Sciatica

Earn CME/CE in your profession:


Continuing Education Activity

Sciatica is characterized by excruciating pain and paresthesias in the sciatic nerve distribution or associated lumbosacral nerve root and can severely impact the quality of life of those affected. This course delves into the specifics of sciatica, emphasizing the importance of distinguishing this condition from other low back or radicular leg pain.

Participants will learn about the sciatic nerve's anatomy, motor and sensory functions and the critical differences between inflammatory conditions and direct compression--which have varying implications for diagnosis and treatment.
This course will guide participants through effective strategies for evaluating and managing sciatica. Learners will explore the vital role of the interprofessional team in enhancing care for patients with this condition. By the end of this course, participants will be equipped with the knowledge and skills to effectively diagnose, manage, and improve the lives of patients suffering from sciatica.

Objectives:

  • Identify clinical presentations and symptoms indicative of sciatica, distinguishing it from other sources of low back pain and radicular leg pain.

  • Implement evidence-based interventions and treatment strategies, tailoring them to sciatica's specific characteristics and underlying causes.

  • Apply in-depth knowledge of sciatica's anatomy and etiology to inform diagnostic and therapeutic decision-making.

  • Identify the importance of collaboration and communication among the interprofessional team to educate the patient on the importance of lifestyle changes and physical therapy, which will improve patient outcomes.

Introduction

Sciatica represents a debilitating condition characterized by pain or paresthesias within the sciatic nerve distribution or an associated lumbosacral nerve root. A prevalent misconception often mislabeles any low back pain or radicular leg pain as sciatica. Sciatica entails pain directly resulting from sciatic nerve or root pathology. Comprising nerve roots from L4 to S3, the sciatic nerve, with a diameter of up to 2 cm, stands as the body's largest nerve. Pain associated with sciatica is exacerbated by lumbar spine flexion, twisting, bending, or coughing.

The sciatic nerve plays a pivotal role, providing direct motor function to the hamstrings and lower extremity adductors and indirect motor function to the calf muscles, anterior lower leg muscles, and select intrinsic foot muscles. Furthermore, its terminal branches indirectly contribute to sensation in the posterior and lateral lower leg and the plantar aspect of the foot. Importantly, sciatica predominantly arises from an inflammatory condition, leading to sciatic nerve irritation. Conversely, direct nerve compression results in more pronounced motor dysfunction, necessitating a thorough and prompt diagnostic evaluation if present.[1][2][3]

Etiology

Any condition structurally impacting or compressing the sciatic nerve may cause sciatica symptoms. The most common cause of sciatica is a herniated or bulging lumbar intervertebral disc. In older patients, lumbar spinal stenosis may cause these symptoms as well. Spondylolisthesis or a relative misalignment of one vertebra relative to another may also result in sciatic symptoms. Additionally, lumbar or pelvic muscular spasms or inflammation may impinge a lumbar or sacral nerve root, causing sciatic symptoms. A spinal or paraspinal mass, including malignancy, epidural hematoma, or epidural abscess, may also cause a mass-like effect and sciatica symptoms.[4][5]

Epidemiology

Sciatica has some unique epidemiologic characteristics:[6]

  • There appears to be no gender predominance.
  • Peak incidence occurs in patients in their fourth decade.
  • Lifetime incidence is reported to be between 10% to 40%.
  • An annual incidence of 1% to 5%.
  • No association with body height has been established except in patients aged 50 to 60.
  • It rarely occurs before age 20 unless secondary to trauma.
  • Some studies do suggest a genetic predisposition.
  • Physical activity increases incidence in those with prior sciatic symptoms and decreases in those with no prior symptoms
  • Occupational predisposition has been shown in machine operators, truck drivers, and jobs where workers are subject to physically awkward positions.[6]

Pathophysiology

The sciatic nerve is comprised of the L4 through S3 nerve roots. These nerve roots fuse to create the large sciatic nerve in the pelvic cavity. The sciatic nerve then exits the pelvis through the sciatic foramen posteriorly. After leaving the pelvis, the nerve courses inferior and anterior to the piriformis and posterior to the gemellus superior, gemellus inferior, obturator internus, and quadratus femoris. Then the sciatic nerve enters the posterior thigh and courses through the biceps femoris and terminates at the knee posteriorly in the popliteal fossa, giving rise to the tibial and common fibular nerves. Sciatica symptoms occur when there is pathology anywhere along this course of the nerve. This pathology can be any of the conditions listed in the differential diagnosis.[7]

History and Physical

Patients with sciatica usually experience unilateral pain in the lumbar spine; however, a common characteristic is pain radiating to the ipsilateral affected extremity. Patients may also describe pain or a burning sensation with accompanying paresthesia deep in the buttocks. Less commonly, there is associated ipsilateral leg weakness, where patients may describe the affected leg as "feeling heavy." 

