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HISTORICAL NEUROLOGY: How did stroke become of interest to neurologists?: A slow 19th century saga
HISTORICAL NEUROLOGY: How did stroke become of interest to neurologists?: A slow 19th century saga
Paciaroni and Bogousslavsky (1 September 2009)
[Abstract][Full text][PDF]
How did stroke become of interest to neurologists?: A slow 19th century saga How did stroke become of interest to neurologists?: A slow 19th century saga
20 November 2009
Helio A. Teive, Federal University of Parana Rua General Carneiro 1103/102, Curitiba, PR 80060-150 Brazil, Renato P. Munhoz
Drs. Paciaroni and Bogousslavsky present an excellent historical review of the growing interest of stroke among neurologists sparked by the development of clinical-topographical correlation studies. These early studies were conducted by Dejérine, Marie, and particularly Foix. [1]
The authors stated that stroke was never a field of critical interest in the Salpêtrière and Pitié Schools when Vulpian and Charcot were the leading figures. However, one of Charcot`s major interests in this area was brain hemorrhage, particularly describing the well known aneurysms of Charcot-Bouchard. [2]
In addition, three of Charcot's pupils studied stroke including Henri Duret who performed the first modern anatomical studies of the cerebral arteries. [3] The study of lacunes was one of the most important contributions of Pierre Marie to the field of neurology. [4] Charles Foix, a pupil of Marie, also developed seminal works on brain infarction. [5]
Even though stroke was not the main interest of Charcot´s group, their contributions in this area were relevant.
References
1. Paciaroni M, Bogousslavsky J. How did stroke become of interest to neurologists? A slow 19th century saga. Neurology 2009;73:724-728.
2. 2. Charcot JM, Bouchard C. Nouvelles recherchers sur la pathogenie de l´hémorragie cerébrale. Arch Physiol Norm Pathol 1868;1:110-127,643-665,725-734.
3.Duret H. Recherches anatomiques sur la circulation de l´encéphale. Arch Physiol Norm Pathol 1874;1:60-91,316-353,664-693,919-957.
4. Marie P. Des foyers lacunaires de désintégration et de différents autres états cavitaries du cerveau. Rev Med 1901;31:281-298.
Disclosures: Dr. Teive is a member of editorial board of the Arquivos de Neuropsiquiatria (Brazilian Journal of Neurology and Psychiatry) and Parkinsonism and Related Disorders Journals. Dr. Munhoz reports no disclosures.
How did stroke become of interest to neurologists?: A slow 19th century saga Reply from the authors
20 November 2009
Maurizio Paciaroni, University of Perugia Stroke Unit, Santa Maria della Misercordia Hospital, University of Perugia, Perugia, Italy, Julien Bogousslavsky
mpaciaroni{at}med.unipg.it Maurizio Paciaroni, et al.
We thanks Drs. Teive and Munhoz for their interest in our article. [1] We agree that Charcot and his pupils contributed to relevant studies of stroke and we are addressing this topic. [5] Charcot and his group presented several works dealing with cerebrovascular disease, including histological studies of brain “softening”, paraneoplastic infarction, and consequences of stroke including arthropathies, vegetative changes, contractures, and abnormal movements.
Brain localization, one of Charcot’s major neurological topics, was also largely based on stroke case studies. Charcot’s work on stroke is poorly recognized because his interest focused on other fields such as hysteria and hypnotism.
Furthermore, after the mid-1860s, Charcot and his immediate followers no longer made significant contributions to stroke. This was particularly striking during the last decade of Charcot’s life (1883-1893), since the topic of stroke is not represented within the scientific literature of his group.
Reference
5. Bogousslavsky J, Paciaroni M. Did Jean-Martin Charcot contribute to stroke? Cerebrovasc Dis (In press).
Disclosure: Dr. Paciaroni has served on the speakers' bureaus of Sanofi Aventis and Boehringer Ingelheim. Dr. Bogousslavsky serves as an editorial board member of Clinical Neurology and Neurosurgery, International Journal of Neural System, BMC Neuroscience, as chief editor of European Neurology, Frontier in Neurology and Neuroscience, and as guest editor of Cerebrovascular Diseases.
