title: Pharmacological enhancement of disc diffusion and differentiation of healthy, ageing and degenerated discs : Results from in-vivo serial post-contrast MRI studies in 365 human lumbar discs.
abstract: Degenerative disc disease (DDD) is still a poorly understood phenomenon because of the lack of availability of precise definition of healthy, ageing and degenerated discs. Decreased nutrition is the final common pathway for DDD and the status of the endplate (EP) plays a crucial role in controlling the extent of diffusion, which is the only source of nutrition. The vascular channels in the subchondral plate have muscarinic receptors but the possibility of enhancing diffusion pharmacologically by dilation of these vessels has not been probed. Although it is well accepted that EP damage will affect diffusion and thereby nutrition, there is no described method to quantify the extent of EP damage. Precise definitions with an objective method of differentiating healthy, ageing and degenerated discs on the basis of anatomical integrity of the disc and physiological basis of altered nutrition will be useful. This information is an urgent necessity for better understanding of DDD and also strategizing prevention and treatment. Seven hundred and thirty endplates of 365 lumbar discs from 73 individuals (26 healthy volunteers and 47 patients) with age ranging from 10-64 years were evaluated by pre-contrast and 10 min, 2, 4, 6 and 12 h post contrast MRI after IV injection of 0.3 mmol/kg of Gadodiamide. End plates were classified according to the extent of damage into six grades and an incremental score was given for each category. A total endplate score (TEPS) was derived by adding the EP score of the two endplates for each concerned disc. The base line value (SI(base)) and the signal intensity at particular time periods were used to derive the enhancement percentage for each time period (Enhancement (%) = SI(tp) - SI(base)/SI(base) x 100). The enhancement percentage for each time period, the time for peak enhancement (T-max) and the time intensity curve (TIC) over 12 h were used to study and compare the diffusion characteristics. The differences in pattern of diffusion were obvious visually at 4 h which was categorized into five patterns-Pattern A representing normal diffusion to Pattern E representing a total abnormality in diffusion. Degeneration was classified according to Pfirrmann's grading and this was correlated to the TEPS and the alterations in diffusion patterns. The relationship of TEPS on the increase in DDD was evaluated by a logistic curve and the cut point for severe DDD was found by ROC curve. The influence of the variables of age, level, Modic changes, instability, annulus fibrosis defect (DEBIT), TEPS and diffusion patterns on DDD was analyzed by multiple and stepwise regression analysis. Oral nimodipine study: Additional forty lumbar end-plates from four young healthy volunteers were studied to document the effect of oral nimodipine. Pre-drug diffusion levels were studied by pre and post contrast MRI (0.3 mmol/kg of gadodiamide) at 10 min, 2, 4, 6, 12 and 24 h. Oral nimodipine was administered (30 mg QID) for 5 days and post-contrast MRI studies were performed similarly. Enhancement was calculated at vertebral body-VB; subchondral bone-SCB; Endplate Zone-EPZ and at superior and inferior peripheral nucleus pulposus-PNP and central nucleus pulposus-CNP, using appropriate cursors by a blinded investigator. Paired sample t test and area under curve (AUC) measurements were done.The incidence of disc degeneration had a significant correlation with increasing TEPS (Trend Chi-square, P < 0.01). Only one out of 83 (1.2%) disc had either Pfirrmann Grade IV or V when the score was 4 or below when compared to 34/190 (17.9%) for scores 5-7; 41 of 72 (56.9%) for scores 8-10 and 18 of 20 (90%) for scores 11 and 12 (P < 0.001 for all groups). Pearson's correlation between TEPS and DDD was statistically significant, irrespective of the level of disc or different age groups (r value was above 0.6 and P < 0.01 for all age groups). Logistic curve fit analysis and ROC curve analysis showed that the incidence of DDD increased abruptly when the TEPS crossed six. With a progressive increase of end plate damage, five different patterns of diffusion were visualized. Pattern D and E represented totally altered diffusion pattern questioning the application of biological method of treatment in such situations. Four types of time intensity curves (TIC) were noted which helped to differentiate between healthy, aged and degenerated discs. Multiple and stepwise regression analysis indicated that pattern of disc diffusion and TEPS to be the most significant factors influencing DDD, irrespective of age. Nimodipine increased the average signal intensity for all regions-by 7.6% for VB, 8% for SCB and EPZ and 11% for CNP at all time intervals (P < 0.01 for all cases). Although the increase was high at all time intervals, the maximum increase was at 2 h for VB, SCB and EPZ; 4 h for PNP and 12 h for CNP. It was also interesting that post-nimodipine, the peak signal intensity was attained early, was higher and maintained longer compared to pre-nimodipine values. Our study has helped to establish that EP damage as a crucial event leading to structural failure thereby precipitating DDD. An EP damage score has been devised which had a good correlation to DDD and discs with a score of six and above can be considered 'at risk' for severe DDD. New data on disc diffusion patterns were obtained which may help to differentiate healthy, ageing and degenerated discs in in-vivo conditions. This is also the first study to document an increase in diffusion of human lumbar discs by oral nimodipine and poses interesting possibility of pharmacological enhancement of lumbar disc nutrition.
authors: Department of Orthopaedics and Spine Surgery, Ganga Hospital, Coimbatore 641043, India. sr@gangahospital.com
authors: S
authors: S
authors: Rajasekaran
authors: K
authors: K
authors: Venkatadass
authors: J
authors: J
authors: Naresh Babu
authors: K
authors: K
authors: Ganesh
authors: Ajoy P
authors: AP
authors: Shetty
mesh_terms: D000293:Adolescent; D000328:Adult; D000375:Aging / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002121:Calcium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D002648:Child; D003287:Contrast Media; D004058:Diffusion / Q000187:drug effects; D005260:Female; D019786:Gadolinium DTPA; D006801:Humans; D007403:Intervertebral Disc / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007405:Intervertebral Disc Displacement / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008159:Lumbar Vertebrae / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009553:Nimodipine / Q000494:pharmacology* / Q000627:therapeutic use; D011446:Prospective Studies
chemical_list: D002121:Calcium Channel Blockers; D003287:Contrast Media; D009553:Nimodipine; C064925:gadodiamide; D019786:Gadolinium DTPA