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Show Literature Commentary Spiegel R, Kalla R, Rettinger N, Schneider E, Straumann D, Marti S, Glasauer S, Brandt T, Strupp M. Head position during resting modifies spontaneous daytime decrease of downbeat nystagmus. Neurology. 2010;75:1928-1932. Background: The intensity of downbeat nystagmus (DBN) decreases during the daytime when the head is in upright position. Objective: This prospective study investigated whether resting in different head positions (upright, supine, prone) modulates the intensity of DBN after resting. Methods: Eye movements of 9 patients with DBN due to cerebellar (n = 2) or unknown etiology (n = 7) were re-corded with video-oculography. Mean slow-phase veloci-ties (SPV) of DBN were determined in the upright position before resting at 9 AM and then after 2 hours (11 AM) and after 4 hours (1 PM) of resting. Whole-body positions during resting were upright, supine, or prone. The effects of all the 3 resting positions were assessed on 3 separate days in each patient. Results: Before resting (9 AM), the average SPV ranged from 3.05 /s to 3.6 /s on the separate days of mea-surement. After resting in an upright position, the average SPV at 11 AM and 1 PM was 0.65 /s, which was less (P , 0.05) than after resting in supine (2.1 /s) or prone (2.22 /sec) position. Conclusion: DBN measured during the daytime in an up-right position becomes minimal after the patient has rested upright. The spontaneous decrease of DBN is less pronounced when patients lie down to rest. This indicates a modulation by otolithic input. We recommend that pa-tients with DBN rest in an upright position during the daytime. Classification of Evidence: This study provides Class II evidence that for patients with DBN, 2 hours of rest in the upright position decreases nystagmus more than 2 hours of rest in the supine or prone positions (relative improvement, 79% upright, 33% supine, and 38% prone; P , 0.05). The authors measured slow-phase velocity (SPV) of downbeat nystagmus (DBN) before and after 2 hours of resting in the supine, prone, and upright positions. The SPV improved by about 30%-40% after resting in prone and supine positions and by about 80% after resting in the upright position. They did not find a difference between resting in the light or in the dark while upright. This could be a practical pearl for patients with DBN. They could dramatically improve their DBN by resting in the upright position. I would also ask patients to consider even sleeping in the upright position overnight to see if it resulted in better or longer improvement in nystagmus. I am disappointed that the authors did not grade sub-jective patient responses to corroborate their eye movement recordings. Without this data, it is difficult to know how beneficial this truly is. -Michael S. Lee, MD This is an interesting finding from the eye movement laboratory. However, I don't think it translates into useful information for our clinical world. The authors' suggestion ‘‘. . . to advise patients with DBN to rest in an upright position during the day in order to alleviate distressing oscillopsia . . .'' seems premature. First, they don't report if any patients perceived a symptomatic improvement. Sec-ond, we don't know if the benefit of 4 hours of rest in the upright position persists for any length of time. So, if the patient then gets up and walks 10 feet, is he/she back to baseline? How practical is it to sit upright without moving for hours for a brief benefit? If this truly works, I think some observant patients (e.g., sitting for hours watching a football game on TV) would have figured it out for themselves and would have told us. Let's consider this as interesting lab-oratory information that may be a first step toward a strategy for improvement in these patients. -Mark L. Moster, MD Galetta KM, Barrett J, Allen M, Madda F, Delicata D, Tennant AT, Branas CC, Maguire MG, Messner LV, Devick S, Galetta SL, Balcer LJ. The King-Devick test as a determinant of head trauma and concussion in boxers and MMA fighters. Neurology. 