CLINICAL/SCIENTIFIC NOTES: SEVERE CARDIAC FAILURE IN A PATIENT WITH MULTIPLE SCLEROSIS FOLLOWING LOW-DOSE MITOXANTRONE TREATMENT
Dörr et al. (22 September 2009)
[Full text][PDF]
SEVERE CARDIAC FAILURE IN A PATIENT WITH MULTIPLE SCLEROSIS FOLLOWING LOW-DOSE MITOXANTRONE... SEVERE CARDIAC FAILURE IN A PATIENT WITH MS FOLLOWING LOW-DOSE MITOXANTRONE TREATMENT
20 November 2009
Joep Killestein, VU Medical Center, Dept of Neurology PO Box 7057, 1007MB Amsterdam, The Netherlands, Marieke L. van der Meer, Josien C. Regelink, Peter C. Huijgens, Chris H. Polman
Mitoxantrone (MiTX) reduces relapse frequency and MRI evidence of disease activity in relapsing-remitting MS (RRMS). MiTX is a toxic agent that must be carefully administered to reduce the likelihood of bone marrow suppression, opportunistic infection, leukemia, and cardiomyopathy. The risk of cardiomyopathy is generally assumed to be dose dependent. Dörr et al. suggest that toxic cardiomyopathy may occur after a relatively low dose (i.e., two infusions) given very early after treatment is initiated. [1] This challenges the assumption that MiTX given below a certain cumulative dose can be considered safe regarding the risk of heart failure.
We present a case of severe heart failure that occurred 26 months after the final (sixth) infusion of MiTX in a 48-year-old woman with RRMS. The total cumulative dose had only been 72 mg/m2 (12 mg/m2 body surface area per infusion at three months intervals). The patient had baseline and follow-up echocardiograms that were all normal (left ventricular ejection fraction [LVEF] 58% at baseline, 59% after the second [month 6] and 60% after the fourth infusion [month 12 after the start of treatment]). She did not have additional echocardiograms as no further infusions were scheduled after the eighteenth month. More than two years after her last MiTX infusion, she visited a cardiologist because of progressive fatigue and edema in both legs. A severe dilated cardiomyopathy was diagnosed (LVEF 20%).
This is an unusual report of severe delayed heart failure following a low cumulative dose of mitoxantrone in MS. Cases of severe delayed cardiac failure were described after cumulative doses of at least 144 mg/m2. [2] Our findings support the FDA safety notices of July 2008, [3] which recommend that all MS patients receiving MiTX should undergo reevaluation of LVEF before receipt of each dose of MiTX. In addition, patients should receive a yearly quantitative LVEF evaluation after stopping MiTX to monitor late-occurring cardiotoxicity.
References
1. Dörr J, Bitsch A, Schmailzl KJ, et al. Severe cardiac failure in a patient with multiple sclerosis following low-dose mitoxantrone treatment. Neurology 2009;73:991-993.
2. Goffette S, van Pesch V, Vanoverschelde JL, Morandini E, Sindic CJ. Severe delayed heart failure in three multiple sclerosis patients previously treated with mitoxantrone. J Neurol 2005;252:1217-1222.
3. FDA MedWatch Safety Alert. Mitoxantrone Hydrochloride (marketed as Novantrone and generics). July 29, 2008. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm092708.htm. Accessed October 15, 2009.
Disclosure: Dr Killestein received research support from Teva, Genzyme, Novartis, Merck Serono, Biogen Idec and Bayer Schering and has received research support paid to his institution. Dr van der Meer, Dr Regelink and Prof Huijgens report no disclosures. Dr. Polman has served on advisory or data monitoring committees of Actelion, Biogen Idec, Bayer Schering, Teva, Merck-Serono, Novartis, GlaxoSmithKline, UCB, Roche and Antisense Therapeutics; has received speaker honoraria from Biogen Idec, Schering AG, Novartis, and Teva; receives research support from Biogen Idec, Bayer Schering, GlaxoSmithKline, Novartis, UCB, Merck-Serono, Teva, the European Community [NABINMS contract 018926 (PI)], and the Dutch Multiple Sclerosis Society [02/358b (PI), 05/358c (PI)]; and serves as an editorial board member of Lancet Neurology and Multiple Sclerosis.
SEVERE CARDIAC FAILURE IN A PATIENT WITH MULTIPLE SCLEROSIS FOLLOWING LOW-DOSE MITOXANTRONE... Reply from the author
20 November 2009
Jan Dörr, NeuroCure Clinical Research Center, Charite Universitätsmedizin Berlin Chariteplatz 1, 10117 Berlin, Germany
Killestein et al. report another case of severe cardiac failure in a patient with MS after the relatively low mitoxantrone dose of 72 mg/m2. The fact that the delayed type cardiac failure in this patient occurred more than two years after termination of low-dose mitoxantrone treatment is uncommon for mitoxantrone-mediated cardiotoxicity. Because mitoxantrone is still an important therapeutic option in severe and progressive MS courses, alternative causes of cardiac failure should be sufficiently excluded before mitoxantrone is considered as an underlying cause. This report further challenges the assumption that a safe cumulative mitoxantrone dose exists. In addition, it underscores the importance of regular cardiologic follow-up examinations in mitoxantrone-treated patients and the need for reliable markers for patients at risk. [4]
Reference
4. Cotte S, von Ahsen N, Kruse N, et al. ABC-transporter gene-polymorphisms are potential pharmacogenetic markers for mitoxantrone response in multiple sclerosis. Brain 2009;132:2517-2530.
