Handbook of Neurosurgery 7th Ed

32. Intracerebral hemorrhage

Intracerebral hemorrhage (ICH) is a hemorrhage within the brain parenchyma. Formerly commonly referred to as “hypertensive hemorrhage”, but hypertension is a debatable etiology in many cases (see Hypertension as a cause?, page 1122).

32.1. Intracerebral hemorrhage in adults

Key concepts:

• the second most common form of stroke (15-30% of strokes), but the most deadly

• unlike ischemic infarct: smooth progressive onset over minutes to hours, often with severe headache, vomiting and alterations in level of consciousness

• unenhanced CT scan of the brain is the initial diagnostic study of choice

• the volume of the hematoma correlates highly with morbidity and mortality

• the clot enlarges in at least 33% of cases within the first 3 hours of onset

• angiography is recommended (as long as it doesn’t delay emergent treatment) except for patients > 45 yrs of age with preexisting hypertension and ICH in thalamus, putamen or posterior fossa

• treatment

still controversial. The initial promise of rFVIIa has not been actualized

the usefulness of surgery is still controversial, but seems limited to some cerebellar hemorrhages and select supratentorial hemorrhages that come within 1 cm of the cortical surface

EPIDEMIOLOGY

INCIDENCE

The second most common form of stroke (≈ 15-30% of all strokes, and the most deadly. Approximately 12-15 cases per 100,000/yr. Approximately twice the incidence as SAH¹. Onset is usually during activity (rarely during sleep), which may be related to elevation of BP or increased CBF (see Etiologies below).

Table 32-1 Relative risk of ICH with EtOH consumption

Period prior to ICH	Amount* (g EtOH)	Relative risk
24 hours	41-120	4.6
	> 120	11.3
1 week	1-150	2.0
	151-300	4.3
	> 300	6.5

* 1 standard drink = 12 g EtOH

Risk factors

The following are epidemiologic risk factors, also see Etiologies, page 1119 for others.

1. age: the incidence increases significantly after age 55 years and doubles with each decade of age until age > 80 yrs where incidence is 25 times that during previous decade. Relative risk for age > 70 yrs is 7

2. gender: more common in men

3. race: in the U.S., ICH affects blacks more than whites. May be related to higher prevalence of HTN in blacks. Incidence may also be higher in orientals²

4. previous CVA (any type) increases risk to 23:1

5. alcohol consumption^{2, 3}:

A. recent use: moderate or heavy alcohol consumption both within the 24 hours and the week preceding the ICH were risk factors for ICH⁴ as shown in Table 32-1

B. chronic use: one study suggests that consuming > 3 drinks a day increases the risk of ICH by ≈ 7 times^{5 (p 15)}

C. ICH in patients with high ethanol consumption were more commonly lobar⁶

6. cigarette smoking: does not increase the risk of ICH^{7, 8}

7. street drugs: cocaine, amphetamines, phencyclidine⁹

8. liver dysfunction: hemostasis may be impaired on the basis of thrombocytopenia, reduced coagulation factors, and hyperfibrinolysis¹⁰

LOCATIONS OF HEMORRHAGE

Common sites of ICH are shown in Table 32-2. Common arterial feeders of ICHs:

• lenticulostriates: the source of putaminal hemorrhages (possibly secondary to microaneurysms of Charcot-Bouchard, see below)

• thalamoperforators

• paramedian branches of BA

Table 32-2 Common sites for ICH (modified¹¹)

%	Location
50%	striate body (basal ganglia); putamen most common; also includes: lenticular nucleus, internal capsule, globus pallidus
15%	thalamus
10-15%	pons (≈90% of these are hypertensive)
10%	cerebellum
10-20%	cerebral white matter
1-6%	brain stem

Lobar hemorrhage

Incorporates primary hemorrhages into the occipital, temporal, frontal and parietal lobes (including ICH arising from cortex and subcortical white matter), as opposed to hemorrhage of deep structures (e.g. basal ganglion, thalamus, and infratentorial structures)¹². Accounts for 10-32% of nontraumatic ICHs¹². With large hemorrhages, it may be difficult to make a distinction between lobar and deep ICH.

Lobar hemorrhages are more likely to be associated with structural abnormalities than deep hemorrhages (see below). They may also be more common in patients with high alcohol consumption (see above). Lobar hemorrhages may also have a more benign outcome than ganglionic-thalamic hemorrhages¹².

Etiologies: Although many causes of ICH can produce lobar hemorrhages (see below for a detailed list), those that are more likely to produce lobar hemorrhages include:

1. extension of a deep hemorrhage

2. cerebral amyloid angiopathy: the most common cause of lobar ICH in elderly normotensive patients (see page 1122)

3. trauma

4. hemorrhagic transformation of an ischemic infarct: see below

5. tumor: see page 1123. Multiple lobar hemorrhages may occur with metastases

6. cerebrovascular malformation (especially AVM): see page 1098

7. rupture of an aneurysm: see below for circumstances likely to produce this

8. idiopathic

Internal capsule

There may be prognostic significance with regard to contralateral motor function if the hemorrhage is medial to and/or extending through the internal capsule (IC), or lateral to the IC and merely compressing it, making the clot more accessible to surgical treatment without damaging the IC.

ETIOLOGIES

History check list

Based on information in this section, the following check-list is presented to assist in the gathering of historical information important in evaluating the adult with ICH:

1. hypertension

2. drugs:

A. sympathomimetics:

1. amphetamines, cocaine

2. appetite suppressants or nasal decongestants (phenylpropanolamine, pseudoephedrine)

B. dietary supplements: especially ephedra alkaloids (ma huang)

C. anticoagulants: warfarin in particular

D. antiplatelet drugs: aspirin, NSAIDs, Plavix

E. birth control pills: questionable association

3. history of alcohol abuse

4. coagulopathies

5. leukemia

6. previous stroke

7. history of known vascular abnormalities (AVM, venous angioma…)

8. tumor: known history of cancer, especially those that tend to go to brain (lung, breast, GI, renal, melanoma…)

9. recent surgery: especially carotid endarterectomy, procedures requiring heparin…

10. recent childbirth and/or eclampsia or preeclampsia

11. history of recent trauma

ETIOLOGIES

1. “hypertension” (debatable as a cause or effect, see below) but is a risk factor

A. acute hypertension (HTN): as may occur in eclampsia (see below) or with use of certain drugs (e.g. cocaine, phenylpropanolamine…, see page 1121)

B. chronic HTN: possibly causes degenerative changes within blood vessels

2. possibly associated with acutely increased CBF (globally or focally)¹³, especially to areas previously rendered ischemic:

A. following carotid endarterectomy^{14, 15}

B. following repair of congenital heart defects in children¹⁶

C. previous CVA (embolic¹⁷ or otherwise): hemorrhagic transformation may occur in up to 43% of CVAs during the first month¹⁸. May follow dislodgment or recanalization of an arterial occlusion, although it has been demonstrated with persistent occlusion¹⁹. May occur as early as ≤ 24 hrs after a CVA in patients with a negative CT done within 6 hours²⁰. Two types^{18, 21}:

• type 1: diffuse or multifocal. Heterogeneous or mottled appearance within the boundaries of the CVA. Less hyperdense than primary ICH

• type 2: extensive hematoma. Probably unifocal source. As hyperdense as primary ICH and may extend outside the original CVA boundaries. Unlike type 1, classically associated with anticoagulation therapy, and tends to occur in initial few days after CVA and is often associated with clinical worsening. May be difficult to distinguish from primary ICH, and may be frequently misdiagnosed as such²⁰

D. migraine: during²² or following²³ a migraine attack (probably an exceedingly rare event)

E. following surgery to remove an AVM: “normal perfusion pressure breakthrough”. Some cases may be due to incomplete AVM excision

F. physical factors: following strenuous physical exertion²⁴, exposure to cold²⁵…

3. vascular anomalies

A. AVM: rupture (see Arteriovenous malformation, page 1098)

B. aneurysm rupture

1. saccular (“berry”) aneurysms:

a. aneurysms of the circle of Willis (COW): ICH may be more likely with aneurysms that have become adherent to brain surface by fibrosis from inflammation or previous hemorrhages. May produce ICH when they rupture instead of the usual SAH

b. aneurysms distal to the COW (e.g. MCA aneurysms)

2. microaneurysms of Charcot-Bouchard: see below

C. venous angioma rupture

4. “arteriopathies”

