BRAIN INJURY,

1998,

VOL.

12,

NO .

9, 805 808

Female TBI patients recover better than males

Z EEV G RO SW A SSER, M AR IO CO H EN and OFER KEREN
Department of Brain Injury Rehabilitation, Loewenstein Rehabilitation Hospital Raanana, Israel and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel (Received 25 February 1998; accepted 8 April 1998 ) The purpose of the present study was to look at possible gender differences in outcome after severe traumatic brain injury. Three hundred and thirty four consecutive patients, 72 females and 262 males, age range 5 65 years, were included in the study. Age range and severity of injury, evaluated by duration of unconsciousness, did not differ between male and female patients. Predicted outcome at the time of discharge from an in-patient rehabilitation programme was evaluated according to work capacity. Female TBI patients had a better predicted outcome (p < 0 . 015). It is suggested that progesterone, acting as a neuroprotective agent, may explain this difference in outcome.

Introd uctio n Clinicians are often puzzled by differences in outcome of traumatic brain injured (TBI) patients suffering from trauma which seems to be of almost similar severity. The possible influence of existing genetic differences on outcome following TBI was recently pointed out by Teasdale et al. [1] who described the influence of the presence of Apoe e4 allele on outcome after TBI. An overlooked genetic parameter regarding outcome after traumatic brain injury is the gender of the patient. Differences in outcome between male and female TBI patients were not described in the past, most probably because male TBI patients outnumber females by 3 : 1 in most if not all series describing outcome after TBI. The series are therefore not large enough to pick up large numbers of female patients in order to provide reliable statistical analysis. P a tien ts a nd m ethod s All 334 consecutive patients in the age group of 5 65 years who were referred for in-patient rehabilitation during a period of 5 years were included in the study. Male/female ratio in the present study was 3 . 63 : 1 and the total number of female patients was 72 (33.8% ). No age differences were noted between male and female patients and the severity of injury, evaluated by duration of unconsciousness, was similar for both groups. Predicted outcome was determined at the time of discharge. Outcome was determined by the ability to return to school for patients under 18 years of age and for adults by return to work. Young patients returning to the pre-trauma school
Correspondence to: Zeev Groswasser, MD, MPH, Department of Brain Injury Rehabilitation, Loewenstein Rehabilitation Hospital Raanana, 278 Achuza St, PO Box 3, Raanana 43100, Israel Present address: Alyn Hospital, Jerusalem, Israel.
0269 9052/98 $12 00

1998 Taylor & Francis Ltd.

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Table 1.

Z. Groswasser et al.
Predicted outcome of TBI patients: comparison between females and males
Sheltered conditions n %

Working in open market Previous level n % Lower level n % Unemployable n % n Total %

Males Females Total

79 34 113

30.2 69.7 47.2 30.3 33.8

113 23 136

43.1 83.1 31.9 16.9 40.7

42 13 55

16.0 76.4 18.1 25.6 16.5

28 2 30

10.7 93.3 2.8 6.7 9.0

262 72 334

78.4 21.6 100.0

p < 0. 015 (Chi square).

classes were grouped together with patients returning to their pre-trauma working level (gainful employment, previous level); those returning to normal classes but in need of extra tuition were grouped with adult patients able to work in the open market but at a lower level in comparison to their pre-morbid employment (gainful employment, lower level). Patients able to return to only special education systems were grouped together with adults able to work under sheltered conditions (nongainful work sheltered conditions). Children unable to attend any kind of school system were grouped with patients classified as unemployable. Adult female patients who were housewives prior to injury, were evaluated according to the sam e functional lines, i.e. those able to resume their full responsibilities were classified as `working in the open market at their previous level; those resuming most duties were grouped under `working in the open market at a lower level; those being at home with just a minor role were classified as `sheltered conditions.

Res ults Functional outcome was significantly better for female TBI patients (p comparison to male patients as shown in table 1.

< 0 . 016) in

D is c us s io n Female TBI patients were found to have a better predicted functional outcome at the time of discharge from an in-patient rehabilitation programme. It is well know that the actual outcome found at a later stage while the patient is in the community differs from the predicted one [2]. Psychosocial factors influence to a large extent the late outcome while the predicted one at the time of discharge is more closely linked to biological factors. A possible explanation for this difference in outcome may reside in the different organization of brain functions in males and females [3]. However, as all female patients in the present series suffered from blunt head trauma leading to diffuse axonal injury, and although a detailed study of the focal lesions was not performed, it seems unlikely, in view of the relatively large number of patients in the series, that this factor is playing a role in determining outcome.