A straight-leg raise has variable sensitivity and specificity and may or may not be present depending on the underlying cause. The straight-leg test is a passive examination where the patient first lies in a relaxed, supine position. The examiner then lifts the leg from the posterior aspect, flexing at the hip joint and keeping the knee in full extension or keeping the leg straight. Typically, pain that is reproduced between 30° to 70° of hip flexion and experienced primarily in the back is likely due to a lumbar disc herniation. Pain and parenthesis felt in the leg are possible due to lateralizing compression of a peripheral nerve. While not absolute, musculoskeletal causes of the pain usually reproduce pain above 70° of flexion and below 30° of flexion.

Further, a straight leg raise (SLR) test is a neurological maneuver performed while examining a patient presenting with lower back pain. This test is conducted with the patient lying supine while keeping the symptomatic leg straight by flexing the quadriceps. The examiner elevates the leg progressively at a slow pace. The test is deemed positive if it reproduces the patient's symptoms (pain and paresthesia) at an angle lower than 70° with radiation below the knee (Lasegue sign). This test is most helpful in diagnosing L4, L5, and S1 radiculopathies. The patient is asked to dorsiflex the foot while the examiner raises the leg (Bragaad sign) to increase the test's sensitivity. When executing the straight leg raise test, the examiner will slightly bend the patient's knee by 20° to 30°, which will lessen the pain. Then, manual pressure is applied in the popliteal fossa. The Bowstring sign is considered positive if it causes the same level of discomfort that the patient feels during a straight leg raise.[8] The Naffziger test involves reproducing pain via coughing.[9]

Another maneuver is the crossed straight leg test, similar to the straight leg raise test but is conducted on the asymptomatic leg instead. The crossed straight leg test is considered positive if the patient reports pain in the symptomatic leg while the asymptomatic leg is at a 40° angle, representing a central disc herniation with severe nerve root irritation. L3 radiculopathy includes weakness of hip adduction, knee extension, and sensory pain in the anteromedial dermatome of the thigh. Ankle dorsiflexion weakness and absent patellar reflex are present in L4 radiculopathy. Hip abduction and big toe extension weakness show L5 radiculopathy. S1 nerve root compression presents as absent ankle reflexes.

Evaluation

Sciatica is a clinical diagnosis, so a thorough history and physical examination are necessary for a complete evaluation and diagnosis. Imaging is initially of little value; if warranted, plain lumbosacral spine films may be evaluated for fracture or spondylolisthesis. A non-contrast computerized tomography scan may evaluate fracture if plain films are negative. Additionally, pain that has been persistent for 6 to 8 weeks and not responding to conservative management should be imaged. In this case, magnetic resonance imaging is the modality of choice. In cases where the neurologic deficit is present, or mass effect is suspected, immediate magnetic resonance imaging is the standard of care in establishing the cause of the pain and ruling out pressing surgical pathology.[10][11]

Treatment / Management

The following recommendations can help patients manage sciatica pain:

Patient Education [12]

  • Use hot or cold packs for comfort and to decrease inflammation
  • Avoid inciting activities or prolonged sitting or standing
  • Practice good, erect posture
  • Engage in exercises to increase core strength
  • Gently stretch the lumbar spine and hamstrings
  • Participate in regular light exercises such as walking, swimming, or aqua-therapy
  • Use of proper lifting techniques

Medical Therapies [13][14]

  • A short course of oral nonsteroidal anti-inflammatory drugs, NSAIDs
  • Opioid and nonopioid analgesics
  • Muscle relaxants
  • Anticonvulsants for neurogenic pain
  • If oral NSAIDs are insufficient, oral corticosteroids may be beneficial
  • Localized corticosteroid injections
  • Spinal manipulation
  • Deep tissue massage may be helpful
  • Physical therapy consultation
  • Surgical evaluation and correction of any structural abnormalities such as disc herniation, epidural hematoma, epidural abscess, or tumor
  • Acupuncture [15]

