Incidenceofpainfulneuromainpatientswith

digitalamputations

Researchinternshipreport

Student:MargotA.Vlot

Studentnumber:s1987690

Facultysupervisor:Prof.dr.C.G.M.Kallenberg

Externalsupervisor:SuzanneC.Wilkens,MD

Institution:MassachusettsGeneralHospital,OrthopaedicHand&UpperExtremity

Service

Location:Boston,Massachusetts,UnitedStatesofAmerica

Date:September30th,2016

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Summary

A neuroma is a bulbousgrowth or tumor of nerve tissue. After a peripheral nerve is severed in amputation injuries, formation of a neuroma is inevitable. Development of painful neuroma after traumatic digital amputation can be debilitating, limiting overall limb function. Specific prognostic factors that predispose an individual to formation of painful neuroma have not been described. In this study, we aimed to study the incidence of painful neuroma in patients with traumatic, digital amputations and the revision rate for surgery. We hypothesized that there are no factors independently associated with development of painful neuroma after traumatic digital amputation. We retrospectively identified 1,083 patients who underwent revision amputation for traumatic amputation injury of one or more digits. We recorded patients’ demographic information, details on injury and treatment and we recorded if the patients returned with symptomatic neuroma. For neuroma patients, we recorded details on the treatment for neuroma symptoms. We found 71 patients (6.6%) with painful neuroma at follow up, with a mean time to presentation with neuroma symptoms of 6.9 months after the initial amputation procedure. Forty-seven patients underwent surgery for painful neuroma (66%) with a mean time to revision surgery of 12 months. Eleven patients had a recurrent symptomatic neuroma (15%) and 3 patients had a secondary recurrence of painful neuroma (4.2%). In multivariable logistic regression analysis, we found that amputation injury of the index finger and avulsion injury are independently associated with higher odds of developing painful neuroma. We believe that an initial approach with desensitization and hand therapy is warranted for all patients with neuroma pain, and those patients with persistent or debilitating symptoms may be a candidate for surgical intervention.

Samenvatting

Een neuroom is een knopachtige zwelling van zenuwweefsel. Als een perifere zenuw beschadigd raakt bij amputatieletsel is het ontstaan van een neuroom onvermijdelijk. Het ontwikkelen van een pijnlijk neuroom op de hand kan leiden tot ernstige invaliditeit. Specifieke prognostische factoren die een individu meer kans op een pijnlijk neuroom geven zijn onbekend. In dit onderzoek hebben wij geprobeerd de incidentie van symptomatisch neuroom na amputatietrauma in de hand te bepalen en de mate waarin deze patiënten opnieuw worden geopereerd vanwege neuroompijn. Onze nulhypothese was dat er geen onafhankelijke factoren geassocieerd zijn met het ontwikkelen van een pijnlijk neuroom na traumatische vingeramputatie. Wij hebben 1.083 patienten met een traumatische vingeramputatie retrospectief geincludeerd en hebben handmatig patiënteninformatie, details over het letsel en details over de behandeling opgezocht. Voor patiënten met een symptomatisch neuroom zochten we aanvullende details op over de behandeling en het beloop in de tijd. We vonden 71 patiënten (6,6%) met een pijnlijk neuroom, die zich presenteerden met pijn na gemiddeld 6,4 maanden. Zevenenveertig patiënten werden operatief behandeld (66%), gemiddeld 11 maanden na de initiële operatie. Elf patiënten hadden een recidiverend neuroom (15%) en 3 patiënten hadden een tweede recidief (4.2%). In de multivariabele logistische regressieanalyse waren amputatie van de wijsvinger en avulsieletsel onafhankelijk geassocieerd met een hogere kans op het ontwikkelen van een pijnlijk neuroom. Wanneer een patiënt lijdt aan neuropatische pijn na een traumatische amputatie, veronderstellen wij dat een initiële aanpak met desensitizatie en handtherapie op zijn plaats is. Patiënten met aanhoudende of invaliderende symptomen zouden baat kunnen hebben bij een chirurgische behandeling.

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Table of contents

Summary / Samenvatting 2

Introduction 4 History of the neuroma 4 Diagnosis of neuroma 5 Classification of nerve injuries 5 Phantom limb pain vs. amputation stump pain 5 Non-operative treatment of painful neuroma 6 Surgical treatment of painful neuroma 6 Incidence of neuroma 7 Research questions 7

Methods 8 Ethics 8 Population 8 Outcome measures and explanatory variables 9 Statistical analysis 10

Results 12

Discussion 15 Comparison to the literature 15 Associated factors 15 Trends in the data 16 Treatment in the Emergency Department 16 Diagnosis of neuroma 16 Timing of surgery and occupational therapy 17 Surgical technique 17 Limitations 17 Future research 18

References 19

Attachment – One-page protocol for IRB review 21

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Introduction

A neuron has incredible regenerative qualities. When a nerve is severed, axons regenerate by branching out in multiple directions(1). These new axon branches can bridge a gap as wide as 12 millimeters, to restore neurological function(2). In amputation patients, there is no distal nerve to connect to the branches of the proximal nerve end. This does not stop the axons from branching out. The tender axons can infiltrate all types of tissues and reinnervate an amputation stump, sometimes making it more sensitive than before. This sensitization is due to sensory neurons producing twice as many axons as motoneurons during regeneration(3–5). The proximal nerve stump produces an average of 5 regenerated axons after a crush injury and can produce as many as 20 axons if the distal nerve end cannot be reached(4,5). The branching axons may form a bulbous structure called a neuroma (figure 1). This bulb consists, aside from axons, of Schwann cells, fibroblasts and blood vessels(6). The formation of a neuroma is inevitable and part of normal physiology(1). The development of debilitating hypersensitivity or pain, however, is considered unusual and pathological and requires treatment. In upper extremity amputation patients, neuroma formation is a common reason for patients not to wear a prosthesis(2,7). Fortunately, amputation of the upper extremity more proximal than the digits is uncommon(7).