A. amyloid angiopathy: usually → repeated lobar hemorrhages (see below)

B. fibrinoid necrosis^{26, 27} (sometimes seen in cases of amyloid angiopathy)

C. lipohyalinosis: subintimal lipid-rich hyaline material²⁸

D. cerebral arteritis (including necrotizing angiitis)

5. brain tumor (primary or met): see Hemorrhagic brain tumors below

6. coagulation or clotting disorders

A. iatrogenic

1. patients receiving anticoagulation therapy: see page 1123

2. thrombolytic therapy:

a. for acute ischemic CVA: incidence of symptomatic ICH within 36 hrs of treatment with rtPA is 6.4% (vs. 0.6% in the placebo treated group)²⁹ (see page 1017)

b. for acute MI or other thrombosis: incidence is ≈ 0.36-2%^30-32. Risk is increased with higher doses than the recommended 100 mg of alteplase (Activase®, recombinant tissue plasminogen activator (rt-PA))³³, in older patients, in those with anterior MI or higher Killip class, and with bolus administration (vs. infusion)³⁴. When heparin was used adjunctively, higher doses were associated with higher risk of ICH³⁵. ICH is thought to occur in those patients with some preexisting underlying vascular abnormality³⁶. Immediate coronary angioplasty is safer than rtPA when available³²

3. aspirin:

a. one ASA qod was associated with increased risk of ICH³⁷, with a rate of 0.2-0.8% per year³⁸

b. ASA 100 mg/d did not increase the risk of significant ICH in patients > 60 yrs with mild to moderate head injury (GCS ≥ 9)³⁹

B. leukemia

C. thrombocytopenia:

1. thrombotic thrombocytopenic purpura

2. aplastic anemia

7. CNS infection:

A. especially fungal, which attack blood vessels

B. granulomas

C. herpes simplex encephalitis: may initially produce low density lesions that progress to hemorrhagic ones

8. venous or dural sinus thrombosis: see page 1166

9. drug related

A. substance abuse

1. alcohol: > 3 drinks/day increases the risk of ICH ≈ 7-fold (see page 1118)

2. drug abuse: especially sympathomimetics (cocaine^{40, 41}, amphetamine⁴²

B. drugs that raise BP:

1. alpha-adrenergic agonists (sympathomimetics): phenylpropanolamine^{43, 44} (may also cause ischemic CVA, see page 1025) which was removed from OTC nasal decongestants and appetite suppressants, but other OTC alpha agonists (including phenylephrine, ephedrine⁴⁵, and pseudoephedrine⁴⁶) are also problematic⁴⁷

2. ephedra alkaloids: sold as a dietary supplement (ma huang) to suppress appetite and increase energy. Associated in case reports with HTN, SAH, ICH, seizures and death⁴⁸

10. post-traumatic: often in a delayed fashion^{49, 50} (see Hemorrhagic contusion, page 893)

11. pregnancy related: the risk of ICH in pregnancy and puerperium (up to 6 weeks post partum) is ≈ 1 in 9,500 births⁵¹

A. most commonly associated with eclampsia or preeclampsia: the mortality of eclampsia is ≈ 6% with ICH being the most frequent direct cause⁵² (also see Pregnancy & intracranial hemorrhage, page 1086)

B. postpartum ICH (median 8 days, range 3-35 days) in the absence of eclampsia has been reported⁵³; when associated with vasculopathy the term post-partum cerebral angiopathy has been used

C. vascular findings:

1. some cases associated with isolated cerebral vasculopathy in the absence of systemic vasculitis⁵⁴

2. some cases demonstrate vasospasm

3. some cases show findings (e.g. patchy enhancement in occipital lobes) suggestive of cerebrovascular dysautoregulation (see page 73)

4. some cases show no vascular-related abnormalities

12. post-operative:

A. following carotid endarterectomy (see above)

B. following craniotomy:

1. at site of craniotomy⁵⁵: risk factors identified

a. especially within residual astrocytoma after subtotal resection

b. following craniotomy for AVM (see above)

2. at site remote from craniotomy. In a series of 37 patients, unlike hematomas at craniotomy site, the following were identified as not being related to risk of hemorrhage: HTN, coagulopathy, CSF drainage, underlying occult lesion

a. following drainage of chronic SDH: see page 901

b. cerebellar hemorrhage

i. following pterional craniotomy⁵⁶ (this author incriminated possibly rapid overdrainage of CSF)

ii. following temporal lobectomy⁵⁷

13. idiopathic¹²

Cerebellar hemorrhage etiologies

Etiologies are similar to ICH of any location, however, some nuances:

1. HTN is a factor in up to two-thirds of cerebellar hemorrhages

2. AVM is a consideration, aneurysm is very rare (possibly AICA aneurysm, but usually only in association with other high-flow lesion, e.g. AVM⁵⁸)

3. may be related to recent previous spinal or supratentorial surgery

HYPERTENSION AS A CAUSE?

Hypertension (HTN) is controversial as cause of ICH since the incidence of both ICH and HTN increases with age (66% of patients > 65 yrs have HTN). The relative risk for ICH with HTN is 3.9-5.4, depending on the definition of HTN used⁵⁹. Many patients with ICH are dramatically hypertensive on presentation, however, acute elevations of ICP from the hemorrhage may actually precipitate HTN (part of Cushing’s triad, see Table 27-17, page 868). HTN is probably a risk factor primarily for pontine/cerebellar ICH and is probably not a factor in at least 35% of basal ganglion hemorrhages.

MICROANEURYSMS OF CHARCOT-BOUCHARD

AKA miliary aneurysms⁶⁰. Occur primarily at bifurcation of small (< 300 μm) perforating branches of lateral lenticulostriate arteries in basal ganglia, more common in hypertensive patients⁶¹. Possibly the origin of some “hypertensive” ganglionic (putaminal) hemorrhages⁶², but this is controversial.

(CEREBRAL) AMYLOID ANGIOPATHY

Cerebral amyloid angiopathy (CAA) AKA congophilic angiopathy. Pathologic deposition of beta amyloid protein (appears as birefringent “apple-green” under polarized light when stained with congo red) within the media of small meningeal and cortical vessels (especially those in white matter) without evidence of systemic amyloidosis⁶³. Some vessels may show fibrinoid necrosis of vessel wall^{64, 65}.

CAA should be suspected in patients with recurrent hemorrhages (uncommon with “hypertensive hemorrhages”⁶⁶) that are lobar in location (see page 1119). Gradient-echo MRI may identify petechial hemorrhages or hemosiderin deposits from small cortical hemorrhages which may be associated with CAA⁶⁷. Less likely in the case of basal ganglion or brain stem hemorrhages¹².

Table 32-3 Criteria for the diagnosis of CAA⁷¹

Definite CAA	Full postmortem exam showing all 3 of the following:
	A. lobar, cortical, or corticosubcortical hemorrhage B. severe CAA C. absence of another diagnostic lesion
Probable CAA with supporting pathological evidence	Clinical data & pathological tissue showing all 3 of the following:
	A. lobar, cortical, or corticosubcortical hemorrhage B. some degree of vascular amyloid deposition in specimen C. absence of another diagnostic lesion
Probable CAA	Clinical data and MRI findings showing all 3 of the following:
	A. age ≥ 60 yrs B. multiple hemorrhages restricted to the lobar, cortical, or corticosubcortical region C. absence of another cause of hemorrhage*
Possible CAA	Clinical data and MRI findings:
	A. age ≥ 60 yrs B. single lobar, cortical, or corticosubcortical hemorrhage without another cause*, or multiple hemorrhages with a possible but not a definite cause* or with some hemorrhages in an atypical location (e.g. brain stem)

* e.g. excessive anticoagulation (INR > 3.0), head trauma, ischemic CVA, CNS tumor, cerebrovascular malformation, vasculitis or blood dyscrasia

Incidence increases with age: CAA is present in ≈ 50% of those over 70 years of age⁶⁸, however, most do not hemorrhage. CAA is probably responsible for ≈ 10% of cases of ICH. May be associated with genetic factors (including the apolipoprotein E 4 allele⁶⁹), and may be more prevalent in patients with Down syndrome. Although they are distinct diseases, there is some overlap between CAA and Alzheimer’s disease; the amyloid in CAA is identical to that found in senile plaques of Alzheimer’s disease. CAA may increase the risk of ICH by potentiating plasminogen⁷⁰ (may be of special relevance to patients receiving tissue plasminogen activator (t-PA) to treat MI or CVA).

Patients with CAA may present with a TIA-like prodrome (see below).

Among patients with lobar hemorrhage, those with the apoE 4 allele typically have their first hemorrhage > 5 yrs earlier than noncarriers (73 ± 8 yrs vs./79 ± 7 yrs)⁶⁹.

Diagnostic tests are useful mainly to rule-out other conditions. The definitive diagnosis of CAA requires pathologic evaluation of brain tissue. Criteria for the diagnosis of CAA are shown in Table 32-3⁷¹.

