Correspondence
Intrathecal Methylprednisolone for Postherpetic Neuralgia
N Engl J Med 2001; 344:1019-1022March 29, 2001
- Article
To the Editor:
Kotani and colleagues (Nov. 23 issue)1 recommend intrathecal methylprednisolone acetate for treatment of intractable postherpetic neuralgia due to persistent inflammation. But the abnormalities in the cerebrospinal fluid and on magnetic resonance imaging in patients with acute herpes zoster are not persistent. The neuropathological reference that Kotani et al. cite2 does not demonstrate polymorphonuclear leukocytes or “marked inflammation around the spinal cord, with massive infiltration and accumulation of lymphocytes.” The usual association between neutrophil inflammation and interleukin-8 calls into question reliance on the level of interleukin-8 in acellular cerebrospinal fluid.3 The authors' hypothesis that “postherpetic neuralgia provokes an intense inflammatory reaction in the spinal cord” is inverted.
The risk of complications is more important than the data on efficacy. We found that chemical meningitis accounts for half the serious complications resulting from a single intrathecal injection of 40 to 80 mg of methylprednisolone; the other complications are transverse myelitis, cauda equina syndrome, lumbar radiculitis, intractable headache, and urinary retention.4,5 Chronic arachnoiditis with severe pain is most often associated with multiple injections. The neurotoxic effects of intrathecal steroid formulations have been attributed to sensitivity to the local anesthetic, the steroid, hyperbaric mixtures, or the steroid preservative (benzyl alcohol, benzalkonium chloride, or polyethylene glycol).4,5 Kotani et al. misidentify polyethylene glycol as “propylene glycol.”
In the accompanying editorial,6 Watson describes the natural history of improvement of the illness. This supports our belief that it is neither ethical nor wise to withhold analgesic and opiate medications in favor of an invasive treatment that may cause permanent injury.
6 ReferencesDewey A. Nelson, M.D.
206 N. Spring Valley Rd., Wilmington, DE 19807William M. Landau, M.D.
Washington University School of Medicine, St. Louis, MO 631101
Kotani N ,Kushikata T ,Hashimoto H , et al. Intrathecal methylprednisolone for intractable postherpetic neuralgia. N Engl J Med 2000;343:1514-1519
Full Text | Web of Science | Medline2
Watson CPN ,Deck JH ,Morshead C ,Van der Kooy D ,Evans RJ . Post-herpetic neuralgia: further post-mortem studies of cases with and without pain. Pain 1991;44:105-117
CrossRef | Web of Science | Medline3
Lopez-Cortes LF ,Cruz-Ruiz M ,Gomez-Mateos J ,Viciana-Fernandez P ,Martinez-Marcos FJ ,Pachon J . Interleukin-8 in cerebrospinal fluid from patients with meningitis of different etiologies: its possible role as neutrophil chemotactic factor. J Infect Dis 1995;172:581-584
CrossRef | Web of Science | Medline4
Nelson DA . Intraspinal therapy using methylprednisolone acetate: twenty-three years of clinical controversy. Spine 1993;18:278-286
CrossRef | Web of Science | Medline5
Nelson DA, Landau WM. Intraspinal steroids: history, efficacy, accidentality and controversy with review of U.S. Food and Drug Administration (FDA) reports. J Neurol Neurosurg Psychiatry (in press).
6
Watson CPN . A new treatment for postherpetic neuralgia. N Engl J Med 2000;343:1563-1565
Full Text | Web of Science | Medline
To the Editor:
Kotani et al. suggest that the intrathecal administration of methylprednisolone is an effective therapy for postherpetic neuralgia. However, we are concerned about the potential risks of this treatment. After the acute infection, the varicella–zoster virus enters the peripheral nervous system and produces a latent infection of dorsal-root ganglia. The precise mechanisms of reactivation have not been identified.1 During latency, DNA, messenger RNA, and proteins specific to the varicella–zoster virus are detectable.