A nerve does not need to be cut completely to be able to form a neuroma. Damaged nerves that are still partially intact can form what is called a neuroma-in-continuity. If several axons and a part of the perineureum are damaged, regenerating axons can sprout and form a neuroma-in-continuity(8). The damaged nerve will still have some function left, but a neuroma-in-continuity can make exciting that nerve very painful. Neuromas can be found in many types of tissue, from skin to muscle to connective tissue. There has even been one case report of an upper extremity neuroma that was found in the lumen of an artery(9).

History of the neuroma

The peripheral nervous system was first described by Hippocrates in the fourth century BCE, but there was no knowledge on regenerative properties of peripheral nerves. In 1634, Ambroise Pare described the symptoms of a painful neuroma, which were treated with oil and massage. The term ‘neuroma’ was later introduced by Wood in 1828, who performed the first pathologic studies on the bulb-like stump of a severed nerve(10). For centuries, the physiology of the nervous system was poorly understood and therefore, resolutions for neuroma pain were often unsuccessful and frustrating(10). Now that we know more about the physiology of a severed nerve, up to 150 different ways of treatment have been described(11). De presence of so many different treatment options suggests that there is not one of them that works in all patients(1). Treatment options can be divided into a non-

Figure 1: schematic representation of a digital neuroma.

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operative group and an operative group. Although non-operative treatment options are numerous, the different surgical techniques make up the majority of the options for treatment.

Diagnosis of neuroma

The diagnosis of painful neuroma is usually clinical. Neuroma patients describe a painful amputation stump with neuropathic pain symptoms such as sharp, shooting, burning or shock-like pain. In many cases, a Tinel’s sign is present. Tinel’s sign is known to be a shooting, electrical pain elicited by light tapping on the neuroma location. The shooting pains may be felt proximal or distal from the nerve injury, and Tinel’s sign can sometimes be

elicited by tapping the nerve proximal or distal of the neuroma site(11,12).

Classification of nerve injuries

A widely used gradation of nerve injury was developed in 1943 by Sir Herbert Seddon(13). He divided nerve injuries in neurapraxia (a blunt injury, or contusion of the nerve), axonotmesis (axonal damage without damage to the connective tissue around the axons) and neurotmesis (complete discontinuation of the nerve). Sir Sydney Sunderland expanded this

system in 1951 into five grades of injury (figure 2)(14,15). The first two degrees are equal to neurapraxia and axonotmesis. Seddon’s third degree is divided into three categories: damage

to the axons (grade III), damage to the perineureum (grade IV) and damage to the epineureum (grade V). In

1988, Mackinnon and Dellon added a sixth grade to the Sunderland classification to describe multiple degrees of injury at multiple levels in one nerve.(16,17) Neuroma patients have always suffered either fifth or sixth degree injury to their nerves.

Phantom limb pain vs. amputation stump pain

There is a distinct difference between phantom limb pain and stump pain, but both of these problems can be of great discomfort for the patient. Phantom pain is defined as persistent painful feeling of the body part after it has been excised. Stump pain is pain resulting from the body part that is still remaining and can take on many forms(18). Patients can complain of stump pain due to poor prosthetic fit, joint problems, ischemia, painful neuroma, skin problems or inadequate covering (padding) of underlying bone. Distal finger amputees can furthermore be bothered by nail remnants, which can grow into the flesh and cause irritation and infection.

Figure 2: classification of nerve injury, as described by Seddon and Sunderland (33).

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Non-operative treatment of painful neuroma

Desensitization therapy is based on percussion therapy, introduced by Granville and Ross in the 1880’s. Percussion is a time-consuming therapy and can be very painful for the patient. Repeated pressure is put on the site of the neuroma, to eventually block the conduction of a nerve. The regenerating axons are vulnerable to this pressure and degenerate under the influence of percussion, usually leading to a decrease in tenderness(2).

In contemporary daily practice, this means that patients with upper extremity amputations need to repeatedly tap their amputation stump on a hard surface. This therapy requires diligence, as the tapping, hitting or banging exercise has to be repeated three to four times a day. Patients with neuromas which are too tender for desensitization can also rely on infiltration with local anesthetics during therapy.

Pain resulting from a neuroma can be treated with adjuvant pain medication such as antidepressants and anticonvulsants, but the role of pain medication should be minimal in finger amputations(19,20). There is a certain window of opportunity for desensitization therapy and surgery. If neuroma pain persists too long, changes can occur in the central nervous system, which lead to central sensitization. This condition results in more chronic pain symptoms and is much more difficult to treat(19).

Surgical treatment of painful neuroma

The surgical treatment of neuroma is for the most part aimed at either preventing the proximal nerve stump from branching out, or redirecting the axonal growth. (21).

