Subarachnoid HemorrhageSeminar 1

• Incidence

• Genetic Factors

• Diagnosis

• Natural History

William S. Tucker and Mubarak Al-Gahtany

Incidence of Aneurysmal SAH

Studies suggest that the incidence in the USA and Europe is 10 to 11 cases per 100,000 population per year

Autopsy Series

Total # Percentage

Author #of Series of Cases with aneurysms Rupt’d Unrupt’d

Jellinger 12 87,772 1.6 (0.2 to 9) 1 0.6

Bannerman 8 51,360 1.43 1.09 0.34

Overall, it is a reasonable approximation that less than 2% of the entire population will have an aneurysm; an intracranial aneurysm will rupture in less than 1% of the population and will be the cause of death in 0.5%

Age and the Incidence of Aneurysmal SAH

• Aneurysmal rupture is extremely rare in the first decade of life

• Incidence gradually increases each decade and peaks in the sixth decade

Gender and the Incidence of Aneurysmal SAH

• There is a clear female preponderance overall; the ratio of females to males in the Cooperative Study on Timing of Surgery was 1.6: 1

• Before age 40 males and females were equally affected; after age 40 there is an increasingly strong predominance of females

Natural HistoryPrognosis for Surgically Untreated Saccular

Intracranial Aneurysms

OVERVIEW• Highest mortality occurs immediately after the

hemorrhage and then decreases rapidly• Rebleeding is estimated to occur in 50% of

ruptured aneurysms within 6 months of the first hemorrhage, and afterwards at 3% per year

• 50-60% of patients die after rebleeding and 25% are left disabled

Probably the best natural history data come from S Pakarinen: (Incidence, aetiology, and prognosis of primary subarachnoid hemorrhage: a

study based on 589 cases diagnosed in a defined urban population during a defined period. Neurol Scand (Suppl) 1967; 29:1-128)

• Unselected series, involving the entire city of Helsinki, from 1954 to 1961; minimal surgical withdrawals; all sudden deaths were autopsied

• Mortality at 1 day was 32%

• Mortality at 1 week was 43%

• Mortality at 1 month was 56%

• Mortality at 6 months was 60%

Diagnosis of Subarachnoid Hemorrhage (Avoiding Pitfalls in the Diagnosis of Subarachnoid Hemorrhage,

N Engl J Med. 2000; 342:29-36)

• Headaches accounts for 1-2% of visits to ER; 1% of theses have SAH; this rises to 12% for ‘worst headache to their life’ but normal neurological examination and 25% when the examination is abnormal

• About 80% of patients with nontraumatic SAH have a ruptured saccular aneurysm; of the other 20%, about 1/2 have nonaneurysmal perimesencephalic hemorrhages

• Misdiagnosis of SAH remains common and is an important cause of increased clinical morbidity and mortality and of litigation

• Tragically, misdiagnosis is commoner in good-grade patients than in more severe cases (Misdiagnosis of Symptomatic Cerebral Aneurysm. Stroke. 1996; 27:1558-63)

• Misdiagnosis results in worsening of the condition, usually from rebleeding, before definitive treatment is begun

• In the International Cooperative Study on the Timing of Aneurysm Surgery, involving 68 centres in 14 countries, nearly 1/2 of the eligible patients with aneurysmal SAH were excluded because of a delay of more than 3 days before referral

• Causes of diagnostic error: Failure to

– appreciate the spectrum of clinical presentation;

– understand the limitations of CT;

perform and correctly interpret the results of LP

•The first diagnostic test should be non-contrast CT scanning; very thin cuts through the base of the brain are best (3 mm thickness), as thicker cuts miss small collections of blood; anemia below 10 g/dl may not product the increased signal associated with higher hemoglobin concentrations

•Timing of the CT scan in relation to SAH ictus is important; positive results decrease with time; using modern, third-generation CT scanners, interpreted by neuroradiologists, 98-100% are positive up to 12 hours after the ictus and 93% are positive in the first 24 hours

Diagnosis of Subarachnoid Hemorrhage .../cont’d

• LP should be performed in patients whose clinical presentation suggests SAH and whose CT is negative