Several observations support the hypothesis that in patients with postherpetic neuralgia, the varicella–zoster virus persists in ganglia at higher levels than those reached during latency.2 The effects on the varicella–zoster virus of the intrathecal injection of methylprednisolone are unknown. Aseptic meningitis has been described after intrathecal injections of steroids.3 Therefore, viral replication, which may have increased after therapy with intrathecal methylprednisolone, could be confused with this well-known complication.
In the study by Kotani et al., the cerebrospinal fluid was examined only by routine cytologic and biochemical tests. To rule out enhanced viral reactivation resulting from intrathecal corticosteroid therapy, we suggest screening patients for both viral DNA and antibodies to varicella–zoster virus in the cerebrospinal fluid.2 Moreover, patients should be informed about the risk of increased viral replication that may follow treatment of postherpetic neuralgia with intrathecal injections of methylprednisolone.
3 ReferencesJohannes B. Lampe, M.D.
Claudia Hindinger, M.D.
Heinz Reichmann, M.D.
Technical University of Dresden, 01307 Dresden, Germany1
Ahmed R, Morrison LA, Knipe DM. Persistence of viruses. In: Fields BN, Knipe DM, Howley PM, eds. Fields virology. Vol. 1. Philadelphia: Lippincott-Raven, 1996:219-49.
2
Gilden DH ,Kleinschmidt-DeMasters BK ,LaGuardia JJ ,Mahalingam R ,Cohrs RJ . Neurologic complications of the reactivation of varicella-zoster virus. N Engl J Med 2000;342:635-645[Erratum, N Engl J Med 2000;342:1063.]
Full Text | Web of Science | Medline3
Abram SE . Intrathecal steroid injection for postherpetic neuralgia: what are the risks? Reg Anesth Pain Med 1999;24:283-285
CrossRef | Web of Science | Medline
To the Editor:
Although the results of the treatment of intractable postherpetic neuralgia with intrathecal methylprednisolone in the study by Kotani et al. are promising, I would like to sound a note of caution. The study did not include a methylprednisolone-only group. Intrathecal hyperbaric lidocaine at the dosages used by Kotani et al. has been associated with a number of neurologic side effects, including cauda equina syndrome1 and transient radicular irritation2 and is commonly associated with hypotension, bradycardia, and cardiac arrest even in healthy people.3 Were the patients enrolled in the study by Kotani et al. informed of these adverse effects?
Intrathecal injection of methylprednisolone is not a procedure to be undertaken lightly in an office setting by personnel unfamiliar with resuscitation techniques. At a minimum, there must be appropriate monitoring, including pulse oximetry and blood-pressure monitoring; an immediately available source of oxygen and the means to administer it both passively and actively with positive-pressure ventilation; and the means to provide full resuscitative measures.
Most patients with postherpetic neuralgia are elderly and will often have associated diseases such as cardiac, cerebrovascular, and respiratory disorders. A sustained drop in blood pressure can have devastating effects on older patients.
3 ReferencesGeraint Lewis, F.R.C.P.C.
University of Ottawa, Ottawa, ON K1H 8M5, Canada1
Gerancher JC . Cauda equina syndrome following a single spinal administration of 5% hyperbaric lidocaine through a 25-gauge Whitacre needle. Anesthesiology 1997;87:687-689
CrossRef | Web of Science | Medline2
Tarkkila P ,Huhtala J ,Tuominen M . Transient radicular irritation after spinal anaesthesia with hyperbaric 5% lignocaine. Br J Anaesth 1995;74:328-329
CrossRef | Web of Science | Medline3
Caplan RA ,Ward RJ ,Posner K ,Cheney FW . Unexpected cardiac arrest during spinal anesthesia: a closed claims analysis of predisposing factors. Anesthesiology 1988;68:5-11
CrossRef | Web of Science | Medline
To the Editor:
The impressive results of Kotani et al. require some clarification. Although a combination of methylprednisolone and lidocaine was used, the discussion refers to methylprednisolone alone. This is unjustified, because only the combination may be effective. Why was the efficacy of methylprednisolone alone not assessed? It would be clinically important to know whether comparable results could be achieved if lidocaine were omitted. Lidocaine is neurotoxic not only when injected into the nerves but also when injected intrathecally at concentrations greater than 2 percent.1,2
Bringing a patient into a position in which the head is tilted downward immediately after intrathecal administration of 3 ml of 3 percent hyperbaric lidocaine may cause hypotension, bradycardia, and dyspnea due to blockade of the thoracic sympathetic nerves and the nerves innervating the respiratory muscles. Surprisingly, Kotani et al. provide no details regarding the hemodynamic and respiratory responses. Intrathecal methylprednisolone should be administered only by persons experienced in cardiopulmonary resuscitation.
