Neurosurg Rev

DOI 10.1007/s10143-017-0827-y

REVIEW

An introduction to the pathophysiology of aneurysmal

subarachnoid hemorrhage
Jasper H. van Lieshout 1 & Maxine Dibué-Adjei 1 & Jan F. Cornelius 1 & Philipp J. Slotty 1 &
Toni Schneider 2 & Tanja Restin 3,4 & Hieronymus D. Boogaarts 5 & Hans-Jakob Steiger 1 &
Athanasios K. Petridis 1 & Marcel A. Kamp 1

Received: 7 November 2016 / Revised: 24 January 2017 / Accepted: 31 January 2017

# Springer-Verlag Berlin Heidelberg 2017

Abstract Pathophysiological processes following subarachnoid associated process. A causal connection between DCI and early
hemorrhage (SAH) present survivors of the initial bleeding with brain injury (EBI) would mean that future therapies should ad-
a high risk of morbidity and mortality during the course of the dress EBI more specifically. If the mechanisms following SAH
disease. As angiographic vasospasm is strongly associated with display no causal pathophysiological connection but are rather
delayed cerebral ischemia (DCI) and clinical outcome, clinical evoked by the subarachnoid blood and its degradation produc-
trials in the last few decades focused on prevention of these tion, multiple treatment strategies addressing the different patho-
angiographic spasms. Despite all efforts, no new pharmacologi- physiological mechanisms are required. The discrepancy be-
cal agents have shown to improve patient outcome. As such, it tween experimental and clinical SAH could be one reason for
has become clear that our understanding of the pathophysiology unsuccessful translational results.
of SAH is incomplete and we need to reevaluate our concepts on
the complex pathophysiological process following SAH.
Keywords Subarachnoid hemorrhage . Physiopathology .
Angiographic vasospasm is probably important. However, a uni-
Review . Early brain injury . Delayed cerebral ischemia
fying theory for the pathophysiological changes following SAH
has yet not been described. Some of these changes may be caus-
ally connected or present themselves as an epiphenomenon of an
Background
Athanasios K. Petridis and Marcel A. Kamp contributed equally to this The incidence of non-traumatic subarachnoid hemorrhage
article.
(SAH) based on nationwide epidemiological data has shown
to be more or less homogeneous and displays minor differ-
* Jasper H. van Lieshout
Jasper.vanLieshout@med.uni-duesseldorf.de ences based on different age distributions, study periods, and
autopsy rates [85, 86]. Cerebral aneurysm rupture is the cause
of spontaneous SAH in up to 85–98.9% of the patients [86,
1
Department of Neurosurgery, Medical Faculty, 162]. With a mean age of 55 at rupture, the average age is
Heinrich-Heine-University Düsseldorf, Moorenstraße 5,
40225 Düsseldorf, Germany
significantly lower compared to other types of stroke [40, 109,
2
162]. Not just the initial hemorrhage, but also pathophysio-
Institute for Neurophysiology, Medical Faculty, University of
Cologne, Robert-Koch-Str. 39, 50931 Köln, Germany
logical processes following SAH present survivors with sig-
3
nificant mortality and morbidity that have major personal and
Zurich Centre for Integrative Human Physiology, Institute of
Physiology, University of Zurich, Winterthurerstrasse 190,
socio-economic impact [40, 61, 99, 100, 148, 149, 162]. As
8057 Zurich, Switzerland angiographic vasospasm is strongly associated with delayed
4
Institute of Anesthesiology, Medical Faculty, University Hospital
cerebral ischemia (DCI) and clinical outcome, clinical trials in
Zurich, Rämistrasse 100, 8091 Zurich, Switzerland the last few decades focused on prevention of these angio-
5
Department of Neurosurgery, Medical Faculty, Radboud University
graphic spasms [38, 104]. However, despite all efforts, no
Nijmegen, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, the pharmacological agents have shown to improve patient out-
Netherlands come [38]. In this respect, we aim to reevaluate some of the

