Comparative analysis of functional evaluation performed in medullary injury in animals

Abstracts

A avaliação comportamental após, a contusão da medula espinhal, enfocou por um tempo a locomoção em campo aberto usando uma escala de classificação desenvolvida por Tarlov et al.(18). Tarlov(17) realizou estudos experimentais em cães, produzindo compressão medular com atribuição de zero a cinco para graduação dos movimentos do animal. Contudo, esta escala tem sido modificada por pesquisadores e suas alterações feitas por vários grupos tornaram as comparações das medidas do resultado locomotor difíceis. Um aspecto crítico da pesquisa utilizando lesão medular em animais é a padronização da avaliação da recuperação locomotora. A escala desenvolvida por Tator(19) é simples e de fácil utilização, porém pode não analisar todos os aspectos necessários . Basso, Beattie e Bresnahan(2,3) apresentaram uma escala de classificação com índice de recuperação locomotora em ratos que sofreram lesão medular produzida em laboratório. Os dados indicam que a escala BBB é uma medida válida para a recuperação locomotora capaz de distinguir os resultados comportamentais em função de ferimentos diferentes e para prever alterações anatômicas no centro da lesão. O propósito deste estudo foi analisar e comparar escalas de classificação locomotora sem ambigüidade, eficientes e expandida para se padronizar as medidas resultantes nos laboratórios.

Lesão experimental da medula espinhal; Recuperação motora; Trauma

UPDATE ARTICLE

Comparative analysis of functional evaluation performed in medullary injury in animals

Alessandra Iague Molina^I; Alexandre Fogaça Cristante^II; Tarcísio Eloy Pessoa de Barros Filho^III

^IPostgraduate student of São Paulo University - Medical School

^IIDoctor Preceptor of the Orthopedics and Traumatology Department at the General Hospital of the São Paulo University - Medical School

IIIChairman of Orthopedics and Traumatology Institute at the General Hospital of São Paulo University- Medical School

^{Correspondence}

SUMMARY

The behavior evaluation after a spinal medulla injury focused the locomotion in field during a certain time, using a classification scale developed by Tarlov et al.⁽¹⁸⁾. Tarlov⁽¹⁷⁾ performed experimental studies in dogs, producing medullary compression and assigning a graduation from zero to five to the animal movements. However, this scale has been changed by researchers and its changes, made by several groups, became difficult the comparisons of the measures of the locomotor result. One critical aspect of the research with medullary injury in animals is the standardization of the locomotor recovery evaluation. The scale developed by Tator⁽¹⁹⁾ is simple and easy to use but it can't analyze all the necessary aspects.

Basso, Beattie e Bresnahan^(2,3) showed a classification scale with a locomotor recovery level in rats presenting a medullary injury produced in laboratory. The data show that the BBB scale is a valid measure to the locomotor recovery and it makes it possible to distinguish the behavior responses in function of the different wounds and to antecipate the anatomical changes in the center of the injury.

The purpose of the study was the analysis and comparison of locomotor classification scales, without ambiguity, efficient and expanded in order to standardize the final measures in laboratories.

Key words: Spinal medulla experimental injury, Motor recovery, Trauma

INTRODUCTION

An evaluation of the behavior after the spinal medulla injury is necessary to determine the therapeutical effectiveness. The resulting well-defined behavior measures can also identify the potential mechanisms of functional recovery. Several researchers developed tests in order to measure the locomotor and sensorial reflection function in the medullary injury in animals. Such results varied from the simple qualitative descriptions of walking to the elaboration of test combinations intending to detect many demonstrations in CNS (Central Nervous System) function.

Normally, there isn't and agreement about which type of behavior evaluation tool is the most useful or important to describe the functional recovery.

The sensibility of elaborated tests can make them more adequate to detailed investigations of the recovery mechanisms, but in general impracticable for use in pre-clinical tests. Although they are simple to apply, they normally present a limited sensibility because of the reliability regarding the subjective observations. In pre-clinical test use, the ideal evaluation tool would be easy to use, sensible for small details and able to evaluate rapidly in a general way, the motor function in a great number of animals in the experiences.

Allen⁽¹⁾ developed an experimental model to produce medullary injury and qualified the injury as a product weight in gram by the height in centimeters (g/cm). Tarlov⁽¹⁷) and Tarlov et al.⁽¹⁸⁾ performed an experimental study in dogs producing medullary compression and presented a locomotor evaluation method.

