EDITORIAL
Nonaneurysmal Subarachnoid Hemorrhage One usually associates acute, nontraumatic subarachnoid hemorrhage (SAH) with a ruptured saccular aneurysm and a critically ill patient. Despite advances in diagnosis and treatment, patients with ruptured aneurysms remain at high risk for recurrent bleeding, ischemic stroke, and death. In approximately 15 to 20% of patients with SAH, however, the cause of bleeding is undetermined [l-61. Patients with SAH of unknown etialogy have a better prognosis than patients with aneurysmal SAH, but their survival rates do not quite equal the survival rates of age- and sex-matched controls {2}. There is a small but real risk of rebleedmg or delayed cerebral ischemia in patients with SAH and normal angiography-rates of up to 10% have been reported for both complications [3, 5,6}. The theoretical causes of SAH in these patients include an undiscovered bleeding diathesis, rupture of a small penetrating arteriole or venule, rupture of an arteriographically occult vascular malformation, and bleeding from an obliterated or partially thrombosed aneurysm [1, 41. Still other causes may exist. Patients with SAH of unknown etiology are most likely a heterogeneous group with variable pathophysiology and prognosis. Until rccently, however, no one had identified a distinct subset of these patients. The advent of computed tomography (CT) of the brain has greatly aided the diagnosis of SAH. When performed within the first three days of the ictus, CT is very sensitive in detecting subarachnoid blood [7]. Unlike lumbar puncture, it is also useful in detecting intracranial complications of SAH, such as hydrocephalus and infarction, as well as identifying causes of SAH occasionally overlooked in the pre-CT era, such as intracerebral hemorrhage. In patients with aneurysmal SAH, blood is most often detected in the sylvian fissure, the interhemispheric fissure, or the basal cisterns. In 1985, van Gijn and colleagues [ 8 ] carefully studied the patterns of hemorrhage on CT in 120 patients with SAH. They identified a pattern predominantly limited to the perimesencephalic cisterns in 13 of 28 patients with nonaneurysmal SAH. This pattern was seen in only 1 of 92 patients with aneurysmal SAH. At three months, none of the 13 patients with perimesencephalic nonaneurysmal SAH had rebled or suffered cerebral infarction. In a more recent follow-up study of 37 such patients by the same group, no patient had rebled after a mean of 45 months {9]. In this issue of Annals of Nearology, the same group of investigators from the Netherlands describes the early clinical course of 65 patients with perimesencephalic nonaneurysmal SAH [lo]. They compared
these patients to 49 patients with aneurysmal SAH who presented in a similar clinical grade and with a similar amount of cisternal blood on CT. Owing to their selection criteria, 73% of the control group of patients with ruptured aneurysms had a favorable outcome, results better than those reported in other studies of SAH. Still, the patients with perimesencephalic nonaneurysmal SAH fared even better: none had recurrent hemorrhage or vasospasm-induced ischemic stroke, none died, and all had satisfactory outcomes. The conclusions of this paper are important for the management of patients with SAH. T o diagnose perimesencephalic nonaneurysmal hemorrhage, one must perform CT within 72 hours of the event, since CT becomes far less sensitive in detecting SAH beyond that time period [7]. Hemorrhage confined to the perimesencephalic cisterns is highly suggestive of a nonaneurysmal etiology, but in an earlier report these investigators noted that one patient with perimesencephalic hemorrhage had a basilar artery aneurysm [8]. Thus, four-vessel cerebral arteriography is mandatory in the initial workup of these patients. A second arteriogram, however, is probably unnecessary if the initial study is negative and does not demonstrate vasospasm. Follow-up arteriography is likely to be more important in patients with “idiopathic” SAH and blood in locations other than that restricted to the perimesencephalic cisterns. Patients with perimesencephalic nonaneurysmal hemorrhage are not critically ill, usually have a normal level of consciousness, and are at low risk for major complications or death. Thus, their