Simple, proximal ligation of the nerve is the most common treatment for neuroma, and this technique is also commonly used in the prevention of painful neuroma. Before cutting the nerve, the surgeon pulls the nerve slightly to create some tension, resulting in the retraction of the proximal ending after the nerve is cut. This way, the nerve ending is not located directly at the tip of the amputation stump and therefore, branching axons are less likely to form a painful neuroma at the tip of the amputation stump (figure 3)(7). Aside from sharply cutting the nerve, the nerve can also be crushed, cut with electrocautery, injected with alcohol, phenol or steroids, or ablated with cryosurgery(22).

Embedding the nerve ending in muscle, fat or bone is also a commonly used technique for neuroma surgery. The aim of the transposition is to control axonal growth by surrounding it in tissue that will not excite the nerve endings as much as the original location would. Transposing the neuroma itself to a location with less stress without excising it is a technique that relies on the same principle(22).

Figure 3: neuroma formation before (upper circle) and after (lower circle) proximal ligation of nerve endings.

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Nerve grafting is a technique more commonly used in larger nerves such as the sciatic nerve in the lower limb, where autologous nerve grafts are attached to divided sections of the severed nerve and then redirected into fat, muscle or bone. Division and redirection of nerve endings without nerve grafting can also be a neuroma treatment. An autologous nerve graft is mimicked in techniques where the surgeon makes an additional cut more proximal to the severed nerve. This prompts the nerve to regenerate at the proximal cut first, hereby slowing the regeneration process and neuroma formation at the distal cut location. Another nerve grafting technique is the use of a neurovascular island flap, which is supposed to preserve skin sensation in the amputation stump(23). This technique is most appropriate when there is substantial soft tissue loss of the thumb or index finger. Surgeons also have tried to inhibit axonal growth by capping the nerve ending with different materials, such as silicone(8,10,12,24).

All of the treatment options mentioned above are not without failure or recurrence of painful neuroma and it greatly depends on the surgeon which technique is used in the treatment and prevention of neuroma(25). According to the literature, surgical intervention for recurrent painful neuroma is most often not feasible. Conservative treatment and referral to a pain specialist is recommended, regarding the risk of central sensitization(11).

Incidence of neuroma

Fisher et al. reported the incidence of symptomatic neuroma as being unpredictable(2). Other authors have reported incidence rates ranging from 4% to 25% (2,12,26). These studies analyzed patient groups of less than 200 patients. There has not been any published data on incidence of neuroma in a large patient population and there has not been any recently published data from the United States on this topic. Specific prognostic factors that predispose an individual to formation of painful neuroma have not been described.

Research questions

This study aims to answer the following research questions:

1. What is the incidence of symptomatic neuroma among patients with traumatic upper extremity amputation?

2. What is the rate of reoperation for symptomatic neuroma? 3. Are there any factors independently associated with developing a painful neuroma after

traumatic upper extremity amputation?

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Methods

This study was conducted at the Massachusetts General Hospital (MGH) in Boston, MA, United States. MGH is part of Partners Healthcare group, a non-profit hospital network that binds together nine hospitals and their research facilities. Partners Healthcare owns a clinical data repository called the Research Patient Data Registry (RPDR). The RPDR is a centralized clinical data registry that comprises International Classification of Disease, Ninth Revision (ICD9) codes, Current Procedural Terminology (CPT) codes, demographic information, radiology and operative reports, and visit notes. This data warehouse collects patient information from the hospitals in the Partners network and makes it accessible to researchers with an online query tool. The tool allows researchers to investigate if their study ideas are feasible and helps identify subjects for prospective and retrospective studies. The RPDR also allows for text searches in patient’s medical chart to find specific phrases, diagnoses or patient characteristics(27). In this study, we retrospectively identified patients using the RPDR.

Ethics

The Orthopaedic Hand & Upper Extremity Service at MGH is obligated to submit all of their research proposals to the Institutional Review Board (IRB) at Partners Healthcare. The IRB is in charge of making sure that all research being done within the Partners network is ethical and safe for all parties involved. The IRB has approved a protocol that allows retrospective RPDR studies to qualify as exempt research, as long as they expose included patients to minimal risk. This exemption entails that when a protocol falls into six federally-defined categories, there is a much less rigorous review of the protocol compared to a full IRB review. For review of this study, the IRB required a one-page protocol listing a short background, hypothesis and methods section. The one-page protocol as submitted can be found as an attachment to this paper.

Population

Patients were identified using CPT codes for amputation or excision of neuroma and ICD9 codes for amputation or neuroma. The codes that were used are:

CPT: 24920, 24925, 24931, 25900, 25905, 25907, 25920, 25922, 25927, 25929, 26910, 26951, 26952, 64776, 64774, 64778, 64782, 64783, 64784, 64787

ICD9: 885, 886, 887.0, 887.1, 887.2, 887.3, 887.6, 887.7, 905.9, 997.6

Before looking into the medical charts, we made sure that all underage patients were not included in our database. For patients with multiple treatment codes, we kept the record of the oldest code that was available. This left us with a database of 3,914 individuals. Taking into account the time that it would take to review all medical records, we decided to reduce the number of individuals by excluding all patients seen in 2004 and 2005. This resulted in a total of 3,103 medical records that were manually reviewed.

We reviewed all adult patients presenting to one of the Partners hospitals with traumatic amputation, treated with revision amputation between January 2006 and December 2014.

