Peripheral neuropathy associated with hereditary and sporadic inclusion body myositis: confirmation by electron microscopy and morphometry

Journal of the Neurological Sciences 179 (2000) 92–102 www.elsevier.com / locate / jns

Peripheral neuropathy associated with hereditary and sporadic inclusion body myositis: confirmation by electron microscopy and morphometry q ¨ * Benita Hermanns, Maria Molnar 1 , J. Michael Schroder ¨ Neuropathologie, Universitatsklinikum ¨ ¨ der Rheinisch-Westf alischen Technischen Hochschule Aachen, Pauwelsstraße 30, D-52074 Aachen, Institut f ur Germany Received 26 May 1998; received in revised form 14 December 1999; accepted 28 July 2000

Abstract Inclusion body myositis (IBM) is a disabling myopathy affecting proximal and distal muscle groups. The involvement of peripheral nerves in IBM is still a controversial matter. In a previous morphometric study at the light microscopic level only, we described a peripheral neuropathy in sural nerve biopsies of eight patients with sporadic IBM (s-IBM). Here we present a larger series of 14 cases in which a combined muscle and nerve biopsy was available for additional electron microscopic investigation. In two of the new cases, the IBM had a hereditary background (h-IBM). The presence of neuropathy was confirmed in all 14 cases studied. Morphometry using an optic–electronic, digital evaluation system showed large variation of severity presumably due to age and coincidal factors such as diabetes mellitus or lymphoma. Ultrastructural analysis revealed a variety of changes considered to be non-specific. Signs of axonal damage predominated. In addition, there were numerous changes in Schwann cells and myelin sheaths. Neither inflammatory changes nor tubulofilamentous inclusions were detectable in the sural nerves. Peripheral neuropathy, although occasionally without apparent clinical manifestation, appears to be a common and aggravating feature in IBM; its pathogenesis, however, remains elusive.  2000 Elsevier Science B.V. All rights reserved. Keywords: Inclusion body myositis; Inclusion body myopathy; Peripheral neuropathy; Mitochondria; Electron microscopy

1. Introduction Sporadic inclusion body myositis (s-IBM) is a chronic progressive inflammatory myopathy usually beginning after the age of 50 years, characterized by rimmed vacuoles, typical 15–21 nm tubulofilamentous inclusions, q Presented in part at the 42nd Annual Meeting of the Deutsche ¨ Neuropathologie und Neuroanatomie, October 8–11, Gesellschaft fur 1997, in Magdeburg, Germany, and at the Meeting of the Arbeit¨ sgemeinschaft Rheinisch-Westfalischer Pathologen, October 25, 1997, in Essen, Germany. *Corresponding author. Tel.: 149-241-808-9428; fax: 149-241-8888416. E-mail address: [email protected] (J.M. ¨ Schroder). 1 Present address: Department of Neurology, University Medical School Debrecen, Nagyerdei krt. 98, H-4012 Debrecen, Hungary.

slowly progressive proximal and / or distal weakness, prominent muscle atrophy, hyporeflexia, and poor response to corticosteroids [1–3]. Sivakumar et al. [4] described families in which siblings of a single generation were affected by an HLA-DR3 associated inflammatory myopathy strongly resembling s-IBM. More recently twin cases with inflammatory changes have been reported [5]. These cases of familial IBM were indistinguishable from classic s-IBM. On the other hand, most patients with hereditary IBM (h-IBM) suffer from non-inflammatory myopathies, but rimmed vacuoles and tubulofilamentous inclusions are similar to those in s-IBM. Autosomal dominant h-IBM by definition occurs in more than one generation and has predilection for certain ethnic groups [6–11] although autosomal recessive inheritance may occur and recent cases show no such ethnic predilection. On the other hand, there is a strong association with HLA

