Phantom Limb Pain and Low Vision

Capstone project completed at University of Pittsburgh Complications that occur with limb loss may significantly hinder a person’s health-related quality of life (HRQL). In the United States, it is estimated that 40,000 amputations occur each year, with a majority of limb loss occurring secondary to diabetes mellitus, followed by trauma, infection, and malignancy. 1,2 Of the many complications that may arise following limb loss, phantom limb pain (PLP) is among one of the most commonly reported issues, affecting up to 80 percent of individuals with limb loss. PLP is characterized as pain in the limb that is no longer there; the pain in the missing limb can be described as neuropathic, such as shooting, sharp, and electrical-like or more nociceptive, such as squeezing or cramping. These symptoms may occur after the first six months following amputation or be delayed, lasting for months or years. 2,3 Although there has been a lot of published literature to investigate the underlying cause of PLP, the pathophysiology is still not thoroughly understood. Recent advances in technology have indicated that changes in the brain, spinal cord, and peripheral nerves are all multifactorial mechanisms contributing to PLP. 2 The supraspinal mechanisms affecting PLP involve reorganization within the somatosensory cortex of the deafferented limb. 2 This maladaptive phenomenon occurs when neighboring areas of the cortex representing the missing limb adopt this region and can further explain why nociceptive stimulation of these neighboring areas causes pain in the interrupted afferent signals of the missing limb. 3 Changes in the spinal cord occur when afferent signals of the dorsal horn are disrupted by the damage to the peripheral nerves. This leads to decreased impulses of the brain stem that work to release inhibitory transmission, which result in increased autonomous activity. 3 The increase in neural activity may also be referred to as central sensitization, which causes hypersensitivity of the nerves, indicating another mechanism leading to PLP. 2 The trauma that occurs to the peripheral nerves during amputation leads to the regenerative sprouting of neuromas; the afferent signals that are altered in this process display nonfunctional connections that are hyperexcitable and discharge spontaneously to increase pain. 2,3 Although psychosocial factors have not been directly proven to cause PLP, evidence has shown that they may affect the course and severity of the associated pain. 4 As the current body of knowledge regarding PLP continues to develop, so do the treatment options. However, there has been no evidence to support any one superior method of treatment nor have any guidelines been established. Pharmacological treatment options such as non-steroidal anti-inflammatory medications are most commonly prescribed to relieve the symptoms of PLP, but they do not address the root of the problem and only provide short-term relief. 4,5 Opioids have also been proven to reduce PLP. Huse et al., in a case study of three patients, showed there was a reduction in cortical reorganization following oral treatment at six and 12 months for one patient and at the end of follow-up for another. 6 However, the use of opioids offers adverse effects such as dependence, sedation, and vertigo. Other studies exploring pharmacological treatment options like antidepressants, beta blockers, and topical analgesics show conflicting data and do not provide level-one evidence. 2,7 Neuromodulary surgeries that aim to correct the maladaptive neuroplastic changes at the brain, spinal, and supraspinal regions have also been introduced for the treatment of PLP; peripheral nerve stimulation places electrodes along the nerve trunk and has been shown to provide relief in the residual limb of a case study but does not directly address PLP. 3 Other surgical treatments including dorsal root stimulation, spinal cord stimulation, and deep brain stimulation have been shown to be effective for the reduction of chronic pain but have only been addressed by case reports in regard to their effect on PLP. 3,8 In addition to the more invasive treatment options, there are nonpharmacological treatments that have been investigated. One study by Roos et al. investigated the effect of a psychological treatment directed at processing the emotional and somatosensory memories associated with PLP. 9 The results of this study indicated significant decreases of reported PLP at long-term follow-up after eye movement destination and reprocessing (EDMR) intervention, though further investigation of similar techniques using larger trials are necessary to support the efficacy of EDMR as an effective treatment option. 9 Targeted muscle intervention, transcutaneous electrical nerve stimulation, and percutaneous nerve stimulation have also been hypothesized to relieve PLP, but there is an absence of randomly controlled clinical trials to provide significant data. The effects of noninvasive brain stimulation (NIBS) on PLP was observed by Kikkert et al. in which they found one session of intervention to significantly relieve PLP; their discovery elicits further investigation for better targeted NIBS interventions. 