Disclosure: The author reports no disclosures.
ARTICLES: Randomized, controlled trial of telcagepant for the acute treatment of migraine
Connor et al. (22 September 2009)
[Abstract][Full text][PDF]
Randomized, controlled trial of telcagepant for the acute treatment of migraine Randomized, controlled trial of telcagepant for the acute treatment of migraine
20 November 2009
Rachel Nardin, Cambridge Health Alliance 1493 Cambridge St. Macht 420, Cambridge MA 02139
Connor et al. report that the use of 150 mg of telcagepant results in pain relief at 2 hours in 54% of migraine patients compared to 33% of patients achieving this endpoint with placebo. [1] This industry-sponsored trial written by industry employees raises serious concerns.
Triptans are the standard care for moderate to severe migraine. Sumatriptan 50 mg, now available as a generic, results in pain relief at 2 hours in 50% to 59% of migraine patients compared to 17% to 26% for placebo. [2] The relevant question for patients and physicians is whether telcagepant offers any advantage over sumatriptan.
The authors justify comparing telcagepant to placebo—rather than to active treatment— because it may be used in patients with coronary artery or cerebrovascular disease, in whom triptans are contraindicated. However, if this is the population of interest for telcagepant, it should be tested in this population.
There is sufficient preliminary data supporting the superiority of telcagepant to placebo. A placebo-controlled trial in the population of patients eligible for triptan treatment before a trial in the clinically relevant population of migraineurs with coronary artery and cerebrovascular disease was not needed.[3]
The objective of this trial appears to be to bolster FDA drug approval and marketing efforts.
References
1. Connor KM, Shapiro RE, Diener H-C et al. Randomized, controlled trial of telcagepant for the acute treatment of migraine. Neurology 2009;73:970-977.
3. Tepper SJ, Cleves C. Telcagepant, a calcitonin gene-related peptide antagonist for the treatment of migraine. Curr Opin Investig Drugs 2009;10:711-720.
Disclosure: Dr. Nardin serves on the editorial board of Muscle & Nerve; has received honoraria from academic institutions for giving grand rounds; and receives royalties from UpToDate.
Randomized, controlled trial of telcagepant for the acute treatment of migraine Reply from the authors
20 November 2009
Tony W. Ho, Merck Research Laboratories UG 4C-18, PO Box 1000, North Wales, PA 19454-1099, Kathryn M. Connor, Robert E. Shapiro, Hans-Christoph Diener, Sylvia Lucas, James Kost, Xiaoyin Fan, Kaiyin Fei, Christopher Assaid, Christopher Lines
Dr. Nardin questions the value of our second pivotal trial of telcagepant [1], stating that there were already sufficient data to support the superiority of telcagepant to placebo.
The regulatory approval process for new migraine medicines is rigorous and requires substantial evidence of efficacy and safety. This is usually achieved through conducting two well-controlled pivotal trials. At an alpha=0.05 level, there is a 1 in 20 risk of a false positive efficacy result within one trial. With two independent pivotal studies, the probability of a false positive in both studies is 1 in 400. Dr. Nardin states that “The publication of this trial raises serious concerns.” On the contrary, it would be a serious cause for concern if we had failed to publish it. In addition, the data was considered of high enough priority to publish.
Dr. Nardin mentions a possible study of patients with coronary artery or cerebrovascular disease. This study has recently been completed [4] and the results will be published. In addition to benefiting cardiovascular disease patients, CGRP receptor antagonists may benefit those intolerant of or poorly responsive to existing treatments due to the antagonists’ alternative mechanism.
Recent data suggest that only 19% of migraineurs use triptans over a one-year period. [5] This figure is low considering that 17% use opioid or barbiturate drugs, [5] which can result in migraine chronification [6] and may be associated with abuse/dependence concerns. These observations confirm that there are unmet treatment needs. CGRP receptor antagonists represent another choice for migraine sufferers.
Dr. Nardin also questions the sponsorship and authorship of our study. Novel medicines are developed by pharmaceutical companies in collaboration with academic experts and clinical investigators. Optimally, the process of developing pharmaceuticals that meet important medical needs should be guided by the clinical experiences of health care providers to help clarify those needs on behalf of patients.
Reasonable compensation of physicians for their efforts and expertise in drug development is appropriate as long as disclosure is transparent as was the case for our paper. We believe that a collaborative approach to developing new medicines serves the interests of patients.
