Brain, Nerve, and Muscle Biopsy

John F. Crary

Thomas H. Brannagan III

Kurenai Tanji

INTRODUCTION

Biopsy of nervous and muscle tissue remains a critical tool. Any potential benefits associated with having a tissue-based diagnosis must be carefully weighed against the risks associated with the procedure. Brain, muscle, and nerve biopsies are always performed in the context of an interdisciplinary team, which can include neurologists, internists, neuroradiologists, neurosurgeons, and neuropathologists. To ensure appropriate assessment of the biopsy, a high level of communication between providers is of the utmost importance. In most cases, brain biopsy should be a last resort, reserved for clinical settings where all other diagnostic modalities have been exhausted. However, modern surgical techniques have helped to minimize complications and the risk of obtaining a non-diagnostic biopsy in some disorders, the benefit in establishing a diagnosis and thus treatment plan may outweigh the risks of the procedure. In addition, modern molecular techniques are increasingly being applied, greatly increasing the use of biopsy specimens. Although the widespread deployment of next-generation sequencing technology has obviated the need for biopsy in some settings, these modern ancillary studies have not supplanted classical histomorphologic analysis. In this chapter, we will provide an overview of the critical issues associated with the brain, muscle, and nerve biopsy. We will also discuss the use of skin biopsies for epidermal nerve fiber density analysis.

BRAIN BIOPSY

INDICATIONS

Certain general considerations must be weighed before referring a patient for a brain biopsy. General risks associated with brain biopsy are similar to those associated with any surgical procedure, including deep vein thrombosis, postoperative hemorrhage, infection, etc. Patients on anticoagulant treatment might need to make adjustments given the risk of postoperative intracranial hemorrhage in the brain. Other complications include stroke, seizures, and cerebrospinal fluid (CSF) leak (fistula). Given the risks, it is generally accepted that all other diagnostic modalities must be exhausted before proceeding to brain biopsy.

An essential consideration prior to biopsy is determining the likelihood that the answer will lead to a change in patient management. Should, for example, the expected diagnoses have similar or no disease-modifying treatments, then the decision to proceed to a biopsy should be questioned. Furthermore, there is often a window of opportunity for the biopsy to be useful clinically. If the patient has deteriorated beyond the point to which a reasonable recovery in function can be anticipated, the biopsy might also be of limited value. Further, the ability of the neuropathologist to recognize diagnostic features in the tissue is highest during the active phase of a disease. Once the pathology has run its course, secondary changes in the tissue can predominate and increase the likelihood of a nondiagnostic biopsy. Treatment effects, such as brain irradiation or steroids, may also mask diagnostic changes. For example, in a patient with a possible diagnosis of central nervous system (CNS) lymphoma, the use of systemic steroids should be deferred unless essential in the context of clinical care (i.e., as a component of treating brain herniation), as treatment can make the biopsy nondiagnostic. Thus, it is essential that empiric treatments be used judiciously should a patient be a candidate for brain biopsy.

Brain biopsies have a prominent place in the treatment and management of CNS neoplasms. For mass lesions, partial brain resection and/or biopsy may be performed, depending on the functional importance of the region that contains the lesion. For malignant brain tumors, resections have the additional advantage of being both diagnostic and therapeutic in the form of debulking. Watchful waiting might be considered for benign brain tumors. Certain brain tumors in vital regions of the brain, such as brain stem gliomas, or eloquent cortical regions might not be amenable to a full resection, but guided stereotactic biopsy might be performed in some cases.

Brain biopsies are generally not required for most CNS infections, as other forms of diagnosis are often definitive. Viral, bacterial, and fungal organisms can be identified with other diagnostic modalities, including with CSF sampling. In ambiguous contexts, a brain biopsy might be performed. Such biopsies are often of highest clinical use when two pathogenic processes with contradictory treatments are under consideration, for example, infectious versus autoimmune. Immunocompromised patients also provide a special setting where a broad differential diagnosis might trigger consideration of a brain biopsy.

