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Original Article

Vascular and Endovascular Surgery


2024, Vol. 58(2) 142–150
Phantom Limb Pain and Painful Neuroma © The Author(s) 2023

After Dysvascular Lower-Extremity Article reuse guidelines:


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Amputation: A Systematic Review and DOI: 10.1177/15385744231197097
journals.sagepub.com/home/ves
Meta-Analysis

Mirte Langeveld, MD, MPH1,2 , Romy Bosman, BSc1,2, Caroline A. Hundepool, MD, PhD1,
Liron S. Duraku, MD, PhD3, Christopher McGhee, BNurs2, J. Michiel Zuidam, MD, PhD1,
Tom Barker, MD, FRCS4, Maciej Juszczak, PhD, FRCS4, and
Dominic M. Power, MA, MB BChir (Cantab), FRCS (Tr & Orth)2

Abstract
Background: Phantom limb pain (PLP) and symptomatic neuroma can be debilitating and significantly impact the quality of life
of amputees. However, the prevalence of PLP and symptomatic neuromas in patients following dysvascular lower limb
amputation (LLA) has not been reliably established. This systematic review and meta-analysis evaluates the prevalence and
incidence of phantom limb pain and symptomatic neuroma after dysvascular LLA. Methods: Four databases (Embase,
MEDLINE, Cochrane Central, and Web of Science) were searched on October 5th, 2022. Prospective or retrospective
observational cohort studies or cross-sectional studies reporting either the prevalence or incidence of phantom limb pain and/
or symptomatic neuroma following dysvascular LLA were identified. Two reviewers independently conducted the screening,
data extraction, and the risk of bias assessment according to the PRISMA guidelines. To estimate the prevalence of phantom limb
pain, a meta-analysis using a random effects model was performed. Results: Twelve articles were included in the quantitative
analysis, including 1924 amputees. A meta-analysis demonstrated that 69% of patients after dysvascular LLA experience
phantom limb pain (95% CI 53-86%). The reported pain intensity on a scale from 0-10 in LLA patients ranged between 2.3 ± 1.4
and 5.5 ± .7. A single study reported an incidence of symptomatic neuroma following dysvascular LLA of 5%. Conclusions: This
meta-analysis demonstrates the high prevalence of phantom limb pain after dysvascular LLA. Given the often prolonged and
disabling nature of neuropathic pain and the difficulties managing it, more consideration needs to be given to strategies to
prevent it at the time of amputation.

Keywords
lower limb amputation, dysvascular amputation, neuropathic pain, phantom limb pain, neuroma

Introduction
Amputation of the lower extremity is one of the most frequently 1
Department of Plastic, Reconstructive Surgery and Hand Surgery, Erasmus
performed surgical interventions worldwide,1 with national in- Medical Center, Rotterdam, The Netherlands
cidences ranging from 5.8 to 31 per 100,000.2 With the rapid rise 2
Hand and Peripheral Nerve Injury Service, Queen Elizabeth Hospital,
in the prevalence of diabetes mellitus, particularly in low- and University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
3
middle-income countries, the rates of associated peripheral ar- Department of Plastic, Reconstructive Surgery and Hand Surgery,
Amsterdam UMC, Amsterdam, the Netherlands
terial occlusive disease (PAD), diabetic neuropathy, and soft 4
Department of Vascular Surgery, Birmingham Heartlands Hospital,
tissue sepsis have increased as well.3,4 Together, PAD and University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
complications from diabetes mellitus have become the leading
cause of lower extremity amputation (LLA), with dysvascularity Corresponding Author:
responsible for 82% of limb loss in the United States.5 Dominic M. Power, MA, MB BChir (Cantab), FRCS (Tr & Orth), The HaPPeN
research group, NIHR Surgical Reconstruction and Microbiology Research
Over 70% of amputees experience pain in the residual Centre, North Block, 4th Floor, Heritage Building (Queen Elizabeth
limb.6 Residual limb pain can have many causes, including Hospital), Mindelsohn Way, Edgbaston, Birmingham B15 2TH, UK.
bone spurs, pressure points, or deep tissue infections, but can Email: dominicpower1@gmail.com
Langeveld et al. 143