Differential Diagnosis

A thorough differential list is essential in considering a diagnosis of sciatica and should include the following:

  • Herniated lumbosacral disc
  • Muscle spasm
  • Nerve root impingement
  • Epidural abscess
  • Epidural hematoma
  • Tumor
  • Pott disease, also known as spinal tuberculosis
  • Piriformis syndrome

Piriformis Syndrome

Piriformis syndrome is a specific condition of special mention as this is often misdiagnosed and unrecognized. The piriformis muscle connects the sacral spine to the upper portions of the femur and aids in hip extension and leg rotation. Due to the proximity of the sciatic nerve, any injury or inflammation of the piriformis muscle can cause "sciatica symptoms." Overuse injuries, particularly in runners or other endurance athletes, cause inflammation of the piriformis muscle, and the ensuing symptoms mimic sciatica. Freiberg (forceful internal rotation of the extended thigh) and FAIR (flexion, adduction, internal rotation) maneuvers help diagnose this piriformis syndrome. Patients with overuse injuries tend to have increased pain when applying direct pressure to the piriformis muscle, increased pain when walking up inclines or stairs, and decreased range of motion of the hip joint. Piriformis-specific and hamstring stretches help release this muscle tension and treat this painful condition. Lumbar and sacroiliac manipulation may also prove beneficial for some patients.[16] In addition, rest from the activity causing the pain is helpful.[17]

Herniated Lumbosacral Disc

A careful and thorough neurological examination can help localize the level of lumbar disc herniation if causing radiculopathy. The radiculopathy associated with lumbar disc herniation varies based on the herniation type and the level at which the herniation occurred. In paracentral or lateral herniation, the transversing nerve root is usually affected. A lateral herniation at L4 to L5 would cause L5 radiculopathy. Extreme lateral (far lateral) herniations typically affect the exiting nerve root; far lateral herniation at L4 to L5 would cause L4 radiculopathy. A straight leg raise test at an angle lower than 70° suggests radiculopathies. 

Spondylolisthesis

Spondylolisthesis is commonly classified as one of 5 major etiologies: degenerative, isthmic, traumatic, dysplastic, or pathologic. Forward translation of the vertebrae may cause a spinal canal narrowing at the slip's level. In severe L5/S1 slips, the L5 nerve root is most commonly affected by central and lateral recess stenosis, whereas foraminal stenosis results in L4 nerve root compression. The anteroposterior and lateral plain films and lateral flexion-extension plain films are the standard for the initial diagnosis of spondylolisthesis.[18][19]

Spinal Stenosis

Spinal stenosis is a disease resulting from the narrowing of the vertebral spinal canal and the lateral recesses; this often leads to the compression of the structures within the spinal canal, including the spinal cord, nearby nerve tissue, and cerebrospinal fluid. Multiple factors can lead to the narrowing, including herniation of the nucleus pulposus posteriorly, epidural fat deposition, hypertrophy of the posterior longitudinal ligament or the ligamentum flavum, and hypertrophy of the facet joints. Diagnosis is made through imaging with an extended-release x-ray, computerized tomography, and magnetic resonance imaging.[20][21]

Pott Disease

Back pain in tuberculosis can be related to the active disease (secondary to inflammation), bone destruction, and instability. Rest pain is pathognomonic, and rarely, radicular pain can be the main presenting symptom. Constitutional symptoms, including weight or appetite loss, fever, malaise, and fatigue, are less commonly associated with extrapulmonary tuberculosis than pulmonary disease. The initial compression in tuberculosis is secondary to vertebral body collapse, leading to anterior spinal tract involvement (exaggerated deep tendon reflexes and Babinski sign, further progression to upper motor neuron-type motor deficit). Further, the lateral spinal tracts are progressively involved (with loss of crude touch, pain, and temperature), followed by posterior column deficit (eg, sphincter disturbances and complete sensory loss).[22]

Prognosis

Most cases of sciatica resolve in less than 4 to 6 weeks with no long-term complications, even if no medical therapy is sought. In more severe cases or cases where the neurologic deficit is present, the patient may have a more prolonged recovery course. However, recovery is still excellent. Some studies have shown that poor occupational mechanics, psychological depression, and poor socioeconomic situations lead to an increased chance of chronic, recurrent sciatica.[23]

