Functional Recovery in Refractory Lower-Limb Complex Regional Pain Syndrome Following KAFO-Assisted Rehabilitation: A Longitudinal Case Report

A 62‐year‐old woman presented with a history of chronic pelvic pain since adolescence due to severe endometriosis involving all three phenotypes, for which she had undergone bilateral ovarian cystectomy. Her medical history was also notable for anorexia nervosa, persistent depressive disorder, premature menopause at 29 years of age, and osteoporosis diagnosed at 37 years. She had multiple risk factors for skeletal fragility, including periods of low body mass index, long‐term smoking (48 pack‐years), chronic use of anticonvulsants, selective serotonin reuptake inhibitors, and antipsychotics, as well as previous treatment with GnRH agonists. Family history was notable for maternal osteoporosis and familial aggregation of migraine, fibromyalgia, and CRPS (Figure  S1 ). In June 2007, the patient sustained an inversion sprain of the right ankle, initially managed conservatively. In the following weeks, she developed intense and persistent pain in the right ankle and foot, associated with edema, erythema, increased local temperature, and allodynia, consistent with early‐stage CRPS type I. The pain was initially predominantly nociceptive in nature; with progression, a burning pain emerged with paresthesias, evolving into episodes of spontaneous deep lancinating pain. Magnetic resonance imaging ( MRI ) of the right ankle revealed no significant abnormalities. She underwent right ankle arthroscopy in August 2007, after which the pain worsened. Vascular investigations revealed no significant abnormalities. From November 2007 onward, sensory and motor disturbances were observed, including phenomena suggestive of sensorimotor conflict (Table  1 ). Patient‐reported sensorimotor and body representation disturbances. Due to persistence of symptoms, she underwent lumbar sympathectomy in January 2008, with partial and transient relief. Throughout 2008, the patient continued to experience severe pain, allodynia, vasomotor changes, and progressive functional deterioration, requiring crutches for ambulation (Figure  S2 ). Bone scintigraphy showed a pattern consistent with CRPS . In October 2008, a spinal cord stimulator was implanted due to refractory pain, with initial improvement followed by progressive loss of efficacy. In October 2009, the patient reported exacerbation of pain and anxiety triggered by observing movement in another person. At that time, she presented difficulty in left–right discrimination of her own lower limbs, relying on tactile input for identification. The clinical course was marked by multiple fragility fractures, reflecting progressive skeletal fragility and functional decline. In 2009, following a fall, she sustained a right tibial plateau fracture (Figure  1 ). In the same year, after surgical manipulation for foot dystonia (Figure  S3 ), she developed an iatrogenic distal fracture of the right femur (Figure  1 ). Following this fracture, the patient reported proximal extension of pain, with a burning sensation reaching the mid‐thigh and deep constrictive pain. Subsequently, in 2011, she sustained a vertebral fracture at T12 and underwent kyphoplasty, with additional vertebral augmentation at L1 (Figure  1 ). In 2013, she sustained a subcapital fracture of the right femur requiring arthroplasty (Figure  1 ). Representative fragility fractures during disease progression. (A) Tibial plateau insufficiency fracture of the right knee (February 2009). (B) Distal femur fragility fracture (November 2009). (C) T12 vertebral fragility fracture (January 2011). (D) Vertebral collapse at T8 and chronic collapse at T12, with prior vertebral augmentation at T12 and L1 (May 2019). Panels A–D are shown from left to right. This trajectory of poorly controlled chronic pain, associated with fragility fractures and reduced weight‐bearing capacity of the right lower limb, culminated in wheelchair dependence from 2013 onward. At the 2017 assessment in a Physical and Rehabilitation Medicine consultation, the patient reported continuous pain in the right lower limb extending to the thigh, associated with edema and vasomotor and trophic changes. On physical examination, there was muscle atrophy, severe limitation of ankle mobility, muscle weakness (1/5 distally and 2/5 proximally), mechanical allodynia, hyperpathia, and tactile and nociceptive hypoesthesia. At baseline, the patient was fully wheelchair‐dependent and unable to perform assisted ambulation, reflecting severe functional impairment of the affected lower limb. She remained independent in transfers. Clinically relevant memory impairment was also noted, with consistent difficulty recalling previously discussed information during clinical encounters.

Humberto Marreiros: writing – review and editing, writing – original draft, methodology, data curation, supervision, conceptualization, visualization, validation.

The author declares that the procedures followed were in accordance with the regulations of the responsible Clinical Research and Ethics Committee and with the World Medical Association Declaration of Helsinki.