also be the consequence of neuroma formation. Furthermore, arterial disease (PAD), embolism, or diabetes mellitus (DM).
many patients experience phantom limb pain (PLP) following If studies reported the outcomes of LLA for multiple etiologies
lower extremity amputation. PLP is the sensation of burning, (e.g., traumatic, dysvascular, and oncological), outcomes for
tingling, or electrical shooting pain originating from an area of patients with dysvascular LLA had to be individually dis-
body tissue that is not physically present.7 PLP and neuro- cernable. Studies with less than 30 patients were excluded.
pathic pain from a symptomatic neuroma can be debilitating Experimental studies, case reports, animal studies, reviews,
and significantly impact the quality of life of amputees and be conference abstracts, and poster presentations were excluded,
difficult to manage. The pain decreases the patient’s ability as well as non-English articles and articles without full-text
and desire to wear prosthetics, impairing mobility status and available. Disagreements between the authors were discussed
function of the limb.8 in consensus meetings.
The prevalence of PLP and symptomatic neuromas in
patients following dysvascular LLA has not been reliably
Data Extraction and Quality Scoring
established. The traditional rationale was that dysvascular
amputees were thought to experience less neuropathic pain Two authors (R.B. and M.L.) extracted data from the selected
and PLP due to longstanding peripheral neuropathy as a articles. Collected variables included the year of publication,
consequence of diabetes mellitus, leading to loss of sensation country, number of patients, age of patients, level of ampu-
and pain.7 However, research by Clark et al7 reported no tation, time to follow-up, and reported outcome measure.
significant difference in PLP between dysvascular and non- The primary outcome was the proportion of patients that
dysvascular amputees. The impact of PLP and symptomatic experienced PLP after LLA. PLP was defined as pain that is
neuromas on the patient’s mobility status and quality of life felt in the portion of the limb that has been amputated.
make it essential to gain an understanding of the magnitude of Secondary outcomes were the proportion of patients with a
the problem in this patient population that already experiences symptomatic neuroma in the amputation stump of the affected
higher complication and mortality rates than non-vascular lower limb following LLA, and pain score measured with the
amputees.9,10 This systematic review examines the preva- Visual Analog Scale (VAS)/Numerical Rating Scale (NRS).
lence and incidence of phantom limb pain and symptomatic The Jovell and Narvarro-Rubio classification was used to
neuroma after dysvascular LLA. classify eligible articles by strength of evidence (Appendix,
Supplemental Digital Content 3). A quality assessment was
performed using the Study Quality Assessment Tools of the
Methods
National Institutes of Health (NIH) (Appendix, Supplemental
Literature Search Digital Content 4) (2).
A systematic review was conducted to study the prevalence and/
or incidence of phantom limb pain and symptomatic neuroma Statistical Analysis
following dysvascular LLA. The study was performed in ac- Descriptive data was summarized in tables. For each study, the
cordance with the Preferred Reporting Items for Systematic absolute number and proportion of patients reporting PLP was
Reviews and Meta-analyses statement (PRISMA guidelines, determined. Those numbers were statistically combined in a
Appendix, Supplemental Digital Content 1).11 Databases Em- meta-analysis to generate an overall pooled proportion with a
base, MEDLINE, Web of Science Core Collection, and Co- 95% confidence interval. This proportional meta-analysis was
chrane Central were searched from inception to 5th October 2022 performed in R (version 4.0.5.) using a random-effects model
(Appendix, Supplemental Digital Content 2). with logit transformation. The random-effects model was
selected because of the expected heterogeneity between the
included studies. In this model, studies are equally weighted.
Study Selection
A back-transformation from logit was performed to provide
Two authors (R.B. and M.L.) independently identified rele- the pooled proportion of PLP. Heterogeneity testing was
vant studies meeting the eligibility criteria based on title and performed with a generalized/weighted least-squares exten-
abstract. All articles were screened for the following inclusion sion of Cochran’s Q-test. The results of the analysis are
criteria: prospective or retrospective observational cohort graphically presented in a forest plot. A funnel plot was used
studies or cross-sectional studies reporting the prevalence (for to analyze publication bias.
cross-sectional studies) or incidence (for prospective cohort
studies) of PLP and/or symptomatic neuromas following
Results
dysvascular LLA, where LLA included transtibial amputation,
transfemoral amputation, foot amputation, knee disarticula- The literature search yielded 5668 publications (Figure 1).
tion and hip disarticulation (Table 1). Dysvascular LLA was After duplicates were removed and abstracts were screened,
defined as amputation of the lower extremity that is dys- 5610 articles were excluded. Fifty-eight studies were read in
vascular in etiology due to complications from peripheral full text and assessed for eligibility. In twenty-six studies the
144 Vascular and Endovascular Surgery 58(2)

Table 1. Baseline Characteristics of Included Studies.

