Figure
Study funding: This study is not industry-sponsored. DNA extraction work was undertaken at University College London Hospitals, University College London, which received a portion of funding from the Department of Health’s National Institute for Health Research Biomedical Research Centres funding.
Family pedigree (family 1)
There are 3 members with levodopa-responsive parkinsonism and multiple lipomatosis.
families would argue against a mitochondrial-encoded genetic defect in these cases. Autosomal dominant familial multiple lipomatosis (FML) and its subgroup of familial angiolipomatosis are well-described; however, no genes have been identified. Patients have multiple painless subcutaneous lipomas over the torso and limbs, usually noticeable after the third decade of life, as in our patients.5,6 Since FML can be confused with hamartoma syndromes like neurofibromatosis and more importantly PTEN-related disorders, we excluded known PTEN and NF1 mutations in our patients. A causal relationship between these patients’ parkinsonism and lipomas cannot be directly established. Additional families and genetic tests will be needed to unravel the possible underlying genetic etiologies of this syndrome, which may well be heterogenous. From the UCL Institute of Neurology (M.S., U.-M.S., N.W., K.P.B.), London, UK; Attiko Hospital (M.S.), University of Athens, Greece; and Philipps University (M.S.), Marburg, Germany. Author contributions: Maria Stamelou, U.M. Sheerin: drafting/ revising the manuscript for content, including medical writing for content; analysis or interpretation of data; acquisition of data. Nick W. Wood: drafting/revising the manuscript for content, including medical writing for content. Kailash P. Bhatia: study concept and design; drafting/revising the manuscript for content, including medical writing for content; supervision.
Omar Al-Louzi, MD Howard Hauptman, MD Shiv Saidha, MBBCh, MD, MRCPI
1674
BIOPSY-NEGATIVE PET-POSITIVE GIANT-CELL ARTERITIS
Giant-cell arteritis (GCA) is the most common systemic vasculitis of the elderly, with a lifetime risk of 1% in women and 0.5% in men.1 Failure to identify the early signs of GCA can result in treatment delay, predisposing patients to a number of potentially disabling and life-threatening complications, including anterior ischemic optic neuropathy, stroke, aortic aneurysm, and dissection.2 We present a case of biopsy-negative GCA in which PET-CT revealed evidence of extensive largevessel vasculitis.
Neurology 83
October 28, 2014
Disclosure: M. Stamelou, U. Sheerin, and N. Wood report no disclosures relevant to the manuscript. K. Bhatia serves on the editorial boards of Movement Disorders and Therapeutic Advances in Neurological Disorders; receives royalties from the publication of Oxford Specialist Handbook of Parkinson’s Disease and Other Movement Disorders (Oxford University Press, 2008); received speaker honoraria and travel from GlaxoSmithKline, Ipsen, Merz Pharmaceuticals, LLC, Novartis, and Sun Pharmaceutical Industries Ltd.; received personal compensation for scientific advisory board for GSK and Boehringer Ingelheim; and received research support from Ipsen and from the Halley Stewart Trust through Dystonia Society UK and the Wellcome Trust MRC strategic neurodegenerative disease initiative award (ref. number WT089698), a grant from the Dystonia Coalition, and a grant from Parkinson’s UK (ref. number G-1009). Go to Neurology.org for full disclosures. Received February 10, 2014. Accepted in final form May 22, 2014. Correspondence to Dr. Bhatia: [email protected] © 2014 American Academy of Neurology 1.
Klein C, Schneider SA, Lang AE. Hereditary parkinsonism: Parkinson disease look-alikes: an algorithm for clinicians to “PARK” genes and beyond. Mov Disord 2009;24:
2.
2042–2058. Siciliano G, Mancuso M, Ceravolo R, Lombardi V, Iudice A, Bonuccelli U. Mitochondrial DNA rearrangements in young onset parkinsonism: two case reports.
3.
4.
5.
6.
