Peripheral neuropathy and nerve compression syndromes lead to substantial morbidity following burn injury. Patients present with pain, paresthesias, or weakness along a specific nerve distribution or experience generalized peripheral neuropathy. The symptoms manifest at various times from within one week of hospitalization to many months after wound closure. Peripheral neuropathy may be caused by vascular occlusion of vasa nervorum, inflammation, neurotoxin production leading to apoptosis, and direct destruction of nerves from the burn injury. This article discusses the natural history, diagnosis, current treatments, and future directions for potential interventions for peripheral neuropathy and nerve compression syndromes related to burn injury.
Key points
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Peripheral neuropathy and nerve compression syndromes lead to substantial morbidity following burn injury.
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Early and effective treatment to minimize the long-term sequelae of peripheral neuropathy and nerve compression syndromes leads to improved outcomes.
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Future directions focused on early diagnosis and treatment will minimize the morbidity associated with postburn neuropathic pain.
Introduction
Peripheral neuropathy and nerve compression syndromes lead to postburn morbidity that can often be difficult to recognize and manage. Entrapment or compression of the peripheral nerves is associated with common symptoms of pain, weakness, and paresthesia, often requiring acute decompressive fasciotomies or escharotomies. Muscle wasting and weakness are late symptoms of nerve compression that yield distinct symptoms based on the nerve affected. Postburn peripheral neuropathy and nerve compression syndromes can also be present in a delayed fashion by the formation of scar tissue or heterotopic bone. Heterotopic ossification (HO) is the formation of new bone in nonosseous tissue. Although HO is a rare but well-known complication of burns, it results in decreased range of motion, painful and/or swollen joints, or nerve deficits. It most commonly involves the elbow joint, often leading to symptoms of ulnar nerve compression, regardless of the location of the burn. Irrespective of the cause, the development of peripheral neuropathy or nerve compression syndromes is often recognized late after the burn injury and results in substantial impairment of the activities of daily living in patients who may already be functionally limited by their burns. Thus, postburn peripheral neuropathy and nerve compression syndromes remain an unmet challenge that requires adequate diagnosis and treatment in a timely fashion.
Introduction
Peripheral neuropathy and nerve compression syndromes lead to postburn morbidity that can often be difficult to recognize and manage. Entrapment or compression of the peripheral nerves is associated with common symptoms of pain, weakness, and paresthesia, often requiring acute decompressive fasciotomies or escharotomies. Muscle wasting and weakness are late symptoms of nerve compression that yield distinct symptoms based on the nerve affected. Postburn peripheral neuropathy and nerve compression syndromes can also be present in a delayed fashion by the formation of scar tissue or heterotopic bone. Heterotopic ossification (HO) is the formation of new bone in nonosseous tissue. Although HO is a rare but well-known complication of burns, it results in decreased range of motion, painful and/or swollen joints, or nerve deficits. It most commonly involves the elbow joint, often leading to symptoms of ulnar nerve compression, regardless of the location of the burn. Irrespective of the cause, the development of peripheral neuropathy or nerve compression syndromes is often recognized late after the burn injury and results in substantial impairment of the activities of daily living in patients who may already be functionally limited by their burns. Thus, postburn peripheral neuropathy and nerve compression syndromes remain an unmet challenge that requires adequate diagnosis and treatment in a timely fashion.
Epidemiology
The association between peripheral neuropathy and burns has been found to vary widely from 2% to 52% of patients depending on the study methodology. Studies surveying patients with burns with electrodiagnostic evaluations and clinical assessments showed higher rates of peripheral neuropathy, in the range of 11% to 52% ( Table 1 ). The incidence of neuropathy after burn injury was first well described by Henderson and colleagues in 1971. Of the 249 hospitalized patients with burns who underwent electrodiagnostic testing, 44 patients showed conduction slowing in 2 or more nerves. In 1977, in a prospective study analyzing a cohort of patients with burns, the investigators found peripheral neuropathy in 24 of the 66 patients (36%) with clinical evidence of weakness. Helm and colleagues evaluated an additional 88 patients with burns and confirmed peripheral neuropathy with electrodiagnostic testing in 46 patients (52%). More recently, Kowalske and colleagues found that the incidence of mononeuropathy and/or generalized peripheral neuropathy totaled 11%. The large variability in the incidences in these prospective studies is likely attributed to the significant variability in total body surface area (TBSA) injured and depth of the burn, as more severe burns have been shown to correlate with a higher incidence of peripheral neuropathy.
