J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.48.9.882 on 1 September 1985. Downloaded from

Journal of , Neurosurgery, and Psychiatry 1985;48:882-886

Tubular aggregates: their association with myalgia

ENAYAT NIAKAN,* YADOLLAH HARATI,* MORIS J DANONt From the Department ofNeurology, Baylor College of Medicine, Houston * and Department ofNeurologyt University of Illinois Medical Center, Chicago, USA

SUMMARY Three thousand consecutive muscle biopsies were reviewed for the presence of tubular aggregates and their association with clinical symptomatology. Tubular aggregates were detected in 19 patients (0.6%). Twelve of these nineteen patients had severe myalgia, and the most abundant tubular aggregates were found in biopsies of patients with myalgia. Seven patients had only myalgia as their clinical symptomatology with normal physical examination. An additional five patients with tubular aggregates and myalgia had concomitant amyotrophic lateral sclerosis (2) or neuropathy (3). The high incidence of myalgia associated with tubular aggregates in our patients and the fact that tubular aggregates originate from sarcoplasmic reticulum suggest a role played by this structure in the pathogenesis of myalgia. guest. Protected by copyright. Tubular aggregates are visible by light microscopy quadriceps or biceps muscles. For histochemical studies, within Type II muscle fibres as a mass in the subsar- tissue had been frozen with liquid nitrogen, sectioned colemmal region with strong NADH-tetrazolium at 10,1L in a cryostat, and stained with the following reductase (NADH-TR) and negative succinic methods: Modified Gomori Trichrome (TRI), NADH-TR, adenosine triphosphatase (ATPase) at pH 9-4, succinic dehydrogenase reactions. Ultrastructurally they are dehydrogenase and phosphorylase. For electon micros- closely packed, parallel, double-walled tubules copy, tissue had been fixed in 1 % glutaraldehyde buffered which appear to be a proliferation of sarcoplasmic at pH 7-4 for 11/2 h and then fixed in 1% osmium tetroxide reticulum.' The diagnostic importance of tubular for another hour. Some material was then embedded in aggregates is uncertain because they are present in Epon and sections 1 ,u thick were cut for all blocks, stained muscles of patients with a wide variety of disor- with toluidine blue and examined under the light micros- ders.' -21 Recently tubular aggregates have been copy. Thin sections for electron microscopy were then described in muscle biopsy specimens of patients stained with uranyl acetate and with lead citrate. with myalgia who are otherwise normal.2'26 The fact that tubular aggregates originates from sarco- Results plasmic reticulum, which has an important role in regulation of muscle and relaxation, Among 3000 patients 19 (0.6%) had histochemi- suggests a relationship between tubular aggregates, cally typical tubular aggregates; 17 patients were sarcoplasmic reticulum and myalgia. To clarify this male and two female. With the TRI stain, the tubu- we reviewed muscle biopsy specimens lar aggregates appeared as bright red staining sub- relationship, seen for the presence of tubular aggregates and their sarcolemmal material. Tubular aggregates were http://jnnp.bmj.com/ association with clinical symptomatology. only in the Type II fibres, were darkly stained by the NADH-TR, and unstained by ATPase and succi- Methods nate dehydrogenase (fig 1). Further studies includ- ing electron microscope and epoxy resin histology We analysed all 3000 muscle biopsy specimens at our were done in some cases which showed closely institution in the preceeding seven years. All were from the packed, parallel, double-walled tubules (fig 2). Five biopsies showed less than 1% fibres affected Presented in part at the Thirty-Sixth Annual Meeting of the and

six between on September 30, 2021 by Boston, April, 1984 with tubular aggregates, 1-10%, American Academy of Neurology, eight had more than 10% fibres with tubular aggre- Address for reprint requests: Dr Harati, Department of Neurology, gates. This was determined after obtaining a 10OX Baylor College of Medicine, 6501 Fannin, Houston, Texas 77030, photograph of each biopsy specimen and counting USA. the number of tubular aggregates per 200 muscle Received 5 June 1984 and in revised form 27 August 1984 fibres. Accepted 1 September 1984 Clinically, 12 of 19 patients had severe myalgia, 882 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.48.9.882 on 1 September 1985. Downloaded from

Tubular aggregates: their association with myalgia 883

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884 Niakan, Harati, Danon

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and the most abundant tubular aggregates were fibres. The differential diagnosis of tubular aggre- found in specimens from these patients. Seven gates include other tubular structures within muscle patients had only myalgia as their clinical symp- fibres.'2 16 Honeycomb structures are round empty tomatology with normal physical examination and spaces in an hexagonal arrangement that can resem- laboratory tests. Three of them had muscle tender- ble tubular aggregates. Tubular aggregates should ness on palpation. Tubular aggregates was the pre- also be differentiated from cylindrical spirals, which dominant abnormality in the muscle of these have also been reported in patients with different patients. Two patients with tubular aggregates and clinical presentations." 27-29 Histochemically, the myalgia had amyotrophic lateral sclerosis and three appearance of cylindrical spirals is similar to tubular http://jnnp.bmj.com/ had . The seven remaining aggregates.'" 27 29 They also affect Type II fibres cases who did not have myalgia had neuropathy exclusively, but their unique electron microscopic (two) amyotrophic lateral sclerosis (one), systemic appearances differentiate them from tubular aggre- erythematosis (one), congenital gates.'" 27-29 They may, however, be associated with (one), and two of the patients had muscle tubular aggregates.'" 27 The origin and significance of with undetermined aetiology. No patient had tubu- cylindrical spirals are uncertain. lar aggregates associated with drug use. Tubular aggregates have been reported in a wide variety of disorders including alcoholic on September 30, 2021 by Discussion myopathy,'6 '7 gyrate atrophy of the eye,2 con- genital myasthenia gravis,4-I 14 myotonia,7 Tubular aggregates are distinguished from ragged hypokalaemic periodic paralysis,' 8 9 18-21 hyper- red fibres on the basis of strong NADH-TR and kalaemic periodic paralysis,' normokalaemic negative succinate dehydrogenase reactions and periodic paralysis,'3 inflammatory myopathy,2' because tubular aggregates only affect Type II diabetic ,3 hyperaldosteronism,'2 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.48.9.882 on 1 September 1985. Downloaded from