Complications

Sciatica results from pressure on the sciatic nerve. Complications may develop if measures are not taken to relieve the pressure. Potential complications of unresolved sciatic nerve compression include:

  • Increased pain over time
  • Paresthesias in the affected leg
  • Loss of muscular strength in the affected leg
  • Loss of bowel or bladder function
  • Permanent nerve damage [24]

Consultations

In general, sciatica can be managed conservatively. However, if the spinal mass effect is diagnosed (eg, epidural abscess or epidural hematoma), immediate consultation with a spinal surgeon should be obtained.

Pearls and Other Issues

Clinicians should always look for red flags when evaluating sciatica or patients with low back pain. Simple sciatica is a benign disease, and the presence of red flags would prompt much more consideration of the differential diagnosis to ensure a more serious underlying medical or surgical cause of the back pain is not present. History of intravenous drug abuse is a risk for epidural abscess and seeding of bacteria anywhere in the body (causing endocarditis, cerebral abscess, etc). Additionally, those with human immunodeficiency virus, diabetes, or are in any way immunocompromised have a much higher risk of all infections, and epidural abscess must be considered.

Any history of bowel or bladder incontinence, urinary retention, or lower extremity weakness suggests acute neurologic deficit and should prompt a more aggressive workup. Anticoagulant use is a risk for all sources of bleeding, including epidural abscesses. A history of trauma, malignancy, or tuberculosis may suggest fracture, metastasis, and more severe causes of back pain should be ruled out before making a simple diagnosis of sciatica. Lastly, fevers, night sweats, and chills would not be typical symptoms seen in simple sciatica and thus should prompt further consideration in the workup.

Enhancing Healthcare Team Outcomes

The key to managing sciatica is patient education. There are many causes of sciatica, and the disorder is managed best with an interprofessional team of healthcare professionals that includes clinicians, mid-level practitioners, orthopedic surgeons, osteopaths and chiropractors, physical therapists, neurologists, rehabilitation nurses, and a pain specialist. Unless there is an acute compression of the spinal nerves, most sciatica cases are best managed conservatively. Patients should be encouraged by the clinician and nurse to lose weight, cease smoking, and enroll in a physical therapy program. Bed rest should be limited. For some etiologies, manipulation/manual therapy may be an option. The pharmacist should caution the patient against using prescription-strength medications to avoid dependence and other adverse effects. If opioids are used, the pharmacist should assist the team by ensuring the course is concise and not refilled. Surgery should only be undertaken when conservative methods have failed, but the patient must be educated on the risks of surgery and the potential complications. Finally, even after surgery, participation in regular exercise is essential.[25][26] 

Outcomes

The outcomes of patients with sciatica are difficult to analyze. Every surgical study measures different parameters as good outcomes, so the data are misinterpreted or exaggerated. In general, patients with chronic pain (more than 6 months) have a poorer outcome following surgery than patients with acute pain (less than 6 months). Results from some studies reported a cure rate of more than 75%, but others reported cure rates of less than 50%. There are several newer orthopedic procedures to manage sciatica, and all report success rates of 70% and above in the short term. Irrespective of the short-term result, the majority of patients with sciatica tend to have residual or recurrent pain in the long term. Many continue to be dependent on pain medications, are disabled, and have a poor quality of life.[2][27][28] 


Details

Author

David Davis

Author

Muhammad Taqi

Updated:

1/4/2024 12:30:55 AM

Looking for an easier read?

Click here for a simplified version

References


[1]

Lagerbäck T, Fritzell P, Hägg O, Nordvall D, Lønne G, Solberg TK, Andersen MØ, Eiskjær S, Gehrchen M, Jacobs WC, van Hooff ML, Gerdhem P. Effectiveness of surgery for sciatica with disc herniation is not substantially affected by differences in surgical incidences among three countries: results from the Danish, Swedish and Norwegian spine registries. European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society. 2019 Nov:28(11):2562-2571. doi: 10.1007/s00586-018-5768-9. Epub 2018 Sep 29     [PubMed PMID: 30269234]


[2]