Patients Amputation level Mean follow-up months


Author, year Country Study type LoE (n) Age (yr) (n) (range)

AlMehmam et al, Saudi Arabia Cross-sectional VIII 78 57.5 ± 12.0 NRS NR


2022 study
Borsje et al, 2004 The Cross-sectional VIII 127 NRS NRS NR
Netherlands study
Clark et al, 2013 United Cross-sectional VIII 50 70.5 ± 1.45 Above knee: 11 1.5 y ± 0.2 y
Kingdom study Below knee: 39
Dijkstra et al, 2002 The Cross-sectional VIII 216 NRS Above knee: 167 18.8 y ± 18.1 y
Netherlands study Below knee: 266
Durovic et al, 2007 Servia Prospective cohort VI 38 NRS Above knee: 11 2m
Below knee: 24
Foot: 3
Ephraim et al, 2005 United States Cross-sectional VIII 335a 55.6 ± 10.9 Above knee: 93 3 y (1 y-48 y)b
study Below knee: 178
Bilateral: 64
Lans et al, 2022 United States Retrospective VI 643 60.5 ± 16.2 NRS NRS
cohort
Mayo et al, 2022 Canada Cross-sectional VIII 231 63.4 (31-95)b Above knee: 24 40.3 m(6 m - 20 y)b
study Below knee: 171
Bilateral: 36
Penna et al, 2017 Australia Retrospective VI 40 NRS NRS 12 m
cohort
Richardson et al, United Prospective cohort VI 52 63.8 ± 10.4 Above knee: 25 6m
2006 Kingdom Below knee: 24
Bilateral: 3
Richardson et al, United Cross-sectional VIII 89 65.5 ± 11.4 Above knee: 57 2.9 m ± 4.6 m
2015 Kingdom study Below knee: 32
Weiss and lindell, United States Retrospective VI 45 NRS NRS NR
1996 cohort
Values are presented as mean ± Standard Deviation.
LoE: Level of Evidence assessed with the classification of strength of evidence by Jovell and Navarro-Rubio.
NR: not reported; NRS: not reported specifically for dysvascular MLA patients; NA: not applicable.
a
The patient population includes 5 patients (1.5%) with upper limb amputation.
b
Value is presented as mean (range).

outcome of interest in dysvascular patients was non- (Table 2).1,12,13,17,21 Three studies included bilateral
distinguishable from other causes for major limb amputa- amputations.16,18,19 The mean age of included patients in each
tion. Other reasons for exclusion were no outcome of interest study ranged between 57.7 and 70.5 years (Table 2).
(n = 2), sample size below 30 patients (n = 1), article not Articles used various outcome measures to assess the
available in the English language (n = 3) and previously presence of PLP and symptomatic neuroma. Ten studies used
unidentified duplicative articles (n = 3). Eleven articles were questionnaires including the Kooijman Phantom Pain Ques-
not available in full text. A total of 12 articles were included tionnaire, the Groningen Questionnaire of Problems after Leg
in qualitative analysis and 11 in quantitative analysis Amputation, the Dysvascular Conditions Scale Questionnaire,
(Table 2).1,7,12-21 the Phantom phenomena questionnaire and Haber’s Phantom
Seven of the 12 included articles were cross-sectional Limb Questionnaire (Table 2).7,12-16,18-21 One study by Lans
studies (Table 2),7,12-14,16,18,20 two prospective cohort et al17 retrospectively based the prevalence of PLP on re-
studies,15,19 and three retrospective cohort studies.1,15,17,19,21 porting in medical charts. A single study by Penna et al1
The studies were conducted in seven different countries and evaluated symptomatic neuroma’s presence by combining
published between 1996 and 2022. The number of patients in clinical signs with radiological or histological confirmation.
each study ranged between 38 and 643, with a median of 70.5 Five studies used numerical pain scores to assess the severity
(Table 2). Seven studies included both above and below-knee of the PLP. Four studies used the 0-10 VAS scale or 0-10 NRS
amputations,7,14-16,18-20,22 while five studies did not report scale.7,15,19,20 Weiss and Lindell21 used a 0-6 verbal pain
amputation levels specifically for dysvascular MLA patients scale.
Langeveld et al. 145

Figure 1. Flowchart regarding the selection of included articles according to the PRISMA standards.