treatment should be different from that of patients with ruptured aneurysms. Symptomatic care, cardiac monitoring, and control of medical complications such as hyponatremia are warranted. Monitoring for signs and symptoms of hydrocephalus is necessary; patients may require repeat CT and possibly ventricular shunting. The likelihood of early rebleeding appears to be nil; thus, there is little reason to prescribe forced bed rest, restricted activities, vigorous control of blood pressure, or antifibrinolytic drugs. The long-term risk of recurrent hemorrhage is also very small, so patients need not suffer constraints on activities or work. Hypervolemic hemodilution therapy and calcium channel blocking drugs are probably not indicated, since patients with perimesencephalic nonaneurysmal hemorrhage have a very low probability of suffering ischemic stroke. The results of this paper also provide insights into the pathophysiology of certain complications of SAH. Rinkel and associates [lo] noted that the rates of car-
Copyright 0 1991 by the American Neurological Association
461
diac arrhythmias and hyponatremia were the same for patients with aneurysmal or nonaneurysmal perimesencephalic hemorrhage. Conversely, no patients with perimesencephalic nonaneurysmal hemorrhage suffered an ischemic stroke, compared to 8% of patients with an aneurysmal etiology. This suggests that the amount and location of subarachnoid blood are not the only factors in the development of vasospasm-the etiology of SAH remains an important factor, though the relationship between aneurysmal rupture and vasospasm still awaits definition. Finally, the results of the research of Rinkel and colleagues [lo] have an impact on clinical trials of promising therapies for management of SAH. Patients with perimesencephalic nonaneurysmal hemorrhage have a very favorable prognosis regardless of treatment and thus should not be enrolled in clinical trials aimed at prevention of either rebleeding or vasospasm. Maldistribution of entry of these patients into one arm of a clinical trial could severely bias results. One should interpret cautiously the results of a trial purporting to show the benefit of a therapy tested in all patients with SAH. Future trials of promising interventions for treatment of patients with SAH should require confirmation of an aneurysm as well as either CT or cerebrospinal fluid evidence of bleeding as prerequisites for entry into the study. Harold P. Adams, Jr, M D David Lee Gordon, M D Depurtmeiat of hTetl~oIogy Uniuersity of Iowu
College of Medicine lowa City, IA
462 Annals of Neurology Vol 29 No 5
May 1991
References 1. Hayward RD. Subarachnoid haemorrhage of unknown aetiology. A clinical and radiological study of 5 1 cases. J Neurol Neurosurg Psychiatry 1977;40:926-93 1 2. Nishioka H, Torner JC, Graf CJ, et al. Cooperative study of intracranial aneurysms and subarachnoid hemorrhage: a Iongterm prognostic study. 111. Subarachnoid hemorrhage of undetermined etiology. Arch Neurol 1984;41:1147-1151 3. Ruelle A, Lasio G, Boccardo M, et al. Long-term prognosis of subarachnoid hemorrhages of uuknown etiology. J Neurology 1985;232:277-279 4. Alexander MSM, D i a PS, Uttley D. Spontaneous subarachnoid hemorrhage and negative cerebral panangiography. Review of 140 cases. J Neurosurg 1986:64:537-542 5. Giombini S, Bruzzone MG, Pluchino F. Subarachnoid hemorrhage of unexplained cause. Neurosurgery 1988;22:3 13-116 6. Cioffi F, Pasqualin A, Cavazzini P, et al. Subarachnoid haemorrhage of unknown origin: clinical and tOmOgrdphiCdl aspects. Acca Neurochir 1989;97:31-39 7 Adams H P Jr, Kassell NF, Torner JC, et al. Computed tomographic findings and clinical correlates in recent aneurysmal subarachnoid hemorrhage. A preliminary report of the Cooperative Aneurysm Study. Neurology 1983;33:981-988 8 van Gijn J, van Dongen KJ, Vermeulen M, et al. Perimesencephalic hemorrhage. A nonaneurysmal and benign form of subarachnoid hemorrhage. Neurology 1985;35:493-497 9 Rinkel GJE, Wijdicks EFM, Vermeulen M, et al. Outcome in perimesencephalic (nonaneurysmal) subarachnoid hemorrhage: a follow-up study in 37 patients. Neurology 1990;40:11301132 10 Rinkel W E , Wijdicks EFM, Vermeulen M, et al. The clinical course of perimesencephalic nonaneurysmal subarachnoid hemorrhage. Ann Neurol 1990;29:463-468
