1/2/2021 Muscle Biopsy and Clinical and Laboratory Features of Neuromuscular Disease: Background, Indications, Myopathies That Might

t Might Not Req…

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Muscle Biopsy and Clinical and

Laboratory Features of
Neuromuscular Disease
Updated: Jun 26, 2019
Author: Roberta J Seidman, MD; Chief Editor: Erik D Schraga, MD more...

Background
The biopsy of skeletal muscle tissue (muscle biopsy), plays an integral role in evaluation of the patient
with neuromuscular disease. With some exceptions, it is an essential element in the assessment of a
patient with suspected myopathy. [1] Muscle biopsy is also sometimes indicated for the diagnosis of
various systemic disorders that can be accompanied by pathology of skeletal muscle tissue. It is
relatively commonly part of the evaluation of suspected neuropathic disease, often for the purpose of
assisting the clinician to distinguish between a neurogenic disorder with an atypical presentation and a
primary myopathic disorder.

The surgical procedure to obtain a muscle biopsy is relatively simple and poses little risk to the
patient. It is, however, a specialized procedure and must be properly performed to optimize the
information it can yield for the benefit of the patient.

The clinician must first arrive at a rational differential diagnosis by synthesizing information obtained
from the clinical history, physical examination, and laboratory and electrodiagnostic studies. This
information is used to influence the details of each procedure. The choices of the right time for biopsy,
which muscle to select, how many specimens to obtain, and how to handle the specimen immediately
following excision are individualized for each patient on the basis of these clinical findings.

After the biopsy specimen arrives in the pathology laboratory, it undergoes multiple procedures and
studies. The pathologist uses knowledge of the clinical features to assist in interpretation of the
constellation of pathologic findings in the biopsy, as well as to help determine whether additional
studies are indicated for a given patient on the basis of the composite of the specific clinical features
and biopsy findings.

Muscle biopsy therefore is somewhat complex, in that an optimal outcome requires coordination of the
clinician, surgical team, pathologist, and technical staff in the pathology laboratory. Because muscle
biopsies are often processed and interpreted at specialized centers, it may also be necessary to
involve a courier service or shipping company in the process.

A portion of this article serves as a primer on the technical aspects of muscle biopsy, which are critical
for the success of the procedure. The aim is to help familiarize the reader with the basic concepts of
how biopsies should be performed and what happens to the tissue that is obtained, as well as to
provide some background information to help nonpathologists understand the pathology reports that
they receive.
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An introduction to the clinical features of neuromuscular disease is included in this article (see Clinical
Features of Neuromuscular Disorders, below) because knowledge of the clinical history is crucial for
correct interpretation of the histologic findings in a skeletal muscle sample, most of which are not by
themselves specifically diagnostic. Because muscle biopsy can help determine whether a patient has
a neurogenic or a myogenic disorder, which is a relatively common issue prompting performance of a
biopsy, a brief discussion of clinical features and some laboratory findings in peripheral neuropathies
is included.

The general introduction to selected categories of skeletal muscle disease provides information about
the classic clinical presentations of several different specific groups of myopathies and how these
disorders are diagnosed.

It is instructive to compare the structure and histology of normal skeletal muscle (see Skeletal Muscle
- Structure and Histology) with the pathologic alterations observed in muscle (see Skeletal Muscle
Pathology). The knowledge gained from this exercise provides a basis for understanding the
pathophysiology of some of these disorders, assisting the reader to visualize the effect of disease at
the tissue level and providing insight into the process by which histopathologic diagnoses are
formulated.

Indications
When a clinical diagnosis of myopathy is considered, muscle biopsy is often required for definitive
diagnosis (for exceptions to this requirement, see Myopathies That Might Not Require Muscle Biopsy,
below).

Muscle biopsy is a fundamental component of the evaluation of a patient with possible muscle
disease, also known as myopathy. At present, muscle biopsy is an essential part of the diagnostic
investigation of most categories of muscle diseases, including inflammatory myopathies and many
metabolic and congenital myopathies and many of the muscular dystrophies.

A major reason why muscle biopsy is often required for the diagnosis of neuromuscular disease is that
there is overlap in the clinical presentations of many myopathies and neurogenic processes, and
different types of neuromuscular disorders cannot always be confidently distinguished from each other
solely on the basis of the clinical features. A newer reason for performance of muscle biopsy is to
determine the significance of genomic variations identified by genetic testing.

Concurrent with the proliferation of genetic tests and the widespread availability of genetic testing for
neuromuscular diseases, ever-increasing numbers of genetic variants that are of uncertain clinical
significance have been identified. These findings not infrequently necessitate performance of muscle
biopsy after genetic testing has been performed to determine whether the genetic variants discovered
by this testing are responsible for an individual's neuromuscular disorder or are simply an unrelated
finding or an epiphenomenon.

Today, among myopathies, the most specific and effective therapies are for the inflammatory
myopathies. [2] Sometimes, a patient is too seriously ill to allow a delay of even a few days before
initiating therapy; however, whenever possible, muscle biopsy should be performed before therapy is
initiated, for the following reasons:

The risk of treatment, including steroids, immunosuppressive agents, and, in some cases,
intravenous immunoglobulin, which often must be administered for prolonged courses, is great
enough that the diagnosis should be confirmed before therapy is started

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A delay often occurs between the initiation of therapy and a clinical response; to persevere with
treatment in the absence of a prompt clinical response, it is beneficial to have complete
confidence in the diagnosis before instituting therapy
Treatment can alter the histopathologic findings; if treatment is started and the biopsy is
subsequently performed because of a lack of clinical response to the therapy, the pathologic
findings can be difficult or impossible to interpret because the intervention may have altered
them

Repeat muscle biopsy is occasionally indicated for evaluation of the patient with known inflammatory
myopathy who, after improvement with steroid or other immunosuppressive therapy, develops
increasing weakness. Biopsy findings can help distinguish between recurrence of the inflammatory
disorder and steroid myopathy or other treatment-associated myopathic effect.

