Diffuse Idiopathic Skeletal Hyperostosis (DISH)

    

                                  Dr. KS Dhillon

Introduction

Diffuse idiopathic skeletal hyperostosis (DISH) is also known as Forestier disease. It describes a phenomenon that is characterized by a tendency toward ossification of ligaments. It usually affects the spine [1,2].  Ossification of the longitudinal ligaments, especially the anterior ligaments, of the spine produces a tortuous paravertebral mass anterior to and distinct from the vertebral bodies (fig 1) [3]. When the thoracic anterior longitudinal ligament is ossified, the areas of ossification usually meet without fusion. Motion is actually possible, unlike lumbar vertebral bridging, which is associated with loss of lumbar motion. The zygapophyseal and sacroiliac joints are not involved in DISH. The intervening intervertebral disk space is preserved.

DISH is a phenomenon that is primarily age-related, rather than a disease. It is usually asymptomatic and is discovered incidentally on imaging studies taken for some other reason. Clinical manifestations, such as stiffness and back pain [4], may result from neuropathy or from physical impingement by bony overgrowth. 

There is no cure for DISH. Treatment is symptomatic and empirical. Surgery may be indicated to provide relief of severe symptoms, such as dysphagia or airway obstruction.

Fig 1 

Background

Diffuse idiopathic skeletal hyperostosis (DISH) was first described by Forestier and Rotes-Querol in 1948. They reported nine patients, ranging in age from 50 to 73 years, who suffered from spinal rigidity and had exuberant osteophytes on radiologic studies. The authors termed the condition as senile vertebral ankylosing hyperostosis [5].

DISH is well represented in the paleontologic and zoologic records. It is found in 1-3% of monkeys and baboons, as well as in gorillas, bears, horses, camels, bison, canids, musk oxen, felids, and whales [6,7,8,9,10, 11,12]. DISH was also present in dinosaurs [13,14,15]. It occurs in 15-25% of older mammals.

Pathophysiology

Diffuse idiopathic skeletal hyperostosis (DISH) is characterized by a tendency toward ossification of tendons, ligaments, and joint capsule insertions [16]. DISH is usually a completely asymptomatic phenomenon, with no alterations detectable on history taking or through physical examination.

Etiology

The causes of DISH are unknown. DISH results from calcification of entheses. Higher rates of DISH are seen with age over 50 years, in men compared with women, and in the White population compared with Black [4].  Additional risk factors include [17] :

• Hypertension

• Metabolic syndrome

• Obesity

• Type 2 diabetes mellitus

• Hyperuricemia

A study by Lantsman et al [18] found that abdominal computed tomography showed significantly more visceral adipose tissue, as well as a significantly higher ratio of visceral to subcutaneous adipose tissue, in 43 patients with DISH as compared to 42 controls. The authors also noted that visceral adipose tissue is by itself associated with bone proliferation. They suggested that it is potentially a pathogenic pathway for enthesopathic excessive bone production in DISH.

Epidemiology

In the United States DISH is present in approximately 19% of men and 4% of women older than 50 years [19].

Mori et al [20] carried out a study of 3013 Japanese patients (1261 females and 1752 males) with a mean age of 65 years. The computed tomography based prevalence of thoracic DISH was 8.7%. The posterior longitudinal ligament of the cervical spine is ossified in 2% of Japanese people and in  0.16% of white people [21]. The anterior longitudinal ligament is calcified in 24% of patients who have posterior longitudinal ligament ossification [22].

In the Netherlands, DISH was reported in 17% of individuals [23]. A South African study of patients 40 years of age and older found that the prevalence of DISH in African blacks was 3.8% in men and 4.2% in women. The prevalence increased with increasing age, from 1% in the 40-49 year age group to 13.6% in those over 70 years of age [24].

DISH is present in approximately 19% of men over the age of 50 years but is found in only 4% of women in the same age group. It is uncommon in patients less than 50 years of age and is extremely rare in patients who are younger than 40 years.

