Perimesencephalic Subarachnoid Haemorrhage Research Articles

Treatment and outcomes of non-aneurysmal perimesencephalic subarachnoid haemorrhage: A 5 year retrospective study in a tertiary care centre

PurposePerimesencephalic Subarachnoid Haemorrhage (PMSAH) is an uncommon type of SAH. Severity of PMSAH can be graded by the presence of blood in the Sylvian fissure. No study compares the outcomes from PMSAH with blood present or absent in the Sylvian fissure. Furthermore, the use of Nimodipine lacks evidence base in PMSAH. We investigated whether continuing Nimodipine to 21 days in PMSAH with or without blood in the Sylvian fissure made any significant difference to patient outcome. MethodsRetrospective study of 93 cases admitted to tertiary centre from 2016 to 2020. We compared prevalence of cases with blood in Sylvian fissure, and analysed outcomes including complications and changes to patient modified rankin scale (MRS). We also audited use of Nimodipine in these cases and analysed whether Nimodipine made any significant difference in preventing complications. Results91 % of PMSAH were grade 1, 24 cases (26 %) had blood in the Sylvian fissure. Sylvian fissure positive (Sylvian-positive) cases were statistically significantly more likely to have higher rates of complication compared to Sylvian fissure negative (Sylvian-negative) cases. Our centre stopped Nimodipine 56 % of the time in Sylvian-negative cases and 45 % of the time in Sylvian-positive cases. There was no statistically significant difference in outcomes when Nimodipine was continued to 21 days or ceased after negative angiogram; this result extended to both Sylvian-positive and Sylvian-negative subgroups when directly comparing Sylvian-positive cases with each other and Sylvian-negative cases likewise. DiscussionSylvian-positive cases have a significantly higher rate of complication, as well as an increase in MRS. This may be because of the inflammatory properties of haemoglobin in the subarachnoid space post-bleed. Furthermore, acknowledging the limitations of our retrospective data, we did not find a statistically significant difference in continuing Nimodipine to 21 days with relation to PMSAH outcomes in all subgroups.

Fatigue is Associated with Reduced Participation and Health-Related Quality of Life Five Years After Perimesencephalic Subarachnoid Haemorrhage: A Multicentre Cross-Sectional Study.

ObjectiveTo determine whether fatigue is associated with participation and health-related quality of life 5 years after perimesencephalic subarachnoid haemorrhage.DesignMulticentre cross-sectional study.SubjectsForty-six patients with perimesencephalic subarachnoid haemorrhage.MethodsFatigue was assessed with the Fatigue Severity Scale, participation (frequency, restrictions, satisfaction) with the Utrecht Scale for Evaluation of Rehabilitation-Participation, health-related quality of life with the Stroke-Specific Quality of Life Scale-12, symptoms of depression and anxiety with the Hospital Anxiety and Depression Scale, and coping with the Coping Inventory for Stressful Situations.ResultsA total of 46 patients were included (63% men, mean age 50.4 ± 9.4 years), with a mean time of 4.7 ± 1.6 years after perimesencephalic subarachnoid haemorrhage onset. Fatigued patients (33%) had worse participation (p < 0.01) and health-related quality of life (p < 0.001) than non-fatigued patients, and more often had hypertension, depression, anxiety and emotion-oriented coping (p < 0.05). Fatigue severity was inversely and independently (p < 0.005) associated with participation frequency (B = –3.62), satisfaction (B = –4.54), having restrictions (odds ratio = 2.48, 95% confidence interval 1.079–5.685), and health-related quality of life (B = –0.19), adjusted for depression, anxiety, and/or hypertension.ConclusionFive years after perimesencephalic subarachnoid haemorrhage, one-third of patients still reported fatigue, which was associated with worse participation and health-related quality of life. Future studies should examine whether these patients may benefit from rehabilitation aimed at fatigue.LAY ABSTRACTA subarachnoid haemorrhage (SAH) is a subtype of stroke. Of all patients with SAH, approximately 10% are diagnosed with non-aneurysmal perimesencephalic subarachnoid haemorrhage (PM-SAH). PM-SAH is generally considered a benign form of SAH; however we have previously found that one-third of patients with PM-SAH are still fatigued 5 years after PM-SAH. Fatigue may be related to reduced participation and health-related quality of life, both of which are considered important rehabilitation outcomes. Therefore, this study examined whether fatigue is associated with participation and health-related quality of life after PM-SAH. The results showed that, 5 years after PM-SAH, fatigued patients had worse participation and quality of life than non-fatigued patients. In addition, more severe fatigue was associated with worse participation, regarding frequency, satisfaction and restrictions, and with worse health-related quality of life. Further studies are necessary to determine whether patients with PM-SAH may benefit from rehabilitation aimed at fatigue.