For other disorders with therapeutic options that are less definitive than those for inflammatory
myopathies, a precise diagnosis is important for the following reasons:

Therapies that may be beneficial and may decrease symptoms or slow the progression of
disease, though not curative, are available for some disorders
Patients with certain disorders are eligible for therapeutic clinical trials
Many myopathic disorders are hereditary diseases, and diagnosis is required for proper genetic
counseling
Patients often derive benefit and comfort from prognostic information; uncertainty about what is
the cause of symptoms can be terrifying
Biopsy can exclude the presence of another disorder that might be more amenable to therapy

One common indication for muscle biopsy is to distinguish between myopathy and neuropathy. The
classic presentations of these two processes are clearly distinct; however, in practice, the clinical
histories and physical and laboratory findings often overlap. Neuropathy and myopathy may also
coexist, making a diagnosis based on clinical features alone particularly difficult or even impossible.

Myopathies That Might Not Require Muscle Biopsy

Several categories of myopathies do not typically require muscle biopsy for a diagnosis. This section
discusses circumstances in which a muscle biopsy is not always required for diagnosis of a myopathy.

The main exceptions to the requirement for muscle biopsy for accurate diagnosis of possible
myopathy include various hereditary neuromuscular disorders with characteristic clinical presentations
in which genetic testing reveals genetic alterations that are known to be pathogenic and associated
with the suspected disorder, such as the following:

Suspected dystrophinopathies, particularly when the clinical presentation has features that are
highly characteristic of the dystrophies that are still commonly referred to as Duchenne or
Becker muscular dystrophies
Some congenital and limb-girdle dystrophies [3] or other muscular dystrophies with presentations
that make them fairly easily recognizable and distinguishable from other myopathies [4]
Myotonic dystrophy
Certain mitochondrial disorders
Certain metabolic disorders (disorders of glycogen or lipid metabolism)
Periodic paralyses

Other exceptions to the requirement for muscle biopsy include endocrine myopathies.

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Muscular dystrophies, including dystrophinopathies

Advances in molecular genetics have eliminated the need for muscle biopsy in most patients with
dystrophinopathies and many other muscular dystrophies that have typical clinical presentations by
permitting specific diagnosis of these disorders through genetic testing performed on a sample of
blood. Increasingly, however, the significance of some findings with genetic testing is uncertain (see
the final paragraph in this section, below), necessitating the performance of a muscle biopsy after
genetic testing has been performed.

(The reader should be advised that even in the setting of a clinical presentation characteristic of a
specific muscular dystrophy in which one might want to omit muscle biopsy and proceed directly to
directed genetic testing for a certain dystrophy, it may sometimes be necessary to perform a muscle
biopsy first to provide histologic evidence of a muscular dystrophy so that insurance coverage for
genetic testing can be obtained. Before you send a specimen for potentially costly genetic testing,
please verify that the patient's insurance or another source will cover the cost or, if not, that the patient
can bear the potentially substantial financial costs of these studies.)

In patients with dystrophinopathies, mutations (most commonly deletions) can be demonstrated in the
gene for dystrophin, located on the X chromosome (Xp21). This extremely large (2 million base pairs)
gene codes for a structural protein of skeletal muscle located on the internal surface of the
sarcolemma (muscle plasma membrane).

Until relatively recently, the large size of the dystrophin gene precluded searching the entire gene for
point mutations; however, dystrophin gene sequencing is now commercially available and is routinely
performed. Some laboratories first test for the common deletions and duplications in the dystrophin
gene that are known to be associated with dystrophinopathies and then sequence the entire gene if
the initial deletion/duplication studies are negative.

Dystrophinopathies most commonly present in young boys in the preschool and elementary-school
age range. Among individuals ultimately diagnosed with a dystrophinopathy, muscle biopsy now is
usually performed only in patients with clinical syndromes that differ from typical dystrophinopathies
(eg, adults with progressive limb-girdle syndromes or certain other unique or unusual clinical
circumstances). This category includes some women who carry a single X-chromosome with a
dystrophin mutation, in whom an unfortunate pattern of random inactivation of X-chromosomes gives
rise to clinical myopathy because the number of muscle fibers expressing the mutant dystrophin gene
is great enough to produce symptoms.

In some of these cases, there will be a family history of a dystrophinopathy, and in this situation, even
if an individual does not exhibit one of the classical syndromes of dystrophinopathies, muscle biopsy
may be avoided. Some cases of dystrophinopathies are due to de-novo mutations in individuals, and
thus there will be no family history in these cases that could serve to raise the index of suspicion for
these disorders.

Genetic testing of blood samples is available for abnormalities of genes for other muscle membrane,
structural, and myofibrillar-associated proteins that can present as limb-girdle syndromes, such as any
of the four sarcoglycans, dysferlin, caveolin-3, calpain, lamin A/C, fukutin-related protein, and, now,
many others. [5] Sometimes, muscle biopsy is still performed first to narrow the diagnostic possibilities
and to exclude an inflammatory myopathy and is then followed by directed genetic testing if an
alternative diagnosis is not identified on muscle biopsy.

Genetic testing is available for facioscapulohumeral dystrophy and Perlecan deficiency (Schwartz-
Jampel syndrome). Therefore, muscle biopsy, which would demonstrate only nonspecific myopathic
findings, is generally not indicated to diagnose these disorders. There are numerous other hereditary

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myopathies with characteristic clinical presentations for which directed genetic testing can be
performed that can obviate the need for muscle biopsy in these cases.

When genetic testing in an individual suspected of having a hereditary myopathy reveals a mutation
that is known to be pathogenic and that fits with the individual's clinical syndrome, muscle biopsy is
not needed. Unfortunately, the results of genetic testing sometimes are not definitive, and muscle
biopsy might then be indicated in cases with negative or ambiguous results from genetic testing.