In the case of age-related neurodegenerative disorders, brain biopsy is rarely performed. However, a biopsy may be considered in the setting of a rapidly progressive dementia, when there is a reasonable chance that a treatable cause might be uncovered, which cannot be diagnosed by other means. Recent advances have led to the ability to diagnose specific autoimmune encephalitides using antisera. Moreover, CSF biomarkers have shown increasing use in diagnosing Alzheimer disease and prion disease. These advances have altered referral patterns, perhaps decreasing the total number of subjects undergoing brain biopsy for rapidly progressive dementia but increasing the diagnostic yield.

Brain biopsy is not indicated for ischemic stroke, but brain tissue may be sampled in the setting of hemorrhagic stroke to assess the vasculature for cerebral amyloid angiopathy. Vascular abnormalities may be resected surgically, and histopathologic analysis of such lesions is generally of only modest use.

BRAIN BIOPSY REQUIRES AN INTERDISCIPLINARY APPROACH

Brain biopsies are always performed in the context of an interdisciplinary team. The neurologist plays a critical role in the clinical workup and referring patients to biopsy only when all other
diagnostic modalities have been exhausted. Next, the neurologist will work closely with both the neuroradiologist and neurosurgeon to identify a radiographically evident lesion that is amenable to biopsy. Although “blind” biopsies of the nondominant (usually right) frontal cortex are often performed, targeting a specific lesion is thought to provide the most informative results. If a biopsy is indicated, an open biopsy consisting of 1 cm³ full-thickness biopsy that contains gray matter, leptomeninges, and subcortical white matter is considered optimal by most neuropathologists. However, if the lesion is located within a vital or eloquent brain region, stereotactic core biopsies, sometimes measuring just a few millimeters, can provide diagnostic material.

During surgery, neurosurgeons often call on the neuropathologist to perform a frozen section. These intraoperative consultations are a means to rapidly obtain some diagnostic information and involve rapidly freezing tissue and cutting followed by hematoxylin and eosin (H&E) staining. Although these tissue sections are of only limited diagnostic value, given the severe tissue artifacts that develop, the information provided may be helpful to guide surgical decision making. Another use of the frozen section is confirming the presence of lesional tissue within the biopsy, which also decreases the likelihood of a nondiagnostic biopsy. Critically, the preliminary diagnostic impression obtained through a frozen section must be interpreted with caution, as it is not uncommon for revision following additional sampling and ancillary studies.

NEUROPATHOLOGIC INTERPRETATION OF THE BRAIN BIOPSY

Classical histopathologic examination by a neuropathologist remains the foundation of brain biopsy interpretation. Tissue sections from formalin-fixed brain are mounted on glass slides, stained with the H&E, and examined microscopically. The H&E stain allows for visualization of the cytoarchitecture and all the cellular types in the brain, including neurons and glia. Other stains are in routine use, including variations of the Bielschowsky silver stain, which is excellent for visualizing neuronal processes. Connective tissue stains such as trichrome, reticulin, or van Gieson are particularly useful for vascular pathology. Congo red and thioflavin are useful for visualizing amyloid. Gram, Gömöri methenamine silver (GMS), and the Ziehl-Neelsen (acid-fast bacilli) stains are routinely used for microorganisms.

Various ancillary studies are routinely used in neuropathology. Immunohistochemical stains are commonly employed in various contexts, particularly in the setting of neoplasms, where molecular alterations can be detected with both diagnostic and prognostic relevance. Many molecular tests require fresh (nonfixed) frozen tissue, and a portion of the specimen must be set aside for this purpose prior to processing. Should an infectious etiology be a consideration, tissue cultures are ideally performed using swabs of the surgical site, but fragments of fresh tissue can be submitted after surgery provided that it has not been fixed or contaminated. If lymphoma is a consideration, brain tissue can be used for flow cytometry to characterize the neoplastic population, but CNS lymphoma is most often of the diffuse large B-cell type, and these fragile cells generally do not perform well for this test. Alternatively, cultures of the tissue may be grown for cytogenetic analysis. Electron microscopy is generally of only very limited use in the setting of brain biopsies. Next-generation DNA and RNA sequencing is increasingly being applied to brain tumors for subclassification and targeted treatments. Also, next-generation sequencing can detect very low levels of pathogen DNA/RNA and may become more widely deployed in the future for this use.

MUSCLE BIOPSY

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