Transcript Subarachnoid Hemorrhage Seminar 1

Subarachnoid Hemorrhage
Seminar 1
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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 History
Prognosis 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
Diagnosis of Subarachnoid Hemorrhage
.../cont’d
• 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 followup period of 3.3 years (Lancet 1988; 2:68-70)
Clinical Grading Scales for SAH
Grade
1
2
3
4
5
Description
Botterell Scale
Conscious with or without signs of blood in the
subarachnoid space
Drowsy without significant neurological deficit
Drowsy with neurological deficit and probably
intracerebral hematoma
Major neurological deficit and deterioration due to large
intracerebral clot, or older age withless severe neurological
deficit but pre-existing cerebrovascular disease
Moribund or near-moribund with failing vital centres and
extensor rigidity
Clinical Grading Scales for SAH
Grade
1
2
3
4
5
.../cont’d
Description
Hunt and Hess Scale
Asymptomatic or minimal headache and slight nuchal
rigidity
Moderate to severe headache, nuchal rigidity, no
neurological deficit other than cranial nerve palsy
Drowsiness, confusion, or mild focal deficit
Stupor, moderate to severe hemiparesis, possible early
decerebrate rigidity and vegetative disturbances
Deep coma, decerebrate rigidity, moribund appearance
Clinical Grading Scales for SAH
Grade
1
2
3
4
5
.../cont’d
Description
World Federation of Neurological Surgeons Scale
Glasgow coma scale 15, no motor deficit
GCS 13 to 14, no motor deficit
GCS 13 to 14, with motor deficit
GCS 7 to 12, with or without motor deficit
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
Subarachnoid
Blood
None
No.
Cases
11
SlightModerate
2
Signs of
Severe Severe Vasospasm
2
0
None
7
Diffuse
only
7
4
3
0
0
Clot or Thick
Layer
24
0
1
23
23
Diffuse or
None, with
Cerebral of
Ventricular
Blood
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)
Prognostic Factors in Aneurysmal SAH .../cont’d
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
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)
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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)
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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)
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In Group I, the significant predictors of rupture were size and location: Aneurysms 1024 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: 172533, 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 Aneurysms
Ref. 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
Inheritance
Pattern
Locus
Gene
Gene Product
Achondroplasia
AD
4p16.3
FGFR3
Alkaptonuria
AR
3q2
AKU
Fibroblast growth
factor receptor 3
?
ADPKD
AD
16p13.3
PKD1
Polycystin
Cohen syndrome
AR
8q22
CHS1
?
Ehlers-Danlos
Syndrome type I
Ehlers-Danlos
Syndrome type IV
Fabry disease
AD
9q
COL5A1
Ollagen type V
AD
2q31
COL3A1
Collagen type III
AR
XL-R
Xq22.1
Kahn syndrome
AR
?
?
Marfan’s syndrome
AD
15q21.1
FBN1
NF1
AD
17q11.2
NF1
Neurofibromin
Noonan syndrome
AD
12q22
NS1
?
-galactosidase A
?
Fibrillin-1
Heritable Disorders Associated with
Intracranial Aneurysms …/cont’d
Disorder
Inheritance
Pattern
Locus
Gene
Gene Product
AD
9q34.1
HHT1
Endoglin
AD
17q22.1
COL1A1
Collagen type 1
AR
17q23
GAA
-Glucosidase
Pseudoxanthoma
elasticum
Rambaud
syndrome
Tuberous sclerosis
AD & AR
?
?
?
AR
?
?
?
AD
9q34/16p13.3
TSC1/TSC2
Wermer syndrome
AD
11q13
MEN1
?
3M syndrome
AR
?
?
?
1-Antitrypsin
deficiency
AcoD
14q32.1
P1
Osler-RenduWeber disease
Osteogenesis
imperfecta type 1
Pompe disease
?/Tuberin
1-Antitrypsin