The current widespread use of panels of genetic tests for a large number of muscular dystrophy and
other myopathy-associated genes [6] has led to a new problem, which is the uncovering of variants of
unknown significance (VOUS or VUS) in a gene or genes. Muscle biopsy may be needed to determine
if a given VUS is myopathic. For example, if genetic testing of an individual reveals a VUS in the gene
for dystrophin, muscle biopsy can be performed to look for myopathic features in the muscle and to
establish whether there is normal or abnormal expression of the dystrophin protein in the muscle,
thereby providing assistance in determining whether the VUS might be the underlying cause of a
myopathy.

Thus, despite the great strides that are being made in elucidating the molecular biology of many
myopathies, the performance of genetic testing does not always eliminate the need for muscle biopsy.

Myotonic dystrophies
Myotonic dystrophy type 1 is definitively diagnosed by means of genetic testing on a sample of blood,
which reveals a characteristic increase in the number of CTG triplet repeats in the gene for muscle
protein kinase on chromosome 19. Myotonic dystrophy type 2 (proximal myotonic myopathy
[PROMM]) is due to increased CCTG quadruplet repeats in a zinc finger protein gene on chromosome
3, also detectable by testing on a sample of blood.

Athough some of the histopathologic findings on muscle biopsy in these disorders are fairly
characteristic, they are not specifically diagnostic; thus, if these disorders are suspected on the basis
of the clinical presentation, genetic testing of blood, rather than muscle biopsy, is indicated.

Periodic paralyses

Periodic paralyses are uncommon disorders that result from mutations in various genes for muscle
membrane ion channels that have unique clinical, biochemical, and electrodiagnostic features.
Because they lack specifically diagnostic findings on muscle biopsy, genetic testing is the proper way
to confirm the suspected diagnosis of one of these disorders.

Dilatation of the T-tubule system is found in some patients with hypokalemic periodic paralysis, which
produces vacuoles in histologic sections, but this finding is not specific enough to be diagnostic.
Muscle biopsy can also demonstrate a nonspecific myopathic picture in these disorders. (See Skeletal
Muscle Pathology for examples of nonspecific myopathic features.)

Endocrine myopathies
Myopathy can be a feature of disorders of thyroid, parathyroid, and adrenal function. The correct way
to diagnose endocrine myopathies is to recognize their clinical presentations and perform serologic
testing for appropriate components of the hypothalamic-pituitary-endocrine organ axis.

Myotonic dystrophy, periodic paralyses, and endocrine myopathies are not considered further in this
article. More information about myotonic dystrophy is available from the Myotonic Dystrophy
Organization.

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Anesthesia
Open muscle biopsy is performed with local anesthesia for most adult patients. General anesthesia is
typically required for infants and young children.

If surgery is performed under local anesthesia, care should be taken not to inject the anesthetic
directly into the biopsy site. This minimizes the risk of introducing a track from the needle and the
anesthetic into the muscle, which can interfere with interpretation of the biopsy. The local anesthetic
should be injected just under the skin in an oval area, whose length is approximately 1.5 times that of
the incision.

Percutaneous needle biopsies are not discussed here.

Clinical Features of Neuromuscular Disorders

Importance of provision of clinical information
Few findings in a muscle biopsy are pathognomonic for a specific diagnosis. Instead, a typical muscle
biopsy sample presents a constellation of findings that by themselves could have multiple potential
interpretations and that must be analyzed within the context of the clinical features of the individual
case. In other words, to be able to properly assess the significance of histologic findings in a particular
muscle biopsy sample, the pathologist must have information about the clinical presentation of a given
patient.

As an example of the necessity of clinical information to determine the significance of

histopathological findings, clear cytoplasmic vacuoles are often present in hematoxylin and eosin
(H&E) sections of muscle biopsies. The most common reason for their presence is technical artifact
due to ice crystal formation when a tissue sample is frozen to permit the preparation of cryostat
sections, in which case the vacuoles have no diagnostic significance. However, clear vacuoles are
also present in many myopathic disorders, including (but not limited to) certain glycogen storage
diseases, lipid myopathies, periodic paralyses, and toxic myopathies that can result from treatment
with colchicine, chloroquine, or amiodarone.

Knowledge of the clinical history allows the pathologist to decide which diagnostic considerations are
reasonable in a given case and assists in the determination of whether additional special studies are
indicated. For example, in the case of clear vacuoles, if a biopsy shows only a few myofibers with
vacuoles, the pathologist must decide whether the vacuoles are insignificant technical effects or
whether they are the key diagnostic finding. The clinical history provides guidance for the pathologist
in interpreting the significance of the finding.

Interpretation of a muscle biopsy is similar to the process of clinical diagnosis, in which one
synthesizes all of the information available about an individual patient to arrive at the correct diagnosis
for that patient. If you are ever involved in requesting or performing a muscle biopsy for a patient,
please allow the muscle pathologist to fully perform his/her function by providing reasonably detailed
clinical information that can permit this physician to fully interpret biopsy findings that are not, by
themselves, diagnostically specific. Provision of the necessary information with a biopsy to make
optimal interpretation possible is not for the benefit of the pathologist, it is for the benefit of the patient,
the human being who is undergoing a surgical procedure with the hope of finding the cause of his/her
symptoms.
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Against this background, the technical issues that must be addressed by the physicians involved with
muscle biopsies are as follows:

Proper selection of a muscle for biopsy

Biopsy procedure and immediate handling of the tissue in the operating room
Studies performed on the biopsy sample

These considerations are addressed more fully below (see Technical Issues in Muscle Biopsy).

Signs, symptoms, and initial laboratory testing of suspected neuromuscular

disorders
Signs and symptoms

Disease of skeletal muscle tissue can be expressed in very few ways, as follows:

Weakness or decreased movement

Muscle ache, also referred to as myalgia
Cramps
Abnormal variations in power as a result of physical activity

The main clinical hallmark of neuromuscular disease, whether of neurogenic or of myopathic origin, is
weakness. Weakness is manifested in age-related variations. For example, weakness in utero can be
expressed as decreased fetal movements and may be recognized by a woman who has had previous
pregnancies.

