Dalfampridine may activate latent trigeminal neuralgia in patients with multiple sclerosis Gary Birnbaum, MD Jane Iverson, RN
ABSTRACT
Objective: To determine the effect of dalfampridine (4-aminopyridine), a broad-spectrum, voltagedependent potassium channel blocker, on patients with trigeminal nerve dysfunction due to multiple sclerosis (MS).
Correspondence to Dr. Birnbaum: [email protected]
Methods: We reviewed histories of 71 patients in our clinic with clinically definite MS who were treated with dalfampridine for at least 2 to 3 months. Of the 71 patients, 5 had a history of either trigeminal neuralgia or altered facial sensation.
Results: Of these 5 patients, 3 with preexisting trigeminal neuralgia had a marked worsening of facial pain in close proximity to starting dalfampridine. One patient with altered facial sensation developed trigeminal pain after being on dalfampridine for 18 months. Pain in this individual rapidly subsided when dalfampridine was discontinued. Pain in the worsened 3 patients persisted, became more refractory to previously effective medications, and in one instance required trigeminal surgery for pain control. Conclusions: Dalfampridine should be used with caution in persons with trigeminal neuralgia due to MS.
Classification of evidence: This study provides Class IV evidence that treatment with dalfampridine may precipitate or exacerbate preexisting trigeminal neuralgia. Neurology® 2014;83:1610–1612 GLOSSARY MS 5 multiple sclerosis.
Dalfampridine (4-aminopyridine) is a broad-spectrum, voltage-dependent potassium channel blocker that inhibits functioning of exposed potassium channels in paranodal and internodal axonal membranes. In so doing, it improves action potential conduction in demyelinated motor axons. Several clinical trials demonstrated that such improved conduction resulted in improvement of ambulation in a subset of persons with either relapsing or progressive multiple sclerosis (MS) as measured by the timed 25-foot walk.1–3 While improvement in action potential conduction in motor nerves is of benefit to a subset of persons with MS, increased action potential conduction in injured sensory nerves may result in increased abnormal sensations that could be either paresthetic or dysesthetic symptoms. We propose that this was the case in 4 persons with clinically definite MS, treated with dalfampridine, who experienced either recurrent or new onset of severe facial pain characteristic of trigeminal neuralgia. In 2 patients, symptoms were only partially ameliorated by stopping the dalfampridine, and required additional therapeutic intervention. RESULTS Patient populations. Seventy-one patients with clinically definite MS from the population of individuals being cared for at the MS Treatment and Research Center of the Minneapolis Clinic of Neurology were treated with dalfampridine to improve their ambulatory abilities. All were diagnosed and treated by the first author of this report. All had normal renal function and normal urinalyses. All met the criteria for treatment with dalfampridine as described in the phase III clinical trials of dalfampridine, and now required for drug approval by patients’ health insurance companies, namely, the ability to ambulate 25 feet in more than 8, From the MS Treatment and Research Center, Minneapolis Clinic of Neurology, Golden Valley, MN. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. 1610
© 2014 American Academy of Neurology
but less than 45, seconds.1,2 Treatment with dalfampridine was at least for 1 to 2 months, with discontinuation in one patient because of seizures and in others because of lack of efficacy. Of the 71 dalfampridine-treated patients, 5 had a history of preexisting trigeminal nerve dysfunction. Brain MRIs had been performed on all of these individuals, and no structural causes, other than brainstem demyelination, were noted. Three of the 5 patients had preexisting unilateral, lancinating, extremely severe, episodic facial pain, both spontaneous, and triggered by facial touch or eating, in the distribution of one or more divisions of a trigeminal nerve, in a pattern consistent with trigeminal neuralgia. Two had a history of episodic, unilateral altered facial sensation. In the 3 patients with trigeminal neuralgia, pain was controlled with combinations of carbamazepine, pregabalin, gabapentin, and occasionally a short course of steroids. The table summarizes the data on 4 of the 5 patients. Three patients had previous symptoms of unilateral trigeminal neuralgia resulting from their MS, with recurrences of severe facial pain over the years of their illness. All had symptoms reasonably well controlled with daily doses of medications, such as carbamazepine, pregabalin, and gabapentin, with occasional