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In answer to the three questions posed by Dispenzieri and Kumar: first, our protocol was consistent with current guidelines that recommend treatment of smoldering myeloma only once myeloma-related symptoms develop. The use of active treatment at the time of biologic relapse in the observation group may be an interesting preemptive strategy for future research. Second, in our study, biologic progression before full CRAB progression occurred in 12 of 62 of patients within the observation group (19%) at a median of 6.5 months from study inclusion (range, 2.0 to 21.0). Third, both groups had identical testing intensity, since all tests, including serum and urinary levels of the monoclonal component, were assessed monthly until study discontinuation. Mahesh raises concern regarding thromboprophylaxis. Our trial imposed the thromboprophylaxis protocol recommended by the Inter­ national Myeloma Working Group guidelines3: aspirin for patients with one or no risk factors for venous thromboembolism, and low-molecular-weight heparin for those with more than one

risk factor for venous thromboembolism. The lower incidence of venous thromboembolism in our study as compared with that in previous studies could be due to the inclusion of patients with a low risk of venous thromboembolism (with no myeloma-related symptoms, a low tumor burden, the use of low-dose dexamethasone, and no significant coexisting conditions). María-Victoria Mateos, M.D., Ph.D. Jesús-F. San Miguel, M.D., Ph.D. University Hospital of Salamanca Salamanca, Spain [email protected] Since publication of their article, the authors report no further potential conflict of interest. 1. Kyle RA, Remstein ED, Therneau TM, et al. Clinical course

and prognosis of smoldering (asymptomatic) multiple myeloma. N Engl J Med 2007;356:2582-90. 2. Mateos MV, San Miguel JF. New approaches to smoldering myeloma. Curr Hematol Malig Rep 2013 August 23 (Epub ahead of print). 3. Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia 2008;22:414-23. DOI: 10.1056/NEJMc1310911

Herpes Zoster No potential conflict of interest relevant to this letter was reTo the Editor: In his review article on herpes ported. 1 zoster, Cohen (July 18 issue) reports that the live attenuated herpes zoster vaccine can be given to 1. Cohen JI. Herpes zoster. N Engl J Med 2013;369:255-63. 2. Yawn BP, Wollan PC, Kurland MJ, St Sauver JL, Saddier P. persons with a history of herpes zoster. However, Herpes zoster recurrences more frequent than previously reportstudies have shown that the risk of a recurrence ed. Mayo Clin Proc 2011;86:88-93. of herpes zoster in an elderly immunocompetent 3. Tseng HF, Chi M, Smith N, Marcy SM, Sy LS, Jacobsen SJ. Herpes zoster vaccine and the incidence of recurrent herpes zosperson is less than 1% per year, and results from ter in an immunocompetent elderly population. J Infect Dis a major vaccine trial in this age group led to 2012;206:190-6. an estimate of 0.1 to 0.2% per year through 4. Morrison VA, Oxman MN, Levin MJ, et al. Safety of zoster vaccine in elderly adults following documented herpes zoster. 6 years.2,3 Although the herpes zoster vaccine is J Infect Dis 2013;208:559-63. safe in patients with a history of herpes zoster,4 5. Schmader KE, Oxman MN, Levin MJ, et al. Persistence of the Cohen provides no evidence that it further re- efficacy of zoster vaccine in the Shingles Prevention Study and the Short-Term Persistence Substudy. Clin Infect Dis 2012;55: duces the rate of recurrence or the rate of post- 1320-8. herpetic neuralgia in this specific group. More- DOI: 10.1056/NEJMc1310369 over, the efficacy of the vaccine wanes over the first 5 years.5 Why, then, does he recommend vaccination of elderly immunocompetent pa- To the Editor: It was surprising that Cohen tients with a well-documented history of a previ- does not provide interventional (i.e., injectionous episode of herpes zoster? based) options for the treatment of pain associated with acute shingles that is unresponsive to Jan V. Hirschmann, M.D. medical therapies. Although data are lacking Puget Sound VA Medical Center from randomized, controlled trials to show the Seattle, WA [email protected] benefits of such interventions, case series sug-