References
4. Treatment of Migraine in Patients With Stable Vascular Disease. NCT00662818. Available at: http://www.clinicaltrials.gov/. Access October 18, 2009.
5. Bigal ME, Borucho S, Serrano D, Lipton RB. The acute treatment of episodic and chronic migraine in the USA. Cephalalgia 2009;29:891-897.
6. Bigal ME, Lipton RB. Excessive acute migraine medication use and migraine progression. Neurology 2008;71:1821-1828.
Disclosures: Drs. Connor, Kost, Fan, Fei, Assaid, Lines, and Ho are employees of, and own stock and/or stock options in, Merck & Co., Inc. Dr. Shapiro serves or has served on scientific advisory boards for, and received honoraria and funding for travel from Merck & Co, Inc., MAP Pharmaceuticals, and NuPathe; and has received research support from Merck & Co, Inc. and the NIH [NHLBI #R01HL71944 (Co-Investigator)]. Dr. Diener has received honoraria for participation in clinical trials, contribution to advisory boards or lectures from Addex Pharma, Allergan, Almirall, AstraZeneca, Bayer Vital, Berlin Chemie, Coherex Medical, CoLucid, Böhringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Grünenthal, Janssen-Cilag, Lilly, La Roche, 3M Medica , Minster, MSD, Novartis, Johnson & Johnson, Pierre Fabre, Pfizer, Schaper and Brümmer, SanofiAventis, and Weber & Weber; has received research support from Allergan, Almirall, AstraZeneca, Bayer, GSK, Janssen-Cilag, and Pfizer. Headache research at the Department of Neurology in Essen is supported by the German Research Council (DFG), the German Ministry of Education and Research (BMBF), and the European Union. Dr. Lucas has served on scientific advisory boards for GlaxoSmithKline, Merck & Co. Inc., and Bayer (formerly Berlex); has received honoraria from Allergan, GlaxoSmithKline, Merck & Co. Inc., EMD Serono, Biogen Idec, Pfizer, Endo, OMP, Teva Neuroscience, the National Multiple Sclerosis Society, and Headache Cooperative of the Pacific; has served on the speaker's bureaus of GlaxoSmithKline, Merck & Co. Inc., EMD Serono, Biogen Idec, and Pfizer; has received research support from GlaxoSmithKline, Merck & Co. Inc., Allergan, Nupathe, MAP, Biogen Idec, Sanofi-Aventis, and AGA.
ARTICLES: Embolic stroke associated with injection of buprenorphine tablets
Lim et al. (15 September 2009)
[Abstract][Full text][PDF]
Embolic stroke associated with injection of buprenorphine tablets Embolic stroke associated with injection of buprenorphine tablets
10 November 2009
E. Douglas Kramer, Kensington Pharmaceuticals, LLC 71 Kensington Rd, Stamford, CT 06905, Nabarun Dasgupta, MPH (University of North Carolina at Chapel Hill)
The recent report by Lim et al. describes patients with neurologic complications after injecting buprenorphine tablets. [1] However, as these authors note, "neurologic sequelae of buprenorphine injection have not been previously well established in the literature." We agree.
The information presented does not support the conclusion that the complications observed are specifically attributable to injection of Subutex®. Embolic complications are associated with the injection use of pharmaceutical tablets containing insoluble excipients such as talc or microcrystalline cellulose. Intra-arterial injection of microcrystalline cellulose, an excipient found in many oral formulations of benzodiazepines,[2] has been associated with gangrene. [3] Since neither Subutex nor Suboxone® contains talc or microcrystalline cellulose,[4] we believe that the cases reported by Lim et al. are likely due to the reported concurrent injection of oral benzodiazepine formulations by these patients, rather than attributable to Subutex alone.
This distinction has important policy and clinical implications. It has been shown that Buprenorphine is regularly injected by drug users, including those in maintenance pharmacotherapy. The reason that Subutex and Suboxone are suitable for office-based treatment of opioid dependence is because they do not contain excipients that are harmful to injection drug users, such as microcrystalline cellulose or talc. Regrettably, generic Subutex in the UK contains talc, and if the same formulation is approved in the US in October, use of generic Subutex may incur additional risk to patients. [5]
References
1. Lim CC, Lee SH, Wong YC, Hui F. Embolic stroke associated with injection of buprenorphine tablets. Neurology. 2009 Sep 15;73:876-879.
2. Available at http://dailymed.nlm.nih.gov/dailymed/about.cfm. Accessed September 21, 2009.
3. Goldberg I, Bahar A, Yosipovitch Z. Gangrene of the upper extremity following intra-arterial injection of drugs. A case report and review of the literature. Clin Orthop Relat Res 1984;188:223-229.