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B. Hermanns et al. / Journal of the Neurological Sciences 179 (2000) 92 – 102

class II (HLA-DR3) suggesting a role for genes in the major histocompatibility complex (MHC) in the predisposition to this disease, mapped to the region between HLADR and C4 [12,13]. In addition, methionine homozygosity at prion gene codon 129 may also predispose to sIBM [14]. The association of IBM with peripheral neuropathy was first suggested by electrophysiological investigations [15– 18], and later substantiated by studies on intramuscular nerve fascicles [19] and by light microscopic morphometric analysis of sural nerves [20]. The electromyographical observations of Luciano and Dalakas [21] and Barkhaus et al. [22], however, did not support the presence of a neurogenic component in the examined muscles of IBM cases. To clarify this issue, additional light microscopic, morphometric, and electron microscopic investigations were performed on sural nerve biopsies which happened to be available in 12 patients with s-IBM and two with h-IBM.

2. Material and methods Morphometric, light microscopic results on sural nerve biopsies in eight of the 12 sporadic cases of the present series have been briefly mentioned before (cases 5, 8–11, and 14 [23]). This study comprises six additional s-IBM and two additional h-IBM cases (mean age: 59 years, age range: 16–78 years; Table 1) in which a sural nerve biopsy was available for morphometric and electron microscopic investigation. Two further sural nerve biopsies could not be evaluated morphometrically because of excision artefacts, therefore they are not included in the present study

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although there was some evidence of an axonal type of neuropathy. The diagnosis was based on clinical, electrophysiological, light and electron microscopic features of muscle biopsies [23] (Fig. 1). In cases 1 and 2, the family history was indicative of hereditary IBM. The disease phenotype could be traced through at least two generations (Fig. 2). In these two cases, muscle biopsy did not reveal endomysial mononuclear infiltrates. In all other cases the IBM was sporadic and showed characteristic cellular infiltrates. The main clinical and morphological findings are summarized in Table 1. A myopathic EMG pattern was found in two of the 14 cases, four of which showed evidence of an additional neurogenic component. In seven cases motor unit potentials (MUPs) and spontaneous activities were characteristic of a neurogenic lesion. (In case 3 no EMG data were available.) The electroneurogram (ENG) was normal in eight patients, three cases presented with evidence of axonal lesions, i.e. decreased amplitudes of compound muscle action potentials (cMAPs) and sensory nerve action potentials (SNAPs). Case 14 was considered as ‘predominantly demyelinating neuropathy’. (In cases 4 and 10 no ENG data were available.) Cryostat sections of the muscle biopsies were stained with hematoxylin-eosin, modified Gomori trichrome, PAS, oil red O, methylene blue, and for NADH-TR, acid phosphatase, and myofibrillar ATPase after preincubation at pH 9.4, 4.6, and 4.2. One part of the muscle and of the sural nerve biopsy specimen was embedded in epoxy resin according to routine procedures. Semithin sections were stained with toluidine blue and para-phenylenediamine for light microscopy. Ultrathin sections were contrast en-

Fig. 1. (a, b) Case 2. Muscle fibers showing rimmed vacuoles. H&E 3360. (c) Accumulation of characteristic tubulofilamentous structures adjacent to a rimmed vacuole with myelin-like structures, 310 800. (d) The tubulofilamentous structures measure about 18 nm in diameter, 336 900.

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Table 1 Main clinical and morphological findings in two hereditary (cases 1 and 2) and 10 sporadic cases (cases 3–12) of IBM a EMG/ENG results

Light microscopy

EMG: neurogenic and myogenic changes Myelin breakdown products, ENG: axonal neuropathy DTMs 2%, CRFs 2%

NF/ MA A/M Electron microscopy mm 2 (%) ratio

1

48/M

Bulbar speech, myopathic face, distal muscle weakness in the lower limbs; positive family history

7305 20

2

70/F

Ophthalmoplegia externa, swallowing disturbances, bulbar EMG: neurogenic MUPs Atrophic axons, myelin breakdown products, 5360 16 speech, proximal paresis in the lower limbs, absence of deep ENG: severe axonal neuropathy of lower DTMs 4%, CRFs 10% tendon reflexes, disturbed vibration sensation; positive limb nerves family history