Nonaneurysmal Subarachnoid Hemorrhage One usually associates acute, nontraumatic subarachnoid hemorrhage (SAH) with a ruptured saccular aneurysm and a critically ill patient. Despite advances in diagnosis and treatment, patients with ruptured aneurysms remain at high risk for recurrent bleeding, ischemic stroke, and death. In approximately 15 to 20% of patients with SAH, however, the cause of bleeding is undetermined [l-61. Patients with SAH of unknown etialogy have a better prognosis than patients with aneurysmal SAH, but their survival rates do not quite equal the survival rates of age- and sex-matched controls {2}. There is a small but real risk of rebleedmg or delayed cerebral ischemia in patients with SAH and normal angiography-rates of up to 10% have been reported for both complications [3, 5,6}. The theoretical causes of SAH in these patients include an undiscovered bleeding diathesis, rupture of a small penetrating arteriole or venule, rupture of an arteriographically occult vascular malformation, and bleeding from an obliterated or partially thrombosed aneurysm [1, 41. Still other causes may exist. Patients with SAH of unknown etiology are most likely a heterogeneous group with variable pathophysiology and prognosis. Until rccently, however, no one had identified a distinct subset of these patients. The advent of computed tomography (CT) of the brain has greatly aided the diagnosis of SAH. When performed within the first three days of the ictus, CT is very sensitive in detecting subarachnoid blood [7]. Unlike lumbar puncture, it is also useful in detecting intracranial complications of SAH, such as hydrocephalus and infarction, as well as identifying causes of SAH occasionally overlooked in the pre-CT era, such as intracerebral hemorrhage. In patients with aneurysmal SAH, blood is most often detected in the sylvian fissure, the interhemispheric fissure, or the basal cisterns. In 1985, van Gijn and colleagues [ 8 ] carefully studied the patterns of hemorrhage on CT in 120 patients with SAH. They identified a pattern predominantly limited to the perimesencephalic cisterns in 13 of 28 patients with nonaneurysmal SAH. This pattern was seen in only 1 of 92 patients with aneurysmal SAH. At three months, none of the 13 patients with perimesencephalic nonaneurysmal SAH had rebled or suffered cerebral infarction. In a more recent follow-up study of 37 such patients by the same group, no patient had rebled after a mean of 45 months {9]. In this issue of Annals of Nearology, the same group of investigators from the Netherlands describes the early clinical course of 65 patients with perimesencephalic nonaneurysmal SAH [lo]. They compared
these patients to 49 patients with aneurysmal SAH who presented in a similar clinical grade and with a similar amount of cisternal blood on CT. Owing to their selection criteria, 73% of the control group of patients with ruptured aneurysms had a favorable outcome, results better than those reported in other studies of SAH. Still, the patients with perimesencephalic nonaneurysmal SAH fared even better: none had recurrent hemorrhage or vasospasm-induced ischemic stroke, none died, and all had satisfactory outcomes. The conclusions of this paper are important for the management of patients with SAH. T o diagnose perimesencephalic nonaneurysmal hemorrhage, one must perform CT within 72 hours of the event, since CT becomes far less sensitive in detecting SAH beyond that time period [7]. Hemorrhage confined to the perimesencephalic cisterns is highly suggestive of a nonaneurysmal etiology, but in an earlier report these investigators noted that one patient with perimesencephalic hemorrhage had a basilar artery aneurysm [8]. Thus, four-vessel cerebral arteriography is mandatory in the initial workup of these patients. A second arteriogram, however, is probably unnecessary if the initial study is negative and does not demonstrate vasospasm. Follow-up arteriography is likely to be more important in patients with “idiopathic” SAH and blood in locations other than that restricted to the perimesencephalic cisterns. Patients with perimesencephalic nonaneurysmal hemorrhage are not critically ill, usually have a normal level of consciousness, and are at low risk for major complications or death. Thus, their treatment