4. Available at http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=7840. Accessed September 21, 2009.
5. Public Assessment Report: Decentralised Procedure. Available at http://www.mhra.gov.uk/home/groups/pl-a/documents/websiteresources/con018234.pdf. Accessed September 21, 2009.
Disclosures
Dr. Kramer has served as an independent consultant for the pharmaceutical industry; and was employed by Schering Plough. Mr. Dasgupta has consulted for King, Neuromed, Pain Therapeutics, Schering-Plough; serves on risk management advisory board for Cephalon; serves as a consultant for the RADARS System (Rocky Mountain Poison & Drug Center, Denver Health); and serves as a consultant for Pinney Associates and Analgesic Research.
Embolic stroke associated with injection of buprenorphine tablets Reply from the authors
10 November 2009
CC Lim, Department of Neuroradiology, National Neuroscience Institute, 11 Jalan Tan Tock Tock Seng, Singapore 308433, Lee SH, Wong YC, Hui F.
We thank Dr. Kramer and Mr. Dasgupta for their comments related to buprenorphine tablet injection. We described seven cases of injectors who were admitted to the hospital with neurological complications. This group was a part of a wider sample of drug addicts who crushed, dissolved, and injected Subutex® tablets. [6]
Some users suffered ischemic limb and local injection complications. [7, 8] We found, despite the lack of data on the constituents of injected tablets [9], that "...blood toxicology showed a combination of buprenorphine and either midazolam or diazepam." [1] Although a discussion about the causative particles responsible for presumptive embolization was outside the scope of our report, we stated that "the possibility of other tablets such as midazolam or even inadvertent injection of gas bubbles as a cause of embolic cerebral infarction cannot be excluded."
With new information on the excipients used in the manufacturing of buprenorphine and benzodiazepine tablets, we hope to continue our investigation into the medical and social implications of this phenomenon. A multidisciplinary and collaborative effort would benefit this investigation. Neurologists and radiologists should be aware of the characteristic MRI findings of carotid artery embolic infarction, especially in drug injectors with needle marks on the neck.
References
6. Lee CE. Tackling Subutex abuse in Singapore. Singapore Med J 2006;47:919–921.
7. Loo HW, Yam AK, Tan TC, Peng YP, Teoh LC. Severe upper limb complications from parenteral abuse of Subutex. Ann Acad Med Singapore 2005;34:575–578.
8. Lo HY, Leong CS. Surgical complications in parenteral Subutex abusers. Singapore Med J 2006;47:924-927.
9. Rautio R, Keski-Nisula L. Inadvertent intra-arterial drug injections: the role of angiographic and clinical findings. Acta Radiol 2006;47:554-558.
Disclosures: Dr. Lim serves on the Editorial Advisory Board of the Singapore Medical Journal; received research support from the National Medical Research Council, Biomedical Research Council, and Singapore Radiological Society Trust Fund; and holds US Patent 7047235 (awarded 2006) and US Patent Application 20070118550 (filed 2004). Dr. Lee, Dr. Wong, and Dr. Hui report no disclosures.
RESIDENT AND FELLOW SECTION: Clinical Reasoning:: A 22-year-old woman with headache and diplopia
Kim (7 July 2009)
[Full text][PDF]
Clinical Reasoning:: A 22-year-old woman with headache and diplopia Clinical Reasoning:: A 22-year-old woman with headache and diplopia
10 November 2009
Timothy J. Counihan, National University of Ireland, Galway Galway, Ireland, Jennifer Dineen
timothy.counihan{at}hse.ie Timothy J. Counihan, et al.
Dr. Kim presents a case of a woman with sudden-onset headache and diplopia following a neck massage who is ultimately diagnosed with idiopathic intracranial hypertension (IIH). [1] The case is presented as an exercise in clinical reasoning.
Although the final diagnosis is incontrovertible, the discussant fails to demonstrate appropriate clinical reasoning in arriving at the diagnosis. Dr. Kim states that in a young obese patient with sudden severe headache and diplopia without other focal neurologic signs, IIH "should be the top differential." We believe that clinical reasoning should direct the clinician to first exclude vertebral artery dissection (headache and focal neurologic signs after neck manipulation) and perhaps cerebral aneurysm (sudden-onset severe headache and diplopia). IIH should only be considered when further clinical information becomes available such as the presence of papilledema, normal imaging, and raised CSF pressure.
Attributing acute severe headache to IIH is questionable. [2] More importantly, clinical reasoning is context-dependent and hypothesis-driven. [3] The working diagnosis in Dr. Kim's case should have been to exclude vertebral artery dissection given the clinical context. It is the right diagnosis but the reasoning is flawed.
