Atraumatic Bilateral Acute Compartment Syndrome of the Lower Legs: A Review of the Literature

Bilateral acute compartment syndrome of the legs is a very rare presentation that requires emergency surgical intervention. Atraumatic bilateral cases are almost unheard of in medicine. There is currently no link between compartment syndrome and cognitive impairment or mental health. A systematic literature search was performed in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines using the following keywords in multiple databases: compartment syndrome, atraumatic, spontaneous, bilateral, both, lower leg, acute, compartmental pressure, and fasciotomy. Atraumatic, bilateral, acute, and confirmed compartment syndrome cases were included. In total, 33 cases of atraumatic bilateral acute compartment syndrome (ABACS) were identified, of those 72.7% of cases were males. A form of cognitive impairment was found in 66% of cases. The medical history of the cases included substance abuse (nine patients), mental health illness (seven patients), and hypothyroidism (four patients). Within the reports, there was evidence of a misdiagnosis or delayed management in 19 cases (57.6%). Creatinine kinase (CK) was measured in 28 cases with a mean CK of 110,893 IU/L. Compartment pressure measurements were used in only 12 cases. A total of 29 cases were managed with bilateral four-compartment fasciotomy. This review highlights that ABACS is a condition with high rates of misdiagnosis or delay in treatment. Associations found included patients with cognitive impairment on presentation, mental health conditions, substance misuse, and elevated levels of CK. In addition, this review demonstrates that this condition is less rare than previously thought with serious morbidity and mortality.


Introduction And Background
Acute compartment syndrome is an orthopaedic emergency. If left untreated, it leads to limb ischemia and potentially devastating sequelae including permanent nerve damage and disability, amputation, and death [1,2]. The most common causes of acute compartment syndrome are fractures (open/closed), soft tissue injury, rhabdomyolysis, and vascular impairment. Less commonly, burns, immobility, and infectious myositis can be causes [1,3]. Acute bilateral cases of compartment syndrome are a rare presentation outside the context of trauma or extreme exercise. They can be diagnostically challenging and may be underrecognised, leading to delayed diagnosis and poor outcomes [2].
Compartment syndrome occurs as a result of increased intra-compartmental pressure (ICP) impairing blood circulation to the limb. Blood circulation from high-pressure arteries to low-pressure veins depends upon the arteriovenous (AV) pressure gradient [2]. Increasing the ICP reduces the AV gradient and initially causes a reduction in the drainage of deoxygenated venous blood [2]. This reduction leads to the third spacing of the fluid, further increasing the ICP, resulting in a vicious cycle being established. Continuous increase in the ICP impairs the supply of oxygenated arterial blood to the limb, leading to irreversible ischaemia and necrosis of the muscles and nerves [2].
Diagnosis of compartment syndrome is often clinical, relying on the recognition of pain out of proportion to an apparent injury. Later signs such as paraesthesia, paralysis, or pulselessness typically occur at a stage of irreversible damage [2]. The pain associated with compartment syndrome is severe, out of proportion to the injury, and not relieved by analgesia or loosening of tight casts. On clinical examination, the compartments are often swollen and tense. The pain can be exacerbated by passively stretching the muscles within the compartments. However, these clinical signs require patients to verbalise symptoms which may not be possible in severely unwell or intubated patients [4]. In addition to clinical examination, measuring ICP can aid diagnosis. Normal compartment pressures range from 0 to 8 mmHg, with compartment pressures greater than 30 mmHg being indicative of compartment syndrome and warranting surgical intervention [2].
Despite recognition that compartment syndrome can occur in the absence of trauma, there is limited literature on the topic and even less data exist for acute bilateral atraumatic compartment syndrome (ABACS). In this literature review, we identify some of the main factors associated with this condition to The most frequently occurring medical history of the cases included substance abuse (nine patients), mental health illness (seven patients), and hypothyroidism (four patients). A form of cognitive impairment was noted in 21 (63.6%) cases. Of those, six were under anaesthesia (at the time or recently), six were unconscious, six were intoxicated, and three had some form of mental disturbance.
The most likely causes for ABACS are presented in Figure 3, with the most common causes being related to substance abuse (33%), followed by post-operative, infection, and hormonal (serotonin syndrome, hypothyroid, and psychogenic polydipsia). No cause was identified or mentioned for five cases [9][10][11][12][13] (Figure  3). Within the reports, there was evidence of a misdiagnosis or delayed management in 19 (57.6%) cases ( Table 1). Creatine kinase (CK) was measured in 28 cases, with the mean average CK of 110,893 (IU/L). Compartment pressure was used for diagnosis in 12 (36.4%) cases, with some studies reporting multiple sets of up to eight pressure readings at a time. Due to inconsistency in reporting compartment pressures, it was not possible to provide a representative mean pressure reading.   Not all cases were isolated ABACS; one case had only bilateral anterior compartment syndrome [14], and another case had bilateral anterolateral compartment syndrome of the lower legs [13]. Other cases also had compartment syndrome in other areas of the body. Four cases underwent fasciotomy in one or more thighs as well as both lower legs [12,[15][16][17]. Two other patients required fasciotomy of both forearms [18,19].
In total, 29 out of 33 cases were managed operatively with emergency bilateral fasciotomy. Only two cases were managed conservatively; one showed minimal improvement after stopping medication that was suspected to have caused it [20], and the other required a tibialis posterior transfer procedure to walk without orthotics [21]. Two cases did not contain sufficient information about management.
Associated conditions were reported in 29 cases, two had no other associated conditions [13,22], and two did not have information available [16,23]. The most frequently occurring complications or associated conditions were renal impairment (14 patients), rhabdomyolysis (12 patients), and infection (11 patients) ( Table 2). Two patients required above the knee amputations; one patient had necrotizing fasciitis following a Vibrio vulnificus infection [24], and the other was after a prolonged kneeling [25]. Neither of the two cases reported a delay in diagnosis or management. Two patients died; one with delayed diagnosis after prolonged kneeling [26], and another without delay was likely due to drug abuse [8].  Positional/Alcohol n/a n/a n/a n/a n/a