• ‘Traumatic Tap’ occurs in up to 20% of LPs; Released hemoglobin is metabolized to the pigmented molecular oxyhemoglobin (reddish pink) and bilirubin (yellow), resulting in xanthochromia. Oxyhemoglobin can be detected within hours, but the formation of bilirubin, and enzyme-dependent process, is diagnostically more reliable, but requires up to 12 hours to occur. Timing therefore matters, and CSF should be centrifuged and examined promptly so that RBCs from bleeding at the LP do not undergo lysis in vitro, producing xanthochromia from oxyhemoblobin

• Of 71 patients with thunderclap headache whose results on CT and LP were negative, none of the patients had SAH during an average follow-up period of 3.3 years (Lancet 1988; 2:68-70)

Diagnosis of Subarachnoid Hemorrhage .../cont’d

Clinical Grading Scales for SAHGrade Description

Botterell Scale

1 Conscious with or without signs of blood in the subarachnoid space

2 Drowsy without significant neurological deficit

3 Drowsy with neurological deficit and probably intracerebral hematoma

4 Major neurological deficit and deterioration due to large intracerebral clot, or older age withless severe neurological deficit but pre-existing cerebrovascular disease

5 Moribund or near-moribund with failing vital centres and extensor rigidity

Clinical Grading Scales for SAH .../cont’d

Grade Description

Hunt and Hess Scale

1 Asymptomatic or minimal headache and slight nuchal rigidity

2 Moderate to severe headache, nuchal rigidity, no neurological deficit other than cranial nerve palsy

3 Drowsiness, confusion, or mild focal deficit

4 Stupor, moderate to severe hemiparesis, possible early decerebrate rigidity and vegetative disturbances

5 Deep coma, decerebrate rigidity, moribund appearance

Clinical Grading Scales for SAH .../cont’d

Grade Description

World Federation of Neurological Surgeons Scale

1 Glasgow coma scale 15, no motor deficit

2 GCS 13 to 14, no motor deficit

3 GCS 13 to 14, with motor deficit

4 GCS 7 to 12, with or without motor deficit

5 GCS 3 to 6, with or without motor deficit

The Fisher Grading of SAH as Demonstrated by CT scan

(Relation of Cerebral Vasospasm to Subarachnoid Hemorrhage Visualized by Computerized Tomographic Scanning. CM Fisher et al. Neurosurgery, 6:1-9, 1980)

Group (Grade)

1

2

3

4

Description

No blood detected

A diffuse deposition or thin layer with all vertical layers of blood (interhemispheric fissure, insular cistern, ambient cistern) less than 1 mm thick)

Localized clots and/or vertical layers of blood 1 mm or greater in thickness

Diffuse or no subarachnoid blood, but with intracerebral or intraventricular clots

Summary of the Relationship between the Amount of Subarachnoid Blood and the

Development of Vasospasm(CM Fisher et al. Neurosurgery, 6:1-9, 1980)

VASPSPASM

SubarachnoidBlood

No.Cases None

Slight-Moderate Severe

Signs ofSevere Vasospasm

None 11 7 2 2 0

Diffuseonly

7 4 3 0 0

Clot or ThickLayer

24 0 1 23 23

Diffuse orNone, withCerebral ofVentricularBlood

5 3 2 0 0

TOTAL 47 14 8 25 23

Prognostic Factors in Aneurysmal SAH(L Disney, B Weir, M Grace et al. Factors Influencing the Outcome of Aneurysm Rupture in

Poor Grade Patients: A Prospective Series. Neurosurgery 23: 1-9 1988)

Using a discriminant function analysis, the relative importance of factors

prognostic for outcome was, in order of importance:

1. Whether the patient was treated surgically:

Patients subjected to definitive obliteration of the aneurysm (65%) did much better than those whose aneurysms were not clipped, with a mortality of 25% compared to 86% (P<0.001)

2. Neurological grade on admission:

a) Hunt and Hess: Mortality increased with worsening neurological grade, being 23% for Grade III, 44% for Grade IV and 91% for Grade V. Good outcome occurred in 30% of Grade III, 14% of Grade IV and no Grade V patients (P<0.001)

b) GCS: Mortality was inversely related to admission GCS at 29% for GCS 11 to 14, 42% for GCS 7 to 10 and 70% for GCS 3 to 6. Good outcome occurred in 29% for GCS 11-14, 14% for GCS 7-10 and 7% for GCS 3-6 (P=0.01)

3. Age:

Younger patients had more good outcomes and lower mortality. The mean age for good outcome was 46 and for death, 58

years.