J Neurol Neurosurg Psychiatry 2001;71:685–687. Orsucci D, Caldarazzo Ienco E, Mancuso M, Siciliano G. POLG1-related and other “mitochondrial Parkinsonisms”: an overview. J Mol Neurosci 2011;44:17–24. Mancuso M, Orsucci D, Angelini C, et al. Phenotypic heterogeneity of the 8344A.G mtDNA “MERRF” mutation. Neurology 2013;80:2049–2054. Gologorsky Y, Gologorsky D, Yarygina AS, Surti U, Zirwas MJ. Familial multiple lipomatosis: report of a new family. Cutis 2007;79:227–232. Abbasi NR, Brownell I, Fangman W. Familial multiple angiolipomatosis. Dermatol Online J 2007;13:3.
Case report. A 64-year-old woman with a history of hypertension and dyslipidemia presented with a 2-month history of occipital headaches, horizontal diplopia, and 10-pound weight loss. Evaluation by her general practitioner, neurologist, and ophthalmologist revealed right temporal artery tenderness and an elevated erythrocyte sedimentation rate (ESR), raising suspicion for GCA. Oral prednisolone was empirically instituted, but then discontinued following a normal right-sided temporal artery biopsy (TAB). At this stage, the patient was reassured that GCA was unlikely. Two weeks later, however, the headache recurred together with new-onset jaw claudication,
Figure
PET/CT images illustrate large-vessel vasculitis
FDG-PET (A) and fused axial CT (B) at baseline demonstrate diffuse, confluent radionuclide uptake in the walls of the ascending aorta, descending aorta, abdominal aorta, subclavian, and common carotid arteries (A and B, arrows). Repeat imaging with fused axial PET/CT shows partial resolution after 4 months of steroid therapy (C).
scalp tenderness (especially while combing hair), and pelvic and shoulder pain. The patient was referred to our center for further neurologic assessment, as the etiology of her symptoms was unclear. Neurologic examination was unremarkable, without clinical evidence of temporal artery abnormalities. ESR and C-reactive protein were markedly elevated (107 mm/hour and 158.1 mg/L, respectively). Syphilis testing was negative. The patient was reluctant to undergo further invasive investigations, including contralateral TAB. PET/CT imaging was therefore performed, which revealed major vessel hypermetabolism, consistent with a large-vessel vasculitis (figure, A and B). GCA was considered the most likely diagnosis, with Takayasu arteritis a less likely differential. High-dose oral prednisolone was instituted, resulting in resolution of symptomatology. Methotrexate was also commenced, and has been slowly titrated, and the dose of prednisolone gradually tapered, without any clinical recurrence. Repeat PET/CT following 4 months of therapy revealed partial resolution of the vasculitis (figure, C). Discussion. TAB demonstrating granulomatous inflammation is the gold standard for diagnosing GCA. Nevertheless, the estimated false-negative rate of TAB ranges from 7% to 61%, a finding likely explained by the segmental (“skipping”) nature of the inflammation in GCA, especially if the biopsy is obtained in an arteritis-free
segment.3,4 The investigation of choice in “biopsynegative” or atypical cases of GCA remains controversial. In one case series, thoracic vascular fluoro-18-deoxyglucose uptake had a sensitivity and specificity of 56% and 98%, respectively, for diagnosing GCA.5 Duplex ultrasonography of the temporal arteries also has utility. In a meta-analysis of temporal artery ultrasonography in GCA, the sensitivity and specificity of the halo sign (a hypoechoic shadow surrounding the temporal artery lumen indicating arterial wall edema) were 69% and 82%, respectively, with the detection of arterial stenosis or occlusion being described as another equally sensitive sign.6 However, spurious detection of temporal artery abnormalities on ultrasonography is reported in 9%–18% of control subjects, notably in the setting of atherosclerosis.6,7 In the current case, we believed that PET/CT imaging would be preferable to temporal artery ultrasonography given the patient’s multiple atherosclerotic risk factors. Skip lesions are not uncommon in GCA and may result in false-negative biopsy results. Neurologists should remain vigilant for this possibility and recognize that further investigations (such as PET/CT imaging or temporal artery ultrasonography) may be necessary to confirm the diagnosis of GCA, which, if untreated, can result in potentially lifethreatening complications. From Johns Hopkins Hospital, Baltimore, MD. Neurology 83
October 28, 2014
1675
Author contributions: Dr. Al-Louzi: data collection and drafting of manuscript. Dr. Hauptman: data collection, drafting, and revision of manuscript. Dr. Saidha: data collection, drafting, revision, and concept of manuscript.