References
1. Kim, JS. Clinical Reasoning: A 22-year-old woman with heasdache and diplopia. Neurology 2009;73:e1-7. Accessed online July 27, 2009.
2. Wall M. The headache profile of idiopathic intracranial hypertension. Cephalalgia 1990;10:331-335.
3. Kassirer JP and Kopelman RI. Learning Clinical Reasoning. Baltimore: Williams and Wilkins; 1991.
Disclosure: The authors report no disclosures.
Clinical Reasoning:: A 22-year-old woman with headache and diplopia Reply from the author
10 November 2009
Ji S. Kim, Department of Neurology, Seoul National University College of Medicine 300 Gumi-dong, Bundang-gu, Seongnam-si, Gyeonggi-do, 427-090, Korea
I thank Drs. Counihan and Dineen for their interest in my article. [1] Given the history of neck massage and sudden severe headache with a focal neurological deficit, they contend that vertebral artery dissection and cerebral aneurysm should be initially considered in the differential diagnosis.
Drs. Counihan and Dineen correctly note that clinical reasoning should be context-dependent and hypothesis-driven, but they did not consider all the information required for clinical reasoning in my patient. My patient had isolated horizontal diplopia one week after the neck massage. Even though vertebral artery dissection may be possible in a patient with headache and focal neurologic signs after neck massage, isolated horizontal diplopia as a focal neuralgic deficit should be an exception in vertebral artery dissection. [4] Vertebral artery dissection often causes dizziness and focal neurological signs from the lateral medulla. [4] It would also be unusual that horizontal diplopia would develop one week after the aneurysmal rupture without headache in an otherwise healthy young woman.
As Drs. Counihan and Dineen indicated, sudden severe headache after neck massage is unusual in IIH. [2] I included vertebral artery dissection and aneurysmal rupture in the differential diagnosis of the patient. [1] I believe that IIH should be the top differential in this young obese woman with symptoms and signs of increased intracranial pressure without other focal neurological deficits, irrespective of suddenness or severity of the headache. Furthermore, since IIH is a diagnosis of exclusion, there is little risk. Although medical adage is useful and informative, it should be interpreted with caution in individual patients.
Disclosure: Dr. Kim serves as an Associate Editor of the Journal of Korean Neurological Association; serves as an editorial board member of the Journal of Korean Society for Clinical Neurophysiology; receives funding from the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (A080750); and received institutional support from Seoul National University Bundang Hospital.
ARTICLES: Optical coherence tomography is less sensitive than visual evoked potentials in optic neuritis
Naismith et al. (7 July 2009)
[Abstract][Full text][PDF]
Optical coherence tomography is less sensitive than visual evoked potentials in... Optical coherence tomography is less sensitive than visual evoked potentials in optic neuritis
10 November 2009
Ari Green, UCSF 350 Parnassus Ave Suite 908, San Francisco, CA 94117, Pablo Villoslada, MD
We read the article by Naismith et al. with great interest. [1] The authors sought to determine the utility of optical coherence tomography (OCT) for confirming anterior visual pathway (AVP) injury after optic neuritis (ON). The other objective was to detect [2] subclinical ON compared to traditional full field pattern reversal visual evoked potential (ffVEP) as well as to [3] explore the relationship between OCT scores and established clinical variables including the Expanded Disability Status Score (EDSS) in patients with ON. There are several major issues undermining the authors’ conclusions.
It is unclear whether the authors evaluated sensitivity—in statistical terms—for any of the measures detecting subclinical ON. Their selection of a gold standard for subclinical ON was determined by an abnormality on any of the three measures taken. This may lead to the conclusion that the modality with the highest rate of an abnormal outcome is most “sensitive” regardless of whether this abnormality truly represented AVP.
The population they studied was heterogeneous. A finding of subclinical ON in over a third of their patients (idiopathic ON and NMO) would be atypical. [2,3] Furthermore, many of the MS patients were early in the course of their disease (average EDSS 3.0). A modality which detects subclinical ON in this setting could be identifying many false positives. This may imply that even if their conclusions regarding sensitivity were correct, ffVEP could be less specific than OCT.
The investigators chose to model OCT interpretation on ffVEP studies choosing a cut-point for defining normal or abnormal. In a cross-sectional evaluation, an abnormality on OCT would be better estimated by comparison with the fellow eye or by comparison with a population matched by sex and eye length/refractive error. The control population cited by the authors is a reference database of limited size with a broad distribution of ages, leading to a small number of subjects in the age range of the patients actually studied. Presumably, the range of normal for ffVEP was based on a locally defined control population. The same laboratory-specific evaluation of normality should have been undertaken with regard to OCT.
