Introduction 

   Primary pontine hemorrhages (PPH) are rare in hemorrhagic stroke patients and accounts approximately for about 5~10% of intracranial hemorrhages.⁵⁾¹⁹⁾ PPH usually causes severe disturbances of consciousness, pupillary abnormalities, quadriparesis, and respiratory failure.¹⁴⁾ In recent studies, the prognosis was still found to be highly fatal, with the overall mortality rate being 40~50%.^11)14)20) Previous known predictors for a poor outcome were coma on admission, intraventricular extension, and acute hydrocephalus.^4)6)18) Although stereotactic surgical treatment was reported by Takahama et al and Hara et al, who found a significantly better functional outcome in patients treated surgically compared with those treated conservatively,⁷⁾¹⁷⁾ but surgical therapy is still not a standard therapy for PPH and might be limited to selected indications in specialized centers. In this study, we analyzed the correlation between the prognosis and radiological or clinical findings in 35 patients with primary pontine hemorrhage. Then, we combined the data from the literature and our study to make guidelines for surgical indications. 

Materials and Methods 

   We reviewed and analyzed the data of 35 patients with PPH who were admitted to our department between 2000 and 2006 retrospectively. Mean age was 54.9 years, with a range of 30~89 years (8 women and 27 men). Twenty-one patients (60%) had a hypertension history. Magnetic resonance imaging and magnetic resonance angiographies were performed for the patients who survived to exclude the patients with vascular or tumoral conditions. But vascular malformation and tumor were not found. The Glasgow Coma Scale (GCS) on admission, and Glasgow Outcome Scale (GOS) scores were assessed retrospectively. All patients were investigated with cranial CT. The volume of the hemorrhage was measured by using the ellipsoid formulation of Kothari et al²⁾¹³⁾: hemorrhage volume (in mL) = (A×B×C)/2, where A=greatest hemorrhage diameter (in cm at CT), B=diameter 90.to A (in cm at CT), and C=approximate number of CT sections with hemorrhage x section thickness (cm). Patients were divided into two groups: a " good" and a " poor" outcome group, according to the GOS score (1, death; 2, persistent vegetative state; 3, severe disability; 4, moderate disability; 5, good recovery).⁸⁾ The good outcome group was defined as patients with a GOS score of 3~5, who required none or partial assistance in daily life. The poor outcome group comprised patients with a GOS score of 1~2. The patients where further divided into groups of those with a hematoma volume of 4 mL or greater and those with a hematoma volume less than 4 mL, to evaluate the clinical significance of hematoma volume.¹⁾¹⁹⁾ According to the CT classification of Chung and Park,⁴⁾ the hemorrhages where divided into four types: massive, basal, bilateral tegmental and unilateral tegmental (Fig. 1). The hematoma was when the location of the PPH was uni- or bilateral tegmental, sparing the base pontis classified as unilateral and bilateral. The basal type consisted of those hematoma occupying the ventral base pontis and the junction between the bilateral tegmentum. The massive type defined hematoma occupying the base pontis and the bilateral tegmentum with extension to the midbrain. Then, we analyzed the clinical and radiologic differences between the good outcome group and the poor outcome group. 

Statistical calculation 
   The following factors were assessed to determine possible predictive values: gender, age, hematoma volume, hematoma location, initial score of GCS, pinpoint pupillary abnormalities, need for mechanical ventilation, intraventricular extension and GOS scores on discharge. Variables were compared with a Pearson chi-square test for categorical. The factors proven to be significant with univariate analysis were analyzed again with multivariate regression analysis. Significance level was accepted as p<0.05. 

Results 

   Mean age of 35 patients was 54.9±14.1 years with a range of 30~89 years. 27 of the patients (77%) were men and 8 patients (23%) were women. 20 of the patients (57%) survived. Arterial hypertension was described in the history of 21 patients (60%). The mean hematoma volume was 8.7 ±5.9 mL and the range was 1~18 mL. A basal hemorrhage was found in 5 (14%) of the 35 patients, unilateral tegmental in 9 (26%), bilateral tegmental in 10 (29%) and a massive PPH with extension to the midbrain was found in 11 (31%) of the 35 patients. Intraventricular extension, particularly in the fourth ventricle, was found in 13 patients (37%). Mechanical ventilation was necessary in 22 patients (63%) and in 15 of them died. Admission GCS score of patients is shown in Fig. 2. 
   A high correlation was observed between a poor outcome and hematoma volume greater than 4 mL (P<0.001) (Fig. 3), location of hemorrhage (P=0.001) (Fig. 4), coma on admission (P=0.013), intraventricular hemorrhage (P=0.041) and necessity for mechanical ventilation (P<0.001). In patients with hematomas less than 4 mL in volume, a significantly better outcome was found (P<0.001). Pupillary abnormalities, sex, age, acute hydrocephalus, and hypertension did not correlate to outcome. Eleven (31.4%) of the 35 patients had massive hemorrhage, 10 patients (28.6%) had bilateral tegmental hemorrhage and 9 (25.7%) had unilateral tegmental hemorrhage. The parameters proven to be significant in univariate analysis were reanalyzed with multivariate regression analysis. The mortality rate was significantly higher in patients with massive and bilateral tegmental hemorrhage than the patients with unilateral tegmental hemorrhage. The comparison of the parameters with univariate analysis is shown in Table 1, 2. 