recent concepts on the pathophysiological mechanisms fol-
lowing spontaneous SAH.
The pathophysiology of subarachnoid hemorrhage—an
introduction
As aneurysm rupture and early pathophysiological responses
usually do not occur under medical monitoring, most data
regarding the very early phase of SAH result from experimen-
tal SAH, observations made during aneurysmal re-rupture in
hospitalized SAH patients or post-mortem data. Commonly,
two phases are distinguished in the course of SAH: initial
pathophysiological changes within the first 3 days were given
the term Bearly brain injury^ (EBI), whereas Bdelayed cerebral
ischemia^ (DCI) describes a complex of reactions that occur
later during the course of disease. DCI usually appears 3–
4 days after ictus; the highest incidence and severity are
reached after 6–8 days and usually resolve after 12–14 days
[59, 175]. Few case reports document late onset DCI beyond
14 days [81, 118].
The concept of EBI has been coined more recently and
evolved after the full mechanisms of action behind angio-
graphic vasospasms resulted in a cornucopia of theories and
refers to the events that occur in the brain before the develop-
ment of DCI [15, 93, 145]. The etiology of EBI lies at the
pathophysiological mechanisms that have been initiated by
the initial bleeding that predisposes the brain to secondary
injury. It has also been suggested that the etiology of DCI
and EBI are linked. However, causality between the two pro-
cesses has not yet been established.
In contrast, DCI has first been reported over 150 years ago,
and in the 1970, the association between delayed neurological
deficits and angiographic vasospasm led to a rational assump-
tion of causation [42, 43, 103, 175]. As angiographic vaso-
spasm is strongly associated with DCI and clinical outcome,
clinical trials in the last few decades focused on prevention of
vasospasm with the aim to improve clinical outcome.
However, DCI is likely to consist of a complex pathophysio-
logical complex involving microvascular dysfunction, throm-
bosis of cerebral—especially cortical vessels, cortical spread-
ing depolarizations and depressions and ischemia or inflam-
matory reactions.
The following sections will broadly cover the complex
pathophysiological mechanisms following aneurysmal SAH.
Early brain injury
The extravasation of blood in the subarachnoid space leads to
intense headache and an increase in intracranial pressure
(ICP). ICP can rise up to similar values as the diastolic blood
pressure or more [6, 7, 75, 137, e.g. 157, 158, 168, 176, 177].
ICP usually decreases within 10 to 15 min but may also be
sustained. High levels of ICP and arrest of cerebral circulation
Neurosurg Rev
might be aggravated by mechanical factors such as cerebral
edema and acute hydrocephalus as they can increase ICP and
promote cerebral hypoperfusion [6, 7, 75, 137, e.g. 157, 158,
168, 176, 177].
An increase in ICP results in a significant reduction of
regional cerebral blood flow (rCBF) and cerebral perfusion
pressure (CPP). These pathophysiological responses are well
documented under experimental and clinical conditions [2, 6,
7, 52, 75, 115, 116, 124, 137, 169, 177]. Clinical studies
assessing early cerebral perfusion within 72 h after ictus de-
scribed a correlation between the initial impairment of perfu-
sion parameters, occurrence of DCI, and outcome [37, 60, 76,
138, 142, 155, 159, 161].
Cerebral autoregulation (comprising both pressure
autoregulation and chemoregulation) seems to be fre-
quently impaired after SAH and is expected to be a major
factor contributing to initial rCBF impairment [35, 69, 72,
127, 140]. It may therefore be a prognostic factor for the
occurrence of DCI and poor outcome [12, 13, 67, 68].
