Etiology and Pathogenesis Toshihiko Taguchi

Etiology and Pathogenesis

Toshihiko Taguchi

Ossifi cation of the posterior longitudinal ligament (OPLL) in an autopsy case was fi rst described by Tsukimoto [1] in 1960. Since then a number of clinical and pathological studies of this disease have been reported [2–6]. Increased recognition of OPLL led the Ministry of Public Health and Welfare of Japan to appoint, in 1974, a special study group, the Investigation Committee on OPLL, to make extensive studies ranging from basic research to clinical investigation. To date, various systemic and regional factors have been reported concerning the etiology and pathogenesis of OPLL.

The pathogenesis of OPLL has two aspects: the patho- genesis of ossifi cation of the posterior longitudinal liga- ment and the pathogenesis of the myelopathy induced when OPLL compresses the spinal cord. It is not fully understood why the posterior longitudinal ligament becomes ossifi ed, although it is clear that the occur- rence of OPLL has a genetic background [7–11]. This is supported by family studies, twin studies, and HLA haplotype analysis. The pathological gene of OPLL has not yet been identifi ed. Details of the genetic back- ground of OPLL are described in another part of this book.

The occurrence and development of OPLL involve many environmental, systemic, and local factors. One environmental factor is dietary life. An example of a systemic factor is the metabolic or endocrinological background of an individual, and a common local factor is mechanical stress on the cervical spine.

There are racial differences in the incidence of OPLL.

OPLL used to be called a Japanese disease because it was rarely found in other countries. Because of this, one of the causes of OPLL is thought to be life style, espe- cially dietary factors. There are reports that patients with OPLL prefer vegetable protein to animal protein, in comparison with controls [12,13], but this hypothesis has not been confi rmed by well-designed control studies.

The relation between vitamin A and OPLL has been investigated. Tosti and colleagues [14] reported a

patient on long-term vitamin A therapy who had an increased tendency to develop hyperostosis and who developed OPLL. Imamura et al. [15] radiographically evaluated nine patients who were treated with etreti- nate for disorders of keratinization. Five patients showed ossifi cation of the cervical spinal ligament and developed ossifi cation during therapy. It is possible that taking an excess of vitamin A puts one at risk for OPLL, but there is no conclusive proof of this.

A high incidence of OPLL has been reported in patients with metabolic and endocrinological disorders.

Such disorders include derangements in mineral metabolism such as hypoparathyroidism and vitamin D-resistant hypophosphatemic rickets, disturbances in glucose metabolism, and growth hormone secretion or actions.

There have been many studies of the correlation between calcium metabolic abnormality and OPLL.

Patients with OPLL were reported to show an increase in systemic bone mineral density [16]. Bone alkaline phosphatase and osteocalcin also were investigated in OPLL patients [17,18], but the authors of these studies did not reach a defi nite conclusion. Seichi et al. noted that patients with OPLL showed a signifi - cantly low response to the oral calcium tolerance test.

This result suggests that the development of OPLL is associated with decreased intestinal calcium absorption [19].

In an investigation of the relation between OPLL and hypoparathyroidism, Okazaki et al. reported that 9 of 12 patients with hypoparathyroidism were found to have OPLL [20], although there was a case report that a patient with hyperparathyroidism also had OPLL.

There is no general agreement concerning the relation between OPLL and hypoparathyroidism.

Vitamin D-resistant hypophosphatemic rickets [21]

is well known to be associated with OPLL. The occur- rence of OPLL is suspected to be related to a derange- ment in calcium and phosphate metabolism, but the incidence of OPLL combined with vitamin D-resistant hypophosphatemic rickets is obscure because the sample of patients is small. These study results suggest that calcium metabolic abnormality is related to the occurrence and development of OPLL.

