Targeted nerve biopsy: A technique in evolution (2018)

Nerve biopsies are often the most definitive test for the diagnosis of uncommon neurologic dysfunction. Historically, nontargeted biopsies of distal cutaneous (sensory) nerves (e.g., sural nerve) have been performed widely due to their expendable nature, accessibility, and ease of surgery, but they have had a relatively low yield (Hart et al., 2013). Nontargeted biopsy of motor nerve branches (e.g., obturator nerve (Riva et al., 2011), nerve to pronator teres (Dy et al., 2012), and superficial fibular (peroneal) nerve (D'Amico and Winfree, 2017)), has also been occasionally utilized with some early success. Fifteen years ago, targeted fascicular biopsy of a major (mixed) peripheral nerve was introduced as a new technique whereby pathology is localized using a combination of careful clinical examination, electrophysiological studies and focused nerve-based imaging. MRI targeted fascicular biopsy increased the diagnostic yield from 20%-50% to 74%-85% (Capek et al., 2015; Laumonerie et al., 2017). While the risk associated with this procedure at a tertiary care facility has been acceptably low, the procedure of performing a biopsy of a major nerve or plexus has not yet been widely adopted. Recently, this targeted technique has been refined to biopsy cutaneous nerves in select cases (Marek et al., 2017) and proposed as a safer and easier alternative to targeted fascicular biopsy. In one of these cases, pathology was confirmed by both a targeted cutaneous branch and a motor branch (nerve to the subclavius muscle). In this article, several cases are presented to extend this diagnostic approach by targeting a motor branch. The goal of targeting smaller sensory and motor branches is to minimize risk of worsening neurologic function secondary to biopsy, while still providing enough histopathological tissue to be diagnostic. We present three illustrative cases where pathology was affecting major peripheral nerves, including their motor nerve branches. Approval from our Institutional Review Board was obtained prior to this study. A 14-year-old boy presented with longstanding right leg length discrepancy and mild-to-moderate weakness of his right leg affecting both tibial and common fibular nerve distribution. The patient was noted to have a cavovarus right foot. The right ankle reflex was absent. Sensation of the right foot was normal. EMG was consistent with a lesion localized in the right sciatic. MRI showed fusiform enlargement of the right sciatic nerve in the thigh and buttock region with mild contrast enhancement. On detailed review of the MRI, atrophy could be seen in the hamstring muscle and an abnormal sciatic nerve branch to the hamstring was identified at the level of the ischial tuberosity (Fig. 1A,B). To minimize injury to the abnormal but still functional sciatic nerve, biopsy of only this hamstring nerve branch was performed (Fig. 1C). Pathology was consistent with a neuromuscular choristoma. While unknown at the time of biopsy, neuromuscular choristoma has been associated with the development of desmoid tumors (Hebert-Blouin et al., 2013), and despite this minimally invasive approach (biopsy of only the muscular branch), this patient went on to develop a desmoid tumor. Case 1. MRI study of the neuromuscular choristoma and open biopsy of the redundant hamstring branch. A: An axial T-1 weighted fat saturated SPGR (spoiled gradient recalled) post gadolinium image of the right upper thigh demonstrating marked fusiform enlargement and thickening of the sciatic nerve (arrow) consistent with neuromuscular choristoma. B: Photographic magnification of the same image as in A showing fusiform enlargement and thickening of the sciatic nerve in detail (arrow). A small hamstring branch is visible (arrowhead) and the atrophy of hamstring can be appreciated (dashed line). C: An operative photo showing biopsy of the redundant hamstring branch (arrowhead). Enlarged sciatic nerve (S) can be seen in the top left segment of the image. Proximal (P) and distal (D) orientation is indicated. A 65-year-old woman with a history of breast carcinoma was referred for evaluation of a progressive left brachial plexopathy. A painless lump and abnormal mammography led to the diagnosis of invasive ductal carcinoma grade 2 with estrogen and progesterone receptor positive and Her2/Neu negative typing. She underwent lumpectomy with adjuvant chemotherapy and radiotherapy (not including the brachial plexus). Postoperatively, the patient developed lymphedema of the left arm and 13 years after her initial diagnosis, she was found to have frontal calvarial metastases. These new lesions were successfully treated with resection and a second round of chemotherapy. Approximately, 16 years after her initial diagnosis, she developed severe pain and weakness of her left upper extremity over several months. Physical