Cerebral perfusion impairment is likely to result in func-
tional disturbances of the brain: in experimental SAH,
raised ICP and cerebral hypoperfusion are accompanied
by a profound suppression of total EEG power [3, 6,
75]. Temporary ischemia may underlie the observed im-
pairment of cortical function, and total ECoG impairment
may be the result of global transient ischemia. The obser-
vation that electrocorticographic activity recovers in par-
allel to normalization of cerebral perfusion suggests a
possible causality [3, 6, 75]. Alternatively, the
neurovascular coupling of cortical activity and rCBF
might lead to the reduction of rCBF when cortical signal-
ing is disrupted [6, 75].
Impaired rCBF may lead to either transient global or focal
ischemia, which initiates a cascade of further pathophysiolog-
ical events [47, 66, 70, 83]. Initial hypoxia leads to early
metabolic failure, disturbed ionic hemostasis and to cytotoxic,
ionic and vasogenic cerebral edema [83]. Moreover, ischemia
initiates apoptosis of neurons, astrocytes, and vascular cells by
activation of caspase-dependent and -independent pathways
[1, 14, 15, 30, 47, 108, 121, 125, 180, 185]. These pathways
might be the target of new therapeutic strategies that aim to the
effects of early brain injury, such as hypothermia mediating
the caspase-3-, PI3K/AKT-, and NF-κB-dependent pathways
[48, 101]. Hypoxia also activates inflammatory pathways and
the coagulation system [126, 141, 144].
The steep rise in ICP with subsequent possible herniation
and destruction of brain tissue contributes to the pathology of
SAH. Physiological responses following SAH result in re-
duced cerebral perfusion and induce several pathophysiolog-
ical changes within minutes after ictus (Fig. 1). Many patients
with SAH survive this initial phase but suffer from cerebral
perfusion impairment due to DCI in a later course of disease
which may result in further neurological deterioration.
Neurosurg Rev
Fig. 1 Early brain injury (EBI).
The figure depicts the
pathophysiological changes
occurring within the first 72 h
after aneurysm rupture. However,
its mechanisms are complex and
poorly understood
Angiographic vasospasm and delayed cerebral ischemia
DCI can be reversible or it may progress to cerebral infarction.
As many as half of the patients suffering from SAH develop
delayed neurological deficits caused by DCI [8, 9, 23, 25, 28,
119, 131, 172]. In 2010, Vergouwen et al. proposed a standard
definition for DCI and cerebral infarction which separates the
concept of angiographic vasospasm form DCI, which is a
clinical diagnosis, and cerebral infarction, a radiological diag-
nosis [167].
After the first observation of arterial narrowing following
SAH by Ecker and Riemenschneider (1951), angiographic
vasospasms were believed to induce a causal chain of cerebral
hypoperfusion with infarctions, neurological deterioration,
and poor outcome [36]. The development of ischemic damage
often coincides with angiographic vasospasm [22]. However,
DCI can develop in absence of angiographic vasospasms, and
angiographic vasospasm may resolve without causing ische-
mic lesions [22, 41]. The occurrence of angiographic vaso-
spasms is related to the amount of subarachnoid blood [41,
128], and indeed, blood breakdown products have been
shown to induce arterial spasms [73]. In fact, about 70% of
SAH patients show angiographic vasospasms [28, 119, 131,
172]. However, not all SAH patients that present with angio-
graphic vasospasms develop DCI-related cerebral perfusion
impairment [22, 41], and the percentage of patients that devel-
op actual neurological deterioration due to DCI lies at 30% [8,
9, 23, 25, 28, 119, 131, 172].
Angiographic vasospasm-induced ischemia has been
regarded as a target for therapeutic management of DCI.