Tubular aggregates: their association with myalgia 885 prophyria cutanea tarda' and chronic drug expos- tubular aggregates in our patients and previous ure.' A similar abnormality has been found in mus- reports of similar cases,2'-26 suggest a role played by cles of mice after anoxia30 and after local injection of this structure in the pathogenesis of myalgia. The botulinum,3' tetanus toxin,3' and perhexiline male- relationship between tubular aggregates, sarco- ate33 and in murine dystrophic heterozygotes.34 plasmic reticulum and calcium metabolism may also Tubular aggregates have also been described in explain why tubular aggregates are seen only in the association with myalgia in otherwise normal indi- Type II fibres. Type II fibres have considerably more viduals.226 Twelve of 19 of our patients with tubu- sarcoplasmic reticulum than the Type I fibres.35 In lar aggregates had severe myalgia. Seven patients Type II fibres, the sarcoplasmic reticulum is possibly had myalgia as their sole clinical symptomatology qualitatively different from that of the Type 1 fibre.' and despite extensive investigation, no definite Also it has been shown in rabbits that white muscle diagnosis could be made. Like patients reported by fibres (Type II) have more active calcium- Rosenberg et al,2' myalgia was not necessarily pre- concentrating microsoms than red muscle fibres cipitated by exercise. Three of these cases had (Type 1).36 These structural differences may predis- severe muscle on palpation. Tubular pose Type II fibres to tubular aggregates formation. aggregates was the prominent abnormality in the In spite of relationships between tubular aggre- muscle of these patients. Five other patients with gates, sarcoplasmic reticulum and myalgia, tubular tubular aggregates and myalgia had concomitant aggregates are not always associated with myalgia. amyotrophic lateral sclerosis or neuropathy. In these There may be different types of tubular aggre- patients myalgia was one of their major complaints. gates,'2 16 7 37 38 but there are classic forms of tubular It is generally accepted that tubular aggregates aggregates in patients who never complain of myal- originate in the sarcoplasmic reticulum, but their gia. Also, in our patients who had electron micros- guest. Protected by copyright. pathogenesis is unknown. Based on the finding of copic studies, the pattern of tubular aggregates was tubular aggregates in muscle biopsies of patients similar in cases with or without myalgia. Degree of chronically using large amounts of - muscle fibre involvement with tubular aggregates narcotic drugs and ,' 16 it has been postulated may be an important factor for appearance of myal- that they may form in response to exogenous or gia since the most abundant tubular aggregates were endogenous toxin. However, these reports failed to found in our patients with myalgia. indicate why these medications were taken or why Based on our observation and review of litera- the muscle biopsies were performed,' 16 and it may tures, we suggest the association of myalgia and be that the reason for chronic analgesic use was for tubular aggregates may be important. Although relief of myalgia.'6 It has also been suggested that myalgia is the most prominent feature in the symp- tubular aggregates may represent adaptive hyper- tomatology of a wide variety of conditions, in many plastic sarcoplasmic reticulum derivatives to patients no firm diagnosis can be made despite improve calcium uptake in alcoholic myopathy.'7 extensive investigation.39 Therefore, the presence of However, there was no history of chronic drug use tubular aggregates in patients complaining of mayl- or alcoholic abuse in our cases. We also doubt that gia may be a hallmark and should not be regarded as this is a -induced lesion as postulated by a nonspecific finding. Recognition of these combina- Dunkle et al'8 and Bergman,89 since no evidence of tions in time may lead to a better understanding of viral infection of muscle was seen. There is thus no the significance of tubular aggregates. This relation- satisfactory explanation for the formation of tubular ship between tubular aggregates, sarcoplasmic aggregates, nor for their occurrence in a wide variety reticulum and myalgia may also have important http://jnnp.bmj.com/ of , but there may be an explanation of the therapeutic implications, since drugs which are high incidence of myalgia associated with them. known to affect these structures may prove benefi- Sarcoplasmic reticulum has an important role in cial in alleviating symptoms of myalgia. contraction and relaxation of muscle. The function of the sarcoplasmic reticulum is regulation of the We thank Mr Karam Matta, and Ms C Zultner, for calcium concentration in the vicinity of actin and the technical assistance. Supported in part by a grant myosin interaction. This regulation of calcium con- from the Frost Foundation. centration is the control factor for turning on and off on September 30, 2021 by the basic contractile unit, the sarcomere. It is well known that malfunction of sarcoplasmic reticulum References interferes with normal contraction and relaxation, 'Engel WK, Bishop DW, Cunningham GG. Tubular and it may cause myalgia. The fact that tubular aggregates in Type II muscle fibers: Ultrastructural aggregates originates from sarcoplasmic reticulum and histochemical correlation. Ultrastructure Research and the high incidence of myalgia associated with 1970;31: 507-25. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.48.9.882 on 1 September 1985. Downloaded from

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