LETTERS TO THE EDITOR

POLYMYALGIA RHEUMATICAFOLLOWING INFLUENZA VACCINATION

A 61-year-old man with a previous history of diabetes typeII controlled with diet received a trivalent influenza vacci-nation (Inflexal Berna 1998–99: A/Sidney/5/97, A/Bei-jing/262/95, B/Beijing/184/93). Three weeks prior tovaccination, examination by his family practitioner andlaboratory tests, including erythrocyte sedimentation rate(ESR), were normal. Two weeks after vaccination, he ex-perienced stiffness and pain in the shoulder and hipmuscles, malaise, fatigue, anorexia, and slight weight loss.He was hospitalized 1 month later for evaluation. Physicalexamination showed only stiffness and pain in the musclesof the neck, shoulders, and hips. Laboratory studies re-vealed an ESR of 80 mm/h, and an elevated C-reactiveprotein (CRP). Findings of routine blood chemistry pro-file, including creatine kinase and myoglobin, were nor-mal. A chest radiograph and needle electromyography(EMG) of proximal muscles were normal. Further investi-gations showed normal titers of antinuclear and antineu-trophil cytoplasmic antibodies, as well as normal levels ofcomplement components and rheumatoid factor. Serol-ogy for parvovirus B19, viral hepatitis, Mycoplasma pneu-moniae, human immunodeficiency virus infection, Q fever,Brucella species, Chlamydia species, Borrelia burgdorferi, cy-tomegalovirus, Epstein–Barr virus, and Treponema pallidum,was normal. Typing of HLA revealed the presence ofDRB1*0404 allele. A temporal artery biopsy was negative.A presumptive diagnosis of polymyalgia rheumatica(PMR) was made and he was treated with prednisone 15mg daily, with rapid and complete clearing of his symp-toms. At 12-month follow-up, he is being treated with pred-nisone (5 mg/day), without recurrence of his symptoms,and with a normal ESR and CRP.

Influenza vaccination has been associated rarely withserious side effects, such as Guillain–Barre syndrome,4 vas-culitis,3 and rheumatic complications.1 To our knowledge,

PMR has been reported in the English-language literaturein only one other case following influenza vaccination.1

PMR is a disease of the elderly, with symptoms such asaching and morning stiffness in the neck, shoulders, andpelvic girdle, along with evidence of an underlying inflam-matory reaction.6 Most genetic studies of PMR have in-volved the major histocompatibility complex (MHC) onthe short arm of chromosome 6, as one genetic determi-nant for PMR.7 This complex encodes the histocompat-ibility antigens (the HLA system) that present peptide an-tigens to T cells, which regulate the immune responsesagainst protein antigens.5 Recently, Haworth et al.2 re-ported that PMR is associated with both HLA-DRB1*0401and DRB1*0404 alleles.

This previously healthy patient developed a disorderthat met the criteria for classification as PMR6 after influ-enza vaccination. The close temporal relationship betweeninfluenza vaccination and the onset of PMR suggests thatinfluenza vaccination may have induced PMR in a geneti-cally predisposed individual supported by the presence ofthe HLA-DRB1*0404 allele. The mechanism by which in-fluenza vaccination may have induced PMR in this patientis unclear. One possible explanation is that interplay be-tween the HLA-DRB1*0404 as a class II molecule in theantigen-presenting cells with influenza vaccination anti-gen, and CD4+ helper T lymphocytes could produce anautoimmune reaction, clinically manifested as PMR.Therefore, influenza vaccination may have triggered PMRin a patient with the HLA-DRB1*0404 allele, which predis-posed to PMR. Other similar observations could confirmthis hypothesis.

Carlos Perez, MD1

Elias Maravi, MD2

1Department of Internal Medicine, Hospital Virgen del Camino,31008 Pamplona, Spain2Department of Neurology, Hospital Virgen del Camino, 31008Pamplona, Spain

1. Brown MA, Bertouch JV. Rheumatic complications of influ-enza vaccination. Aust NZ J Med 1994;24:572–573.

2. Haworth S, Ridgeway J, Steward I, Dyer PA, Pepper L, OllierW. Polymyalgia rheumatica is associated with both HLA-DRB1*0401 and DRB1*0404. Br J Rheumatol 1996;35:632–635.

© 2000 John Wiley & Sons, Inc. The letter by McGill and Lateva is a USGovernment work and, as such, is in the public domain in the UnitedStates of America.