However, a systematic review of several studies (including the
CONSCIOUS-1 trail) showed that the pharmacological reduc-
tion of angiographic vasospasm did not translate into im-
proved clinical outcome [38, 104]. The reason for the
unsatisfying translation of experimental results into clinical
practice is unclear, and one may only speculate about the
reasons: one reason for this observation might be that drug
side effects may negate the benefit of the investigated phar-
maceuticals or that insensitive outcome measures result in
unspecific results [38, 89]. However, it seems unlikely that
all investigated drugs have side effects negating its benefits.
Second, the connection between DCI and EBI is unknown:
EBI-related pathophysiological changes might not be a pre-
requisite for DCI. Both EBI and DCI could present themselves
as an epiphenomenon of an associated process that itself is the
true cause of infarction or independently caused by an associ-
ated process [22]. In fact, fresh subarachnoid blood causes
EBI, and a cocktail of blood degradation production can result
in cerebral vasoconstriction and likely also in a neuronal dys-
function [73]. Conversely, as discussed in the previous sec-
tion, EBI could have a causal relationship with DCI [15, 145].
The pathophysiological processes during EBI including tran-
sient global ischemia might initiate the later cerebral ischemia
and dysfunction of neuronal signaling after the third day fol-
lowing SAH ictus. Indeed, EBI incorporates several patho-
physiological changes such as transient global ischemia, apo-
ptosis, early metabolic failure, and induction of inflammation,
which could promote a later ischemia and neuronal dysfunc-
tion. In this view, a targeted treatment of EBI-related patho-
physiological changes might also address DCI, and treatment
of DCI alone and without treatment of EBI would not improve
the clinical results. If EBI and DCI exhibit a causal pathophys-
iological connection remains unclear. A final reason for the
disappointing therapeutic management of DCI might be that
the pathophysiological mechanisms of DCI go far beyond
angiographic vasospasm of the major cerebral vessels and an
ischemia in the downstream territory. Ischemia seems to be
crucial factor during DCI as several experimental and clinical
studies suggested (e.g., for experimental SAH in mouse
models: [17, 54, 75, 91, 107, 135, 136, 160]). However, var-
ious other pathophysiological processes next to vasoconstric-
tion of the major cerebral vessels were considered to contrib-
ute to ischemia, such as microvascular dysfunction,
microthrombosis, cortical spreading depolarization, and in-
flammation, and their possible contribution to the develop-
ment of DCI in SAH patients is discussed in the following
section.
Microvascular dysfunction
Angiographic vasospasm of the cerebral microvascula-
ture has been observed in different experimental animal
models of SAH [45, 58, 117, 136]. These microvascular
Neurosurg Rev
spasms have been reported to affect up to 70% of all
arterioles [46] and were thought to be caused by blood
components, in particular oxygenated hemoglobin and
partially by breakdown products such as bilirubin oxi-
dation products (BOXes) which have a direct vasospas-
tic effect [20, 98]. Other factors such as swollen astro-
cytic endfeets, constricted pericytes, and cerebral edema
might also directly narrow small vessels and reduce
rCBF [120, 143].
Recently, the attention has shifted toward the role of
pericytes located around cerebral arterioles, capillaries, and
venules (e.g., summarized by [19]). Pericytes are considered
as the main factor of microcirculation regulation in SAH pa-
thology. Especially, the postcapillary system is easily com-
pressed and provides little access for therapeutic interventions
[19]. rCBF may even reverse after constriction of pericytes,
also known as the no-reflow phenomenon [19]. Pericyte con-
traction often leads to their programmed cell death, increased
capillary transit time heterogeneity, and microcirculation
maintaining shut down [19, 120].
Occlusion and narrowing of the microvasculature induce
several changes in cerebral microcirculation. Maintaining ce-
rebral microcirculation is essential as cerebral oxygenation
depends on both cerebral blood flow (CBF) and the micro-
scopic distribution of blood, the so-called capillary transit time
heterogeneity (CTH) (Ostergaard et al. 2013). Elevated CTH
after SAH could therefore lead to tissue hypoxia in the ab-
sence of severe CBF reductions. Paradoxically, reduction in
CBF improves brain oxygenation if CTH is critically elevated
(Ostergaard et al. 2013). In this respect, angiographic vaso-
spasm and inverted rCBF might reduce capillary transit time
heterogeneity and therefore improve net tissue oxygen extrac-
tion. Whether treatment of increased microcirculatory hetero-
geneity through reduction of CBF results in better long-term
clinical outcome remains to be evaluated in further clinical
and experimental studies.
Microthrombosis
Microthrombosis is initiated in the early course of the disease,
around the second day after SAH [134]. It is the result of a
multifactorial process which includes activation of the coagu-
lation cascade with a procoagulant activity, impairment of the
fibrinolytic activity, platelet aggregation in cerebral vessels,
arteriole and capillary lumen narrowing by swollen astrocytic
endfeet, and cerebral edema or inflammatory processes [45,
120, 143, 166, 181]. It is thought to contribute to microvascu-
lar dysfunction, increased capillary transit time heterogeneity
subsequently leading to ischemia and if changes are irrevers-
ible, to degenerative changes and permanent neurocognitive
impairment.
In autopsy studies, microthrombosis has been correlated to
DCI [150] and death due to symptomatic angiographic
Neurosurg Rev
vasospasm [152]. In the clinical setting, microthrombosis has
also been correlated to DCI, and microemboli are detected in
30 to 70% of the patients with SAH [4, 129, 130]. Indeed, the