| Study, Year | Study Type | Findings |
|---|---|---|
| Margherita et al, 1995 | Prospective | At 6 wk, peripheral neuropathy persistent in 27% of patients |
| Hayes et al, 2002 | Prospective | After 6 mo, 78% of patients still had peripheral neuropathy After 12 mo, 56% of patients still had peripheral neuropathy |
| Schneider et al, 2006 | Retrospective | Of the patients with peripheral neuropathy, improvement in symptoms was noted starting around 7 ± 0.8 mo |
| Wu et al, 2013 | Retrospective | Most patients reported subjective improvement of symptoms (82%), whereas 18% of patients showed no improvement by 4 mo |
In contrast, studies that rely on clinical diagnosis followed by electrodiagnostic testing, including nerve conduction studies, showed much lower incidences, ranging from 2% to 7% (see Table 1 ). In these studies, Dagum and colleagues found that 9 out of the 121 patients with burns (7.4%) analyzed had severe peripheral neuropathy. In 1993, Marquez and colleagues performed a retrospective study that showed peripheral neuropathy in 19 out of 800 patients (2%). The patients studied in this retrospective study were referred to a tertiary center for electrodiagnostic testing following initial complaints of neuropathic pain. Additional retrospective studies performed by Lee and colleagues and Tamam and colleagues showed an incidence of 4% and 7% respectively. The incidence in these retrospective studies may be lower because they relied on clinical diagnosis, which may not be as sensitive as electrodiagnostic studies.
The exact quantification of the true incidence of peripheral neuropathy remains a challenge because it requires diagnostic testing at the time of injury and at different intervals during healing, which is time consuming, expensive, and may be uncomfortable for the patient. Additional variables such as TBSA burned and depth of burn injury adds an additional layer of difficulty in assessing the true incidence. Furthermore, neuropathic pain may not be clinically evident because of the comprehensive pain control regimens administered to burn patients.
Onset of disease
Neuropathic pain following burn injuries has been reported to develop as early as the first week of hospitalization. However, other reports have shown nerve compression syndromes developing between 50 and 130 days following the initial injury. Marquez and colleagues postulated that the delay in diagnosis may be related to several factors, including the severity of the medical condition initially, the level of sensitivity to neuropathic pain as the patient recovers from the original burn injury, and the increasing pain experienced when the patients begin to return to their activities of daily living. The second argument is that the compression neuropathy is progressive. Together, identifying neuropathic pain is essential in the early stages in order to appropriately treat patients and minimize the sequelae of long-term pain.
Mononeuropathy, mononeuropathy multiplex, and polyneuropathy
Several factors have been associated with a significantly higher incidence of peripheral neuropathy after burn injury ( Table 2 ). These factors include age more than 20 years, injury resulting in full-thickness burn wounds, and burns involving a surface area of more than 20%. The types of peripheral neuropathy experienced by patients with burns have been further divided into mononeuropathy, mononeuropathy multiplex, and polyneuropathy. The development of the type of neuropathy has been shown to be related to the mechanism of injury, percentage of TBSA injured, and percentage of full-thickness burn.
| Study, Year | Study Type | No. with Peripheral Neuropathy (%) | Diagnostic Criteria | Findings |
|---|---|---|---|---|
| Henderson et al, 1971 | Prospective | 36 of 249 (15) | EMG/NCS | Polyneuropathy was more common in burns >20% TBSA |
| Marquez et al, 1993 | Retrospective | 19 of 800 (2) | Clinical assessment followed by EMG/NCS | Most patients with peripheral neuropathy had multiple nerves affected (3 or more) Of the patients that presented with peripheral neuropathy, 69% were severely burned with TBSA >20%. The number of nerves affected correlated with the full-thickness burn area |
| Khedr et al, 1997 | Prospective | 16 of 55 (29) | EMG/NCS followed by clinical assessment | Mononeuropathy multiplex was diagnosed in 56% of patients. Generalized peripheral neuropathy was noted in 31% of patients Higher prevalence of neuropathy associated with age >20 y, burns involving full-thickness wounds, and TBSA >20% |
| Kowalske et al, 2001 | Retrospective | 64 of 572 (11) | Clinical assessment | Of the patients who presented with peripheral neuropathy, 56 (88%) had mononeuropathy, whereas 18 (28%) had polyneuropathy. Of these, 10 (16%) had both mononeuropathy and polyneuropathy Higher prevalence of neuropathy associated with severe burn injury in patients who were older (>40 y), critically ill, had an electrical injury, or a history of alcohol abuse |
| Lee et al, 2009 | Retrospective | 35 of 868 (4) | Clinical assessment followed by EMG/NCS | Flame injuries and full-thickness burn injuries were most common in patients with peripheral neuropathy |
| Tamam et al, 2013 | Retrospective | 47 of 648 (7) | Clinical assessment followed by EMG/NCS | Of the patients with peripheral neuropathy, 68% had mononeuropathy, whereas 42% had polyneuropathy Most frequent cause of mononeuropathy was low-voltage electrical injury (<1000 V) (50%) |
Mononeuropathy is characterized as weakness and sensory loss that follows a specific peripheral nerve distribution. Marquez and colleagues showed that the incidence of isolated mononeuropathy was 19%. Isolated mononeuropathy is caused by local factors injuring the nerve. Damage to individual nerves or nerve fascicles has been shown to occur iatrogenically through escharotomy, fasciotomy, or multiple intramuscular injections. Injury can also occur from compression by circumferential burns, bulky tight dressings, or HO. Faulty positioning during splinting, forceful exercise, and skeletal suspension have also been shown to cause mononeuropathy. Therefore, it is essential to be meticulous when performing these procedures to minimize the iatrogenic causes intraoperatively and postoperatively.