Quality Assessment of Included Studies Lindell evaluated pain intensity on a 0-6 pain scale and re-
ported a score of 2.6 ± 1.8.21
Five cohort studies scored a level of evidence of six according
to the classification of strength of evidence according to the
Jovell and Navarro-Rubio classification.1,15,17,19,21 The re- Proportion of Patients with Symptomatic Neuroma
maining seven cross-sectional studies scored a level of evi- Following Dysvascular LLA
dence of eight.7,12-14,16,18,20 When scored with the NIH Risk
of Bias tool, all studies had an average risk of bias (Appendix, A single study reported the number of patients that developed
Supplemental Digital Content 4). No studies were excluded a symptomatic neuroma following dysvascular LLA.1 In a
based on the quality assessment or risk of bias tool. study population of 40, Penna et al1 reported that two patients
(5%) developed a symptomatic neuroma (Table 3).

Proportion of Patients with PLP Following


Dysvascular LLA Discussion
Eleven studies reported phantom limb pain for a total of 1924 PLP and symptomatic neuromas can significantly impact an
LLA (Table 3).7,12-21 A meta-analysis of these studies dem- amputee’s quality of life and mobility status, and insight into the
onstrated that 69% of the patients experience phantom limb magnitude of the problem is necessary. This systematic review
pain (95% CI 53-86%) (Figure 2). aimed to examine the prevalence of PLP and symptomatic
neuroma after dysvascular LLA. Overall, 69% of patients report
experiencing PLP following LLA (95% CI 53-86%). In current
Pain Intensity of PLP
literature and this review, evidence for the percentage of
Reported pain intensity scores of PLP on the 0-10 VAS/NRS symptomatic neuroma following dysvascular LLA is lacking.
scale ranged between 2.3 ± 1.4 and 5.5 ± .7 (Table 3). Weis and However, a single study reported an incidence of 5%.1
146 Vascular and Endovascular Surgery 58(2)

Table 2. The Reported Presence of Phantom Limb Pain and Symptomatic Neuroma.

Number of patients with Number of patients with Pain


Author, year Method of outcome measurement phantom limb pain (%) symptomatic neuroma (%) score

Almehmam et al, Kooijman phantom pain questionnaire 47 (60.3%) NR NR


2022
Borsje et al, 2004 The Groningen questionnaire of problems 90 (71%) NR NR
after leg amputation
Clark et al, 2013 Questionnaire 41 (82%) NR 3.9 ± 0.4
Dijkstra et al, Questionnaire 169 (78.2%) NR NR
2002
Durovic et al, Questionnaire 22 (57.9%) NR 2.3 ± 1.4
2007
Ephraim et al, Questionnaire 281 (83.9%)a NR NR
2005
Lans et al, 2022 Phantom limb pain reported in medical 227 (35%) NRS NR
chart
Mayo et al, 2022 Dysvascular conditions scale questionnaire 162 (70.1%) NR NR
Penna et al, 2017 Clinical signs in combination with NR 2 (5%) NR
radiological or histological confirmation.
Richardson et al, Phantom phenomena questionnaire 41 (78.8%) NR 2.7 ± 1.6
2006
Richardson et al, Phantom phenomena questionnaire 56 (63%) NR 5.5 ± .7b
2015
Weiss and lindell, Haber’s phantom limb questionnaire 33 (73.3%) NR 2.6 ± 1.8c
1996
Values are presented as mean ± Standard Deviation.
NR: not reported; NRS: not reported specifically for dysvascular MLA patients.
a
The patient population includes 5 patients (1.5%) with upper limb amputation.
b
The pain score was only recorded for outpatient patients (n = 25).
c
Pain was recorded on a 0-6 verbal pain scale.

Figure 2. Meta-analysis of proportions of PLP in LLA.

In this systematic review, we report a similar prevalence of in surgical and traumatic amputations and reported a pooled
PLP in dysvascular amputees as has been established in lit- prevalence estimate of PLP of 64% (95% CI 60.01-68.05).
erature for the total population of all-cause amputees. Li- Additionally, Schwingler et al24 reported a pooled prevalence
makatso et al23 systematically reviewed the prevalence of PLP of PLP of 53% (95% CI 40%-66%) following all-cause LLA.
Langeveld et al. 147