In the neonatal period, the infant may be hypotonic; this is termed the floppy infant syndrome.
(Neuromuscular disease is only one of a number of potential causes of the floppy infant syndrome.) In
later infancy and during the toddler years, delay in acquisition of motor-developmental milestones is
typically a major sign of myopathy. From childhood through adulthood, diminished muscle power,
reported by affected patients and ascertained by direct testing of the strength of individual muscle
groups, is a characteristic clinical feature of neuromuscular disease.

The classic clinical signs of myopathy include the following:

Weakness, which usually affects the proximal muscle groups, most often the shoulder and limb
girdles; axial muscles can also be affected in some disorders
Relative preservation of muscle-stretch reflexes until relatively late in the course of the disorder
Absence of abnormalities of somatosensation

Variation of strength with activity can occur in some patients with muscle disease. This can mean
either decremental or incremental change in strength with a degree of activity that would not result in
this change in a healthy individual.

Fluctuation of muscle power or symptoms that develop during activity can suggest a metabolic
myopathy. For example, in McArdle disease, myophosphorylase deficiency leads to inability to
mobilize glycogen that is needed for muscular activity for movement or for development of isometric
tension needed to hold or carry heavy objects. A patient with this disorder has pain (sometimes
cramps) and weakness during the anaerobic phase of exercise. If the patient can exercise at a low
level during the anaerobic phase to avoid drawing on glycogen stores, when the aerobic phase is
finally reached and glycogenolysis is no longer needed because free fatty acids can be used for
generation of energy, the patient's performance improves and symptoms can be avoided.

In addition, during the aerobic phase of energy metabolism, more energy is produced per unit of
glucose metabolized, and therefore less glycogen is needed and less glucose is required to generate
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more energy than is produced by anaerobic metabolism.

Fatigability denotes progressive loss of muscle power with exertion that improves with rest. This is
often a defining clinical feature of myasthenia gravis, a disorder of impaired neuromuscular
transmission. Muscle biopsy is typically not performed for myasthenia gravis. Myasthenia gravis is
usually diagnosed on the basis of the following:

Clinical presentation
Electrodiagnostic studies showing a decremental response in the muscle with repetitive
stimulation of the motor nerve
Presence of serum antibodies to the acetylcholine receptor or to certain other serum antibodies
known to be associated with this disorder

Myalgia is present in some patients with inflammatory myopathy. This symptom sometimes is present
in noninflammatory disorders in which there is necrosis of myofibers. Myalgia is also found in some
patients with metabolic diseases affecting muscle and occurs when the energy supply of the muscle is
depleted and lactic acid builds up (cramps sometimes occur).

In contrast to myopathy, the classic clinical features of peripheral neuropathy include the following:

Weakness, predominantly affecting distal musculature

Decrease of muscle-stretch reflexes, particularly in demyelinating neuropathies
Fasciculations, when abnormal excitability of the motor neuron is present
Concomitant somatosensory abnormalities, which occur in many peripheral neuropathies,
though they are not present in pure motor neuropathies

In their conventional clinical presentations, distinguishing muscle disease from peripheral nerve
disease is a straightforward matter. In practice, however, this distinction is not always simple. There
are several reasons why it may be difficult to determine whether a patient has neuropathy or
myopathy on clinical evaluation.

One reason is that some myopathies affect distal muscles. Myotonic dystrophy, sporadic inclusion
body myositis (sIBM), hereditary IBM, some of the myofibrillar myopathies, and several other distal
myopathies can all affect distal muscle groups.

In addition, some neurogenic disorders, including diabetic amyotrophy and motor neuron disease,
may affect proximal muscles.

Some patients may have combined neurogenic and myopathic disorders. For example, a patient with
diabetic neuropathy can also acquire an inflammatory myopathy. A patient who has peripheral
neuropathy caused by chemotherapy for cancer may develop dermatomyositis as a paraneoplastic
syndrome or other paraneoplastic inflammatory myopathy. A patient can have both radiculopathy
caused by degenerative joint disease in the vertebral column and a primary myopathy. In these
examples, the clinical findings are complicated, which can make it difficult to arrive at a diagnostic
category based solely upon the clinical features.

For an excellent and more detailed discussion of clinical evaluation of patients with neuromuscular
disease that is beyond the scope of this article, see chapter 1, "Approach to patients with
neuromuscular disease," in the second edition of Neuromuscular Disorders, by Anthony Amato and
James Russell. [7]

A very old but nonetheless superb and well-written monograph by Michael H Brooke, A Clinician's
View of Neuromuscular Diseases, provides insight into the clinical assessment of patients with
neuromuscular disease. [8] Although it was written before the explosion of information regarding the

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molecular genetics of neuromuscular disease, it remains a unique and valuable tool. It is out of print,
but copies can still be found for purchase and in libraries.

Laboratory studies

The serum creatine kinase (CK) level is the single most important blood value to obtain when
myopathy is being considered. A representative normal reference range from one laboratory is 24-196
international units per liter (IU/L); each laboratory has its own reference range, with the upper limit of
normal usually below 250 IU/L. The CK level is useful, but not definitive, in determining whether
myopathy is present and in distinguishing between neuropathy or myopathy.

Moderately to extremely elevated levels of CK (>1500 IU/L) usually indicate muscle disease. Mildly
elevated levels (200-800 IU/L) can be observed in either neurogenic or myopathic disorders. Normal
levels are not very likely to be found in the patient with myopathy, but patients with myopathy who
have reduced residual muscle mass may have serum CK levels that fall within the normal range. In
large patients with substantial muscle mass, CK levels above the normal range in the absence of
disease are not uncommon.

The serum aldolase level can be helpful in providing evidence of myopathy. An abnormal aldolase
level is less specific for skeletal muscle disease than the CK level, but because of its longer half-life in
serum, the serum aldolase level is sometimes elevated in the setting of myopathy when the CK level
is normal. If the CK level is already known to be abnormal, there is no reason to obtain testing for the
aldolase level.