0.24 Mitochondrial clusters in Schwann cells, adaxonal amorphous deposits, collagen pockets, empty Schwann cell processes; enlarged axons with lysosomal structures or zebra bodies, accumulation of glycogen granules and dilated vacuoles

3

16/F

Distal paresis in the lower and proximal paresis in the upper limbs

ENG: normal

Myelin breakdown products, DTMs 3%, CRFs 1%

0.33 Numerous empty Schwann cells processes, axonal swelling,

4

30/F

Swallowing difficulties, bulbar speech, tetraparesis

EMG: long duration polyphasic MUPs

Endoneurial edema, degenerating nerve fibers, 4422 19 CRFs 3%

0.33 Axonal glycogen accumulation, mitochondria with large matrix granules, adaxonal deposits

5

39/M

Generalized muscle weakness, proximal tetraparesis, EMG: repetitive discharges, signs of absence of tendon reflexes, distal hypesthesia, further denervation, neurogenic MUPs disorders: T-cell lymphoma, autoimmune hemolytic anemia ENG: normal

Endoneurial edema, DTMs 1%, CRFs 2%, microangiopathy

3104 14

0.21 Collagen pockets, Schwann cells with needle-like inclusion and leptomer fibrils; tubular inclusions and vesicular structures in axons

6

56/M

Weakness of lower limb muscles, proximal tetraparesis, decreased deep tendon reflexes, CK: increased

EMG: signs of myogenic lesion ENG: normal

Endoneurial edema, DTMs 1%, atrophic axons, CRFs 2%, myelin breakdown products

5372 16

0.26 Collagen pockets, myelin breakdown products, paracrystalline inclusions in mitochondria; occasional clusters of mitochondria in axons

7

62/F

Muscle weakness and atrophy, absence of deep tendon reflexes

EMG: signs of denervation, neurogenic MUPs ENG: normal

DTMs 5%, CRFs 10%, few degenerating nerve fibers, myelin breakdown products

4959 13

0.44 Collagen pockets and empty Schwann cell processes; abnormal granular inclusions in SLI; uneven density of myelin lamellae; adaxonal vacuoles and occasional widening of inner myelin loops; tubuloreticular or pleomorphic lysosomal inclusions in axons

5872 16

0.33 Transnodal remyelination, empty Schwann cell processes, collagen pockets, lysosomal structures, glycogen granules, accumulation of mitochondria

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Case Age (years)/ Clinical findings no. Sex

65/F

Weakness in the proximal lower limbs, decreased deep tendon reflexes, CK: increased

EMG: signs of denervation, neurogenic MUPs ENG: normal

Myelin breakdown products, DTMs 1%, CRFs 3%, atrophic axons

3512 10

0.28 Adaxonal inclusions, irregular Schmidt–Lanterman incisures, endoneurial fibroblast with cytoplasmatic nuclear inclusion, axon with vacuoles

9

66/M

Weakness of lower limb muscles, atrophy of proximal lower and upper limbs, chloroquine treatment; further disorders: alcoholism

EMG: signs of neurogenic and myogenic lesion ENG: normal

Endoneurial edema, DTMs 3%, CRFs 3%, myelin breakdown products, microangiopathy

5660 15

0.37 Structural alterations at the Schmidt–Lanterman incisures, collagen pockets, rare polyglucosan bodies, glycogen granules, mitochondria with large matrix granules and vacuoles in axons

10

71/F

Predominantly proximal paresis of lower limb muscles, CK increased

EMG: myopathic MUPs

Signs of mild demyelination and remyelination, DTMs 1%, CRFs 1%

5904 16

0.34 Uncompacted myelin sheaths, myelin breakdown products, intralamellar granular deposits; a few large mitochondria, glycogen accumulation in axons and Schwann cells

11

72/F

Myalgia, distal muscle weakness in the lower limbs, distal hypesthesia, latent diabetes mellitus, malabsorption of vitamin B 12