Electrical burns have also been associated with the development of mononeuropathy. Since electricity follows the path of least resistance and nerves have the least resistance, electrical burns causes the highest incidence of nerve injury. The heat generated by electrical currents can cause direct nerve injury, scar tissue formation around nerves, and neuropathy from postinjury tissue edema. Tamam and colleagues found that 90% of patients with electrical injury presented with mononeuropathy. In a 17-year review of burn unit admissions, permanent nerve injuries were found in 22% of electrocuted patients. The upper limb was most commonly involved, with the median and ulnar nerves most commonly injured.
Mononeuropathy multiplex is the simultaneous malfunction of 2 or more peripheral nerves in separate areas of the body. Mononeuropathy multiplex has been reported as the most common type of peripheral neuropathy, occurring in 56% to 69% of patients with burns. Mononeuropathy multiplex has been shown to be more common in patients who sustained burns involving more than 20% of the TBSA and having greater than 15% full-thickness burns. Patients with more extensive burns were more likely to develop mononeuropathy multiplex.
In contrast, polyneuropathy or generalized peripheral neuropathy is characterized by distal sensory loss and weakness in a symmetric pattern and is least common among patients with burns. In the case of severe burns, the prevalence of peripheral neuropathy has not been shown to exceed 20%. Risk factors for the development of polyneuropathy following burn injury include older age (>40 years) and staying in the intensive care unit for an extended period of time (>20 days). Studies have found that symptoms of peripheral neuropathy often gradually decreased within a few months after the injury.
Mechanism
Pain is processed in a neuronal network, and the interaction between neurons, microglia, and astrocytes is critical for the initiation and maintenance of chronic pain. Activation of glia cells, such as astrocytes and microglia, contributes to that pathogenesis of chronic pain through the interactions between glial cells and neurons. The activation of astrocytes results in the upregulation of nuclear factor-kappa B, extracellular regulated kinase, and Jun N-terminal kinase signaling pathways, whereas the activation of spinal microglial results in the activation of p38 mitogen-activated protein kinase. The activation of these key signaling factors in astrocytes and microglial cells produces proinflammatory cytokines including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), nitric oxide, prostaglandin, and neurotrophins following burn injury. These inflammatory mediators in turn increase cyclooxygenase-2 (COX-2) activity, causing sensitization of peripheral nociceptors and generation of chronic pain.
With respect to the reduction in motor and sensory conduction velocity following burn injury, several animal models have been instrumental in the understanding of the pathophysiology ( Fig. 1 ). In rats, histologic evaluation of nerve fibers following burn injury has shown wallerian degeneration of axons, disintegration of the myelin sheath, and degeneration of the motor end plate. A decrease in the caliber of large axons has been shown with histologic studies. Furthermore, increased platelet aggregation, accelerated fibrin deposition, and clot formation have been shown to occur following burn injury, leading to vascular occlusion of the vasa nervorum. Additional studies have shown that cutaneous burns induce the release of large molecules from damaged epidermal and dermal cells, which increases interstitial oncotic pressure and stimulates fluid loss leading to edema formation. Furthermore, damaged cells secrete inflammatory cytokines that have been shown to activate inflammatory response pathways. Together, these local and systemic reactions have been postulated to effect changes in the conduction velocity of peripheral nerves leading to neuropathy in the short term and long term.
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