2011;76: 1456-1462. Objective: Sports-related concussion has received in-creasing attention as a cause of short- and long-term neurologic symptoms among athletes. The King-Devick (K-D) test is based on the measurement of the speed of rapid number naming (reading aloud single-digit numbers from 3 test cards) and captures impairment of eye movements, attention, language, and other correlates of suboptimal brain function. We investigated the K-D test as a potential rapid sideline screening for concussion in a cohort of boxers and mixed martial arts fighters. Methods: The K-D test was administered prefight and postfight. The Military Acute Concussion Evaluation Section Editors: Mark L. Moster, MD Michael S. Lee, MD Moster and Lee: J Neuro-Ophthalmol 2011; 31: 187-191 187 Literature Commentary Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. (MACE) was administered as a more comprehensive but longer test for concussion. Differences in postfight K-D scores and changes in scores from prefight to postfight were compared for athletes with head trauma during the fight vs those without. Results: Postfight K-D scores (n = 39 participants) were significantly higher (worse) for those with head trauma during the match (59.1 6 7.4 vs 41.0 6 6.7 seconds; P , 0.0001, Wilcoxon rank sum test). Those with loss of consciousness showed the greatest worsening from pre-fight to postfight. Worse postfight K-D scores (r (s) = 20.79; P = 0.0001) and greater worsening of scores (r (s) = 0.90; P , 0.0001) correlated well with postfight MACE scores. Worsening of K-D scores by $5 seconds was a distinguishing characteristic noted only among participants with head trauma. High levels of test-retest reliability were observed (intraclass correlation coef-ficient, 0.97 [95% confidence interval, 0.90-1.0]). Conclusion: The K-D test is an accurate and reliable method for identifying athletes with head trauma and is a strong candidate rapid sideline screening test for con-cussion. The King-Devick (K-D) test is a set of 3 cards filled with numbers that are separated by variable spacing. The test measures how rapidly a person can read all of numbers accurately. The authors measured boxers and mixed martial arts fighters prefight and postfight. Those without head trauma read the cards faster after fight. Fighters with head trauma slowed down by 5 or more seconds on the postfight evaluation. The authors suggest that the K-D test could represent a rapid screening test for concussion. I see some huge advantages here: 1) The test is easy to take. I believe a 6-year-old athlete could take this test without difficulty. 2) It does not require a lot of training to administer. Many youth sports do not have a neurologist or sports medicine doctor on the sidelines. Lay people could easily administer the K-D test. 3) The outcome is very easy to interpret. Athletes who take more than 5 seconds over the baseline to complete the test require further evaluation. 4) It takes less than 2 minutes to administer, which means an unaffected athlete can get back into the game quickly. However, I see one potential issue with the K-D test. I could envision an athlete in a contact sport purposely slowing down the pregame K-D test time. For instance, let's suppose that a football player slows down his baseline test to 60 seconds. He sustains a head on collision during the game and his second test takes 58 seconds. He passes the K-D test and may not be identified. It might be worth establishing age-matched normal to avoid this. -Michael S. Lee, MD In recent years, the awareness of the dangers of sports concussions has grown rapidly. This is beginning to over-come the prior pressures of keeping the athlete in the game at all cost. Professional sports, school organizations, states, and others are developing guidelines for sports injuries, which will translate into better neurologic outcomes for athletes. Having a simple, rapid, and reliable test for concussion, as demonstrated for the K-D test in this article, will make it easier to achieve the task of keeping our athletes safe. -Mark L. Moster, MD Marmor MF, Kellner U, Lai TYY, Lyons JS, Mieler WF. Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy. Ophthalmology. 2011;118:415-422. Background: The American Academy of Ophthalmology recommendations for screening of chloroquine (CQ) and hydroxychloroquine (HCQ) retinopathy were published in 2002, but improved screening tools and new knowledge about the prevalence of toxicity have appeared in the ensuing years. No treatment exists as yet for this disor-der, so it is imperative that patients and their physicians be aware of the best practices for minimizing toxic damage. Risk of Toxicity: New data have shown that the risk of toxicity increases sharply toward 1% after 5 to 7 years of use, or a cumulative dose of 1,000 g, of HCQ. The risk increases further with continued use of the drug. Dosage: The prior recommendation