The authors’ decision to define all patients with subjectively poor vision and an unidentifiable waveform on ffVEP as abnormal—designated as a fixed latency delay of 170 ms—heavily biases their study in favor of greater “sensitivity” for ffVEP.
The authors included OCT studies with borderline signal to noise ratio and included patients with severe/profound visual loss using external fixation. Both of these decisions likely introduced unnecessary noise into their OCT estimates. Time-domain OCT is particularly susceptible to noise (and inaccuracy in measurement) with the eye movements anticipated with poor fixation. Again this approach is likely to bias results against OCT.
The lack of association between thickness of OCT measures and EDSS could be related to the cross-sectional design of their study, the heterogeneous population, and the small sample size. Longitudinal studies are more accurate for assessing the relationships between clinical variables. [4,5] Furthermore, the population heterogeneity weakens the power, especially because no relationship between EDSS and retinal nerve fiber layer (RNFL) scores may be evident in non-MS populations.
We do not see the tension between OCT and VEP implied by the design of this study. Instead, we consider these techniques as a complementary means for assessing injury to the AVP. Further investigations performed as these techniques evolve will provide more reliable methods for assessing, diagnosing, and following patients in MS clinics.
References
1. Naismith RT, Tutlam NT, Xu J, et al. Optical coherence tomography is less sensitive than visual evoked potentials in optic neuritis. Neurology 2009;73:46-52.
2. Wingerchuk DM, Pittock SJ, Lucchinetti CF, Lennon VA, Weinshenker BG. A secondary progressive clinical course is uncommon in neuromyelitis optica. Neurology 2007;68:603-605.
3. Green AJ, Cree BA. Distinctive retinal nerve fiber layer and vascular changes in neuromyelitis optica. J Neurol Neurosurg Psychiatry 2009;80:1002-1005.
4. Sepulcre J, Murie-Fernandez M, Salinas-Alaman A, Garcia-Layana A, Bejarano B, Villoslada P. Diagnostic accuracy of retinal abnormalities in predicting disease activity in MS. Neurology 2007;68:1488-1494.
5. Gordon-Lipkin E, Chodkowski B, Reich DS, et al. Retinal nerve fiber layer is associated with brain atrophy in multiple sclerosis. Neurology 2007;69:1603-1609.
Disclosure: Dr. Green received honararia from Novartis and Genentech for serving on scientific advisory boards and from Google, Inc and ProCE for educational programs; received consulting fees from Itero Pharmaceuticals and compensation for participation on an end-point adjudication committee from Biogen via Applied Clinical Intelligence. Dr. Villoslada served on the scientific advisory board of Roche, Novartis, Allergan, Digna Biotech and Neurotech-Pharma; receives funding from Instituto Salud Carlos III, Spain grants PI060117, PSE-010000-2006-1, RD07/0060/0001, European Comission contracts 043241 and PITN-GA- 212877; received grant support from the Fundacion Mutua Madrileña grant FMM-2008-061; received funding for a trip from Merk-Serono; and received honoraria for speaking at workshops supported by Serono Foundation.
Optical coherence tomography is less sensitive than visual evoked potentials in... Reply from the Authors
10 November 2009
Robert T. Naismith, Department of Neurology, Washington University, Campus Box 8111, 660 S. Euclid Ave., St. Louis, MO 63110, Anne H. Cross
naismithr{at}neuro.wustl.edu Robert T. Naismith, et al.
We thank Drs. Green and Villoslada for the opportunity to further clarify our findings. [1] Our objective was to determine whether OCT could be used in clinical practice to definitively confirm remote ON and detect subclinical ON. Our hypothesis was that OCT would be a valuable tool, but this was disproved due to large RNFL variability among normal subjects (1 SD was >10% of the mean).
Our results confirm prior population-based MS studies that demonstrate the RNFL after ON in MS typically falls between 1-2 SD of the population norm. [6] VEP is particularly well-suited for detecting remote ON because of its low variability among controls (1 SD is <5% of the mean). Perhaps one reason the VEP performed better is the high biologic variability of the nerve structure but low biologic variability of the physiologic conduction delay.
We would like to emphasize that while VEP demonstrates superior sensitivity for detecting past ON (i.e., threshold of injury), we did not suggest that VEP was superior to OCT in discriminating clinical visual outcomes (i.e., acuity or contract sensitivity).