2 ReferencesHenner Niebergall, M.D.
Hans-Joachim Priebe, M.D.
University Hospital Freiburg, D-79106 Freiburg, Germany1
Loo CC ,Irestedt L . Cauda equina syndrome after spinal anaesthesia with hyperbaric 5% lignocaine: a review of six cases of cauda equina syndrome reported to the Swedish Pharmaceutical Insurance 1993-1997. Acta Anaesthesiol Scand 1999;43:371-379
CrossRef | Web of Science | Medline2
Hodgson PS ,Neal JM ,Pollock JE ,Liu SS . The neurotoxicity of drugs given intrathecally (spinal). Anesth Analg 1999;88:797-809
CrossRef | Web of Science | Medline
To the Editor:
Kotani et al. propose an effective treatment for postherpetic neuralgia. However, there are several problems with their study.
An additional group is needed. Why was no group of patients given methylprednisolone alone? Is lidocaine a useful additive? This is not just a methodologic question; lidocaine administered by the intrathecal route may generate serious side effects.
Intrathecal administration of lidocaine is no longer recommended because of its neurotoxic effects.1 Intrathecal lidocaine is responsible for the transient neurologic syndrome, defined as pain in the buttocks and legs, paresthesias, and motor weakness.2 These symptoms usually disappear within a few days. Nevertheless, for these reasons lidocaine is probably not a good additive to intrathecal methylprednisolone.
The authors injected patients with 90 mg of lidocaine, a dose that leads to profound spinal anesthesia with hemodynamic changes, such as hypotension and bradycardia. Placing patients in the head-down position can lead to respiratory arrest as a consequence of respiratory-muscle blockade and severe hemodynamic effects such as vasovagal syncope. The risks associated with spinal anesthesia were not clearly described in the study.
If a local anesthetic is needed, prilocaine or bupivacaine should be used instead of lidocaine because of their lower neurologic toxicity.3 Such treatment should be administered only in recovery or operating rooms, and the presence of a physician skilled in the management of spinal anesthesia is essential.
3 ReferencesPaul J. Zetlaoui, M.D.
Hôpital de Bicêtre, 94270 le Kremlin Bicêtre CEDEX, FranceJulie Cosserat, M.D.
Institut Mutualiste Montsouris, 75014 Paris, France1
Gaiser RR . Should intrathecal lidocaine be used in the 21st century? J Clin Anesth 2000;12:476-481
CrossRef | Web of Science | Medline2
Hampl KF ,Schneider MC ,Ummenhofer W ,Drewe J . Transient neurologic symptoms after spinal anesthesia. Anesth Analg 1995;81:1148-1153
CrossRef | Web of Science | Medline3
Hampl KF ,Heinzmann-Wiedmer S ,Luginbuehl I , et al. Transient neurologic symptoms after spinal anesthesia: a lower incidence with prilocaine and bupivacaine than with lidocaine. Anesthesiology 1998;88:629-633
CrossRef | Web of Science | Medline
To the Editor:
I would like to share some of the difficulties my colleagues and I encountered in our attempt to duplicate the protocol of the study reported by Kotani et al. and to administer the intrathecal injection of methylprednisolone acetate plus lidocaine for the treatment of postherpetic neuralgia. In contrast to the findings of the authors, we were unable to obtain a homogeneous solution of methylprednisolone in the minimal amount of solute required. In response to our inquiry, the drug manufacturer (Pharmacia–Upjohn) stated that the firm did not recommend intrathecal injection because of the solubility properties of the drug.