2.
Study funding: No targeted funding reported. Disclosure: O. Al-Louzi and H. Hauptman report no disclosures. S. Saidha receives funding support from the Race to Erase MS and has received consulting fees from Medical Logix for the development of CME programs in neurology, consulting fees from Axon Advisors LLC, educational grant support from Novartis & Teva Neurosciences, and speaking honoraria from the National Association of Managed Care Physicians. Go to Neurology.org for full disclosures.
3.
4. 5.
Received February 25, 2014. Accepted in final form June 18, 2014. Correspondence to Dr. Saidha: [email protected]
6.
© 2014 American Academy of Neurology 1.
Crowson CS, Matteson EL, Myasoedova E, et al. The lifetime risk of adult-onset rheumatoid arthritis and other inflammatory autoimmune rheumatic diseases. Arthritis Rheum 2011;63:633–639.
7.
Schmidt J, Warrington KJ. Polymyalgia rheumatica and giant cell arteritis in older patients: diagnosis and pharmacological management. Drugs Aging 2011;28: 651–666. Mahr A, Saba M, Kambouchner M, et al. Temporal artery biopsy for diagnosing giant cell arteritis: the longer, the better? Ann Rheum Dis 2006;65:826–828. Alberts M. Temporal arteritis: improving patient evaluation with a new protocol. Perm J 2013;17:56–62. Blockmans D, Stroobants S, Maes A, Mortelmans L. Positron emission tomography in giant cell arteritis and polymyalgia rheumatica: evidence for inflammation of the aortic arch. Am J Med 2000;108:246–249. Karassa FB, Matsagas MI, Schmidt WA, Ioannidis JPA. Meta-analysis: test performance of ultrasonography for giant-cell arteritis. Ann Intern Med 2005;142:359–369. Schmidt WA, Kraft HE, Vorpahl K, Völker L, GromnicaIhle EJ. Color duplex ultrasonography in the diagnosis of temporal arteritis. N Engl J Med 1997;337: 1336–1342.
Free Michael J. Fox DVD, Video on Parkinson’s Disease The AAN and the American Brain Foundation present actor and Parkinson’s disease patient Michael J. Fox hosting Parkinson’s Disease: A Guide for Patients and Families. This new patient education video is now available free to members and the public, either on DVD or online. The free DVD can be ordered while supplies last by visiting AAN.com/view/PatientEducationVideos or calling (800) 879-1960. The video can be viewed online at YouTube.com/AANChannel with other patient education DVDs produced by the AAN.
WriteClick® rapid online correspondence The editors encourage comments about recent articles through WriteClick: Go to Neurology.org and click on the “WriteClick” tab at the top of the page. Responses will be posted within 72 hours of submission. Before using WriteClick, remember the following:
• WriteClick is restricted to comments about studies published in Neurology within the last eight weeks • Read previously posted comments; redundant comments will not be posted • Your submission must be 200 words or less and have a maximum of five references; reference one must be the article on which you are commenting • You can include a maximum of five authors (including yourself)
1676
Neurology 83
October 28, 2014
Biopsy-negative PET-positive giant-cell arteritis Omar Al-Louzi, Howard Hauptman and Shiv Saidha Neurology 2014;83;1674-1676 Published Online before print October 1, 2014 DOI 10.1212/WNL.0000000000000940 This information is current as of October 1, 2014 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/83/18/1674.full.html
References
This article cites 7 articles, 1 of which you can access for free at: http://www.neurology.org/content/83/18/1674.full.html##ref-list-1
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): All Headache http://www.neurology.org//cgi/collection/all_headache CT http://www.neurology.org//cgi/collection/ct PET http://www.neurology.org//cgi/collection/pet Secondary headache disorders http://www.neurology.org//cgi/collection/secondary_headache_disorder s
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.