need for high-dose steroids. In all 3 patients, recurrences of facial pain started within 1 month of initiating treatment with dalfampridine. In the one patient with previous symptoms of facial dysesthesias but no actual pain, the appearance of severe facial pain occurred after 18 months of dalfampridine therapy. Dalfampridine was immediately discontinued in all patients at the time of worsening of their pain, or, in the case of the latter patient, at onset of facial pain. All patients noted an initial improvement in their pain syndrome, but in only one patient, the individual with no antecedent trigeminal neuralgia, did pain resolve completely. In 2 of the remaining 3 patients, subsequent bouts of pain were much more difficult to control, requiring higher doses of previously effective drugs. In the third patient, pain became refractory to
Table
high doses of previously effective medications, administered to the point of unacceptable side effects. The resulting intractable pain syndrome led to severe depression with suicidal ideation. Surgical intervention, in the form of trigeminal rhizotomy, was required to relieve symptoms. DISCUSSION Of the 71 patients treated with dalfampridine in our practice, 5 had a history of trigeminal nerve dysfunction, and 4 of these 5 worsened with dalfampridine therapy. There are other reports of worsening neurologic symptoms after the administration of dalfampridine. Thaera et al.4 noted recurrences of trigeminal neuralgia in 2 patients with progressive MS within 1 month of starting treatment with dalfampridine. Hypertonicity was noted in a subset of patients receiving dalfampridine treatment in the report by Cornblath et al.5 Of anecdotal interest, the fifth patient of the group with previous trigeminal nerve symptoms did not develop facial pain with initiation of dalfampridine therapy, but rapidly developed marked worsening of lower extremity weakness, which improved spontaneously with drug cessation. Toxicity from dalfampridine thus may not be limited to the trigeminal nerve. Our observations on the 4 patients noted above do not prove that dalfampridine was the cause of their neurologic worsening. However, the proximate association between their worsening in 3 of the 4 individuals and the administration of the drug suggests a cause and effect relationship. While the relationship between the administration of dalfampridine and the onset of a trigeminal pain syndrome in the fourth patient is more tenuous, given the longer duration of treatment on dalfampridine, a possible cause and effect cannot be excluded. The rapid cessation of pain after termination of dalfampridine suggests a causal association. The possible mechanism for the worsening of trigeminal neuralgia upon exposure to dalfampridine in our patients is not known. However, one can hypothesize that increasing nerve conduction in
Data of 4 of the 5 patients
Patient
Sex
Age, y
Phase of MS
Interval between starting dalfampridine and worsening/new TN
1
F
52
Secondary progressive
1 wk
Pain improved but the higher doses of medications required to control pain could not be tolerated because of drug toxicity. Patient required unilateral trigeminal rhizotomy to adequately control pain
2
M
49
Relapsing
18 mo
Pain rapidly subsided with minimal medications needed
3
F
62
Secondary progressive
1 mo
Pain initially subsided rapidly but then recurred several months later, increasingly refractory to higher dosages of medications
4
F
61
Secondary progressive
1–2 wk
Initial rapid improvement of pain, but continuing relapses, more severe and difficult to control with medications
Outcome after stopping dalfampridine
Abbreviations: MS 5 multiple sclerosis; TN 5 trigeminal neuralgia. Neurology 83
October 28, 2014
1611
already-injured nerves may substantively increase their metabolic demands. Energy metabolism is greatly impaired in demyelinated axons in MS, as shown by severely reduced mitochondrial function.6–9 The inability of injured axons to meet the increased metabolic demands, possibly due to dalfampridine exposure, may have resulted in additional nerve injury.10 In 3 of our patients, the refractoriness of their facial pain to formerly successful therapies suggests that such injuries may be irreversible. We suggest that dalfampridine be used with caution in individuals with either a history of MS-related trigeminal neuralgia or those with altered trigeminal nerve function as a result of this illness. AUTHOR CONTRIBUTIONS Gary Birnbaum: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, accepts responsibility for conduct of research and will give final approval. Jane Iverson: study concept or design, accepts responsibility for conduct of research and will give final approval, acquisition of data, study supervision.