HEMORRHAGIC BRAIN TUMORS

Although any brain tumor can hemorrhage, tumoral ICH is usually associated with malignancies. Tumors can also produce SAH(see page 1034) or subdural hematomas.

Malignant tumors most commonly associated with ICH:

1. glioblastoma

2. lymphoma

3. metastatic tumors

A. melanoma^{72, 73}: ≈ 40% hemorrhage

B. choriocarcinoma^{72, 74, 75}: ≈ 60% hemorrhage

C. renal cell carcinoma

D. bronchogenic carcinoma: although only ≈ 9% hemorrhage, this tumor is such a frequent source of cerebral mets that it therefore is a more common source of tumoral ICH

Malignant tumors that hemorrhage less commonly include:

1. medulloblastoma^76-79 (most commonly in children)

2. gliomas^{80, 81}

Some benign brain tumors that have been associated with ICH include:

1. meningiomas have been associated with intratumoral, subdural, and nearby parenchymal hemorrhage^82-85. Tendency to bleed is similar for angioblastic variety as for other highly vascular meningiomas

2. pituitary adenoma (see Pituitary apoplexy, page 635)

3. oligodendroglioma (relatively benign): rarely presents with hemorrhage⁸⁶, classically after years of causing seizures

4. hemangioblastoma⁸⁷

5. vestibular schwannoma^88-90

6. cerebellar astrocytoma⁹¹

ANTICOAGULATION PRECEDING ICH

10% of patients on warfarin develop a significant bleeding complication per year, including ICH (65% mortality in this group). The risk of ICH in patients treated with warfarin for A-fib varies between 0-0.3% per year³⁸(historically, this was as high as ≈ 1.8% in older studies⁹² from the 1960’s and 70’s), but when an elderly subgroup (mean age 80 yrs) was analyzed, this rate was 1.8% per year³⁸. ICH was the only cause of fatal bleeding complications of warfarin therapy in one series where the cumulative risk of a fatal hemorrhage was 1% at 1 year and 2% at 3 yrs⁹³.

The risk of hemorrhagic complications was increased with the length and also the variability of the PT, and during the first three months of anticoagulation⁹³. Patients with cerebral amyloid angiopathy (CAA)(see above) are also at increased risk of ICH following administration of antiplatelet drugs or anticoagulants⁷¹.

CLINICAL

In general, the neurologic deficit with ICH is characterized by a smooth progressive onset over minutes to hours, unlike embolic/ischemic CVA where deficit is maximal at onset. With ICH, severe headache, vomiting and alterations in level of consciousness may be more common (H/A may not be more prevalent than in embolic CVA, but it is often a first and prominent symptom¹²).

Prodrome

TIA-like symptoms may precede lobar hemorrhages^{94, 95} in patients with CAA, and may occur in up to ≈ 50% of patients for whom a complete history is obtainable. Unlike typical TIAs, these usually consist of numbness, tingling or weakness (involving the area where the hemorrhage will subsequently occur) that gradually spreads in a manner reminiscent of a Jacksonian-march and may spill-over vascular territories (probably an electrical phenomenon rather than an ischemic event). This is suggestive of but not pathognomonic for the subsequent development of lobar ICH.

CONCOMITANTS OF SPECIFIC LESIONS IN ICH

Putaminal hemorrhage

The most common site for ICH. Smooth gradual deterioration in 62% (maximal deficit at onset in 30%); never fluctuating. Contralateral hemiparesis, may progress to hemiplegia or even coma or death. H/A in 14% at onset. No H/A at any time in 72%. Papilledema and subhyaloid preretinal hemorrhage are rare.

Thalamic hemorrhage

Classically, contralateral hemisensory loss. Also hemiparesis when the internal capsule is involved. Extension into upper brain stem → vertical gaze palsy, retraction nystagmus, skew deviation, loss of convergence, ptosis, miosis, anisocoria, ± unreactive pupils. H/A in 20-40%. Motor deficit similar to putaminal hemorrhage, but contralateral sensory deficit widespread and striking. Hydrocephalus may occur from compression of CSF pathways.

In 41 patients, when hemorrhage > 3.3 cm on CT, all died. Smaller hematomas usually caused permanent disability.

Cerebellar hemorrhage

May include any combination of the following:

1. symptoms of increased ICP (lethargy, N/V, HTN with bradycardia…) due to hydrocephalus which may occur as a result of:

A. compression of the 4th ventricle → obstruction of CSF

B. extension of the hemorrhage into the ventricular system

2. direct compression of brain stem may produce:

A. facial palsy: due to pressure on the facial colliculus

B. these patients classically become comatose without first having hemiparesis, unlike many supratentorial etiologies

Lobar hemorrhage

Syndromes associated with hemorrhage in the 4 cerebral lobes¹² (≈ 50% have H/A):

1. frontal lobe (the most distinctive of the syndromes): frontal H/A with contralateral hemiparesis, usually in the arm with mild leg and facial weakness

2. parietal lobe: contralateral hemisensory deficit and mild hemiparesis

3. occipital lobe: ipsilateral eye pain and contralateral homonymous hemianopsia, some may spare superior quadrant

4. temporal lobe: on dominant side, produces fluent dysphasia with poor auditory comprehension but relatively good repetition

DELAYED DETERIORATION

Deterioration after the initial hemorrhage is usually due to any combination of:

1. rebleeding: see below

2. edema: see below

3. hydrocephalus: higher risk with intraventricular extension or posterior fossa ICH

4. seizures

Rebleeding or extension of bleed

Early rebleeding: Rebleeding (more so in basal ganglion hemorrhages than in lobar hemorrhages) has been documented during the first hour by “ultra-early” scanning and repeating CT scans. Rebleeding is usually accompanied by clinical deterioration⁹⁶. The incidence of hematoma enlargement decreases with time, 33-38% in 1-3 hours⁹⁷, 16% in 3-6 hrs, and 14% between 24 hrs of onset and a second CT within 24 hrs of the first⁹⁸. Patients with enlarging hematomas were more likely to have larger hematomas and/or coagulopathy, and had a worse outcome⁹⁸. Rebleeding may still occur following surgical evacuation of clot even with satisfactory intraoperative hemostasis. Hemostatic agents (e.g. NovoSeven®) may reduce this risk, see page 1127. The “spot sign”⁹⁹ on CTA (small enhancing foci within acute ICH) correlated with increased risk of hematoma expansion.

Late rebleeding: Quoted rates for late rebleeding from ICH range from 1.8–5.3% (depending on length of follow-up)¹⁰⁰. Diastolic BP was significantly higher in the group with recurrent hemorrhage, with a 10%/yr risk for DBP > 90 mm Hg vs. < 1.5% for DBP ≤ 90 (mean F/U of 67 months)¹⁰⁰. Other risk factors include diabetes and tobacco and alcohol abuse¹⁰¹. Recurrent hemorrhages may indicate underlying vascular malformations or amyloid angiopathy (lobar rebleeding is likely to be due to amyloid angiopathy¹⁰¹).

Edema

Edema and ischemic necrosis around the hemorrhage may cause delayed deterioration²⁶. Although necrosis from mass effect of the clot contributes a small part to the edema, by itself, the mass effect is insufficient to account for the amount of edema that occurs. It is believed that an edemogenic toxin is released from the clot. Experiments with various components of blood clots has disclosed that thrombin in concentrations that could be released from the clot causes increased permeability of the blood-brain-barrier, and is also a potent vasoconstrictor. This is the leading suspect as the major cause of delayed edema and deterioration. Also see Cerebral edema, page 109.

EVALUATION

CT SCAN

CT scan is rapid, and easily demonstrates blood as high density within the brain parenchyma immediately after hemorrhage. Although mass effect is common, the tendency for the hemorrhage to dissect through brain tissue often results in less mass effect than would be anticipated from the size of the clot.

Clot volume carries prognostic significance (see page 1129). It can be measured volumetrically using computer algorithms available in some CT scanners, or it can very simply be approximated by the ellipsoid method¹⁰²(originally developed for AVMs, based on the principal that the volume of an ellipsoid is approximately half of that of a parallelepiped into which it is placed)¹⁰³ and is simpler than other slightly more accurate estimation methods¹⁰⁴as shown in Eq 32-1, where AP, LAT and HT are the diameters of the clot in each of the 3 dimensions (antero-posterior, lateral, and height^A).