824 Letters to the Editor MUSCLE & NERVE May 2000

3. Kelsall JT, Chalmers A, Sherlock CH, Tron VA, Kelsall AC.Microscopic polyangiitis after influenza vaccination. J Rheu-matol 1997;24:1198–1202.

4. Langmuir AD, Bregman DJ, Kurland LT, Nathanson N, VictorM. An epidemiologic and clinical evaluation of Guillain–Barre syndrome reported in association with the administra-tion of swine influenza vaccines. Am J Epidemiol 1984;119:841–879.

5. Owen M, Steward M. Antigen recognition. In: Roitt I, BrostoffJ, Male D, editors. Immunology. London: Mosby; 1998. p107–119.

6. Salvarani C, Macchioni P, Boiardi L. Polymyalgia rheumatica.Lancet 1997;350:43–47.

7. Weyand CM, Hunder NNH, Hicok KC, Hunder GG, GoronzyJJ. HLA-DRB1 alleles in polymyalgia rheumatica, giant cellarteritis, and rheumatoid arthritis. Arthritis Rheum 1994;37:514–520.

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DIABETIC MUSCULAR INFARCTION

Diabetic muscle infarction (DMI) is a rare but well-documented entity presenting abruptly as a painful, swol-len, tender mass in the thigh in patients with poorly con-trolled, long-duration diabetes. Although recurrences arenot uncommon, the short-term prognosis has been de-scribed as excellent, with complete recovery in a few weeksor months.1–5

A 34-year-old woman with insulin-dependent diabetesmellitus since the age of 20 years was admitted to ourinstitution because of diarrhea secondary to diabetic en-teropathy. For the previous 10 months, the patient hadsuffered from pain in both thighs, especially when walking.During her admission, the patient complained of severepain together with tenderness, swelling, and weakness inboth lower extremities that worsened over the followingfew days. On examination, the patient was pale and inpoor general health. There was diffuse swelling in the an-terior and posterior aspects of both thighs and legs, whichwere extremely painful to the touch. The skin was pale andindurated. The posterior tibial and dorsalis pedis pulseswere reduced bilaterally. The tendon reflexes were all ab-sent. The patient had severe weakness in the lower ex-tremities (Medical Research Council grade 0/5 proxi-mally; 3/5 distally) and hypoesthesia to all modalities in asock-and-glove distribution in the four limbs.

Investigations revealed that hematocrit was 20%; he-moglobin, 6.4 g/dL; mean corpuscular volume, 85 fL;erythrocyte sedimentation rate, 91 mm/h; and white cellcount, 14,800/mm3 (neutrophils, 90%; lymphocytes, 8%).Fasting serum glucose was 13 mmol/L (normal, 3.8–7.8mmol/L); albumin, 38 g/L (normal, 39–49 g/L); and cre-atine kinase, 1,080 IU/L (normal, 42–270 IU/L). Dopplerultrasound study of the lower extremities was negative.

Nerve conduction studies showed absent ulnar and pe-roneal sensory nerve action potentials (SNAPs). Mediansensory conduction velocity was 40 m/s with a 7.7 µV an-tidromic SNAP. Ulnar motor conduction velocity was 48.4

m/s (elbow-to-wrist segment) with a compound muscleaction potential (CMAP) of 0.9 mV; median motor con-duction velocity was 44.1 (elbow-to-wrist segment) with aCMAP of 1.5 mV. Needle electromyography showed fibril-lation potentials and positive sharp waves in proximal anddistal muscles of the legs and a mixed pattern of large andsmall motor unit potentials with early recruitment in someareas and reduced interference pattern in others. Someareas of the muscles, however, were electrically silent, bothat rest and after voluntary contraction, thus indicating re-placement of muscle fibers by fibrous tissue.

Magnetic resonance imaging showed diffuse swellingof the quadriceps, thigh adductors, and gastrocnemius ofboth extremities, with abnormal high signal within themuscle on T2-weighted images. A muscle biopsy of thevastus medialis showed large areas of muscle fiber hemor-rhagic necrosis and scattered regenerating fibers. Therewere focal inflammatory infiltrates of lymphocytes andmacrophages. Thrombosis of the intramuscular vessels wasalso present, but no evidence of vasculitis was found (Fig.1). Two months after symptom onset, the pain lessenedand the swelling gradually decreased, but induration wasstill present. Over the following months, the patient con-tinued to improve, but walking with support was delayeduntil 9 months after the initial symptoms.