degree of vasoconstriction correlates with the microclot bur-
den [45]. Also, there seems to be a correlation between the
microclot burden and the amount of subarachnoid hemorrhage
[150]. However, not all patients that show histological evi-
dence of cerebral ischemia and microthrombosis suffer from
clinically apparent DCI [150].
It is likely that microthrombosis is a significant feature in the
pathophysiology of SAH and a possible target for new therapeu-
tic strategies. However, vessels subjected to microthrombosis
cannot be reached by interventional or surgical efforts.
Therapeutic approaches therefore mainly focus on a pharmaceu-
tical reduction of clot development. So far, limited treatment
modalities are available. In a meta-analysis analyzing the impact
of antiplatelet therapy to inhibit microclot formation after SAH, a
trend of improved outcome and reduced secondary brain ische-
mia [27] was found. However, these results did not reach statis-
tical significance [27].
Cortical spreading depolarization, depression, and ischemia
Cortical spreading depolarization and depression (CSD) is a
well-known phenomenon since the 1940s, and its pathophys-
iological relevance after SAH has been investigated in a series
of experimental and clinical studies mainly by Dreier and
coworkers since 1998 [29–34]. Spreading depolarization is
propagating, polyphasic slow potential changes and is charac-
terized by waves of neuronal depolarization [94, 95]. CSD are
a cerebral reaction to various stimuli such as ion imbalances,
trauma, ischemia, electrical stimulation, or pharmaceutical
agents. These brief states of hyperexcitability are followed
by depression of neuronal activity leading to negative tissue
potentials which last at least 1 min in normal brain tissue [94].
CSD causes depression of cortical activity and can be associ-
ated with cortical spreading or non-spreading depression.
Therefore, depression is an epiphenomena of spreading depo-
larization [29] and is defined as depression of EEG activity
propagating with a velocity across the brain cortex of 2 to
5 mm/min [94, 95].
CSD are associated with various changes at the cellular
level. This includes a disturbance in cerebral ion hemostasis:
extracellular K+ ion levels increase, whereas Na+, Ca2+ ion
levels and the pH decrease [39, 88, 94, 113, 147, 163]. This
change in cerebral ion hemostasis results in a net shift of water
from the extracellular space into neurons causing neuronal
edema with a swelling and distortion of the dendritic spines
[87, 153, 184]. Excitatory transmitters such as glutatmate and
aspartate are already released during the depolarization before
CSD [39, 94, 112, 163]. Elevated extracellular K+ and/ or the
elevated concentration of excitatory transmitters can promote
propagation of spreading depolarization [51, 92].
Cerebral resistance vessels respond with tone alterations. In
normal cerebral tissue, cortical spreading depolarizations in-
duce a net increase in rCBF similar to physiological neuronal
activity. This increase can result in spreading hyperemia and
lasts for several minutes [29]. The typical vascular response of
cortical spreading depolarization and CSD is a large hyperper-
fusion followed by a protracted hypoperfusion [94].
Hyperemia may not be fully adequate to sufficiently supply
distant territories. Therefore, focal ischemia may occur despite
hyperemia [29]. In injured cerebral tissue, neuro-vascular cou-
pling may further be inverted and CSD may result in a net
vasoconstriction, ischemia, and Bspreading ischemia,^ with a
significant delay of the energy-dependent recovery from
spreading depolarization [29, 31, 178]. In tissue already at risk
for progressive damage, this will contribute to lesion progres-
sion. Local microvascular dysfunction was suggested to be
one of the major factors contributing to initiation of spreading
ischemia and may act together with spreading ischemia in
lesion progression: spreading ischemia may promote micro-
vascular dysfunction and decrease neurovascular reactivity as
CSD rises the extracellular K+ and reduces NO [31].
Clinically, electrophysiological evidence exists that CSD
occurs in a multitude of patients with aneurysmal subarach-
noid hemorrhage and other types of stroke. After SAH, CSD
were detected by implantation of subdural strip electrodes in
18 patients in a prospective multicenter study [34]. Nearly 300
spreading depolarizations were observed in 72% of patients
[34]. Recurrent spreading depolarization occurred in parallel
to delayed ischemia induced deficits with positive and nega-
tive predictive values of 86 and 100%, respectively [34].
Furthermore, patients developing SAH-related strokes had as-
sociated progressive prolongation of electrocorticographic de-
pression periods to >60 min [34]. In a further prospective
multicenter study with 13 SAH patients, a subdural electrode
was implanted allowing simultaneous recording of the ECoG,
laser-Doppler flowmetry/rCBF, and tissue partial pressure of
oxygen [ptiO2, 34]. Isolated cortical spreading depolariza-
tions are associated with a physiological response resulting
in either hyperemia, tissue hyperoxia, or in an absent or in-
verse vascular response leading to hypoxemia and hypoxia
[inverse response, 32]. Clusters of cortical spreading depolar-
izations were detected in patients that developed structural
brain damage as observed by neuroimaging. They were asso-
ciated with a significant depression of high-frequency-ECoG
power, an inverse hemodynamic response and a sustained
reduction of ptiO2 [10, 32]. In experimental SAH, inverse
hemodynamic response of cortical spreading depolarization
led to a harmful prolongation of depolarization—ultimately
to terminal depolarization—and severe spreading ischemia
and cortical necrosis [30, 32].
In ischemic stroke, cortical activation increases oxygen de-
mand, worsens the supply-demand mismatch, and therefore
leads to episodic hypoxemia or hypotension and triggers peri-