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gest remarkable improvement in pain.1,2 The simplest option is the subcutaneous injection (with or without a glucocorticoid) under the painful lesions. Although such therapy is possible only in patients with limited painful areas, the benefits of local-infiltration analgesia typically far outlast the duration of the anesthetic. Given the ease of application and low risk of this option, especially in comparison with the systemic side effects of opioids, gabapentin, and antidepressants, local injection is an option that warrants consideration.3-5 Jeffrey A. Katz, M.D. Northwestern University Medical School Chicago, IL [email protected] No potential conflict of interest relevant to this letter was reported. 1. Makharita MY, Amr YM, El-Bayoumy Y. Effect of early stel-

late ganglion blockade for facial pain from acute herpes zoster and incidence of postherpetic neuralgia. Pain Physician 2012;15: 467-74. 2. Benzon HT, Chekka K, Darnule A, Chung B, Wille O, Malik K. Evidence-based case report: the prevention and management of postherpetic neuralgia with emphasis on interventional procedures. Reg Anesth Pain Med 2009;34:514-21. 3. Epstein E. Treatment of herpes zoster and postzoster neuralgia by subcutaneous injection of triamcinolone. Int J Dermatol 1981;20:65-8. 4. Idem. Triamcinolone-procaine in the treatment of zoster and postzoster neuralgia. Calif Med 1971;115:6-10. 5. Puri N. Modified Jaipur block for the treatment of post-herpetic neuralgia. Int J Dermatol 2011;50:1417-20. DOI: 10.1056/NEJMc1310369

To the Editor: In his article on herpes zoster, Cohen overstates the efficacy and safety of herpes zoster vaccine in the elderly. Cohen correctly notes the efficacy of the herpes zoster vaccine in preventing infection is 38% for persons 70 years of age or older, but this is only part of the story. For persons 80 years of age or older in the Shingles Prevention Study,1 the herpes zoster vaccine was no better than placebo for the prevention of herpes zoster or postherpetic neuralgia but resulted in a more than a doubling in the rate of serious adverse events in the first 42 days after vaccination (P = 0.19). A safety study mandated by the Food and Drug Administration showed a 26% increase in the rate of serious adverse events in the first 42 days after herpes zoster vaccination (P = 0.16).2,3 When the results of this safety study were combined with those of the Shingles Prevention Study, there was a 36% increase in the rate of serious adverse events associated with the herpes zoster vaccine 1766

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in persons 60 years of age or older (P = 0.01).3,4 The efficacy and safety of the herpes zoster vaccine in the elderly are questionable. Roy E. Fried, M.D., M.H.S. Premier Senior Care Bethesda, MD [email protected] No potential conflict of interest relevant to this letter was reported. 1. Merck. Zostavax: prescribing information (http://www.merck

.com/product/usa/pi_circulars/z/zostavax/zostavax_pi2.pdf). 2. Food and Drug Administration. Approval letter — Zostavax. May 25, 2006 (http://www.fda.gov/biologicsbloodvaccines/vaccines/ approvedproducts/ucm132873.htm). 3. Murray AV, Reisinger KS, Kerzner B, et al. Safety and tolerability of zoster vaccine in adults ≥60 years old. Hum Vaccin 2011;7:1130-6. 4. Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 2005;352:2271-84. DOI: 10.1056/NEJMc1310369

The author replies: Hirschmann asks about the basis of the Advisory Committee on Immunization Practices’ recommendation that persons with a history of herpes zoster be vaccinated. Reasons for vaccinating such persons include a lack of certainty about the validity of a history of herpes zoster, uncertainty about the degree and duration of protection from previous herpes zoster, and the safety of the vaccine in persons with a history of herpes zoster.1 Although the risk of recurrent herpes zoster is low during the first few years after reactivation, the risk probably increases with time as varicella–zoster virus–specific cell immunity declines. Thus, one might delay vaccination for a few years after a well-documented case of herpes zoster. Katz points out that acute pain associated with herpes zoster may not respond to conventional therapy and suggests that injection of a local anesthetic with or without glucocorticoids may reduce such pain. In a recent controlled, doubleblind trial of repeat ganglion-blockade injections in patients with herpes zoster who were already receiving gabapentin, Makharita et al.2 acknowledged that such injections could have serious complications and that a multicenter trial was needed to confirm their promising results. New treatments, tested in controlled trials, are needed for the treatment of pain associated with herpes zoster. Fried raises an important question regarding the safety and efficacy of the herpes zoster vaccine in persons 80 years of age or older. In the