Study funding: This study is not industry-sponsored. DNA extraction work was undertaken at University College London Hospitals, University College London, which received a portion of funding from the Department of Health’s National Institute for Health Research Biomedical Research Centres funding.
Family pedigree (family 1)
There are 3 members with levodopa-responsive parkinsonism and multiple lipomatosis.
families would argue against a mitochondrial-encoded genetic defect in these cases. Autosomal dominant familial multiple lipomatosis (FML) and its subgroup of familial angiolipomatosis are well-described; however, no genes have been identified. Patients have multiple painless subcutaneous lipomas over the torso and limbs, usually noticeable after the third decade of life, as in our patients.5,6 Since FML can be confused with hamartoma syndromes like neurofibromatosis and more importantly PTEN-related disorders, we excluded known PTEN and NF1 mutations in our patients. A causal relationship between these patients’ parkinsonism and lipomas cannot be directly established. Additional families and genetic tests will be needed to unravel the possible underlying genetic etiologies of this syndrome, which may well be heterogenous. From the UCL Institute of Neurology (M.S., U.-M.S., N.W., K.P.B.), London, UK; Attiko Hospital (M.S.), University of Athens, Greece; and Philipps University (M.S.), Marburg, Germany. Author contributions: Maria Stamelou, U.M. Sheerin: drafting/ revising the manuscript for content, including medical writing for content; analysis or interpretation of data; acquisition of data. Nick W. Wood: drafting/revising the manuscript for content, including medical writing for content. Kailash P. Bhatia: study concept and design; drafting/revising the manuscript for content, including medical writing for content; supervision.
Omar Al-Louzi, MD Howard Hauptman, MD Shiv Saidha, MBBCh, MD, MRCPI
1674
BIOPSY-NEGATIVE PET-POSITIVE GIANT-CELL ARTERITIS
Giant-cell arteritis (GCA) is the most common systemic vasculitis of the elderly, with a lifetime risk of 1% in women and 0.5% in men.1 Failure to identify the early signs of GCA can result in treatment delay, predisposing patients to a number of potentially disabling and life-threatening complications, including anterior ischemic optic neuropathy, stroke, aortic aneurysm, and dissection.2 We present a case of biopsy-negative GCA in which PET-CT revealed evidence of extensive largevessel vasculitis.
Neurology 83
October 28, 2014
Disclosure: M. Stamelou, U. Sheerin, and N. Wood report no disclosures relevant to the manuscript. K. Bhatia serves on the editorial boards of Movement Disorders and Therapeutic Advances in Neurological Disorders; receives royalties from the publication of Oxford Specialist Handbook of Parkinson’s Disease and Other Movement Disorders (Oxford University Press, 2008); received speaker honoraria and travel from GlaxoSmithKline, Ipsen, Merz Pharmaceuticals, LLC, Novartis, and Sun Pharmaceutical Industries Ltd.; received personal compensation for scientific advisory board for GSK and Boehringer Ingelheim; and received research support from Ipsen and from the Halley Stewart Trust through Dystonia Society UK and the Wellcome Trust MRC strategic neurodegenerative disease initiative award (ref. number WT089698), a grant from the Dystonia Coalition, and a grant from Parkinson’s UK (ref. number G-1009). Go to Neurology.org for full disclosures. Received February 10, 2014. Accepted in final form May 22, 2014. Correspondence to Dr. Bhatia: [email protected] © 2014 American Academy of Neurology 1.
Klein C, Schneider SA, Lang AE. Hereditary parkinsonism: Parkinson disease look-alikes: an algorithm for clinicians to “PARK” genes and beyond. Mov Disord 2009;24:
2.
2042–2058. Siciliano G, Mancuso M, Ceravolo R, Lombardi V, Iudice A, Bonuccelli U. Mitochondrial DNA rearrangements in young onset parkinsonism: two case reports.
3.
4.
5.
6.