infarct depolarization [171]. Therapies targeting CSD, mini-
mizing neuronal activity, or inverting the hemodynamic re-
sponse may therefore reduce neuronal damage.
Inflammation
Inflammatory reactions following SAH have been assumed to
play a crucial role in the pathophysiology of SAH, leading to
secondary complications associated with angiographic vaso-
spasm, EBI, and microthrombosis as various inflammatory
cascades are being activated within the first hours after ictus
[11, 53, 82, 105, 111, 154]. Systemic inflammatory markers
such as C-reactive protein (CRP) and cytokines may increase
in response to SAH and are correlated with poor clinical out-
come [44, 53, 62, 71, 82, 84, 90, 105, 111, 132, 154]. After
SAH, an inflammatory environment develops in the subarach-
noid space and adjacent brain parenchyma [summarized by
110]. Therefore, several inflammatory agents and cascades
were hypothesized to promote EBI as well as DCI.
Sadly, there has been very little success in clinical trials for
anti-inflammatory strategies with immune-modulating drugs
(e.g., steroids, cyclosporin A, nafamostat) [50, 106, 133, 179].
With the exception of methylprednisolone, none of these phar-
macological agents demonstrated an improvement in out-
come. The use of steroids showed improved patient outcome
but displayed no effect on either angiographic vasospasm or
DCI [50]. One of the key factors that may complicate clinical
trials with immune-modulating drugs is the interpersonal var-
iability of the injury and inflammatory response [110].
A recently published study demonstrates the role of
microglial activation after SAH and proposes a new concept
referred to as Bcortical spreading inflammation^: a mechanism
of delayed brain injury after SAH that could offer novel ap-
proaches for treatment of the long-term effects of SAH. In
experimental SAH as well as in SAH patients, SAH induced
an intracerebral accumulation of immune cells [141]. The
spread of immune cells was accompanied by an increase of
pro-inflammatory cytokines (IL-6; TNFα), axonal and neuro-
nal injury with increased intracerebral accumulation of the
extracellular amyloid precursor protein and an increased rate
of neuronal cell death [141]. Using a chimeric mouse model
for green fluorescent protein-labeled peripheral leukocytes,
the spreading immune cells were identified as resident mi-
croglia [141]. The authors further conclude that microglia ac-
tivation causes secondary brain injury after SAH, and
microglial activation may therefore correlate with patient out-
come [141].
Voltage-gated calcium channels in delayed cerebral ischemia
Calcium antagonists reduce the risk of DCI-related complications
after SAH. Prophylactic administration of dihydropyridine L-
type calcium (Ca 2+ ) channel antagonists is currently
Neurosurg Rev
recommended in clinical practice for the prevention and treat-
ment of DCI [102]. Evidence for L-type Ca2+ channel antago-
nists in the treatment of angiographic vasospasm and DCI is well
documented [26]. However, other types of voltage-gated Ca2+
channels might also contribute to the pathophysiology of DCI
and provide novel means of treatment:
In total, ten different types of voltage-gated Ca2+
channels have been described of which only four can
be attributed to L-type Ca2+ channels (Table 1). Recent
studies revealed a possible significance of other voltage-
gated calcium channels (VGCCs): between the fourth
and 21st day after ictus, HVA VGCCs are significantly
decreased and LVA VGCC currents increase during ex-
perimental SAH in dogs [114]. In parallel, protein ex-
pression of the Cav1.2 and Cav1.3 L-type α1 subunits
decreases in the dog basilar artery during DCI while
expression of Cav3.1 and Cav3.3 T-type α1 subunits
and Ca v 2.3-containing R-type VGCCs are increased
[114]. In rabbit cerebral artery myocytes, SAH induces
an increase of Cav2.3 transcripts and protein as well as
R-type currents [65]. In contrast to the study of Nikitina
and coworkers (2010), induction of Cav2.3 transcripts
and protein occurred only in small resistance cerebral
vessels but not in the basilar artery [65]. SAH may
therefore differently impact vessels of different sizes
[64, 74]: Cav2.3 (R-type) VGCCs were suggested to
have their pathophysiological significance in small di-
ameter arteries [64, 74]: the Cav2.3 VGCC antagonist
SNX-482 improves DCI-related rCBF impairment after
SAH in rats [173]. SNX-482 reverses oxyHb-induced
vasoconstriction 5 days after exposure of cultured rabbit
cerebral arteries to oxyHb more than L-type blocker
diltiazem [98]. Furthermore, the beneficial effects of
dihydropyridine antagonists in prevention and treatment
of DCI might not solely be attributed to its effects on
L-type VGCCs. As Nimodipine reaches comparatively
high serum concentrations during treatment, its specific-
ity on L-type Ca2+ channels reduces, leading to addi-
tionally therapeutic effects on other types of voltage-
gated Ca2+ channels, such as R-type VGCCs [16, 24,
151, 174].
In addition to R-type VGCCs, T-type Ca2+ channels
may also have a functional significance: in response to
experimentally induced SAH, Cav3.1 and Cav3.3 α1 sub-
units are upregulated [114]. However, the functional role
of these T-type Ca2+ channels remains unclear. Cisternal
injection of the T-type blocker mibefradil did not attenu-
ate angiographic vasospasms as assessed by CT angiogra-
phy in cynomolgus macaques—in contrast to the
dihydropyridine nicardipine [21]. However, mibefradil is
not a very selective drug that is used in submicromolar
concentrations used to block T-type channels. As SAH
leads to a cell depolarization, T-type VGCCs may further
Neurosurg Rev