emphasized dosing by weight. However, most patients are routinely given 400mg of HCQ daily (or 250 mg CQ). This dose is now considered acceptable, except for individuals of short stature, for whom the dose should be determined on the basis of ideal body weight to avoid overdosage. Screening Schedule: A baseline examination is advised for patients starting these drugs to serve as a reference point and to rule out maculopathy, which might be a contraindication to their use. Annual screening should begin after 5 years (or sooner if there are unusual risk factors). Screening Tests: Newer objective tests, such as multi-focal electroretinogram (mfERG), spectral-domain optical coherence tomography (SD-OCT), and fundus auto-fluorescence (FAF), can be more sensitive than visual fields. It is now recommended that along with 10-2 au-tomated fields, at least one of these procedures be used for routine screening where available. When fields are performed independently, even the most subtle 10-2 field changes should be taken seriously and are an indication for the evaluation by objective testing. Because mfERG testing is an objective test that evaluates function, it may be used in place of visual fields. Amsler grid testing is no longer recommended. Fundus examinations are advised for documentation, but visible bull's-eye maculopathy is a late change, and the goal of screening is to recognize toxicity at an earlier stage. Counseling: Patients should be aware of the risk of tox-icity and the rationale for screening (to detect early changes and minimize visual loss not necessarily to pre-vent it). The drugs should be stopped if possible when toxicity is recognized or strongly suspected, but this is a decision to be made in conjunction with patients and their medical physicians. In 2002, the American Academy of Ophthalmology (AAO) published Preferred Practice Patterns to screen for hydroxychloroquine and chloroquine retinal toxicity. In this 188 Moster and Lee: J Neuro-Ophthalmol 2011; 31: 187-191 Literature Commentary Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. article, the AAO updates these recommendations. While many neuro-ophthalmologists do not spend their time screening for these toxicities, we have all seen patients with unexplained symptoms from hydroxychloroquine retinop-athy and I think this represents useful reading. This evidence-based article notes that Amsler grid, color vision testing, fluorescein angiography, full-field ERG, EOG, and time-domain OCT are NOT helpful because either their yield is low or it catches these patients too late. The authors recommend as the best screening test an automated visual field 10-2 with a white stimulus. Any abnormality at all on the 10-2 is worth reinvestigating for repeatability. Because of the subjective nature of perimetry, the recommendations describe benefits of objective retinal testing. Multifocal ERG (mfERG), spectral-domain OCT (SD-OCT), and fundus autofluorescence (FAF) can show evidence of toxicity prior to the onset of visual field loss or in the setting of unreliable field testing. We as neuro-ophthalmologists should consider these objective tests to help rule in or rule out subtle retinal toxicity, despite a referral from the retinal specialist. The mfERG shows paracentral depression of P1 amplitudes with an intact foveal amplitude. SD-OCT shows loss of the inner segment/outer segment junction of the outer retinal layers. Finally, FAF shows an increased autofluorescence in the parafoveal macula. -Michael S. Lee, MD This article from the AAO makes a few important points. First, it refers to many patients who have the nonspecific VF changes on the central 10-2 program ig-nored by the ophthalmologist. Most of the patients who I've diagnosed with hydroxychloroquine retinopathy have been conscientiously followed with VFs that have clear pro-gressive ‘‘nonspecific defects.'' The second point of importance is that finding a ‘‘bull's-eye maculopathy'' on funduscopy is really too late. Two of the 3 last cases I've seen were followed by retina specialists who did not make the diagnosis because fundus examina-tion (and in one case time-domain OCT) was normal. The third point is that patients don't need screening every 6 months in the beginning when they start the medication. It is okay to wait up to 5 years after the baseline examination. Having sensitive tests, such as SD-OCT, mERG and FAF, is great. I do have a concern that on further study, mERG may turn out to be too sensitive and would cause