EMG: repetitive discharges, small polyphasic MUPs ENG: normal

DTMs 1%, onion bulb formations with regenerated axons, CRFs 1%

3525 16

0.39 Myelin sheaths with widened myelin lamellae, lysosomal structures, empty Schwann cell processes forming collagen pockets; atrophic nerve fibers

12

73/F

Distal paresis in the upper and lower limbs, proximal and distal muscle weakness and atrophy of lower and upper limb muscles

EMG: signs of denervation, neurogenic MUPs ENG: normal

DTMs 2%, Myelin breakdown products, CRFs 2%, microangiopathy

4442 11

0.50 Granular inclusions in SLI; microvesicular disintegration of myelin lamellae; adaxonal vacuoles, pycnotic empty Schwann cell processes; collagen pockets; degenerating or dystrophic unmyelinated axons, glycogen accumulation in axons

13

76/F

Proximal muscle weakness, absence of deep tendon reflexes, ANA, AMA positive

EMG: signs of denervation. ENG: mild axonal neuropathy

Myelin breakdown products, DTMs 3%, onion bulb formations, CRFs 8%, microangiopathy

2071 10

0.26 Collagen pockets, enlarged mitochondria with large matrix granules; dystrophic axons, glycogen granules, increase of the axoplasmatic reticulum

14

78/M

Gait disturbance, muscle weakness and atrophy, absence of deep tendon reflexes, tetraparesis, sensory loss of stocking distribution

EMG: signs of denervation ENG: severe reduction of NCVs of lower limb nerves

Myelin breakdown products, endoneurial edema, DTMs 5%, CRFs 35%, degenerated axons, microangiopathy

1515 5

0.20 Empty Schwann cell processes, adaxonal granular deposits in Schwann cell cytoplasm and vacuolar degeneration of myelin lamellae

a Abbreviations: A / M, mean axon area per myelin area; AMA, antimitochondrial antibodies; ANA, antinuclear antibodies; CK, creatinine kinase; CRFs, clusters of regenerated fibers; DTMs, disproportionately thin myelin sheaths; EMG, electromyography, ENG, electroneurography; MA, percentage of myelin area per endoneural area; MUPs, motor unit action potentials; NCVs, nerve conduction velocity; NF, nerve fibers; RF, percentage of regenerating fibers; SLI, Schmidt–Lanterman incisures; TM, percentage of disproportionately thin myelin sheaths.

B. Hermanns et al. / Journal of the Neurological Sciences 179 (2000) 92 – 102

8

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B. Hermanns et al. / Journal of the Neurological Sciences 179 (2000) 92 – 102

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Fig. 2. Family tree of case 2 (number II.4) which is suggestive of autosomal dominant inheritance.

hanced with uranyl acetate and lead citrate, and examined with a Philips T400 electron microscope. The degree of neuropathy was determined on semithin sections using the morphometric Kontron Electronic Imaging System KS 300 (Eching / Munich, Germany). The myelin area per endoneurial area in percent [MA (%)], the number of myelinated nerve fibers per mm 2 (NF / mm 2 ), and the ratio between the axonal area and the myelin area (A / M) were determined (Table 1 and 2) in addition to several other, less important measures. A series of 133 sural nerves from a former study [24,25] were used as controls. These values including those of a series of cases with mitochondrial myopathy are included in Fig. 3 for comparison because IBM may also be associated with mitochondrial DNA mutations [20,26,27].