Electrodiagnostic studies

Electrodiagnostic studies are often extremely useful in determining whether a neuropathic, myopathic,
or mixed disorder is present.

Changes in nerve conduction velocities, the compound muscle-action potential, or both can be
present in neurogenic disorders.

Electromyography (EMG) demonstrates different findings in neurogenic and myopathic disorders and
can be useful to help distinguish them; specific details are beyond the scope of this chapter. Avoiding
EMG in a muscle that will undergo biopsy is of critical importance. EMG inflicts damage on the muscle
that can interfere with proper interpretation of a biopsy for 1-2 months. In patients with suspected
myopathy, needle EMG should be performed on muscles on only one side of the body; a subsequent
muscle biopsy should be performed on the other side.

Technical Issues in Muscle Biopsy

Selection of muscle for biopsy
Biopsy of a clinically involved muscle is important. Most disorders preferentially or more severely
affect certain muscles while relatively or completely sparing other muscles. It must be kept in mind
that some disease processes have a patchy distribution rather than being diffusely distributed in the
affected muscles; thus, it occasionally happens that even if an affected muscle is biopsied, the biopsy
might not sample the pathology.

To increase the likelihood of sampling the pathologic process, it is important to select a symptomatic
muscle. Selection of a muscle should also be based on the expected distribution of the leading clinical

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diagnosis. For example, if the leading diagnostic consideration is polymyositis, a proximal muscle,
such as the vastus lateralis of the quadriceps, is usually the best choice for biopsy.

When possible, biopsy should be performed on a mildly symptomatic muscle (power of 4/5 on the
Medical Research Council scale used to grade strength), but not one that is too weak or atrophic,
because this may result in obtaining a sample of end-stage muscle (see the first image below). In end-
stage muscle, loss of myofibers is severe, and the myofibers are replaced by fibrovascular and
adipose tissue, typically without residual clues to the process that caused the muscle damage. On
occasion, only the presence of a muscle spindle confirms that the specimen is a biopsy sample of
skeletal muscle (see the second image below).

Hematoxylin-eosin (H&E) paraffin section of muscle biopsy sample reveals end-stage muscle. Fibrovascular and adipose
tissue have entirely replaced this muscle, which can therefore impart no information about patient's underlying pathologic
process.

Hematoxylin-eosin (H&E) paraffin section of muscle biopsy sample revealing end-stage muscle. Structure in center of image,
consisting of cluster of small muscle fibers surrounded by capsule, is muscle spindle; this finding confirms that specimen is
indeed skeletal muscle.

Biopsy procedure and immediate tissue handling

In performing a muscle biopsy, it is essential to cause as little trauma to the muscle tissue as possible
so as to reduce the risk of disrupting the muscle architecture and minimize the risk of introducing
contraction band artifact and other technical artifacts. Electrocautery should not be used to obtain a
specimen for muscle biopsy.

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The images below demonstrate effects of the application of electrocautery to skeletal muscle muscle
during biopsy. The first shows an area of tissue coagulation that results from application of
electrocautery, and the second shows severe contraction band artifact that is caused by the electric
current; both of these technical effects interfere with interpretation of a muscle biopsy, particularly if
they are widespread. Electrocautery can also cause lack of staining of myofibers with the stains that
are performed on cryostat (frozen) sections of muscle, particularly the enzyme histochemical stains
that are frequently performed on muscle biopsies (not shown).

Hematoxylin and eosin paraffin section of region of skeletal muscle sample coagulated by application of electrocautery to
tissue during biopsy procedure. Tissue is unrecognizable.

This hematoxylin and eosin (H&E) paraffin section shows severe contraction band artifact in myofibers in this area of muscle
biopsy, which results from application of electrocautery. This area of sample is not coagulated, as seen in previous image of
this case (above), and thus can be recognized as skeletal muscle, but there is severe disruption of architecture of affected
myofibers, which can significantly interfere with interpretation of muscle biopsy.

The specimens required and the details of the preferred method of biopsy handling vary among
medical centers and commercial laboratories that process muscle biopsies. It is essential to consult
the laboratory at the center that will receive the biopsy sample so as to learn the requirements and the
preferred method of handling and shipping the tissue. Ultimately, of course, the surgeon must
determine the precise surgical method for each patient, but he/she should perform the procedure with
knowledge of what is required by the laboratory where the specimen will be processed.
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The information below is an example of the procedure adapted for one specific medical center and
should be considered a general guide. These considerations should be tailored to meet the needs of
the individual patient and institution.

Please note that these procedures cannot be used for evaluation of a biopsy for malignant
hyperthermia; if this disorder is under consideration, please consult the website of the Malignant
Hyperthermia Association of the United States, https://www.mhaus.org/.

The typical muscle biopsy sample consists of two specimens: fresh and fixed. In certain special
clinical circumstances, a third sample for biochemical analysis may contribute to the specific
diagnosis. Today, the most common use of this third special sample of muscle is for assay of the
activities of mitochondrial enzymes; this assay is performed by only a limited number of laboratories
and is indicated in only select clinical circumstances. This sample is also suitable for genetic testing
performed by certain laboratories.

On occasion, a muscle biopsy sample consists only of a single fresh specimen, usually in the form of
multiple minute fragments, obtained by means of needle biopsy. In one center, with a strong research
program in muscle disease, a strong motivation to perfect the technique, and physicians experienced
with the procedure, needle biopsy is the preferred method of muscle biopsy, with a diagnostic yield
reportedly comparable to that of open biopsy [9] ; however, a full open biopsy is preferred by most
medical centers and laboratories that process muscle biopsies. Occasional laboratories simply do not
have the level of technical expertise required to adequately process and section tiny needle biopsies.