Discussion
To the authors' knowledge, this is the largest literature review of ABACS to date. A previous study from 2012 identified eight cases published between 1993 and 2009 [9]. Our study identified 15 cases from the same time frame, along with 17 reported in the 12 years since. There are undoubtedly unpublished cases, making this condition more prevalent than previously thought [9]. While still rare, ABACS should be considered a recognised phenomenon and always be included in the differential diagnosis for patients presenting with bilateral leg pain, even in the absence of trauma. Our study has also identified correlated features which can hopefully expedite the diagnosis of this limb-threatening condition.
The most striking finding from our study is the high association with a history of mental health conditions and cognitive impairment. This may be due to the clinical features of the conditions, side effects of medication, or higher rates of substance abuse and associated behavioural factors.
Two patients in our review with known mental health disorders suffered from schizophrenia, which can be associated with hyposensitivity to pain. The cause of this is unknown but has previously been noted in an atypical presentation of compartment syndrome following a tibial fracture [40,41]. Rhabdomyolysis has been recognised as a rare complication of several anti-psychotic medications and is known to be associated with compartment syndrome, with some reporting it in up to 23% of cases [42,43].
The added complication of cognitive impairment makes diagnosis extremely difficult and likely contributes to the high rate of delayed diagnosis in this series. In trauma management, we recognise the difficulty of diagnosing compartment syndrome in moribund patients and have a high index of suspicion because of low thresholds for compartment pressure monitoring [44]. Similarly, a high level of clinical vigilance and continuous monitoring is needed in those with impaired cognitive function if patients are unable to fully cooperate with a clinical examination or clearly articulate their symptoms [45].
Multiple cases in our review highlight the association between intoxication from both alcohol and drug use, resulting in a prolonged state of immobilisation, and the subsequent presentation of compartment syndrome complicated by rhabdomyolysis. Acute alcohol intoxication with prolonged immobilisation is one of the most common causes of rhabdomyolysis [46], and abnormal CK levels are present in almost half of those who attend the emergency department following recreational drug use [47].
Other causes included hypothyroidism [20,21] and rhabdomyolysis secondary to influenza infection [17,19]. The aetiology of hypothyroidism-induced compartment syndrome is not clear, although theories involving the alteration of the synthesis of glycosaminoglycans have been suggested [48]. Direct viral infection of the muscle with influenza causes myositis, resulting in muscle oedema and swelling and subsequent compartment syndrome [49].
Over half of the patients in this review (57.6%) had a delayed or missed diagnosis. A delay of 6-120 hours is known to be associated with high rates of amputation [50,51]. The most common complication from delayed diagnosis in our review was a bilateral peroneal nerve palsy, with 12 (36.4%) patients having varying degrees of long-term impairment ranging from numbness and foot drop and two patients requiring a tendon transfer to improve mobility. Delay in the treatment of compartment syndrome worsens the severity of nerve injury [52].
Measurement of CK may aid in the diagnosis, although it is not currently recommended in the United Kingdom [53]. One study using CK as an adjunctive marker found that levels greater than 4,000 U/L are suggestive of the condition. CK levels in our study were 10 times higher on average, which may be attributed to more extensive damage demonstrated by bilateral symptoms or could be related to increased muscle death from delayed diagnosis [54].
Diagnosing compartment syndrome using clinical findings is challenging as the findings have low sensitivity and positive predictive value and their absence may be more useful to exclude the diagnosis [55]. Among clinicians, there is a wide variation on what constitutes a diagnosis of compartment syndrome based on clinical signs, which can lead to unnecessary operations or potential delays to theatre [56]. In our review, measurement of compartment pressures occurred in 12 (36.4%) cases. Although there are potentially numerous limitations to compartment pressure monitoring [57], many have shown ICP monitoring to be accurate, sensitive, and reliable with various available techniques [44,58]. In cases of diagnostic uncertainty or where the patient is unable to cooperate with the examination, ICP monitoring is important to avoid a delay in diagnosis [44,59].
The greatest limitation of this review is that it was limited to case studies of ABACS; however, we believe this represents the highest level of evidence currently available for this rare presentation. Associations with cognitive impairment and alcohol or drug intoxication need to be clarified with larger studies but may aid clinicians in recognising this life-changing condition. Future research could also assess whether greater use of compartment pressure monitoring and early measurement of CK improves time to diagnosis or reduces morbidity.

Conclusions
ABACS should be considered a recognised phenomenon and always included in the differential diagnosis for patients presenting with bilateral leg pain, even in the absence of trauma. The cases identified were predominantly males approximately 30 years of age. There was also a high prevalence of cognitive impairment in published cases for this condition and many had a background of mental health conditions. Typical presentations include those who have taken or are under the influence of alcohol or other drugs, where a period of a long lie secondary to a comatose state has occurred.
CK is often elevated and can be a useful adjunct in helping to make the diagnosis in case of doubt, although this is not currently part of UK guidelines. More extensive use of ICP monitoring may help reduce delay in diagnosis and treatment in cases where clinical signs are equivocal. Clinicians should be wary about the potential complication of rhabdomyolysis with subsequent renal impairment and should monitor these patients closely. More than half of the patients with ABACS have a delayed diagnosis or misdiagnosis for a condition with high morbidity and mortality; this paper aims to improve the diagnosis moving forward.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.