Stankevicius et al25 conducted a rapid systematic review decrease in neuropathic pain in patients who underwent TMR
without a meta-analysis and reported a wide range in point at the time of amputation.30 The rationale is that providing the
prevalences of PLP in included studies between 6.7%-88.1% transected nerves with a physiological target for reinnervation
and lifetime prevalences between 76%-87% in all-cause upper prevents hypersensitivity and the formation of symptomatic
and lower limb amputations. Individual studies also corrob- neuromas. Alternatively, during RPNI, the transected pe-
orate our findings that the prevalence of PLP in dysvascular ripheral nerves are implanted into autologous free, denervated,
LLA patients is not lower than that in non-dysvascular am- and devascularized muscle grafts.31,32 Multiple studies have
putees. Clark et al7 compared the prevalence of PLP between reported that performing prophylactic TMR during limb
dysvascular LLA and non-dysvascular amputations and found amputation significantly reduces the development of phantom
no difference between the groups. limb pain, residual limb pain, and symptomatic neuroma.33-35
Conflicting theories have been previously proposed for For example, Valerio et al33 demonstrated an incidence of
dysvascular amputees experiencing either less or more neu- phantom limb pain in 55.8% of the patients treated with
ropathic pain than non-dysvascular amputees. Traditionally, prophylactic TMR compared to 78.6% of the controls. In one
patients with dysvascular LLA were hypothesized to experi- study it was reported that prophylactic RPNI significantly
ence less PLP and neuropathic pain than non-dysvascular reduced the incidence of painful neuroma and PLP, following
amputees.7,26 The rationale is that the high prevalence of LLA from 91% in the control group to 51% in the RPNI
diabetes mellitus in this population and the associated long- group.36 Most studies have excluded dysvascular amputations
standing peripheral diabetic neuropathy leads to a loss of focusing instead on amputation of trauma or oncological
sensation in the limb and, as a result, less pain. In their ret- aetiology.
rospective cohort study, Lans et al17 reported diabetes mellitus In dysvascular patients, there are several factors that could
as a protective factor for developing PLP and symptomatic dissuade the surgeon from using TMR or RPNI preventively,
neuroma, with the hypothesis that nerve regeneration potential including higher re-amputation rates, higher complication and
is inhibited in patients with diabetes mellitus, making them wound infection rates, and a peri-operative mortality of 10-
less prone to develop neuropathic pain. Our meta-analysis 15%.37-39 Furthermore, TMR and RPNI lengthen the opera-
disputes this theory, and we found a similar prevalence of PLP tive time and often necessitate making additional surgical
in dysvascular amputees as has been reported for all-cause wounds. However, a recent study by Chang et al40 used
amputees. Alternatively, dysvascularity may be associated prophylactic TMR in 100 patients at the time of below-knee
with identified risk factors of PLP, like pre-amputation pain amputation in a highly comorbid cohort and compared the
and depression, making dysvascular patients more likely to outcomes with 100 patients treated with amputation with
develop neuropathic pain.23 While a significant portion of standard traction neurectomy in a non-randomized study. Of
dysvascular amputees have a diagnosis of diabetic neuropathy this cohort, 76% of patients underwent amputation for a di-
that pre-dates the amputation, a pathophysiological associa- abetic wound or arterial or venous ulcer, 15% for a failed
tion between diabetic neuropathy and the development of Charcot reconstruction and 10% for ischemic pain. Chang
post-amputation neuropathic pain has not been sufficiently et al40 reported significantly less pain and PLP in the TMR
studied.27 The mechanisms that lead to diabetic neuropathic cohort, with 71% of TMR patients being pain-free at 9.6 ±
pain are not yet fully understood either, although it is thought 5.7 months follow-up compared to 36% of non-TMR patients
that the toxic effects of hyperglycemia play an important (P < .01), and PLP occurring in 19% of the TMR patients vs
role.28 Other theories proposed by Schreiber et al28 include 47% in the non-TMR patients (P < .01). Additionally, the
changes in blood vessels that supply the peripheral nerves, TMR cohort’s ambulation rate was significantly higher, while
changes in sodium and calcium channels, metabolic and complications requiring revision or debridement occurred less
autoimmune disorders accompanied by glial cell activation, than in the cohort treated with standard traction neurectomy.
and central pain mechanisms. However, whether these factors On average, preventive TMR added an additional 34.8 ±
also influence phantom limb pain development or symp- 75 minutes to the operative time.40 These demonstrate that use
tomatic neuroma formation is not currently known. of PLP preventive strategies at the time of dysvascular LLA in
Due to the potentially debilitating nature of PLP and selected patients may significantly reduce pain and improve
symptomatic neuromas, various surgical strategies have been quality of life and overall health.
proposed to inhibit the development of neuropathic pain. There are several limitations to this study. The most sig-
Targeted Muscle Reinnervation (TMR) and Regenerative nificant limitation is the varying methods of outcome mea-
Peripheral Nerve Interfaces (RPNI) have been proposed as surements used to assess PLP. As no universally accepted
preventive procedures performed during major limb ampu- criteria exist for PLP, studies used varying definitions to
tation. TMR is a procedure where the peripheral nerves are evaluate its presence, such as ‘pain in the missing part of the
coapted to motor branches supplying functionally expendable limb’ or ‘an unpleasant sensation in the nerve distribution of
portions of muscle in the vicinity of the nerve.29 Originally the missing body part’. Furthermore, no validated method of
developed to provide intuitive control of upper limb pros- outcome measurement exists for PLP. Most included articles
theses, Dumanian et al first noted the improvement in PLP and used unvalidated questionnaires, while others reported PLP
148 Vascular and Endovascular Surgery 58(2)