The author has nothing to report.

After several years of wheelchair dependence, the orthosis allowed me to stand and walk again. I gradually regained confidence and felt safer during movement. Over time, my leg started to feel more stable and more “part of my body” again. This improvement allowed me to resume daily activities and return to work, with a significant positive impact on my quality of life.

Following the individualized rehabilitation program with a carbon‐fiber KAFO (Figure  2 ), the patient showed clinically meaningful functional improvement. The main clinical and functional outcomes are summarized in Table  2 . Pain decreased from 9/10 to 2/10 on the Numeric Rating Scale, and the Barthel Index improved from 50 to 85. Assisted ambulation was regained for distances of up to 150 m with two crutches, and the patient returned to work under a teleworking arrangement with occasional on‐site attendance. Clinical and functional outcomes before and after KAFO‐assisted rehabilitation. She also reported a subjective sense of integration of the orthosis into the affected limb, accompanied by improvement in the previously described difficulty with limb laterality recognition. At reassessment (March 27, 2019), the patient rated her general health as “fair.” On the SF ‐36v2 Health Transition item, she reported that her health was “much better now than one year ago,” indicating marked subjective improvement. In the same year, three‐dimensional assessment of the lower limbs demonstrated hypotrophy of the right leg (Figure  S4 ). Subsequently, the patient remained under multidisciplinary follow‐up. In 2019, she sustained an additional osteoporotic complication, namely a vertebral fracture at T8 (Figure  1 ), after which treatment with teriparatide was initiated, resulting in clinical stabilization. Since 2020, episodes of inflammatory polyarthralgia and vasomotor changes in the hands have been reported and are currently under etiological investigation. At present, the patient maintains some degree of functional limitation, with occasional pain exacerbations managed by treatment adjustment. Nevertheless, clinically meaningful improvement is evident compared to the pre‐rehabilitation period, with preserved independent ambulation using a KAFO and two crutches, together with a sustained subjective perception of improved quality of life (Figure  3 ; Figure  S5 ; Video  S1 ). Clinical timeline of disease progression and functional recovery. The timeline illustrates the clinical course from CRPS onset after right ankle trauma in 2007. Despite multiple interventions, including sympathectomy and spinal cord stimulation (SCS), the condition evolved with recurrent fragility fractures, loss of weight‐bearing capacity, and wheelchair dependence. KAFO‐assisted rehabilitation introduced in 2018 enabled functional recovery and sustained assisted ambulation. During the etiological investigation of premature menopause and skeletal fragility, an FMR1 premutation was identified.

Complex regional pain syndrome (CRPS) may result in severe and persistent functional impairment, particularly in patients with multimorbidity. Meaningful functional recovery may be achievable even in advanced and refractory CRPS. Knee–ankle–foot orthosis (KAFO)–assisted rehabilitation can enable safe weight‐bearing and recovery of ambulation. Orthotic‐assisted rehabilitation may contribute to improved body perception and sensorimotor integration beyond biomechanical stabilization.