4. Initial systolic blood pressure:

When categorized by initial systolic BP (<141, 141-180, >180), patients with higher systolic BP were less likely to have a good outcome and had a higher mortality rate (P<0.05)

5. Aneurysm size:

A bad outcome was seen in 72% of patients with aneurysm diameter >21 mm and 56% with aneurysm diameter 4-6 mm

Prognostic Factors in Aneurysmal SAH .../cont’d

SAH of Unknown Etiology(Subarachnoid Hemorrhage of Unknown Etiology. AH Friedman. Chapter 235 in Neurosurgery, 2nd Ed.,

Vol II, Edited by RH Wilkins and SS Rengachary, McGraw-Hill, 1966)

• With modern imaging, 75-80% of cases of spontaneous SAH will be found to have an aneurysm. AVM, including dural fistulae, spinal cause, and a variety of rare causes occur, but in some cases no cause for the SAH is ever found

• Many of these cases will show a predominance of perimesencephalic SAH on CT scan. These patients are more likely to have negative CT scans, and are less likely to show SAH in the sylvian and interhemispheric fissures

• Hypertension is the only known risk factor for such cases• Patients tend to be in better clinical condition: 75% are Hunt-Hess Grades I-II, while only 49% of

cases with an aneurysm are Hunt-Hess Grades I-II• 80% will have a good outcome, with return to work (compared to 50% with an aneurysmal SAH)• Repeat angiography is controversial. ACA and MCA are likeliest sites to find an aneurysm. 3.6%

of modern series show an aneurysm on repeat angiography. Without a second angiogram, 4% of patients with rebleed early (<3 months) and 0.8% per year for at least the next 3 years

• Friedman’s group recommends selective repeat angiography when: 1) Vasospasm compromised the first study; 2) Part of the cerebral circulation is not well seen; 3) CT shows large amount of diffuse or focal SAH; 4) A second SAH occurs

Unruptured Intracranial Aneurysms(Unruptured Intracranial Aneurysm - Risk of Rupture and Risks of Surgical Intervention. The ISUIA

Investigators. N Engl J Med 1998; 339: 1725-33)

• There appears to be a major difference in the incidence of rupture between cases with no prior hx of SAH and a small (<10 mm aneurysm), Group I, 0.05% per year, and those with prior hemorrhage from a definitively treated aneurysm, Group II (11 fold increase, to 0.5% per year) (Editorial comment: The validity of the distinction between Groups I and II depends on the treating surgeons’ ability to select and treat the ruptured lesion when multiple aneurysms are identified. A small error in this selection could amount for much of the apparent difference between Groups I and II. WST)

• In Group I, the significant predictors of rupture were size and location: Aneurysms 10-24 mm in diameter were 11.6X more likely to rupture than those <10 mm; those 25 mm or more were 59X more likely to rupturethan those <10 mm. The relative risk of rupture was 13.8 for basilar tip aneurysms and 13.6 for those in the vertebrobasilar or posterior cerebral distributions

• In Group II, size did not predict rupture risk, but location was still significant. Aneurysms at the basilar tip were 5.1X more likely to rupture

• The morbidity and mortality of repair of these intact lesions were higher than expected, with age being the only significant predictor of a poor surgical outcome (worse with advancing age)

• The overall rate of surgery-related morbidity and mortality was 17.5% in Group I and 13.6% in Group II at 30 days, and was 15.7% and 13.1%, respectively, at 1 year.

Unruptured Aneurysms:A Different Perspective from ISUIA:

(S. Juvela, M. Porras & K. Poussa. Natural history of unruptured intracranial aneursyms: probability of

and risk factors for aneurysm rupture. J. Neurosurg, 93: 379-387, 2000)

• 142 patients with 181 unruptured aneurysms, followed from the 1950’s until death, SAH or 1997-98 (mean 19.7 yrs). No surgical selection.

