Complex regional pain syndrome (CRPS) is a condition characterized by the coexistence of prolonged and disproportionate to primary trauma pain and autonomic disorders (1). Afflicted persons living with CRPS experience abnormal pain, which places a heavy physical and psychological burden on them (2). Other obligatory symptoms include sensory abnormalities, changes in skin color, temperature, hair and nail growth, sweating and/or swelling of limbs despite the fact that any body part can be affected (3). The condition is remarkably rare, affecting 6.28–26.2 per 100,000 person-years. Several risk factors have been associated with the development of CRPS, including injuries—particularly to the foot—smoking, poor peripheral circulation, diabetes, autoimmune disorders, and a history of nerve damage (2). CRPS is more commonly diagnosed around the age of 40–50, but it can occur at any age, and women are most likely to be affected (4). There are two main types of CRPS: more prevalent CRPS type1 related to any soft tissue trauma, and CRPS type 2 related to an injury of a specific nerve, though both types are treated similarly (1). Also, there have been described cases with no history of previous trauma at all, in which the patients developed the same disabling conditions (5).

The pathophysiology of CRPS is still not fully understood. It is considered to involve simultaneous malfunctioning of both central and peripheral nerve systems (3). CRPS is characterized by a cascade of complex interactions, such as inappropriate tissue inflammatory response to injury, abnormal sensitization of the peripheral and central nervous systems along with accompanying autoimmune and autonomic dysfunction. It is also thought that hereditary and psychological factors may contribute to the development of CRPS (4).

The Budapest Criteria, which have remained relevant for many years, are the gold standard for the clinical diagnosis of CRPS (2, 6). The diagnosis is made clinically because no single confirmatory test can support CRPS (3). A history of recent trauma and a thorough examination can give clues. Nerve conduction studies (NCS) and electromyography (EMG) can detect most nerve injuries associated with CRPS type 2, but the results of these studies would be normal for CRPS type 1, although they are extremely difficult to perform in patients with severe pain syndrome. Ultrasound or magnetic resonance imaging (MRI) may reveal underlying nerve and tissue damage, or help rule out other conditions whose symptoms may mimic CRPS.

A 32-year-old male patient was referred to a neurophysiology laboratory for electrodiagnostic evaluation to assess a suspected nerve injury. The case history revealed that six months before the presentation, the patient had sustained a left lower extremity injury secondary to an anti-tank mine explosion during military engagement. Notably, the injury occurred without shrapnel contamination or any penetrating trauma. Immediately following the incident, the patient reported no acute neurological or vascular abnormalities, and no swelling in the affected limb. However, after a two-week observation period in a field hospital, he developed progressive weakness and sensory loss in the left foot, which manifested in the absence of pain. Subsequently, he observed persistent hypothermia and intermittent cyanotic discoloration of the left leg distal to the knee.

Initial therapeutic interventions included self-prescribed food supplements, neuromuscular electrical stimulation and acupuncture, none of which yielded clinical improvement. Three months post-injury, the patient was admitted to a specialized outpatient clinic for comprehensive neurological and vascular assessment (Figure 1A). The patient reported no history of chronic diseases and had not been under continuous medical care previously.

In 1993 in a prospective study of CRPS carried out by Veldman et al. (8) of 829 patients 7% did not experience pain, although pain remained among the most common and invariable symptoms along with color differences, temperature differences, paresis and increase complaints after exercise.

In 2003, Eisenberg and Melamed (9) presented 5 cases of patients who developed a full clinical picture of CRPS subsequent to the trauma with the exception of pain. Interestingly, 4 out of 5 patients had a nerve or nerve root injury confirmed with NCS and EMG suggesting that CRPS type 2 could be painless as well. The authors even suggested a special term for this condition—complex regional painless syndrome (CRPLS).

Kumar et al. (10) in 2009 described two cases of CRPS-like changes in the absence of pain in patients after hip surgery. The authors pointed out to relationship between the symptoms and the period of non-weight bearing. In these cases, abnormal sensitization of the peripheral and central nervous systems due to lack of proprioception alongside with an increase in flow mediated dilatation of arteries and a decrease in venous capacitance might contribute to the development of CRPS-like symptoms.

