This study evaluates the neuroprotective effects of geranylgeranylacetone (GGA), which is known as an antiulcer agent and more recently as a heat-shock and other neuroprotective protein inducer,on secondary degeneration after spinal cord injury in rats. Crush injuries were produced at the T8 level using an extradural approach. Optimal administration conditions of GGA were established in an initial experiment by evaluating the appearance of lesions 24 hours after injury in sections stained with H-E. Then, in a second experiment, animals treated with the optimal condition (600 mg/kg, 24 hours before injury and thereafter every 24 hours) were allowed to survive for 6 and 24 hours and 1, 3, and 8 weeks after injury, and spinal cords were prepared for histological evaluation by staining for H-E for general histopathology and by silver staining for axons. There was a significant reduction (46%) in lesion volume 24 hours after injury in animals treated with optimal administration conditions. The increase in tumor necrosis factor-α (TNF-α) and the accumulation of neutrophils in the damaged segment of the spinal cord 4 hours after injury were significantly inhibited in animals that received GGA. Lesion size and cavitation area remained smaller in treated animals throughout the post-injury survival interval. These results suggest that GGA administration significantly reduces the secondary degeneration that would otherwise occur. The mechanism by which GGA exerts its beneficial effect is unknown but may involve reduction of TNF-α activation at the injured cord and/or inhibition of inflammation.
Cerebral ischemia has been believed to be an important mechanism of secondary neuronal injury in traumatic brain injury (TBI). In this study, we performed 15O2-positron emission tomography (PET) studies to measure the cerebral blood flow (CBF) and oxygen metabolism (CMRO2) in pericontusional region in a total of 15 patients (11 male, 4 female, aged 15 – 81 years) who sustained TBI with contusional hematoma. PET studies were performed a mean of 13.5 ± 9.1 days (range 2 – 33 days) after TBI occurred. The areas of pericontusional tissues located 10 mm away from cerebral contusion exhibited mildly decreased CBF (89%) and severely suppressed CMRO2 (67%) when comparison was made with the contralateral cerebral cortex. Severely suppressed oxygen metabolism in the pericontusional tissue was observed not only in the acute stage but also in the subacute stage after TBI, whereas blood flow was slightly recovered in the subacute stage. We also compared the PET findings obtained in the acute or sbacute stage after TBI and structural abnormalities on late-stage MRI in 5 patients. The area of flow defect on the CBF-PET image developed into irreversible tissue damage (necrosis) in the chronic stage. The area of hypoperfusion surrounding the lesion partly resulted in tissue necrosis, however large part of hypoperfused tissue survived in the chronic stage. Again, significant portion of oxygen hypometabolism surrounding the lesion did not develop into tissue necrosis. The authors conclude that impaired cerebral blood flow and metabolism in the pericontusional region is observed even in the subacute stage after TBI and is unlikely to cause severe further neuronal damage.
Purpose: In order to assess the severity of the primary diffuse brain injury, we propose a new grading system classified by the degree of the initial force expressed by presence or absence, and the duration of the loss of consciousness.
Grading system of the diffuse brain injury: It is divided into 4 grades as follows:
Grade I (no damage): no consciousness disturbance* immediately after injury.
Grade II (minor damage): transient consciousness disturbance or some duration of amnesia immediately after injury.
Grade III (moderate damage): consciousness disturbance immediately after injury, which recovers within 6 hrs.
Grade IV (severe damage): consciousness disturbance immediately after injury, which continues over 6 hrs.
Discussion and conclusion: Currently morphological diagnosis of the head injury is quite easy with the computed tomography, but the classification of the grade of the severity is not easy. There are several types of classification of the traumatic brain injury either using conventional terminologies, or based on the severity of conscious disturbance, or CT findings. It seems clear that the severity of the initial force is the primary factor which influences the clinical course after the head injury. Therefore, we propose a new grading system of the primary diffuse brain injury by means of the degree of the initial force assessed by the presence or absence, and the duration of the loss of consciousness. This new grading system could be used to evaluate the effectiveness of any kinds of treatments and predict the outcome at the early stage.