Balasubramaniam Srinivasan, M.D.
40 E. Hannum Blvd., Saginaw, MI 48602-1910Author/Editor Response
The authors reply:
To the Editor: We were fully aware that intrathecal methylprednisolone can be neurotoxic, and we therefore carefully designed our study1 as well as a previous study2 to minimize and fully evaluate potential complications. Complications of the use of intrathecal methylprednisolone have generally been observed after the treatment of multiple sclerosis, and multiple injections increase the risk. We therefore excluded patients with neurologic disease and gave just four injections at weekly intervals, regardless of the intensity of neuralgia. We followed all patients for two years, and none reported treatment-related side effects or recurrent herpes zoster.
Our study population was restricted to patients with intractable postherpetic neuralgia that had lasted at least one full year and had been resistant to conventional treatments. In this population, “natural” improvement, as described by Nelson and Landau, is rare.
Our informed-consent form included detailed information about the possibility of serious adverse effects, including life-long paralysis, exacerbation of pain, recurrence of herpes zoster, and even death. We agree that the simplest and safest approaches should be used initially, as suggested in the editorial by Watson.3 However, the benefit-to-risk ratio is high in patients suffering from intractable postherpetic neuralgia because conventional treatments are ineffective.
Because interleukin-8 in the cerebrospinal fluid is a well-known inflammatory mediator, and because this property was closely related to treatment efficacy, we thought that an antiinflammatory reaction was a plausible mechanism for analgesia. Although interleukin-8 is produced by neutrophils, macrophages, and monocytes, the number of leukocytes does not always correlate with the concentration of interleukin-8. In fact, Chaka and coworkers4 reported that there is no leukocytosis in cerebrospinal fluid during meningitis, despite high interleukin-8 concentrations.
Srinivasan points out that methylprednisolone does not fully dissolve in lidocaine, leaving a white deposit. We measured the specific gravity of the supernatant. Lewis, Niebergall and Priebe, and Zetlaoui and Cosserat criticize our use of lidocaine. However, a local anesthetic was necessary to identify and control the cephalad spread of methylprednisolone in the 60 percent of our patients who had cervical and upper thoracic neuralgia. Lewis, Niebergall and Priebe, and Zetlaoui and Cosserat argue that our results do not eliminate an interaction between lidocaine and methylprednisolone. However, we compared the outcomes for a control group that received lidocaine only with those for the lidocaine-plus-methylprednisolone group, and our results indicate that the benefits of intrathecal methylprednisolone in patients with postherpetic neuralgia are not due to lidocaine.
Spinal anesthesia is a routine procedure that is used millions of times each year. It is safe and rarely associated with neurologic complications.5 Spinal anesthesia is, of course, often accompanied by transient hemodynamic and respiratory depression. Our procedure should thus be performed only by anesthesiologists, with appropriate monitoring and equipment.
5 ReferencesNaoki Kotani, M.D.
Akitomo Matsuki, M.D.
University of Hirosaki School of Medicine, Hirosaki 035-8562, Japan1
Kotani N ,Kushikata T ,Hashimoto H , et al. Intrathecal methylprednisolone for intractable postherpetic neuralgia. N Engl J Med 2000;343:1514-1519
Full Text | Web of Science | Medline2
Kikuchi A ,Kotani N ,Sato T ,Takamura K ,Sakai I ,Matsuki A . Comparative therapeutic evaluation of intrathecal versus epidural methylprednisolone for long-term analgesia in patients with intractable postherpetic neuralgia. Reg Anesth Pain Med 1999;24:287-293
Web of Science | Medline3
Watson CPN . A new treatment for postherpetic neuralgia. N Engl J Med 2000;343:1563-1565
Full Text | Web of Science | Medline4
Chaka W ,Heyderman R ,Gangaidzo I , et al. Cytokine profiles in cerebrospinal fluid of human immunodeficiency virus-infected patients with cryptococcal meningitis: no leukocytosis despite high interleukin-8 levels. J Infect Dis 1997;176:1633-1636
CrossRef | Web of Science | Medline5
Horlocker TT ,McGregor DG ,Matsushige DK ,Schroeder DR ,Besse JA . A retrospective review of 4767 consecutive spinal anesthetics: central nervous system complications. Anesth Analg 1997;84:578-584
CrossRef | Web of Science | Medline
Author/Editor Response
The editorialist replies:
To the Editor: There has been a great deal of interest from all over the world with regard to the use of methylprednisolone acetate for the treatment of postherpetic neuralgia, as evidenced by the requests I have had for further information. These letters raise the important issue of the safety of this therapy.