Department of Orthopedic Surgery, Yamaguchi University School of Medicine, 1-1 Minami Kogushi, 1-Chome, Ube 755- 8505 , Yamaguchi, Japan

33

34 T. Taguchi

A considerable number of studies have been con- ducted regarding the relation between OPLL and diabetes mellitus. Diabetes mellitus patients have been reported to have a high incidence of OPLL of the cervi- cal spine compared with the general population. Kojima et al. investigated 97 persons found to have OPLL on cervical radiography [22]; they found that more than half of them were obese, and 92% had disturbed glucose metabolism. Similar results were reported by other authors as well [19,20]. Miyamoto [23] reported that 16 % of 74 patients with OPLL had disturbed glucose metabolism. Shingyouchi et al. [24] examined lateral cervical radiographs, 75-g oral glucose tolerance test results, and the bone mass index (BMI) of 4802 Japanese men and found that obesity and glucose intolerance were risk factors for OPLL. A total of 100 patients with OPLL were investigated with regard to indices of glucose metabolism: fasting plasma glucose and serum insulin level, hemoglobin A

level, insulinogenic index. They found that the indices as well as age and BMI correlated with the extent of ossifi cation [25]. The extent of OPLL was not correlated with the fasting plasma glucose or hemoglobin A

level, but it was correlated with age, BMI, and the insulinogenic index. Summarizing these studies, we concluded that diabetes mellitus does not directly take part in osteogenesis, but obesity and dis- turbances in glucose metabolism do induce OPLL.

Acromegaly is sometimes reported to accompany OPLL. There is a possibility that changes in growth hormone secretion or actions infl uence the develop- ment of OPLL [26].

At present, none of these derangements has been directly shown to play a causative role in the develop- ment of OPLL. Hence it is necessary to accumulate evidence that these derangements have such an infl uence.

OPLL is not always related to a clinical symptom.

Observation of the natural course of the disease has revealed that the development of OPLL does not always lead to myelopathy, and some patients have been shown to have OPLL with no symptoms. It is not clear why these persons have no symptoms under chronic com- pression of the spinal cord. Okano et al. [27] reported that 16% of OPLL sufferers without myelopathy eventu- ally develop it. Therefore, physicians should discrimi- nate between persons who have OPLL with no symptoms and OPLL patients with symptoms. Neck trauma is the cause of myelopathy in 13% of persons with OPLL [28].

However, persons with OPLL can reduce the risk to 2%

when they are aware of their OPLL and are careful to avoid neck trauma in daily life [29]. Informed consent concerning the possibility of developing trauma- induced myelopathy may be important for OPLL patients without myelopathy. Families with OPLL patients should be informed about the hereditary nature of this disease. It would be better not to emphasize too

much that OPLL is related to cervical myelopathy, so families with OPLL patients do not feel anxiety about the disease.

There are reports that the occurrence of myelopathy is related directly to the narrowing ratio of the spinal canal by OPLL. Myelopathy always occurs if the nar- rowing ratio is greater than 60% [6], and there is a high risk of myelopathy when the ratio is greater than 50%

[30].

Ono and colleagues [6] reported that Japanese patients with an anteroposterior (AP) dimension of the cervical canal that is decreased by more than 40% on cervical spine fi lms can develop severe spinal cord symptoms. Nishiura et al. showed that 57% of patients with a narrowing ratio greater than 50% developed myelopathy [30], and Kawaguchi et al. [31] reported that some patients exhibit slight symptoms when the AP dimension is decreased by more than 40%. These fi ndings show that cervical myelopathy due to OPLL results not only from static factors but also from dynamic factors. Persons who have discontinuous-type OPLL tend to develop myelopathy more often than persons who have continuous-type OPLL. The discon- tinuous site of OPLL has more movement than continu- ous sites of OPLL, and this movement is a dynamic factor that compresses the spinal cord and induces myelopathy [32].

The pathogenesis of OPLL cannot be fully clarifi ed.

OPLL seems to occur and develop as a result of systemic and regional factors in combination with a genetic abnormality.