This case describes a nulliparous woman with a severe and chronic form of CRPS type I of the lower limb in the context of complex multimorbidity, including endometriosis, anorexia nervosa, premature menopause, and fragility osteoporosis. Although CRPS is more frequently described in the upper limbs, lower‐limb involvement is well documented [ 14 ]. The clinical course was characterized by persistent pain, progressive loss of mobility, and multiple fragility fractures, culminating in marked functional decline. In the context of multimorbidity, the coexistence of multiple conditions may have acted synergistically as both predisposing and amplifying factors, contributing to a severe, chronic, and refractory phenotype. Endometriosis is an estrogen‐dependent inflammatory disease [ 15 , 16 ] and is frequently associated with chronic pelvic pain [ 17 ]. In the present case, symptom onset occurred during adolescence, consistent with evidence that a substantial proportion of patients experience early manifestations of the disease [ 18 , 19 , 20 ]. Endometriosis‐associated chronic pelvic pain has been linked to a pro‐inflammatory state and central sensitization [ 21 , 22 , 23 , 24 ], potentially altering the response to peripheral trauma and contributing to pain chronification [ 25 ]. The FMR1 premutation has been associated with chronic pain syndromes, including migraine, fibromyalgia, allodynia, and chronic fatigue syndrome, suggesting altered nociceptive processing and increased susceptibility to chronic pain [ 26 ]. The familial aggregation of migraine, fibromyalgia, and CRPS across two generations (Figure  S1 ) further supports a potential shared biological susceptibility, although FMR1 premutation status in other family members could not be confirmed. CRPS occurs more frequently with increasing age and predominantly affects females, with the highest incidence reported between 50 and 80 years of age [ 27 , 28 ]. In this case, it developed following a right ankle sprain, one of the most common triggers, surpassed only by fractures [ 9 , 13 , 29 , 30 ]. The condition is typically unilateral [ 31 ], and symptoms usually arise within the first month after trauma or immobilization [ 9 , 14 , 27 , 31 ], as observed in this patient. Other risk factors present included severe initial pain [ 10 , 27 ], pre‐existing osteoporosis [ 29 , 32 ], and long‐term smoking, which has been associated with microvascular injury and worse prognosis [ 10 , 33 ]. The diagnosis of CRPS is clinical and based on the Budapest criteria [ 11 , 34 ], which were fulfilled in this case. Three‐phase bone scintigraphy supported the diagnosis, showing increased radiotracer uptake in the mineralization phase [ 14 , 35 ]. The early presence of disproportionate pain and swelling after trauma, in the absence of significant findings on MRI, was also consistent with CRPS [ 5 ]. De Rooij et al. [ 36 ] identified 31 families with two or more affected members, totaling 84 patients, and found that familial cases were associated with earlier onset, higher frequency of dystonia, and a more severe phenotype compared with sporadic forms. The present case, corresponding to the third affected individual across two generations, shows features compatible with a possible familial form of CRPS, namely early onset and the presence of dystonia. CRPS is a heterogeneous condition involving neurogenic inflammation, autonomic dysfunction, and central nervous system changes [ 9 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 ]. In the early phase, the patient presented regional inflammatory signs consistent with the “warm” form of CRPS [ 9 ]. With disease progression, the clinical picture became fluctuating, with alternating “warm” and “cold” phases, suggesting persistent vasomotor dysfunction and possible microcirculatory impairment [ 9 , 13 , 52 , 53 ]. Despite attenuation of peripheral inflammatory signs, pain, motor disturbances, and trophic changes persisted. The patient's pain evolved from an initially predominantly nociceptive pattern to a mixed phenotype with neuropathic features, extending beyond the initial injury site and becoming persistent, consistent with the typical progression of CRPS [ 27 ]. The regional distribution of symptoms, without correspondence to a specific peripheral nerve or dermatome, was characteristic of CRPS [ 6 , 9 , 13 , 14 ]. Evidence suggests that CRPS type I is associated with predominant small‐fiber nerve injury [ 13 , 48 ], which may contribute to neuropathic pain as well as vasomotor and autonomic disturbances. Motor abnormalities in CRPS are thought to arise not only from peripheral dysfunction but also from impaired sensorimotor integration and maladaptive cortical reorganization [ 50 , 54 , 55 ]. Consistent with these clinical features, our patient developed trophic changes, weakness, myoclonus, and dystonia during the chronic phase, whereas three‐dimensional assessment confirmed hypotrophy of the affected lower limb. The early phase of CRPS is also characterized by local inflammation