A Finnish study [25] revealed the age frequency in Finnish men to be as follows:

40-49 years - 0.3%

50-59 years - 2.7%

60-69 years - 8.4%

70 years or older - 11.2%

The same study showed the age frequency in Finnish women to be as follows:

40-49 years - 0.2%

50-59 years - 1.7%

60-69 years - 4.3%

70 years or older - 6.9%

A study of middle-aged and elderly people in a rural town in Japan identified DISH in 17.5% of the 413 participants. The prevalence of DISH tends to increase with age, from 3.1% in individuals in their 50s to 14.0% in those in their 60s, 24.3% in those in their 70s, and 29.0% in those in their 80s. Besides aging, other independent factors associated with DISH were hypertension, male sex, and elevated body mass index [27].

Prognosis

Patients with DISH have an excellent prognosis. The condition is rarely life-threatening and it causes limited morbidity.

DISH does not appear to be a disease but it appears to be a phenomenon. A double-blind controlled evaluation in which controls and patients with DISH were drawn from the same population revealed no associated pathology. The incidence of arthritis, bursitis, and tendinitis is the same in patients with DISH and in controls. The character of back pain and duration is the same in patients with DISH and in controls. A history of back injury was found to be twice as frequent in control subjects as compared to patients with DISH. Back flexibility was also similar in the two groups.  Patients with DISH who had decreased lumbar spinal motion had a lower incidence of back pain, implying that DISH may have a protective effect [19,27].  One study has shown that DISH may be protective against back pain [28].

Another study showed that people with DISH were more likely to experience physical functional impairment. This included a 1.72-fold increased odds of self-reported difficulty in bending and worse grip strength [29].

A study by Yamada et al [30] involving 1063 patients treated surgically for lumbar spinal stenosis found that reoperations were more frequent in patients with DISH that extended to the lumbar segment. Twenty-two percent of such patients underwent reoperation as compared with 7.3% of patients without lumbar DISH. The authors were of the opinion that the unfavorable outcomes in patients with lumbar DISH may be due to the decreased number of mobile lumbar segments.

Excessive ligamentous calcification can impinge on other structures such as the esophagus. There are reports of stridor and dysphagia in patients with DISH [31,32]. When compression of the larynx occurs patients can develop vocal cord paresis and airway obstruction [33].

Ossification of the posterior longitudinal ligament can impinge on the spinal cord on rare occasions.

Reduced vertebral column flexibility that occurs with DISH predisposes to fractures of the vertebra. Sixty percent of the fractures occur in the cervical spine, 34.5% in the thoracic spine, and 5.5% in the lumbar spine. These fractures result from minor trauma, preoperative and postoperative positioning, or intraoperative maneuvers [3,34,35].  Besides fully ankylosed spines, partially ankylosed spines also are at risk, with fractures occurring adjacent to the fused regions [36]. The risk of fracture increases with the number of ankylosed vertebrae [37].  Obesity is an additional risk factor for fracture [38].  

Clinical Presentation

DISH is usually an asymptomatic phenomenon. It is usually discovered incidentally on imaging studies taken for some other reason.

Clinical manifestations, which may result from neuropathy or from physical impingement by bony overgrowth include [1] :

• Acute monoarticular synovitis

• Limited range of spinal motion

• Polyarticular pain

• Neck/thoracic/lumbar/extremity pain

• Dysphagia [39]

• Increased susceptibility to unstable spinal fractures

• Airway obstruction of varying degrees

If vertebral fusion is quite extensive physical examination will show reduction in the range of spinal motion [40]. Since uniform vertebral involvement is extremely rare, usually there are no relatable findings.

Diagnostic Considerations

Other problems to consider in the differential diagnosis are:

• Hypervitaminosis A

• Retinoids

• Pachydermoperiostosis

• Spondylosis deformans

• Fluorosis

• Osteomalacia

• Acromegaly

• Hypophosphatemia

• Hypoparathyroidism

• Ossified posterior longitudinal ligament (OPLL)

 

Differential Diagnoses

• Ankylosing Spondylitis

• Ankylosing Spondylitis and Undifferentiated Spondyloarthropathy

Laboratory Studies

No laboratory tests are needed. Studies have found that there is no difference between patients with vertebral hyperostosis and control patients for prevalence of diabetes mellitus, and plasma glucose [41,42].

Imaging Studies

DISH involves the thoracic vertebrae in 100% of cases, the lumbar vertebrae in 68-90%, and the cervical vertebrae in 65-78% of the cases. Ligamentous ossification affects both sides of the lumbar vertebral column. Generally, it tends to be unilateral in the human spine.

