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Indications and Usefulness of Nerve Biopsy
Gérard Said, MD
Arch Neurol. 2002;59:1532-1535.
INTRODUCTION
Progress in neurophysiology and neurogenetics as well as previous neuropathological
findings have all improved our knowledge of the pathophysiological characteristics
of peripheral nerve disorders.1-3 Thanks
to these improvements, the indications of nerve biopsy have decreased during
the past decade, making this invasive procedure unnecessary in the vast majority
of patients with peripheral neuropathy.
However, a recent prospective study has shown that nerve biopsy improves
treatment in an estimated 60% of patients,4 a
figure close to that of an earlier retrospective study.5 The
yield of nerve biopsy depends on a number of factors, including selection
of patients, expertise of the laboratory, and techniques used. In this article,
I will briefly review the main indications and factors that can increase the
usefulness of nerve biopsy.
SELECTION OF PATIENTS
When performed in unselected patients with peripheral neuropathy, nerve
biopsy can be very disappointing because of the lack of specificity of nerve
fiber lesions. In addition, patients may complain of discomfort and allodynia
for months afterward.6 The purpose of the biopsy
and likely benefit to the patient must be determined. It must be kept in mind
that nerve biopsy is used to address specific questions, not to confirm that
a patient does or does not have peripheral neuropathy. Clinical examination
and electrophysiological tests answer this question easily. Thus, before considering
performing a nerve biopsy, the neuropathy must be investigated carefully and
characterized by its inheritance, distribution, course, the general context
in which it has developed, associated cerebrospinal and electrodiagnostic
findings, and availability of DNA testing in the case of hereditary disease.
Hereditary Neuropathies
With hereditary neuropathies, it is now seldom necessary to perform
a morphological study of a nerve biopsy specimen. In patients with well-defined
hereditary Charcot-Marie-Tooth disease (CMT), it is necessary first to determine
the axonal or demyelinating pattern of the disease, by electrophysiological
testing, and the mode of transmission (dominant, recessive, or X-linked),
to orient the molecular genetic testing.7 In
patients with demyelinating CMT, molecular genetic testing has the greater
chance of identifying the abnormality.8 In
truly or apparently recessively transmitted demyelinating polyneuropathy,
the so-called Dejerine-Sottas disease, molecular genetics has identified a
series of abnormalities in approximately two thirds of cases.9 In
the others, morphological abnormalities such as hyperfolded myelin, characteristic
of the so-called CMT-4b type, can be found in nerve biopsy specimens. In patients
whose family histories do not suggest a recessive transmission and in whom
molecular genetic testing did not reveal hereditary neuropathy, especially
patients with asymmetrical slowing of nerve conduction, nerve biopsy may demonstrate
inflammatory lesions caused by an early-onset chronic inflammatory demyelinating
polyneuropathy that could respond to immunomodulatory treatments. In axonal
CMT, neither molecular genetic tests nor nerve biopsy findings contribute
to diagnosis or treatment in the vast majority of cases.
Patients with hereditary liability to pressure palsies usually have
focal or multifocal deficits. Most of them carry the characteristic 1.5-megabase
DNA deletion at chromosome 17p11.2-12 and seldom have other patterns of mutations
of the PMP22 gene. It is only when gene abnormalities
have not been found that nerve biopsy is indicated in this setting to demonstrate
characteristic multiple enlargement of the myelin sheath, show tomacula on
teased fiber preparations, or disclose another cause.
Until very recently, searching for amyloid deposits was an unchallenged
indication for nerve biopsy, even though deposits could be missed in a small
percentage of cases because of their multifocal pattern. Amyloid polyneuropathy,
which is invariably a life-threatening, predominantly sensory, and autonomic
polyneuropathy, is either acquired secondary to any pattern of monoclonal
gammopathy, or inherited as a dominant trait that is mostly due to one of
the many mutations of the transthyretin gene.10 When
a familial amyloid polyneuropathy is suspected in patients with a family history
of severe sensory and autonomic polyneuropathy, molecular genetic testing
for these mutations is recommended, starting with a search for the Portuguese
mutation (Val30Met), which accounts for more than half of the mutations worldwide.
In other rare hereditary neuropathies, including Fabry disease, Tangier disease,
or giant axonal neuropathy, nerve biopsy is still useful.
Acquired Neuropathies
Distal, Symmetrical Polyneuropathies
Acquired, distal, symmetrical, fiber length–dependent polyneuropathies
are predominantly sensory and mostly of toxic, especially drug-induced, or
metabolic origin. In length-dependent polyneuropathy, a biopsy specimen of
a distal nerve can indicate the severity and activity of the neuropathy but
is unlikely to show any specific lesions. In length-dependent polyneuropathy,
nerve biopsy findings are usually not diagnostic, but the combination of pathological
findings with clinical and electrophysiological data can be useful to assess
the severity and progression of a neuropathy and the involvement of unmyelinated
fibers, which is not routinely explored by electrophysiological techniques.