Discussion 

   The patients with primary pontine hemorrhage are presented with coma, quadriplegia, and pinpoint pupils in general.¹⁷⁾²⁰⁾ In the past days, PPH have been thought as fatal. Mortality due to pontine hemorrhages is determined different in various studies, between 30 and 90%.^4)14)20) In our study the overall mortality rate was found as 43%. In most patients with centrally located hematoma, consciousness disturbances due to destruction of ascending reticular activating system, pinpoint pupils and ophthalmoparasis due to the involvement of cranial nerves and irregular breathing patterns that require mechanical ventilation occur. K. Balci et al. presented prognostic factors for a fatal outcome in patients with coma on admission, large hematoma, intraventricular extension, hydrocephalus, and requirement of mechanical ventilation.^1)11)14)20) Initial GCS score, size and location of the hematoma, coma on admission, need for mechanical ventilation and intraventricular extension were significantly correlated to poor outcome in our patients. In 1992, Chung and Park suggested a new CT classification for PPH: type 1, small unilateral tegmental; type 2, basal tegmental; type 3, bilateral tegmental; and type 4, massive, in which case survival rate is highest in the unilateral tegmental type and lowest in the massive type.⁴⁾ Murata et al found that the horizontal diameter of the hematoma is the most reliable predicting factor of outcome.¹⁴⁾ Other authors emphasize cross-sectional diameter as well as the transverse and vertical extension of the hematoma as the most exact predictor of outcome.^6)12)13)15) All these parameters offer a good tool for determining the prognosis of patients with PPH because the size of the hematoma is strongly correlated to the parenchymal damage. PPH of the basal and massive types result from rupture of parenchymal midpontine branches of the basilar artery. The bleeding vessel is probably a paramedian perforator in its distal portion and forms the initial hematoma at the junction of the tegmentum and the basis pontis. The vessels causing the unilateral or bilateral tegmental, type of PPH have the same origin, but the degree and direction of the hematoma differ. It is caused by rupture of the penetrating, long circumferential vessels that enter the tegmentum dorsally and course medially.³⁾⁹⁾ In this study, massive and basal located hemorrhage shows high mortality than others. The hematoma location was highly significantly correlated to functional outcome (GOS score): patients with a unilateral tegmental located hematoma had a good outcome, and patients with a basal or massive hematoma had a a poor outcome. A possible mechanism causing the unfavorable outcome in patients with basal hematomas could be the effect on the cranial nuclei leading to dysarthria, dysphagia, aspiration pneumonia, and abnormal breathing patterns requiring mechanical ventilation. The poor prognosis of the massive type can be explained by the rapid brain stem destruction with early coma, need for mechanical ventilation due to the effect on the reticular activating system in the upper third of the pontine tegmentum, and acute hydrocephalus. But our study shows no correlation with acute hydrocephalus. The presence of intraventricular extension was significantly correlated to poor prognostic patients. Similar result to the analysis of Murata et al and Wijdicks and St. Louis,¹⁴⁾²⁰⁾ we couldn't find any correlations between functional outcome and age. But age is a very important factor in supratentorial intracerebral hemorrhage and Murata et al. and Wessels et al. reported significant correlation between death and age.¹⁴⁾¹⁹⁾ Many studies presented about prognostic factors for PPH, but overall mortality of it does not improved and treatment modalities remained unchanged in last several decades. And only a few authors experienced surgical treatments and report it, so almost neurosurgeons still adhere to treat as classical methods. We need to change the paradigm for treating primary pontine hemorrhage to reduce mortality. In studies reported up to date and our results definitely point some significant prognostic factors. Those are coma on admission, intraventricular extension, massive hemorrhage, large hematoma (above 4cc) and mechanical ventilation. Clinically these poor prognostic factors were observed in a same patient and they died with rapid deterioration after admission. So we think these patients must be excluded from a surgical treatment. Another inconsistent group with surgery are patients who have a minimal neurologic deficiency. The mortality and morbidity of stereotactic surgery for the PPH is not clear, so we must apply surgery for them after confirmation about it. Hara T. et al. reported about the good results of stereotactic surgery for PPH patients.⁷⁾ Another important aspect for surgery is surgical equipments. Neurosurgical field achieved a remarkable development in technique and equipments like a frameless stereotactic equipment. So we can operate more safely and accurately. So we propose using the prognostic factors, some patients must candidate for surgery who are not full comatose or alert. Then we could improve surgical experience and new equipments on this field, we could reduce mortality and improve functional outcome on PPH eventually. 