In the thoracic spine, DISH prominence is seen on the right lateral aspect. This is apparently related to aortic pulsations. The left-sided overgrowth is much reduced, also probably because of the influence of aortic pulsations. There is left-sided prominence in individuals with situs inversus.

The earliest sign of DISH appears to be new bone formation adjacent to the midportion of the vertebral body. Radiologically there is a dense line paralleling the longitudinal axis of the spine but separated by a clearly definable space.

The most commonly used diagnostic criteria for DISH are those set by Resnick and Niwayama [43,44]. The criteria include:

• Calcification and ossification along the ventrolateral aspects of at least four contiguous vertebral bodies. There may or may not be localized pointed excrescences at intervening vertebral body–disk junctions.

• Relative preservation of intervertebral disc height in the involved areas, with the absence of extensive radiographic changes of degenerative disc disease, including vacuum phenomena and vertebral body marginal sclerosis.

• Absence of apophyseal joint bony ankylosis and sacroiliac joint sclerosis, erosion, or intra-articular bony fusion

Julkunen and colleagues [45] also suggested similar criteria as those from Resnick and Niwayama but also included the presence of bridges connecting two vertebral bodies in at least two sites on the thoracic spine. are as follows:

The ligamentous ossification phenomenon is not limited to the spine. Exuberant ossification at sites of tendon, ligamentous, or joint capsule insertion is suggestive of the diagnosis. Such ossification can occur at any site of ligament and perhaps tendon insertion. A study by Slonimsky et al [46] found pelvic enthesopathy on CT to be significantly more prevalent in patients with DISH compared with matched control patients. 

Entheseal reaction at the iliac crest and ischial tuberosities is referred to as pelvic whiskering. It is usually quite exuberant. Such whiskering has been noted in two-thirds of iliac crests studied and in 53% of ischial tuberosities. Entheseal reaction has been noted in 42% of lesser and 36% of greater trochanters of the femur. Enthesial spurs at the site of insertion of the quadriceps into the patella were present in 29% of patients studied. Osseous bridging of the tibia and fibula was noted in 10% of patients. Distal metacarpal and phalangeal capsular hyperostosis was present in 13% of patients with DISH [19].

DISH is associated with greater kyphosis in older men and women. DISH, however, is not significantly associated with a change in kyphosis over 4-5 years. In women followed over 15 years, those with DISH had less progression of kyphosis than those without DISH [47].

In patients with DISH who have experienced low-impact trauma,

whole spine computed tomography (CT) is mandatory. The rigid spinal structure resulting from DISH increases susceptibility to spinal fracture, and radiographs have low specificity for detecting those fractures.

Lantsman et al in their study of 147 patients with verified DISH who presented to the emergency department after low-energy trauma found that there were significantly more acute fractures on whole-spine CT than on radiographs [48].

The authors also found that in 57% of acute fractures, the site of tenderness was not indicative of the fractured spinal segment. Furthermore, two patients with tenderness at the site of one fracture also had asymptomatic distant fractures [48].

Histopathology

Histologic examination of vertebral specimens from patients with DISH shows partial or complete bone bridges. These bridges consist of cortical haversian bone, accompanied by morphological changes in the adjacent intervertebral disc [49]. Ossified tissues in DISH are composed of normal-appearing haversian bone [50].

Treatment

There is no cure for diffuse idiopathic skeletal hyperostosis. Treatment is symptomatic and empirical. The treatment includes the following [2] :

• Anti-inflammatory drugs

• Muscle relaxants

• Physical therapy

• Analgesics

• Sedation

Breathing difficulty treated with nighttime continuous positive airway pressure therapy has been reported [51].

Surgery may be indicated in patients with severe symptoms, such as airway obstruction or dysphagia, that have not responded to conservative treatment [2]. Tracheotomy is the treatment of choice in most cases of DISH-related airway obstruction. Yosimatsu et al [52] reported a case of successful treatment of airway obstruction with careful airway management and surgical osteophytectomy [52].

Conclusion

DISH is a common disease that is usually asymptomatic and is characterized by new bone formation. The etiology remains unknown. In patients with DISH, there are extensive proliferative processes in the musculoskeletal system. DISH pathogenesis is polygenic. It is influenced by the interaction of many gene variants and environmental factors. There are potential disturbances in various genes with different chromosomal localizations and expressions. Molecular studies are required to clarify and verify the diagnostic criteria. Studying the molecular mechanisms involved in the formation of bone along with identifying the genetic markers associated with DISH, can help to discover the ossification pathogenesis of ligaments and tendon attachments. This could lead to targeted and effective therapies.