STUDY FUNDING No targeted funding reported.
DISCLOSURE The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.
Received December 27, 2013. Accepted in final form July 28, 2014.
REFERENCES 1. Dunn J, Blight A. Dalfampridine: a brief review of its mechanism of action and efficacy as a treatment to improve walking in patients with multiple sclerosis. Curr Med Res Opin 2011;27:1415–1423. 2. Goodman AD, Brown TR, Edwards KR, et al. A phase 3 trial of extended release oral dalfampridine in multiple sclerosis. Ann Neurol 2010;68:494–502. 3. Limone BL, Sidovar MF, Coleman CI. Estimation of the effect of dalfampridine on health utility by mapping the MSWS-12 to the EQ-5D in multiple sclerosis patients. Health Qual Life Outcomes 2013;11:105. 4. Thaera G, Wingerchuk D, Carter J. Trigeminal neuralgia with initiation of dalfampridine for multiple sclerosis. Neurology 2012;78:P06.P177. Abstract. 5. Cornblath DR, Bienen EJ, Blight AR. The safety profile of dalfampridine extended release in multiple sclerosis clinical trials. Clin Ther 2012;34:1056–1069. 6. Campbell GR, Ziabreva I, Reeve AK, et al. Mitochondrial DNA deletions and neurodegeneration in multiple sclerosis. Ann Neurol 2011;69:481–492. 7. Lassmann H. Pathology and disease mechanisms in different stages of multiple sclerosis. J Neurol Sci 2013;333:1–4. 8. Mahad DJ, Ziabreva I, Campbell G, et al. Mitochondrial changes within axons in multiple sclerosis. Brain 2009; 132:1161–1174. 9. Su K, Bourdette D, Forte M. Mitochondrial dysfunction and neurodegeneration in multiple sclerosis. Front Physiol 2013;4:169. 10. Dutta R, McDonough J, Yin X, et al. Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients. Ann Neurol 2006;59:478–489.
Enjoy Big Savings on NEW 2014 AAN Practice Management Webinars Subscriptions The American Academy of Neurology offers 14 cost-effective Practice Management Webinars you can attend live or listen to recordings posted online. AAN members can purchase one webinar for $149 or subscribe to the entire series for only $199. This is new pricing for 2014 and significantly less than 2013—and big savings from the new 2014 nonmember price of $199 per webinar or $649 for the subscription. Register today for these and other 2014 webinars at AAN.com/view/pmw14: Online Now – ICD-10: Are you Ready? Ensure Your Practice Does Not Receive Payment Interruptions Online Now – Protecting the Solo and Small Practice Neurologist Online Now – Accountable Care Organizations: The Role of Neurologists in New Health Care Models Online Now – E/M: Minimize Mistakes, Maximize Reimbursement Online Now – How Is Your Care Measuring Up?
1612
Neurology 83
October 28, 2014
Dalfampridine may activate latent trigeminal neuralgia in patients with multiple sclerosis Gary Birnbaum and Jane Iverson Neurology 2014;83;1610-1612 Published Online before print September 26, 2014 DOI 10.1212/WNL.0000000000000931 This information is current as of September 26, 2014 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/83/18/1610.full.html
References
This article cites 10 articles, 1 of which you can access for free at: http://www.neurology.org/content/83/18/1610.full.html##ref-list-1
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): All Clinical Neurology http://www.neurology.org//cgi/collection/all_clinical_neurology Class IV http://www.neurology.org//cgi/collection/class_iv Multiple sclerosis http://www.neurology.org//cgi/collection/multiple_sclerosis Trigeminal neuralgia http://www.neurology.org//cgi/collection/trigeminal_neuralgia
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
ABSTRACT
Objective: To determine the effect of dalfampridine (4-aminopyridine), a broad-spectrum, voltagedependent potassium channel blocker, on patients with trigeminal nerve dysfunction due to multiple sclerosis (MS).