us to discontinue the medication in patients who otherwise might benefit and never lose vision from retinal toxicity. -Mark L. Moster, MD I would agree with you on your last point. I just saw a patient with a central depression on mfERG who is low-risk by all the criteria in this article. She has a couple of nonspecific changes on her visual field, is this an over-call on the toxicity based on mfERG or is this the earliest findings of the toxicity? -Michael S. Lee, MD Durmus H, Laval SH, Deymeer F, Parman Y, Kiyan E, Gokyigiti M, Ertekin C, Ercan I, Solakoglu S, Karcagi V, Straub V, Bushby K, Lochmuller H, Serdaroglu-Oflazer P. Oculopharyngodistal myopathy is a distinct entity: clinical and genetic features of 47 patients. Neurology. 2011;76: 227-235. Background: Oculopharyngodistal myopathy (OPDM) has been reported as a rare, adult-onset hereditary muscle disease with putative autosomal dominant and autosomal recessive inheritance. Patients with OPDM present with progressive ocular, pharyngeal, and distal limb muscle involvement. The genetic defect causing OPDM has not been elucidated. Methods: Clinical and genetic findings of 47 patients from 9 unrelated Turkish families diagnosed with OPDM at the Department of Neurology, Istanbul Faculty of Medicine, between 1982 and 2009 were evaluated. Results: The mean age at the onset was around 22 years. Both autosomal dominant and autosomal recessive traits were observed, without any clear difference in clinical phenotype or severity. The most common initial symptom was ptosis, followed by oropharyngeal symptoms and distal weakness, which started after the fifth disease year. Intrafamilial variability of disease phenotype and severity was notable in the largest autosomal dominant family. Atypical presentations, such as absence of limb weakness in long-term follow-up in 9, proximal predominant weakness in 4, and asymmetric ptosis in 3 patients, were observed. Swallowing difficulty was due to oropharyngeal dysphagia with myopathic origin. Serum creatine kinase levels were slightly increased, and EMG revealed myopathic pattern with occasional myotonic discharges. Myopathologic findings included rimmed and autophagic vacuoles and chronic myopathic changes. Importantly, a considerable proportion of patients de-veloped respiratory muscle weakness while still ambu-lant. Linkage to the genetic loci for all known muscular dystrophies, and for distal and myofibrillar myopathies, was excluded in the largest autosomal dominant and autosomal recessive OPDM families. Conclusion: We suggest that OPDM is a clinically and genetically distinct myopathy. The report by Durmus et al on oculopharyngodistal myopathy (OPDM) is the largest to date and almost triples the world literature on this rare disorder. They characterize 47 patients with this disorder from 9 families. There is phenotypic overlap with oculopharyngeal dystrophy (OPMD), as well as EMG (but not clinical) features of myotonia in these patients, so it is good that the authors have done genetic testing to exclude OPMD, myotonic dystrophy, and most other known muscular dystrophies in these families. The inheritance pattern is either autosomal dominant or autosomal recessive, but in some families, the pattern is not well defined. Moster and Lee: J Neuro-Ophthalmol 2011; 31: 187-191 189 Literature Commentary Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. With some variability, the following are the impor-tant clinical features for the practicing neuro-ophthalmologist: 1. Onset: Most often in 20s and 30s, Men 1.38 as women. 2. First 5 years characterized by ptosis, followed by ophthalmoparesis. 3. After 5 years distal.proximal extremity weakness progresses. 4. Prominent features after 5 years also include severe facial weakness, dysphagia, dyspnea. and vocal cord changes. 5. Limited long-term follow-up revealed 6 disease-re-lated deaths at an average age of 40. Creatine kinase ranged from normal to 8 times normal. EMG reveals myogenic potentials with myotonia in around half the patients studied. Muscle biopsy reveals myopathic changes with rimmed vacuoles. For the clinician, distinguishing features from OPMD include earlier onset and progression, prominent oph-thalmoparesis, facial weakness, and distal weakness, as well as the lack of autosomal dominant inheritance in some cases. -Mark L. Moster, MD I found it interesting that the ophthalmoparesis affected lateral gaze first and more severely in this group with OPDM. Unfortunately, this is a clinical diagnosis and a diagnosis of exclusion-you have to exclude OPMD, myotonic dystrophy 1, and facioscapulohumeral dystrophy via genetic testing. Muscle biopsy possesses no unique characteristic to seal the diagnosis. -Michael S. Lee, MD Giordano C,MontopoliM, Perli E, Orlandi M, Fantin M, Ross-Cisneros FN, Caparrotta L, Martinuzzi A, Ragazzi E, Ghelli A. Oestrogens ameliorate mitochondrial dysfunction in Leber's hereditary optic neuropathy. Brain. 