VARIOUS CAUSES AND pathologic processes, such as

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1 ORIGINAL ARTICLE Incidence of Nontraumatic Spinal Cord Injury: A Spanish Cohort Study ( ) Maayken E.L. van den Berg, PhD, Juan M. Castellote, MD, PhD, Ignacio Mahillo-Fernandez, MSc, Jesús de Pedro-Cuesta, MD, PhD ABSTRACT. van den Berg MEL, Castellote JM, Mahillo- Fernandez I, Pedro-Cuesta J. Incidence of nontraumatic spinal cord injury: a Spanish cohort study ( ). Arch Phys Med Rehabil 2012;93: Objectives: To assess the incidence of nontraumatic spinal cord injury (SCI) in a determined catchment area in Spain, and to evaluate clinical presentations and trends over time. Design: Retrospective cohort study between January 1972 and December Setting: A hospital with a specialized SCI unit in a delimited health area in Spain. Participants: Hospital inpatients and outpatients with nontraumatic SCI. Interventions: Not applicable. Main Outcome Measures: Age- and sex-specific incidence rates. Results: An adjusted incidence rate of 11.4 per million population was found for this region (12.3 for males, 10.4 for females). A total of 541 cases (53% male) were reported over the 37-year study period. Incidence rates increased with age, with a peak in the 60- to 69-year age group. Tumors were the major cause of SCI. Most of the lesions were at the thoracic level, and C and D were the most frequently observed American Spinal Injury Association grades. Conclusions: Nontraumatic SCI shows a relatively even sex distribution and tends to affect older adults. Injuries are mainly attributable to age-related conditions and result mostly in incomplete lesions, which present with paraplegia. This study revealed that although incidence rates for nontraumatic SCI are similar to those previously reported for traumatic SCI in the same area and during the same period, demographic and clinical characteristics are different. These findings have important implications regarding the delivery of rehabilitation and support services to this group of patients, and suggest the need for health policies that involve improved care and prevention resources. Key Words: Epidemiology; Incidence; Rehabilitation; Spain; Spinal cord injuries, nontraumatic by the American Congress of Rehabilitation Medicine From the National School of Occupational Medicine (van den Berg, Castellote) and National Centre of Epidemiology (Mahillo-Fernandez, Pedro-Cuesta), Carlos III Institute of Health, Madrid; Department of Physical Medicine and Rehabilitation, School of Medicine, Complutense University of Madrid, Madrid (Castellote); and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, (Pedro-Cuesta (CIBERNED)), Madrid, Spain. Supported by grants from the Ministry of Education (grant no. SB ), and the Instituto de Salud Carlos III (grant nos. TPY 1115/07, TPY 1529/07, TPY 1444/08). No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit on the authors or on any organization with which the authors are associated. Correspondence to Juan M. Castellote, MD, PhD, Physical Medicine and Rehabilitation Department, Faculty of Medicine, Universidad Complutense de Madrid, C/Ciudad Universitaria s/n, Madrid, Spain, jmcastel@med.ucm.es. Reprints are not available from the authors /12/ $36.00/0 doi: /j.apmr VARIOUS CAUSES AND pathologic processes, such as tumors and degenerative nervous system diseases, are involved in nontraumatic spinal cord injury (SCI), and consequently, underlying etiologies result in different clinical presentations that have different rates of progression. The pathologic process may progress slowly, as is commonly seen with benign tumors; a stepwise progression with periods of stability is typically seen with the onset of spinal stenosis; cases with disk protrusion are often sudden and acute; and spinal infections may evolve quickly in time. 1-5 The kind and occurrence of secondary complications after nontraumatic SCI are considered to be less severe than after traumatic cases. 6,7 Individuals with nontraumatic SCI account for an important proportion (up to 50%) of the SCI cases admitted to rehabilitation settings. 8,9 However, studies reporting on populationbased epidemiology, demographics, injury damage patterns, and functional outcomes of individuals with SCI have been mainly focused on traumatic SCI, and relatively few studies 1,9-13 of nontraumatic SCI have been done in Europe, hampering the ability to forecast health resource needs. The incidence rate is a measure of the frequency with which a disease occurs in a population during a specific period, and therefore accounts for the spatial variability of the population size instead of the number of cases only. 14 Longitudinal, population-based clinical incidence studies are helpful in determining the magnitude of health problems in the community, predicting burden in the clinical settings, and predicting trends over time. 15,16 Rehabilitation units may benefit from these studies in 2 ways: (1) in resource