After nerve injury, disorganized or incomplete regeneration may result in a neuroma, a localized growth or tumor of nerve tissue. Neuromas are firm, bulbous, often tender to palpation, and may have significant associated pain, along with numbness or paresthesias.1–6 The true incidence of symptomatic neuroma is unknown, although it has been estimated to occur in at least 5% to 10% in patients sustaining a nerve injury and is most likely higher in patients sustaining an amputation.2,3,7
Traditionally, the diagnosis of symptomatic neuroma centers on patient history, symptoms, physical examination, and the anatomic location and distribution of neuropathic pain. Other important components of diagnosis include the presence of a Tinel sign, radiographic imaging (magnetic resonance imaging [MRI] or ultrasound [US]), and response to diagnostic nerve block.1–4,8,9 Symptomatic neuromas are often difficult to treat and may cause significant morbidity.
Although a combination of clinical examination, judgment, and experience is used to diagnose symptomatic neuroma, there are no established or accepted diagnostic criteria. Given the impact of a neuroma diagnosis and the many surgical and nonsurgical options for treatment, establishing diagnostic criteria is important for both patients and providers. The aims of this study are to review existing literature on the diagnostic criteria for symptomatic neuromas and develop criteria for the clinical diagnosis of symptomatic neuromas.
For this study, we followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and searched PubMed, Embase, and the Cochrane Library for all relevant articles addressing neuroma after nerve injury and amputation, with a subsearch addressing the hand and digits specifically (Appendix 1 and Fig. 1). No date restrictions were applied. We searched for specific terms “amputation” and “neurorrhaphy” in combination with “neuroma” to find articles most relevant to this study but also searched more general terms such as “peripheral nerve injury” and “extremity and injury” to not miss any articles on nerve injuries that may include neuromas. We searched key words/mesh terms, title, and abstract. We also reviewed references and included any relevant articles.
Articles were first filtered by language, including English, Dutch, and German; both first and second authors were proficient to include these 3 languages. Duplicates were identified and excluded. Next, the articles were screened by title and abstract for relevance. Nonhuman animal studies and nonextremity neuromas were excluded. Morton neuroma and Bowler thumb were also excluded, because these entities are generally considered chronic, repetitive nerve injuries rather than sequelae after acute trauma to a nerve. If an article was considered potentially relevant, the full article was reviewed. Reasons and numbers for exclusions are noted in Table 1.
After careful consideration, articles containing relevant information were summarized and included (Table 2). Relevant articles were those in which information could be extrapolated to generate diagnostic criteria. Fifty articles in total were included in this systematic literature review. All relevant diagnostic measures for evaluation of symptomatic neuroma were included, whether they were used as inclusion or selection criteria, subject of study, or more generally described.
We identified 50 studies in the search (Table 2), which described various diagnostic modalities (Table 3).
Pain, as mentioned by 32 of 50 articles, is the most common feature of symptomatic neuroma and is essential for diagnosis. The pain can be described by patients in many different terms but usually includes electric, shooting, burning, aching, or sharp characteristics.3,4,6,7,11,12,15,18,22,24–26,28,30–32,34,35,37,40,43,45 This pain most often is present in the distribution of the involved nerve(s) and should be localized and not diffusely present throughout the extremity or other anatomic location. In addition, hypesthesia (an increase in sensitivity in the area around the injury) or dysesthesia (altered sensation in the distribution of the nerve) is often present. Paresthesia, hyperalgesia, hypoesthesia, and anesthesia are also commonly reported (19 of 50 articles).2,4,5,7,10–12,15,19,20,25,28,30,31,35,36,38,46
Light mechanical stimulation such as manual pressure or heat can also cause significant pain (allodynia, mentioned by 10 of 50 articles).2,4,10,12,19,20,28,31,37,38 The precise reasons for this are unclear, but it has been suggested that the absence of a myelin sheath in neuroma fibers is the cause of this altered sensitivity.10 Peripheral upregulation of various ion channels and receptors (sodium channels, TRPA1, CGRP, alpha-1C receptors, and nerve growth factor) are found in symptomatic neuromas and may also contribute to the neuropathic pain.31,45
It is important to quantify the pain, and one way in which to do this is through use of a visual analog scale. Watson et al35 suggest a modified Hendler's back pain rating scale to evaluate pain associated with neuromas. This scale consists of the following 3 components: a body diagram pain drawing, a numerical scale, and a list of pain descriptors.35 There is no formally accepted way to measure pain in the presence of neuroma, but it is important to quantify and objectively determine the level of discomfort to determine the impact of any treatment.