Ford⁽¹²⁾ modified the injury method by Allen and performed medullary injury in cats. Wrathall et al^.(22) purposed a protocol to evaluate the functional deficit after a medullary injury produced in rats, as the Tarlov scale wasn't reproduced in a reliable way in other laboratories. The results showed different injury degrees, permitting the classification in light, moderate and severe.

Noble e Wrathall⁽¹⁶⁾ promoted a graduated medullary injury in rats and used one evaluation scale of motor function that was a change of the Tarlov's test.

Basso et al.⁽²⁾ assured that the locomotor recovery studies in rats that presented a medullary injury had followed changes in Tarlov's scale. Some authors assure that the closest to the ideal are the qualitative and semi-qualitative scales, as those ones originally developed by Tarlov et al.⁽¹⁸⁾, and posterior modified by other investigators, for example.

The present study compares a motor evaluation scale for experimental medullary injury as the modified Tarlov's scale that is correlated to the anatomical result and to the physical description of the wound in animals (e.g.: displacement, force, transitory impulse) to the qualitative scale presented by Basso et al.⁽²⁾ aiming to evaluate its sensibility and appliance.

Some observed problems could be a result from the failure in Tarlov's scale in reflecting the functional recovery process in progress in a safer way. The choice of working definitions of locomotor elements should also facilitate the transfer of accurate data among laboratories.

This way, we analyzed these scales trying to compare data in order to obtain a more sensitive and trustful scale in locomotor evaluation of medullary injury in animals.

MATERIAL AND METHODS

Methodology

The applied methodology was the literature review using Bireme source, and the data banks of Medline, Lilacs besides magazines articles. The libraries of the Orthopedics Institute and the Neurology Institute of São Paulo University – Medical School were consulted as well as the library of the Instituto do Coração.

BBB scale sample

A total of 85 female rats (250-300 g) presented medullary contusion and was used to develop or validate the BBB scale. Some rats were used to develop and validate the scale, while other were exclusively used to validation; from the 11 rats presenting light OSU contusions, 6 were used to development and to validation (parameters of severity). The 5-resting rats were only used to validation (parameters of severity, anatomy and change). One Sprague-Dawley rat was killed during the postoperative week in function of the anatomy and a Long-Evans rat died of unknown causes during the eleventh postoperative week.

Surgical Procedures

All the rats underwent surgical procedures in the Ohio State University (OSU). Rapidly, the rats were anesthetized with ketamine (80 mg/kg) and xylazine (10 mg/kg) and these ones received prophylactic antibiotics (gentamicin sulfate 1 mg/kg).

After a medius thoracic laminectomy exposure, segment level of cord T7, T8 or T9, the rats were bruised with OSU Impactor or with the New York University (NYU) Impactor. The groups were mentioned as OSU light, OSU moderate, NYU light and NYU moderate. The NYU Impactor is an electromagnetic device that produces a contusion by displacing the surface of the medulla from a particular distance. In the present study, the spinal medulla was displaced 0,8 or 00,9 mm to produce light contusions and 1,1 mm to moderate contusions.

The NYU Impactor is a device with weight that discharges a nail of 10g from several heights on the open medulla. The movements of the impact nail and the spinal cord are registered by otic potentiometers. For the present study, the nail was dropped from 6,25-mm height for light contusions and from 12,5 mm and 25 mm for moderate contusions. Two rats fell from the spinal tongs with the impact of 12,5 or 25-mm height and the Impactor hit the bone instead of the dura mater; other rat presented contusion from 12,5 mm height. This way, these rats maintained a shorter contusion force in impact and were included in the light category instead of the moderate one.

Presented procedures

Three ambience of field were used in this study: an enclosure in circular metal (106,7 cm of diameter and 61 cm of height), a plastic pool modeled with grooves on the floor (100 cm of diameter and 21 cm of height) and a smaller plastic pool with plain floor. (90 cm of diameter and 7 cm of height). The rats were exposed to the test ambient diary during at least 10 days or twice a day for at least 5 days. Most of the sessions occurred consecutively. Several rats were placed in field once during each 30/60-minute session in order to get used to the movement while they were in field. The pre-tests sessions were continuous until the rats didn't show any sign of fear (running from the examiner, little or no locomotion, frequent urine and feces, vocalization, hair erection).

Tests procedures

Two examiners participate of all field tests and were positioned transversally in order to observe the two sides of the rat. The rats were tested alone for 4 minutes or in pairs for 5 minutes. The experience showed that the 4-minute sessions provide enough time to observe and register the recovery in individual rats with minimum risk of losing key finds. The rats were individually evaluated during the reliability tests among the classifications and the validation of the scale.