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807

Experimental evidence showing the beneficial effect of progesterone on outcome was provided in recent years. Recovery was better in female rats, subjected to ablation of the medial frontal cortex, under high progesterone conditions than in normal cycling female rats [4]. Contusion model experiments in female rats, which are more similar to human blunt head injury causing diffuse axonal injury, showed that under high progesterone conditions (pseudopregnancy) female rats showed no evidence of brain oedema in the lesion area, indicating that endogenous levels of progesterone were sufficient to protect the brain [5]. Progesterone treatment given to male rats prior to experimental injury reduced oedema and improved functional recovery [6]. Protective effect of progesterone was shown in experiments during which progesterone was given after inducing brain lesion [7]. The experimental findings may support the clinical observation that female patients, most of them injured during the productive phase of their life, do recover better than male patients. It may be that progesterone plays a role in this phenomenon. The finding that 10 year survival of female patients suffering from carcinoma of the breast, operated during the second phase of the menstrual cycle, was higher than in patients operated during the first phase should be noted in relation to the possible protective role of progesterone [8]. Describing the role of progesterone as a CNS protector is beyond the scope of this paper. However, it should be mentioned that progesterone was shown to induce a protective effect on the brain as it counteracts the known devastating effect of excitatory amino acids like glutamate, released from neurons and glial cells post-injury, by probably up-regulating GABA or GABA receptors [9, 10]; it may well act against the vasogenic oedema caused by free radicals induced lipid peroxidation [11, 12]. The experimental findings support the clinical observation that female TBI patients do recover better than male patients, probably due to the beneficial effect of progesterone. It may well be of use to record in the anamnesis of female TBI patients the exact day of the menstrual cycle in order to determine if there is a difference in outcome in relation to the phase of the menstrual cycle. The finding may also call for future well designed clinical trials administrating progesterone at the immediate post-traumatic phase in order to evaluate its usefulness as a neuroprotective agent in humans.

Referenc es
1. TEASDALE , G. M., N ICOLL , J. A. R., M URRA Y , G. et al.: Association of apolipoprotein E polymorphism with outcome after head injury. Lancet, 350: 1069 1071, 1997. 2. N AJ ENSON, T., GROSWA SSER, Z., M ENDELSON , L. et al.: Rehabilitation outcome of brain damaged patients after severe head injury. International Rehabilitation Medicine, 2: 17 22, 1980. 3. K IMURA , D. : Are mens and womens brains really different? Canadian Psychology, 28: 133 147, 1987. 4. A TELLA , M. J., N A TTINVILLE, A. and S TEIN D. G.: Hormonal state affects recovery from frontal cortex lesions in adult female rats. Behavioral and Neural Biology, 48: 352 367, 1987. 5. R OOF, R. L., D UVDEVANI , R., B RASW ELL , L. et al.: progesterone treatment attenuated brain edema following contusions in male and female rats. Restorative Neurology and Neuroscience, 4: 425 427, 1992. 6. R OOF, R. L., D UVDEVA NI , R., B RASWELL , L. et al.: Progesterone facilitates cognitive recovery and reduces secondary neural loss caused by cortical contusion injury in male rats. Experimental neurology, 129: 64 69, 1994.

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7. R OOF, R. L., D UVDEVA NI , R., HEYBURN, J. W. et al.: Progesterone rapidly decreases brain edema: treatment delayed up to 24 hours is still effective. Experimental Neurology, 138: 246 251, 1996. 8. B A DW E, R. A., GREGORY , W. M., CHAUDRA Y , M. A. et al.: Timing of surgery during menstrual cycle and survival of premenopausal women with operable breast cancer. Lancet, 337: 1261 1264, 1991. 9. S MITH , S. S. : Progesterone administration attenuates excitatory amino acids responses of cerebellar Purkinje cells. Neuroscience, 42: 309 320, 1991. 10. S MITH , S. S. : Female sex steroids hormones: from receptors to network performance actions on the sensory system. Progress in Neurobiology, 44: 55 88, 1994. 11. B RAUGHLER, J. M. and HA LL , E. D. : Involvement of lipid peroxidation in CNS injury. Journal of Neurotrauma , 9: 1 7, 1992. 12. R OOF, R. L., HOFFMAN, S. W. and S TEIN, D. : Progesterone protects against lipid peroxidation following traumatic brain injury in rats. Molecular and Chemical Neuropathology, 31: 1 11, 1997.