A. to estimate height of a lesion when only axial images are available (as on most initial CTs), count the number of images on which the lesion is seen, and multiply by the slice thickness of the CT cuts^{102, 104, 105} (this information is usually printed on the CT), or, subtract the table position (usually printed on CT) of the highest cut that shows the clot from the table position of the lowest cut showing clot

On the average, the size of the clot decreases ≈ 0.75 mm/day, and the density decreases by ≈ 2 CT units/day, with little change for 1st 2 wks.

MRI

Usually not the procedure of choice for initial study. Does not show blood well within the first few hours. Difficult to ventilate or access patient during the study. Slower and more expensive than CT. May be useful later, e.g. to help diagnose cerebral amyloid angiopathy (CAA) (see page 1122).

The appearance of ICH on MRI is very complicated. It is highly dependent on the age of the clot¹⁰⁶ with 5 stages identified (see Table 32-4).

CEREBRAL ANGIOGRAPHY

For making the diagnosis of the ICH itself, angiography cannot reliably differentiate the mass effect from an ICH from that due to an ischemic infarct or tumor¹⁰⁷. May demonstrate AVMs and aneurysms when they are associated with the ICH. The yield may be increased by delaying the study¹². May demonstrate vascular blush in some cases of tumor. Normal arteriography cannot eliminate cerebral amyloid angiopathy¹⁰⁸.

For indications for cerebral angiography in ICH, see below.

ICH SCORE

The system of Hemphill et al.¹⁰⁹ assigns points based on 5 features as indicated in Table 32-5. The points are then summed for the “ICH score”. The associated 30 day mortality based on the ICH score is tabulated in Table 32-6.

Table 32-5 ICH Score¹⁰⁹

Feature	Finding	Points
GCS score (Table 12-1, page 279)	3-4	2
	5-12	1
	13-15	0
Age*	≥ 80 years	1
	< 80	0
Location	infratentorial	1
	supratentorial	0
ICH volume (Eq 32-1)	≥ 30 cc	1
	< 30 cc	0
Intraventricular blood	yes	1
	no	0
“ICH Score” = Total Points		0-6

* possible bias since treatment decisions in elderly patients may have differed from younger ones

Table 32-6 Mortality based on ICH Score

ICH Score*	30 day mortality
0	0% (26 pts)
1	13% (32 pts)
2	26% (27 pts)
3	72% (32 pts)
4	97% (29 pts)
5	100% (6 pts)
6	? 100%† (0 pts)

* from Table 32-5

^† no pt. in the study had a score of 6, but “it is expected this would be associated with high rate of mortality”

INITIAL MANAGEMENT OF ICH

There is not uniform agreement on almost all aspects of the management of ICH from the optimal BP to the indications for surgery. The following is offered as a guide.

1. patients should be managed in an ICU

2. HTN: controversial. Issues: HTN may contribute to further bleeding, especially within the first hour⁹⁶. However, some HTN may be needed to maintain perfusion^A. Some say reduce MAP to pre-morbid level if known, or by ≈ 20% if unknown

Σ	Treat HTN. Suggested target BP ≈ 140/90. Avoid overcorrection (relative or absolute hypotension)

3. intubate if stuporous or comatose

4. maintain euglycemia

5. maintain normothermia

6. anticonvulsants

A. seizures are treated with appropriate AEDs

B. prophylactic AEDs: optional. May decrease risk of early seizures in patients with lobar hemorrhages

C. AED options

1. Keppra has a very favorable therapeutic/toxic profile. Dose 500 mg BID

2. phenytoin (load with 17 mg/kg slow IV over 1 hour, follow with 100 mg q 8 hrs, see phenytoin (PHT) (Dilantin®), page 409)

7. hemostatic issues:

A. check INR (or PT), PTT & platelet count (PC), platelet function assay (PFA)

1. correct coagulopathies (see Correction of coagulopathies or reversal of anticoagulants, page 40)

2. platelets

a. thrombocytopenia: although platelet transfusions are generally recommended only for PC < 50K, ICH is so serious that a suggestion is to keep PC > 75K

b. patients on platelet inhibiting drugs (e.g. aspirin or Plavix®) should receive platelets

c. when needed: start with 6 units of platelets (see Platelets on page 34)

B. bleeding time: not generally helpful

C. hemostatic agents: NovoSeven® (recombinant activated coagulation factor VII (rFVIIa)) given IV within 4 hours of onset¹¹¹, see below

8. steroids: controversial. No benefit from dexamethasone in ICH, with significantly more complications (primarily infectious, GI bleeding and diabetogenic)¹¹². Consider use if significant peri-hemorrhage edema on imaging (suggested dosage¹¹³: 4 mg dexamethasone IV q 6 hrs, tapered over 7-14 days)

9. treat intracranial hypertension presumptively: mannitol and/or furosemide as tolerated, also helps with HTN (for more, see Treatment measures for elevated ICP, page 876) If significant problems from suspected increased ICP, consider ICP monitor

10. follow electrolytes and osmolarity

A. aggressively treat hyperglycemia (insulin drip if problematic)

B. watch for SIADH

11. angiography: primarily to R/O underlying vascular malformation, but also to R/O aneurysm (a less common cause of ICH), and tumor (which is usually better diagnosed on contrast CT or MRI)

A. if urgent surgery is indicated (e.g. for herniation), the delay in obtaining an angiogram may be detrimental and it may be best deferred to post-op

B. indications: angiography is recommended except for patients > 45 yrs of age with preexisting hypertension and ICH in thalamus, putamen or posterior fossa due to a 0% yield out of 29 patients in this group¹¹⁴ and low yield in all patients with isolated deep ICH¹¹⁵

1. patients > 45 yrs with HTN and a lobar ICH: angiography had a 10% yield¹¹⁴, with the ratio of AVM:aneurysm ≈ 4.3:1

2. patients with intraventricular hemorrhage (without parenchymal hematoma): the yield of angiography was ≈ 65%¹¹⁴, primarily AVM

C. an underlying lesion may be obliterated by ICH, especially acutely. If initial angio is negative, repeat after CT shows resorption of clot (≈ in 2-3 mos). If still negative, follow CT or MRI q 4–6 mos for ≈ 1 year to R/O tumor²⁶. Delaying the initial angiogram for several weeks may increase the yield and is also an option¹²

D. MRI/MRA has ≈ 90% sensitivity for detecting structural abnormalities in this setting, and so a negative study cannot completely exclude this¹¹⁴

E. the yield of angiography in ICH would be expected to be lower in patients at increased risk of ICH: patients on warfarin, chronic alcoholics, patients with amyloid angiopathy…

A. a study of 8 ICHs showed autoregulation was maintained, but with an elevated lower limit. However, CBF fell when MAP was lowered pharmacologically below the usual MAP, which averaged 80% of the admission MAP (admission HTN followed the ICH)¹¹⁰

NovoSeven® (recombinant activated coagulation factor VII (rFVIIa))

At the site of a tissue factor (TF) bearing cell, rFVIIa forms a complex with TF resulting in thrombin production. It also converts factor X to its active form, Xa on the surface of activated platelets resulting in a “thrombin burst” at the site of damage¹¹⁶. Half life: 2.6 hrs. Expensive (≈ $10,000 per dose).

FDA approved for various bleeding diatheses (including hemophiliacs with antibodies to factor VIII or IX). Phase II “off label” Factor Seven for Acute Hemorrhagic Stroke (FAST) study for ICH¹¹¹ appeared promising, however, preliminary results of the phase 3 trial showed no difference in death or major disability at 90 days.

Rx for ICH. Doses studied: 40, 80 & 160 mcg/kg IV over 1-2 minutes given IV within 4 hours of symptom onset reduces 90 day morbidity & mortality, with a dose-related reduction in mean increase of ICH volume at 24 hrs, and a small increase in thrombotic complications^A. SIDE EFFECTS: thrombotic events (MI, CVA…) primarily with higher doses (≥ 120 μg/kg)¹¹⁷, risk may be increased in presence of DIC, predisposing coagulopathy, advanced atherosclerotic disease, crush injury, septicemia, or concomitant treatment with activated or nonactivated prothrombin complex concentrates (aPCC/PCCs) due to increased levels of circulating TF.

A. studied in patients with GCS > 5, with no plan for surgical evacuation within 24 hours and no history of thrombotic or vaso-occlusive disease

ANTICOAGULATION FOLLOWING ICH

Patients with ICH who require anticoagulation pose a management dilemma. In the case of embolic disease, the fear of extending an ICH or of converting it to a hematoma has traditionally outweighed the possible benefit of protection from further embolization. However, an anecdotal (retrospective uncontrolled) report of 12 such patients found no incidence of increased intracranial bleeding with either continued anticoagulation (6 patients) or resumption of anticoagulation after an hiatus (several days in 4 patients, 5 days in 1, and 14 days in 1)¹¹⁸. In another study¹¹⁹ none of 35 patients who had resumption of warfarin had recurrent intracranial hemorrhage (ICH, SAH or subdural hematoma). While this does not prove that anticoagulation is safe after ICH, it does demonstrate that if there is a strong indication for anticoagulation, and if there is not an acceptable alternative (e.g. Greenfield filter for DVT), that anticoagulation in this setting is not always met with disastrous results.