• Asymptomatic incidental aneurysms - 5 patients

Symptomatic intact aneurysms - 6 patients

SAH from another repaired aneurysm - 131 patients

(How did they determine the rupture site pre-CT? WST comment)• In 2575 person-years of FU, 33 first-time episodes of SAH from previously unruptured

aneurysms for an average annual incidence of 1.3%. SAH fatal in 17 cases.• The cumulative rate of bleeding was 10.5% at 10 yrs, 23% at 20 yrs and 30.3% at 30 yrs.• Risk factors:

– Diameter of the aneurysm– Patient age at diagnosis (inverse)– Active smoking status at the time of diagnosis

Selected References

1. Avoiding Pitfalls in the Diagnosis of Subarachnoid Hemorrhage. JA Edlow and LR Caplan. N Engl J Med 342:29-36, 2000

2. Unruptured Intracranial Aneurysms - Risk of Rupture and Risks of Surgical Intervention. ISUIA Investigators. N Engl J Med; 339: 1725-33, 1998

3. Intracranial Aneurysms and Subarachnoid Hemorrhage: An Overview. B Weir and RL Macdonald. Chapter 214 (pp 2191-2213) in Neurosurgery, 2nd edition, volume II, 1996, editors RH Wilkins and SS Rengachary, published by McGraw-Hill

4. Relation of Cerebral Vasospasm to Subarachnoid Hemorrhage Visualized by Computerized Tomographic Scanning. CM Fisher JP Kistler and JM Davis. Neurosurgery, 6:1-9, 1980

5. Factors Influencing the Outcome of Aneurysm Rupture in Poor Grade Patients: A Prospective Series. L Disney, B Weir, M Grace et al Neurosurgery 23: 1-9 1988

Genetics of Intracranial AneurysmsRef. Neurosurgery clinics of North America, July 1998, pp 485-493

Observations to suggest genetic involvement:

Association of various heritable disorders with ICA

The familial aggregation of ICA in the absence of known systemic disorder

Heritable Disorders associated with ICA:

Heritable CT disorder account for at least 5% of the cases of ICA

True frequency may be higher due to variability in phenotypic expression and negative family history due to new mutation

The most important ones are:

Ehlers-Danlos type IV

Marfan’s syndrome

NF1

ADPKD

Ehlers-Danlos Syndrome Type IV

Defeciency of collagen type 3

Mutation in the gene encoding for pro 1(III) chain of type III collagen

Joint hypermobility, hyperelastic/fragile skin, abnormal scaring

Type IV is least common and the most lethal

Prevalence 1/50,000-500,000

Vascular catastrophes account for the great majority of deaths

Clues to the diagnosis

Facial appearance: thin nasal bridge, thin lips, lobeless ears, prematurely aged appearance

Bruising tendency, MVP, spontaneous pneumothorax, abnormal scarring, varicose veins

ICA:

Prevalence?, 14 in 202 patient

Saccular or fusiform, located in the cavernous sinus

Thin walled, difficult to repair

Marfan’s syndrome

Mutation in gene encoding fibrillin-1 (glycoprotein, major component of microfbrils in ECM and elastic tissues)

Prevalence 1/10,000-20,000

Abnormalities of the skeleton, cardiovascular system, eyes, spinal meninges

Variability in the phenotypic expression

ICA:

Saccular or fusiform, dissecting aneurysms

Propensity to the proximal internal carotid artery

Fragility of the connective tissue is not a major problem

Ectasia and tortuosity of the vessels

Neurofibromatosis type 1

Mutation in NF1 gene encoding neurofibromin which may have regulatory role in the development of connective tissue

Prevalence 1/3000-5000

Café-au-lait spot, lish nodule, neurofibroma

Vascular complication; stenosis rupture, aneurysm, fistula

ICA:

Saccular or fusiform

Vascular fragility, distorted anatomy

Association with intracranial arterial occlusive disease

ADPKD

Mutation in two genes PKD1 and PKD2

PKD1 linked disease is more severe

Polycystin encoded by PKD1 is an integral membrane protein, play a role in the integrity of ECM of CT

