 21 patients with unilateral first-ever ON were followed over the course of 1 year. Standard visual tests, visual evoked potentials, and optical coherence tomography were assessed repeatedly. In addition, we developed a novel set of motion perceptual tasks to test dynamic visual deficits. fMRI examinations were performed to study the neuronal correlates for the behavioral findings. Results: Four months after the acute phase, the affected eyes had returned to normal performance levels in the routine visual testing. However, motion perception remained im-paired throughout the 12-month period. In agreement with the clinical findings, fMRI studies showed recovery in cortical activation during static object recognition, as opposed to sustained deficit in tasks that require motion perception. Conclusions: Sustained motion perception deficit following ON may explain the continued visual complaints of patients long after the recovery of visual acuity. Cortical activation patterns suggest that if plastic processes in higher visual regions contribute to the recovery of vision, this may be limited to static visual functions. Alternatively, cortical activa-tion may reflect the visual percept (intact for visual acuity and impaired for motion perception), rather than demonstrating plastic processes. We suggest that motion perception should be included in the routine ophthalmologic tests following ON. The authors prospectively and longitudinally evaluated multiple static (acuity, visual field, contrast sensitivity), dynamic (motion detection, identification of moving objects), and functional (VEP, functional MRI) tests among patients with a first attack of unilateral optic neuritis. Overall, they found that the static tests returned to normal at 4-month follow-up. The dynamic and functional tests remained abnormal compared to fellow eyes and control eyes for more than a year. We know from the Optic Neuritis Treatment Trial that treatment with intravenous Solu-Medrol does not affect the final visual outcome with regard to visual acuity and visual field. Many minimalists in our specialty point to this as support for doing nothing for patients with optic neuritis. This study makes me wonder if intravenous corticosteroid therapy would affect recovery of motion detection or not. I do not know if any of these patients were treated or not. Finally, this article can also help manage expectations of patients with an acute optic neuritis. -Michael S. Lee, MD This is an interesting article demonstrating persistent deficits in motion perception after final recovery in optic neuritis, even in those with complete recovery of contrast sensitivity. It would be helpful to know if there is a correlation of these test findings with patients' symptoms. As another feature that doesn't fully recover, motion per-ception will be an excellent parameter to measure in clinical trials of medications for MS or optic neuritis. -Mark L. Moster, MD Magaña SM, Keegan BM, Weinshenker BG, Erickson BJ, Pittock SJ, Lennon VA, Rodriguez M, Thomsen K, Weigand S, Mandrekar J, Linbo L, Lucchinetti CF. Beneficial plasma exchange response in central nervous system inflammatory demyelination. Arch Neurol. 2011;68:870-878. Background: Plasma exchange (PLEX) is a beneficial rescue therapy for acute, steroid-refractory, central nervous system inflammatory demyelinating disease (CNS-IDD). Despite the approximately 45% PLEX response rate reported among patients with CNS-IDD, determinants of interindividual differences in PLEX response are not well characterized. Objective: To perform an exploratory analysis of clinical, radiographic, and serological features associated with beneficial PLEX response. Design: Historical cohort study. Setting: Neurology practice, Mayo Clinic College of Medi-cine, Rochester, MN. Patients: All Mayo Clinic patients treated with PLEX between January 5, 1999, and November 12, 2007, for a steroid-refractory CNS-IDD attack. Main Outcome Measure: The PLEX response in attack-related, targeted neurological deficit(s) assessed within the 6-month period following PLEX. Results: We identified 153 patients treated with PLEX for a steroid-refractory CNS-IDD, of whom 90 (59%) exhibited moderate to marked functional neurological improvement within 6 months following the treatment. Pre-PLEX clinical features associated with a beneficial PLEX response were shorter disease duration (P = 0.02) and preserved deep ten-don reflexes (P = 0.001); post-PLEX variables included a di-agnosis of relapsing-remitting multiple sclerosis (P = 0.008) and a lower Expanded Disability Status Scale score 388 Moster and Lee: J Neuro-Ophthalmol 2011; 31: 388-392 Literature Commentary Section Editors: Mark L. Moster, MD Michael S. Lee, MD Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. (P = 0.001) at the last follow-up. Plasma exchange was less effective for patients with multiple sclerosis who subse-quently developed a progressive disease course (P = 0.046). Radiographic features associated with a beneficial PLEX response were the presence of ring-enhancing lesions (odds ratio = 4.00; P = 0.03) and/or mass effect (odds ratio = 3.00; P = 0.02). No association was found between neuro-myelitis optica-IgG serostatus and PLEX response. Conclusions: We have identified clinical and radiographic features that may aid in identifying patients with fulminant, steroid-refractory, CNS-IDD attacks who are more likely to respond to PLEX. Studies have demonstrated improvement in neurologic function in patients with CNS demyelinating episodes without spontaneous recovery who received plasma exchange (PLEX). In prior reports, features associated with a beneficial response to PLEX included early initiation of treatment, preserved deep tendon reflexes (DTRs), and male sex. It has been proposed that PLEX might work by removing inflammatory and humoral factors contributing to reversible conduction block, prior to permanent axonal damage. The current study, which is the largest to date, found a slightly different set of features associated with moderate to marked improvement, namely, shorter disease duration, preserved DTRs, a lower EDSS score, a relapsing-remitting course, and MRI with ring-enhancing lesions or mass effect. This study included patients with MS or NMO and because it included varied types of demyelinating episode, it is hard to glean detailed information about optic neuritis. However, 14% of patients are listed as having optic neuritis, with approximately 35%-40% with moderate to marked improvement, somewhat less than the overall 59% im-provement rate. There was similar improvement in a group of patients listed with "visual field defects." In patients with an NMO-type presentation (34 patients), there was no statistical difference in response between NMO seronega-tive (83%) and seropositive (68%) status. The median time from index event to treatment in this study was 23 days (range, 0-186). Such early treatment raises criticism that the beneficial outcome may merely be sponta-neous recovery. However, in contrast to findings of prior studies, the benefits were similar for patients treated within 20 days (60%), 21-60 days (60%), and >60 days (55%). This study is important, and I hope it will encourage further study of PLEX for optic neuritis with suboptimal outcome. While PLEX is commonly employed for NMO patients, it is not frequently used in non-NMO demyelin-ating optic neuritis. We are likely missing a window of opportunity to improve vision in some of these patients with PLEX in the first few months. With increasing ability to predict nonrecovery (e.g., early RNFL thinning) in optic neuritis than with other demyelinating presentations, we may be able to identify which patients may benefit most from PLEX. -Mark L. Moster, MD There just is not enough detail in this article to determine the effectiveness of PLEX in optic neuritis. It is hard to know how many of these "optic neuritis" were NMO patients or MS patients or CIS patients. Mark, I agree with you that there may be more effective treatments for optic neuritis than observation or intrave-nous corticosteroids. Perhaps, a pilot study of PLEX in optic neuritis utilizing RNFL and motion detection as outcome measures may be in order. However, with the rising cost of medical care and the generally good visual recovery of patients with optic neuritis, it would be wise to evaluate the cost effectiveness. -Michael S. Lee, MD Kupersmith MJ, Sibony P, Mandel G, Durbin M, Kardon RH. Optical coherence tomography of the swollen optic nerve head: deformation of the peripapillary RPE layer in papilledema. Invest Ophthalmol Vis Sci. 2011;52:6558-6564. Purpose: To examine the biomechanical deformation of load-bearing structures of the optic nerve head (ONH) resulting from raised intracranial pressure, using high-definition optical coherence tomography (HD-OCT). We postulate that elevated intracranial pressure induces forces in the retrolaminar subarachnoid space that can deform ONH structures, particularly the peripapillary Bruch mem-brane (BM) and retinal pigment epithelial (RPE) layers. Methods: We compared HD-OCT optic nerve and peripapil-lary retinal nerve fiber layer (RNFL) findings in eyes with papilledema due to raised intracranial pressure to findings in eyes with optic disc swelling due to optic neuritis and nonarteritic anterior ischemic optic neuropathy (NAION), conditions without intracranial hypertension. We measured average thickness of the RNFL and the angle of the RPE/BM at the temporal and nasal borders of the neural canal opening. The angle was