The probability of having an ischemic stroke at 30 days following cessation of warfarin for a median of 10 days are approximately 2.9% for patients who had originally been treated with warfarin for prosthetic heart valves, 2.6% for those treated for atrial fibrillation, and 4.8% for those treated for cardioembolic stroke^119A (see Cardiogenic brain embolism, page 1022 for more details).

Antiplatelet therapy after ICH is not associated with a substantially increased risk of recurrent ICH¹²² (prospective cohort study).

Recommendation

A-fib: long-term anticoagulation should be avoided after ICH¹²³.

Mechanical heart valves: 1-2 weeks off anticoagulation (to observe ICH, or to evacuate a SDH or clip an aneurysm)^{119, 124}. Patients with deep hemispheric ICH at high-risk for thromboembolic stroke may benefit from resumption of long-term anticoagulation)¹²³.

Patients requiring hemodialysis after ICH: heparin-free dialysis may be used.

SURGICAL TREATMENT

Booking the case - craniotomy for ICH

Also see defaults & disclaimers (page v).

1. position: (depends on location of bleed)

2. equipment:

A. microscope (not used for all cases)

B. image guided navigation (not typically used)

3. post op: ICU

4. consent (in lay terms for the patient - not all-inclusive):

A. procedure: surgery through the skull to remove blood clot, stop any bleeding identified, possible placement of external (ventricular) drain

B. alternatives: nonsurgical management

C. complications: (usual craniotomy complications - see page v) plus further bleeding which may cause problems (especially in patients taking blood thinners, antiplatelet drugs including aspirin, or those with coagulation abnormalities or previous bleeds) and may require further surgery, areas of the brain that have already been damaged by the bleeding are not likely to recover, hydrocephalus

INDICATIONS

Amazingly, after repeated attempts to penetrate this dilemma, considerable controversy persists regarding indications for surgery. Surgery may lower morbidity from rebleeding (especially if aneurysm or AVM are identified as the cause of the ICH), edema, or necrosis from mass effect of hematoma (unproven), but rarely causes neurologic improvement. Meta-analyses^{125, 126} yield inconclusive or conflicting results.

Randomized prospective studies (RPS) in the current CT/surgical era

One RPS¹²⁷ found lower mortality for patients with GCS 7-10 treated surgically^B. However, survivors in this group were all severely disabled (none were independent).

A. these numbers may be gross underestimates as many patients died within 2 weeks, and follow-up imaging was scant¹²⁰. Another study¹²¹ showed a much higher rate of 20%

B. note: only 20% of these patients were operated on < 8 hrs from the bleed, and the mean time for all patients to operation was 14.5 hours (range: 6-48 hrs), which may be long

Another¹¹³ found no benefit from surgery for putaminal hemorrhages, also with poor outcomes in all patients.

International STICH¹²⁸: enrolled 1,033 patient. Study shortcomings: possible selection bias (the responsible neurosurgeon had to be uncertain of the benefits of medical vs. surgical treatment), “early surgery” had a somewhat long median time to treatment of 30 hours, and 26% of medically treated patients crossed over and had surgery at a mean of 60 hours (late). Given these limitations, the conclusion was that for supratentorial ICH there was no benefit of early surgery (although there may have been some benefit in the subgroup with a hematoma within 1 cm of the cortical surface). This trial may be more accurately considered to be a comparison of early vs. delayed surgery in patients subjectively judged to need surgery by the investigator.

A pilot study to investigate minimally invasive procedures (stereotactic instillation of tPA and then aspiration of the clot) is planned.

Conclusion

The decision to operate therefore must be individualized based on patient’s neurologic condition, size and location of hematoma, patient’s age, and the patient’s and the family’s wishes concerning “heroic” measures in the face of catastrophic illness.

Guidelines for considering surgery vs. medical management

(for separate indications for surgery for cerebellar hemorrhage, see below)

1. NON-SURGICAL: factors that favor medical management

A. minimally symptomatic lesions: e.g. alert patient with subtle hemiparesis (especially patients with GCS > 10127)

B. situations with little chance of good outcome

1. high ICH score (see page 1126), which overlaps with the following

2. massive hemorrhage with significant neuronal destruction (see below)

3. large hemorrhage in dominant hemisphere

4. poor neurologic condition: e.g. comatose with posturing (i.e. GCS ≤ 5), loss of brain stem function (fixed pupils, posturing…)

5. ≈ age > 75 yrs: do not do well with surgery for this

C. severe coagulopathy or other significant underlying medical disorder(s): in the event of herniation, rapid decompression may be considered in spite of the risks

D. basal ganglion (putaminal) or thalamic hemorrhage: surgery is no better than medical management, and both have little to offer^{113, 129} (see below)

2. SURGICAL: factors that favor rapid surgical removal of the blood clot

A. lesions with marked mass effect, edema, or midline shift on imaging (removal is considered due to the potential for herniation)

B. lesions where the symptoms (e.g. hemiparesis/plegia, aphasia, or sometimes just confusion or agitation…) appear to be due to increased ICP or to mass effect from the clot or surrounding edema. Symptoms attributable directly to brain injury from the hemorrhage are unlikely to be reversed by surgical evacuation

C. volume: surgery for moderate volume hematomas (i.e. ≈ 10-30 cc) (see Eq 32-1, page 1125) may be more appropriate than with:

1. ✖ small clot (< 10 cc): mass effect is usually not significant

2. ✖ large clot

a. > 30 cc: associated with poor outcome (only 1 of 71 patients could function independently at 30 days¹³⁰)

b. massive hemorrhage

i. > 60 cc with GCS ≤ 8: 91% 30-day mortality¹³⁰

ii. > 85 cc (the volume of a sphere with a diameter of 5.5 cm): no patient survived, regardless of treatment in one series¹³¹

D. persistent elevated ICP in spite of therapy (failure of medical management). Evacuating clot definitely lowers ICP, but the effect on outcome is uncertain

E. rapid deterioration (especially with signs of brain stem compression) regardless of location in a patient considered to be salvageable

F. favorable location, for example:

1. lobar (as opposed to deep hemispheric): in spite of optimistic results in a non-randomized study done in 1983 indicating good outcomes in patients with deep hemorrhages treated with early surgery⁶², a later randomized study failed to confirm this benefit¹¹³

2. cerebellar: see below

3. external capsule

4. non-dominant hemisphere

G. young patient (especially age ≤ 50 yrs): they tolerate surgery better than elderly patients, and, unlike elderly patients with brain atrophy, they also have less room in the head to accommodate the mass effect of clot + edema

H. early intervention following hemorrhage: surgery after 24 hrs from onset of symptoms or deterioration may be of less benefit¹²⁷

Management of cerebellar hemorrhage: Recommendations¹³²:

1. patients with a Glasgow Coma Scale (GCS) score ≥ 14 and hematoma < 4 cm diameter: treat conservatively

2. patients with GCS ≤ 13 or with a hematoma ≥ 4 cm: surgical evacuation

3. patients with absent brain stem reflexes and flaccid quadriplegia: intensive therapy is not indicated^A

4. patients with hydrocephalus: ventricular catheter (if no coagulopathy). Caution: do not overdrain to avoid upward cerebellar herniation (see page 285). Most cases with hydrocephalus also require evacuation of the clot

A. some authors contend that the loss of brain stem reflexes from direct compression may not be irreversible¹³³, and that cerebellar hemorrhage represents a surgical emergency (and that the above criteria would thus deny potentially helpful surgery to some, see page 1021 for a discussion of cerebellar infarction and decompression)

SURGICAL CONSIDERATIONS

1. send specimens (hematoma, abnormal looking tangle of blood vessels if present, and possibly biopsy walls of hematoma cavity) to pathology for analysis¹³⁴ (to rule-out tumor, AVM, amyloid angiopathy…)

2. surgical options:

A. “standard approach”: craniotomy with evacuation of the clot under direct vision (with or without microscope)

B. stereotactic aspiration with thrombolytic agents has also been used (see Stereotactic surgery, evacuation of intracerebral hemorrhage on page 782)

C. endoscopic surgery¹³⁵

Surgical techniques for cerebellar hemorrhage

1. position: lateral oblique with the involved side up (see page 154)

2. if rapidity is crucial, a midline skin incision is preferred because it can be taken down quickly with little fear of encountering a vertebral artery

3. craniectomy is preferred over craniotomy to accommodate post-op swelling

4. a prophylactic Frazier burr hole is recommended to allow rapid treatment if postop hydrocephalus develops (see page 156 for placement, and page 158 for use), or, a ventricular catheter may be placed to monitor ICP and allow CSF drainage post-op

5. in cases where there has been rupture into the ventricular system, the surgical microscope should be used to follow the clot to the fourth ventricle which is then cleared of clot

VENTRICULOSTOMY (IVC) AKA EXTERNAL VENTRICULAR DRAINAGE (EVD)

May be used in patients with intraventricular extension of blood causing acute obstruction of the third ventricular outlet. In these cases, the IVC is usually placed in the lateral ventricle contralateral to the hemorrhage (to avoid putting the catheter directly in clot, which may obstruct the inlets). The prognosis for patients with a significant volume of intraventricular blood is poor. It may be difficult to maintain the patency of the catheter due to occlusion by clot, tissue plasminogen activator may help (see below).