Most common monogenetic disorder

Prevalence 1/400-1000

Cysts in kidney, liver, spleen, pancreas, ovaries

Cardiovascular abnormalities: MVP, aortic and cervicocephalic dissection, coronary and AAA

ICA:

Saccular, fusiform, dissecting

Vascular fragility

Ruputre occurs in earlier age, increased risk of developing new ICA

ICA in 25% of patient with ADPKD at autopsy, 10% on MRA

Family screening with MRA yields ICA in 20-25%

Cause of death in one-fifth

ADPKD account for 2-7% of all ICA

Familial ICA

First described by Chamber et al. In 1954

With the exception of ADPKD, Ehlers-Danlos IV, Pompe disease, Idiopathic nonarteriosclerotic cerebral calcification there is no association with heritable CT disease

7-20% of first or second-degree relatives of patient with SAH have ICA

First-degree relatives of patient with SAH have twice to fivefold increase risk of having ICA

First-degree relatives have threefold increased risk compared to second-degree relatives

Inheritance pattern is unknown, most likely multifactorial, or AD

ICA:

Rupture at younger age (5 year earlier), 71% has ruptured by age of 50 Vs 42% in nonfamilial ICA

Anterior communicating artery aneurysms are underrepresented, MCA is overrepresented

Rupture at smaller size

Increase female preponderance

Larger multiplicity

Siblings are more likely to harbor aneurysms at the same side at mirror sites

Severity of hemorrhage is similar to nonfamilial ones

Screening for familial ICA

Why?

Poor prognosis once ruptured

Low surgical risk for the nonruptured (5% morbidity, 2% mortality)

Caveat: aneurysms may develop over short period of time

Indication for surgery for asymptomatic ICA is still unclear (critical size)

Who?

Families with two or more affected members

Restricted to first-degree relatives (yield 9-29%)

Monozygotic twin

When?

Screening between the ages of 35-65

Youngest patient with familial ICA is 6 years old

De novo aneurysms occur at a rate of 2% per year

Repeat screening at 6-month to 5-year intervals

Screening for familial ICA …/cont’d

How?

MRA is the most widely used

Critical size for detection 3-5 mm

Helical CT angiography

Coventional angiography

ICA gene

Current approaches

Screen the human genome for ICA gene by testing a large number of distinct highly pleomorphic genetic markers

Analyze variations in the sharing of marker alleles among affected sibling pairs

Candidate gene sequence analysis e.g., PKD1 or COL3A1

Heritable Disorders Associated with Intracranial Aneurysms

Disorder InheritancePattern

Locus Gene Gene Product

Achondroplasia AD 4p16.3 FGFR3 Fibroblast growthfactor receptor 3

Alkaptonuria AR 3q2 AKU ?

ADPKD AD 16p13.3 PKD1 Polycystin

Cohen syndrome AR 8q22 CHS1 ?

Ehlers-DanlosSyndrome type I

AD 9q COL5A1 Ollagen type V

Ehlers-DanlosSyndrome type IV

AD 2q31 COL3A1 Collagen type III

Fabry disease AR XL-R Xq22.1 -galactosidase A

Kahn syndrome AR ? ? ?

Marfan’s syndrome AD 15q21.1 FBN1 Fibrillin-1

NF1 AD 17q11.2 NF1 Neurofibromin

Noonan syndrome AD 12q22 NS1 ?

Heritable Disorders Associated with Intracranial Aneurysms …/cont’d

Disorder InheritancePattern

Locus Gene Gene Product

Osler-Rendu-Weber disease

AD 9q34.1 HHT1 Endoglin

Osteogenesisimperfecta type 1

AD 17q22.1 COL1A1 Collagen type 1

Pompe disease AR 17q23 GAA -Glucosidase

Pseudoxanthomaelasticum

AD & AR ? ? ?

Rambaudsyndrome

AR ? ? ?

Tuberous sclerosis AD 9q34/16p13.3 TSC1/TSC2 ?/Tuberin

Wermer syndrome AD 11q13 MEN1 ?

3M syndrome AR ? ? ?

1-Antitrypsindeficiency

AcoD 14q32.1 P1 1-Antitrypsin