Unruptured Vascular Malformation and Subarachnoid Hemorrhage
John R. Østergaard
Nabih M. Ramadan
International Headache Society (IHS) code and diagnoses:
6.2.2. Headache attributed to subarachnoid hemorrhage
6.3. Headache attributed to unruptured vascular malformation
6.3.1. Headache attributed to saccular aneurysm
6.3.2. Headache attributed to arteriovenous malformation (AVM)
6.3.3. Headache attributed to dural arteriovenous fistula
6.3.4. Headache attributed to cavernous angioma
World Health Organization (WHO) codes and diagnoses: G44.810
644.810 Headache attributed to subarachnoid hemorrhage
644.811 Headache attributed to saccular aneurysm
644.811 Headache attributed to arteriovenous malformation
644.811 Headache attributed to dural arteriovenous fistula
644.811 Headache attributed to cavernous angioma
Short description: Subarachnoid hemorrhage (SAH) occurs when blood leaks between the layers of the pia-arachnoid membrane. Arteries and veins passing through this potential space are both possible sources of bleeding. The majority of SAHs arise from ruptured saccular aneurysms or AVMs (38). Miscellaneous causes include cavernous and venous malformations and capillary telangiectasias. The headache of SAH typically is abrupt in onset, developing within seconds, and is often described as the worst ever experienced. The headache is usually followed by pain radiating into the occipital or cervical region and is often accompanied by blunting of consciousness, vomiting, phono- and photophobia, and neck stiffness. The headache remains severe for hours and then clears over several days to a few weeks.
Patients with AVMs usually present with either an intraparenchymal hemorrhage (50 to 60%) or seizures (30%) (5,21,71). Patients with perimesencephalic or pretruncal SAH, in whom a saccular aneurysm or AVM cannot be demonstrated, may develop an explosive headache similar to that described by patients with an aneurysm, but loss of consciousness is exceptional and the course of the illness is generally benign (62,70).
Unruptured saccular aneurysms often remain asymptomatic for many years but may suddenly produce warning symptoms, including headache, because of either impending rupture (25,47) or progressive enlargement, leading to compression of neighboring structures (47). Unruptured AVMs may mimic migraine (8,31). Epilepsy is the most common clinical presentation of cavernous malformations (54), followed by signs and symptoms of cerebral hemorrhage. Venous malformations are incidental findings in patients presenting with seizures or headache. In the majority, a causal relationship between the angioma and the presenting symptoms is not established (49).
EPIDEMIOLOGY
The true prevalence of saccular aneurysms and other intracranial vascular malformations is not precisely known. Venous malformations and capillary telangiectasias have a low risk of bleeding or causing symptoms by other mechanisms and are often found incidentally at autopsy (71). They occur in approximately 2.6% of subjects (71).
The prevalence of cavernous malformations is 0.5% in autopsy series and 0.4 to 0.9% in serial magnetic resonance (MR) studies (55). They affect both sexes with equal frequency. Most cavernous malformations appear as solitary lesions; however, they have been reported in association with other vascular lesions such as capillary telangiectasias, AVMs, and venous malformations (55). The
prevalence of cavernous malformations range between 0.02% in autopsy series and 0.9% in MR studies (40).
prevalence of cavernous malformations range between 0.02% in autopsy series and 0.9% in MR studies (40).
One retrospective MR angiography study indicated that unsuspected aneurysms are seen in 2.8% of studies (24). Conversely, their frequency in prospective studies is 3 to 6% (53). Postmortem studies of consecutive autopsies indicate that approximately 5% of the population may harbor one or more saccular aneurysm (9,60). In these studies, more than half of the demonstrated aneurysms were unruptured and unrecognized prior to death. Long-term follow-up studies of patients harboring incidentally discovered cerebral aneurysms suggest that the vast majority never rupture or cause any symptoms (68).
The annual risk of rupture of incidental aneurysms less than 7 mm in diameter is low (0.1%), but the risk is higher (1.5% with aneurysms between 7 and 12 mm). The annual risks for additionally discovered aneurysms are 0.4% and 0.8%, respectively (41).
