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Practneurol-2019-002465 1..11 HOW TO UNDERSTAND IT Pract Neurol: first published as 10.1136/practneurol-2019-002465 on 5 June 2020. Downloaded from Muscle biopsy: what and why and when? Jon Walters,1 Atik Barborie2 1Neurology, Morriston Hospital, ABSTRACT tendinous insertions and can obtain an Swansea, UK Skeletal muscle biopsy remains an important adequate specimen for biochemical stu- 2Department of Cellular Pathology, University Hospital of investigative tool in the diagnosis of a variety of dies, which is potentially important in Wales, Cardiff, UK muscle disorders. Traditionally, someone with mitochondrial disease, as we shall see. a limb-girdle muscle weakness, myopathic The person taking the biopsy needs ade- Correspondence to Dr Jon Walters, Neurology, changes on electrophysiology and raised serum quate experience, skill and interest. In Morriston Hospital, Swansea creatine kinase (CK) would have a muscle biopsy. adult practice, open biopsy is generally SA6 6NL, UK; richard.walters@ However, we are living through a genetics favoured. wales.nhs.uk revolution, and so do all such patients still need An open biopsy is undertaken in a sterile Accepted 30 April 2020 a biopsy? When should we undertake a muscle operating theatre. The skin and subcuta- biopsy in patients with a distal, scapuloperoneal or neous tissue are infiltrated with a local other patterns of muscle weakness? When should anaesthetic, avoiding the muscle. The inci- patients with myositis, rhabdomyolysis, myalgia, sion is 4–6 cm along the long axis of the hyperCKaemia or a drug-related myopathy have limb. The skin, subcutaneous fat and fascia a muscle biopsy? What does normal muscle overlying the muscle are dissected, and the histology look like and what changes occur in biopsy is taken with muscle fibre fascicles neurogenic and myopathic disorders? As with running longitudinally. Complications are Kipling’s six honest serving men, we hope that by rare but include infection, delayed haema- addressing these issues we can all become more toma formation, muscle herniation through confident about when to request a muscle biopsy fascial defect and wound dehiscence. and develop clearer insights into muscle The biopsy, usually about 15×10×5 mm pathology. in size, is laid on a non-absorbent card in a dry specimen container. The principle is to ‘snap freeze’ the muscle in isopentane INTRODUCTION cooled by liquid nitrogen (to approxi- http://pn.bmj.com/ Before considering when you might request mately −160°C). This renders the sample a muscle biopsy, it is worth considering in as life-like a state as possible without how a biopsy is done and what can be learnt using a chemical fixative. ‘Snap freezing’ from it. Having an understanding of muscle allows the tissue to be cut for diagnostic pathology enables us to communicate with investigations and prevents the damage pathology colleagues and, when results are caused by formalin fixation or ice crystal on September 27, 2021 by guest. Protected copyright. available, to translate muscle biopsy results formation (slow freezing) (contrast figures ’ for our patients benefit. We already recog- 1 with 2). nise how such a similar investment helps our discussions with neuroradiology colleagues. Which muscles should be biopsied? Select a muscle that is weak but can over- What is a muscle biopsy? come gravity. Very weak muscles show Muscle biopsy can be either open or marked loss of muscle fibres with fatty or closed (needle or punch) and both have connective tissue replacement and reveal ©Author(s)(ortheir employer(s)) 2020. Re-use their champions. A closed biopsy has the no remnant of the underlying disease pro- permitted under CC BY-NC. advantages of being more cosmetically cess: an ‘end-stage’ biopsy. Avoid muscles No commercial re-use. See appealing, minimally invasive and poten- that have been injured, injected or rights and permissions. Published by BMJ. tially yielding more than one specimen. sampled by neurophysiology within 6 The small sample size, however, creates months, as these situations can result in To cite: Walters J, Barborie challenges with handling and orientation; finding misleading inflammation. A. Pract Neurol Epub ahead of print: [please include Day if pathology is patchy it may be missed. A limited number of muscles are biop- Month Year]. doi:10.1136/ An open biopsy is more invasive, but sied: in the upper limb, biceps brachii or practneurol-2019-002465 the operator can see the muscle, avoid deltoid; in the lower limb, quadriceps Walters J, Barborie A. Pract Neurol 2020;0:1–11. doi:10.1136/practneurol-2019-002465 1 HOW TO UNDERSTAND IT transverse tubular system. Nuclei occupy the periph- Pract Neurol: first published as 10.1136/practneurol-2019-002465 on 5 June 2020. Downloaded from ery of the fibres (figure 