2011;134:220-234. Leber hereditary optic neuropathy, the most frequent mitochondrial disease due to mitochondrial DNA point mutations in complex I, is characterized by the selective degeneration of retinal ganglion cells, leading to optic atrophy and loss of central vision prevalently in young men. The current study investigated the reasons for the higher prevalence of Leber hereditary optic neuropathy in men, exploring the potential compensatory effects of estrogens on mutant cell metabolism. Control and Leber hereditary optic neuropathy osteosarcoma-derived cybrids (11778/ND4, 3460/ND1, and 14484/ND6) were grown in glucose or glucose-free galactose-supplemented medium. After having shown the nuclear and mitochondrial localization of estrogen receptors in cybrids, experiments were carried out by adding 100 nM of 17b-estradiol. In a set of experiments, cells were preincubated with the estrogen receptor antagonist ICI 182780. Leber hereditary optic neuropathy cybrids in galactose medium presented overproduction of reactive oxygen species, which led to decrease in mitochondrial membrane potential, increased apoptotic rate, loss of cell viability, and hyperfragmented mitochondrial mor-phology compared with control cybrids. Treatment with 17b-estradiol significantly rescued these pathological features and led to the activation of the antioxidant enzyme superoxide dismutase 2. In addition, 17b-estradiol induced a general activation of mitochondrial biogenesis and a small, although significant, improve-ment in energetic competence. All these effects were estrogen receptor mediated. Finally, we showed that the estrogen receptor b localizes to the mitochondrial net-work of human retinal ganglion cells. Our results strongly support a metabolic basis for the unexplained male prevalence in Leber hereditary optic neuropathy and hold promises for a therapeutic use for estrogen-like molecules. LHON has been a baffling illness from many aspects, mainly the explanation of the sudden and sequential onset and the predominant male prevalence. Prior reports have suggested that there may be an X-linked modifying gene that may play a role in the gender prevalence (1). The current study provides evidence for a completely different mechanism for the gender difference, namely, metabolic protection by estrogen. The study demonstrates the presence of estrogen-beta receptors on mitochondria in retinal ganglion cells. In this study, osteosarcoma-derived cybrids were used. A cybrid is a hybrid cell that combines the nuclear genome from one source with the mitochondrial genome from another source, allowing a dissociation of the contribution of the 2 sources of DNA. Cybrids bearing the LHON mutation showed over-production of reactive oxygen species, which led to de-creased mitochondrial membrane potential, increased apoptotic rate, loss of cell viability and hyperfragmented mitochondrial morphology. Treatment with 17b estradiol diminished these pathologic features and led to activation of superoxide dismutase 2, an antioxidant enzyme, as well as induced activation of mitochondrial biogenesis and a small improvement in energetic competence. Pretreatment with an estrogen receptor antagonist abolished the beneficial effects of the estradiol. This is an exciting line of research, which may explain a mysterious difference in sexual prevalence of LHON, but more importantly may give rise to a different treatment strategy, hormonal treatments that may preserve vision in LHON patients at risk. -Mark L. Moster, MD This is a very cool study that sets the groundwork for looking at estrogen-like molecules to improve visual prognosis in patients with LHON. The questions that arise include 190 Moster and Lee: J Neuro-Ophthalmol 2011; 31: 187-191 Literature Commentary Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. which estrogens to use, when and how long to try the estrogen, how to give it, and what kinds of side effects may occur? -Michael S. Lee, MD Denuelle M, Boulloche N, Payoux P, Fabre N, Trotter Y, Geraud G. A PET study of photophobia during spontaneous migraine attacks. Neurology. 