10 Other pain-related interventions, such as acupuncture, have also been investigated to relieve PLP, but future definitive trials are needed to actuate the feasibility of these findings. 11 Psychosocial interventions, like cognitive behavior therapy, biofeedback, and guided imagery offer inexpensive and minimally invasive treatment options but there have been no large scale trials. Nunzio et al.’s multimodal study implemented a visual and tactile training intervention using EMG activity generated at the muscles of the residual limb to provide volatile control of the missing limb and were found to reduce PLP by 32 percent among ten participants. 12 These findings indicate a need for further investigation of multimodal training interventions. Mirror therapy (MT) has been commonly used to relieve the symptoms of PLP in clinical and at-home settings; this technique aims to resolve the visual proprioceptive dissociation in the brain by creating an illusion of the sound side limb to appear as the amputated limb from the reflection of a mirror. 9,13 MT influences cortical reorganization by allowing visual feedback to overcome somatosensory feedback. 8 One study compared the use of MT to exercise in 41 randomly assigned participants to relieve PLP, and the results indicated improvement in both groups with a greater reduction among the MT treatment group. 14 Although there have been multiple larger scaled randomized controlled trials (RCTs) following the work by Chan et al., further investigation is necessary to strengthen the efficacy for MT and to better understand why MT may not be effective for all patients. Similar application of visual feedback and motor control has recently been demonstrated by a more technologically advanced form of MT through virtual and augmented reality. These systems allow a more lifelike kinematic approach for deceiving the brain to inhabit motor control over the missing limb, but there is a lack of clinical trials that provide sufficient evidence. Hagura et al. investigated the role that the posterior parietal cortex has in the multisensory processing that can occur when vision overrides kinesthetic information. 15 Their intervention consisted of a vibratory stimulation to create an illusionary flexion moment while either observing the vibrating or nonvibrating hand; although their outcome measures do not assess PLP as a factor, they did find supporting evidence of visual dominance over kinesthesia. 15 This information is relevant for future consideration of treatment options for PLP. One recent RCT created a brain-computer interface (BCI) to assess whether controlling the image of a phantom hand would reduce PLP. 16 The results of the study found a significant reduction in PLP following the visual feedback intervention. The BCI intervention had similar aims of cortical reorganization to improve PLP, but it is differentiated from MT and virtual reality by allowing movement focus on the residual limb side rather than the intact limb side. Vision plays an evident critical role in nonpharmacological treatment options for reducing PLP. The current understanding of cortical reorganization that occurs following amputation has also been hypothesized to occur similarly among adults with low vision, leading to hypersensitivity to pain. 17 There are currently no studies investigating the presence or lack of PLP among visually impaired amputees. 3 Considering that diabetic retinopathy is the most frequent complication of diabetes, and 54 percent of amputations are the result of dysvascular disease, with two-thirds having a comorbid diagnosis of diabetes, investigation of amputees with visual impairment is necessary. 18 The purpose of my study was to identify whether visual impairments affect the perception of PLP. If we can better understand the role that vision plays in the perception of PLP, then future research may be able to provide alternative treatment options. Methods The study I conducted received internal review board approval, and participants were recruited through an email subscription of the OANDP-L listserv. Other participants were invited to complete the survey through posts to private and public Facebook (FB) groups. A limited budget of FB advertising funded through the University of Pittsburgh’s School of Health and Rehabilitation Sciences was used for further recruitment based on FB-suggested key terms for appropriate populations. Groups were found using FB’s suggested target population. An available QR code was also printed and displayed on a poster at the Pennsylvania American Academy of Orthotists and Prosthetists chapter meeting. Inclusion criteria called for participants 18 years of age or older who had experienced any upper-limb or lower-limb amputation and had a best-corrected visual acuity (BCVA) of < 20/200 (legal blindness) or BVCA of < 20/400 (blindness). An anonymous mixed-methods survey of qualitative and quantitative questions was asked using Qualtrics XM (Version Jan 2022) software. To begin the questionnaire, informed consent was obtained with a statement with information regarding the purpose of the study. The survey consisted of 17 questions that pertain to demographics, degree of visual impairment, and items relating to the amputation. The McGill pain questionnaire short form (SF-MPQ) was used to assess PLP. The SF-MPQ consists of 15 descriptors (four sensory referring to nociceptive pain experience and 11 affective, referring to the emotional impact of the pain experience). 