Such study requires quantitative electron microscopic examination of thin
nerve sections by experienced investigators, which is time-consuming and has
many pitfalls. An acquired, severe length-dependent sensory and autonomic
polyneuropathy can be the only manifestation of a light chain amyloidosis
in patients with monoclonal gammopathy. In such cases, nerve biopsy remains
necessary to detect amyloid deposits in light chain amyloid neuropathy.
Multifocal Neuropathies
In multifocal neuropathy, nerve biopsy more often contributes to the
diagnosis than in the other patterns of neuropathy. In patients with multifocal
neurological deficit of peripheral origin, it is first necessary to determine
if the lesions are located in the spinal roots or in peripheral nerves by
clinical examination, electrophysiological testing, and cerebrospinal fluid
analysis.
In mononeuritis multiplex, a nerve biopsy is required to search for
alterations of vasa nervorum, abnormal deposits, or inflammatory infiltrates,
many of which are treatable. A whole-thickness nerve biopsy must then be performed
because these processes are asymmetrical within and between nerve fascicles
and often located in the epineurial space. Vasculitis is the most common cause
of mononeuritis multiplex, and searching for vasculitis is certainly the main
indication of nerve biopsy.
Vasculitic Neuropathies.
The sural nerve, which is invariably affected in length-dependent polyneuropathies,
such as length-dependent diabetic neuropathy or alcoholic neuropathy, is not
the most commonly affected nerve in vasculitic neuropathies.11-12 Although
sural nerve biopsy has been considered a standard method of diagnosing vasculitic
neuropathy, the procedure yields unequivocal evidence of vasculitis in only
20% of patients in whom biopsies are performed for this indication.13-14 A recent multicenter prospective
study12 confirmed the higher yield for performing
a biopsy of the superficial peroneal nerve combined with a peroneus brevis
muscle biopsy to search for vasculitis because of the higher frequency of
involvement of the peroneal nerve in vasculitic neuropathy and the frequent
involvement of muscle arteries.11
Nerve biopsies are most useful in focal and multifocal neuropathies;
more than 75% of histologically confirmed vasculitic neuropathies fall into
this pattern.11 In the other cases, the neuropathic
deficit was distal, bilateral, and roughly symmetrical. The diagnosis of vasculitis
is easily suspected when a multifocal neuropathy is associated with polysystemic
manifestations, but a substantial proportion of patients have isolated neuropathy,
sometimes without clinical or biological signs of inflammation.15 Vasculitis
is found in the muscle specimen in the same proportion of patients in this
subgroup as in those with symptomatic multisystemic involvement.11
Focal and Multifocal Neuropathies in Patients With
Diabetes Mellitus.
Diabetes mellitus is responsible for a variety of neuropathic patterns,
the most common of which is distal, symmetrical, length-dependent, sensory
polyneuropathy, which is often associated with autonomic dysfunction. This
pattern of neuropathy, which constitutes the bulk of diabetic neuropathy,
requires morphological confirmation only in atypical manifestations. Conversely,
patients with diabetes can also develop focal or multifocal neuropathy, which
may be related to diabetes, a superimposed ischemic-inflammatory process,
or another cause of neuropathy. This group of patients with diabetes thus
needs to be investigated in the same way as nondiabetic patients with multifocal
neuropathy, and a nerve biopsy should be performed in most cases.16
Leprous Neuropathy.
Leprosy is still a common cause of neuropathy in subtropical developing
countries. Patients with the lepromatous or tuberculoid forms of leprosy seek
treatment with isolated peripheral neuropathy. The diagnosis is easily suspected
in endemic areas but may pose problems in nonendemic areas. When skin lesions
are missing, performing a biopsy of an affected nerve is mandatory.17
Other Causes of Multifocal Neuropathies.
The other causes of multifocal neuropathy are far less common. Peripheral
neuropathy is occasionally a manifestation of sarcoidosis. In this setting,
it is of interest to note that muscle biopsy specimens were positive in 10
of 11 patients with granulomas in their nerve biopsy specimens.18 This
again underlines the usefulness of combined nerve and muscle biopsy in patients
with systemic diseases. Malignant lymphomas and other tumors can invade peripheral
nerves, but they are more often responsible for multiple radiculopathies than
for multiple cutaneous nerve involvement.
Acquired Demyelinating Polyneuropathies
In chronic inflammatory demyelinating polyneuropathies, nerve biopsy
is not necessary for diagnosis, except when there is some discrepancy between
clinical, electrophysiological, and cerebrospinal fluid findings. Also, evaluation
of axonal loss during morphometric studies of nerve biopsy specimens can have
prognostic value because axon loss is the main prognostic factor in chronic
inflammatory demyelinating polyneuropathies.19 In
neuropathies associated with monoclonal gammopathies of unknown origin, nerve
biopsy specimens can demonstrate the presence of amyloid in patients with
a severe progression of sensory and motor polyneuropathy with autonomic disturbances.