2011;76:213-218. Background: Photophobia is an abnormal sensitivity to light experienced by migraineurs during attacks. The pathophysiology of photophobia is poorly understood. Nevertheless, 2 facts appear to have a link with photo-phobia: visual cortex hyperexcitability on the one hand and interactions between visual pathway and trigeminal nociception on the other. Methods: We used H(2)(15)O PET to study photophobia induced by continuous luminous stimulation covering the whole visual field in 8 migraineurs during spontaneous migraine attacks, after headache relief by sumatriptan, and during attack-free interval. The intensity of the lu-minous stimulation provoking photophobia with sub-sequent headache enhancement was specifically determined for each patient. Results: We found that low luminous stimulation (median of 240 Cd/m2) activated the visual cortex during migraine attacks and after headache relief but not during the attack-free interval. The visual cortex activation was statistically stronger during migraine headache than after pain relief. Conclusion: These findings suggest that ictal photopho-bia is linked with a visual cortex hyperexcitability. The mechanism of this cortical hyperexcitability could not be explained only by trigeminal nociception because it per-sisted after headache relief. We hypothesize that modu-lation of cortical excitability during migraine attack could be under brainstem nuclei control. This study used 15O PET to study the response of the occipital cortex to a light stimulus and showed an increase in blood flow during an attack of migraine without aura. After finding the light intensity required to induce an increase in pain, they used the same intensity to measure blood flow. The findings included that there was an increase in CBF during the migraine as well a continued but lesser increase in CBF after relief of headache with sumatriptan. This increase occurred even though there was no photophobia or pain after sumatriptan treatment. The authors deduce that although pain may stimulate the increase in CBF, it cannot be the only cause, since it occurs when the patient became pain free. They also speculate that the findings reflect abnormal brainstem modulation of cortical excitability. However, this is only one plausible explanation. As the accompanying editorial by Brennan (1) suggests, this study confirms that migraine without aura is a cortical disease not just a brainstem disease. He suggests that pro-phylaxis is more important than mere pain relief since migraine ‘‘is so much more than pain.'' Demonstration of cortical excitability in these patients may help in future treatments in migraine. It would be reasonable to study cortical responses to light stimuli in our other populations with photophobia, including those who seem to have nonorganic disease. We may be surprised to find some organic changes in the occipital cortex in these patients. -Mark L. Moster, MD I don't know that this study promotes greater interest in prophylaxis. The authors waited only 10 minutes after pain subsided before performing the PET scan again. Who knows? It may be that the increased CBF is only present for 15-20 minutes after migraine pain resolves. Additionally, I am not aware that the postictal increase in CBF in the occipital lobes is harmful and warrants greater motivation to treat prophylactically. The brainstem modulation consideration is based on previous work. These same authors (2) published a similar study in which they studied 7 patients with a history of migraine and 7 healthy nonheadache controls. The controls showed no increased in CBF to light stimulation, but if given a painful stimulus in V1 (increased the temperature of a probe until it hurt), then the CBF increased in the primary and secondary visual cortex. The response was exaggerated in migraineurs. This suggests that pain in V1 somehow activates the visual cortex, but it may not be unique to migraine patients. -Michael S. Lee, MD REFERENCES 1. Brennan KC. Turn down the lights! An irritable occipital cortex in migraine without aura. Neurology. 2011;76: 206-207. 2. Boulloche N, Denuelle M, Payoux P, Fabre N, Trotter Y, Geraud G. Photophobia in migraine: an interictal PET study of cortical hyperexcitability and its modulation by pain. J Neurol Neurosurg Psychiatry. 2010;81:978-984. Moster and Lee: J Neuro-Ophthalmol 2011; 31: 187-191 191 Literature Commentary Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. |