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Shingles Prevention Study, no significant difference was noted in the rate of serious adverse events among persons in this age group who received the vaccine versus those who received placebo.3 In another study, the relative risk of serious adverse events within 42 days after receiving the herpes zoster vaccine was 1.66 for participants between the ages of 60 to 69 years, 1.03 for those between the age of ages 70 and 79 years, and 1.18 for those 80 years of age or older.4 Thus, the vaccine does not appear to be less safe in the elderly. The Shingles Prevention Study showed that although the efficacy of the herpes zoster vaccine in preventing shingles was reduced in older persons, the efficacy of the vaccine in preventing postherpetic neuralgia did not decline in persons 70 years of age or older.5 Although the vaccine’s package insert indicates that the efficacy of the vaccine in preventing postherpetic neuralgia was lower in persons 80 years of age or older, the total number of persons with postherpetic neuralgia was very small (seven participants). Since the elderly have the highest fre-

quency of both herpes zoster and postherpetic neuralgia, they would be expected to receive the most benefit from the vaccine, even if its efficacy were to be modestly reduced as compared with that in younger persons. Jeffrey I. Cohen, M.D. National Institutes of Health Bethesda, MD [email protected] Since publication of his article, the author reports no further potential conflict of interest. 1. Morrison VA, Oxman MN, Levin MJ, et al. Safety of zoster

vaccine in elderly adults following documented herpes zoster. J Infect Dis 2013;208:559-63. 2. Makharita MY, Amr YM, El-Bayoumy Y. Effect of early stellate ganglion blockade for facial pain from acute herpes zoster and incidence of postherpetic neuralgia. Pain Physician 2012; 15:467-74. 3. Simberkoff MS, Arbeit RD, Johnson GR, et al. Safety of herpes zoster vaccine in the Shingles Prevention Study: a randomized trial. Ann Intern Med 2010;152:545-54. 4. Murray AV, Reisinger KS, Kerzner B, et al. Safety and tolerability of zoster vaccine in adults ≥60 years old. Hum Vaccin 2011;7:1130-6. 5. Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 2005;352:2271-84. DOI: 10.1056/NEJMc1310369

Case 23-2013: A 54-Year-Old Woman with Metformin Toxicity To the Editor: Methanol or ethylene glycol toxicity cannot be ruled out on the basis of the absence of an elevated osmolal gap, as is indicated in the Case Record by Kalantar-Zadeh et al. (July 25 issue).1 The osmolal gap in these toxicities is caused by the parent compounds, but not by the metabolites. The osmolal gap increases shortly after exposure and then begins to decrease, often with a concomitant increase in the anion gap caused by the toxic metabolites.2 When the woman in the Case Record presented 3 days after her illness began, the osmolal gap would not have been significantly elevated, even if she had clinically significant toxic alcohol exposure. This highlights the difficulty in diagnosing toxic alcohol exposures. Urine fluorescence, oxalate crystals, and the osmolal gap are neither sensitive nor specific, and plasma levels are rarely available immediately. The patient history is notoriously inaccurate, and there are no specific signs on examination. Therefore, physicians must have a high diagnostic suspicion for toxic alcohol exposures and a low threshold to use fomepizole, which has

a very low rate of toxicity, to avoid the potentially catastrophic consequences of methanol or ethylene glycol ingestion. Michael Goldman, M.D. Jamaica Hospital Medical Center Jamaica, NY

Norbert Shtaynberg, D.O. Staten Island University Hospital Staten Island, NY No potential conflict of interest relevant to this letter was reported. 1. Case Records of the Massachusetts General Hospital (Case

23-2013). N Engl J Med 2013;369:374-82.

2. Kraut JA, Kurtz I. Toxic alcohol ingestions: clinical features,

diagnosis, and management. Clin J Am Soc Nephrol 2008;3: 208-25. DOI: 10.1056/NEJMc1310560

To the Editor: Kalantar-Zadeh et al. elegantly describe metformin-induced type B lactic acidosis in a patient with probable pancreatitis. The authors also mention a number of medications that can cause lactic acidosis through impairment of normal lactate metabolism. However, they do

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