Correspondence to Dr. Birnbaum: [email protected]
Methods: We reviewed histories of 71 patients in our clinic with clinically definite MS who were treated with dalfampridine for at least 2 to 3 months. Of the 71 patients, 5 had a history of either trigeminal neuralgia or altered facial sensation.
Results: Of these 5 patients, 3 with preexisting trigeminal neuralgia had a marked worsening of facial pain in close proximity to starting dalfampridine. One patient with altered facial sensation developed trigeminal pain after being on dalfampridine for 18 months. Pain in this individual rapidly subsided when dalfampridine was discontinued. Pain in the worsened 3 patients persisted, became more refractory to previously effective medications, and in one instance required trigeminal surgery for pain control. Conclusions: Dalfampridine should be used with caution in persons with trigeminal neuralgia due to MS.
Classification of evidence: This study provides Class IV evidence that treatment with dalfampridine may precipitate or exacerbate preexisting trigeminal neuralgia. Neurology® 2014;83:1610–1612 GLOSSARY MS 5 multiple sclerosis.
Dalfampridine (4-aminopyridine) is a broad-spectrum, voltage-dependent potassium channel blocker that inhibits functioning of exposed potassium channels in paranodal and internodal axonal membranes. In so doing, it improves action potential conduction in demyelinated motor axons. Several clinical trials demonstrated that such improved conduction resulted in improvement of ambulation in a subset of persons with either relapsing or progressive multiple sclerosis (MS) as measured by the timed 25-foot walk.1–3 While improvement in action potential conduction in motor nerves is of benefit to a subset of persons with MS, increased action potential conduction in injured sensory nerves may result in increased abnormal sensations that could be either paresthetic or dysesthetic symptoms. We propose that this was the case in 4 persons with clinically definite MS, treated with dalfampridine, who experienced either recurrent or new onset of severe facial pain characteristic of trigeminal neuralgia. In 2 patients, symptoms were only partially ameliorated by stopping the dalfampridine, and required additional therapeutic intervention. RESULTS Patient populations. Seventy-one patients with clinically definite MS from the population of individuals being cared for at the MS Treatment and Research Center of the Minneapolis Clinic of Neurology were treated with dalfampridine to improve their ambulatory abilities. All were diagnosed and treated by the first author of this report. All had normal renal function and normal urinalyses. All met the criteria for treatment with dalfampridine as described in the phase III clinical trials of dalfampridine, and now required for drug approval by patients’ health insurance companies, namely, the ability to ambulate 25 feet in more than 8, From the MS Treatment and Research Center, Minneapolis Clinic of Neurology, Golden Valley, MN. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. 1610
© 2014 American Academy of Neurology
but less than 45, seconds.1,2 Treatment with dalfampridine was at least for 1 to 2 months, with discontinuation in one patient because of seizures and in others because of lack of efficacy. Of the 71 dalfampridine-treated patients, 5 had a history of preexisting trigeminal nerve dysfunction. Brain MRIs had been performed on all of these individuals, and no structural causes, other than brainstem demyelination, were noted. Three of the 5 patients had preexisting unilateral, lancinating, extremely severe, episodic facial pain, both spontaneous, and triggered by facial touch or eating, in the distribution of one or more divisions of a trigeminal nerve, in a pattern consistent with trigeminal neuralgia. Two had a history of episodic, unilateral altered facial sensation. In the 3 patients with trigeminal neuralgia, pain was controlled with combinations of carbamazepine, pregabalin, gabapentin, and occasionally a short course of steroids. The table summarizes the data on 4 of the 5 patients. Three patients had previous symptoms of unilateral trigeminal neuralgia resulting from their MS, with recurrences of severe facial pain over the years of their illness. All had symptoms reasonably well controlled with daily doses of medications, such as carbamazepine, pregabalin, and gabapentin, with occasional need for high-dose steroids. In all 3 patients, recurrences of facial pain started within 1 month of initiating treatment with dalfampridine. In the one patient with previous symptoms of facial dysesthesias but no actual pain, the appearance of severe facial pain occurred after 18 months of dalfampridine therapy. Dalfampridine was immediately discontinued in all patients at the time of worsening of their pain, or, in the case of the latter patient, at onset of facial pain. All patients noted an initial improvement in their pain syndrome, but in only one patient, the individual with no antecedent trigeminal neuralgia, did pain resolve completely. In 2 of the remaining 3 patients, subsequent bouts of pain were much more difficult to control, requiring higher doses of previously effective drugs. In the third patient, pain became refractory to