Alrwaily M, Almutiri M, Schneider M. Assessment of variability in traction interventions for patients with low back pain: a systematic review. Chiropractic & manual therapies. 2018:26():35. doi: 10.1186/s12998-018-0205-z. Epub 2018 Sep 17     [PubMed PMID: 30237870]

Level 1 (high-level) evidence

[3]

Hong X, Shi R, Wang YT, Liu L, Bao JP, Wu XT. Lumbar disc herniation treated by microendoscopic discectomy : Prognostic predictors of long-term postoperative outcome. Der Orthopade. 2018 Dec:47(12):993-1002. doi: 10.1007/s00132-018-3624-6. Epub     [PubMed PMID: 30171289]


[4]

Flug JA, Burge A, Melisaratos D, Miller TT, Carrino JA. Post-operative extra-spinal etiologies of sciatic nerve impingement. Skeletal radiology. 2018 Jul:47(7):913-921. doi: 10.1007/s00256-018-2879-7. Epub 2018 Feb 8     [PubMed PMID: 29423723]


[5]

Hicks BL, Lam JC, Varacallo M. Piriformis Syndrome. StatPearls. 2024 Jan:():     [PubMed PMID: 28846222]


[6]

Stafford MA, Peng P, Hill DA. Sciatica: a review of history, epidemiology, pathogenesis, and the role of epidural steroid injection in management. British journal of anaesthesia. 2007 Oct:99(4):461-73     [PubMed PMID: 17704089]


[7]

Delgado-López PD, Rodríguez-Salazar A, Martín-Alonso J, Martín-Velasco V. [Lumbar disc herniation: Natural history, role of physical examination, timing of surgery, treatment options and conflicts of interests]. Neurocirugia (Asturias, Spain). 2017 May-Jun:28(3):124-134. doi: 10.1016/j.neucir.2016.11.004. Epub 2017 Jan 25     [PubMed PMID: 28130015]


[8]

Supik LF, Broom MJ. Sciatic tension signs and lumbar disc herniation. Spine. 1994 May 1:19(9):1066-9     [PubMed PMID: 8029743]


[9]

Vroomen PC, de Krom MC, Knottnerus JA. Consistency of history taking and physical examination in patients with suspected lumbar nerve root involvement. Spine. 2000 Jan:25(1):91-6; discussion 97     [PubMed PMID: 10647166]


[10]

Stynes S, Konstantinou K, Ogollah R, Hay EM, Dunn KM. Clinical diagnostic model for sciatica developed in primary care patients with low back-related leg pain. PloS one. 2018:13(4):e0191852. doi: 10.1371/journal.pone.0191852. Epub 2018 Apr 5     [PubMed PMID: 29621243]


[11]

Ro TH, Edmonds L. Diagnosis and Management of Piriformis Syndrome: A Rare Anatomic Variant Analyzed by Magnetic Resonance Imaging. Journal of clinical imaging science. 2018:8():6. doi: 10.4103/jcis.JCIS_58_17. Epub 2018 Feb 21     [PubMed PMID: 29541492]


[12]

Wheeler AH. Diagnosis and management of low back pain and sciatica. American family physician. 1995 Oct:52(5):1333-41, 1347-8     [PubMed PMID: 7572557]


[13]

Koes BW, van Tulder MW, Peul WC. Diagnosis and treatment of sciatica. BMJ (Clinical research ed.). 2007 Jun 23:334(7607):1313-7     [PubMed PMID: 17585160]


[14]

Ostelo RW. Physiotherapy management of sciatica. Journal of physiotherapy. 2020 Apr:66(2):83-88. doi: 10.1016/j.jphys.2020.03.005. Epub 2020 Apr 11     [PubMed PMID: 32291226]


[15]

Ji M, Wang X, Chen M, Shen Y, Zhang X, Yang J. The Efficacy of Acupuncture for the Treatment of Sciatica: A Systematic Review and Meta-Analysis. Evidence-based complementary and alternative medicine : eCAM. 2015:2015():192808. doi: 10.1155/2015/192808. Epub 2015 Sep 6     [PubMed PMID: 26425130]

Level 1 (high-level) evidence

[16]

Snyder MJ, Hawks MK, Moss DA, Crawford PF 3rd. Integrative Medicine: Manual Therapy. FP essentials. 2021 Jun:505():11-17     [PubMed PMID: 34128626]


[17]