During the field tests, the rats were stimulated to move continuously. The rats that stopped during more than 15/20 seconds were incited to move by a pencil, a piece of paper that they should follow

or by slaps or light scratches. If the animal failed in responding to these stimuli, they were caught and placed in the center of the field, what normally forced them to move to the sides. It was taken a special care, avoiding touching the nail and/or the back during the tests because this stimulus appeared to affect the motor performance. In the tests that evaluated pairs of rats, the observation periods lasted more than five minutes to obtain more accurate evaluations on the discharge of toes, feet position or coordination of frontal and posterior members.

In cases where the locomotor performance was limitrophe or in those where there were differences among the examiners, the results that showed the highest deficits were adopted. All posterior members movements were registered except those that obviously were part of a reflection or selected by an examiner or other animal touch. For example, one single reflection observed right after the contusion, therefore not registered as a locomotor component was diminished by the lumbar spine, nail twisting and extensive bilateral flexion of the hip, knee and heel together. This reflection can be a response of the perineal stimulus when the rat threw itself ahead using the frontal members.

Functional Evaluation – Basso, Beatie and Bresnahan (B.B.B.) scale

The BBB scale observes the articulation movements of the hip, knee and ankle, besides the trunk, tail and posterior feet position. From these observations, points from zero to 21 were attributed. The zero corresponded to the total lack of movements and the 21 to the normal presence of movements.

0 – non-observation of movement in posterior members (PM)

1 – soft movement of one or two articulations, normally the hip and/or the knee.

2 – extensive movement of an articulation or extensive movement of an articulation and soft movement of another articulation

3 – extensive movement of two articulations of PM

4 – soft movement of more than three articulations PM

5 – soft movement of two articulations and extensive movement of a third one

6 – extensive movement of two articulations and soft movement of a third one – extensive movement of all the three articulations of PM

7 – wide movement without a support weight or plantar placement of the foot without a support weight.

8 – plantar placement of the foot with a support weight in posture (when stopped) or occasional, frequent or consistent weight support in the dorsal step and no support in plantar step, soft movements without supporting the body weight.

9 – occasional weight support in the plantar step, no SM-PM coordination

10 – constant frequency of weight support in plantar step, no SM-PM coordination

11 – constant frequency of weight support in plantar step and occasional SM of coordination

12 – constant frequency of weight support in the plantar step and frequent SM-PM of coordination

13 – constant weight support in the plantar step, constant SM-PM of coordination

14 – constant plantar step and constant SM-PM with coordination and predominance of feet position in rotation (internal or external) when the initial contact with the surface starts before getting up at the end of the posture or frequent plantar step, constant SM-PM with coordination and occasional dorsal step

15 – constant plantar step constant SM-PM coordinate, no movement of toes or occasional movement of toes during the advance of the following member.

Predominant position of the foot, parallel with the body at the first contact

16 – constant plantar step and constant SM-PM coordination during the walk and free toes. This frequently occurs during the anterior members advance. Predominantly, the feet are parallel at the first contact and rotated when getting up.

17 – constant plantar step and constant SM-PM coordination during the walk, free toes. It frequently occurs during the anterior members advance. feet predominantly in parallel at the first contact and when getting up.

18 – constant plantar step and constant SM-PM coordination during the walk, free toes. It constantly occurs during anterior members advance. feet position predominantly in parallel at the first contact e rotated when getting up.

19 – constant plantar step and constant SM-PM coordination during the walk, free toes. It constantly occurs during the anterior members advance. feet position predominantly in parallel at the first contact and when getting up; the tail remains turned down all the time or almost all te the time.

20 – constant plantar step and constant coordination during the walk, constant free movements of toes, feet position predominantly in parallel at the first contact and when getting up; instability of trunk, nail constantly turned up.

21 – constant plantar step and coordinate walk, constant free movements of feet, feet position predominantly in parallel during the posture, constant trunk stability, tail constantly turned up.

Scale development

To develop the scale, the movement standards the rats presented during the recovery were registered. The soft and moderate groups were tested in pairs for 5 minutes; 42 rats used to develop the scale took part of another study and were verified weekly. One preliminary checklist of several motor standards was elaborated from the knowledge about locomotor recovery and the previous classification scale.

Additional behavior categories were included in this checklist and they became clearer. These categories were the basis to the BBB scale. One classification form was produced in order to attend the BBB scale and provide a fast and accurate description of the locomotor performance, what could be easily translated into a locomotor result. The classification form was organized in three wide sessions representing the initial, intermediate and advanced stages of recovery.