Table 1 The ion-conducting Cav of voltage-gated calcium channels (adapted after Kamp et al. 2005)

Channel type Cav α1 subunit Chromosomal Typical blocker

location

High-voltage-activated calcium channel

Cav1 subfamily: BL^-type calcium channels
L Cav 1.1 α1S 1q31-q32 L-type calcium channel antagonists, such as 1,4-dihydropyridines
L Cav 1.2 α1C 12p13.3 (nimodipine; nicardipine); phenylalkylamine
L Cav 1.3 α1D 3p14.3 (verapamil) or benzothiazepine (diltiazem)
L Cav 1.4 α1F Xp11.23
Cav2 subfamily: Bnon L^-type calcium channels
P/Q Cav 2.1 α1A 19p13.1-p13.2 ω-agatoxin IVA, ω-agatoxin IVB
N Cav 2.2 α1B 9q34 ω -conotoxin-GIVA and MVIIA
E−/R- Cav 2.3 α1E 1q25-q31 SNX-482
Low-voltage-activated calcium channel
Cav3 subfamily: BT^-type calcium channels
T Cav 3.1 α1G 17q22 Non selective antagonists such as Ni+, kurtoxin,
T Cav 3.2 α1H 16p13.3 Protoxin I&II, amiloride, mibefradil
T Cav 3.3 α1I 22q12.3-q13.2

be inactivated at resting membrane potentials around −75
to −65 mV.
Clinical significance of voltage-gated calcium channel
blockade in the treatment of delayed cerebral ischemia
The dihydropyridine L-type VGCC blockers are the only
pharmaceuticals which improve clinical outcome and reduce
DCI after SAH [ 26]. Nimodipine is a lipophilic
dihydrophyridine L-type VGCC blocker and was introduced
for the treatment of cerebral disorders in Europe in 1985 and
approved 3 years later by the US Food and Drug
Administration [103]. Nimodipine is administered either oral-
ly or intra-venously. A meta-analysis and Cochrane Review
showed the beneficial effect of VGCC antagonists following
SAH. L-type Ca2+ channel antagonists reduce the risk of poor
outcome (relative risk: 0.81; 95% confidence interval 0.72–
0.92; number need to treat: 19) by preventing secondary is-
chemia [26]. Furthermore, administration of VGCC blockers
causes a favorable trend toward improvement of case fatality
[26]. The pathophysiological mechanism through which
dihydropyridines prevent secondary ischemia and subse-
quently improve outcome following subarachnoid hemor-
rhage has not been clearly identified. It has been proposed that
Nimodipin exerts its effect through changes in rCBF, reduc-
tion of angiographic microvasospasms, cortical spreading is-
chemia, and microthrombi formation [30, 164–166].
Additionally, a possible neuro-protective effect of
dihydropyridines has been discussed. However, this concept
remains controversial as its application in treatment of acute
ischemic stroke has shown no beneficial effect on clinical
outcome or case fatality [183].
Although oral or intravenously administrated dihydropyridine
antagonists show a benefit following SAH, they are not capable
of completely preventing DCI. Intrathecal application of
dihydropyridines was considered to be a promising alternative
to improve effectivity compared to oral or intravenous applica-
tion. Intrathecal administration of nimodipine was successfully
evaluated in experimental SAH in the 1980s [49, 97, 170, 182].
Later, nicardipine, another dihydropyridine L-type VGCC antag-
onist, was formulated in prolonged release implants: intrathecal
application of these nicardipine prolonged release implants was
analyzed in a few retrospective studies and may reduce the risk of
angiographic vasospasms, DCI associated neurological deficits,
and secondary brain ischemic lesions [5, 78–80, 156]. More
recently, nimodipine was formulated in prolonged release micro-
particles for intrathecal application. Intrathecal application of
EG-1962 nimodipine prolonged release microparticles reduces
angiographic vasospasm in experimental SAH in a rat SAH
model [57]. More importantly, the recently published
NEWTON trial (Nimodipine Microparticles to Enhance
Recovery While Reducing TOxicity After subarachNoid
Hemorrhage) showed that intrathecal application was safe and
associated with not only a reduced DCI and rescue therapy but
also improved clinical outcome as measured by the extended
Glasgow Outcome score [55, 56].
Subcellular organelles
The importance of the functional disturbance of subcellular
organelles in the pathophysiology of SAH is gaining interest
and could provide novel modes of treatment for patients with
SAH. Most of the available data stems from preclinical studies
but shows that the nucleus, the endoplasmatic reticulum (ER),