References

1 . Tsukimoto H (1960) A case report: autopsy of syndrome of compression of spinal cord owing to ossifi cation within spinal canal of cervical spines (in Japanese). Nihon Geka Hokan (Arch Jpn Chir) 29:1003–1007

2 . Okamoto Y, Yasuma T (1967) Ossifi cation of the posterior longitudinal ligament of cervical spine with or without myelopathy (in Japanese). J Jpn Orthop Assoc 40:

1349 –1360

3 . Onji Y, Akiyam H, Shimomura Y, Ono K, Hukuda S, Mizuno S (1967) Posterior paravertebral ossifi cation causing cervical myelopathy: a report of eighteen cases.

J Bone Joint Surg Am 49:1314–1328

4 . Yamaura I (1975) A clinicopathological study of the ossifying process in the cervical posterior longitudinal ligament (in Japanese). Saigaiigaku (Traumatol Med) 18 :651–662

5 . Tsuyama N (1984) Ossifi cation of the posterior longitudi- nal ligament of the spine. Clin Orthop 184:71–84 6 . Ono K, Ota H, Tada K, Hamada H, Takaoka K (1977)

Ossifi ed posterior longitudinal ligament: a clinicopatho- logic study. Spine 2:126–132

7 . Sakou T, Taketomi E, Matsunaga S, Yamaguchi M,

Sonoda S, Yashiki S (1991) Genetic study of ossifi cation

of the posterior longitudinal ligament in the cervical

Etiology and Pathogenesis 35

spine with human leukocyte antigen haplotype. Spine 6 :1249–1252

8 . Terayam K, Wada K, Ohtsuka K, Tsuyam N, Kurokawa T, Ohtani K, Yamauchi H, Yamaura I, Miura S, Kaneda S, Harata S, Kokubun S, Inoue S, Motegi M, Miyazaki K, Ono K, Kataoka O, Ikata T, Hattori S, Sakou T, Furusho T (1984) Genetic study of the family of patients with ossifi - cation of the posterior longitudinal ligament in the cervi- cal spine (in Japanese). In: Investigation committee 1983 report on the ossifi cation of the spinal ligament. Japanese Ministry of Public Health and Welfare, Tokyo, pp 17–23 9 . Terayam K (1987) Family study of ossifi cation of the pos-

terior longitudinal ligament (in Japanese). In: Investiga- tion committee 1986 report on the ossifi cation of the spinal ligament. Japanese Ministry of Public Health and Welfare, Tokyo, pp 10–11

10 . Terayam K (1989) Genetic study on ossifi cation of the posterior longitudinal ligament of the spine. Spine 14 :1184–1191

11 . Matsunaga S, Sakou T, Taketomi E, Yamaguchi M, Hayasi K, Koga H (1993) Ossifi cation of the spinal ligament and human leukocyte antigen haplotype (in Japanese). Spine Spinal Cord 6:781–785

12 . Musya Y (1990) Etiological study on spinal ligament ossi- fi cation with special reference to dietary habits and serum sex hormones. J Jpn Orthop Assoc 64:1059–1071 13 . Morisu M (1994) Infl uence of foods on the posterior lon-

gitudinal ligament of the cervical spine and serum sex hormone. J Jpn Orthop Assoc 68:1056–1067

14 . Tosti A, Albisinni U, Bettoli V, Merlini L, Lama L (1987) Ossifi cation of the posterior longitudinal ligament associ- ated with etretinate therapy. Dermatologica 175:57–58 15 . Imamura K, Sakou T, Taketomi E, Matsunaga S (1993)

Retinoid induced ossifi cation of the spinal ligament.

Orthop Traumatol 42:1540–1542

16 . Mamada T, Hoshino Y, Ohnishi I, Seichi A, Saita K, Kurokawa T (1994) Bone mineral density in the whole body of patients with the ossifi cation of the posterior lon- gitudinal ligament of the cervical spine (in Japanese).

Seikei Geka (Orthop Surg) 45:1229–1233

17 . Ikeda Y, Goto S, Yamazaki M, Nishogaki H, Nakajima H, Minami N, Ikeda O, Ogasawara A, Moriya H (1997) Study of biochemical markers and bone mineral density in types of ossifi cation of posterior longitudinal ligament of the cervical spine. In: Investigation committee 1996 report on the ossifi cation of the spinal ligament. Japanese Min- istry of Public Health and Welfare, Tokyo, pp 67–70 18 . Tamano K, Ikata T, Katoh S, Takada S (1997) Evaluation

of markers for bone formation in patients with ossifi ca- tion of the spinal ligament. In: Investigation committee 1996 report on the ossifi cation of the spinal ligament.