References

1. Holgate RL, Steyn M. Diffuse idiopathic skeletal hyperostosis: Diagnostic, clinical, and paleopathological considerations. Clin Anat. 2016 Mar 23.

2. Nascimento FA, Gatto LA, Lages RO, Neto HM, Demartini Z, Koppe GL. Diffuse idiopathic skeletal hyperostosis: A review. Surg Neurol Int. 2014. 5 (Suppl 3): S122-5.

3. Westerveld LA, Verlaan JJ, Oner FC. Spinal fractures in patients with ankylosing spinal disorders: a systematic review of the literature on treatment, neurological status and complications. Eur Spine J. 2009 Feb. 18(2):145-56. 

4. Luo TD, Varacallo M. Diffuse Idiopathic Skeletal Hyperostosis (DISH). 2020 Jan.

5. Rotés-Querol J. Clinical manifestations of diffuse idiopathic skeletal hyperostosis (DISH). Br J Rheumatol. 1996 Dec. 35 (12):1193-4.

6. Rothschild BM, Woods R. Old World spondylarthropathy: the gorilla connection. Arthritis Rheum. 1988 Jul. 31(7):934-5. 

7. Ferigolo J. Estudos multidisciplinares. Goncalves de Araujo AJ, Ferreira LF, eds. Non-human Vertebrate Paleopathology. Brazil: Panorama; 1988. 213-34.

8. Bjorkengren AG, Sartoris DJ, Shermis S, et al. Patterns of paravertebral ossification in the prehistoric saber-toothed cat. AJR Am J Roentgenol. 1987 Apr. 148(4):779-82. 

9. McDonald JN, Bartlett CS Jr. An associated musk ox skeleton from Saltville, Virginia. J Vert Paleontol. 1983. 2:453-470.

10. Moodie RL. Studies in Paleopathology: XX. Vertebral lesions in the sabre-tooth, Pleistocene of California, resembling the so-called Myositis Ossificans Progressiva, compared with certain ossifications in the dinosaurs. Ann Med Hist. 1927. 9:91-102.

11. Rothschild BM. Scientifically rigorous reptile and amphibian osseous pathology: Lessons for forensic herpetology from comparative and paleo-pathology. Applied Herpetology. 2008. 10:39-116.

12. Rothschild BM. Skeletal paleopathology of rheumatic diseases: the subprimate connection. McCarty DJ, ed. Arthritis and Allied Conditions. 11th ed. Philadelphia, Pa: Lea and Febiger; 1989. 3-7.

13. Rothschild BM. Diffuse idiopathic skeletal hyperostosis as reflected in the paleontologic record: dinosaurs and early mammals. Semin Arthritis Rheum. 1987 Nov. 17(2):119-25. 

14. Rothschild BM, Berman D. Fusion of caudal vertebrae in late Jurassic sauropods. J Vert Paleontol. 1991. 11(1):29-36.

15. Rothschild BM, Martin LD. Paleopathology: Disease in the Fossil Record. Boca Raton, Fla: CRC Press;. 1993.

16. Fornasier VL, Littlejohn G, Urowitz MB, et al. Spinal entheseal new bone formation: the early changes of spinal diffuse idiopathic skeletal hyperostosis. J Rheumatol. 1983 Dec. 10(6):939-47.

17. Merkel PA. Rheumatic Disease and Endocrinopathies. Klippel JH, Stone JH, Crofford LJ, White PH, eds. Primer on the Rheumatic Diseases. 13th ed. New York: Springer; 2008. 479-83.

18. Dan Lantsman C, Herman A, Verlaan JJ, Stern M, Mader R, Eshed I. Abdominal fat distribution in diffuse idiopathic skeletal hyperostosis and ankylosing spondylitis patients compared to controls. Clin Radiol. 2018 Oct. 73 (10):910.e15-910.e20.

19. Rothschild BM. Diffuse idiopathic skeletal hyperostosis (DISH): misconceptions and reality. Clin Rheumatol. 1985. 4:207-12.