20 One additional open-ended section at the end of the survey was made available for any additional comments that the participants may have felt was important to share. Qualtrics analysis features were used to create frequency and cross tabulation pages of data to be exported and further examined in Excel. SAS systems software (2022) was used to create chi square comparisons and run Fishers Exact Tests with p-value set at P Results A total of 54 respondents started the survey. Excluding incomplete responses left a sample of 48 for analysis (Table 1). [caption id="attachment_239265" align="alignnone" width="450"] Table 1. Demographic and clinical characteristics of the study sample.[/caption] Visual Impairments On the question regarding BCVA of less than 20/200 (legal blindness), 6 people (12.77 percent) indicated yes. Fewer participants (N = 4) indicated having a BCVA of less than 20/400 (blindness). Half (N = 24) of the participants indicated using correctable devices to improve their vision. When asked about having visual impairments before or after amputation, 21 (75 percent) indicated having visual impairments before amputation, and 7 (25 percent) indicated having visual impairments after amputation. PLP Of the respondents able to complete the question, 40 (90.91 percent) had experienced PLP before, while 4 (9.09 percent) had never experienced any PLP. Participants were asked when they first experienced PLP; 29 (72.5 percent) said immediately following amputation, six (15 percent) said one month after amputation, three (7.5 percent) said six months after amputation, one said one year after amputation, and one participant said more than two years after amputation. When asked how often the participants experienced PLP, 12 (30 percent) indicated not often at all, 13 (32.5 percent) indicated moderately often, seven (17.5 percent) indicated quite often, and eight (20 percent) indicated extremely often. The survey inquired about treatment options for PLP. Twenty-three (41.82 percent) reportedly tried medication, eight (14.55 percent) tried MT, two (3.64 percent) tried functional electrical stimulation, 12 (21.82 percent) had not tried any treatment options, and ten (18.18 percent) had tried other methods of therapy and were asked if they could specify. Other treatment options mentioned included transcutaneous electrical nerve stimulation therapy, acupuncture, medical marijuana, and CBD oil. Fishers Exact Test to determine if there was a significant association between amputees with low vision and the presence of PLP showed no statistically significant association between the variables (Tables 2 and 3). [caption id="attachment_239263" align="alignright" width="484"] Table 3. Fishers Exact Test output[/caption] [caption id="attachment_239262" align="alignleft" width="449"] Table 2. Frequency procedure of the cross-tabulation examination comparing adults with visual impairments and those with no visual impairments.[/caption] Discussion Findings, while not showing a statistically significant association between vision impairment and PLP, suggested that there is a tendential connection between those variables. The results of the SF-MPQ cross tabulation (Table 4) found that the highest percentage of participants indicating “none” on the scale from none to severe when asked to describe their PLP, were among the adults who selected “I have no visual impairments” or “no” to having a BCVA of < 20/200 (legal blindness). These results were consistent with the terms “throbbing, cramping, gnawing, heavy, tender ,splitting , sickening, fearful, punishing/cruel.” When further investigating the results of the SF-MPQ, the highest percentages of participants indicating “severe” on the pain scale were among the participants that answered “yes” to having a BCVA of < 20/400 (blindness). These results were consistent with the pain-describing terms (throbbing, shooting, hot/burning, aching, tiring/exhausting). Of the participants who were asked to describe how often they experienced PLP, 66.7 percent of respondents with a BCVA of < 20/400 (blindness) described having PLP “extremely often” compared to 16.7 percent of participants without visual impairments. Of the participants with visual impairments, 50 percent indicated using pharmacological treatments for PLP, while the other 50 percent indicated that they had not tried treatment for their PLP. This information supports the purpose of the study, indicating that treatment options for adults with PLP and low vision are limited. The results of this study did not provide statistically significant data but have provided enough support for further research. [caption id="attachment_239264" align="alignnone" width="805"] Table 4. One example (throbbing) of the cross tabulation from the SF-MPQ, comparing responses of adults with a best corrected visual acuity of less than 20/200 (legal blindness), participants with a BCVA of less than 20/400 (blindness), and those indicating no visual impairments.