and osteopenia, reflecting altered bone metabolism [ 56 ], with increased expression of pro‐inflammatory cytokines such as TNF‐α, IL‐1, and IL‐6 [ 35 , 56 , 57 , 58 ]. Dysregulation of the RANK–RANKL–OPG axis may further contribute to abnormal bone remodeling [ 56 , 59 ]. Although the initial trigger was an ankle sprain, subsequent fragility fractures were temporally associated with proximal extension of pain. This observation raises the possibility that bone injury may have contributed to pain propagation and persistence; however, causality cannot be established. Premature menopause at the age of 29 years was a major determinant in this case, likely contributing to early skeletal fragility and increased fracture risk [ 60 ]. Additional risk factors included periods of low body mass index, nulliparity, smoking, prior GnRH agonist therapy [ 61 ], prolonged physical inactivity [ 62 ], and a history of anorexia nervosa [ 63 , 64 ]. Endometriosis, ovarian surgery [ 65 , 66 ], and the FMR1 premutation [ 67 ] may also have contributed to premature ovarian insufficiency and increased skeletal fragility. Overall, the coexistence of these factors likely had a cumulative effect on fracture risk. In CRPS, the central nervous system plays a key role in maintaining pain, motor disturbances, and alterations in body perception. Chronic pain induces functional and structural changes leading to central sensitization and altered processing of sensory and emotional aspects of pain [ 9 , 13 , 54 , 68 ]. These mechanisms contribute to hyperalgesia, allodynia, and spread of pain beyond the initial injury site. Neuroimaging studies have demonstrated cortical reorganization in CRPS, including changes in regions involved in sensorimotor integration and body schema [ 54 ]. In this context, the sensory and motor disturbances summarized in Table  1 are consistent with disruption of body representation and sensorimotor integration. The exacerbation of pain and anxiety triggered by observing movement in another person further suggests a role for action–observation mechanisms, potentially mediated by the mirror neuron system [ 54 ], although this remains a pathophysiological hypothesis. Despite optimized treatment, the patient experienced persistent pain and progressive disability with only partial and transient improvement. She was managed within a multidisciplinary approach. Lumbar sympathectomy provided transient relief, and a spinal cord stimulator was implanted 14–15 months after CRPS onset for refractory pain, in line with current recommendations [ 5 , 31 ]. As reported, its efficacy decreased over time [ 31 , 69 ]. Severe osteoporosis and recurrent multifactorial fragility fractures contributed to progressive functional deterioration. Pain, motor impairment with severe muscle weakness, ankle stiffness, and skeletal fragility increased fall risk and precluded safe weight‐bearing exercise. The KAFO was initially prescribed to enable safe standing and facilitate short‐distance ambulation. Clinical improvement preceded and enabled the reduction of pharmacological treatment. It represented a key intervention, allowing controlled load transfer and restoration of safe orthostatism, without which gait training and functional rehabilitation would not have been possible. The choice of a KAFO rather than a simpler ankle–foot orthosis (AFO) was based on the need to ensure global limb stability and safe weight‐bearing in the context of severe weakness, proximal instability, and high fracture risk, as a more distal orthosis would not adequately address the risk of knee collapse or allow controlled load transfer. From a neurophysiological perspective, CRPS is associated with altered cortical representation and impaired sensorimotor integration [ 54 , 55 ]. These alterations may contribute not only to pain but also to motor dysfunction through disrupted sensorimotor control. It can be hypothesized that the KAFO, by providing structured tactile input, alignment, and weight‐bearing, contributed to improved body perception and sensorimotor integration, thereby facilitating motor control and influencing central pain processing [ 55 ]. However, the specific contribution of the orthosis cannot be fully dissociated from the overall rehabilitation program. A conceptual model summarizing this pathway is presented in Figure  4 . This case suggests that in advanced CRPS, restoration of safe weight‐bearing may represent a critical prerequisite for functional rehabilitation and may contribute to recovery through both biomechanical and sensorimotor mechanisms. Conceptual model of KAFO‐assisted functional recovery in chronic CRPS. KAFO‐assisted rehabilitation acted as an enabling intervention by restoring safe weight‐bearing, allowing gait training, repetitive sensorimotor input, improved sensorimotor integration, and subsequent functional recovery. The proposed mechanisms should therefore be interpreted as a biologically plausible hypothesis rather than evidence of causality and require confirmation in future studies.