3. Results The muscle biopsy specimens of all s-IBM patients

showed the characteristic morphological features of IBM consisting of rimmed vacuoles, tubulofilamentous cytoplasmatic or intranuclear inclusions, and mononuclear inflammatory cell infiltrates. In h-IBM, there were rimmed vacuoles and tubulofilamentous inclusions (Fig. 1) in the only available muscle biopsies of the index cases (cases 1 and 2) who had several affected family members (Fig. 2); but no inflammatory cell infiltrates were detected in these cases. All cases revealed at least some degree of a peripheral neuropathy. In seven cases a mild, in five cases a moderate, and in two cases a severe reduction of myelinated nerve fibers was found (Figs. 3 and 4a,b; Table 1). In all cases, clusters of small regenerated axons were present (Fig. 4a). Atrophic axons and evidence of recent wallerian degeneration were observed in three cases; myelin breakdown products were present in 10 of the 14 patients. Myelin sheaths, too thin for the diameter of the axon, were identified in 11 patients. Mononuclear infiltrates were not detected in the sural nerves, neither in cases with s-IBM nor in cases with h-IBM. At the ultrastructural level, there were pleomorphic changes of Schwann cells, myelin sheaths, and axons (Figs. 4c,d and 5–7). These included a complex arrangement of Schwann cell processes surrounding a thin myelin sheath which again surrounded collagen fibrils and a small axon indicating proceeding demyelination and transnodal remyelination (Fig. 4d). Typical onion bulb formations were not seen but clusters of regenerated fibers imitating onion bulbs occurred repeatedly (Fig. 6b). In two patients there was amorphous material in the

Fig. 3. Diagram indicating the myelin sheath area per endoneurial area in the cases with sporadic inclusion body myositis (s-IBM) and hereditary IBM (h-IBM) in comparison to a series of corresponding data in control cases and cases with mitochondrial myopathy. There is a wide range of severity of neuropathy which appears to be age dependent to a certain degree. Neuropathy in mitochondrial myopathy tends to be more severe than in s-IBM and h-IBM.

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Fig. 4. (a) Case 10. There is a moderate reduction of myelinated nerve fibers. Clusters of small regenerating axons, and occasional axons with disproportionately thin myelin sheaths are also apparent, 3340. (b) Case 7. The number of large myelinated nerve fibers is severely reduced in this area, 3340. Semithin sections, toluidine blue. (c) Case 2. There are amorphous or granular deposits in the adaxonal Schwann cell processes, 310 700. (d) Case 1. The unusual arrangement of Schwann cell processes, basal laminae, and collagen fibrils around a small axon surrounded by a very thin myelin sheath indicates aberrant transnodal remyelination, 318 000.

adaxonal terminal myelin loops (Figs. 4c and 6c). Finely dispersed granules deposited between widened myelin lamellae were a rare finding (Fig. 6c). In case 5, Schmidt– Lanterman incisures were irregularly distributed and termi-

nal loops were discontinuously attached to the axon at ¨ various sites (Fig. 8 in Schroder [28]). Other changes included axonal shrinkage, an occasional polyglucosan body (Fig. 6a), and abnormal lysosomes (Fig. 7a–c). In the

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Fig. 5. (a) Case 11. A m-granule-like structure includes two mitochondria (arrow) in the Schwann cell cytoplasm of a paranodal myelin loop (arrow), 39900. (b) Case 1. Glycogen granules accumulated between the inner and outer membrane of a mitochondrion (arrow), 39900. (c) Case 2. An enlarged mitochondrion containing homogeneous material is observed in a Schwann cell (arrowhead), 39100. (d) Case 10. Paranodal accumulation of mitochondria, 315 700. (e) Case 4. A large mitochondrion in an unmyelinated nerve fiber (arrowhead) contains an increased amount of homogeneous matrix material and two large matrix granules, 314 900.

younger patients (cases 3, 4 and 5), minor mitochondrial changes were apparent. The number of mitochondria was focally increased in axons (not illustrated) and in Schwann cells (Fig. 5d). Some mitochondria in Schwann cells were enlarged (Fig. 5c) and occasionally filled with amorphous

material or with glycogen granules. Mitochondria with large matrix granules in axons were noted in two cases (Fig. 5e). Tubulofilamentous structures with a diameter of 15 to 21-nm were not found in the peripheral nerve. Only intermediate filaments and microtubules were noted in a

B. Hermanns et al. / Journal of the Neurological Sciences 179 (2000) 92 – 102

Fig. 6. (a) Case 8. This unusual nerve fiber shows an axon which is filled with microtubules, small vesicles, and granules and shows an intramyelinic protrusion that contains a polyglucosan body, 32900. (b) Case 8. Cluster of regenerated fibers imitating an onion bulb formation includes a medium sized myelinated fiber and several unmyelinated axons (arrowheads), 34700. (c) Case 8. There are deposits of granular material in the myelin sheath (arrowhead). The adaxonal Schwann cell process is distended by finely granular material (arrow), 36700.

variable number in axons and Schwann cells. Cholesterol crystals derived from myelin breakdown could imitate tubules but consisted of membranous sheets. Degenerating endoneurial macrophages (Fig. 7a) as a nonspecific finding [29] were noted in several cases.

