Letters COMMENT & RESPONSE

Multiple Sclerosis and Alcohol Misuse To the Editor I read with interest the article by Pakpoor and colleagues1 investigating the risk for hospital admission for multiple sclerosis (MS) after admission for alcohol misuse. While interesting, the study is far from proving a causal relationship of alcohol misuse on MS risk. As likely seen in another study by the same team,2 there is an issue of reverse causality that is not remedied by excluding admissions in the same year because MS risk factors likely act many years before the clinical onset of the disease.3 Furthermore, because MS has significant psychological impact, it is likely that alcohol misuse is a result of the impact of having MS.4 Therefore, the authors should test whether there is a risk for alcohol misuse admission in patients with MS. Furthermore, it is notable that the association is seen primarily in men, suggesting that the association is a result of having MS (as documented in the literature5) rather than reflecting confounding. Claudio Voci, BA Author Affiliation: University of Bologna, Bologna, Italy. Corresponding Author: Claudio Voci, BA, University of Bologna, Via Zamboni 33, 40126 Bologna, Italy ([email protected]). Conflict of Interest Disclosures: None reported. 1. Pakpoor J, Goldacre R, Disanto G, Giovannoni G, Goldacre MJ. Alcohol misuse disorders and multiple sclerosis risk. JAMA Neurol. 2014;71(9):1188-1189. 2. Pakpoor J, Goldacre R, Schmierer K, Giovannoni G, Goldacre MJ. Testicular hypofunction and multiple sclerosis risk: a record-linkage study. Ann Neurol. 2014;76(4):625-628. 3. Ascherio A. Environmental factors in multiple sclerosis. Expert Rev Neurother. 2013;13(12)(suppl):3-9. 4. Stenager EN, Jensen B, Stenager M, Stenager K, Stenager E. Suicide attempts in multiple sclerosis. Mult Scler. 2011;17(10):1265-1268. 5. Beier M, D’Orio V, Spat J, Shuman M, Foley FW. Alcohol and substance use in multiple sclerosis. J Neurol Sci. 2014;338(1-2):122-127.

rate ratios were 0.84 (95% CI, 0.42-1.50; P = .65), 0.98 (95% CI, 0.86-1.11; P = .82), and 0.88 (95% CI, 0.77-1.00; P = .06) for alcohol use, abuse, and dependence, respectively. Although not significant, low rates of alcohol misuse disorders in the later years after first MS diagnosis lead us to speculate that perhaps, after a diagnosis of MS, people with it become more health conscious. These findings—combined with our previous results that there was a significantly elevated risk for MS within 1 year of first admission for alcohol abuse only and a significantly elevated risk for MS following all alcohol misuse disorders with an interval of more than 1 year between first recorded admission with the alcohol misuse disorder and firstrecorded admission with MS—make us consider reverse causality to be unlikely to explain our findings. Of note, Dr Voci’s comment that reverse causality is likely seen in another study reported from this data set is not supported by the results of that study where, as we have previously reported, the positive association was similarly only significant in 1 direction.2 We hope our study of a positive association between alcohol misuse disorders and subsequent MS, in combination with the findings reported by Hedström et al,3 stimulates further work to confirm or refute our findings in striving to establish the currently largely uncharacterized role of alcohol in MS pathophysiology. Julia Pakpoor, BA Raph Goldacre, BA Michael J. Goldacre, FFPH, FRCP Author Affiliations: Oxford University Medical School, John Radcliffe Hospital, Oxford, England (Pakpoor); Unit of Health-Care Epidemiology, Nuffield Department of Population Health, University of Oxford, Oxford, England (R. Goldacre, M. J. Goldacre). Corresponding Author: Michael J. Goldacre, FFPH, FRCP, Unit of Health-Care Epidemiology, Nuffield Department of Population Health, University of Oxford, Old Road Campus, Oxford, Oxfordshire OX3 7LF, England (michael.goldacre @dph.ox.ac.uk). Conflict of Interest Disclosures: None reported.