management and (2) in information dissemination. A recent review 17 on the incidence of SCI worldwide has shown that incidence cases and crude incidence rates, studied during different periods, vary greatly worldwide, from 12.1 to 57.8 SCI cases per million population. To facilitate health care resource management, it seems fundamental to explore trends in incidence rates of nontraumatic SCI, including demographic characteristics, the level and extent of damage, and the etiology. Accordingly, the aim of this study was to provide a full analysis of incidence trends over time, with information on (1) age- and sex-specific incidence rates, (2) neurologic level of injury, (3) functional status, and (4) cause of damage. METHODS Study Population, Geography, and Services Spain has a public health system with 13 specialized SCI units. Because of the decentralization of national health services to its administrative regions, patients are treated and followed up mainly in the region where they live. ASIA SCI List of Abbreviations American Spinal Injury Association spinal cord injury 325

2 326 INCIDENCE OF NONTRAUMATIC SCI IN SPAIN, van den Berg date of birth), date of reported SCI, age at injury, neurologic level of injury, etiology, and severity (paraplegia/tetraplegia) and completeness on the American Spinal Injury Association (ASIA) scale (or previous Frankel scale), when available, at first discharge. ASIA has been referred to as a predictor of motor recovery 19 and late disability. 20 Additionally, age- and sex-specific population data for Aragón for each year from 1972 through 2008 were obtained from the Statistics National Institute, maintained by the government of Spain. 21 To avoid the risk of double counting, identified cases were ordered by sex, age, date of birth, diagnosis with date, and level of injury. Clinicians from the unit were asked for case identification and resolution in case any doubt persisted. Fig 1. Study location map. Average population for Aragón region in study period : 1,201,230. The center from which information was taken for this study (Servet Hospital, Zaragoza) is a tertiary referral hospital in northeastern Spain with a full complement of services such as pediatrics, surgery, and oncology departments. The SCI unit of this center is the only specialized SCI unit that covers the surrounding catchment area of the autonomous community Aragón (fig 1). Health centers in the region may send patients with nontraumatic SCI to that hospital as inpatients or outpatients for follow-up, including external consultation, ambulatory care, or both. If an accident or illness onset occurs outside the region of residence, ultimately the patient is transferred back to the region of residence for follow-up. Data Sources This study was based on information acquired from files and medical records available at the SCI unit of the Servet Hospital. These included information on inpatients and outpatients, and their consults and referrals from other hospital wards. Moreover, to identify those cases not followed up within the SCI unit, hospital archives and central databases were consulted. In addition to computerized identification of cases, classified according to the Minimum Basic Data Set (CIE-9-MC), a manual search of information in the hospital archives was also performed. Inclusion and Exclusion Criteria The following inclusion criteria were applied: (1) acquired and congenital spinal cord lesions of nontraumatic origin; (2) hospitalization between January 1972 and December 2008; and (3) medical care assistance received in Aragón after the acute stabilization period, regardless of the place of diagnosis and immediate care. Cases of nontraumatic SCI were defined as damage to the spinal cord by means other than an external physical force, such as tumors (primary and metastasis), infections, vascular diseases (including aneurysms, arteriovenous malformations, and cord infarctions), congenital disorders (including spina bifida), multiple sclerosis, mechanical diseases (including spinal stenosis, disk degeneration, and spondylosis), and others (including also unknown causes). 18 Individuals with traumatic SCI were excluded. Data Collection Information obtained from the SCI unit and hospital archives included incidence case, patient case demographics (ie, sex and Ethics Ethical approval was provided by the local Health Research Ethics Board at the Carlos III Institute of Health, Madrid, Spain. Statistical Analyses To facilitate detecting trends over time, the studied period was split into 4 decades or subsequent intervals. Incidence rates were calculated for each decade of age. Incidence cases were grouped according to sex, age at time of lesion, and decade. Annual age- and sex-specific incidence rates were calculated with regional population data as denominators, taking the midyear population census for the computation of aggregated data. Finally, crude incidence rates were age- and sex-adjusted to the European population to address the fact that comparability across populations can be hindered by differences in population age distributions. RESULTS A total of 1114 SCI cases of traumatic and nontraumatic origin, which all had received (follow-up) medical care in Aragón, were identified during the 37-year study. Forty-nine cases, after the initial care period, received follow-up care outside the region and were therefore excluded from further analysis. In this study, the 541 cases requiring hospitalization because of nontraumatic SCI are analyzed and presented. Only 1.5% of the identified SCI cases were captured from hospital records not archived in the SCI unit. Those of traumatic origin have been reported elsewhere. 