J Neurol Neurosurg Psychiatry 2001;71:685–687. Orsucci D, Caldarazzo Ienco E, Mancuso M, Siciliano G. POLG1-related and other “mitochondrial Parkinsonisms”: an overview. J Mol Neurosci 2011;44:17–24. Mancuso M, Orsucci D, Angelini C, et al. Phenotypic heterogeneity of the 8344A.G mtDNA “MERRF” mutation. Neurology 2013;80:2049–2054. Gologorsky Y, Gologorsky D, Yarygina AS, Surti U, Zirwas MJ. Familial multiple lipomatosis: report of a new family. Cutis 2007;79:227–232. Abbasi NR, Brownell I, Fangman W. Familial multiple angiolipomatosis. Dermatol Online J 2007;13:3.
Case report. A 64-year-old woman with a history of hypertension and dyslipidemia presented with a 2-month history of occipital headaches, horizontal diplopia, and 10-pound weight loss. Evaluation by her general practitioner, neurologist, and ophthalmologist revealed right temporal artery tenderness and an elevated erythrocyte sedimentation rate (ESR), raising suspicion for GCA. Oral prednisolone was empirically instituted, but then discontinued following a normal right-sided temporal artery biopsy (TAB). At this stage, the patient was reassured that GCA was unlikely. Two weeks later, however, the headache recurred together with new-onset jaw claudication,
Figure
PET/CT images illustrate large-vessel vasculitis
FDG-PET (A) and fused axial CT (B) at baseline demonstrate diffuse, confluent radionuclide uptake in the walls of the ascending aorta, descending aorta, abdominal aorta, subclavian, and common carotid arteries (A and B, arrows). Repeat imaging with fused axial PET/CT shows partial resolution after 4 months of steroid therapy (C).
scalp tenderness (especially while combing hair), and pelvic and shoulder pain. The patient was referred to our center for further neurologic assessment, as the etiology of her symptoms was unclear. Neurologic examination was unremarkable, without clinical evidence of temporal artery abnormalities. ESR and C-reactive protein were markedly elevated (107 mm/hour and 158.1 mg/L, respectively). Syphilis testing was negative. The patient was reluctant to undergo further invasive investigations, including contralateral TAB. PET/CT imaging was therefore performed, which revealed major vessel hypermetabolism, consistent with a large-vessel vasculitis (figure, A and B). GCA was considered the most likely diagnosis, with Takayasu arteritis a less likely differential. High-dose oral prednisolone was instituted, resulting in resolution of symptomatology. Methotrexate was also commenced, and has been slowly titrated, and the dose of prednisolone gradually tapered, without any clinical recurrence. Repeat PET/CT following 4 months of therapy revealed partial resolution of the vasculitis (figure, C). Discussion. TAB demonstrating granulomatous inflammation is the gold standard for diagnosing GCA. Nevertheless, the estimated false-negative rate of TAB ranges from 7% to 61%, a finding likely explained by the segmental (“skipping”) nature of the inflammation in GCA, especially if the biopsy is obtained in an arteritis-free
segment.3,4 The investigation of choice in “biopsynegative” or atypical cases of GCA remains controversial. In one case series, thoracic vascular fluoro-18-deoxyglucose uptake had a sensitivity and specificity of 56% and 98%, respectively, for diagnosing GCA.5 Duplex ultrasonography of the temporal arteries also has utility. In a meta-analysis of temporal artery ultrasonography in GCA, the sensitivity and specificity of the halo sign (a hypoechoic shadow surrounding the temporal artery lumen indicating arterial wall edema) were 69% and 82%, respectively, with the detection of arterial stenosis or occlusion being described as another equally sensitive sign.6 However, spurious detection of temporal artery abnormalities on ultrasonography is reported in 9%–18% of control subjects, notably in the setting of atherosclerosis.6,7 In the current case, we believed that PET/CT imaging would be preferable to temporal artery ultrasonography given the patient’s multiple atherosclerotic risk factors. Skip lesions are not uncommon in GCA and may result in false-negative biopsy results. Neurologists should remain vigilant for this possibility and recognize that further investigations (such as PET/CT imaging or temporal artery ultrasonography) may be necessary to confirm the diagnosis of GCA, which, if untreated, can result in potentially lifethreatening complications. From Johns Hopkins Hospital, Baltimore, MD. Neurology 83
October 28, 2014
1675
Author contributions: Dr. Al-Louzi: data collection and drafting of manuscript. Dr. Hauptman: data collection, drafting, and revision of manuscript. Dr. Saidha: data collection, drafting, revision, and concept of manuscript.
