Method/search strategy
An
information specialist (TK) worked with the lead author (JDBD) to
develop the search strategy. We conducted the search on Medline (Ovid),
Embase (Ovid), the Cochrane Central Register of Controlled Trials
(Ovid), and Scopus (Elsevier). Keywords and Medical Subject Heading
(MeSH) terms related to our research question were used. The search
terms used included the combinations and truncations of the following:
subarachnoid hemorrhage, mood disorders, depression, anxiety, seizure,
epilepsy, convulsion, sexual dysfunction, dyspareunia, erectile
dysfunction, impotence, vaginismus, premature ejaculation, cognition,
mental fatigue, brain fog, neuropsychiatric, headache, cephalgia, and
migraine. The full search strategy according to each database is
available from the authors upon reasonable request.
Each
outcome was addressed using a tailored search strategy for prevalence,
and a separate distinct search strategy for questionnaires was employed
across all outcomes. The results were then integrated into Covidence, an
online systematic review tool aimed at enhancing collaboration and
streamlining literature review processes. Lead authors (YJ, CL, AE, MKD,
ND) were assigned to specific topics and provided access to a curated
list of potential publications within their respective subtopics.
Collaborating with the primary author (JDBD), they assessed the
relevance and significance of these publications for inclusion in the
review. Relevant articles were additionally manually searched to
identify further pertinent literature.
Ethics
The study did not require ethics approval as it does not involve any patient data.
Anxiety and depression
Symptoms
of depression and anxiety are relatively common in patients with
intracranial aneurysms. Multiple evidence synthesis studies indicate
that approximately three out of ten individuals who survived aSAH may
develop symptoms of depression and anxiety (figure 1).6 7
Depression and anxiety symptoms associated with aSAH may have a
substantial effect on patients’ lives. Systematic reviews revealed a
negative association between depression/anxiety and health-related
quality of life, and the presence of depression may also predict poorer
quality of life in aSAH survivors.6 7 Depression was also found to be a significant predictor of unemployment.8
Depression after aSAH was found to be more common among females, those
with premorbid depression or psychiatric illness, and those with
substance use disorder. Further, having cognitive symptoms, fatigue, and
higher physical disability also increases the risk of having depression
after SAH.9
Figure 1 Summary
of prevalence of long-term neuropsychiatic complications following
aneurysmal subarachnoid hemorrhage (figure created with BioRender.com).
The
2023 American Heart Association (AHA)/American Stroke Association (ASA)
guideline indicates that patients with aSAH with depression are
recommended to undergo psychotherapy and drug therapy.5
Potential treatments for these symptoms were derived from therapies
used for people with mental health conditions and from data on stroke
survivors. Selective serotonin reuptake inhibitors (SSRIs) have been
considered first-line therapy for major depressive and anxiety
disorders.10 Among the SSRIs, fluoxetine has been recommended based on several randomized controlled trials (RCTs) in stroke patients.5
Furthermore, a recent 2023 Cochrane Living Systematic Review involving
65 trials on patients with stroke (n=5831) indicated significant
reductions in reducing the prevalence of depression when they compared
pharmacological therapies (SSRIs and other antidepressants) versus
placebo (relative risk (RR) 0.70; 95% CI 0.55 to 0.88; 8 RCTs; n=1025),
psychological (cognitive–behavioral therapy and others) versus usual
care/attention control (RR 0.77; 95% CI 0.62 to 0.95; 6 trials; n=521),
and the combination of non-invasive brain stimulation (transcranial
magnetic stimulation) with pharmacological intervention versus
pharmacological therapy only (RR 0.77; 95% CI 0.64 to 0.91; 3 RCTs;
n=392).11
While
improving outcomes in aSAH requires effective therapies for these
psychiatric conditions, a prerequisite to this is the accurate
identification of SAH survivors with anxiety and depressive disorders. A
recent systematic review identified the nine most common depression and
screening instruments used in patients with aSAH.12
These instruments include the Beck Depression Inventory-II (BDI-II),
Hospital Anxiety and Depression Scale (HADS), Center for Epidemiologic
Studies Depression Scale (CESDS), Zung Self-Rating Depression Scale,
Geriatric Depression Scale, Montgomery–Asberg Depression Rating Scale
(MADRS), Patient Health Questionnaire-9 (PHQ-9), EQ-5D
Anxiety/Depression, and Stroke Specific Quality of Life. HADS has been
validated for post-stroke patients and found to have a sensitivity of
86.8% and a specificity of 69.9% with a total cut-off score of 11.13 However, none of these tools have been validated for individuals with aSAH.12 Conducting further studies is essential to verify the validity of these screening techniques for aSAH.