Table
high doses of previously effective medications, administered to the point of unacceptable side effects. The resulting intractable pain syndrome led to severe depression with suicidal ideation. Surgical intervention, in the form of trigeminal rhizotomy, was required to relieve symptoms. DISCUSSION Of the 71 patients treated with dalfampridine in our practice, 5 had a history of trigeminal nerve dysfunction, and 4 of these 5 worsened with dalfampridine therapy. There are other reports of worsening neurologic symptoms after the administration of dalfampridine. Thaera et al.4 noted recurrences of trigeminal neuralgia in 2 patients with progressive MS within 1 month of starting treatment with dalfampridine. Hypertonicity was noted in a subset of patients receiving dalfampridine treatment in the report by Cornblath et al.5 Of anecdotal interest, the fifth patient of the group with previous trigeminal nerve symptoms did not develop facial pain with initiation of dalfampridine therapy, but rapidly developed marked worsening of lower extremity weakness, which improved spontaneously with drug cessation. Toxicity from dalfampridine thus may not be limited to the trigeminal nerve. Our observations on the 4 patients noted above do not prove that dalfampridine was the cause of their neurologic worsening. However, the proximate association between their worsening in 3 of the 4 individuals and the administration of the drug suggests a cause and effect relationship. While the relationship between the administration of dalfampridine and the onset of a trigeminal pain syndrome in the fourth patient is more tenuous, given the longer duration of treatment on dalfampridine, a possible cause and effect cannot be excluded. The rapid cessation of pain after termination of dalfampridine suggests a causal association. The possible mechanism for the worsening of trigeminal neuralgia upon exposure to dalfampridine in our patients is not known. However, one can hypothesize that increasing nerve conduction in
Data of 4 of the 5 patients
Patient
Sex
Age, y
Phase of MS
Interval between starting dalfampridine and worsening/new TN
1
F
52
Secondary progressive
1 wk
Pain improved but the higher doses of medications required to control pain could not be tolerated because of drug toxicity. Patient required unilateral trigeminal rhizotomy to adequately control pain
2
M
49
Relapsing
18 mo
Pain rapidly subsided with minimal medications needed
3
F
62
Secondary progressive
1 mo
Pain initially subsided rapidly but then recurred several months later, increasingly refractory to higher dosages of medications
4
F
61
Secondary progressive
1–2 wk
Initial rapid improvement of pain, but continuing relapses, more severe and difficult to control with medications
Outcome after stopping dalfampridine
Abbreviations: MS 5 multiple sclerosis; TN 5 trigeminal neuralgia. Neurology 83
October 28, 2014
1611
already-injured nerves may substantively increase their metabolic demands. Energy metabolism is greatly impaired in demyelinated axons in MS, as shown by severely reduced mitochondrial function.6–9 The inability of injured axons to meet the increased metabolic demands, possibly due to dalfampridine exposure, may have resulted in additional nerve injury.10 In 3 of our patients, the refractoriness of their facial pain to formerly successful therapies suggests that such injuries may be irreversible. We suggest that dalfampridine be used with caution in individuals with either a history of MS-related trigeminal neuralgia or those with altered trigeminal nerve function as a result of this illness. AUTHOR CONTRIBUTIONS Gary Birnbaum: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, accepts responsibility for conduct of research and will give final approval. Jane Iverson: study concept or design, accepts responsibility for conduct of research and will give final approval, acquisition of data, study supervision.