Cold intolerance or sensitivity can be a frequent symptom in patients with symptomatic neuroma, as mentioned by 10 articles.2,4,5,7,28,37–39,45,46 One study found that 91% (30/33) of patients planned to undergo operative treatment of neuroma had cold intolerance preoperatively, defined as a Cold Intolerance Symptom Severity (CISS) questionnaire score of 30 or higher. There seems to be a correlation between cold intolerance severity and visual analogue scale pain score.2,39
Altered expression of neurotransmitters, upregulation of voltage-sensitive sodium channels, downregulation of potassium channels, and development of ephapses (new nonfunctional connections between axons) cause an increased spontaneous afferent input to the spinal cord, which may lead to spontaneous pain and may explain cold intolerance.28
PHYSICAL EXAMINATION FINDINGS
Physical examination for patients with neuroma focuses on careful evaluation of the location of neuropathic symptoms. There will be diminished nerve function (sensory or motor) in the involved nerve territory. During examination, a painful soft tissue mass, as described in 5 of 50 articles, may be present and is often indicative of a neuroma.11,17,22,29,41 Denervation atrophy at site of injury or distally in the distribution of the nerve can also be observed36 as well as loss of skin creases.
In addition to a careful history and physical examination, the Tinel sign is the most referenced physical examination finding for the diagnosis of neuroma, as it is mentioned in 41 of 50 articles.2–4,6,7,10–16,17,19–23,25–32,34–43,45,46,48,49,51 A Tinel sign is present when light tapping on the area of suspected neuroma elicits paresthesias or pain in the territory of the nerve. An advancing Tinel sign (over serial examinations) can also indicate axonal regeneration in a recovering nerve; however, a static or nonadvancing Tinel sign is more consistent with neuroma.25
A Tinel sign was used as a diagnostic criterion to diagnose symptomatic neuroma in almost all reviewed studies, but no studies specifically report the sensitivity and specificity of this test for neuroma diagnosis. It has been mentioned, however, that the sensitivity and specificity are low and wide interobserver variability exists.2–4 In addition, there is substantial variation among physicians in how a Tinel sign is performed. If a Tinel sign has remained in the same location with associated local pain, there is a higher probability of the presence of a neuroma.13
A Tinel sign is a helpful indicator of neuroma but is not always present depending on the anatomic location of the nerve. A proximal sciatic nerve neuroma is located deep within the tissues of the posterior thigh and it is not possible to elicit a Tinel sign because of the distance between the nerve and the cutaneous surface. For this reason, it is a useful physical examination finding but not necessarily present for all neuromas.
Two-Point Discrimination and Monofilament Tests
These tools can be used to characterize nerve dysfunction and are mentioned by 1 article.2 Two-point discrimination reflects innervation density, whereas monofilament testing reflects the cutaneous threshold function. These tests are often difficult to administer in patients with hypesthesia or dysthesthesia, but if a patient tolerates, these can be useful clinically.
DIAGNOSTIC NERVE BLOCKS
Diagnostic Nerve Block
Another useful diagnostic test in the office is a nerve block with local anesthetic, commonly performed with lidocaine or bupivacaine. This was mentioned by 17 articles.2,11,12,19,25,26,32,34,38,39–43,48–50 This test can achieve the 2 goals: it confirms the specific anatomic territory of the injured nerve1 and it confirms that the pain can be modified peripherally (ie, that it is not entirely centralized and can be potentially improved with peripheral intervention).2 In some studies, improvement after diagnostic block is a requirement before operative treatment.2,42,50 It has also been suggested that clinical mapping with a diagnostic nerve block might improve the primary success rate of surgical intervention,12 and helps the patient understand the nerve territory and the potential area of numbness after surgery.25 In 1 study, Stokvis and Coert2 successful nerve block on patient satisfaction after surgery was 66.7% and the negative predictive value was 83.3%.