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During manual review, 1,147 patients did not meet our inclusion criteria for several reasons including non-traumatic amputation or treatment with replantation or revascularization of the amputated digit.

After manually reviewing patients’ electronic medical records, a total of 868 patients were excluded from this study for one of the following reasons: inadequate documentation (n= 149), soft tissue amputation without bony involvement (n= 471), initial treatment finalized in another hospital (n= 27), lack of any follow up appointments or follow up of less than one week (n= 221). Furthermore, because our population existed of mainly digit amputations and including other upper extremity injuries would make our statistical analysis weaker, we excluded 17 patients with an amputation level more proximal than the wrist. This resulted in a total of 1,083 patients for analysis.

Outcome measures and explanatory variables

Our primary outcome variable was presentation at follow up with symptomatic neuroma after traumatic amputation. Hypersensitivity symptoms were only recorded as neuroma when the care provider described this as neuroma-like pain.

Variables that were extracted from the RPDR:

• Medical record number • Date of CPT and/or ICD9 code • Age • Sex • Race

Variables recorded manually for all included patients:

• Amputation (yes/no) • Affected side (left/right) • Dominant hand (left/right) • Date of initial treatment • Treatment in Emergency Department or Operating Room • Duration of surgery • Location of amputation (thumb, index finger, middle finger, ring finger, small finger) • Level of amputation (distal phalanx, middle phalanx, proximal phalanx, metacarpal

bone) • Other procedures performed during surgery (i.e. replantation or revascularization)

(yes/no) • Mechanism of injury (sharp, crush, avulsion, burn, blast) • Neuroma (none, one, two, three consecutive neuromas) • Pain at end of follow up (yes/no) • Type of pain (neuropathic, atrophic, other) • Determinant of pain (Tinel’s sign, hypersensitivity, shooting pain, burning pain) • Comorbidities

o Smoking (yes/no) o Alcohol abuse (yes/no) o Diabetes mellitus (yes/no) o Obesity, defined as BMI>30 (yes/no)

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• Workers’ compensation insurance: a system of insurance which pays for an employee’s medical bills if they get injured while working. This insurance is common in manual laborers such as construction workers or factory workers(28).

• Follow up (in months)

Variables recorded manually for neuroma patients only:

• Date of presentation with neuroma pain • Date of treatment for neuroma • Duration of neuroma surgery • Location of neuroma • Pathology report requested (yes/no) • Details of pathology report (type of tissue submitted) • Operation technique for neuroma surgery (i.e. excision or burial) • Hand therapy for neuroma pain (yes/no) • Side of the index finger affected by painful neuroma (radial/ulnar)

Patients who had revision amputation surgery of more than one amputated digit in the same hand were controlled for potential confounding by recording the total number of amputated digits and whether patients had more than one amputated digit, and therefore counted only once in order not to violate the assumption of statistical independence (Bryant et al., 2006). This same approach was done for patients who had revision amputation surgery on multiple levels.

Statistical analysis

We calculated the incidence of neuroma and presented it as a percentage of the total number of patients. Categorical data were presented as frequencies with percentages and continuous data as mean with standard deviation (SD). In bivariate analysis, we used a Fisher exact test to compare the distribution of categorical data among patients who did develop a neuroma and patients who did not, including male sex, race, diabetes, alcohol and smoking status, obesity, workers’ compensation, injury of dominant hand, amputation location, amputation level, more than one finger or level amputated, mechanism of injury, treatment in the ED, treatment of other injuries, operation technique for neuroma surgery, positive pathology report, occupational therapy as treatment, pain at follow up and determinants of pain. A two-sample unpaired Student t-test was used to compare the means of normally distributed continuous data, such as age. We assessed the normality of continuous data by viewing the histogram

Figure4:histogramshowingdistributionofagewitha

normalitycurve.

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(figure 4) and we concluded that age was normally distributed, and time to follow up, time to neuroma presentation and time to neuroma operation were not.

Variables with a P-value of 0.10 or less in the bivariate analysis were entered in a multivariable logistic regression analysis to test the association of explanatory variables with development of painful neuroma, controlling for potential confounding by any of the included variables. Odds ratios are provided with 95% confidence intervals and P-values. A two-tailed P-value of less than 0.05 was considered significant. All statistical analyses were performed using Stata® 14 (StataCorp LP, College Station, TX, USA).

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Results

Of the 1,083 patients with traumatic digit amputation included in this study, 981 were male (91%) and 770 patients were white (71%) with a mean age of 46 years (SD 15, range 18-94 years).The mean time to follow up was 7.2 months (range, 0.23-100 months). Seventy-one patients out of 1,083 (6.6%) developed a neuroma on a total of 77 digits during follow-up. Four patients developed neuromas on two digits (5.6%) and one patient developed neuromas on three digits (1.4%). Eleven neuroma patients had a recurrent neuroma (15%) and three patients had secondary recurrence of neuroma (4.2%). A graphic explaining which fingers and which levels were amputated and where neuromas developed is shown in figure 5.

In bivariate analysis, older age was associated with a decreased risk of developing a neuroma after traumatic digit amputation (P=0.035). Patients with workers’ compensation (P=0.029), patients with amputation of their index finger (P=0.010) and patients with amputation of multiple digits (P=0.025) were more likely to develop neuroma. The categorical variable mechanism of injury was also significant in the bivariate analysis (table 1).