Nelson and Landau are quite correct in stating, as pointed out in my editorial, that there is little pathological evidence of inflammation in chronic cases of postherpetic neuralgia. In fact, only one patient in the study they quote1 had evidence of persistent inflammation several months after the onset of herpes zoster.
An important issue, raised by Nelson and Landau and in my editorial, is the possibility of complications from intrathecal methylprednisolone. The preparations in the United States and Canada consist of a multidose vial of methylprednisolone acetate for intramuscular use that contains, among other ingredients, benzyl alcohol and polyethylene glycol (both of which may be neurotoxic), or a single-dose vial that contains myristyl gamma picolinium chloride. A mixture of methylprednisolone acetate and lidocaine is also available and contains benzyl alcohol, polyethylene glycol, and myristyl gamma picolinium chloride. Methylprednisolone succinate is available for intravenous use. None of these products are recommended for use intrathecally or epidurally by the manufacturer (Pharmacia–Upjohn). I am informed by Pharmacia–Upjohn that it is theoretically possible to manufacture a preservative-free formulation of methylprednisolone, but this would need to be tested for safety and would require a considerable delay before it could be marketed, a situation that creates a barrier to the implementation of this treatment.
Finally, as Nelson and Landau mention and as I concluded in my editorial, patients with postherpetic neuralgia should have an adequate trial of standard therapies before an invasive procedure is considered.
1 ReferencesC. Peter N. Watson, M.D.
University of Toronto, Toronto, ON M5S 3H4, Canada1
Watson CPN ,Deck JH ,Morshead C ,Van der Kooy D ,Evans RJ . Post-herpetic neuralgia: further post-mortem studies of cases with and without pain. Pain 1991;44:105-117
CrossRef | Web of Science | Medline
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Michael C. Rowbotham. (2010) PAIN’s policy on the spinal administration of drugs. PAIN 149:3, 415-416
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Robert W Johnson, Gunnar Wasner, Patricia Saddier, Ralf Baron. (2007) Postherpetic neuralgia: epidemiology, pathophysiology and management. Expert Review of Neurotherapeutics 7:11, 1581-1595
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Robert W. Johnson, Andrew S.C. Rice. (2007) Pain following herpes zoster: The influence of changing population characteristics and medical developments. Pain 128:1-2, 3-5
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Kathleen Hempenstall, Turo J. Nurmikko, Robert W. Johnson, Roger P. A'Hern, Andrew S.C. Rice. (2005) Analgesic Therapy in Postherpetic Neuralgia: A Quantitative Systematic Review. PLoS Medicine 2:7, e164
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Torsten Meier, Gunnar Wasner, Markus Faust, Thierry Kuntzer, François Ochsner, Michael Hueppe, Julien Bogousslavsky, Ralf Baron. (2003) Efficacy of lidocaine patch 5% in the treatment of focal peripheral neuropathic pain syndromes: a randomized, double-blind, placebo-controlled study. Pain 106:1-2, 151-158
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Louis M. Panlilio, Paul J. Christo, Srinivasa N. Raja. (2002) Current Management of Postherpetic Neuralgia. The Neurologist 8:6, 339-350
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Dewey A Nelson, William M Landau. (2002) Intrathecal steroid therapy for postherpetic neuralgia: a review. Expert Review of Neurotherapeutics 2:5, 631-637
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Jennifer A. Santee. (2002) Corticosteroids for Herpes Zoster. American Journal of Clinical Dermatology 3:8, 517-524
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