22 Incidence The annual incidence of nontraumatic SCI was 12.1 per million population for the covered period (table 1). Age and sex adjustment to the European population reduced variation across time and led to an annual incidence of 11.4 per million population (12.3 for males, 10.4 for females). During the second period ( ), an increase was observed that, after a temporary decrease during the third period, returned to higher levels in the fourth period ( ). Recent increases correspond to similar trends in the etiologically defined subgroups of tumors, mechanical diseases, and vascular diseases (see table 1). Age and Sex The results showed an approximately equal sex ratio of 1.1:1 in favor of males. Age- and sex-specific incidence rates, as well as number of cases, are displayed in figure 2. Females showed slightly higher rates up to the second decade of life, after which

3 INCIDENCE OF NONTRAUMATIC SCI IN SPAIN, van den Berg 327 Table 1: Incidence and Features of Nontraumatic SCI Cases in Aragón, Spain, Between 1972 and 2008 Incidence and Characteristics Total Nontraumatic SCI incidence* No. of cases Crude incidence rate Adjusted incidence rate Males Females Crude incidence rate by cause* Tumors Mechanical diseases Vascular diseases Other Sex, male (%) Age (y) Males Females Level of injury Cervical 11 (15.3) 50 (26.0) 36 (31.0) 37 (23.0) 134 (24.8) Thoracic 34 (47.2) 68 (35.4) 48 (41.4) 74 (46.0) 224 (41.4) Lumbar 15 (20.8) 39 (20.3) 9 (7.8) 40 (24.8) 103 (19.0) Sacral 3 (4.2) 12 (6.3) 2 (1.7) 6 (3.7) 23 (4.3) Missing data 9 (12.5) 23 (12.0) 21 (18.1) 4 (2.5) 57 (10.5) NOTE. Values are mean SD, n (%), or as otherwise indicated. *Incidence rates per million per year. males were more dominant. Incidences steadily increased with age for both sexes, with the highest case count and rate (29.0/ for males and 25.4/ for females) occurring in the 60- to 69-year age group. As can be seen in table 1, the results showed that the mean age SD increased steadily, from years in the period 1972 through 1980, to years in the last period, 2001 through An increasing proportion of cases after the age of 60 years was observed across time, from 23.6% before 1980 to 57.1% after Etiology As shown in table 1, the most common cause in all periods (with 34.8%) was a tumor, either primary or metastatic. Sex distribution showed a female predominance (56%). The adjusted incidence rate was 3.59 per million population for males Fig 2. Age- and sex-specific incidence rates and number of cases of nontraumatic SCI.

4 328 INCIDENCE OF NONTRAUMATIC SCI IN SPAIN, van den Berg Fig 3. Nontraumatic SCI incidence by cause and age group. Other causes: other and unknown. Mechanical diseases: syringomyelia, spinal stenosis, and disk disease. Vascular diseases: cord infarction, arteriovenous malformation, aneurysm. Abbreviation: MS, multiple sclerosis. and 4.6 for females. The highest incidence was seen at the sixth decade of life (fig 3). When examining trend over time, an increase in incidence of tumoral SCI was observed during the period 1981 through 1990, followed by a decrease during the period 1991 through 2000, and another increase during the last period, 2001 through Other causes were vascular diseases (15.5%), mechanical diseases (17.6%), infections (9.1%), and multiple sclerosis (7.8%) (see fig 3). During the studied decades, cases of SCI caused by vascular diseases (aneurysm, arteriovenous malformation, and cord infarction) increased (see table 1). Mechanical diseases (spinal stenosis and disk disease) causing SCI strongly increased after the third study period (see table 1), in contrast with the proportion of SCI caused by infections, which decreased from the third study decade onwards. Spina bifida as a cause of SCI decreased during the whole study period (infections and spina bifida included in other causes in table 1). Highest incidences for vascular diseases, mechanical diseases, and infections were seen during the seventh decade of life (see fig 3). Clinical Information The most common neurologic levels of injury were T12 (36 cases), T6-8 (in 78 cases), and L4 (27 cases) (fig 4). Table 1 shows that during the whole study period, damage mainly Fig 4. Nontraumatic SCI cases by neurologic level: males versus females. Abbreviation: S, all sacral levels.