Table1:Bivariateanalysis Traumaticamputation n=1,083 Pvalue Neuroma Noneuroma 71(6.6%) 1,058(93%) Mean(SD) Mean(SD) Age 42(13) 46(15) 0.035 n(%) n(%) Malegender 61(86) 920(91) 0.20Race* 0.13

White 46(65) 724(72) Black 3(4.2) 64(6.3)

Hispanic 12(17) 108(11) Asian 2(2.8) 26(2.6) Other 4(5.6) 21(2.1)

Figure5:A.Overviewoflocationofamputationsperdigit.B.Overviewoflevelofamputation(distal

phalanx,middlephalanx,proximalphalanxormetacarpalbone).C.Locationofneuromasperdigit.

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DiabetesMellitus 6(8.5) 100(9.9) 0.84Smoking 22(31) 290(29) 0.69Alcoholabuse 4(5.6) 32(3.2) 0.29Obesity 14(20) 151(15) 0.30Workers’compensation 14(20) 107(11) 0.029Sideofinjury** 0.80

Dominanthand 28(39) 403(40) Nondominanthand 43(61) 564(56)

Typeofinjury*** 0.047Sharp 33(46) 613(61) Crush 24(34) 288(28)

Avulsion 12(17) 84(8.3) Burn 1(1.4) 11(1.1) Blast 1(1.4) 10(1.0)

Amputateddigit Thumb 16(23) 179(18) 0.34Index 35(49) 343(34) 0.010Long 19(27) 362(36) 0.16Ring 25(35) 263(26) 0.096Small 10(14) 154(15) 0.99

Levelofamputation Distalphalanx 37(52) 625(62) 0.13

Middlephalanx 19(27) 195(19) 0.13Proximalphalanx 21(30) 214(21) 0.10Metacarpalbone 2(2.8) 51(5.0) 0.57

TreatedintheED 18(25) 304(30) 0.50Multiplelevels 8(11) 74(7.3) 0.24Multipledigits 23(32) 210(21) 0.025Otherprocedures 34(48) 429(42) 0.39*Fisherexacttestwasperformedexcludingunknownvalues,n=1,010**Fisherexacttestwasperformedexcludingunknownvalues,n=1,038***Fisherexacttestwasperformedexcludingunknownvalues,n=1,077

In multivariable logistic regression analysis controlling for potential confounding by any of the included variables, amputation of the index finger was independently associated with a higher odds of development of neuroma (odds ratio 2.2; 95% confidence interval 1.2 to 3.8; P=0.008) (table 2), and patients with avulsion injury were more at risk of developing a neuroma after traumatic amputation (OR 2.6; 95% CI 1.2 to 5.4; P=0.011). There was a trend towards significance for an association between age and slightly lower odds of developing neuroma (OR 0.99; 95% CI 0.97 to 1.0; P=0.12). There was also a trend towards significance for an association between ring finger injury (OR 1.7; 95% CI 0.89 to 3.2; P=0.11), workers’ compensation (OR 1.6; 95% CI 0.83 to 3.1; P=0.16), and crush injury (OR 1.5; 95% CI 0.83 to 2.6; P=0.18) and higher odds of developing neuroma.

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Table2:Multivariablelogisticregressionanalysis(n=1,077) Oddsratio(95%confidence

interval)Standarderror Pvalue

Age 0.99(0.97to1.0) 0.0087 0.12Workers’Compensation 1.6(0.83to3.1) 0.53 0.16Typeofinjury

Sharp Reference Crush 1.5(0.83to2.6) 0.42 0.18

Avulsion 2.6(1.2to5.4) 0.96 0.011Burn 0.90(0.10to7.7) 0.99 0.92Blast 1.4(0.17to12) 1.6 0.74

Amputateddigit Indexfinger 2.2(1.2to3.8) 0.62 0.008Ringfinger 1.7(0.89to3.2) 0.55 0.11

Levelofamputation Proximalphalanx 1.4(0.80to2.4) 0.39 0.24

Multipledigitsaffected 1.3(0.66to2.4) 0.48 0.48

Of the patients diagnosed with neuroma, 50 patients (70%) had a diagnostic determination of neuroma available in the medical record; 25 patients (35%) presented with Tinel’s sign, 24 patients (34%) presented with hypersensitivity and 1 patient with shooting pain (1.4%). The remaining 21 patients were diagnosed with symptomatic neuroma without a clear description of symptoms in their medical record. Sixty-three neuroma patients (89%) received occupational therapy for their symptoms. Six patients (13%) did not receive occupational therapy before getting revision surgery for neuroma and two patients (8.3%) did not receive occupational therapy or surgery and had spontaneous relief of their symptoms. Twenty-seven patients had a neuroma on their index finger. Thirteen of these neuromas were located on the radial side of the finger, eight were on the ulnar side and for six patients the side was not documented.