4. Discussion The present study confirms and extends our previous light microscopic findings [20] by electron microscopic investigation of sural nerves showing that inclusion body

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myositis (IBM) is associated with a variable degree of peripheral neuropathy (Fig. 3, Tables 1 and 2). In nine of our 14 cases there were also signs of neurogenic muscle involvement in the EMG. The ENG was mostly normal or revealed an axonal or, in a very severe type of neuronal or axonal neuropathy (case 14), even a ‘demyelinating’ type of neuropathy. It is apparent from the present, fine structural investigations that there is a predominantly axonal type of neuropathy with a large spectrum of non-specific changes in axons, myelin sheaths, Schwann cells, and other peripheral nerve components (Figs. 4–7). The characteristic 15–21 nm tubulofilamentous inclusions, which are the hallmark of sporadic and hereditary IBM (s-IBM and h-IBM), were not seen in Schwann cells or in other endoneurial cells such as fibroblasts or macrophages, or in axons. Perikarya of peripheral motor, sensory or autonomic neurons, however, could not be investigated. These sites would probably be most informative for identifying the pathogenesis of the peripheral neuropathy because the neuropathy is predominantly neuronal or axonal in type primarily affecting the perikaryon or the axon. It might be argued that the neuropathy in our IBM cases may be an age related alteration. The degree of neuropathy in our age-matched control cases, however, does not indicate a similar severity of myelin area loss per endoneurial area as in the s-IBM cases studied (Fig. 3). Few cases including the two h-IBM cases are at the lower level of the normal myelin area density per endoneurial area. One case (case 11) had latent diabetes mellitus. Yet, vascular changes, characteristic of diabetic polyneuropathy, were not prominent so that it is assumed that the diabetes was only of minor importance in the development of the neuropathy in this case. Moreover, mild malabsorption of vitamin B 12 could have aggravated the polyneuropathy in this case. As the patient was 70-years-old, additional aging changes should be taken into account although not to such a severe degree (Table 1). Case 8 had received chloroquine (250 mg / day) and suffered from alcoholism. Other potential causes of peripheral neuropathy were not reported in the clinical records of the patients and were not apparent from the present light and electron microscopic examination of the sural nerves. Case 3 was 16 years old without positive family history. Thus she was attributed to s-IBM although IBM usually occurs in elder persons. However, there are several cases of IBM in younger patients. For example Chou [1] in 1986 reported IBM in two 19-year-old patients. The morphological findings in the sural nerve of the two hereditary IBM cases of the present series (cases 1 and 2 in Table 1) were not essentially different from those in the sporadic cases (cases 3–14). Mononuclear infiltrates were not observed in the sural nerves of our h-IBM cases. There was no obvious correlation between the severity of the myopathy and the degree of the pathological changes in the nerve, nor between the degree of inflammation in the

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Fig. 7. (a) Case 10. This degenerating endoneurial macrophage shows a distended outer nuclear membrane and a large p-granule-like myelin degradation product, 312 200. (b) Case 4. An unusual, presumably lysosomal structure is seen adjacent to an outer myelin sheath protrusion at the site of a Schmidt–Lanterman incisure which includes regular granulated material, 346 300. (c) Case 1. One axon within a cluster of unmyelinated axons contains pleomorphic lysosomal structures, neurosecretory vesicles, and other tubular or vesicular components, 326 400.

muscle and neuropathy. On the other hand, neuropathy was also present in both of the h-IBM cases in which no inflammatory cells were detected, neither in the muscle nor

in the nerve. These observations suggest that peripheral neuropathy in IBM is due to other mechanisms than inflammation.