One potential limitation of a diagnostic nerve block is low specificity, because the local anesthetic might spread to surrounding nociceptive terminals, creating a false-positive response.34 Nerve blocks can be administered proximal to the area of concern to obviate this problem. In addition to physical examination findings, diagnostic nerve blocks are another important component of diagnosis.
DIAGNOSTIC IMAGING STUDIES
Some suggest US is a first-line imaging option for evaluation of neuroma. It was mentioned by 24 of 50 articles. On US, neuromas have varying appearance: a fusiform mass with a radiating network of small neural structures, or alternatively a cylindrical mass resembling a normal but edematous nerve.14,33,34,43,50 Neuromas may have a hypoechoic echotexture with hyperechoic internal bands.15,17,20,29–31,33,50 Usually, the outer border is well defined, but it may be distorted by the formation of scar in the surrounding soft tissues. There is generally minimal vascularity on color Doppler evaluation.15,17,31,43 In 1 study by Toia et al,16 neuromas always showed a greatly increased cross-sectional area compared with the uninjured contralateral nerve (257.8% ± 67.4% of contralateral nerve).
We did not identify studies describing the sensitivity and specificity of US for diagnosis of traumatic neuromas, but US can provide information on the location and structure of the neuroma, originating nerve, and vascularity of the surrounding soft tissues.14,44,47 It may allow the identification of a neuroma of larger nerves (ie, median or ulnar) but also of small terminal branches (digital nerves) or neuromas-in-continuity, distinguishing interrupted fascicles from those in continuity.16 It can also distinguish neuromas from other causes of postamputation pain such as hematomas, abscess, tumors, granulation, foreign bodies, and inflammation/edema.14,29
Furthermore, the US transducer probe can be used to reproduce a Tinel sign, further elucidating the etiology of the patient's symptoms and confirming the source of pain.14–16,20,27,30 Ultrasound may also be a useful imaging technique for serial follow-up, by monitoring the size and structure of the mass and facilitating surgical planning.4,11,13,16 In addition, diagnostic injections can be guided by US, providing visualization during the procedure and confirming needle location and the diagnosis.15,25,27,50
One limitation of US is the depth penetration with high-frequency scanning necessary for high-resolution imaging. Diagnosing a neuroma in the vicinity of extensive scar tissue also poses limitations, because the nerve may become indistinguishable from the scar at the level of the injury.15 Ultrasound is also operator dependent and requires expertise to glean the desired information from the study.
Several studies have highlighted US advantages over computed tomography (CT) and MRI for the diagnosis of neuroma because it is noninvasive, inexpensive, and readily available for use in clinical practice.13–15,31,34,52 Some authors recommend US as first-line diagnostic imaging for masses of suspected neuromas.15,16
Magnetic Resonance Imaging and CT
Magnetic resonance imaging, mentioned in 10 articles, allows fine, detailed evaluation of peripheral nerve anatomy and pathology due to excellent soft tissue contrast and high spatial resolution. The imaging shows the neural anatomy, internal architecture, course, and caliber of the nerve.21 On both MRI and CT, neuromas are characterized by a fusiform mass, the presence of an entering nerve ending in this bulbous mass, and fascicular discontinuity.15,21,29,36,51 On CT, neuromas are hypodense, measuring between 40 and 60 HU and showing only minimal enhancement after contrast.52 Because of the lower resolution for visualization of soft tissues, CT is less useful than other imaging modalities in evaluating neural structures. Four of 50 articles mentioned CT.