examination revealed tenderness over the left supraclavicular part of the brachial plexus, severe weakness of the left deltoid, spinati and biceps brachii muscles and sensory loss in C5–6 distribution. She had moderate lymphedema of the left arm. EMG was consistent with the left brachial plexopathy involving the upper trunk. MRI showed enlargement and post gadolinium enhancement of the left brachial plexus. This enhancement extended from the C5 and C6 nerves into the posterior and lateral cords. MRI also demonstrated atrophy of the pectoralis major, spinati, subscapularis and deltoid muscles. A subtle mass was noted in the medial infraclavicular region surrounding the brachial plexus cords. Increased FDG uptake was appreciated on PET-CT corresponding with MRI findings and was consistent with suspected perineural spread. On reinterpretation of the imaging, the atrophic pectoralis major muscle led to the discovery of an enhancing left lateral pectoral nerve that could be traced to the lateral cord and to the upper trunk of the brachial plexus (Fig. 2A). While the lateral pectoral nerve could have been targeted to prove perineural spread of breast carcinoma, we elected to perform a percutaneous ultrasound guided fine needle biopsy of the mass immediately adjacent to the brachial plexus and the lateral pectoral nerve (Fig. 2B). Needle biopsy of the mass was felt to be less invasive and safer than an open nerve biopsy (Fig. 2C). Recurrent breast carcinoma was confirmed. The major differential for this patient was radiation neuritis versus perineural spread and obtaining this diagnosis was important. Ultimately, palliative radiation therapy of the brachial plexus was recommended to treat her severe pain and halt the progression of her cancer. Case 2. MRI exam and US guided biopsy. A: Axial T-1 weighted fat saturated SPGR (spoiled gradient recalled) post gadolinium image of the left shoulder girdle demonstrating severe atrophy of the pectoralis major muscle (arrowhead). Abnormal enhancement of the lateral pectoral nerve (hollow arrowhead) can be seen between the pectoral major (arrowhead) and pectoral minor (arrow) muscles. B: Sagittal T-1 weighted fat saturated SPGR (spoiled gradient recalled) post gadolinium image at the mid clavicular position showing the lower trunk (arrowhead) and an enhancement of the upper trunk (hollow arrowhead) of the left brachial plexus. The subtle enhancing mass deep to the pectoral muscles and adjacent to the brachial plexus can be seen (arrow). C: US image obtained during biopsy showing the subtle mass (dashed ellipse) and the aspiration needle (arrowheads). A 69-year-old man with a history of suspected dormant sarcoidosis presented with left wrist and finger drop. He developed the sudden onset of left wrist and finger extensor weakness over several hours, which was associated with pain radiating to his left dorsal hand. There was no history of trauma. Physical examination 14 months after the onset of weakness revealed severe wrist and finger extensor weakness and decreased sensation of the dorsal radial aspect of the left hand. Muscle atrophy in the extensor wad of forearm was noted (Fig. 3A). His triceps brachii was normal. There was tenderness on percussion of the radial nerve 2–3 cm above the elbow joint. EMG was consistent with radial nerve neuropathy distal to the triceps brachii, affecting the brachioradialis muscle, extensor digitorum communis and supinator (other distal radial-innervated muscles not tested). MRI revealed an ill-defined 1 cm lesion of the radial nerve at the level of lateral humeral epicondyle. Atrophy and denervation changes were appreciated on MRI within the brachioradialis, extensor carpi radialis longus (Fig. 3B) and brevis and supinator muscles. The patient underwent open exploration and calcification around and within the radial nerve was found. Given the preexisting severe weakness of the brachioradialis muscle, a single motor branch to this muscle was biopsied, in addition to the calcified mass, and the scarred soft tissue surrounding the radial nerve (Fig. 3C). Pathology revealed decreased density of myelinated fibers and interstitial fibrosis with calcification. While a specific named diagnosis was not achieved, there was no evidence of sarcoidosis and the patient avoided empiric high-dose steroid treatment. Case 3. Physical examination, MRI study and an open biopsy. A: Atrophy in the extensor wad of the left arm can be appreciated (arrows). B: A fat suppressed, axial T2-weighted image at the level of the elbow demonstrating atrophy and subacute denervation changes in the extensor carpi radialis longus (ECRL). Distal humerus (H) and olecranon (O) can be seen. C: Open biopsy of the branch to the brachioradialis muscle (arrowhead). Dystrophic calcification is visible (arrow). These cases introduce the rationale for targeted muscular branch biopsy in selected cases. In