Tissue plasminogen activator (rt-PA)

Intraventricular rt-PA may help lyse clot and maintain catheter patency or reopen a clotted catheter. No well-designed randomized study has been done; but anecdotal evidence suggests it is relatively safe. ✖In cases of suspected aneurysm, AVM or other vascular malformation, it cannot be used until the source of bleeding has been corrected^{136, 137}.

Rx: 2-5 mg of rt-PA^{136, 138, 139} in NS is administered through an intraventricular catheter (IVC). The IVC is closed for 2 hours after injection¹³⁹. In the low dose CLEAR-IVH (Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage) trial (a phase II trial with 52 patients), 1 mg tPA intrathecally via a ventricular catheter every 8 hours up to a maximum of 4 days, was associated with a 30 d mortality of 15% (compared to an expected 80-85%)¹⁴⁰. Hemorrhagic complication rate was 6%. A phase III trial is underway to confirm this.

OUTCOME

Thalamic hemorrhages that tend to destroy the internal capsule (IC) are more likely to produce hemiplegia than hemorrhages lateral to the IC that compress but do not disrupt the IC.

Mortality: The chief cause of death is cerebral herniation¹¹², occurring mainly during the first week and mostly in patients with initial Glasgow Coma Scale scores ≤ 7. The in-hospital death rate decreased overall during the 1980s but increased for patients ≥ 65 years of age¹⁴¹.

Quoted mortality rates vary widely, and depend on size and location of clot, age and medical condition of the patient, and etiology of the hemorrhage. Overall, the 30-day mortality rate is ≈ 44% for ICH¹, which is similar to that for SAH (≈ 46%). Patients with lobar hemorrhages (see page 1119) tend to fare better than deep ICH (basal ganglion, thalamus…) with only ≈ 11% mortality in 26 of these patients¹².

32.2. ICH in young adults

In a review of 72 patients age 15-45 yrs suffering nontraumatic ICH¹⁴², a presumed cause was found in 76% (see Table 32-7). 3 patients had labor or post-partum hemorrhages (see page 1121 and also Pregnancy & intracranial hemorrhage on page 1086).

AVM: lobar hemorrhages in this age group are highly suggestive of AVM. Of 40 lobar hemorrhages, 37.5% were found to be from AVMs¹⁴².

Herpes simplex encephalitis: may produce hemorrhagic changes on CT, especially in the temporal lobes (see Herpes simplex encephalitis, page 358).

Drug abuse: especially with sympathomimetics such as cocaine (see page 1121) should also be considered in young adults.

Leukemia: ICH may the initial presentation of leukemia in a young adult (may be due to metastases (chloroma) or to thrombocytopenia).

Table 32-7 Causes of spontaneous ICH in young adults¹⁴²

Etiology	%
ruptured AVM	29.1%
arterial hypertension	15.3%
ruptured saccular aneurysm	9.7%
sympathomimetic drug abuse	6.9%
tumor*	4.2%
acute EtOH intoxication	2.8%
pre-eclampsia/eclampsia	2.8%
superior sagittal sinus thrombosis	1.4%
moyamoya	1.4%
cryoglobulinemia	1.4%
undetermined	23.6%

* hemangioma, ependymoma, metastatic choriocarcinoma… (see Hemorrhagic brain tumors, page 1123)

Outcome

Overall in-hospital survival (including those treated medically) was 87.5%.

32.3. Intracerebral hemorrhage in the newborn

Occurs primarily in premature infants. Alternate terms: subependymal hemorrhage (SEH), germinal matrix hemorrhage (GMH), periventricular-intraventricular hemorrhage (PIVH). Intraventricular hemorrhage (IVH) arises from extension of SEH through ependymal lining of ventricle and occurs in 80% of cases of SEH¹⁴³.

ETIOLOGY

The highly vascular germinal matrix is part of the primordial tissue of the developing brain and is the source of future neurons and glial cells. It is located just beneath the ependymal lining of the lateral ventricles, and undergoes progressive involution until 36 weeks gestational age (GA). Thus, the matrix may persist out of utero in premature infants. A disproportionate amount of the total CBF perfuses the periventricular circulation through these capillaries which are immature and fragile and have impaired autoregulation^{144, 145}. The site of hemorrhage is age dependent. Between 24-28 weeks GA they occur over the body of the caudate nucleus and at 29 weeks GA or greater they arise over the head of the caudate nucleus¹⁴⁶.

PATHOGENESIS OF PIVH IN THE PRE-TERM INFANT

The metabolically active GM is susceptible to hypotension and hypoperfusion which can lead to infarction. The GM is a vulnerable watershed zone supplied by Heubner’s artery (from the anterior cerebral artery), terminal branches of the lateral striate arteries (off the middle cerebral artery) and the anterior choroidal artery (off the internal carotid or middle cerebral artery).

1. postnatal hypoxia due to respiratory distress syndrome related to hyaline membrane disease, pneumothorax and/or anemia can deprive the metabolically active GM of oxygen. This ischemia to the endothelial cells lining the capillaries makes them vulnerable to infarction and then disruption

2. hypercapnia maximally dilates the thin walled vessels of the GM. If this is followed by sudden increases in perfusion the result can be rupture of the vessels

3. increased venous pressure from any cause (labor and delivery, positive pressure ventilation, stimulation, endotracheal suctioning, myocardial failure from ischemia) can result in increased venous pressure in the GM leading to hemorrhage

4. dehydration followed by rapid resuscitation with hyperosmolar solutions increases the intravascular volume by osmotically encouraging the movement of fluid from tissues into the intravascular space. With associated increases in systemic blood pressure the GM capillaries are at increased risk of rupture

RISK FACTORS FOR PIVH

Increased cerebral perfusion pressure (CPP) with the associated increased cerebral blood flow (CBF) and hypoxia are the common denominators for most risk factors for PIVH. The elevated pressure may cause the hemorrhage by rupturing the fragile vessels of the germinal matrix, possibly already damaged by previous insults of high or fluctuating CBF and hypoxia.

Risk factors for PIVH include¹⁴⁷:

1. those associated primarily with increased CBF or CPP:

A. asphyxia: including hypercapnia (see above)

B. rapid volume expansion

C. seizures

D. pneumothorax

E. cyanotic heart disease (including PDA)

F. infants being mechanically ventilated having RDS and fluctuating CBF velocity documented by Doppler flow meter¹⁴⁸

G. anemia

H. decreased blood glucose

I. arterial catheterization

J. blood pressure fluctuations

2. younger GA

3. low birth weight

4. acute amnionitis

5. failure to give antenatal steroids during the 48 hours prior to pre-term delivery¹⁴⁹ (i.e. to women at risk of delivering low birth-weight infants): see page 1133

6. APGAR’s < 4 at 1 minute and < 8 at 5 minutes

7. acidosis

8. coagulopathies

9. general anesthesia for C-section

10. extracorporeal membrane oxygenation (ECMO): due to heparinization in addition to increased CPP

11. maternal cocaine abuse¹⁵⁰

12. maternal aspirin use

EPIDEMIOLOGY

INCIDENCE

Depends on the method used for detection (many PIVHs are asymptomatic) and the population being evaluated. 540,000 pre-term infants are born in the United States annually. 85,000 are very pre-term (<32 weeks GA) and 385,000 are late pre-term (34-36 weeks GA). 63,000 very low birth weight (<1500 grams) infants are born each year. Of the preemies weighing < 1500 gm birth weight, 20-25% will suffer from a PIVH^{151, 152}.