20. Mori K, Kasahara T, Mimura T, Nishizawa K, Nakamura A, Imai S. Prevalence of thoracic diffuse idiopathic skeletal hyperostosis (DISH) in Japanese: Results of chest CT-based cross-sectional study. J Orthop Sci. 2017 Jan. 22 (1):38-42.

21. Ono M, Russell WJ, Kudo S, et al. Ossification of the thoracic posterior longitudinal ligament in a fixed population. Radiological and neurological manifestations. Radiology. 1982 May. 143(2):469-74. 

22. Tsuyama N. Ossification of the posterior longitudinal ligament of the spine. Clin Orthop Relat Res. 1984 Apr. 71-84. 

23. Westerveld LA, van Ufford HM, Verlaan JJ, Oner FC. The prevalence of diffuse idiopathic skeletal hyperostosis in an outpatient population in the Netherlands. J Rheumatol. 2008 Aug. 35(8):1635-8. 

24. Cassim B, Mody GM, Rubin DL. The prevalence of diffuse idiopathic skeletal hyperostosis in African blacks. Br J Rheumatol. 1990 Apr. 29 (2):131-2.

25. Julkunen H, Knekt P, Aromaa A. Spondylosis deformans and diffuse idiopathic skeletal hyperostosis (DISH) in Finland. Scand J Rheumatol. 1981. 10(3):193-203.

26. Uehara M, Takahashi J, Ikegami S, Tokida R, Nishimura H, Sakai N, et al. Prevalence of Diffuse Idiopathic Skeletal Hyperostosis in the General Elderly Population: A Japanese Cohort Survey Randomly Sampled From a Basic Resident Registry. Clin Spine Surg. 2020 Apr. 33 (3):123-127.

27. Schlapbach P, Beyeler C, Gerber NJ, et al. Diffuse idiopathic skeletal hyperostosis (DISH) of the spine: a cause of back pain? A controlled study. Br J Rheumatol. 1989 Aug. 28(4):299-303.

28. Holton KF, Denard PJ, Yoo JU, Kado DM, Barrett-Connor E, Marshall LM. Diffuse Idiopathic Skeletal Hyperostosis and Its Relation to Back Pain Among Older Men: The MrOS Study. Semin Arthritis Rheum. 2011 Mar 3.

29. Katzman WB, Huang MH, Kritz-Silverstein D, Barrett-Connor E, Kado DM. Diffuse Idiopathic Skeletal Hyperostosis (DISH) and Impaired Physical Function: The Rancho Bernardo Study. J Am Geriatr Soc. 2017 Jul. 65 (7):1476-1481.

30. Yamada K, Satoh S, Abe Y, Yanagibashi Y, Hyakumachi T, Masuda T. Diffuse Idiopathic Skeletal Hyperostosis Extended to the Lumbar Segment Is a Risk Factor of Reoperation in Patients Treated Surgically for Lumbar Stenosis. Spine (Phila Pa 1976). 2018 Oct 15. 43 (20):1446-1453.

31. Seidler TO, Pèrez Àlvarez JC, Wonneberger K, Hacki T. Dysphagia caused by ventral osteophytes of the cervical spine: clinical and radiographic findings. Eur Arch Otorhinolaryngol. 2008 Jun 28. 

32. Burduk PK, Wierzchowska M, Grzelalak L, Dalke K, Mierzwinski J. Diffuse idiopathic skeletal hyperostosis inducted stridor and dysphagia. Otolaryngol Pol. 2008. 62(2):138-40. 

33. Kosmidou P, Karamatzanis I, Angelis S, Anagiotos A, Aspris A. Cervical Diffuse Idiopathic Skeletal Hyperostosis: Rare Cause of Emergency Tracheostomy. Cureus. 2022 Jan. 14 (1):e20925.

34. Israel Z, Mosheiff R, Gross E, Muggia-Sullam M, Floman Y. Hyperextension fracture-dislocation of the thoracic spine with paraplegia in a patient with diffuse idiopathic skeletal hyperostosis. J Spinal Disord. 1994 Oct. 7(5):455-7.

35. Königshausen M, Dudda M, Merle C, Schildhauer TA, Fehmer T. Thoracic vertebral body fracture after total hip replacement in diffuse idiopathic skeletal hyperostosis. Orthopedics. 2012 Jun. 35(6):e1000-4. 