In this form, the examiner moved from left to right while the rats were recovery. This strategy was developed in order to help the examiners to antecipate the behavior categories, understand their observations and avoid losing the transitions from one category to other. The function of each posterior member (right and left) was observed and registered.

Scale validation

The effectiveness of the BBB scale was evaluated through the analysis of the relationship among the locomotor results and the injury size, sensitivity and severe different injuries and the change of the results among the categories. In order to validate the new scale, the results of the rats presenting different gravity wounds in two groups were compared. If the scale were valid, it should distinguish the damaged rats with soft and moderate contusions

The relationship between the injury size and the final results in field were analyzed in a sub-group of injured rats. The cords included in the analysis represented all the rats of this study. Some animals were excluded from the anatomical analyzes in function of premature death, loss of tissue, deeper anatomical investigations or deformation of the cord in the injury region.

The change among the classifiers was tested in 6 classifiers presenting a classification experience in field that varied from the minimum to the extensive one before the training with the BBB scale. This change was measured twice: once after the examiners have finished 49 tests in field with the BBB scale and it was repeated after the registers of 118 tests. During each session, animals representing the initial, intermediate and advanced stages of the recovery were tested.

During the tests sessions among classifiers, the individual investigators registered the results with the rats first in an independent way and after they discussed in pairs and defined a consensus about the results. Therefore, each animal received 6 individual marks and 3 group marks.

Reliability among classifiers

To evaluate the reliability of the classification scale, the results with the same rats elaborated by 6 examiners were compared. The change of classifiers was estimated from the standard deviation of the results presented by the examiners. The change was clearly low, either for the individual modalities or for the groups. The mean change result for the 6 subjects was in the results category limits for each session (session 1: ± 1,084; session 2:± 0,998). The results change of the groups was lower than the individual results and it was diminished by the experience (± 0,874 and ± 0,589 for sessions 1 and 2, respectively).

The mean standard deviations for the individual and group results diminished with the experience in results. Despite the training, however, the individual results were more variable than the group results. In the attendance study, a detailed analyzes of reliability among classifiers was performed from 8 different laboratories.

BBB scale results

The results show that the BBB scale is an easy and sensitive measure of the locomotor recovery that was developed in order to reflect the progressive recovery after the spinal cord contusion. It provides an expanded scale that shows the behavior in initial, intermediate and advanced stages of the recovery. It can be reproduced with confidence in different laboratories.

The relationship between the final performance in field and the quantity of loose tissue was analyzed through the linear regression. Twelve cords in plastic were excluded from the regression analysis due to their extensive degradation. These rats underwent additional anatomical analysis of the detached descending systems. The spinal medulla of an animal from NYU was also excluded due to its shape that was severely distorted when cut providing inaccurate measures of the area. The locomotor results in field for the rats contused by the OSU and NYU Impactors were compared through the change analysis.

The analyzed factors were the wound gravity (soft, moderate), posterior members (right, left) and tests (postoperative weeks) with repeated measurements of the second and third factors. The locomotor results for 3 NYU rats in the soft group were imputed in two points as the rats presented a recovery to a normal condition (result of 21) and were killed two weeks before the other rats in the group.

The postoperative analysis included a test to a simple effect when an important interaction was found besides the students tests and the corrections for the multiple tests. The change among categories in individual and pair results was measured by the standard deviation of the locomotor result that was measured by several examiners.

Tarlov's method

In 1954, Tarlov⁽¹⁷⁾ produced a gradual and acute compression of the spinal medulla and equine tail in dogs.

The experience was made with balloons settled exactly in the middle of the epidural space of the spinal medulla, in the levels T5-T9 introduced through a small laminectomy in T12. The balloons position was verified by X-ray. The balloons were blown in three different sizes.

When it was full, the big balloon was approximately the same size of the medullary canal and produced complete paralysis in all cases (capacity 1 cc). The capacity of the medium balloon was 0.9 cc and it produced complete paralysis in 90% of the dogs.

The small balloon capacity was 0.8 cc and it was blown in soft compression until the complete paralysis and loss of sensitiveness.

To compress the equine tail, an empty balloon was introduced between L7 and S1 and over the extradural in the middle of the vertebra of L5 through a small laminectomy. It was observed that the nervous roots division of the equine tail produced paralysis in lower members – complete paralysis in the ankles and knees but not always complete in the pelvic cavity. Only the big balloons were used to compress the equine tail because the others failed in producing paralysis. The fact is that the lumbar is bigger than the thoracic vertebral canal and the roots in the equine tail are more resistant to the compression by medullary injury; in fact, the small balloons frequently failed in producing paralysis in the feet posterior.