Since its original description, DMI has been reportedin about 26 cases. In most, muscle infarction occurredunilaterally in thigh muscles or, rarely, in calf muscles.Occlusive arteriosclerosis and abnormalities in the clottingcascade and fibrinolytic pathways have been implicated inits pathogenesis.1–5

Clinical, electrophysiological, and pathological find-ings in our patient were consistent with DMI. The largeextent of the infarcted muscles, affecting both lower limbssimultaneously, together with the replacement of large ar-eas of muscle with fibrous tissue and the existence of asevere axonal polyneuropathy, probably contributed tothe delayed recovery. Taken together, our observations

FIGURE 1. Longitudinal section of the muscle biopsy showingwidespread necrosis, degeneration of muscle fibers, and inflam-matory cells. (Hematoxylin and eosin, original magnification×100.)

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illustrate that DMI may in some cases lead to severe clinicaldeficits followed by a slow and protracted recovery period.

M. Anglada, MDA. Vidaller, MD, PhDF. Bolao, MDDepartment of Internal Medicine, Hospital Príncipes deEspana, Barcelona, Spain

I. Ferrer, MD, PhDNeuropathology Unit, Department of Cellular Biology andPathologic Anatomy, University of Barcelona, HospitalPríncipes de Espana, Barcelona, Spain

M. Olive MD, PhDDepartment of Neurology, Neuromuscular Unit, HospitalPrıncipes de Espana, Barcelona, Spain

1. Angervall L, Stener B. Tumoriform focal muscle degenera-tion in two diabetic patients. Diabetologia 1965;1:39–42.

2. Banker BQ, Chester CS. Infarction of thigh muscle in thediabetic. Neurology 1975;23:667–677.

3. Bodner RA, Younger DS, Rosoklija G. Diabetic muscle infarc-tion. Muscle Nerve 1994;17:949–950.

4. Chester CS, Banker BQ. Focal infarction of muscle in diabet-ics. Diabetes Care 1986;9:623–630.

5. Umpierrez GE, Stiles RG, Kleinbart J, Krendel DA, Watts NB.Diabetic muscle infarction. Am J Med 1996;101:245–250.?

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SLOW REPOLARIZATION PHASE OF THEINTRACELLULAR ACTION POTENTIALINFLUENCES THE MOTOR UNITACTION POTENTIAL

We offer a few comments about the recent article by Du-mitru et al.,2 which discusses the effect of the slow repo-larization phase of the muscle-fiber intracellular action po-tential (IAP) on the duration of the motor unit actionpotential (MUAP).

As the article points out, even though the existence ofthe slow repolarization phase (or “negative afterpoten-tial”) has long been reported in intracellular studies ofsingle muscle fibers, little consideration has been given tothe way in which it affects the extracellular potentials re-corded in clinical EMG. In fact, to the best of our knowl-edge, the realization that traditional IAP models (which donot take the slow repolarization phase into account) areinadequate for describing certain aspects of MUAP mor-phology was made only very recently.1,3,4 The current ar-ticle by Dr. Dumitru and his colleagues, as well as thoseearlier works, now demonstrate that the final segment ofthe MUAP is actually a manifestation of the IAP’s slowrepolarization phase, and that the slow repolarizationphase therefore contributes substantially to MUAP dura-tion.

The article shows that the terminal part of the MUAP

arises from the termination of the action potential at themuscle/tendon junction and that it mirrors the basic mor-phology of the IAP. However, it should be pointed out thatthe shapes of the MUAP terminal part and the IAP are notidentical. For example, in the signals shown in Figure 2C,Dof the article, the “small positive afterwaves” (or “terminalwaves”) can be seen to be considerably wider and moresymmetrical than the IAP spike (Fig. 1B). The reason forthis is that the action potentials of the individual fibers ofthe motor unit reach their respective muscle/tendon junc-tions at different times, owing to differences in conductionvelocity and muscle-fiber semilength. As a result, the ter-minal wave is wider than the IAP spike by an amount equalto the dispersion in arrival times.

The article describes the generation of the MUAP us-ing a leading/trailing dipole model in which the repolar-ization phase of the IAP is modeled as a single, very longtrailing dipole. While this model is useful for understand-ing some aspects of MUAP morphology, it unfortunatelymakes it appear as if the only current sources in the nearvicinity of the propagating action potential are the sourceand sink of the leading dipole and the sink of the trailingdipole (e.g., Fig. 4B–D), with the source of the trailingdipole remaining a considerable distance away at the end-plate. This gives the incorrect impression that at pointsalong the fiber, the passing action potential has more of adipole character than a quadrupole character.