B. Hermanns et al. / Journal of the Neurological Sciences 179 (2000) 92 – 102

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Table 2 Morphometrical and clinical data of control cases a Control cases No.

Sex

Age (years)

Diagnosis

NF (mm 2 )

MA (%)

A/M ratio

1 2 3 4

M F M M

14 16 36 48

8555 7354 7587 7354

20 23 21 19

0.57 0.36 0.33 0.41

M

61

Muscle fiber type disproportion Normal Normal Neurogenic muscle atrophy, sural nerve normal Arteriosclerosis

7504

19

0.44

5 a

Abbreviations: NF, nerve fibers; MA, percentage of myelin area per endoneural area; A / M, mean axon area per myelin area.

Immunogenetic studies showed the presence of DR3 alleles in all IBM patients studied by Garlepp et al. [3], Sivakumar and Dalakas [10], and Kok et al. [13]. According to Sivakumar and Dalakas [10], the clinical, histological, immunopathological, and immunogenetic features were identical in both, classical s-IBM and inflammatory f-IBM. The presence of these rare DR-alleles in other inflammatory diseases suggests [30] that familial and sporadic forms of inflammatory IBM have the same inherited determinants of susceptibility to the inflammatory process. IBM occurs in a variety of other, especially immunemediated conditions [8]. This presumably includes systemic sarcoidosis which may be associated with IBM [31]. In the present series, the 39-year-old patient number 5 was 10 years ago classified as polymyositis. In the last 4 years cutanous T-cell lymphoma and hemolytic anemia were detected before finally IBM was identified in another muscle biopsy. HTLV infection may play a role in the etiology of T-cell lymphoma [32,33] and IBM. Interestingly, Cupler et al. [34] described a woman infected with HTLV-1 and presenting the clinical and morphological diagnostic criteria of sporadic IBM. In one of our s-IBM cases, HTLV-1 infection was also established (unpublished observation); this case is not included in the present series because no sural nerve biopsy was available. In these instances retroviral infection may provide superantigenic stimulation and trigger an endomysial inflammatory response identical to that occurring in sporadic IBM. The increased number of enlarged mitochondria with paracrystalline inclusions in the muscle fibers of IBM cases suggests an impaired mitochondrial function [26]. In IBM and in polymyositis a higher incidence of mitochondrial DNA (mtDNA) deletions was observed than in other neuromuscular disorders or in aged individuals [27,20]. It is therefore of interest, that we noted ragged red fibers in the muscle biopsy of cases 3, 8 and 11; in cases 8 and 11, mtDNA deletions were identified [23], suggesting disturbances of mitochondrial function. On the other hand, mitochondrial disorders appear to be regularly associated with peripheral neuropathy [24,25,35]; but it is quite unlikely that the relatively few mitochondrial alterations in IBM may be causing the neuropathy on a systemic base. In case 2 of the present series, h-IBM wars associated

with ophthalmoplegia. It is of interest in this context that Darin et al. [36] described a variant of h-IBM with ophthalmoplegia and congenital joint contractures. Yet contractures and mitochondrial abnormalities were not seen in our patient. Considering the lack of inflammatory infiltrates and tubulofilamentous structures in the diseased sural nerves, we assume that there are different pathomechanisms for the involvement of peripheral nerves and muscle in this disorder, or different responses to the same pathogenic factor. It is suggested that investigating the spinal ganglia and the spinal cord will help elucidating the pathogenesis of the involvement of the peripheral nervous system in IBM. There is, to the best of our knowledge, only one autopsy record on IBM, documenting as already mentioned, its association with systemic sarcoidosis; yet the spinal ganglia and the spinal cord have not been investigated [31].

Acknowledgements The technical assistance of Astrid Knischewski and Hannelore Mader is gratefully acknowledged. M. Molnar was supported by the Alexander-von-Humboldt Stiftung and by a Grant from the University Medical School Debrecen (Mec 19 / 96).

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