36. Paley D, Schwartz M, Cooper P, Harris WR, Levine AM. Fractures of the spine in diffuse idiopathic skeletal hyperostosis. Clin Orthop Relat Res. 1991 Jun. 22-32. 

37. Hendrix RW, Melany M, Miller F, Rogers LF. Fracture of the spine in patients with ankylosis due to diffuse skeletal hyperostosis: clinical and imaging findings. AJR Am J Roentgenol. 1994 Apr. 162(4):899-904.

38. Matejka J. [Hyperextension injuries of the thoracolumbar spine]. Zentralbl Chir. 2006 Feb. 131(1):75-9.

39. Kaffel D, Kchir H. Dysphagia related to diffuse idiopathic skeletal hyperostosis (DISHphagia). Clin Case Rep. 2019 Nov. 7 (11):2265-2266.

40. Olivieri I, D'Angelo S, Cutro MS, Padula A, Peruz G, Montaruli M, et al. Diffuse idiopathic skeletal hyperostosis may give the typical postural abnormalities of advanced ankylosing spondylitis. Rheumatology (Oxford). 2007 Nov. 46(11):1709-11. 

41. Mader R, Novofestovski I, Adawi M, Lavi I. Metabolic Syndrome and Cardiovascular Risk in Patients with Diffuse Idiopathic Skeletal Hyperostosis. Semin Arthritis Rheum. 2008 Feb 25. 

42. Daragon A, Mejjad O, Czernichow P, et al. Vertebral hyperostosis and diabetes mellitus: a case-control study. Ann Rheum Dis. 1995 May. 54(5):375-8.

43. Resnick D, Niwayama G. Diagnosis of Bone and Joint Disorders. 2nd ed. Philadelphia PA: WB Saunders; 1563-615.

44. Oudkerk SF, de Jong PA, Attrach M, Luijkx T, Buckens CF, Mali WP, et al. Diagnosis of diffuse idiopathic skeletal hyperostosis with chest computed tomography: inter-observer agreement. Eur Radiol. 2017 Jan. 27 (1):188-194.

45. Yunoki M, Suzuki K, Uneda A, Okubo S, Hirashita K, Yoshino K. The Importance of Recognizing Diffuse Idiopathic Skeletal Hyperostosis for Neurosurgeons: A Review. Neurol Med Chir (Tokyo). 2016 Mar 28.

46. Slonimsky E, Leibushor N, Aharoni D, Lidar M, Eshed I. Pelvic enthesopathy on CT is significantly more prevalent in patients with diffuse idiopathic skeletal hyperostosis (DISH) compared with matched control patients. Clin Rheumatol. 2016 Jul. 35 (7):1823-7.

47. Katzman WB, Parimi N, Mansoori Z, Nardo L, Kado DM, Cawthon PM, et al. Cross-Sectional and Longitudinal Associations of Diffuse Idiopathic Skeletal Hyperostosis and Thoracic Kyphosis in Older Men and Women. Arthritis Care Res (Hoboken). 2017 Aug. 69 (8): 1245-1252.

48. Lantsman CD, Barkay G, Friedlander A, Barbi M, Stern M, Eshed I. Whole Spine CT Scan for the Detection of Acute Spinal Fractures in Diffuse Idiopathic Skeletal Hyperostosis Patients Who Sustained Low-energy Trauma. Spine (Phila Pa 1976). 2020 Apr 23.

49. Kuperus JS, Westerveld LA, Rutges JA, Alblas J, van Rijen MH, Bleys RL, et al. Histological characteristics of diffuse idiopathic skeletal hyperostosis. J Orthop Res. 2016 Apr 21. 

50. Seawright AA, English PB, Gartner RJ. Hypervitaminosis A and hyperostosis of the cat. Nature. 1965 Jun 12. 206(989):1171-2.

51. Dell'Era V, Garzaro M, Farri F, Gorris C, Rosa MS, Toso A, et al. Respiratory presentation of diffuse idiopathic skeletal hyperostosis (DISH): Management and review of the literature. Cranio. 2022 Jan. 40 (1):88-91.

52. Yoshimatsu Y, Tobino K, Maeda K, Kubota K, Haruta Y, Adachi H, et al. Management of Airway Obstruction due to Diffuse Idiopathic Skeletal Hyperostosis in the Cervical Spine: A Case Report and Literature Review. Intern Med. 2018 Aug 24.