Of the 71 patients who developed a symptomatic neuroma, 47 (66%) patients underwent revision surgery. Mean time to presentation with neuroma was 6.9 months (range, 0.20-48) and mean time to surgery for neuroma was 12 months (range 0.20-57). In 26 of the operated patients (55%), the neuroma was sharply excised and the nerve ending(s) were cut proximally and allowed to retract. The proximal nerve ending was buried in bone in 12 patients (26%) and buried in fat or muscle in 3 patients (6.4%). There were no procedures involving nerve grafts or encapping the nerve ending, nor was there burning, freezing or crushing of the nerve ending. A total of twelve surgeons performed revision surgeries for neuroma. Four surgeons were responsible for 74% of the surgeries, each treating between 4 and 15 patients. Thirty-three of the 47 patients who had revision surgery for neuroma had the excised tissue analyzed by a pathologist. Twenty-five patients (76%) had a positive pathology report for traumatic neuroma. The specimens that were not confirmed as neuroma mostly consisted of fibrous nerve tissue, scar tissue and chronic inflamed tissue. There was one patient for whom the pathology report showed no abnormalities.

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Discussion

On comparison to published literature

Studies on the incidence of neuroma in upper extremity amputation patients are scarce and are mostly done in small groups of patients. Geraghty and Jones(12) analyzed thirty-two patients with upper-limb amputation in the early 1990’s and found an incidence rate of 25% of painful neuroma. Their study contained mainly patients with transradial and transhumeral amputations, which may be more prone to symptomatic neuroma given the larger size of the nerves. These patients also have more trouble rehabilitating and returning to work, which can compromise the process of desensitization. Van der Avoort et al.(26) concluded their study on digital amputations with an incidence rate for neuroma of 7.8%, which is an outcome similar to our study. Their retrospective study was, aside from sample size (117 vs. 1,083), similar to ours and therefore these comparable results are reassuring.

Geraghty and Jones described the time to onset of stump pain in 36 upper amputation patients as 11.6 months on average(12). Their reported mean time to revision surgery for neuroma was 11 months, which corresponds with the results of this study.

Murray et al.(29) reported a 59% incidence of hypersensitivity after index ray amputation. In our study, ray amputation was marked as an amputation at the metacarpal level. Our data does not support Murray’s statement since our incidence of pain symptoms does not come near the number described in Murray’s paper and we do not see an association between amputation at the metacarpal level and pain symptoms (incidence, 13%, P=0.12), or amputation at metacarpal level and neuroma formation (incidence, 3.7%, P=0.57). We do see an association between index finger amputation and neuroma formation, which is in concurrence with Murray’s publication. His study is from 1977 and we could argue that surgical technique in ray amputations has improved in a way which makes the reported incidence in the article no longer accurate.

One of the strengths of this study is the large sample size. To our knowledge, this is the largest study evaluating digital amputations for the development of symptomatic neuroma. This population is a good representation of amputation patients since these patients are collected from multiple hospitals over a large time span. We can conclude from our results that the stereotypical amputation patient is a white male in his forties, who had a sharply injured finger amputation due to a table saw.

On associated factors

The association between index finger amputation and higher odds of neuroma development can be explained by the increased sensibility in the index finger compared to the other digits. Especially the radial side of the index finger has a larger nerve and could therefore be more inclined to regenerate and form a neuroma. Although we do not have enough power to statistically confirm this, we see that a majority of the neuromas on the index finger are located on the radial side of the digit.

Avulsion injury is associated with higher odds of developing neuroma, which we think is due to the ripping nature of this mechanism. A sharply cut nerve is classified as Sunderland grade V, whereas avulsion injury is almost always a grade VI injury. Stretching and ripping of a nerve can cause damage to the nerve way more proximal than the actual level of amputation. The nerve ending may look healthy during revision amputation, but damage more proximal

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than the level of amputation can still form a neuroma or a neuroma-in-continuity. This type of damage is very difficult to diagnose and to treat.

On trends in the data

We found a trend towards significance for an association between age and lower odds of developing neuroma. This is a logical observation, because most amputation patients are part of the active workforce. A nerve regenerates slower at an older age; therefore it is logical that older patients are less likely to form neuromas. The trend towards significance for ring finger injury is more difficult to explain, since this is not a digit with extra sensibility compared to the other digits. We also found a trend towards significance for an association between workers’ compensation and a higher risk of developing a neuroma. This observation probably works both ways. Patients who are on workers’ compensation are usually involved in a serious work accident involving large machinery. These patients have more extensive injury with more fingers involved and as we saw in the statistical analysis, this results in higher odds of neuroma formation. Patients who are on workers’ compensation may also be more personally invested in their injury, and therefore they could focus more on their pain symptoms, leading to earlier presentation with neuroma-like complaints. Patients who are on workers’ compensation usually do not return to work quickly and therefore do not use their injured hand as much as they should during rehabilitation(30,31). The trend towards significance for crush injury could be due to a more severe injury of the nerve with this mechanism of injury. A crushing injury can damage a nerve in multiple areas just like the way an avulsion injury can, resulting in multiple gradations of injury within one nerve (Sunderland grade VI).

On treatment in the emergency department

An interesting observation in our data was that treatment in the emergency department does not lead to an increased risk of developing neuroma (table 2). One could argue that the limited facilities in the ED lead to less refined surgery and therefore to more neuroma formation, except our data showed that this is not the case. An important side note to this issue is that complicated injuries, such as mangled hand injuries, are always treated in the OR. Since injury to multiple digits was independently associated with a higher risk of developing neuroma, the reason that treatment in the ED was not of influence on development of neuroma might come from the fact that the injuries treated in the ED were less extensive and probably healed with fewer problems.