1). Each fibre is roughly polygonal transversely and packed snuggly alongside its neighbours, with the endomysium squeezed between adjacent fibres. Perimysium binds groups of fibres together, and the fascicles are collected together within the muscle belly, wrapped by the epimysium. What changes do you see in denervated muscle? Muscle fibres that have lost their nerve supply atrophy and become small angulated remnants, squeezed between their normal-sized, innervated neighbours. Denervated muscle fibres attract nerve twigs from healthy neigh- bours; the nerve twig sprouts and reinnervates the neu- Figure 1 Normal adult skeletal muscle: subsarcolemmal rone-deprived myofibre. The reinnervated fibre assumes located nuclei, average fibre size about 40–80 µm, surrounded by the same identity (type 1 or type 2 fibre) as its neighbour, sparse endomysial connective tissue and visible perimysial septae since the reinnervating anterior horn cell exclusively (H&E stain, ×100). innervates either type 1 or type 2 fibres. Reinnervated neighbouring muscle fibres, therefore, assume the same identity, and the normal mosaic distribution of fibre types becomes distorted into sheets of neighbouring fibres that are all the same type (fibre-type grouping). What sort of changes do you see in myopathies? In many myopathies, muscle fibre size is no longer uniform, and instead, there is considerable fibre size variation. Large fibres may split, particularly in muscle dystrophies. Nuclei, usually situated peripherally, start to migrate centrally. Type 1 and 2 fibres may be selectively involved in some myopathies and in other health conditions. Type 2 fibre atrophy, for instance, typically occurs during http://pn.bmj.com/ immobility, corticosteroid use or general ill health. Type 1 atrophy occurs in some congenital myopathies; type 1 fibres tend to be more numerous than type 2 in Figure 2 Freezing artefacts: fine sarcoplasmic holes (caused by congenital myopathies. ice crystals) prevent examination of fibres (H&E, ×100). In many myopathies, the intermyofibrillar network changes appearance, becoming ‘moth-eaten’ and losing on September 27, 2021 by guest. Protected copyright. its characteristic regular cytoarchitecture. femoris (vastus lateralis or rectus femoris) or gastro- The modified Gömöri-trichrome stain may show cnemius. The pathologist needs to know what these inclusions within muscle fibres, including the rod-like muscles look like when healthy. Fibre-type composi- bodies in nemaline myopathy, or the darkly staining tion and the normal range of fibre size will vary accumulation of myofibrillar material characteristic of between muscles, depending upon their functional myofibrillar myopathies (figures 3 and 4). In the core role. If contemplating using another muscle, consult myopathies, oxidative stains such as nicotinamide ade- with pathology colleagues. nine dinucleotide dehydrogenase (NADH)-TR may Timely communication with the person undertaking show well-demarcated areas of reduced or absent stain- the biopsy and pathologist is key, including clinical ing within the sarcoplasm (figure 5). details and our diagnostic suspicions. The endomysium becomes thickened and fibrotic in some muscle diseases and is particularly striking in What does normal muscle look like? muscle dystrophies (figure 6). A transverse section of normal muscle reveals fibres Inflammatory changes may develop in the endomy- of roughly the same size, each comprising hundreds sium of the inflammatory myopathies; immunohisto- of myofibrils. The intermyofibrillar network sits chemistry can identify the types of inflammatory cell between the myofibrils, composed of sarcoplasm, present (table 2). Immunohistochemistry can also iden- mitochondria and sarcoplasmic reticulum with the tify the major histocompatibility antigen 1 (MHC1) on 2 Walters J, Barborie A. Pract Neurol 2020;0:1–11. doi:10.1136/practneurol-2019-002465 HOW TO UNDERSTAND IT Pract Neurol: first published as 10.1136/practneurol-2019-002465 on 5 June 2020. Downloaded from Figure 3 Nemaline myopathy: rod or granular red sarcoplasmic Figure 6 Limb-girdle muscular dystrophy: marked fibre atro- inclusions (Gömöri-trichrome stain ×400). phy, increased endomysial connective tissue suggesting dystro- phy. A focus of lymphocytic infiltrate (top right corner) as sometimes seen in LGMD2B (H&E, ×200). the sarcolemma in inflammatory myopathies or the membrane-attack complex deposit on the capillary endothelium in dermatomyositis. Inflammatory changes occasionally occur in genetic muscle diseases, including facioscapulohumeral dystrophy and dysferli- nopathies (LGMD2B). Western blot or immunoblot is a technique that uses gel electrophoresis to separate individual proteins from a mixture of proteins, according to their weight. Patients
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