Twenty to 30% of patients with cerebral aneurysms have multiple lesions (aneurysms), usually two or three (47,53). Arterial hypertension and the presence of multiple aneurysms highly positively correlate and, considering both experimental and epidemiologic studies, arterial hypertension is considered a risk factor for aneurysm formation (47). The significance of hypertension for aneurysmal rupture, however, is less conclusive (47).
Overall, aneurysmal SAH is more common in women than in men (39,65). However, in considering the gender difference by decade, a 4:1 male:female ratio is encountered in the first decade of life, which becomes 1:1 by the fifth decade of life (67). The increased incidence of aneurysmal SAH in women is most probably related to their greater susceptibility to aneurysm formation, rather than an increased risk of aneurysmal rupture (47). In contrast, there is a modest male preponderance among patients with AVMs (71).
An AVM and a saccular aneurysm coexist in approximately 10% of patients. Because the associated aneurysms have a predilection to the AVM feeding arteries, it is believed that increased blood flow is a major factor in the formation of the saccular aneurysm (76). When bleeding occurs, it is more often from the aneurysm than from the AVM (62).
Estimates of the annual incidence of SAH depend on the population surveyed, the methods used for analysis, and the accuracy and extent of the investigations. Reports can be divided into epidemiologic surveys and referral centers or large-scale cooperative studies. Epidemiologic studies include not only hospitalized patients, but also those 15 to 20% of individuals with SAH who died before receiving medical treatment. In the Western countries, the average annual incidence of SAH is estimated at 11 per 100,000 population, with variations for age, sex, and geographic locations (56,62). The incidence of SAH has remained stable over the last 30 years. Saccular aneurysms account for approximately 85% of SAH; nonaneurysmal perimesencephalic hemorrhage about 10%; and AVMs, cavernous, venous malformations, or capillary telangiectasias the rest (62). Patients with angiographically negative SAH (e.g., perimesencephalic or pretruncal hemorrhage) have an excellent prognosis and are unlikely to rebleed (62,70). Rupture of a dilated vein or venous malformation in the prepontine or interpeduncular cistern is believed to be responsible for the majority of these cases (53).
Up to 50% of patients with saccular aneurysms who are admitted to neurosurgical departments experience warning symptoms in the form of minor bleeding episodes, days or even several months before a major hemorrhage (25,47,65). Headache is the most common symptom of this warning leak (47), occurring in 9 of 10 patients. Minor leaks occur with AVM as well, as evidenced by pathologic documentation of hemosiderin adjacent to the malformation (71). At surgery, at least 10% of AVMs show evidence of minor bleeding episodes. Small AVMs are more likely to cause minor bleeding than large ones (71).
GENETICS
There is no significant genetic predisposition to the development of AVMs (71). In contrast, a familial form of cavernous malformations, which is characterized by multiple lesions and an autosomal-dominant inheritance pattern, is caused by mutations in the CCM1-CCM3 genes on chromosomes 7 and 3, respectively (11,14).
Evidence supporting the role of genetic factors in the pathogenesis of intracranial aneurysms stems from the association of intracranial aneurysms with inherited connective-tissue disorders (e.g., autosomal polycystic kidney disease, Ehlers-Danlos syndrome type IV [vascular EDS]) and their familial occurrence (56). In contrast to sporadic aneurysms, familial ones (a) occur less often on the anterior communicating artery; (b) rupture at a younger age; and (c) are smaller in size at rupture (34). In a segregation analysis of published pedigrees, several possible patterns of inheritance of saccular aneurysms were identified, with autosomal transmission being the most likely (57). This suggests that genetic heterogeneity is an important feature of intracranial saccular aneurysms (56).