On diagnosis of neuroma

The diagnosis of neuroma is usually made by a hand surgeon and is based on the pain symptoms which a patient describes. Local pain symptoms and Tinel’s sign can be tested during a consult, but other symptoms like cold sensitivity are based on a patient’s story. In a prospective study by Stokvis et al.(20), neuroma patients had their affected nerve injected with lidocaïne to objectively assess neuropathic pain symptoms. We did not find any record of diagnostic measures like lidocaïne injection in our study, so all of the neuroma diagnoses in this study were based on a clinical assessment by the treating surgeon.

An interesting observation in our data was that five patients presented with neuroma-like pain within the first month after initial amputation. It is known that a neuron regenerates slowly and needs a couple of weeks to form new axons, making neuroma formation within the first month after amputation very unlikely(32). Whether or not these five patients had developed neuroma unusually quickly or if they were misdiagnosed was unclear. This observation

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taught us to consider the time frame in which neuroma-like symptoms develop and if that time frame matches the usual pattern of presentation. This way, a misdiagnosis can be avoided.

On timing of surgery and occupational therapy

According to our co-investigator and hand surgeon dr. Kyle Eberlin, a normal cascade of events after traumatic upper extremity amputation is as follows; patients go through a primary desensitization process with guidance of an occupational therapist. More therapy is offered if patients return with neuroma-like pain. If pain persists, revision surgery is offered. This sequence of events should provide the patient with enough time to contemplate surgery and it should also provide a window of opportunity for the neuroma symptoms to resolve or improve during therapy. Looking at our database, we saw that 41 (58%) neuroma patients presented with neuroma symptoms within the first three months of follow up. Eleven patients had surgery for their neuroma symptoms during these first three months. Perhaps these patients could have avoided surgery if they had tried to resolve their symptoms by conservative treatment. There was one surgeon who treated seven of these eleven patients. Our study points out that this surgeon’s decisions for surgical intervention may have been somewhat untimely. Patience and perseverance are key components that contribute to the success of desensitization therapy. There were only six patients that did not receive occupational therapy before having revision surgery. There was no particular surgeon responsible for the decisions made for these six patients.

On surgical technique

Compared to how many techniques are mentioned in the literature, there were only a few techniques used by the surgeons who performed revision surgery for neuroma. The approaches were classical and we did not find any new or moderated techniques in the operative reports. We were not able to statistically analyze this data to look for associations between recurrent neuroma and a certain operation technique due to small sample size (n= 47).

On limitations

A limitation of this study is the retrospective nature of the study. Missing data is an inevitable limitation of all retrospective medical file studies, which we encountered while recording multiple variables. Another limitation is the lack of follow-up appointments for our patients. The included hospitals in the Partners Healthcare group were mostly level one trauma centers; therefore many patients came from all over New England to receive treatment. Complicated mangled hand injuries that occurred in a rural area were usually flown into the hospital using Boston’s Med Flight helicopter. These patients probably received follow up care closer to home and were therefore lost to follow up in our study. Other patients that received treatment in the Partners Hospitals returned only once for wound check and are welcome to return to the clinic on an as-needed basis. Patients that did come in for one or more follow up appointments were included in our study and if they did not return with neuroma pain symptoms, we marked them as negative for neuroma. The same principle was used for variables with missing data such as smoking status or BMI. If the smoking status was unknown in the patient’s medical chart, the patient was marked as a non smoker. This may have led to underreporting.

A factor that may be of influence in the development of neuroma is the surgical technique with which the initial revision amputation is carried out. Many different options are available

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for this procedure, including but not limited to: primary closure, closure of a skin defect with a V-Y advancement flap or Moberg flap, or secondary healing. Due to many unclear operative reports and ED documents, we were not able to report this variable. Some operative reports mentioned proximal ligation of the nerve endings and allowing the nerve endings to retract, which shows that surgeons took prevention of neuroma into consideration. Several studies have focused on the prevention of painful neuroma, without pointing out one clearly superior technique(8,21,24). A limitation of this study is that we cannot clarify this issue.

On future research

This study determined the incidence of neuroma after traumatic digit amputation and clarified factors associated with development of neuroma in a large group of patients. With our data we are able to inform surgeons which patients are most likely to form a neuroma. Surgeons can inform their patients on the incidence of neuroma when explaining the risks and complications of revision amputation. Future, preferably prospective research is needed to clarify the best way to prevent neuroma formation in amputation patients.

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19. Stokvis A, Henk Coert J, Van Neck JW. Insufficient pain relief after surgical neuroma treatment: Prognostic factors and central sensitisation. Journal of Plastic, Reconstructive and Aesthetic Surgery. 2010.