Needle biopsy generally provides a specimen of limited size that typically is not well oriented;
however, it may be the method of choice under the following circumstances:

When serial biopsy procedures are required to follow the course of the disease or to monitor the
response to therapy in a patient
When a disease with diffuse distribution is the leading diagnostic consideration so that any
sample of tissue is likely to be pathologic
When a small sample of muscle is needed only for biochemical assay
When a patient will not consent to an open biopsy but will allow a needle biopsy
When open biopsy is contraindicated

A fresh specimen (see the image below) is used for histochemical studies and certain
immunohistochemistry studies that are optimized for cryostat sections and is sometimes used for
immunofluorescence in selected patients, when indicated, by laboratories that are set up to perform
immunofluorescence. The fresh specimen should measure approximately 0.5 × 0.5 cm in cross-
section, or 0.5 cm in diameter, and 1 cm in length along the longitudinal axis of the muscle fibers.

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Fresh specimen is mounted on cork by using gum tragacanth. It is poised above vial of isopentane, which is chilled with liquid
nitrogen coolant. Specimen is frozen by gently immersing it in isopentane. In this photograph, myofibers are oriented
longitudinally in vertical plane. Tissue is sectioned by using cryostat microtome to produce cross-sections.

The fresh sample can be sent to the laboratory on saline-moistened gauze in a sealed container on
ice; in this way, it is kept cold without becoming frozen. The tissue should not be immersed (ie, should
not be floating or drenched) in sodium chloride solution, because this will lead to the formation of ice
crystals in the myofibers when the sample is frozen. Some laboratories use specific transport media
for the fresh specimens.

When the specimen arrives in the laboratory, the technologist mounts it in gum tragacanth (or another
mounting medium) in the appropriate orientation and snap-freezes it in isopentane chilled in liquid
nitrogen. Frozen sections are cut from this sample on a cryostat, which is a microtome that is
maintained at temperatures below freezing. The terms frozen sections and cryostat sections are used
interchangeably.

Optimally, after the biopsy procedure, this fresh specimen is immediately transported to the laboratory
for processing to prevent the tissue from losing any of its enzymatic reactivity (needed for
histochemical studies) or immunogenicity (needed for immunohistochemical studies). In most
situations, however, the sample remains in satisfactory condition for most necessary studies if
refrigerated overnight or even if refrigerated for a few days in the event of an unavoidable delay
(though a delay of longer than overnight is definitely not recommended).

A fixed specimen (see the image below) is used for routine microscopy and possible electron
microscopy (EM). EM is reserved for special situations in which it is expected to substantially
contribute to the diagnosis, on the basis of the clinical history, the light-microscopic histopathologic
findings in the cryostat and paraffin sections, or both. The fixed specimen should have dimensions
similar to those of the fresh specimen. It must be handled properly to maintain orientation of the fibers,
to keep the fibers at rest length, and to prevent contraction.

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Specimen of skeletal muscle on a 10-mm Rayport clamp is fixed in paraformaldehyde. Longitudinal axis of fibers is oriented in
horizontal plane. (Small stray piece of muscle that is not clamped lies obliquely over clamped portion of specimen.)

The sample is optimally removed from the patient by using a special clamp designed for this purpose,
such as the 10-mm Rayport clamp (V. Mueller, McGaw Park, IL; see the image above). There are
other muscle clamps that may be preferred by some surgeons or laboratories.

A segment of muscle of the desired dimensions is dissected. The bottom portion of the clamp is
inserted below this segment of muscle in the posts-up position so that the length of the fibers runs
perpendicular to the jaws of the clamp.

After the bottom portion of the clamp is inserted, the top portion of the Rayport clamp can be folded
over and the holes fitted onto the bottom posts. The surgeon then excises the muscle fibers 1-2 mm
external to the clamp. The specimen is placed in fixative. The preferred fixative in some laboratories is
4% paraformaldehyde.

If a special clamp is not available for the procedure, alternative methods of obtaining the fixed
specimen are available. The sample can be sent as a fresh specimen to the laboratory, where the
technologists perform the procedures needed for immobilization and fixation. Another method involves
suturing or pinning the specimen to a tongue blade or a piece of cork for immobilization prior to
fixation.

If paraformaldehyde is not available, 10% neutral buffered formalin is an acceptable alternative for the
purpose of light microscopy. If, however, EM is needed, the specimen initially fixed in
paraformaldehyde has better ultrastructural preservation than that of a sample fixed in formalin,
although a few hours of formalin fixation prior to placing the sample in a fixative appropriate for EM
should not interfere with this study.

If paraformaldehyde is not available and it is anticipated that EM will be needed, a small portion of
muscle can be placed directly in 3% glutaraldehyde (or other EM-appropriate fixative, such as
Karnovsky's fixative) at the time of biopsy for submission to the EM laboratory. To prevent contraction
of the muscle, the sample should be immobilized at rest length before it is immersed in the fixative.
The specimen to be immersed must be small (1-2 mm wide or deep) because glutaraldehyde
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penetrates tissue slowly. If the specimen is too large, portions of the sample will not be adequately
fixed for EM before they become degraded.

After overnight fixation in paraformaldehyde, the technologist separates a small section and submits it
in glutaraldehyde for embedment for EM. The remainder is submitted for paraffin processing, with the
end(s) of the specimen removed and placed in cross-section and most of the sample submitted in
longitudinal section.

An additional fresh specimen is useful in selected cases where the presence of a metabolic myopathy,
particularly a mitochondrial disorder, is strongly suspected. The sample may be sent to specialized
laboratories for assessment of specific enzymatic activities (eg, mitochondrial enzymes). Such a
sample can be used for measurement of specific protein constituents in muscle (eg, the protein
dystrophin), but in most cases, the availability of genetic testing on a sample of blood has made
Western blot analysis of muscle proteins unnecessary, and this type of study is not frequently done
today.

This additional special specimen should be of dimensions similar to those of the other specimens, and
optimally, it should be snap-frozen in liquid nitrogen at the location of the procedure because of the
lability of some of these cellular constituents. It should be stored in a freezer at –70°C. Laboratory
personnel should be alerted in advance if the need for this type of specimen is anticipated. Many
medical centers are not equipped to perform this service.