A more accurate model of IAP repolarization wouldinclude two trailing dipoles, the first corresponding to therapid phase of repolarization and the second to the slowphase. The first trailing dipole would have a spatial extentof about 6 mm and a dipole moment 80% that of theleading dipole (see Fig. 1C). The second trailing dipolewould have a spatial extent of about 105 mm and a dipolemoment 20% that of the leading dipole. This model wouldmore accurately characterize the appreciable repolariza-tion current associated with the propagating action poten-tial, and it would also make it clear that the terminal wavegenerated when the action potential reaches the muscle/tendon junction is produced by the dipole moment of thefirst trailing dipole being unmasked as the leading dipoledisappears.

The discussion in the article of the way in which theslow repolarization of the IAP gives rise to the final seg-ment of the MUAP might also be subject to misinterpre-tation. Figure 4G,H of the article correctly shows thatwhen the entire length of the muscle fiber is undergoingslow repolarization, the active currents can be modeled asa sink at the muscle/tendon junction and a source at theendplate (along with a second sink/source pair on theother side of the fiber). However, this is not equivalent toa point dipole located at the muscle/tendon junction asFigure 4 implies. Rather, the currents should be modeledindividually, or as a quadrupole source distributed overthe entire length of the muscle fiber.

Finally, it is worthwhile pointing out that the terms“near-field” and “far-field” can lead to a certain amount of

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confusion when applied to MUAP components. For ex-ample, for each of the waveforms shown in Figure 2 of thearticle, the initiation of the MUAP is called “near-field”and the terminal part is called “far-field,” even though thesource of the initiation (the endplate) is as far from, orfarther than the recording electrode than is the source ofthe terminal part (the muscle/tendon junction). Indeed,the initiation exhibits all of the characteristics usually at-tributed to a “far-field” potential5: it has a distant sourceand it does not change significantly in latency, polarity,shape, or amplitude when the recording electrode is re-positioned over short distances. The reason that the ini-tiation is considered “near-field” is that its source is a bal-anced quadrupole, whereas the source of the terminalwave is a dipole. Thus, when using the terms “near-field”and “far-field” to refer to MUAP components, one shouldkeep in mind that these terms do not necessarily refer tothe distance of the source or the local behavior of the field,but rather to the electrical character of the source and thetheoretical asymptotic behavior of the field.

We find it more insightful to think of the MUAP intemporal, rather than spatial, terms—as a record of thesequence of electrical events that take place in themuscle.3,4 Thus, the initiation of the MUAP marks theinitiation of the action potential volley at the endplates,the spike marks the propagation of the volley past therecording electrode, the terminal wave marks the termi-nation of the volley at the muscle/tendon junctions, andthe final return to the baseline (or “slow afterwave”) cor-responds to the slow repolarization of the muscle fibers.This approach focuses on the temporal evolution of theentire potential field and so provides a unified frameworkfor understanding the morphologies of muscle action po-tentials recorded by both needle and surface electrodes atall locations within and outside the muscle.

Kevin C. McGill, PhD1,2

Zoia C. Lateva, PhD1

1Rehabilitation Research and Development Center, VA PaloAlto Health Care System, Palo Alto, California 94304, USA2Department of Functional Restoration, Stanford UniversitySchool of Medicine, Stanford, California 94305, USA

1. Dimitrov GV, Lateva ZC, Dimitrova NA. Model of the slowcomponents of skeletal muscle potentials. Med Biol EngComp 1994;32:432–436.

2. Dumitru D, King JC, Rogers WE. Motor unit action potentialcomponents and physiologic duration. Muscle Nerve 1999;22:733–741.

3. Lateva ZC, McGill KC. The physiological origin of the slowafterwave in muscle action potentials. ElectroencephalogrClin Neurophysiol 1998;109:462–469.

4. Lateva ZC, McGill KC, Burgar CR. Anatomical and electro-physiological determinants of the human thenar compoundmuscle action potential. Muscle Nerve 1996;19:1457–1468.

5. Stegeman DF, Dumitru D, King JC, Roeleveld K. Near- andfar-fields: source characteristics and the conducting mediumin neurophysiology. J Clin Neurophysiol 1997;14:429–442.

REPLY

We thank the Editor for the opportunity to respond to theletter of Drs. McGill and Lateva regarding our work.5 Theinvestigation under discussion is predicated upon our pre-vious basic science and clinical observations regarding mo-tor unit action potential (MUAP) durations in excess of20–30 ms.1–4,6 These works were inspired by the observa-tion of the intracellular action potential’s long repolariza-tion phase and clinical documentation of the similar onsetof a MUAP irrespective of recording location along themuscle fiber.