In order to study clinical subtypes of CRPS beyond the classical dichotomy CRPS 1 and 2 subtypes, Bruehl et al. (11) divided 113 patients into 3 separate groups by their clinical presentations: the first group with the prevalence of the vasomotor and motor/trophic changes, the second one with more prominent pain/sensory symptoms and the third was characterized by the presence in all symptom categories such as pain/sensory, vasomotor, sudomotor/edema, and motor/trophic. Based on the study results the authors offered the following CRPS subtypes: a relatively limited syndrome in which vasomotor signs predominate, a relatively limited syndrome in which neuropathic pain/ sensory abnormalities predominate, and a florid CRPS. Regarding the presentation of pain, the patients with so-called florid CRPS displayed significantly fewer signs of pain/ sensory dysfunction than the patients with a relatively limited syndrome which was associated with nerve injury and neuropathic pain. However, the authors noted that reliable pain rating data were not available for analysis, so it is unclear if there were differences in pain severity between the groups.

Even though since 2004, when the Budapest criteria were first developed, there have been made several changes and adaptations, the presence of continuing pain, disproportionate to the inciting event has always been a prerequisite. For patients who have never met the diagnostic criteria fully, there is a special diagnosis of CRPS Not Otherwise Specified.

However, there is no ultimate list of tests and studies that should be performed in case of suggested CRPS. Different diagnostic algorithms suggest variety of options including plain radiography or bone scintigraphy, quantitative sensory testing, bone mineral density, MRI, computed tomography, skin biopsy, three-phase bone scintigraphy, quantitative sudomotor axon reflex, laser Doppler flowmetry, NCS, and EMG (4). The aim of evaluation is to exclude other vascular disorders and range of neuropathies that could cause similar symptoms.

In the present case, comprehensive neurophysiological assessment played a key diagnostic role, despite the patient's atypical clinical manifestations. NCS and EMG provided crucial insights into the functional integrity of peripheral motor and sensory axons, revealing no evidence of axonal degeneration or demyelination. MEPs and SSEPs confirmed preservation of corticospinal tract integrity and dorsal column-medial lemniscus pathway function, respectively, thus ruling out central nervous system lesions. These findings demonstrated intact neural transmission across both central and peripheral pathways, effectively excluding neuropathies or spinal cord lesions as primary etiologies. Concurrently, vascular evaluation has become an important diagnostic component, given the prevalence of vasomotor abnormalities (e.g., temperature asymmetry, cyanotic skin coloration) and motor deficits in the clinical picture. Non-invasive vascular studies, including Doppler ultrasonography and isotope angiography, were employed to assess peripheral blood flow dynamics and identify potential microvascular dysfunction or autonomic dysregulation. The integration of neurophysiological and vascular data proved instrumental in narrowing the differential diagnosis, distinguishing between post-traumatic neurovascular complications (e.g., complex regional pain syndrome), non-compressive mononeuropathies, and ischemia-mediated tissue injury. This multimodal approach highlights the need to synthesize functional neurodiagnostic findings with hemodynamic profiling to elucidate the pathophysiological interplay between neuronal integrity and vascular homeostasis in blast injury without direct tissue penetration.

It should be mentioned though that the latest studies of CRPS are dedicated to the possibility of using different biomarkers for diagnosing and prognostication of CRPS. Thus, the systematic review by Lopes et al. (12) demonstrates the key role of cytokines (most frequently IL-6 and TNF-α), autoantibodies and immune cell infiltration that may contribute in CRPS diagnostic assessment.

Another important point is that pain management plays a major role in the treatment of CRPS and, when successful, can provide significant relief for the patients. Although pain management in CRPS is still a challenging task, there are not so many pharmacological options for other debilitating symptoms such as vasomotor and sudomotor disorders as RCTs show little efficiency of different approaches so far (13, 14). Physical and occupational therapy as well as psychological support remain the milestones of CRPS treatment.

Despite CRPS being a very rare condition, it is important to remember that there is a possibility of its atypical presence with no actual pain syndrome. These paradoxical cases are not relevant to the existing diagnostic criteria, which can lead to delay in starting treatment. Further research into the pathophysiology of CRPS and related conditions is needed to explain the diversity in clinical presentation of this condition.