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Attachment: One-page protocol for IRB review

Working title: Incidence of neuromas in patients with upper extremity amputation Study objective: to identify the incidence of symptomatic neuromas in the upper extremity after amputation and the incidence of surgery for treatment of these neuromas. Primary null hypothesis: there are no factors independently associated with developing neuroma after surgery for amputation injury in the upper extremity. IRB: Data Repository ClinicalTrials.gov: Not mandatory Authors: Margot Vlot, Suzanne Wilkens, Kyle Eberlin Journal: To be discussed Design: Retrospective Background: Neuropathic pain resulting from neuromas is an important problem for patients with extremity amputations. Neuromas result from nerve transection and may be symptomatic, which can cause severe pain and require surgery. A previous study conducted in the Netherlands by Van der Avoort et al. concluded that the incidence rate of neuroma after finger amputations was 7.3%. Incidence rates and associated factors from the United States are not well reported. The aim of this study is to assess the incidence of neuromas following upper extremity amputation, to determine the rate of reoperation for neuromas in these patients, and to identify factors associated with neuroma development. Subjects: Inclusion criteria: adult patients treated with surgery for amputation injury of the upper extremity at Massachusetts General Hospital (MGH), Brigham and Women’s Hospital (BWH), or Faulkner Hospital (FH) between January 2004 and December 2014. Exclusion criteria: amputation surgery in the upper extremity for other reasons than amputation injury. CPT codes:

• 26951 - Amputation, finger or thumb, primary or secondary, any joint or phalanx, finger, including neurectomies; with direct closure

• 26952 - Amputation, finger or thumb, primary or secondary, any joint or phalanx, finger, including neurectomies; with local advancement flaps (V-Y, hood)

• 26910 - Amputation, metacarpal, with finger or thumb (ray amputation), single, with or without interosseous transfer

• 24900 - Amputation, arm through humerus; with primary closure • 24920 - Amputation, arm through humerus; open, circular (guillotine) • 24925 - Amputation, arm through humerus; secondary closure or scar revision • 24931 - Transhumeral amputation with implant • 25900 - Amputation, forearm, through radius and ulna • 25905 - Amputation, forearm, through radius and ulna; open, circular (guillotine)

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• 25907 - Amputation, forearm, through radius and ulna; secondary closure or scar revision

• 25920 - Disarticulation through wrist • 25922 - Disarticulation through wrist; secondary closure or scar revision • 25927 - Transmetacarpal amputation • 25929 - Transmetacarpal amputation; secondary closure or scar revision • 23920 - Disarticulation of shoulder • 23921 - Disarticulation of shoulder; secondary closure or scar revision

ICD 9 codes for amputation: • Amputation below elbow, unilateral (887.0) • Amputation below elbow, unilateral, complete (887.1) • Amputation above elbow, unilateral (887.2) • Amputation above elbow, unilateral, complete (887.3) • Amputation arm, unilateral NOS (887.4) • Amputation of arm, unilateral NOS, comp (887.5) • Amputation of arm, bilateral (887.6) • Amputation of arm, bilateral, complete (887.7) • Traumatic thumb amputation (885.0) • Traumatic thumb amputation, complete (885.1) • Traumatic finger amputation (886.0) • Traumatic finger amputation, complete (886.1)

Response variables: - Development of symptomatic neuroma in the upper extremity after amputation injury.

Symptomatic neuroma is defined as: Tinel’s sign, burning pain, superficial shooting or electrical pain, rather deep pain, tight feeling, aching or throbbing pain.

- Surgery for symptomatic neuroma in the upper extremity after amputation injury. CPT codes for resection of neuroma:

• 64776 - Excision of neuroma; digital nerve, one or both, same digit • 64774 - Excision of neuroma; cutaneous nerve, surgically identifiable • 64778 - Excision of neuroma; digital nerve, each additional digit • 64782 - Excision of neuroma; hand or foot, except digital nerve • 64783 - Excision of neuroma; hand or foot, each additional nerve, except same digit • 64784 - Excision of neuroma; major peripheral nerve, except sciatic • 64787 - Implantation of nerve end into bone or muscle

CPT codes for revision surgery • 26951 – Amputation, finger or thumb, primary or secondary, any joint or phalanx,

single, including neurectomies; with direct closure. • 26952 Amputation, finger or thumb, primary or secondary, any joint or phalanx,

single, including neurectomies; with local advancement flaps (V-Y, hood) ICD9 codes for complications after amputation

• Amputation stump complication (997.6) (includes neuroma) • Late effect of traumatic amputation (905.9)

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Explanatory variables: - Demographic variables: age, sex, race. - Time between date of injury and surgery. - Time since operation - Operation duration - Provider, specialty - Location of amputation: 1) finger (A: proximal phalanx; B: middle phalanx; C: distal

phalanx), 2) metacarpal, 3) carpal, 4) radius and ulna (A: proximal; B: distal), 5) humerus (A: proximal; B: distal), 6) shoulder.

- Injury mechanism (sharp, crush, etc) - Affected side - Dominant hand - When presenting with neuropathic pain: 1) neuroma, 2) other cause, 3) undefined - Determination of neuroma (Tinel sign, diagnostic local anesthetic block, etc) - PMH: diabetes, obesity. - Alcohol and tobacco use. - Worker’s compensation

Statistical analysis The incidence of neuroma and the reoperation rate will be presented as a percentage of the total number of patients treated with surgery for upper extremity amputation injury. Categorical data will be presented as frequencies and percentages; continuous variables as mean with standard deviation or median with interquartile range depending on distribution. A Fisher exact test will be used to compare dichotomous explanatory variables (sex) and development of a neuroma. Based on the normality of the data, the association between continuous explanatory variables (age, time since surgery) and development of symptomatic neuroma will be assessed using a Student’s t-test or Mann-Whitney-U test. Using multiple logistic regression analyses, the association of explanatory variables (age, sex, race, time since injury, location of injury, injury mechanism, affected side, dominant hand, time of surgery, surgeon, and workers’ compensation) with development of symptomatic neuroma will be tested, accounting for possible confounding by any of the included factors. Also, odds ratios will be calculated.