We investigated prognostic factors to clarify indications for mild hypothermia in treatment of patients with traumatic brain injury (TBI) retrospectively. Between 1997 and 2005, a total of 57 patients with severe TBI, 9 to 74 years of age, were enrolled. The initial Glasgow Coma Scale scores of all patients ranged from 3 to 8 (average: 5.0). All patients but 5 who had intracranial mass lesions with significant midline shift and brain swelling underwent hematoma removal operations and/or craniectomies (SDH 38 cases, contusion 7 and brain swelling 12). Mild hypothermia was induced by surface cooling and continued 3 days at the target temperature at 35˚C principle (a body temperature of 35˚C was reached by 8 hours after injury). Then, the patients were rewarmed at a rate 0.5˚C/day. We assessed the outcome of all patients at discharge and investigated factors associated with outcomes such as the level of consciousness on admission, neurological findings, CT findings, laboratory data and CBF and CMRO2 measured immediately after operations by Xenon-CT. We found that hypo-thermia therapy did not improve the prognoses of patients aged 50 years and above, with higher ICP than 30 mmHg immediately after decompression surgery and large contusion and DAI findings on CT scan. Also subdural hematomas thicker than 18 mm and midline shift of greater than 14 mm on CT were predictive of a poor outcome. GCS on admission, the presence of pupillary abnormalities, body temperature and blood sugar, were not predictable factors of outcome. CBF and CMRO2 values predicted accurately unfavorable outcome. Based on these findings, hypothermia therapy of the present protocol can improve outcome in patients with TBI who are younger than 50 years old without severe brain damage, higher ICP than 30 mmHg and thicker subdural hematoma than 18 mm. CBF and CMRO2 measurement had a very high predictive value for outcome.
Recent studies have revealed that oxidative stress has detrimental effects on central nervous system disorders including subarachnoid hemorrhage (SAH). However, how oxidative stress affects acute brain injury after SAH remains unknown. In this study, we investigated the relationship between oxidative stress and acute brain injury after SAH using SOD1 transgenic (Tg) rats. SAH was produced by endovascular perforation in wild-type (Wt) and SOD1 Tg rats. Apoptotic cell death at 24 h, detected by a cell death assay, was significantly decreased in the cerebral cortex of the SOD1 Tg rats compared with the Wt rats. The mortality rate at 24 h was also significantly decreased in the SOD1 Tg rats. A hydroethidine study demonstrated that superoxide anion production after SAH was reduced in the cerebral cortex of the SOD1 Tg rats. Moreover, phosphorylation of Akt and glycogen synthase kinase-3β (GSK3β), which are survival signals in apoptotic cell death, was more enhanced in the cerebral cortex of the SOD1 Tg rats after SAH using Western blot analysis. These results suggest that reduction in oxidative stress by SOD1 overexpression may attenuate acute brain injury after SAH via activation of Akt/GSK3β survival signaling, which could be the therapeutic target of clinical SAH.
This study was conducted to verify the characteristics of the cases suffering discontinuation of sequential medical intervention for higher cognitive dysfunction after the acute stage of traumatic brain injury (TBI).
Totally 34 concerned cases (D-group) from single institute were analyzed and the data were partly compared to those of other 73 cases (C-group) sharing in the benefit of continuous medical intervention under the same situation.
D-group was composed of 31 males ⁄ 3 females, 28.9 ± 13.4 years-old, and about 5 years passed precedent to be introduced to our institute. The reasons why such delay occurred were mainly drop-out by overlooking of higher cognitive dysfunction and misjudgment of functional outcome at the termination of the therapy in acute stage, and careless follow-up at outpatient clinic. The symptoms recognized by various neuropsychological examinations were memory disturbance (21), attention disturbance (21), decline of general intelligent quotient (20), execution disturbance (15), social behavior disturbance (13), etc. During follow-up period (mean 535 days) to such cognitive dysfunction, single or combined interventions were performed for all cases such as environmental arrangement, individual ⁄ group rehabilitation. Functional outcome-analysis by neuropsychological examinations before ⁄ after such interventions revealed that there was little improvement except attention disturbance. On the other hand, social outcomes were as follows: actual work ⁄ school attendance (8), participation to social life (11), being at home (10), being at hospital ⁄ welfare institute (5). These data indicated that rate of return to actual work ⁄school attendance in D-group (26.7%) was rather lower than that of C-group (39.3%). Furthermore, correlation of the results of neuropsychological examinations and social outcome in D-group was much weaker than those in C-group. It is suggested that environmental arrangement is the most important factor for the return to actual work ⁄ school attendance in D-group.
In conclusion, continuous medical intervention for higher cognitive dysfunction after the acute stage of TBI is much favorable for the improvement of QOL of the people concerned.