measured as positive with inward (toward the vitreous) angulation and as negative with outward angulation. Results: Of 30 eyes with papilledema, 20 eyes (67%) had positive RPE/BM rim angles. One of 8 optic neuritis (12%) eyes and 1 (8%) of the 12 NAION eyes had positive angulation. In 5 papilledema eyes, the RNFL thickening increased, 3 of which developed positive RPE/BM angles. On follow-up, 22 papilledema eyes had reduction of RNFL swelling and 17 of these eyes had less positive RPE/BM angulation. Conclusions: In papilledema, the RPE/BM is commonly deflected inward, in contrast to eyes with NAION or optic neuritis. The RPE/BM angulation is presumed to be due to elevated pressure in the subarachnoid space, does not correlate with the amount of RNFL swelling, and resolves as papilledema subsides. The authors looked at the line raster scans of swollen optic nerves to determine if the RPE/BM deflected differently between patients with and without papilledema. The angle is formed between the unaltered plane of the RPE/BM and the plane of the peripapillary RPE/BM. The authors also Moster and Lee: J Neuro-Ophthalmol 2011; 31: 388-392 389 Literature Commentary Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. tried to correlate the deflection with the change in RNFL thickness. When it comes to papilledema, I think there are a couple of issues that clinicians want addressed with new technology or new tests. The first is whether this is going to help follow a patient with IIH. Although the authors showed some correlation between the change in the nasal RPE/BM angle and the change in RNFL thickness, I don't see the nasal RPE/BM angle replacing RNFL thickness, which most clinicians routinely measure. The other issue is whether the line raster scan will help distinguish papilledema from pseudopapilledema. It seems to me that a patient with borderline appearing optic nerves could have a line scan through the optic disc. If it shows an inward deflection (toward the vitreous), then that could push the clinician to pursue neuroimaging and a lumbar puncture. If it showed a neutral or outward deflection, I don't think it helps substantially since one third of the papilledema patients in this study failed to show a positive RPE/BM rim angle. -Michael S. Lee, MD New technology that helps in definitive diagnosis is most welcome. This study suggests that a positive RPE/BM angulation is often seen in papilledema but rarely in disc swelling associated with NAION or optic neuritis. How-ever, we seldom see a patient in whom we have difficulty distinguishing papilledema from either NAION or optic neuritis. Michael, I agree that the most important distinc-tion is between papilledema and pseudopapilledema. If, on further study, OCT can reliably differentiate between these 2 conditions, we will really have another wonderful use for OCT. -Mark L. Moster, MD Chitravas N, Jung RS, Kofskey DM, Blevins JE, Gambetti P, Leigh RJ, Cohen ML. Treatable neuro-logical disorders misdiagnosed as Creutzfeldt-Jakob disease. Ann Neurol. 2011 April 18 (epub ahead of print). doi:10.1002ana.22454. Objective: Heightened awareness of Creutzfeldt-Jakob dis-ease (CJD) among physicians and the lay public has led to its frequent consideration in the differential diagnosis of patients with rapidly progressive dementia (RPD). Our goal was to determine which treatable disorders are most commonly mistaken for CJD. Methods: We performed a retrospective clinical and neuro-pathological review of prion-negative brain autopsy cases referred to the US National Prion Disease Pathology Surveillance Center at the Case Western Reserve University from January 2006 through December 2009. Results: Of 1,106 brain autopsies, 352 (32%) were negative for prion disease, 304 of which had adequate tissue for histopathological analysis. Alzheimer disease (n = 154) and vascular dementia (n = 36) were the 2 most frequent diagnoses. Seventy-one patients had potentially treatable diseases. Clinical findings included dementia (42 cases), pyramidal (n = 20), cerebellar (n = 14), or extrapyramidal (n = 12) signs, myoclonus (n = 12), visual disturbance (n =9), and akinetic mutism (n = 5); a typical electroencephalogram occurred only once. Neuropathologi-cal diagnoses included immune-mediated disorders (n = 26), neoplasia (n = 25, most often lymphoma), infections (n = 14), and metabolic disorders (n = 6). Interpretation: In patients with RPD, treatable disorders should be considered and excluded before diagnosing CJD. Misdiagnosed patients often did not fulfill World Health Organization criteria. RPD with positive 14-3-3 cerebrospinal fluid protein should not be regarded as sufficient for the diagnosis of CJD. Adherence to revised criteria for CJD, which include distinctive MRI features of prion