Cognitive dysfunction
Cognitive
impairment is a major sequela of aSAH seen in 40–70% of survivors and
has been associated with more reduced quality of life measures (figure 1).14
It falls under the term post-stroke cognitive impairment, which refers
to cognitive decline occurring 3 to 6 months after a stroke.15
Known risk factors for subsequent cognitive dysfunction following aSAH
include acute hydrocephalus requiring cerebrospinal fluid diversion,
seizures, fever, prolonged intensive care unit stay, and development of
delayed cerebral ischemia, although even those with good functional
outcomes and postoperative scores may still harbor cognitive deficits
within the first 3 months to years later.14 16
The
type of cognitive dysfunction depends on factors including location of
the hemorrhage, artery affected, time to treatment, and comorbid
factors,14 15 but domains more commonly involved include attention, executive function, and memory.14 16 Impairment in emotion recognition and social cognition can also be seen16 and may contribute to neuropsychiatric disturbances. Language deficits following aSAH remain understudied,14
although high performance on animal naming and abstraction, which are
language-driven subtests, on cognitive testing like the Montreal
Cognitive Assessment (MoCA) is more closely associated with returning to
work following aSAH.17
All
aSAH patients may undergo neurocognitive assessment for screening and
longitudinal follow-up regardless of functional outcome.15 A proposed framework that captures the natural history of cognitive impairment and post-acute recovery involves a screening test done between onset up to 8–90 days later followed by in-depth testing done as early as 8–90 days up to 1 year and beyond if prior screening is positive.15
A recommended screening test is a 5-minute protocol including the
Orientation, Memory, and Phonemic fluency MoCA subtests for assessment
in the acute setting in addition to screening for delirium, which may
impact longer-term cognitive outcomes.15
Following the acute phase, in-depth testing can be done using a
validated global cognition screening test such as the full MoCA or the
Mini-Mental State Examination (MMSE). The MoCA is an ideal and more
sensitive screening tool than the MMSE as it affords a more granular
assessment of executive, language, and visuospatial skills in addition
to memory.17
Establishing cognitive function using these tools at 3 months post-aSAH
is a useful measure and predictor of health-related quality of life
(HRQoL) at 1-year follow-up.14
Once
cognitive impairment is recognized, a holistic approach to
rehabilitation may be instituted. It is found to be most beneficial
around 6 months following aSAH.14 There remains, however, uncertainty as to the efficacy of cognitive rehabilitation interventions due to lack of robust data.15 Currently, there is no pharmacotherapy approved for post-stroke cognitive impairment.15
Headaches
While
headaches are a prominent clinical feature of aSAH, their persistence
after initial management and stabilization remains unclear. Reported
rates of persistent headaches after aSAH vary between 32% and 41% in the
literature, with some reporting severe headache years after the
inciting event (figure 1).18 19
The natural history of post-aSAH headaches is also poorly defined, with
no strict cut-off point after which SAH-related headaches should
naturally subside. According to the International Classification of
Headache Disorders (3rd edition), headaches persisting 3 months after
resolution of aSAH are classified as “persistent headache attributed to
past non-traumatic subarachnoid hemorrhage”.20
Unlike
the classic thunderclap headache associated with the onset of aSAH,
post-aSAH headaches tend to be more insidious in onset, often described
as a sensation of pressure.18 21
There are no clear prognostic factors for developing chronic aSAH;
clinical presentation, radiographic distribution, aneurysm type nor
location, hydrocephalus, and management of the aSAH have not been
associated with long-term headaches.18 19
In
addition to knowing the type and character of the headaches, it is
important to use questionnaires to understand their impact on a
patient’s daily life. One center utilized the Headache Disability Index
and a series of pain questionnaires (eg, the Short-Form McGill Pain
Questionnaire (SF-MPQ), the German Pain Questionnaire, and the
Depression, Anxiety Stress Scale (DASS)), along with the Health-Related
Quality of Life (HRQOL) questionnaire and 12-item Short Form Health
Survey.18 They found that higher headache scores correlated with reduced quality of life.
The
management of post aSAH headaches is not well-defined, with no specific
targeted therapies. In their narrative review of this topic, Sorrentino
et al note the overall paucity of evidence in this area, with
no evidence specifically focused on the outpatient management of
post-aSAH headaches.21
Pharmaceutical management of headaches after aSAH heavily relies on a
combination of acetaminophen, opioids, and steroids, with the vast
majority of patients requiring more than one type of analgesic.22
Select studies also demonstrate a role for gabapentin, pregabalin, and
intravenous lidocaine for the inpatient management of persistent
headaches; however, the long-term effects are not well-known.21
Of note, most patients (95%) receive inpatient opioids and over 70% are
discharged home with a prescription for opioids; however, there is
little evidence that opioids improve headaches after the immediate SAH
event.22
Seizures and epilepsy
Seizures
and epilepsy are well-described complications of aSAH. Seizures are
distinct from the diagnosis of epilepsy, which is characterized by an
enduring predisposition for epileptic seizures.23
Seizures that occur within 24 hours to 14 days following ictus are
considered acute symptomatic seizures which will likely not require
long-term treatment, whereas those that occur >14 days are consistent
with the diagnosis of epilepsy, requiring early diagnosis and long-term
management.