these three cases, based on the history, rigorous physical examination, electrophysiological testing and high resolution imaging studies we were able to localize and therefore target pathology in small motor branches without necessitating biopsy of their respective parent nerves, which would have originally been the target for our open biopsy. We acknowledge that it is difficult to appreciate subtle changes affecting small motor branches on MRI. High resolution MRI showed the abnormality specifically in the discrete nerve branches retrospectively only in cases 1 and 2. In all cases, denervation was present in the targeted muscles. In these three cases, we review important anatomic and pathologic considerations for this new technique. In all cases involved, biopsy of a redundant or expendable motor branch rather than resecting a fascicle from the parent nerve was performed or considered. In Case 1, a pathologic hamstring branch was biopsied, as the hamstring muscle is known to be supplied by several branches from the sciatic nerve and therefore harvesting a single branch should not have a major effect on function. In Case 2, biopsy of the lateral pectoral branch was considered, appreciating the contribution from the medial pectoral branch and the pattern of perineural spread. In Case 3, even though the brachioradialis was weak but not paralyzed, this radial nerve innervated muscular branch was safely targeted because it was functionally expendable. Elbow flexion is also mediated by the musculocutaneous nerve through the biceps brachii and lateral half of the brachialis muscles (Spinner et al., 2003; Puffer et al., 2011) and further weakening of the brachioradialis should not create a new functional impairment. There are other considerations. The presence of muscle atrophy was important because it helped to localize the abnormal branch pathology that may not be visible on MRI. Case 2 demonstrated an abnormal brachial plexus on MRI and the atrophy of the pectoralis major muscle led to the appreciation of the lateral pectoral nerve abnormality. In Case 3, although the individual nerve branch to the brachioradialis muscle was not seen on MRI, this nerve was targeted given the denervation changes. Biopsy site might be influenced toward a target with severe, chronic (> 1 year) atrophy, avoiding important functional loss that could be reversed (e.g., neurolymphomatosis (Ghobrial et al., 2004) or chronic inflammatory demyelinating polyneuropathy (CIDP) (Capek et al., 2015)). After longstanding denervation, muscular recovery would not be anticipated even with treatment, and sacrificing a compromised nerve seems more logical than attempting to target fascicles in the parent nerve with risk to injure functional elements. The major goal of nerve biopsy is to obtain a diagnosis with the least invasive approach and lowest neurological risk. Targeted biopsy was introduced as a procedure of higher safety and to improve diagnostic yield. With increasing knowledge of clinical anatomy together with more experience in treatment of peripheral neuropathies and higher resolution imaging widely available we are able to precisely target the affected nerve(s) for biopsy. By connecting the dots of atrophic muscles (on exam or by imaging) to obvious radiologic pathology in a parent nerve, we are able to follow the pathologic process (e.g., perineural spread of a tumor) and localize the pathology within small less important nerves (Fig. 4). Targeted biopsy of skin or minor motor branches can still provide the histopathological diagnosis whilst preventing further neurological deficit from fascicular biopsy of the parent nerve. With rapid advancement in imaging technology together with better understanding of pathogenesis of peripheral neuropathies we will continue to refine our biopsy techniques. Based on these cases, we believe that autonomic nerves may also be a safe potential target for biopsy (e.g., in cases of perineural spread of prostate cancer to the lumbosacral plexus) (Fig. 5). An illustration representing the concept of targeted nerve biopsy. By connecting the dots (e.g., combining clinical and imaging information, etc.), we are able to target the pathology in a small, redundant and/or affected motor branch. (with permission, Mayo Foundation, 2018). An illustration demonstrating the evolution of the targeted nerve biopsy concept. By additional knowledge and experience as well as refined imaging techniques, such as higher resolution imaging techniques, we are able to target individual nerve branches affected by pathology for biopsy. The timeline of introduction of individual approaches is indicated with fascicular biopsy preceding targeted biopsy of a sensory (cutaneous) and motor branch. A future application/direction would include targeted autonomic branch biopsy (with permission, Mayo Foundation, 2018). The authors report no conflict of interest.