2.
Study funding: No targeted funding reported. Disclosure: O. Al-Louzi and H. Hauptman report no disclosures. S. Saidha receives funding support from the Race to Erase MS and has received consulting fees from Medical Logix for the development of CME programs in neurology, consulting fees from Axon Advisors LLC, educational grant support from Novartis & Teva Neurosciences, and speaking honoraria from the National Association of Managed Care Physicians. Go to Neurology.org for full disclosures.
3.
4. 5.
Received February 25, 2014. Accepted in final form June 18, 2014. Correspondence to Dr. Saidha: [email protected]
6.
© 2014 American Academy of Neurology 1.
Crowson CS, Matteson EL, Myasoedova E, et al. The lifetime risk of adult-onset rheumatoid arthritis and other inflammatory autoimmune rheumatic diseases. Arthritis Rheum 2011;63:633–639.
7.
Schmidt J, Warrington KJ. Polymyalgia rheumatica and giant cell arteritis in older patients: diagnosis and pharmacological management. Drugs Aging 2011;28: 651–666. Mahr A, Saba M, Kambouchner M, et al. Temporal artery biopsy for diagnosing giant cell arteritis: the longer, the better? Ann Rheum Dis 2006;65:826–828. Alberts M. Temporal arteritis: improving patient evaluation with a new protocol. Perm J 2013;17:56–62. Blockmans D, Stroobants S, Maes A, Mortelmans L. Positron emission tomography in giant cell arteritis and polymyalgia rheumatica: evidence for inflammation of the aortic arch. Am J Med 2000;108:246–249. Karassa FB, Matsagas MI, Schmidt WA, Ioannidis JPA. Meta-analysis: test performance of ultrasonography for giant-cell arteritis. Ann Intern Med 2005;142:359–369. Schmidt WA, Kraft HE, Vorpahl K, Völker L, GromnicaIhle EJ. Color duplex ultrasonography in the diagnosis of temporal arteritis. N Engl J Med 1997;337: 1336–1342.
Free Michael J. Fox DVD, Video on Parkinson’s Disease The AAN and the American Brain Foundation present actor and Parkinson’s disease patient Michael J. Fox hosting Parkinson’s Disease: A Guide for Patients and Families. This new patient education video is now available free to members and the public, either on DVD or online. The free DVD can be ordered while supplies last by visiting AAN.com/view/PatientEducationVideos or calling (800) 879-1960. The video can be viewed online at YouTube.com/AANChannel with other patient education DVDs produced by the AAN.
WriteClick® rapid online correspondence The editors encourage comments about recent articles through WriteClick: Go to Neurology.org and click on the “WriteClick” tab at the top of the page. Responses will be posted within 72 hours of submission. Before using WriteClick, remember the following:
• WriteClick is restricted to comments about studies published in Neurology within the last eight weeks • Read previously posted comments; redundant comments will not be posted • Your submission must be 200 words or less and have a maximum of five references; reference one must be the article on which you are commenting • You can include a maximum of five authors (including yourself)
1676
Neurology 83
October 28, 2014
Biopsy-negative PET-positive giant-cell arteritis Omar Al-Louzi, Howard Hauptman and Shiv Saidha Neurology 2014;83;1674-1676 Published Online before print October 1, 2014 DOI 10.1212/WNL.0000000000000940 This information is current as of October 1, 2014 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/83/18/1674.full.html
References
This article cites 7 articles, 1 of which you can access for free at: http://www.neurology.org/content/83/18/1674.full.html##ref-list-1
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): All Headache http://www.neurology.org//cgi/collection/all_headache CT http://www.neurology.org//cgi/collection/ct PET http://www.neurology.org//cgi/collection/pet Secondary headache disorders http://www.neurology.org//cgi/collection/secondary_headache_disorder s
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.