should be different from that of patients with ruptured aneurysms. Symptomatic care, cardiac monitoring, and control of medical complications such as hyponatremia are warranted. Monitoring for signs and symptoms of hydrocephalus is necessary; patients may require repeat CT and possibly ventricular shunting. The likelihood of early rebleeding appears to be nil; thus, there is little reason to prescribe forced bed rest, restricted activities, vigorous control of blood pressure, or antifibrinolytic drugs. The long-term risk of recurrent hemorrhage is also very small, so patients need not suffer constraints on activities or work. Hypervolemic hemodilution therapy and calcium channel blocking drugs are probably not indicated, since patients with perimesencephalic nonaneurysmal hemorrhage have a very low probability of suffering ischemic stroke. The results of this paper also provide insights into the pathophysiology of certain complications of SAH. Rinkel and associates [lo] noted that the rates of car-
Copyright 0 1991 by the American Neurological Association
461
diac arrhythmias and hyponatremia were the same for patients with aneurysmal or nonaneurysmal perimesencephalic hemorrhage. Conversely, no patients with perimesencephalic nonaneurysmal hemorrhage suffered an ischemic stroke, compared to 8% of patients with an aneurysmal etiology. This suggests that the amount and location of subarachnoid blood are not the only factors in the development of vasospasm-the etiology of SAH remains an important factor, though the relationship between aneurysmal rupture and vasospasm still awaits definition. Finally, the results of the research of Rinkel and colleagues [lo] have an impact on clinical trials of promising therapies for management of SAH. Patients with perimesencephalic nonaneurysmal hemorrhage have a very favorable prognosis regardless of treatment and thus should not be enrolled in clinical trials aimed at prevention of either rebleeding or vasospasm. Maldistribution of entry of these patients into one arm of a clinical trial could severely bias results. One should interpret cautiously the results of a trial purporting to show the benefit of a therapy tested in all patients with SAH. Future trials of promising interventions for treatment of patients with SAH should require confirmation of an aneurysm as well as either CT or cerebrospinal fluid evidence of bleeding as prerequisites for entry into the study. Harold P. Adams, Jr, M D David Lee Gordon, M D Depurtmeiat of hTetl~oIogy Uniuersity of Iowu
College of Medicine lowa City, IA
462 Annals of Neurology Vol 29 No 5
May 1991
References 1. Hayward RD. Subarachnoid haemorrhage of unknown aetiology. A clinical and radiological study of 5 1 cases. J Neurol Neurosurg Psychiatry 1977;40:926-93 1 2. Nishioka H, Torner JC, Graf CJ, et al. Cooperative study of intracranial aneurysms and subarachnoid hemorrhage: a Iongterm prognostic study. 111. Subarachnoid hemorrhage of undetermined etiology. Arch Neurol 1984;41:1147-1151 3. Ruelle A, Lasio G, Boccardo M, et al. Long-term prognosis of subarachnoid hemorrhages of uuknown etiology. J Neurology 1985;232:277-279 4. Alexander MSM, D i a PS, Uttley D. Spontaneous subarachnoid hemorrhage and negative cerebral panangiography. Review of 140 cases. J Neurosurg 1986:64:537-542 5. Giombini S, Bruzzone MG, Pluchino F. Subarachnoid hemorrhage of unexplained cause. Neurosurgery 1988;22:3 13-116 6. Cioffi F, Pasqualin A, Cavazzini P, et al. Subarachnoid haemorrhage of unknown origin: clinical and tOmOgrdphiCdl aspects. Acca Neurochir 1989;97:31-39 7 Adams H P Jr, Kassell NF, Torner JC, et al. Computed tomographic findings and clinical correlates in recent aneurysmal subarachnoid hemorrhage. A preliminary report of the Cooperative Aneurysm Study. Neurology 1983;33:981-988 8 van Gijn J, van Dongen KJ, Vermeulen M, et al. Perimesencephalic hemorrhage. A nonaneurysmal and benign form of subarachnoid hemorrhage. Neurology 1985;35:493-497 9 Rinkel GJE, Wijdicks EFM, Vermeulen M, et al. Outcome in perimesencephalic (nonaneurysmal) subarachnoid hemorrhage: a follow-up study in 37 patients. Neurology 1990;40:11301132 10 Rinkel W E , Wijdicks EFM, Vermeulen M, et al. The clinical course of perimesencephalic nonaneurysmal subarachnoid hemorrhage. Ann Neurol 1990;29:463-468