STUDY FUNDING No targeted funding reported.
DISCLOSURE The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.
Received December 27, 2013. Accepted in final form July 28, 2014.
REFERENCES 1. Dunn J, Blight A. Dalfampridine: a brief review of its mechanism of action and efficacy as a treatment to improve walking in patients with multiple sclerosis. Curr Med Res Opin 2011;27:1415–1423. 2. Goodman AD, Brown TR, Edwards KR, et al. A phase 3 trial of extended release oral dalfampridine in multiple sclerosis. Ann Neurol 2010;68:494–502. 3. Limone BL, Sidovar MF, Coleman CI. Estimation of the effect of dalfampridine on health utility by mapping the MSWS-12 to the EQ-5D in multiple sclerosis patients. Health Qual Life Outcomes 2013;11:105. 4. Thaera G, Wingerchuk D, Carter J. Trigeminal neuralgia with initiation of dalfampridine for multiple sclerosis. Neurology 2012;78:P06.P177. Abstract. 5. Cornblath DR, Bienen EJ, Blight AR. The safety profile of dalfampridine extended release in multiple sclerosis clinical trials. Clin Ther 2012;34:1056–1069. 6. Campbell GR, Ziabreva I, Reeve AK, et al. Mitochondrial DNA deletions and neurodegeneration in multiple sclerosis. Ann Neurol 2011;69:481–492. 7. Lassmann H. Pathology and disease mechanisms in different stages of multiple sclerosis. J Neurol Sci 2013;333:1–4. 8. Mahad DJ, Ziabreva I, Campbell G, et al. Mitochondrial changes within axons in multiple sclerosis. Brain 2009; 132:1161–1174. 9. Su K, Bourdette D, Forte M. Mitochondrial dysfunction and neurodegeneration in multiple sclerosis. Front Physiol 2013;4:169. 10. Dutta R, McDonough J, Yin X, et al. Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients. Ann Neurol 2006;59:478–489.
Enjoy Big Savings on NEW 2014 AAN Practice Management Webinars Subscriptions The American Academy of Neurology offers 14 cost-effective Practice Management Webinars you can attend live or listen to recordings posted online. AAN members can purchase one webinar for $149 or subscribe to the entire series for only $199. This is new pricing for 2014 and significantly less than 2013—and big savings from the new 2014 nonmember price of $199 per webinar or $649 for the subscription. Register today for these and other 2014 webinars at AAN.com/view/pmw14: Online Now – ICD-10: Are you Ready? Ensure Your Practice Does Not Receive Payment Interruptions Online Now – Protecting the Solo and Small Practice Neurologist Online Now – Accountable Care Organizations: The Role of Neurologists in New Health Care Models Online Now – E/M: Minimize Mistakes, Maximize Reimbursement Online Now – How Is Your Care Measuring Up?
1612
Neurology 83
October 28, 2014
Dalfampridine may activate latent trigeminal neuralgia in patients with multiple sclerosis Gary Birnbaum and Jane Iverson Neurology 2014;83;1610-1612 Published Online before print September 26, 2014 DOI 10.1212/WNL.0000000000000931 This information is current as of September 26, 2014 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/83/18/1610.full.html
References
This article cites 10 articles, 1 of which you can access for free at: http://www.neurology.org/content/83/18/1610.full.html##ref-list-1
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): All Clinical Neurology http://www.neurology.org//cgi/collection/all_clinical_neurology Class IV http://www.neurology.org//cgi/collection/class_iv Multiple sclerosis http://www.neurology.org//cgi/collection/multiple_sclerosis Trigeminal neuralgia http://www.neurology.org//cgi/collection/trigeminal_neuralgia
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