Elderly patients (65 years of age or older) suffering traumatic brain injury (TBI) will increase as the population ages. It is found that many more elderly patients with severe TBI have admitted to our hospital in recent years. First, we studied age distribution, mechanisms of injury and outcome in 1025 inpatients after severe TBI during last 25 years. Second, of 318 hospitalized patients suffering mild to severe TBI in recent 2 years 86 cases with moderate or severe disability (MD or SD) were investigated whether or not to begin an early rehabilitation program after discharge from our hospital.
Severe TBI cases revealed a rapid decrease in number from 1980 to 1997 (group 1) followed by an increase from 1998 to 2004 (group 2). The elderly patients significantly increased between two groups (percentages of the elderly, 11% and 21%, respectively; p<0.001). The first and second most common mechanisms of injury in the elderly were traffic accidents (TAs, 58%) and falls (40%) in group 1. In group 2, TAs and falls were almost equal in occurrence (48% and 47%, respectively) and bicycle-related accidents became more frequent in the elderly. The outcome in the elderly at discharge was SD in 9.4%, a vegetative state (VS) in 10.6% and death in 76.5% in group 1, while SD in 27.6%, VS in 3.4% and death in 69.0% in group 2. The frequency of patients with SD was significantly higher in group 2 than in group 1.
Of 86 patients 40 developed MD and 46 became SD. There were more patients with SD in the elderly than in the nonelderly (75%and 49%, respectively). Most elderly individuals transferred to a community hospital (absent department of Neurosurgery) but not to a rehabilitation institute, so they could not participate in an early rehabilitation program.
Abnormal coagulation and fibrinolysis are a frequent complication in patients with severe head injury. Many studies have demonstrated that hemostasis tests are predictors of outcome in these patients. The aim of this investigation was to examine the clinical significance of coagulofibrinolytic abnormalities in patients with traumatic intracranial hemorrhage (TIH) complicated with and without multiple trauma.
Seventy four patients were diagnosed as TIH by initial CT scans performed within 24 hours after insult. Those were assigned into two groups: simple TIH (49 cases; Group S) and TIH with multiple trauma (25 cases; Group M). On admission, peripheral blood samples for coagulation studies (platelet count, fibrin-fibrinogen degradation products (FDP), fibrinogen) were taken. The results were compared with Glasgow Outcome Scale (good outcome: G.R., M.D., poor outcome: S.D., V.S., D.) at discharge in each group.
In the Group S, the FDP level was significantly higher in poor outcome patients compared with good outcome patients (p<0.001). In the Group M, there was no significant difference of FDP level between good outcome and poor outcome patients. The decrease of platelet count or fibrinogen was significant predictor of poor outcome in the Group M (p<0.05), but not in the Group S. Especially, the cause of death was uncontrollable bleeding leading to multiple organ dysfunction syndrome, in three of nine death in the Group M. FDP level was useful for evaluating neurological outcome. In the other hand, we speculated that platelet count and fibrinogen level were important predictors of the neurological outcome in the TIH included in the multiple trauma with a massive bleeding that caused coagulofibrinolytic abnormalities.
The authors report three cases of subdural hematoma associated with coagulopathy.
Case 1: A 88-year-old male with advanced stage of gastric cancer was referred to our department for the evaluation of consciousness disturbance and left hemiparesis after the several episodes of head injury. CT scan of the brain disclosed right subdural hematoma with midline shift as well as subarachnoid hemorrhage at the left parietal area and subdural hematoma above the right cerebellar tentorium. The patient showed bleeding tendency with decreased platelet count and prolonged prothrombin time. After transfusion of the platelet concentrates and fresh frozen plasma, drainage of the right subdural hematoma was performed without irrigation. His neurological symptoms gradually improved postoperatively. He suddenly died 4 days after the operation with unknown causes, but CT did not reveal recurrent intracranial hemorrhage.
Case 2: A 71-year-old female suffering from acute myeloblastic leukemia without remission was referred to our department for the treatment of the right chronic subdural hematoma. After the platelet transfusion, drainage of subudural hematoma without irrigation was carried out. Her neurological symptoms recovered immediately without further recurrence.
Case 3: A 63-year-old male with myelodysplastic syndrome visited our out-patient clinic with a complaint of headache after breath holding. One week after the first visit, he developed left hemiparesis, and Gorei-san (one of the Kampo medicine) was prescribed, which improved his symptoms. Two months' prescription of this drug led to the resolution of subdural hematoma.
In conclusion, subdural hematoma in patients with coagulopathy can be relatively safely treated with the placement of drainage through burr hole after transfusion of platelet concentrates with or without fresh frozen plasma. Prescription of Gorei-san seems to be one of the treatment options in selected patients.