The dogs were tested in intervals during the day; after these intervals, they were evaluated weekly because of the functional reestablishment.

The criterion used to study the motor function of the feet posterior was the following:

0 – no volunteer movement

1 – perceptive movement in articulations

2 – good articular movements but inability to get up

3 – ability to get up and walk

4 – complete recovery

The animals were killed when they were completely recovered or at the moment they had stopped in their recovery course for a long time. Some dogs died before reaching each stage.

Tarlov's scale result

The functional recovery of a medullary injury by compression in dogs depends on the magnitude of the compression force and its length. Although the recovery of the spinal medulla injury can start during the first 5 days after the compression, it is possible that it delays during 30 days after the medullary injury and 59 days after the compression of the equine tail.

The length of the medullary compression is compatible to the longer recovery of the animals – one week or more – what shows a complete loss of motor function and preservation of the pain. When the spinal medulla or the equine tail is compressed, the dogs immediately become irritable, snarl and sometimes defecate, urinate and try to bite.

However, it was observed that some dogs presented complete paralysis of the posterior foot but felt formication on the surface of this member. Ten dogs presented strong pain after the complete paralysis of the posterior members. Studies in control animals showed that the encapsulated tissue caused by the balloons didn't change the spinal medulla.

In his studies, Tator described a new model of medullary injury in rats through the forceps of modified aneurysm that produced a compression force of 180 gr. and providing a localization, force and time of compression control.

Therefore Khan and Griebel et al.⁽¹⁵⁾ compared three techniques of experimental injury: 1) weight drop, b) compression by an aneurysm clip and c) extradural compression with balloon and concluded that the main factor for pathogeny of the medullary injury by the weight drop is mechanical; the use of the forceps of aneurysm and the extradural balloon present mechanical and vascular factors.

Tator et al.⁽¹⁹⁾ performed studies on the neurological recovery results with human patients and compared to the results obtained by Tarlov et al.⁽¹⁸⁾, Wrathall et al.⁽²¹⁾ and Basso et al.^(2,3). According to Tator⁽¹⁹⁾, one of the most notable findings of this experimental study is the clinically significant discovery that the neurological functions can occur with the preservation or recovery of only a small fraction of the axons of the injured region. It was found a good function in skew plain in rats with 10% of preservation of axons corresponding to only 400,000.

Tator's analyses results

The late discoveries on the spinal medulla of adult mammal, of the mother cells that proliferate and the recent methods to increase the axon regeneration show an important significance of the neurological functions after injury in the SNA. The injuries in the spinal medulla can cause innumerous vascular effects that can be divided into systemic and local effects. Investigations have shown that the parallel causes to the vascular system effects and the immediate mechanical damage to the microvascularization of the medulla were followed by secondary injuries of these vessels and this combination produced an ischemia of the spinal medulla that could develop.

DISCUSSION

In the motor scale of Basso et al.⁽²⁾ all the reflection tests (extension of toes, painful stimulus, response of foot posterior, clear in extension and response to the animal ventralization) were performed. The conditions of weight and impact force in the injuries of three different levels (soft, intermediate and advanced) could be determined in a reproductive way due to the high level of sensitiveness. The motor findings and histological results performed in dogs in Tarlov^(16,17)'s research contributed to the development of safer scales. However, it is not possible to evaluate the injuries levels (light, intermediate and advanced) since only the big balloons were used to compress the equine tail while the others failed in producing paralysis, analyzing unsatisfactorily the different levels of the injury.

Tator⁽¹⁹⁾ describes a new experimental model performed in rats with compression by forceps of aneurysm that in spite of having the localization, the force and the time of compression it is not well accepted due to it presents a high level of vascular alteration.

CONCLUSION

Through the provided data analysis it was observed that the experimental model of motor evaluation more accepted is the Basso et al.⁽²⁾'s one therefore it quantifies satisfactorily the recovery of the motor functions in medullary injuries without deviations caused by the observation methodology.

The other studied methods showed technical limitations and physiological responses that interfered negatively in obtaining safe reproductive results in different laboratories.

REFERÊNCIAS BIBLIOGRÁFICAS

Work performed by the Orthopedics and Traumatology Department of São Paulo University Medical School – part of the thesis project to obtain the Master degree.

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Publication Dates

• Publication in this collection
  24 June 2004
• Date of issue
  Mar 2004

History

• Received
  30 June 2003
• Accepted
  16 Feb 2004