Written informed consent from the patient was obtained according to journal guidelines.

Clinical data prior to 2017 were collected retrospectively, and information bias cannot be excluded due to incomplete records or restricted access related to data protection regulations. In addition, interview‐based data collection may have been influenced by the patient's memory impairment, introducing potential inaccuracies. As a single‐case study, the findings are not generalizable. Although a temporal association was observed between orthosis implementation and clinical improvement, a causal relationship cannot be established. Other factors, including the natural course of the disease, functional adaptation, and contextual effects, may have contributed to the observed outcomes. Finally, the observational nature of this report precludes control of confounding variables and does not allow quantification of the relative contribution of each intervention. Therefore, the findings should be interpreted as hypothesis‐generating from both clinical and mechanistic perspectives.

The diagnosis of CRPS was established based on clinical assessment and fulfillment of the Budapest criteria. Three‐phase bone scintigraphy supported the diagnosis by demonstrating increased radiotracer uptake in the mineralization phase. Vascular investigations revealed no significant abnormalities. Due to persistence of symptoms, the patient underwent lumbar sympathectomy in January 2008, with partial and transient relief. Given ongoing severe pain and refractoriness to pharmacological treatment, a spinal cord stimulator was implanted in October 2008, with initial benefit followed by progressive loss of efficacy. In 2018, the patient was admitted to a rehabilitation unit for fitting of a carbon‐fiber knee–ankle–foot orthosis ( KAFO ) as part of an individualized rehabilitation program. Severe weakness and fracture risk precluded safe weight‐bearing. The introduction of the KAFO represented a turning point in the clinical course, enabling controlled load transfer and restoration of safe orthostatism, thereby allowing the initiation of progressive gait training and functional rehabilitation (Figure  2 ). Functional use of a carbon‐fiber knee–ankle–foot orthosis (KAFO). The orthosis includes ischial support, a locking knee joint, plantar‐flexion limitation at the ankle, and a carbon‐fiber footplate. It enables safe weight‐bearing and facilitates assisted ambulation. Clinical improvement preceded and enabled the reduction of pharmacological treatment. A reduction in analgesic medication was observed, including transdermal fentanyl from 50 to 37.5 μg every 3 days. Oral morphine (Oramorph), previously administered as a fixed bedtime dose of 7.5 mg, was discontinued. Tramadol 50 mg, previously prescribed as needed up to six times daily, including one fixed bedtime dose, was changed to an as‐needed regimen of up to five tablets per day; the patient subsequently required only 0‐2 tablets daily.

Multimorbidity is associated with increased diagnostic complexity, polypharmacy, and fragmented care, reflecting the coexistence of multiple chronic conditions within the same individual [ 1 , 2 , 3 , 4 ]. Complex regional pain syndrome ( CRPS ) is a disabling condition characterized by persistent pain disproportionate to the triggering event, accompanied by sensory, motor, autonomic, and trophic disturbances, with substantial impact on function and quality of life [ 5 , 6 , 7 , 8 ]. Diagnosis is clinical and based on the Budapest criteria [ 9 , 10 , 11 ]. Although some patients experience a favorable course, a subgroup develops severe, chronic, and refractory disease [ 12 , 13 ]. Multimorbidity may amplify the complexity of CRPS through shared pathophysiological mechanisms and interactions between coexisting conditions that influence clinical course, functional status, and treatment response. We present a case of lower‐limb CRPS type I in the context of complex multimorbidity, highlighting the clinical challenges and the potential role of individualized rehabilitation incorporating a knee–ankle–foot orthosis ( KAFO ). This report explores whether restoration of safe weight‐bearing may act as a prerequisite for functional and neurophysiological recovery in advanced CRPS . This longitudinal case report includes retrospective and prospective data collected from 2017 onward from clinical records, patient interviews, outpatient follow‐up, validated outcome measures (Numeric Rating Scale, SF ‐36v2, and Barthel Index), pharmacological data, diagnostic investigations, and three‐dimensional structured‐light scanning of the lower limbs. The report was prepared in accordance with CARE guidelines. Written informed consent from the patient was obtained according to journal guidelines.

The author declares no conflicts of interest.

Video S1: Functional mobility and participation in daily life (February 2022). (A) Independent ambulation with KAFO. (B) Community mobility using a scooter. At the time of recording, the KAFO appeared suboptimally fitted, partly in relation to weight changes. Orthotic reassessment is currently underway, with optimization of the existing KAFO. Figure S1: Family pedigree showing aggregation of chronic pain‐related conditions. The pedigree illustrates a possible familial clustering of chronic pain‐related disorders, including migraine, fibromyalgia, and complex regional pain syndrome (CRPS). The proband is indicated by an arrow. Circles represent females and squares represent males. Filled symbols indicate affected individuals. Diagonal slashes indicate deceased individuals. Figure S2: Early inflammatory changes of the affected limb. October 17, 2008: Edema of the right ankle and foot with thin, shiny skin and erythrocyanosis. Figure S3: Motor dysfunction in CRPS. August 2009: Dystonia of the right foot. Figure S4: Three‐dimensional structured‐light scan of both lower limbs. (A) Right leg and foot (affected). (B) Left leg and foot (contralateral). Quantitative analysis demonstrated reduced volume of the affected (right) limb compared with the contralateral side (2842 cm 3 vs. 3202 cm 3 ). Images are displayed in a mirrored orientation for visualization purposes (the right limb appears on the left side of the figure). Although visual inspection of the rendered images may suggest relative prominence of the affected limb, this reflects image acquisition and rendering characteristics rather than true volumetric differences. Detailed morphometric measurements are provided in Table S1. Figure S5: Representative still image from Video S1. Representative frame demonstrating independent ambulation with a KAFO and two crutches following rehabilitation. The complete gait sequence is available in Video S1. Table S1: Volumetric and dimensional measurements of both lower limbs.