based on clinical signs or retrospectively assessed medical Conclusions


records. This may explain why the study by Lans et al reported
a particularly low prevalence of PLP, as it was the only study This systematic review and meta-analysis demonstrates a high
to use retrospective chart review to evaluate the presence of prevalence of PLP after dysvascular LLA. Evidence on the
phantom limb pain, which may have led to underreporting. prevalence of symptomatic neuromas after dysvascular am-
Additionally, the varying criteria for PLP and the variability in putation is still lacking, and further research is needed. There
methods of outcome measurement may have caused the re- is good evidence in non-dysvascular amputations, and a single
ported heterogeneity between the included studies in our meta- study in dysvascular amputation, that use of surgical strategies
analysis. Furthermore, while the I-squared statistic supposedly such as TMR and RNPI at the time of amputation may sig-
indicates significant heterogeneity between included studies in nificantly reduce subsequent PLP. Knowledge of the preva-
the conducted analysis, this statistic should be interpreted lence of PLP and symptomatic neuroma in patients
cautiously. Due to the nature of proportional data, the I- undergoing dysvascular amputation may encourage wider
squared statistic tends to yield high values in proportional adoption of techniques in this patient group.
meta-analyses, primarily due to the fact that even small studies
with limited sample sizes often exhibit small variances in their Acknowledgments
outcomes, leading to high I-squared values.41 Consequently, The authors like to thank Elise Krabbendam, biomedical information
the high I-square value in such cases does not automatically specialist at the Erasmus Medical Center, for her assistance with the
indicate data inconsistency, and a conservative interpretation literature search.
is recommended.41 Therefore, a pooled proportion for PLP
across the included studies was presented in this analysis Declaration of Conflicting Interests
despite the high I-squared value. Lastly, it was impossible to The author(s) declared no potential conflicts of interest with respect to
perform subgroup analyses to evaluate whether the prevalence the research, authorship, and/or publication of this article.
of PLP and symptomatic neuroma differ between levels of
amputation and/or amputation techniques. Previous studies Funding
have reported higher rates of neuropathic pain and PLP in
proximal amputations compared to distal amputations.17,42,43 The author(s) received no financial support for the research, au-
There is a scarcity of literature addressing the prevalence of thorship, and/or publication of this article.
symptomatic neuromas resulting from dysvascular conditions. A
single retrospective study by Penna et al1 reported a prevalence of Ethical Board and Informed Consent
5%. The formation of a neuroma is expected in every severed This manuscript is a systematic review and meta-analysis. As such,
nerve without a distal nerve end, due to disorganized axial re- the article is not subject to ethical approval or informed consent
generation. However, it remains unclear which mechanisms procedures in the Netherlands or the United Kingdom, where the
determine whether a neuroma will cause symptomatic neuro- authors are located.
pathic pain in patients. Further research is necessary to inves-
tigate the influence of dysvascularity on the development of ORCID iD
symptomatic neuromas. The diagnosis of symptomatic neuroma Mirte Langeveld  https://orcid.org/0000-0001-6849-5036
development is further complicated by the absence of universally
accepted diagnostic criteria. To address this issue and facilitate Supplemental Material
consistent diagnosis, diagnostic criteria proposed by Arnold
et al44 have been suggested for adoption in clinical practice and Supplemental material for this article is available online.
future research. To receive a diagnosis of symptomatic neuroma,
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