mitochondria, and the autophagy-lysosomal system display
alternate functions during the course of SAH and could be
implicated in its pathophysiology [18]. Nuclear signaling
pathways such as the factor-erythroid 2-related factor 2
(Nrf2)–antioxidant response element (ARE), and NF-κB sig-
naling are involved in various CNS disorders and play a role
in the pathogenesis of EBI and angiographic vasospasm in
experimental SAH [18, 123, 139]. However, the functional
role of these pathways remains unclear, and further, in vivo
experiments are needed to elucidate the effect of possible ag-
onist or antagonist on the course of disease. In neurons, acti-
vation of autophagy has been detected during EBI [96].
Although autophagy is key to cell homeostasis, excessive au-
tophagy can induce cell death and is linked to SAH [18, 63,
146]. Moreover, in response to lethal conditions, ER stress can
result in apoptosis, and it is hypothesized that this may result
in apoptosis of endothelial cells and results in disruption of the
blood-brain barrier [18, 122]. More research is needed to es-
tablish the exact roles of these organelles in SAH and may
lead to translational results into clinical practice. The clinical
impact could be significant as a multimodal approach that
focuses on subcellular organelles has the potential of being
highly effective since these organelles are interrelated
components.
Perspective and limitations
Yet, a unifying theory explaining all the pathophysiological
changes following SAH has yet not been described. First,
several new concepts and mechanisms were described and
brought forward during the last two decades. Some are quite
new, and their clinical value (e.g., of microcirculatory dys-
function, capillary transit time heterogeneity, or cortical
spreading inflammation) has to be evaluated in further studies.
A clinical impact of cortical spreading depolarization, depres-
sion, and ischemia or early brain injury is documented, and the
role of angiographic vasospasms was questioned as described
above. Second, it remains unknown how these different path-
ophysiological mechanisms following SAH are connected. As
previously discussed, some of them may be causally connect-
ed or present themselves as an epiphenomenon of an associ-
ated process. Further studies are required. If all the mecha-
nisms following SAH have no causal pathophysiological con-
nection and are solely evoked by the subarachnoid blood and
its degradation production, multiple treatment strategies ad-
dressing the different pathophysiological mechanisms are re-
quired. If there is, e.g., a causal connection between DCI and
EBI, future therapies should address EBI more specifically.
Next, experimental SAH and animal models are used to re-
semble the human condition and to study pathophysiological
changes following SAH and the effect of pharmaceuticals and
interventions. However, these experimental findings might
not necessarily mimic the human condition: originating from
Neurosurg Rev
a study comparing inflammatory changes in mice and
humans, a large debate questioned the scientific value of cer-
tain animal models of human diseases. Although data from
inflammatory diseases do not necessarily translate to hemor-
rhagic stroke, pathophysiological changes after experimental
SAH will not completely match human conditions. A recent
meta-analysis aimed to determine case fatality in mouse DCI
models, to compare mortality in mouse DCI models to case
fatality in human SAH patients, and to identify factors
influencing mouse mortality. The study described a significant
lower mean overall mortality rate in mouse DCI models com-
pared to human case fatality rates following aneurysmal SAH
and identified the chosen experimental SAH model
(endovascular vs injection model) as the only significant pre-
dictor for mouse mortality after 48 h [77]. Further analyses are
required to establish whether and to which extent different
D C I m o d e l s a ff e c t m o r t a l i t y a n d r e f l e c t h u m a n
pathophysiology.
Conclusion
A unifying theory for the pathophysiological changes follow-
ing SAH has yet not been described. Angiographic vasospasm
is probably important. Some changes may be causally con-
nected or present themselves as an epiphenomenon of an as-
sociated process. A causal connection between DCI and EBI
would mean that future therapies should address EBI more
specifically. If the mechanisms following SAH display no
causal pathophysiological connection but are rather evoked
by the subarachnoid blood and its degradation production,
multiple treatment strategies addressing the different patho-
physiological mechanisms are required. The discrepancy be-
tween experimental and clinical SAH could be one reason for
unsuccessful translational results.
Compliance with ethical standards
Funding TRs position is funded through the MD-PhD program of the
Swiss National Science Foundation (SNSF), Bern, Switzerland
(323530_158128).
Conflict of interests Dr. Maxine Dibué-Adjei is employed by
LivaNova PLC. All other authors declare that they have no conflict of
interest.
Informed consent For this type of study, formal consent is not
required.
Ethical approval This article does not contain any studies with human
participants or animals performed by any of the authors.
Neurosurg Rev
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