The target sign (low- to intermediate-signal intensity centrally with a ring on high intensity peripherally, seen on US and T2-weighted MRI), fascicular sign (multiple small ring-like structures, seen on T2-weighted MRI), and split fat sign (a peripheral rim of fat seen on T1-weighted MRI) are radiographic signs of neuroma. Neuromas typically show intermediate-signal intensity on T1-weighted MRI and intermediate to high-signal intensity on T2-weighted images.29,36
Despite the higher sensitivity and superior soft tissue contrast compared with US, MRI has not been recommended as first-line diagnostic test because US is more cost-effective, easier, and faster to use. However, certain authors have suggested that MRI may be useful in cases of uncertain diagnosis.25,41
Histology was mentioned in 9 articles. Traditionally, the criterion standard for diagnosis is histology.3,11,46,50,51 On histologic evaluation, a traumatic neuroma is found to be a poorly vascularized, nonneoplastic, nonencapsulated tangled mass of endoneurial and perineurial cells, axons, and Schwann cells in a dense collagenous matrix with surrounding fibroblasts.10,17,29,51,53 This is often only possible to determine after surgical resection of a neuroma, and formal pathologic assessment is often unnecessary and may not contribute to patient care.54
Although symptomatic neuromas are common sequelae after nerve injury or amputation, there are no established criteria for diagnosis. Most surgeons would agree that neuropathic pain, history of nerve injury or surgery, and symptoms in the anatomic distribution of the nerve are important components of diagnosis. The presence of a Tinel sign, improvement of pain after diagnostic nerve block, and radiologic imaging are helpful but alone do not seem to be confirmatory. In the absence of accepted diagnostic criteria, we sought to review the existing literature to create an objective, defined diagnostic scheme for diagnosing symptomatic neuromas.
Based on critical review of the literature, importance and number of references, and collective clinical experience, we propose the following criteria for diagnosis of symptomatic neuroma (Fig. 2). To receive a diagnosis of neuroma, patients must have pain with at least 3 qualifying “neuropathic” characteristics,1 symptoms in a defined neural anatomic distribution,2 and a history of a nerve injury or suspected nerve injury.3 In addition, patients must have at least one of the following 3 findings: positive Tinel sign on examination at/along suspected nerve injury site (for cutaneous nerve),1 positive response to a diagnostic local anesthetic injection,2 and US or MRI confirmation.3
This study has some limitations. Because there have been no previous studies rigorously evaluating the diagnosis of neuroma, this study reviewed all potential articles discussing traumatic neuroma and attempted to extract objective information about diagnosis. This study was performed through a search of English, German, and Dutch languages, but it is possible that articles in other languages were not included in this review.
To effectively intervene and treat patients with symptomatic neuromas, obtaining a correct diagnosis is paramount to success. If the diagnosis is incorrect and the patient's pain is secondary to a nociceptive (rather than neuropathic) source, surgical treatment of the nerve is not likely to improve the symptoms. Establishing criteria for the diagnosis of neuromas is an important step in the surgical care of these patients, as it will allow for more rigorous comparisons between treatment modalities.
Because there are no accepted, studied criteria for diagnosis of symptomatic neuroma, these criteria were designed based on critical review of the literature in conjunction with clinical experience. These criteria should be prospectively evaluated to determine their validity, as well as their impact on potential treatment and intervention.
There are a growing number of surgical techniques to treat traumatic neuroma (both neuroma-in-continuity and stump neuroma), and we have previously categorized the different treatment options and proposed an algorithm for treatment.55 These diagnostic criteria for neuroma will allow for comparative studies to be performed and will facilitate greater equivalency between patient cohorts. Some of the more exciting and novel techniques include targeted muscle reinnervation24 and regenerative peripheral nerve interface,56 which provide a more active approach to the terminal end of the nerve.
The diagnosis of symptomatic neuroma is based on history and physical examination findings of nerve injury, symptoms in a defined neural anatomic distribution, and most importantly pain. In combination with a positive Tinel sign, positive response to a diagnostic local anesthetic injection, or US or MRI confirmation of neuroma, these criteria form the basis of diagnosis of symptomatic neuroma.
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Appendix 1. Search History