If liquid nitrogen is not available, this extra sample can also be immediately frozen by using dry ice.
Care should be taken to insulate this sample from the rest of the biopsy when the specimen is being
transported to the laboratory, so that the other parts of the biopsy do not become frozen.

Studies performed on biopsy sample

For examples of these studies in normal skeletal muscle, see Skeletal Muscle - Structure and
Histology; for examples of these studies in various neuromuscular disorders, see Skeletal Muscle
Pathology.

The actual methods for performing the stains can be found in standard histology textbooks and
pathology laboratory manuals. Immunohistochemical stains must be performed by a laboratory set up
for this purpose. The manufacturer provides instructions for use of each individual antibody, and each
laboratory develops its own modifications to achieve optimal results with the stains.

At Stony Brook Medicine, for every muscle biopsy, a battery of stains is performed on the frozen
sample in addition to the H&E stain. These routine stains assist in screening for and assessing
neurogenic or other types of atrophy, inflammatory myopathies, noninflammatory myopathic disorders,
congenital myopathies, and metabolic diseases, as well as in demonstrating structural changes or
inclusions that are diagnostic of certain specific disorders.

Some of these studies cannot be performed on material that has been fixed and embedded in paraffin.
Some of the structures and materials are dissolved by paraffin processing, so that they can only be
identified in frozen sections. After review of the initial battery of stains, if the composite of clinical and
pathologic findings warrants it, the pathologist may decide to perform additional special studies.

An example of one battery of stains performed on every biopsy include those listed below. (There is
variation with regard to which stains are routinely performed at different institutions.)

H&E is the routine histologic stain used for evaluation of basic tissue organization and cellular
structure.

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With nicotinamide adenine dinucleotide tetrazolium reductase (NADH) staining, the activity of this
group of enzymes is demonstrated by the transfer of hydrogen to a compound that turns gray-blue
when it is reduced. These enzymes are found in mitochondria and endoplasmic reticulum. This stain is
used to assist in evaluating for neurogenic atrophy, mitochondrial disorders, and central core disease,
among others, and it is useful for detecting subtle alterations of intracellular structure in a myofiber
that suggest it is not well.

Fiber-typing stains are also used. Muscle is composed of two main myofiber types: 1 and 2. Some
disease processes characteristically affect one type or the other, resulting in atrophy of either type 1 or
2 myofibers. Other processes, such as neurogenic disorders, can alter the distribution of both types.
Many laboratories use a myosin adenosine triphosphatase (ATPase) stain at multiple pH levels to
demonstrate the different fiber types. This is a labor-intensive stain to perform.

An immunohistochemical stain for the different forms of myosin heavy chains found in type 1 and type
2 myofibers is an alternative method for demonstrating the two types of myofibers. These stains are
adequate for myofiber typing in most cases. Novocastra (Newcastle upon Tyne, England)
recommends an immunohistochemical stain for research purposes only. A stain is now also available
for embryonic myosin heavy chain as well as other subtypes of myosin heavy chain.
Immunohistochemical stains are now available for different forms of myosin ATPase.

The modified Gomori trichrome stain is particularly helpful in evaluating for the presence of
mitochondrial disorders, inclusion body myositis, and nemaline myopathy, among many other uses.

Periodic acid–Schiff (PAS) stains glycogen and other polysaccharides. It is most useful for the
diagnosis of glycogen storage diseases. PAS also stains the basal lamina of blood vessel walls, so it
can be useful for evaluating the structure of vessels.

Fat stains, including Sudan Black, oil-red-O, and osmium, are used to demonstrate the presence of
neutral lipids in muscle, which are normally present but can exist in abnormal amounts or distribution
in carnitine deficiency, some mitochondrial disorders, acquired metabolic disorders (e.g., in
starvation), and nonspecific abnormalities of the myofibers.

Human leukocyte antigen (HLA) class ABC by immunohistochemistry is used to identify and support
the diagnosis of autoimmune or inflammatory myopathies. Other terms for HLA class ABC are HLA
Class I and major histocompatibility complex (MHC) Class I.

Additional special stains that can be performed on the frozen sample when warranted by the clinical
history and findings in the initial battery of stains include the following:

For muscular dystrophies, immunohistochemical studies for dystrophin, sarcoglycans, laminin 2-

alpha (merosin), and other structural proteins can be performed; the results then can be used to
direct special biochemical or genetic analysis that will lead to a specific diagnosis
For some metabolic disorders, studies of the enzymatic activities of myophosphorylase,
phosphofructokinase, myoadenylate deaminase, succinic dehydrogenase (SDH), and
cytochrome oxidase can be performed
A stain for acid phosphatase, a lysosomal enzyme, can be useful for the evaluation of certain
metabolic disorders and some toxic disorders, as well as in some other circumstances;
immunohistochemistry for p62 and LC3, which can be performed on cryostat sections or on
formalin fixed paraffin embedded tissue, can also perform this function
For dermatomyositis and certain other disorders, immunofluorescence or immunohistochemistry
can be performed to look for the membrane attack complex of complement in blood vessel walls
For all immune-mediated (inflammatory) myopathies, immunohistology for MHC class I (ie, HLA
class ABC or HLA class I) can be performed, if this is not already part of the routine panel of
studies

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Alpha naphthyl acetate esterase enzyme histochemistry stain can be used to help identify
denervated myofibers

Paraffin sections are usually stained with H&E. This specimen typically consists of a fairly large
surface of myofibers (muscle cells) oriented in the longitudinal direction and a piece in cross-section.
A relatively large amount of tissue is usually exposed in each paraffin section; therefore, this specimen
is extremely useful for evaluating for processes with a nonuniform distribution (eg, inflammatory
myopathies, vasculitis).

Because the fixed and paraffin-embedded specimen maintains more cytologic detail than the frozen
specimen does, it is the preferred sample for detecting subtle evidence of myofiber necrosis,
determining the type of inflammatory infiltrate present, and examining the structure of blood-vessel
walls.