An analysis of the ISAT study showed a
higher risk of seizures for open surgery (9.6%) compared with
endovascular therapy (5.2%) at 5 years.24 A population-based study showed a 5-year cumulative incidence of 12% (figure 1).25
Differences in reported incidence are likely related to inconsistencies
between definitions of epilepsy, length of follow-up, confounding
factors such as anti-seizure medications (ASM) prescribing practices,
among others. Risk factors for developing epilepsy following aSAH
include acute symptomatic seizures or seizures at onset, non-convulsive
status epilepticus, middle cerebral artery aneurysms, higher Hunt and
Hess and Fisher grades, and the presence of a large intracerebral
hemorrhage.24 25
There
is currently no gold standard or evidence-based guideline regarding the
choice of ASM from epilepsy following aSAH. An earlier retrospective
study of aSAH patients identified phenytoin exposure as a predictor of
poor functional and cognitive outcomes.26
However, a subsequent observational study comparing levetiracetam to
phenytoin showed no significant difference in functional outcome,
seizures, or delayed cerebral ischemia.27
Considerations of ASM choice includes efficacy, safety, and
tolerability as well as comorbid conditions. For patients who do not
achieve seizure-freedom following the use of more than two
well-tolerated ASMs, epilepsy surgery may be considered, assuming a
focal area is identified using advanced functional imaging and
neuropsychiatric testing, an evaluation similar to that done in other
patients with focal epilepsy.
No standardized test or
screening tool is available to help aid in the diagnosis of epilepsy in
the clinic setting following an aSAH. Most epilepsy screening
questionnaires are designed for community screening in epidemiological
studies. Since seizures can present with different semiologies and can
often be subtle, a high index of suspicion should be maintained in
patients with a history of aSAH. Electroencephalography (EEG) is
utilized in patients who present with paroxysmal events concerning for
seizures such as sudden jerking movements, discreet episodes of
cognitive changes, loss of consciousness, or awareness to assess for
epileptiform patterns.
The diagnosis of epilepsy
significantly impacts quality of life, particularly driving
restrictions, employment prospects, and psychosocial stigma. Appropriate
diagnosis and treatment are indispensable in high-risk groups of
patients such as those with a history of aSAH.
Sexual dysfunction
Sexual
dysfunction after aSAH is frequently overlooked in the clinical setting
despite its significant impact on psychosocial functioning and quality
of life. Nonetheless, a cross-sectional study of 33 patients with good
clinical grade aSAH and favorable neurological outcome found a high
prevalence of erectile dysfunction in men (54%) and sexual dysfunction
(47%) and hypoactive sexual desire (100%) in women (figure 1).28
Limited
epidemiological data associate sexual dysfunction with various factors.
Hypothalamic–pituitary dysfunction occurs in 11–50% of cases and may
cause growth hormone, corticotropin, and gonadal hormone deficiencies
predominantly.29
Regions key to sexual experience (anterior/mesial temporal lobes; basal
forebrain) may also be affected, being intimately related to the most
frequent sites of ruptured intracranial aneurysms (anterior/posterior
communicating arteries; middle cerebral artery bifurcation).28
Symptoms may include decreased libido, arousal difficulties, orgasmic
dysfunction, reduced lubrication, pain/discomfort, body image concerns,
and psychological disturbances such as lower self-esteem, emotional
lability, and fear of stroke recurrence.28
As
sexual health is an integral aspect of overall well-being, physicians
should actively probe for symptoms of sexual dysfunction in their
patients.5
Utilizing validated self-report tools specific to sexual dysfunction
can then be done when appropriate. The 15-item International Index of
Erectile Function and 19-item Female Sexual Function Index are
multidimensional questionnaires widely used among men and women,
respectively.28 The Changes in Sexual Functioning Questionnaire measures the impact of illness and medications and can be used in both sexes.30 Before adopting any screening tool, clinicians should consider the specific needs and characteristics of patients.
Our
review demonstrated a lack of literature focused on therapeutic options
for aSAH with sexual dysfunction. Generally, the treatment of
post-stroke sexual dysfunction is often multifaceted, combining medical,
psychological, and rehabilitative approaches. A thorough review of
medications likely contributing to sexual dysfunction is recommended,
with dose adjustments being done as needed. Comorbid conditions such as
depression, anxiety, and other health issues affecting sexual
functioning should also be addressed. Lastly, various
non-pharmacological modalities can also be offered by trained
professionals. These include psychotherapy (eg, sex therapy,
individual/couples counseling, support groups), physiotherapy (eg,
pelvic floor exercises, mobility/balance/endurance training),
occupational therapy (eg, adaptive devices, task modifications), and
proper patient/partner education and communication skills training.31