In Reply We thank Dr Voci for his comments on our article1 reporting a positive association between alcohol misuse disorders and subsequent multiple sclerosis (MS), particularly in men. The possibility of reverse causality whereby alcohol misuse may be a consequence of as yet undiagnosed MS is a necessary consideration. Using the same method and reference cohort as in our original study, we analyzed the data set for the risk for alcohol misuse disorders following an admission for MS. Comparing the MS cohort with the control cohort, the rate ratios were 1.04 (95% CI, 0.59-1.69; P = .98), 1.13 (95% CI, 1.021.25; P = .02), and 1.01 (95% CI, 0.91-1.13; P = .82) for alcohol use, alcohol abuse, and alcohol dependence, respectively. In reducing the possibility of surveillance bias and reverse causality, including only cases of alcohol misuse disorders observed at least 1 year following the first admission for MS, the 238

1. Pakpoor J, Goldacre R, Disanto G, Giovannoni G, Goldacre MJ. Alcohol misuse disorders and multiple sclerosis risk. JAMA Neurol. 2014;71(9):1188-1189. 2. Pakpoor J, Goldacre R, Schmierer K, Giovannoni G, Goldacre MJ. Reply. Ann Neurol. 2014;76(5):765-766. 3. Hedström AK, Hillert J, Olsson T, Alfredsson L. Alcohol as a modifiable lifestyle factor affecting multiple sclerosis risk. JAMA Neurol. 2014;71(3): 300-305.

Autosomal Recessive Cerebellar Ataxia 3 Due to Homozygote c.132dupA Mutation Within the ANO10 Gene To the Editor With great interest we read the article by Renaud et al1 reporting a case series of 9 patients with autosomal recessive cerebellar ataxia type 3 due to ANO10 mutations. The authors discussed the previously reported c.132dupA mutation with a heterozygote carrier frequency of 1/184 and pos-

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tulated that the homozygote state of this mutation would either have a more severe phenotype or not be viable at all. We diagnosed a German patient as having autosomal recessive cerebellar ataxia type 3 with a homozygous c.132dupA mutation in ANO10 (consanguine family) from the University Hospital Bonn using next-generation sequencing. The mutation was validated by Sanger sequencing in the index and both parents were shown to be heterozygous carriers. The female patient experienced tension headache for several months starting at age 20 years and magnetic resonance imaging brain scan revealed prominent cerebellar atrophy. Slight symptoms of ataxia were only noticed afterwards by the patient. With hindsight, the patient mentioned previous clumsiness requiring the use of stair railing but motor milestones were normal. The patient had gait ataxia and rotational vertigo during fast head movements. The tension headache had improved after medication with amitriptyline. Neurological examination revealed cerebellar oculomotor signs, slight dysmetria, bradykinesia, and intention tremor of upper limbs. There was mild ataxia in tandem gait and stance (5 of 40 points in the Scale for the Assessment and Rating of Ataxia2). Tendon reflexes and plantar responses were normal. She presented slight distal atrophy of lower limbs but no fasciculation or paresis. No sensory disturbance was noted and the results of nerve conduction studies and somatosensory evoked potentials were normal. Follow-up at the age of 24 years revealed moderate disease progress with appearance of discrete cerebellar dysarthria (Scale for the Assessment and Rating of Ataxia score 8 of 40 points). The patient’s sister, aged 26 years, also sought medical advice because of occasional vertigo and tension headache but had no further symptoms. Magnetic resonance imaging brain scan revealed cerebellar atrophy but detailed further neurological examination was not requested. Thus, our patient (and most likely also the sister) demonstrates that homozygote c.132dupA mutations exist in patients with autosomal recessive cerebellar ataxia type 3 and do not necessarily lead to a particular severe clinical phenotype. Martina Minnerop, MD Peter Bauer, MD Author Affiliations: Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich GmbH, Jülich, Germany (Minnerop); Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany (Bauer). Corresponding Author: Martina Minnerop, MD, Institute of Neuroscience and Medicine (INM-1), Research Centre Juelich GmbH, D-52425 Jülich, Germany ([email protected]). Conflict of Interest Disclosures: None reported. Funding/Support: Dr Bauer received funding from the Integrated European Project on Omics Research of Rare Neuromuscular and Neurodegenerative Diseases funded by the European Union (grant 2012-305121) and the ANR/Erare JTC 2011 Euro-SCAR (2011-RARE-004-01); part of the genetic data analysis (assay validation) was performed within these projects. No other disclosures were reported. Role of the Funder/Sponsor: The funders had no role in the preparation, review, or approval of the manuscript, and the decision to submit the manuscript for publication Additional Information: The patient gave a signed statement of informed consent to publish (in print and online) the patient description. jamaneurology.com

1. Renaud M, Anheim M, Kamsteeg EJ, et al. Autosomal recessive cerebellar ataxia type 3 due to ANO10 mutations: delineation and genotype-phenotype correlation study. JAMA Neurol. 2014;71(10):1305-1310. 2. Schmitz-Hübsch T, du Montcel ST, Baliko L, et al. Scale for the Assessment and Rating of Ataxia: development of a new clinical scale [published correction appears in Neurology. 2006;67(2):299]. Neurology. 2006;66(11):1717-1720.