Conclusion 

   In conclusion, it is important to know the predictors for mortality in patients with PPH. Some reported data and our studies pointed some factors that correlated with poor outcome strongly. Although large studies need to establish a surgical outcome and prognostic factors, we think to treat this disease with another modality and in the future the surgical procedures may have more value in patients with PPH. 

REFERENCES

1. Balci K, Asil T. Kerimoglu M, Celik Y, Utku U. Clinical and neuroradiological predictors of mortality in patients with primary pontine hemorrhage. Clin Neurol Neurosurg 108:36-9, 2005 

2. Broderick JP, Brott TG, Duldner JE, Tomsick T, Huster G. Volume of intracerebral hemorrhage. A powerful and easy to use predictor of 30 day mortality. Stroke 24:987-93, 1993 

3. Caplan LR, Goodwin JA. Lateral tegmental brainstem hemorrhages. Neurology 32:252-60, 1982 

4. Chung CS, Park CH. Primary pontine hemorrhage: a new CT classification. Neurology :830-4, 1992 

5. Dziewas R, Kremer M, Ludeman P, Nabavi DG, Drager B, Ringelstein EB. The prognostic impact of clinical and CT parameters in patients with pontine hemorrhage. Cerebrovasc Dis 16:224-9, 2003 

6. Goto N, Kaneko M, Hosaka Y, Koga H. Primary pontine hemorrhage: clinicopathologic correlation. Stroke 11(1):84-90, 1980 

7. Hara T, Nagata K, Kawamoto S, Sashida J, Abe T, Wada A, et al. Functional outcome of primary pontine hemorrhage: conservative treatment or stereotaxic surgery. No Shinkei Geka 29(9):823-9, 2001 

8. Jennett B, Bond M. Assessment of outcome after severe brain damage. Lancet 1:480-4, 1975 

9. Kase CS, Caplan LR. Hemorrhage affecting the brain stem and cerebellum. Barrnett H JM, Mohr JP, Stein BM., eds. Stroke: Pathophysiology, Diagnosis and Management. New York: Churchill Livingstone : 1986, Vol 1, pp621-41 

10. Kothari RU, Brott T, Broderick JP, et al. The ABCs of measuring intracerebral hemorrhage volumes. Stroke 27:1304-5, 1996 

11. Kushner MJ, Bresmann SB. The clinical manifestation of pontine hemorrhage. Neurology 35:637-43, 1985 

12. Kuwabara S, Ohta K, Ueda T, Yamane K, Uemura Y, Takahashi M. Clinical study of 20 cases of primary pontine hemorrhage, with special reference to correlations between clinical, computed tomographic, and electroencephalographic findings and outcome. Neurol Med Chir (Tokyo) 22:933-42, 1982 

13. Masiyama S, Niizuma H, Suzuki J. Pontine hemorrhage: a clinical analysis of 26 cases. J Neurol Neurosurg Psychiatry 48:658-62, 1985 

14. Murata Y, Yamaguchi S, Kajikawa H, Yamamura K, Sumioka S, Nakamura S. Relationship between the clinical manifestations, computed tomographic findings and the outcome in 80 patients with primary pontine hemorrhage. J Neurol Sci 167:107-11, 1999 

15. Ochiai C, Sano K, Kobayashi S, Sasaki T, Mayanagi Y. Clinical study of pontine hemorrhage with special reference to CT classification and surgical indication [in Japanese]. No To Shinkei 31:803-11, 1979 

16. Rabinstein AA, Tisch SH, McClelland RL, Wijdicks EFM. Cause is the main predictor of outcome in patients with pontine hemorrhage. Cerebrovasc Dis 17:66-71, 2004 

17. Takahama H, Morii K, Sato M, Sekiguchi K, Sato S. Stereotactic aspiration in hypertensive pontine hemorrhage: comparative study with conservative therapy [in Japanese]. No Shinkei Geka 17:733-9, 1989 

18. Weisberg LA. Primary pontine haemorrhage: clinical and computed tomographic correlations. J Neurol Neurosurg Psychiatry 49:346-52, 1986 

19. Wessels T, Hartmann WM, Noth J, Klotzsch C. CT findings and clinical features as markers for patient outcome in primary pontine hemorrhage. Am J Neuroradiol 25:257-60, 2004 

20. Wijdicks EFM, Louis ES. Clinical profiles predictive of outcome in pontine hemorrhage. Neurology 49:1342-6, 1997