ANATOMY AND PATHOLOGY
After a hemorrhage, the subarachnoid space contains a variable mixture of cerebrospinal fluid (CSF) and clotted and liquid blood. The extent of dissemination varies considerably. Bleeding on the surface of the brain spreads out and collects later at the base, whereas a hemorrhage at the base initially fills the cisterns. In cases of severe SAH, the blood spreads within minutes over the convexities of the cerebral hemispheres. The average SAH releases 7 to 10 mL of blood into the CSF. A red blood cell (RBC)
count of 105 per mm3 indicates that 3 mL of blood entered the CSF. Following the initial hemorrhage, the RBC count decreases, and RBCs remain detectable in the fluid only for 4 to 21 days. The average survival of RBCs in CSF is much shorter than in the circulation. It has been suggested that RBCs in the subarachnoid space lose their cellular integrity, resulting in an immune-mediated hemolysis (50).
count of 105 per mm3 indicates that 3 mL of blood entered the CSF. Following the initial hemorrhage, the RBC count decreases, and RBCs remain detectable in the fluid only for 4 to 21 days. The average survival of RBCs in CSF is much shorter than in the circulation. It has been suggested that RBCs in the subarachnoid space lose their cellular integrity, resulting in an immune-mediated hemolysis (50).
RBC lysis liberates pigments (oxyhemoglobin, methemoglobin, and bilirubin), causing the supernatant of the centrifuged CSF to stain yellow (xanthochromia). By spectrophotometry, oxyhemoglobin can be detected as early as 2 hours after the bleeding, but usually it takes a few hours or more for RBCs to lyse and for xanthochromia to develop. In a large series of patients with SAH, it was shown that xanthochromia could be detected in all patients in whom the CSF was examined within the initial 2 weeks and at least 12 hours after the hemorrhage (62,63).
In the subarachnoid space, extravasated blood causes an aseptic inflammatory reaction (22). The meningeal reaction is evident within 2 hours of the hemorrhage and begins as an outpouring of polymorphonuclear leukocytes, followed by the appearance of lymphocytes and large mononuclear phagocytes. This cellular reaction is transient and persists only as long as blood or products of the breakdown of blood are demonstrated in the subarachnoid space. Thickening and pigmentation of the pia and arachnoid occur, and hemosiderin-containing adhesions are forced among these membranes, the blood vessels, the nerves, and the brain. In case of aneurysmal SAH, the process is most marked at the base of the brain. If the exit foramina of the fourth ventricle are affected, obstructive hydrocephalus may occur. Hydrocephalus is more common after SAH in the territory of the anterior communicating artery, probably because blood is directed into the basal subarachnoid space. Hydrocephalus is also common in patients with multiple episodes of SAH because of the functional impairment of the arachnoid villi and increasing leptomeningeal fibrosis.
Cerebral vasospasm is one of the most important causes of death and disability in patients surviving the first critical days of SAH. Cerebral vasospasm is a syndrome of ischemic consequences of an angiographically proven, time-dependent, transient cerebral arterial narrowing. It is rarely pronounced before day 4 following the initial hemorrhage and peaks at approximately day 7. At that time, 40 to 70% of patients will have some reduction in the caliber of one or more of the arteries of the circle of Willis or its branches (10,28). The clinical symptoms of delayed cerebral ischemia are characterized by an insidious onset of confusion and decreased level of consciousness, followed by focal motor and speech impairment (10,28). Manifest neurologic deficits related to delayed cerebral vasospasm occur in 20 to 30% of patients with aneurysmal SAH, whereas they occur much less frequently in patients with SAH due to AVMs (28).
PATHOPHYSIOLOGY
The initial pain that follows SAH results from local distention, distortion, and stretching of the cerebral vessel and its adjacent arachnoid. It is a referred pain due to stimulation of arteries in the circle of Willis, which derive their innervation from the fifth, ninth, and tenth cranial nerves, and the upper cervical spinal nerves. Sensory fibers are directly stimulated by subarachnoid blood with the resultant release of neuropeptides such as substance P and initiation of head pain (17,37,44). Levels of calcitonin gene-related peptide (CGRP) are low in patients who die after SAH (18,19). Furthermore, there is increased release of CGRP following SAH (26), analogous to what is demonstrated in migraine. Increased intracranial pressure and the later development of hydrocephalus or delayed cerebral ischemia also may contribute to the genesis of headache.