In Reply We identified the c.132dupA mutation of anoctamin 10 (ANO10), coding for an 8 transmembrane putative chloride channel, as being the most frequent mutation causing autosomal recessive cerebellar ataxia type 3 (ARCA3).1 In an attempt to explain why all of our 4 c.132dupA independent cases were compound heterozygous with another ANO10 mutation, rather than being homozygous (which is commonplace for rare recessive disorders), we speculated that c.132dupA homozygote carriers might present with a significantly more severe phenotype (which did not enter our screening criteria) or might not be viable at all. Our identification of a fifth family (M. Koenig and Erik-Jan Kamsteeg; unpublished observation; October 2014) and the publication of 2 additional families with a compound heterozygous c.132dupA mutation2 was consistent with this prediction. However, the discovery of a c.132dupA homozygous family with typical ARCA3 presentation by Minnerop and Bauer, together with the report of another c.132dupA homozygous family identified in an exome cohort of ataxic patients,3 demonstrate that this is not the case but confirm that c.132dupA (also variably named c.123_124insA,3 c.132_133insA, and c.132_133insT2) is definitively the most common ARCA3 mutation. What remains correct is the significantly different age at onset between patients homozygous for the truncating mutation c.1150_1151delTT (onset ranging from 6 to 15 years) and all the other patients, whether they have early truncating mutations (such as c.132dupA), in-frame deletions or splice site mutations, or missense mutations (onset ranging from 17 to 43 years, P < .01). The c.1150_1151delTT mutation may cause the expression of a truncated protein that functionally interferes with other anoctamin family members4 or may be associated with a second mutation in cis, possibly explaining the more severe phenotype of the patients harboring this homozygous mutation. Because c.132dupA heterozygote carriers have a predicted frequency of 1 in 184 among control individuals (Exome Variant Server; http://evs.gs.washington.edu /EVS), the fact that c.132dupA homozygous patients have typical ARCA3 presentation suggests that ARCA3 frequency might be higher than 1 in 135 000 (1/184 × 184 × 4), which would be at least as common as ataxia telangiectasia.5 However, the 1 in 184 frequency of c.132dupA heterozygote carriers might be overestimated because this is based on next-generation sequencing data that are prone to some artifacts, particularly when dealing with sequence of mononucleotide repeat tracts, which is the case of the c.132dupA mutation (the adenylate duplication occurs after a stretch of 9 adenylates). Further screening for patients with ARCA3 is warranted before a conclusion on ARCA3 frequency can be drawn. Michel Koenig, MD, PhD Christine Tranchant, MD Mathieu Anheim, MD, PhD (Reprinted) JAMA Neurology February 2015 Volume 72, Number 2

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Author Affiliations: Laboratoire de Génétique de Maladies Rares, Laboratoire de Génétique Moléculaire, Centre Hospitalo–Universitaire de Montpellier, Institut Universitaire de Recherche Clinique, Université de Montpellier, Montpellier, France (Koenig); Département de Neurologie, Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre, Strasbourg, France (Tranchant, Anheim). Corresponding Author: Michel Koenig, MD, PhD, Laboratoire de Génétique de Maladies Rares, Institut Universitaire de Recherche Clinique, 641 Avenue du Doyen Gaston Giraud, 34093 Montpellier Cedex 5, France (michel.koenig @inserm.fr). Conflict of Interest Disclosures: None reported. Funding/Support: This work was supported by the Agence Nationale de la Recherche/E-rare JTC 2011 Euro-SCAR (grant 2011-RARE-004-54 01 to Dr Koenig). Role of the Funder/Sponsor: The funders had no role in the preparation, review, or approval of the manuscript, and the decision to submit the manuscript for publication Correction: This article was corrected online February 17, 2015, to fix a typographical error. 1. Renaud M, Anheim M, Kamsteeg EJ, et al. Autosomal recessive cerebellar ataxia type 3 due to ANO10 mutations: delineation and genotype-phenotype correlation study. JAMA Neurol. 2014;71(10):1305-1310. 2. Balreira A, Boczonadi V, Barca E, et al. ANO10 mutations cause ataxia and coenzyme Q10 deficiency. J Neurol. 2014;261(11):2192-2198. 3. Fogel BL, Lee H, Deignan JL, et al. Exome sequencing in the clinical diagnosis of sporadic or familial cerebellar ataxia. JAMA Neurol. 2014;71(10): 1237-1246. 4. Sheridan JT, Worthington EN, Yu K, Gabriel SE, Hartzell HC, Tarran R. Characterization of the oligomeric structure of the Ca(2+)-activated Cl- channel Ano1/TMEM16A. J Biol Chem. 2011;286(2):1381-1388. 5. Micol R, Ben Slama L, Suarez F, et al; CEREDIH Network Investigators. Morbidity and mortality from ataxia-telangiectasia are associated with ATM genotype. J Allergy Clin Immunol. 2011;128(2):382-9.e1.