Siddiq MAB. Piriformis Syndrome and Wallet Neuritis: Are They the Same? Cureus. 2018 May 10:10(5):e2606. doi: 10.7759/cureus.2606. Epub 2018 May 10     [PubMed PMID: 30013870]


[18]

Gagnet P, Kern K, Andrews K, Elgafy H, Ebraheim N. Spondylolysis and spondylolisthesis: A review of the literature. Journal of orthopaedics. 2018 Jun:15(2):404-407. doi: 10.1016/j.jor.2018.03.008. Epub 2018 Mar 17     [PubMed PMID: 29881164]


[19]

Chan AK, Sharma V, Robinson LC, Mummaneni PV. Summary of Guidelines for the Treatment of Lumbar Spondylolisthesis. Neurosurgery clinics of North America. 2019 Jul:30(3):353-364. doi: 10.1016/j.nec.2019.02.009. Epub     [PubMed PMID: 31078236]


[20]

Melancia JL, Francisco AF, Antunes JL. Spinal stenosis. Handbook of clinical neurology. 2014:119():541-9. doi: 10.1016/B978-0-7020-4086-3.00035-7. Epub     [PubMed PMID: 24365318]


[21]

Lurie J, Tomkins-Lane C. Management of lumbar spinal stenosis. BMJ (Clinical research ed.). 2016 Jan 4:352():h6234. doi: 10.1136/bmj.h6234. Epub 2016 Jan 4     [PubMed PMID: 26727925]


[22]

Pintor IA, Pereira F, Cavadas S, Lopes P. Pott's disease (tuberculous spondylitis). International journal of mycobacteriology. 2022 Jan-Mar:11(1):113-115. doi: 10.4103/ijmy.ijmy_2_22. Epub     [PubMed PMID: 35295033]


[23]

Tubach F, Beauté J, Leclerc A. Natural history and prognostic indicators of sciatica. Journal of clinical epidemiology. 2004 Feb:57(2):174-9     [PubMed PMID: 15125627]


[24]

Hashemi M, Halabchi F. Changing Concept of Sciatica: A Historical Overview. Iranian Red Crescent medical journal. 2016 Feb:18(2):e21132. doi: 10.5812/ircmj.21132. Epub 2016 Feb 6     [PubMed PMID: 27175300]

Level 3 (low-level) evidence

[25]

Rantonen J, Karppinen J, Vehtari A, Luoto S, Viikari-Juntura E, Hupli M, Malmivaara A, Taimela S. Effectiveness of three interventions for secondary prevention of low back pain in the occupational health setting - a randomised controlled trial with a natural course control. BMC public health. 2018 May 8:18(1):598. doi: 10.1186/s12889-018-5476-8. Epub 2018 May 8     [PubMed PMID: 29739371]

Level 1 (high-level) evidence

[26]

Shiri R, Euro U, Heliövaara M, Hirvensalo M, Husgafvel-Pursiainen K, Karppinen J, Lahti J, Rahkonen O, Raitakari OT, Solovieva S, Yang X, Viikari-Juntura E, Lallukka T. Lifestyle Risk Factors Increase the Risk of Hospitalization for Sciatica: Findings of Four Prospective Cohort Studies. The American journal of medicine. 2017 Dec:130(12):1408-1414.e6. doi: 10.1016/j.amjmed.2017.06.027. Epub 2017 Jul 24     [PubMed PMID: 28750940]


[27]

Lassere MN, Johnson KR, Thom J, Pickard G, Smerdely P. Protocol of the randomised placebo controlled pilot trial of the management of acute sciatica (SCIATICA): a feasibility study. BMJ open. 2018 Jul 5:8(7):e020435. doi: 10.1136/bmjopen-2017-020435. Epub 2018 Jul 5     [PubMed PMID: 29980542]

Level 2 (mid-level) evidence

[28]

Jia H, Lubetkin EI, Barile JP, Horner-Johnson W, DeMichele K, Stark DS, Zack MM, Thompson WW. Quality-adjusted Life Years (QALY) for 15 Chronic Conditions and Combinations of Conditions Among US Adults Aged 65 and Older. Medical care. 2018 Aug:56(8):740-746. doi: 10.1097/MLR.0000000000000943. Epub     [PubMed PMID: 29939910]

Level 2 (mid-level) evidence