Japanese Ministry of Public Health and Welfare, Tokyo, pp 90–93

19 . Seichi A, Mamada T, Hoshino Y (1993) Calcium metabo- lism abnormality in OPLL. Seikeigeka (Orthop Surg) 44 :1012–1016

20 . Okazaki T, Takuwa Y, Yamamoto M, Matsumoto T, Igarashi T, Kurokawa T, Ogata E (1984) Ossifi cation of the paravertebral ligaments; a frequent complication of hypoparathyroidism. Metabolism 33:710–713

21 . Kitajima I, Une F, Kuriyama M, Nakashima H, Igata A (1885) Mother and child cases of familial vitamin D resis- tant rickets: pathogenesis of ankylosing spinal hyperosto- sis. J Jpn Soc Intern Med 74:447–451

22 . Kojima H, Tanaka S, Miyaji Y, Watanabe H, Onomura T (1990) A study on physical disposition in cervical OPLL, with special reference to generalized hyperostosis, obesity and glucose intolerance (in Japanese). Central Jpn J Orthop Surg Traumatol 33:2200–2201

23. Miyamoto M, Takemitsu Y, Harada Y (1990) Serum insulin level of patients with ossifi cation of the posterior longitudinal ligament. J East Jpt. Clin Orthop 2 :251–253

24 . Shingyouchi Y, Nagahama A, Niida M (1996) Ligamen- tous ossifi cation of the cervical spine in the late middle- aged Japanese men: its relation to body mass index and glucose metabolism. Spine 21:2474–2478

25 . Akune T, Ogata N, Seichi A, Ohnishi I, Nakamura K, Kawaguchi H (2001) Insulin secretory response is posi- tively associated with the extent of ossifi cation of the pos- terior longitudinal ligament of the spine. J Bone Joint Surg Am 83:1537–1544

26 . Goto K, Yamazaki M, Tagawa M, Goto S, Kon T, Moriya H, Fujimura S (1998) Involvement of insulin-like growth factor I in development of ossifi cation of the posterior longitudinal ligament of the spine. Calcif Tissue Int 62 :158–165

27 . Okano T, Sakou T, Taketomi E, Matsunaga S, Ijiri K, Iwao S (1994) Natural history of ossifi cation of posterior longi- tudinal ligament (in Japanese). J West Jpn Res Soc Spine 20 :83–86

28 . Matsunaga S, Sakoh T, Taketomi E (1993) The natural course of spinal cord symptoms of ossifi cation of the pos- terior longitudinal ligament (in Japanese). Seikeigeka (Orthop Surg) 44:1127–1131

29 . Matsunaga S, Sakou T, Hayashi K, Ishidou Y, Hirotsu M, Komiya S (2002) Trauma-induced myelopathy in patients with ossifi cation of the posterior longitudinal ligament.

J Neurosurg 97:172–175

30 . Nishiura I, Koyama M, Handa H (1994) Clinical study on 182 cases with OPLL. Spine Spinal Cord 7:126–138 31 . Kawaguchi H, Kurokawa T, Machida H, Hoshino Y,

Hirabayashi S, Oonishi G, Katoh M, Mamada T (1991) Roentgenological manifestation of ossifi cation of the pos- terior longitudinal ligament in the cervical spine causing severe spinal canal stenosis: a group comparison with and without marked spinal cord dysfunction (in Japanese).

J Jpn Orthop Assoc 65:173–180

32 . Jayakumar PN, Kolluri VR, Vasudev MK, Srikanth SG

(1996) Ossifi cation of the posterior longitudinal ligament

of the cervical spine in Asian Indians: a multiracial com-

parison. Clin Neurol Neurosurg 98:142–148