Statins and Intracerebral Hemorrhage To the Editor In an article1 and accompanying editorial2 about intracerebral hemorrhage (ICH) and statins, Flint et al1 and Gonzalez-Castellon and Marshall2 gave too much credence to the controversy about statins causing ICH. Most of this controversy is probably owing to misinterpretation of the results of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial.3 Flint et al1 slightly misquoted my editorial about this topic,4 suggesting that I attributed the increase in ICH to the high crossover rate in SPARCL. The full quote is below, followed by my comments for clarification. I wrote that the “apparent increase of [ICH] in the SPARCL trial, which was largely responsible for the idea that the risk of [ICH] is increased from statins, was largely an artifact of the intention-to-treat analysis. In that study, patients with a previous stroke were randomized to high-dose atorvastatin or placebo. If atorvastatin had been causally related to ICH, levels of [low-density lipoprotein] should have been lower in patients with ICH, but they were not.”4 It is not plausible for low-density lipoprotein levels not to be lower in a group of people taking 80 mg of atorvastatin compared with a group taking placebo. As I continued, the “problem with the intention-to-treat analysis was that a quarter of patients randomized to placebo were crossed over to statin, and the fact that the [low-density lipoprotein] levels were not lower in patients with ICH means that they were not taking statins.”4 The former is why the study underestimated the reduction of stroke with statins, not why there was an excess of ICH. 240

“It is more likely that the ICH occurred because patients who stopped their statins on account of adverse effects also stopped their antihypertensive medication.”4 It is extremely common for patients who experience adverse effects of medication to stop all their pills, not knowing which is responsible for the problem. And finally, I noted that patients “with ICH in SPARCL had higher blood pressures, as would be expected.”4 Patients with ICH in SPARCL were 6 times more likely to have stage 2 hypertension at the last visit before the ICH.5 J. David Spence, MD, FRCPC Author Affiliation: Stroke Prevention and Atherosclerosis Research Centre, Robarts Research Institute, Western University, London, Ontario, Canada. Corresponding Author: J. David Spence, MD, FRCPC, Stroke Prevention and Atherosclerosis Research Centre, 1400 Western Rd, London, ON N6G 2V2, Canada ([email protected]). Conflict of Interest Disclosures: None reported. 1. Flint AC, Conell C, Rao VA, et al. Effect of statin use during hospitalization for intracerebral hemorrhage on mortality and discharge disposition. JAMA Neurol. 2014;71(11):1364-1371. 2. Gonzalez-Castellon MA, Marshall RS. Statin use and brain hemorrhage: real risk or unfounded fear? JAMA Neurol. 2014;71(11):1353-1354. 3. Amarenco P, Bogousslavsky J, Callahan A III, et al; Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355 (6):549-559. 4. Spence JD. Statins do not cause intracerebral hemorrhage. Neurology. 2012; 79(11):1076-1077. 5. Goldstein LB, Amarenco P, Szarek M, et al; SPARCL Investigators. Hemorrhagic stroke in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels Study. Neurology. 2008;70(24, pt 2):2364-2370.

In Reply We appreciate the comments Dr Spence made in response to our article1 and the accompanying editorial.2 While our group is convinced by the arguments he has made in the quoted editorial piece regarding the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial results, it is important to recognize that controversy does persist in the literature when it comes to this issue. As evidence of ongoing controversy on the question of whether long-term high-dose statin therapy may increase intracerebral hemorrhage (ICH) risk, in our article, we cited editorials arguing both sides of the issue. Additionally, the American Heart Association/American Stroke Association guidelines on the management of ICH call out the increased rate of ICH among patients randomized to atorvastatin in SPARCL but go on to state that “there is [sic] insufficient data to recommend restrictions on use of statin agents … (Class IIb, Level of Evidence C).”3 Other authors have recommended the use of a Markov decision model to identify patients with a history of ICH in whom (the authors argued) statins should be avoided.4 While one meta-analysis has argued that no overall relationship between statin use and ICH risk can be found,5 another meta-analysis reported a relationship between lower lipid levels and higher ICH risk.6 On the specific issue raised by Dr Spence concerning crossovers in the SPARCL trial, it was our intent to refer to patients taking statins after assignment to placebo, as well as patients

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Autosomal recessive cerebellar ataxia 3 due to homozygote c.132dupA mutation within the ANO10 gene--reply.

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