5 INCIDENCE OF NONTRAUMATIC SCI IN SPAIN, van den Berg 329 Fig 5. Neurologic impairment of nontraumatic SCI cases: ASIA scores. Frankel scores. Grade A: Absent motor and sensory function. Grade B: Sensation present, absent motor function. Grade C: Sensation present, motor function present but not useful. Grade D: Sensation present, motor function present and useful. Grade E: Normal motor and sensory function. ASIA scores (introduced in 1987). Grade A: Complete: No motor or sensory function is preserved in the sacral segments S4-5. Grade B: Incomplete: Sensory but not motor function is preserved below the neurologic level and includes the sacral segments S4-5. Grade C: Incomplete: Motor function is preserved below the neurologic level, and more than half of key muscles below the neurologic level have a muscle grade less than 3. Grade D: Incomplete: Motor function is preserved below the neurologic level, and at least half of key muscles below the neurologic level have a muscle grade of 3 or more. Grade E: Normal: Motor and sensory function are normal. affected the thoracic region of the spinal cord, followed by the cervical and lumbar levels. Information on ASIA or previous Frankel scoring was available for 28% of the cases in the first decade, 30% in the second, 59% in the third, and 92% of the cases in the last decade. A complete lesion (ASIA grade A) was registered in 9.2% of them. As can been seen in figure 5, grades C and D were most frequently observed, and their prevalence increased over the years, reflecting a trend toward higher functional status at discharge over time. A predominance of grades C and D has also been observed for the most frequent diagnostic group (tumoral SCI). Among those cases in which ASIA status was reported, only 2.8% had a complete tetraplegia and 23.3% an incomplete tetraplegia. The remainder of the reported cases had paraplegia, of which 13.5% were complete and 49.3% incomplete. DISCUSSION This is the first large-scale study describing nontraumatic SCI in the Spanish population, and offers valuable data about clinical presentation and trends over a long period. Results included outcomes such as trends of nontraumatic SCI incidence rates by age and cause during a nearly 40-year period, which have not been identified in previous reports. 1,8,10,11,23-25 A fluctuating trend in adjusted incidence rate was shown, with an overall increase from 6.9 cases per million population in the first studied period, to 13.2 cases per million population in the last period, with a temporary decrease in the third period ( ). Incidence rates increased with age, with a peak in the 60- to 69-year age group. Tumors were the major causes of damage to the spinal cord. Most of the lesions were incomplete and located at the thoracic level. A recent study of New and Sundararajan 25 reported a nontraumatic SCI incidence rate of 26.3 per million population in Victoria, Australia, which is up to twice as high as found in our study during the last period. Also, this rate is more than twice that reported for traumatic SCI in the same Australian region and during the same period. Other rates reported in the literature range from up to cases per million per year, but these studies of nontraumatic SCI have methodological issues that may affect their accuracy, such as the use of a convenience sample instead of case ascertainment of a certain catchment area; the presentation of incidence data without defining the population at risk; the presentation of hospital-based data instead of population-based data; and short study periods. The substantial difference between study results can be partly explained by the current lack of internationally accepted criteria for what etiologies of SCI constitute nontraumatic SCI. To facilitate comparative studies, such criteria should be established. From the figures presented in this study, a national incidence estimate of 704 cases of nontraumatic SCI per year was derived for the whole of Spain. Changes of raw incidence across time did not follow a linear pattern. The lower incidence in the first and third decades, due to different etiologies, may suggest reporting bias. While difficulties in case finding, resulting from the onset period of the SCI unit, likely underlie the first temporary level-down in 1972 through 1980, the second in 1991 through 2000 might be partly due to temporal changes in regional referral patterns or patient flow as a result of changes in an aging population. However, the decrease in incidence remains partly unexplained. New diagnostic and therapeutic techniques related to the main diagnosis, and the recent aging of the Spanish population possibly have both impacted crude rates of age-related conditions, such as tumors, spinal compression, and vascular diseases, during the fourth period ( ). The range of etiologies for nontraumatic SCI found in our study covers the spectrum of conditions previously reported. 8,12,13,28,29 Tumors, including metastases, were the most common cause of spinal cord damage in our study (34.8% of cases). The results showed an increase of tumoral SCI inci-