In a 1978 study, PIVH was found by CT in 43% (20/46) of preemies with birth-weight < 1500 gm¹⁵³. Mortality in infants with PIVH was 55%, compared to 23% in those without PIVH¹⁵³. Ultrasound (U/S)detected PIVH in 90% of 113 preemies < 34 weeks gestation¹⁵⁴ (49% were grade III or IV, see Table 32-8 for grading).

TIMING

The timing of PIVH has a bimodal distribution. A substantial number occur within 6 hours of birth with 50% occurring within 12 hours of birth^{155, 156}. At postnatal days 3-4, a second peak occurs. Only 5% of bleeds will develop after postnatal day 4. Progression of hemorrhage has been documented in 10-20% of infants¹⁵⁶. Early onset PIVH is more likely to progress and has a higher mortality¹⁵⁷.

PREVENTION

Numerous studies have been conducted to find a method of directly reducing the incidence of PIVH among premature infants. Many are controversial. Optimal resuscitation and neonatal care, with an emphasis on measures which minimize cerebral blood flow fluctuations are key.

Methods which are not widely used but are of historical interest:

• antenatal phenobarbital: studies failed to confirm the ability to reduce PIVH¹⁵⁸

• postnatal phenobarbital: meta-analysis of 10 controlled trials by the Cochrane Collaboration concluded that postnatal phenobarbital could not be recommended as prophylaxis to prevent PIVH. Its use was also associated with an increased need for mechanical ventilation¹⁵⁹

• ethamsylate: a 1994 study found that in a series of 334 infants < 32 weeks GA, the ethamsylate group showed no difference from the control group in incidence of PIVH or death¹⁶⁰. Conclusion: there is little evidence to support the use of ethamsylate for the prevention of PIVH

Methods which are more widely accepted:

• good prenatal care and avoiding pre-term labor

• antenatal corticosteroids: administration of one course of antenatal corticosteroids to women at risk of having premature birth infants reduces neonatal mortality, respiratory distress syndrome and PIVH¹⁶¹. Multiple courses of antenatal corticosteroids did not improve outcomes and were associated with decreased head circumference, weight and length at birth¹⁶²

• indomethacin: results in cerebral vasoconstriction and reduces the responsiveness of CBF to changes in CO₂, lowers CBF and increases arterial oxygenation reducing patent ductus arteriosus (PDA). However, use is possibly associated with increased risk of intestinal perforation

• antenatal vitamin K given IM > 4 hrs prior to delivery decreases PIVH from 33% to 5%

• sluicing umbilical cord blood and delaying umbilical cord clamping by 30-120 seconds in premature babies increased hematocrit and decreased PIVH in 5 of 7 studies¹⁶³

• using surfactant to reduce RDS

• minimizing external stimulation (some centers use fentanyl drips)

• steroids to stabilize the GM vessels

CLINICAL

The most commonly used grading system of Papile et al. based on CT or U/S findings is shown in Table 32-8. PIVH may present acutely, subacutely. Most commonly, it is discovered incidentally on surveillance U/S.

There is a direct correlation between younger GA and the severity of PIVH. In infants 24-26 weeks GA, 32% will have a Grade III PIVH and 19% will have a Grade IV PIVH compared with infants 31-32 weeks GA, 11% will have a Grade III PIVH and 5% will have a Grade IV PIVH¹⁶⁴.

Table 32-8 Grading subependymal hemorrhage¹⁵³

Grade	Description
I	subependymal
II	IVH without ventricular dilatation
III	IVH with ventricular dilatation
IV	IVH with parenchymal hemorrhage

PRESENTATION

Asymptomatic PIVH

Most PIVHs will be clinically unsuspected, usually with smaller hemorrhages. Retrospectively, these PIVHs may have been suggested by a fall in Hct or delays in neurologic development. These have a 78% 6-month survival, vs. 20% for PIVH showing signs.

Subacute presentation

Usually smaller or more slowly developing hemorrhages. Clinically may present as irritability, reduced motor activity, or abnormal eye movements.

Acute presentation

• changes in muscle tone or activity: usually decerebrate or decorticate posturing, sometimes flaccid paralysis

• seizures: often subclinical

• tense fontanelle

• hypotension

• respiratory and cardiac irregularities: apnea & bradycardia (“A’s and B’s”)

• unreactive pupils and/or loss of extraocular muscle movements

• Hct drop > 10%

HYDROCEPHALUS

20-50% of infants with PIVH will develop either transient or progressive hydrocephalus (HCP). Grades III and IV are more often associated with progressive ventricular dilatation than are lower grades (however, HCP may develop even after low grade PIVH¹⁶⁵). Younger gestational age infants may be at lower risk.

Post PIVH hydrocephalus usually occurs 1-3 weeks after the hemorrhage. Probably caused by cellular debris and/or the toxic effects of blood breakdown products on the arachnoid granulations (communicating HCP), or by an adhesive arachnoiditis in the posterior fossa or rarely by compression or blockage of critical pathways, e.g. at the sylvian aqueduct (obstructive HCP). In a case of HCP following intrauterine PIVH, aqueductal gliosis was found at autopsy¹⁶⁶.

Possible presentations

Abnormally increasing OFC (crossing percentile curves faster than body weight), lethargy, apnea and bradycardia, vomiting. There is progressive dilatation of the ventricular system on serial U/S or CT.

PATHOPHYSIOLOGY

Deleterious effects of PIVH on the brain are due to¹⁶⁷:

• destruction of the germinal matrix and glial precursors

• direct injury to neural tissue from hematoma: once hemorrhage resorbs may leave patient with porencephaly or cystic lesions

• pressure of hematoma on nearby brain tissue reducing CBF even to parts of the same hemisphere distant from the hemorrhage¹⁶⁸

• diffuse decreased CBF following the hemorrhage¹⁶⁹ due to elevated ICP

• injury from the same hypoxic event that precipitated the PIVH

• decreased CPP leads to periventricular leukomalacia (PVL) and cerebral infarction

• periventricular hemorrhagic infarction

• hydrocephalus (see above): numerous deleterious effects on the CNS

• seizures: repeated or prolonged seizures may be deleterious to neuronal function

DIAGNOSIS

Ultrasound (U/S)

Performed through the open fontanelles¹⁵⁴. Accuracy ≈ 88% (91% sensitivity, 85% specificity)¹⁷⁰. U/S is invaluable because:

• it demonstrates the size of the ventricles, the location and size of the hematoma, and the thickness of the cortical mantle

• it may be brought to the infant’s bedside (obviating transportation)

• it is non-invasive

• it is not adversely affected by occasional infant movements (eliminating the need for sedation)

• there is no exposure to ionizing radiation (radiation from diagnostic imaging in children has long-term risks for cancer¹⁷¹ and damage to the lens)

• it may be followed serially with relative ease

CT scan

Sometimes necessary when U/S is not readily available, or in complicated cases where anatomy is difficult to deduce from U/S images.

TREATMENT

General measures are directed at optimizing CPP without further excessive elevation of CBF by carefully maintaining normal MAP and normalizing pCO₂, and by treating ventriculomegaly as outlined below.

While daily LPs can control the deleterious effects of posthemorrhagic HCP, they do not reduce the frequency of long-term HCP (requiring permanent shunting). Ventricular size must be monitored with serial U/S.

Ventriculomegaly

When detected, need to differentiate the following:

• transient ventriculomegaly: occurs in the first few days after PIVH. This may not cause elevated ICP. As implied, it is self limited

• progressive ventriculomegaly: occurs in 20-50% of cases

• “hydrocephalus ex vacuo”: due to loss of brain tissue or maldevelopment. Is not progressive on serial U/S. OFCs may fall below normal due to lack of growing brain as stimulus for head growth

MEDICAL TREATMENT

• not very effective. Treated patients fared worse in several studies

• osmotic agents: isosorbide, glycerol. Effects are short-lived

• ✖ diuretic therapy: has been used, but a large study showed increased nephrocalcinosis and biochemical abnormalities, resulting in a borderline increase in the risk for motor impairment at one year¹⁷². The results were so compelling, the data-monitoring committee terminated the study prematurely. Furosemide and acetazolamide therapy was deemed neither safe nor effective in treating post-hemorrhagic ventricular dilatation and cannot therefore be recommended¹⁷³

SURGICAL/INTERVENTIONAL TREATMENT

Due to poor operative results, surgical evacuation of an intracerebral hemorrhage in the newborn is not indicated with the possible exception of a posterior fossa hemorrhage causing brain stem compression that does not respond to medical treatment¹⁷⁴. Supportive measures are usually in order.

Intervention for intraventricular blood

34% of infants < 1500 g require shunt/reservoir drainage after failed medical management. Type III and IV PIVH: > 70% of cases develop progressive ventricular dilatation, and 32-47% of this subset will ultimately require shunting¹⁵¹.