disease, is likely to improve diagnostic accuracy. This study, which comes from the National Prion Disease Pathology Surveillance Center (Case Western Reserve University, Cleveland, OH), is important for neuro-ophthalmologists who are often the first to diagnose CJD, particularly with the Heidenhain variant. As one might expect, 32% of biopsies in this study were negative for CJD, most commonly in patients with Alzheimer disease or vascular dementia. However, what is surprising is that 23% of patients (71 of 304) had potentially treatable disease. Nine of these patients (13%) had visual symptoms. A wide spectrum of potentially treatable diseases was found. These included primary angiitis of the CNS (7), acute disseminated encephalomyelitis (6), limbic enceph-alitis (6), neurosarcoidosis (4), paraneoplastic cerebellar degeneration (2), Wegener granulomatosis (1), neoplasms (25), fungal infection (5), viral meningoencephalitis (5), parasitic infection (4), and toxic/metabolic encephalopa-thies (6). One factor that led to a mistaken diagnosis was reliance on a positive 14-3-3 cerebrospinal fluid protein, which the authors point out is sensitive but not specific for CJD and is often positive in other CNS infections. They also point out that recently described MRI finding's characteristics for CJD are helpful in making the correct diagnosis. This study is limited by its retrospective nature and because the data are taken from a national database. Standardized and accurate clinical information on all patients is lacking. Nonetheless, this study heightens our awareness that patients with presentations consistent with CJD may harbor other conditions, which might be treatable and even curable! -Mark L. Moster, MD I can see how misdiagnosis of CJD can occur. I think clinicians have an almost knee-jerk reaction to diagnose a patient with a rapidly progressive dementia and a positive 14-3-3 with CJD (similar to the obese young female with papilledema has idiopathic intracranial hypertension). Since CJD is rare, most clinicians do not know the WHO 390 Moster and Lee: J Neuro-Ophthalmol 2011; 31: 388-392 Literature Commentary Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. diagnostic criteria well, nor realize the low specificity of the 14-3-3 protein. I looked up the MRI findings suggestive of CJD. They include high signal abnormalities on diffusion-weighted imaging or FLAIR in both the caudate nucleus and putamen OR at least 2 cortical lesions in the temporal, parietal, or occipital lobes (1). -Michael S. Lee, MD REFERENCE 1. Zerr I, Kallenberg K, Summers DM, Romero C, Taratuto A, Heinemann U, Breithaupt M, Varges D, Meissner B, Ladogana A, Schuur M, Haik S, Collins SJ, Jansen GH, Stokin GB, Pimentel J, Hewer E, Collie D, Smith P, Roberts H, Brandel JP, van Duijn C, Pocchiari M, Begue C, Cras P, Will RG, Sanchez-Juan P. Updated clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease. Brain. 2009;132:2659-2668. Kim JS, Maheshwary AS, Bartsch DU, Cheng L, Gomez ML, Hartmann K, Freeman WR. The micro-perimetry of resolved cotton-wool spots in eyes of patients with hypertension and diabetes mellitus. Arch Ophthalmol. 2011;129:879-884. Background: Retinal cotton-wool spots (CWSs) are an important manifestation of retinovascular disease in hyper-tension (HTN) and diabetes mellitus (DM). Conventional automated perimetry data have suggested relative scoto-mas in resolved CWSs; however, this has not been well delineated using microperimetry. This study evaluates the retinal sensitivity in documented resolved CWSs using microperimetry. Methods: Retinal CWSs that resolved after 10-119 months (median, 51 months) and normal control areas were photo-graphed to document baseline lesions. Eye-tracking image-stabilized microperimetry with simultaneous scanning laser ophthalmoscopy was performed over resolved CWSs, adja-cent uninvolved areas near the lesion, and in location-matched normal patients (age matched). Results: A total of 16 eyes in patients with DM or HTN (34 resolved CWSs) and 16 normal control eyes (34 areas) were imaged. The mean (SD) sensitivity of resolved CWSs in the eyes of patients with HTN and DM was 11.67 (3.88) dB and 7.21 (5.48) dB, respectively. For adjacent control areas in the eyes of patients with HTN and DM, the mean (SD) sensitivity was 14.00 (2.89) dB and 11.80 (3.45) dB, respectively. Retinal sensitivity was significantly lower in areas of resolved CWSs than in the surrounding controls for patients with HTN (P = 0.01) and those with DM (P < 0.001). Scotomas in patients with DM were denser than those in patients with HTN (P < 0.05). Conclusions: Cotton-wool spots in patients with DM and HTN leave permanent relative scotomas detected by micro-perimetry. Scotomas are denser in eyes of patients with DM than in