6 330 INCIDENCE OF NONTRAUMATIC SCI IN SPAIN, van den Berg dence over time. This is not surprising since most patients with tumoral SCI are older than 50 years, 30 and the aging population is rapidly increasing in Spain in association with low birth rates. Like other authors, 7,9,25,31 we found degenerative disk disease, spinal cord stenosis, vascular diseases, and inflammatory conditions to be other major causes of nontraumatic SCI, with increasing frequencies observed after the central decades of life. The etiologies of nontraumatic SCI vary greatly. The diverse specific pattern of etiologies in each study probably reflects differences in the underlying population characteristics, social and geographic factors, and local referral patterns. For this reason, it might not be feasible to generalize our findings to other countries. We have found a fairly even sex distribution in this nontraumatic SCI population, consistent with previous research. 4,7,8,25 In contrast, in the traumatic SCI population in the same catchment area and covered period, incidence rates up to 7 times more common in men than in women have been reported. 17 Age distribution patterns also differed from those reported in traumatic SCI. 22 Contrary to the bimodal distribution, we found a gradual increase in nontraumatic SCI incidence rate with advancing age, similar to the findings of New and Sundararajan. 25 When comparing the present results with those previously reported in traumatic SCI, 22 our findings are consistent with those of McKinley et al 8 who showed that nontraumatic SCI groups are significantly older and contain more women than traumatic SCI groups. The etiology of nontraumatic SCI, generally associated with age-related conditions, may partly account for these differences. As in previous studies, 4,7,8,23,31-33 cases with incomplete lesions were most observed (49.3%), mainly ASIA grades C and D, and their frequencies increased during the studied periods. Although this would suggest less rigorous injury patterns and better functional outcomes for nontraumatic cases when compared with those of traumatic origin, 22 these results should be interpreted with caution. The assessment of changes in functional patterns across time would require detailed knowledge on aspects, such as the selection introduced by a decreased proportion of missing data, changes introduced by the use of the Frankel scale versus the ASIA scale, the time point of evaluation, and the effectiveness of care including rehabilitation. Our results demonstrated that the thoracic spinal cord accounted for most of the lesions. This is consistent with previous data. 4,23,33 Specifically, tumor invasion of the spinal cord has been mainly described in the thoracic region, 34,35 spinal lesions caused by intervertebral disk herniations have been reported mainly in the lumbar segments, 36 spinal lesions after degenerative spinal stenosis are mostly cervical, 37 and likewise, a lumbosacral involvement is more common in vertebral spondylosis. 8 Individuals with nontraumatic SCI generally show better functional scores at discharge compared with those with traumatic SCI, 8,23 although it should be kept in mind that most cases affect middle-aged and elderly people. Additionally, a high proportion of nontraumatic SCI cases are due to tumor or metastasis, with shortened survival expectations. A recent review 38 has shown that survival after nontraumatic SCI is much lower than after traumatic SCI. These differences in severity, causes, and expected survival of the nontraumatic and traumatic SCI populations must be considered when establishing a rehabilitation program for the nontraumatic SCI population. Study Limitations Limitations of this study should be noted. The study used a retrospective design, and related potential biases, such as the probability of missing information, should be considered. The incidence rate in this study, in the low range of incidence rates reported elsewhere, accepts the possibility of cases missed at recruitment. Although the SCI unit studied is the only one in the catchment area, and hospital data have been searched thoroughly, the regional variability in practice and referral pattern in the catchment area could call into question the external validity of the study findings. It is known that regional data provide a less sensitive type of information than that obtained from national registers. However, it should be stressed that to date, this work has been the largest published study on nontraumatic SCI incidence derived from hospital data in Spain. Covering nearly 4 decades, it provides a sample size allowing for a detailed incidence analyses, and exploration of clinical characteristics and epidemiologic trends. In nontraumatic SCI, the inaccuracies of diagnosis and problems with timely identification of cases could be weaknesses for epidemiologic studies. When damage to the spinal cord presents with comorbidities, the clinicians ability to diagnose SCI may be hampered or delayed because of the entanglement of a multiplicity of symptoms. The results presented missing data in both neurologic level of injury and ASIA scoring and to be used as clinical series our material is likely invalid. However, missing data on these variables has not been a handicap for the calculation of incidence rates for decades of age, sex, time of lesion, and causes. CONCLUSIONS This study has presented the incidence of nontraumatic SCI in a geographically defined population in Spain over a time span of 37 years. The results add to the relative small body of literature, confirming observations that nontraumatic SCI represents an important proportion of the SCI population in rehabilitation settings. It affects males and females almost equally, with a peak incidence in the 60- to 69-year age group and increasing incidence rates over time. Most cases presented with an incomplete paraplegia. A substantial proportion of the etiologies are from age-related conditions, such as tumors, mechanical diseases, or vascular problems, and the increase in the aged population ( 65y) expected over the next 20 years worldwide 39 is likely to result in an increased incidence of nontraumatic SCI. 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