Defining a gold standard for subclinical ON is inherently problematic without pathologic tissue diagnosis. However, it is necessary to detect subclinical ON to aid in establishing dissemination in space. We sought to determine whether OCT produced similar results to the current ‘gold-standard’ of VEP for detection of subclinical ON. Since the threshold of abnormal VEP was stringently defined at 3 SD longer than for the normal population, we would expect <1% to be false positives for a Gaussian distribution. OCT was unable to match the performance of VEP as a test, and yielded very few additional cases which VEP missed. Therefore, we suggest that if clinicians wish to detect subclinical ON in someone with good vision they should start with VEP.
We regard the heterogeneous population of reasonable size as a strength of our study because this type of population helps to generalize the findings into clinical practice. The inclusion of subjects with poor visual outcome helped to increase the sensitivity of OCT, as RNFL in affected eyes was frequently within the 2 SD reference range when vision was better than 20/30 (OCT sensitivity 35%).
The Zeiss RNFL normative dataset was based on 328 subjects from 5 centers, with age and gender appropriately represented between 18-85 years of age. These healthy individuals underwent a full ophthalmologic exam including slit-lamp, intra-ocular pressure, a dilated fundus exam, Humphrey fields, and optic disc photographs. The standard error of the mean is very narrow at 100.1 µm ± 1.2. This dataset is considered the standard reference for interpreting OCT in clinical practice and glaucoma research studies.
In addition, we stratified by age and there were over 250 subjects within the age range of our study in the Zeiss normative dataset. It would be difficult for a single center to produce better normative data. If a center has superior reference values with a smaller deviation, then those may be used. However, the largest published collection of healthy control optic nerves (153 controls) within three academic MS centers found nearly identical means and SDs to the Zeiss dataset (103±12 at Johns Hopkins, 105±12 at U Penn, and 104±11 at UTSW).[7] For the purposes of our study, we chose to define abnormal as 2SD outside of the normative mean since utilizing this test for diagnosing MS requires a high degree of certainty and few false positives. If a patient has confirmed MS, and a clinician wishes to determine whether there is subclinical ON, then a value outside 1 SD may be suggestive of an abnormality.
Defining a maximum VEP P100 of 170 ms for subjects unable to fixate due to poor vision from a past clinical history of optic neuritis (100% of the subjects in this category had ON history) would not skew the sensitivity since these subjects had prolonged and abnormal waveforms. Within this group of subjects with VEP assigned as 170 ms, OCT performed quite well (91% sensitivity, range 35.5 – 87.6 microns). Removing this group from analysis would actually lower the overall sensitivity of OCT. A sensitivity analysis based upon OCT signal strength was not different, with OCT >=7 having a sensitivity in remote ON of 47% (VEP 70%), and a sensitivity of 73% (VEP 82%) in those with signal strength <7.
The relationship between EDSS and OCT was undertaken only in those subjects with MS. As we outlined in our Discussion, the lack of a relationship between OCT results and EDSS may be due to selection of a population with relatively severe optic neuritis. While we would not consider our study as the definitive study for delineating the relationship between OCT and overall disability, we do believe this analysis adds to the balance of the literature.
We agree that OCT is a valuable research tool, can be useful in certain individual patient situations, and may play a role in routine patient management. [8,9] Although VEP is very good at detecting ON, it correlates poorly with visual acuity, and would be difficult to interpret longitudinally. Additionally, OCT is an evolving technology, so perhaps the sensitivity will improve.
References
6. Fisher JB, Jacobs DA, Markowitz CE, et al. Relation of visual function to retinal nerve fiber layer thickness in multiple sclerosis. Ophthalmology 2006;113:324-332.
7. Cettomai D, Pulicken M, Gordon-Lipkin E, et al. Reproducibility of optical coherence tomography in multiple sclerosis. Arch Neurol 2008;65:1218-1222.
8. Naismith RT, Tutlam NT, Xu J, et al. Optical coherence tomography differs in neuromyelitis optica compared with multiple sclerosis. Neurology 2009;72:1077-1082.
9. Naismith RT, Xu J, Tutlam NT, et al. Disability in optic neuritis correlates with diffusion tensor-derived directional diffusivities. Neurology 2009;72:589-594.
Disclosures: Dr. Naismith is a participant in clinical trials for Fampridine SR by Acorda Therapeutics; has received consulting fees and speaking honoraria from Bayer Healthcare, Biogen Idec, Elan Pharmaceuticals, and Teva Neurosciences; and receives research support from the NIH and National Multiple Sclerosis Society. Dr. Cross has received research funding from the NIH, National Multiple Sclerosis Society USA, and Consortium of Multiple Sclerosis Centers; received funding from Acorda Therapeutics, Bayer Healthcare, BioMS, and Teva Neuroscience; and speaking honoraria and consulting fees from Bayer Healthcare, Biogen Idec, Genentech, Inc., Teva Neurosciences, Serono, and Pfizer.