[/caption] A cross modal plasticity hypothesis described by Mancini explains that a lack of vision may lead to reorganization of brain connectivity, causing increased sensitivity to somatosensory inputs. 17 Somatosensory and cortical reorganization that occurs after amputation requires a visual feedback. There is evidence to support the implications for further research on amputees with low vision. The large percentage of adults with limb loss suffering from PLP also elicits further research to provide optimal treatment options that are effective and accessible. Brain remapping and cortical reorganization have been further examined and hypothesized to contribute to PLP. Treatment efforts utilizing these stimulations have been found to reduce some of the pain effects. However, the visual factor that implements some current treatment options is limited for the large percentage of people with visual impairment. The main limitation of this study is the underrepresentation of participants that have a best-corrected visual acuity (BCVA) of < 20/200 (legal blindness) or BVCA of < 20/400 (blindness). With many efforts to recruit participants to complete the survey, it was difficult to identify a large sample population with visual impairments. Efforts to collaborate with the Amputee Coalition research community were approved but were not verified until several months after data collection began, and also limited recruitment attempts. Forced responses were not required for all questions and limited the available descriptive statistics. The small sample size of this study limited the power of the statistical tests performed. Conclusion PLP remains a multifactorial phenomenon. This study was the first to address vision as a factor of PLP. Higher scale studies with larger populations of participants are necessary to further understand the role that vision plays in PLP and cortical reorganization. Kamilla Miller, MSPO, earned her bachelor's degree in exercise science at Towson University. She went on to complete her Master of Prosthetics and Orthotics degree at the University of Pittsburgh. She is currently completing her prosthetic residency with Baker Orthotics and Prosthetics, Houston. References Ziegler-Graham, K., MacKenzie, E. J., Ephraim, P. L., Travison, T. G., & Brookmeyer, R. (2008). Estimating the prevalence of limb loss in the United States: 2005 to 2050. Archives of physical medicine and rehabilitation , 89 (3), 422–429. Hanyu-Deutmeyer, A. A., Cascella, M., & Varacallo, M. (2021). Phantom Limb Pain. In StatPearls . StatPearls Publishing. Hsu, E., & Cohen, S. P. (2013). Postamputation pain: epidemiology, mechanisms, and treatment. Journal of pain research , 6 . Larbig W, Andoh J, Huse E, Stahl-Corino D, Montoya P, Seltzer Z, Flor H. Pre- and postoperative predictors of phantom limb pain. Neurosci Lett. 2019 May 29;702:44-50. doi: 10.1016/j.neulet.2018.11.044. Epub 2018 Nov 29. Smith HS. Potential analgesic mechanisms of acetaminophen. Pain Physician. 2009 Jan-Feb;12(1):269-80. Nikolajsen L, Hansen C, Nielsen J, Keller J, Arendt-Nielsen L, Jensen T. The effect of ketamine on phantom pain: a central neuropathic disorder maintained by peripheral input. 1996;67(1):69–77. Huse E, Larbig W, Flor H, Birbaumer N. The effect of opioids on phantom limb pain and cortical reorganization. 2001;90(1–2):47–55. Subedi, B., & Grossberg, G. T. (2011). Phantom limb pain: mechanisms and treatment approaches. Pain research and treatment , 2011 , 864605. de Roos, C., Veenstra, A. C., de Jongh, A., den Hollander-Gijsman, M., van der Wee, N. J., Zitman, F. 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Intervention for phantom limb pain: A randomized single crossover study of mirror therapy. Indian journal of psychiatry, 59(4), 457–464. Anaforoğlu Külünkoğlu, B., Erbahçeci, F., & Alkan, A. (2019). A comparison of the effects of mirror therapy and phantom exercises on phantom limb pain. Turkish journal of medical sciences , 49 (1), 101–109. Hagura, N., Takei, T., Hirose, S., Aramaki, Y., Matsumura, M., Sadato, N., & Naito, E. (2007). Activity in the posterior parietal cortex mediates visual dominance over kinesthesia. The Journal of neuroscience : the official journal of the Society for Neuroscience , 27 (26), 7047–7053. Yanagisawa, T., Fukuma, R., Seymour, B., Tanaka, M., Hosomi, K., Yamashita, O., Kishima, H., Kamitani, Y., & Saitoh, Y. (2020). BCI training to move a virtual hand reduces phantom limb pain: A randomized crossover trial. Neurology, 95(4), e417–e426. Mancini F. (2013). Focus on pain in the blind. Pain , 154 (10), 1906–1907. Simó-Servat, O., Hernández, C., & Simó, R. (2019). Diabetic Retinopathy in the Context of Patients with Diabetes. Ophthalmic research , 62 (4), 211–217. Chan, T., Friedman, D. S., Bradley, C., & Massof, R. (2018). Estimates of Incidence and Prevalence of Visual Impairment, Low Vision, and Blindness in the United States. JAMA ophthalmology , 136 (1), 12–19. File:Mcgill questionnaire.jpg. (2016, March 9). Physiopedia, . Retrieved 18:39, April 19, 2021 Makin, T. R., & Flor, H. (2020). Brain (re)organisation following amputation: Implications for phantom limb pain. NeuroImage , 218 , 116943.

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