Indications: Intervention for intraventricular blood is indicated in the setting of progressive ventriculomegaly with the OFC crossing percentile curves and clinical evidence of increased ICP (split sutures, tense fontanelle…).

Serial lumbar punctures: Used at many facilities for hemorrhages with intraventricular extension and communicating hydrocephalus (the usual type of HCP that occurs with PIVH)¹⁷⁵.

This should be undertaken with the knowledge that meta-analysis¹⁷⁶ showed sequential lumbar or ventricular taps of ≈ 10 ml/kg/tap for prophylaxis or treatment of progressive hydrocephalus offers no clear benefit over conservative treatment, and had an infection rate of 5-9%. In rare cases, LPs may succeed in temporizing progressive HCP for a few weeks until the infant is large enough for shunt placement.

Infants < 800 gm may not tolerate LPs because of desaturation when lying on their side, or the LP itself may be difficult. In these patients, consider 1-2 ventricular taps to at least obtain fluid for analysis (in some cases nothing further needs to be done).

Serial ventricular taps: May be a viable short-term option for those infants who cannot tolerate LPs or in whom there is obstruction to CSF flow in the lumbar subarachnoid space (e.g. due to spinal subdural hematoma from previous LP). However it is not desirable for long-term use because of repeated trauma to brain (risk of porencephaly) and risk of intracerebral, intraventricular, or subdural hemorrhage.

If continued taps are likely (i.e. large hemorrhage, or rapid recurrence of intracranial hypertension as determined by palpation of fullness of anterior fontanelle (AF) following several taps) the acceptable options include:

• continuing serial LPs (see below)

• ventricular taps: not recommended for more than a few treatments as it causes porencephaly

• placement of a ventricular catheter connected to a subgaleal reservoir (either a Rickham reservoir, or a low profile McComb reservoir¹⁷⁷). These can be inserted safely at the bedside, obviating the need for transport to the O.R.¹⁷⁸

temporary ventricular access: the reservoir can be used for serial percutaneous taps. Usually tapped QD or QOD (see below). Use a 27 Ga butterfly needle, clean with at least 3 betadine stick swabs, withdraw ≈ 10 ml and send for culture. Reported infection rate: 8-12%¹⁷⁹

ventricular-subgaleal shunt: the side-port of the reservoir is left un-capped. A subgaleal pocket must be created at the time of surgery. Fluid is reabsorbed from this potential space. Use has been reported up to 35 days¹⁸⁰. Infection rate: ≈ 6%

the reservoir may be converted to VP shunt if and when appropriate. Not recommended in infants < 1100 gms due to very high infection rate

• external ventricular drainage (EVD): similar to reservoir, but with possibility of inadvertent dislodgment (13%) and comparable infection rate (6%)

• early VP shunting: high infection rate, peritoneal cavity not suitable in many cases, e.g. due to necrotizing enterocolitis (NEC), paucity of subcutaneous tissue through which to pass shunt tube… Not recommended for infants < 2000 gms

Advantages of temporary ventricular access (TVAD)

1. avoids shunt in unhealthy children at risk of infection, skin breakdown or other operative/anesthetic complications

2. clears protein and cellular debris (more favorable for subsequent shunting)

3. avoids repeated penetration of brain with risk of porencephaly

4. provides port for infusion of medication (e.g. antibiotics) PRN

5. avoids cumbersome, easily dislodged EVD with infection risk 6% on average of 13 days of EVD

6. up to 25% of patients will recover and avoid permanent shunt placement^{181, 182}

Disadvantages of TVAD

1. requires services of a neurosurgeon (not always available)

2. increases risk of infection of subsequent permanent shunt from 5% to 13%(183

3. inherent risks of surgery including hemorrhage, infection, ventriculitis, meningitis, CSF leak

4. risks of overdrainage including subdural hematoma, impaired skull growth

Serial taps (via ventricular reservoir or LP)

8-20 cc of fluid are removed initially, and this is repeated daily (or more often if AF become very tense before 24 hours elapse) for several days, and then usually varies from 5-20 cc qod to 15 cc TID depending on response. The frequency and volume of the taps are modified based on:

• fullness of AF: attempt to keep AF from becoming tense

• appearance of ventricles on serial U/S: strive to prevent progressive enlargement, reduction in size can usually be achieved

• follow OFC: should not cross percentile curves (need to differentiate from the so-called “catch-up phase” of brain growth which may occur once the infant overcomes their overall medical problems and is able to adequately utilize nutrition^{184, 185}; serial U/S will show rapid brain growth without progressive ventriculomegaly in cases of catch-up brain growth)

• CSF protein concentration: controversial. Diminishes with serial taps. Some feel that as long as it is ≥ 100 mg/dl it is unlikely that significant spontaneous resorption will occur and continued serial taps will probably be needed

• NB: removal of this volume of fluid may cause electrolyte disturbances, primarily hyponatremia; follow serum electrolytes on regular basis

Follow with serial U/S on day 3-5, and then weekly for several weeks, and then biweekly. A baseline CT scan is often obtained prior to placement of a permanent shunt.

Insertion of VP shunt or conversion of sub-Q reservoir to VP shunt

Indications and requirements:

1. symptomatic hydrocephalus (see Hydrocephalus, page 1134) and/or progressive ventriculomegaly

2. infant is extubated (and thus off ventilator)

3. infant weighs ≥ 2000 grams (some prefer ≥ 2500 grams)

4. no evidence of NEC (might create problems with peritoneal end of catheter)

5. CSF protein ideally < 100 mg/dl (because of concerns about plugging of the shunt, or causing ileus or malabsorption of the fluid^A, and also to see if patient will start reabsorbing CSF on their own)

A. which was not seen with high protein fluid shunted from the subdural space¹⁸⁶

Technical recommendations:

1. do not tap reservoir for at least 24 hrs before inserting a new ventricular catheter (allows ventricles to expand to facilitate catheterization)

2. obtain U/S the day prior to conversion

3. use a low or very-low pressure system (if CSF protein is high, consider a valveless system), upgrade later in infancy if necessary

4. avoid placing shunt hardware in areas on which these debilitated infants tend to lay (to prevent skin breakdown with hardware exposure)

OUTCOME

Short-term

Preemies with PIVH have higher mortality than matched preemies without PIVH.

The incidence of mortality and progression of hemorrhage is higher the earlier the hemorrhage occurs. The more severe the hemorrhage, the higher the mortality and the higher the risk of HCP (see Table 32-9).

Table 32-9 Short-term outcome of PIVH (≈ 250 cases¹⁴³)

Severity of hemorrhage	Deaths (%)	Progressive hydrocephalus (%)
mild	0	0-10
moderate	5-15	15-25
severe	50-65	65-100

Long-term

The effect of low grade PIVH on long-term neurodevelopment has not been studied well. Most investigators feel that higher grades of PIVH are associated with greater degrees of handicaps than matched controls.

In one study of 12 infants with Grade II PIVH treated with serial LPs and in the 7 with progressive ventriculomegaly with VP shunt followed for a mean of 4.5 years found all were ambulatory and 75% had IQ within normal range¹⁸⁷.

A recent study of very low birth weight infants showed that children 18-22 months age with severe PIVH and shunts had significantly lower scores on the Bayley Scales of Infant Development IIR compared with children with no PIVH and children with equal grades of PIVH who did not require a shunt¹⁸⁸.

OTHER CAUSES OF INTRACEREBRAL HEMORRHAGE IN THE NEWBORN

• birth trauma may result in subdural hemorrhage, tentorial hemorrhage, parenchymal hemorrhage and/or subarachnoid blood. This is usually detected by imaging (U/S or CT) when an infant develops seizures, apnea, bradycardia or rarely focal neurological deficits. It rarely requires surgical intervention

• choroid plexus hemorrhage can result in IVH. In some cases HCP can develop and require shunt placement

• hemorrhagic stroke has been identified in 6.2 per 100,000 live births¹⁸⁹. The usual presentation was with encephalopathy (100%) and seizures (65%). 75% of the strokes were idiopathic. Other identified etiologies were thrombocytopenia and a single case of a cavernous malformation. Risk factors for perinatal hemorrhagic stroke include: male gender, fetal distress, emergent c-section, prematurity and post-maturity

• tumors in the neonate can present with hemorrhage

• vascular malformations of any form can present in the neonate with hemorrhage, although this is uncommon. Vein of Galen malformations are diagnosed in the neonate in about 40% of cases¹⁹⁰. Most of these infants present with fulminant congestive heart failure and 50% have ventriculomegaly

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