those with HTN. In addition, among patients with DM, adjacent retinas not involved with CWSs have lower retinal sensitivity than in age-matched controls. The authors used microperimetry to test the sensitivity of the retina in locations where cotton-wool spots had resolved. The ability to eye track and overlay prior fundus photographs ensures accurate localization. As neuro-ophthalmologists, we often receive referrals for unexplained visual field defects. One explanation may be derived from this article-a patient with hypertension or diabetes and a small unexplained relative scotoma could have had a cotton-wool spot that developed and resolved. I also believe that patients with known cotton-wool spots should be counseled about the possibility of permanent relative scotomas. -Michael S. Lee, MD This study provides a good foundation for studying the effect of CWS on subsequent visual function. It will be important to evaluate more patients (only 6 patients each with DM and HTN were evaluated) to see if there is truly worse visual field loss in diabetic individuals than those with hypertension. It will also be important to correlate these findings with visual symptoms and with focal retinal thinning, neither of which were done in this study. -Mark L. Moster, MD Duprez TF, Sindic CJM. Contrast-enhanced mag-netic resonance imaging and perfusion-weighted imaging for monitoring features in severe CLIPPERS. Brain. 2011;134:1-3, e184. This letter to the editor describes a case of CLIPPERS (Chronic Lymphocytic Inflammation with Pontine Peri-vascular Enhancement Responsive to Steroids) syndrome. Although only a case report, I used it as an opportunity to review CLIPPERS, a recently described entity of impor-tance to neuro-ophthalmologists. In late 2010, Pittock et al (1) described 8 patients with a similar clinical, radiographic, and pathologic picture. FIG. 1. Curvilinear enhancement "peppering" the pons on T1 contrast MRI in a patient with CLIPPERS. From Pittock SJ et al (1), with permission from Oxford University Press. Moster and Lee: J Neuro-Ophthalmol 2011; 31: 388-392 391 Literature Commentary Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Median age was 45.5 years with a range of 16-86 years. There were 3 men and 5 women. All patients had subacute onset of diplopia and ataxia, and 7 had dysarthria. Five had tingling or altered sensation of the face and scalp. The diplopia was horizontal, but the examination findings were not described. The characteristic MRI finding was a curvilinear punc-tate pattern of patchy gadolinium enhancement "pepper-ing" the pons (Fig. 1). These changes may spread to the adjacent brainstem, cerebellum, and spinal cord. All patients had CSF examinations with mild protein elevation in 4 and a mild pleocytosis in 1. Oligoclonal bands were noted in 3 of 6 patients. Cytology and cultures were negative in all 8 patients. Four of the 8 patients had brain biopsies, and pathology revealed prominent perivascular infiltration of lymphocytes. Other diseases, including MS, CNS lymphoma, CNS vasculitis, and sarcoidosis, were excluded. Treatment included intravenous corticosteroids with good initial response but recurrence upon taper, requiring pro-longed steroids or immunosuppression. Beneficial medica-tions included mitoxantrone, methotrexate, and azathioprine. This case adds some new imaging information, although it is not biopsy proven. First, perfusion-weighted imaging showed an increase in perfusion in involved areas to 200%- 300% normal, which persisted 3 months later, despite clinical improvement on steroids. Second, severe pontine atrophy was seen at the 20-month MRI. CLIPPERS is a diagnosis neuro-ophthalmologists need to be aware of. Whether this is a single entity or a clinical phenotype representing numerous underlying etiologies is yet to be determined. -Mark L. Moster, MD I had not heard of this entity before; thanks for bringing it up, Mark. Although extremely interesting, CLIPPERS definitely needs a label of "diagnosis of exclusion" even with characteristic MRI findings. Many other entities including CNS lymphoma or infection could present with similar MRI abnormalities and initially respond to corticosteroids. After a nondiagnostic workup, I like the idea that we have a "diagnosis" to give to patients. Yet we are still dealing with limited information on treatment options and prognosis. -Michael S. Lee, MD REFERENCE 1. Pittock SJ, Debruyne J, Krecke KN, Giannini C, van den Ameele J, De Herdt V, McKeon A, Fealey RD, Weinshenker BG, Aksamit AJ, Krueger BR, Shuster EA, Keegan BM. Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). Brain. 2010;133:2626-2634. 392 Moster and Lee: J Neuro-Ophthalmol 2011; 31: 388-392 Literature Commentary Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. |