When indicated, special stains can be performed on the paraffin specimen, including (but not limited
to) the following:

Special stains for microorganisms, such as bacteria, fungi, and parasites

Elastic stains to evaluate for disruption of the elastic lamina of arteries in vasculitis
Immunohistochemical stains to determine the subtypes of inflammatory cells within an infiltrate
and a variety of other purposes
In-situhybridization for identification of viruses
Congo red, thioflavin S or other stains for amyloid

Although a small sample of every muscle biopsy should be set aside for possible EM, performing EM
on muscle biopsy samples is not a routine procedure; rather, it is reserved for selected circumstances
in which the pathologist determines that EM has the potential of contributing significantly to
determining a specific diagnosis. The pathologist uses knowledge of the clinical history and findings of
light-microscopic studies to decide if EM is indicated.

EM is costly and time-consuming and requires a specialized laboratory and technical expertise. Some
technical aspects of EM are described below.

Technical aspects of electron microscopy

If the specimen is initially fixed in paraformaldehyde, it is transferred to 3% glutaraldehyde after

sufficient time has passed for the paraformaldehyde to penetrate the tissue. The length of time
required for this process depends on the size of the specimen, but overnight fixation is more than
satisfactory for the purpose. Glutaraldehyde may provide a bit more cross-linking of the membranes,
which is needed for EM. There are other fixatives that are appropriate for tissue that will be used for
electron microscopy.

If paraformaldehyde is not available, the tissue, held at rest length by pinning to cork, can be placed
directly in glutaraldehyde. Because glutaraldehyde does not penetrate the tissue as well as
paraformaldehyde does, a specimen placed in glutaraldehyde must be small, approximately 1-2 mm in
width and depth. Glutaraldehyde makes tissue brittle and interferes with immunohistochemical
studies; thus, it is not appropriate for the paraffin specimen.

If the tissue is fixed in formalin, it is not as well preserved for EM as it would be with paraformaldehyde
or glutaraldehyde. Performing EM on tissue fixed only in formalin is possible, but this is suboptimal.
Cutting tissue out of a paraffin block or removing it from a slide for EM is possible, but the likelihood of
obtaining useful results with these methods is limited.

After fixation, the tissue is divided into samples of 1 mm3, postfixed with osmium tetroxide, and
embedded in epoxy resin. Samples are oriented in either a longitudinal or a transverse direction
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before polymerization of the resin. The process of embedment requires 2 days.

Survey sections for light microscopy with a thickness of 1 μm, termed semithin (or thick) sections, are
cut from the material embedded in plastic and stained with either toluidine blue or methylene blue-
azure II. The pathologist reviews these sections, and areas of interest are chosen for EM.

An ultramicrotome with a diamond knife is used to cut thin sections for ultrastructural study. These
then are stained with uranyl acetate and lead citrate. They are placed in an electron microscope and
examined.

Selected clinical circumstances in which EM is useful include the following:

When evidence is being sought to support a diagnosis of dermatomyositis, EM can be used to

look for tubuloreticular inclusions (TRIs) in endothelial cells; if the light-microscopic findings are
already diagnostic of dermatomyositis, EM is not necessary
EM can be used to identify inclusions found by light microscopy
EM can help characterize stored material found on light microscopy and define its intracellular
localization
EM can be used to analyze structural abnormalities found by light microscopy
EM can assist in the diagnosis of mitochondrial myopathy
EM is only rarely indicated for a muscle that is normal at the light-microscopic level; if normal
muscle is found with all of the light-microscopic studies, then this is usually what EM will show,
only larger; the only relatively common exception to this guideline occurs when there is a strong
clinical suspicion for dermatomyositis but light-microscopic findings are normal; if TRIs are
found, they can lend some support to this diagnosis, but if the patient has already been treated
with steroids, it is unlikely that TRIs will be present

Pearls
Every muscle pathologist has a series of stories about biopsy procedures that were performed
improperly. In many of these situations, the samples were salvaged and yielded diagnoses, but on
occasion, the specimen was inadequate for the diagnosis under consideration, or some aspect of the
procedure was performed so improperly that the procedure had to be repeated. (For examples of
suboptimal biopsies that underscore the great importance of using proper technique and following
established protocols, see the images of electrocautery coagulation and contraction band artifacts in
Technical Issues in Muscle Biopsy, above, and see Skeletal Muscle - Structure and Histology.)

Occasional situations exist when the biopsy must be repeated for precise diagnosis and no one is at
fault. Such situations include the following:

A normal biopsy result without pathologic findings in the setting of a high level of clinical
suspicion of a disorder that is known to have a patchy distribution (eg, polymyositis)
An atypical presentation of a rare metabolic disorder, which would not ordinarily be suspected
before biopsy, necessitating additional sample for biochemical assay or other special study, if
genetic testing on a sample of blood is not appropriate or available for the disorder of concern

Repeat muscle biopsy is occasionally indicated to evaluate the patient with known inflammatory
myopathy who, after improvement with steroid or other immunosuppressive therapy, develops
progressive weakness. Biopsy findings can help distinguish between exacerbation or recurrence of
the disorder and steroid myopathy or certain other treatment-associated effects.

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Unsuitable, suboptimal, or inadequate biopsy specimens can usually be attributed to lack of planning
and forethought, a lack for which there is no excuse. The single most important task to remember
when one is contemplating muscle biopsy is to call the pathology laboratory in advance for advice
on how to proceed. The specimens required and the preferred method of handling vary among
medical centers. Consulting the center that will receive the biopsy sample is essential for learning the
exact requirements and the preferred method of handling and shipping the tissue.

Contraindications and Complications

Few true contraindications for muscle biopsy are noted. This procedure is contraindicated in someone
with a high risk of intractable bleeding from the procedure or with an obvious infection at the planned
biopsy site.

The surgical procedure to obtain a muscle biopsy is relatively simple and poses little risk to the patient
in the absence of an underlying bleeding or clotting disorder.

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