In other circumstances, nerve biopsy is seldom necessary.
SELECTING THE NERVE TO BIOPSY
The consequences of nerve sampling must be known to investigators and
carefully explained to patients before the biopsy is performed. Selecting
the nerve to biopsy is a very important step. The nerve should be a sensory
nerve in a territory affected by the neuropathic process and easily accessible
to neurophysiological studies prior to the biopsy. Performing a biopsy of
a nerve in a territory with marked sensory loss decreases the risk of adverse
effects and increases the chance of finding significant lesions. Simultaneous
sampling of a muscle increases the chances of finding vasculitis10-11 or
sarcoid granulomas.18 Thus, when the neuropathic
deficit predominates in distal lower limbs, a biopsy of the sural or superficial
peroneal nerve can be performed with simultaneous sampling of an adjacent
muscle. After biopsy of the sural nerve or the superficial peroneal nerve,
we prefer to immobilize the leg in a plastic cast for 7 to 10 days, longer
in patients taking corticosteroids or anticoagulants, to avoid excessive tension
over the incision. In patients with proximal involvement of the lower limbs,
the intermediate cutaneous nerve of the thigh can be selected and a biopsy
of the quadriceps muscle performed during the same procedure.20 When
the upper limbs bear the brunt of the neuropathic process, a biopsy of the
superficial radial nerve or a branch of the ulnar nerve on the dorsal aspect
of the hand can be performed, especially in disorders such as leprous neuropathy
without skin lesions.17
NERVE SPECIMEN PROCESSING
Sural nerve processing is highly specialized and requires a facility
equipped to perform routine as well as sophisticated studies of the nerve.
After its removal under local anesthesia, the nerve specimen is processed
for morphological study, but it is necessary to know beforehand what is being
sought and to adapt the methods of study accordingly. Whereas paraffin-embedded
histologic preparations are useful in demonstrating vasculitis, inflammatory
infiltrates, or amyloid deposits, plastic embedding is required to demonstrate
axonal abnormalities. Serial sections of plastic-embedded specimens are often
needed to visualize characteristic lesions of blood vessels or amyloid deposits.
Light microscopy can discern the density and distribution of myelinated nerve
fibers; however, electron microscopy is useful in assessing unmyelinated nerve
fibers. The old technique of preparing a single osmicated fiber, which allows
longer portions of fibers than longitudinal sections, is useful to identify
and even to estimate the age and incidence of fibers undergoing wallerian
degeneration, segmental demyelination, and, occasionally, a dying-back process.21 A teased nerve preparation may demonstrate demyelination
or active degeneration when this finding is not demonstrated by other studies.
Immunostaining of nerve biopsy specimens for cells or abnormal deposits
seldom contributes to the diagnosis, except occasionally to identify monoclonality
of lymphocytes in invading lymphomas. Unfixed frozen sections or paraformaldehyde-fixed
specimens are recommended for immunolabeling techniques. Systematic morphometric
studies of axon size and myelin thickness, as well as electron microscopic
examination of nerve fiber specimens for the study of unmyelinated fibers,
are seldom necessary. Because of the variability of the normal density of
unmyelinated fibers and the difficulty identifying their pathological changes,
we found quantitative studies of unmyelinated fibers less informative than
careful clinical testing of pain sensation and autonomic functions.
EPIDERMAL NERVE BIOPSY
This remarkable, relatively new technique allowing quantification of
nerve fibers in skin biopsy specimens was developed by Kennedy et al.22 The preparations are usually stained with an antibody
to the neuropeptide called protein gene product 9.5, which selectively decorates
nerve fibers in the skin. Preparations stained by immunofluorescent or immunoperoxidase
methods with anti–protein gene product 9.5 and anticollagen IV antibodies,
can then be studied with light or confocal examination. This method is noninvasive,
can be repeated to follow recovery after treatments, and gives access to terminal
fibers, but it does not permit study of myelinated fibers or allow detection
of the interstitial pathological processes that require a nerve biopsy for
diagnosis. The variability of quantitative data is also higher than with conventional
nerve biopsy.
In conclusion, combined nerve and muscle biopsy remains a useful diagnostic
tool in selected cases, especially in patients with multifocal neuropathy.
Nerve sampling must be performed in an affected territory, and the specimen
must be studied in a laboratory with expertise in the field.
AUTHOR INFORMATION
Accepted for publication June 3, 2002.
Corresponding author and reprints: Gérard Said, MD, Neurology
Service, Bicêtre University Hospital, 94275 Le Kremlin Bicêtre,
France (e-mail: gerard.said{at}bct.ap-hop-paris.fr).
From the Neurology Service and the Louis Ranvier Laboratory, Bicêtre
University Hospital, Assistance Publique des Hôpitaux de Paris, Paris-Sud
University, Paris, France.
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