Though our work demonstrates an empiric relation-ship between the traveling action potential component(defined as the near-field component) and its terminationat the musculoskeletal junction (defined as the far-fieldcomponent) it does not substantiate the specifics of Drs.McGill and Lateva’s work. Their conceptualization of aslow afterwave is not contradicted by our data, but neitheris it specifically corroborated. The suggestion of incorpo-rating a heptapole (leading dipole and two trailing di-poles) to reflect more accurately what is occurring reflectstheir prior conceptualization that two processes are in-volved in repolarization. This point of conjecture is notspecifically addressed by our data, though its possibility iscommented upon in our discussion of transverse tubuledelayed repolarization. In actual fact, an infinite numberof point dipoles would most accurately reflect the mor-phology of the intracellular action potential. However, thedouble dipole is a powerful simplification that helps toexplain and clarify much of what is observed. As a simpli-fied model, it has limitations, however, many of whichwould also occur with Drs. McGill and Lateva’s proposedheptapole model.

The final segment of the motor unit action potentialrepresents the termination of the action potential at themusculotendinous junction. This negative afterpotentialinvolves more than just the slow repolarization terminalphase, which has been the basis upon which Drs. McGilland Lateva have based their incomplete conceptualizationof the entire negative afterpotential. Appreciating the ter-minal musculotendinous junction “far-field” effects is justas important as looking at only the terminal aspects of thissummated mirrored internal action potential. Drs. McGilland Lateva agree with us regarding the reasons for thispotential being somewhat wider than expected of indi-vidual muscle fiber intracellular action potentials, which islargely due to temporal dispersion of the involved fibers.We agree with the issue, that was discussed, of terminologyregarding far-field and near-field difficulties when appliedto these two components.

It is important to appreciate that our work, like that ofDrs. McGill and Lateva, used a sophisticated and quanti-tative volume conductor computerized model steeped inmathematical assumptions. However, we have attemptedto diminished the esoteric nature of volume conductortheory as it applies to clinical situations by using the ad-mittedly simple and qualitative, yet nevertheless powerful,

Letters to the Editor MUSCLE & NERVE May 2000 827

conceptual tool referred to as the leading/trailing dipolemodel. We believe these fundamental concepts of volumeconductor theory should be accessible to clinicians whowish to conceptualize these clinically relevant theories.When utilizing a qualitative model such as that of the lead-ing/trailing dipole, there will, by necessity, be sometradeoffs compared to complex mathematics. The lead-ing/trailing dipole model actually permits a level of un-derstanding, as opposed to merely looking at figures sur-rounded by relatively incomprehensible mathematicalformulae or verbiage that, in effect, says “trust us.” Further,the admittedly simple leading/trailing dipole model actu-ally permits the interested clinician to apply volume con-ductor theory on daily recorded waveforms and actuallyperform meaningful research. This cannot be said for allapproaches. The letter of McGill and Lateva did not sug-gest our presentation was somehow “inaccurate,” butrather that their and our conceptualization of what is oc-curring is not the same, when in fact we have more ideasin common than different. On this issue, we hope that weagree. Additionally, we hope that a greater appreciation ofthe components that summate temporally to create a mo-tor unit action potential will help to clarify the MUAP’sphysiology and lead to more rational criteria for establish-ing MUAP duration than the present empiric basis.

Daniel Dumitru, MD, PhDJohn C. King, MDRehabilitation Medicine

University of Texas Health Science Center

7703 Floyd Curl Drive

San Antonio, Texas 78284-7798, USA

1. Dumitru D, King JC. Concentric needle recording character-istics related to depth of tissue penetration. Electroencepha-logr Clin Neurophysiol 1998;109:124–134.

2. Dumitru D, King JC, Nandedkar SD. Comparison of singlefiber and macro electrode recordings: relationship to motorunit action potential duration. Muscle Nerve 1997;20:1381–1388.

3. Dumitru D, King JC, Nandedkar SD. Motor unit action po-tential duration recorded by monopolar and concentricneedle electrodes: physiologic implications. Am J Phys MedRehabil 1997;76:488–493.

4. Dumitru D, King JC, Nandedkar SD. Motor unit action po-tentials recorded with concentric electrodes: physiologic im-plications. Electroencephalogr Clin Neurophysiol 1997;105:333–339.

5. Dumitru D, King JC, Rogers WE. Motor unit action potentialcomponents and physiologic duration. Muscle Nerve 1999;22:733–741.

6. King JC, Dumitru D, Stegeman D. Monopolar needle elec-trode spatial recording characteristics. Muscle Nerve 1996;19:1310–1319.

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