Clinical profile and evolution of patients with subarachnoid haemorrhage for 11 years

IntroductionSpontaneous subarachnoid haemorrhage is a rare cause of stroke, but it causes great socioeconomic impact and high morbidity and mortality.The aim of this study is to describe the clinical profile and evolution of a series of patients with SAH admitted to a tertiary hospital, as well as the diagnostic and therapeutic management. Material and methodsRetrospective study of 536 patients diagnosed with SAH admitted to the ICU of the Hospital Universitario de A Coruña between 2003 and 2013 (Age: 56.9 ± 14.1 years, female/male ratio: 1.5:1). Demographic characteristics, risk factors, aetiologies and clinical signs, prognostic scales, diagnostic tests and treatment were collected. A comparative analysis was made between the general series and subgroups of patients with aneurysmal (SAH-A) and idiopathic (SAH-I) subarachnoid haemorrhage. ResultsThere were 49.0 ± 15.1 patients/year (2013 incidence: 4.3/100,000 inhabitants). 60.3% presented Glasgow Coma Scale (GCS) 14-15, with scarce symptomatology (Hunt-Hess I-II 61.9%, World Federation Neurosurgeons Scale I-II 60.4%). 50.7% presented Fisher IV.SAH-A was diagnosed in 78.3% (n = 396); perimesencephalic subarachnoid haemorrhage (SAH-PM) in 3.2%; and SAH-I in 17.9%. During the study period there was an increase in the prevalence of aneurysms, causing an increased number of surgeries in recent years. Both SAH-A and SAH-I presented greater severity upon admission. Patients with SAH-A had higher percentage of complications and mortality, with lesser degree of independence at 6 and 12 months. ConclusionsThe incidence of SAH appears to have decreased in recent years, with SAH-I comprising 17.9% of the cases. Patients with SAH-I have better prognosis and lower risk of complications, highlighting the benignity of SAH-PM.

Subarachnoid haemorrhage with negative tomographic angiography without vasospasm: is it necessary to perform angiographic controls?

In about 15% of cases, the lesion causing subarachnoid haemorrhage (SAH) is not detectable by imaging studies, and some controversy exists as regards how the diagnosis should be performed in these patients. To analyse the diagnostic performance of digital subtraction angiography (DSA) carried out on a significant cohort of patients with SAH and negative tomographic angiography, without cerebral vasospasm, based on the distribution of bleeding in a simple CT scan. A retrospective analysis is performed of the centre's radiological database over an eight-year period. The inclusion criteria were patients with SAH of a perimesencephalic or diffuse distribution with a negative tomographic angiography result, without cerebral vasospasm, with at least one DSA control of the brain vessels. A total of 125 patients met the inclusion criteria: 61 had a perimesencephalic SAH and 64 had a diffuse SAH. The first DSA revealed vascular injury in seven patients (5.6%): one was in the perimesencephalic SAH group (1.6% yield) and six in the diffuse SAH group (9.4% yield). A second DSA was performed on 86 patients, a third on 28 and a fourth on five of them. The absence of vasospasm in the first DSA performed in patients with SAH and negative tomographic angiography could be a useful criterion for establishing an optimal follow-up protocol in these patients, without exposing them to unnecessary risks and radiation.

Epileptic seizures and outcome in different subtypes of subarachnoid haemorrhage – Results of a single-center retrospective analysis

BackgroundSymptomatic epileptic seizures are an important complication in subarachnoid haemorrhage (SAH) with a frequency of 0.9–25% with importance for patient outcome. The majority of previous studies investigated the incidence of symptomatic epileptic seizures after aneurysmatic SAH. Here we compared the seizure incidence and its impact on the outcome between non-aneurysmatic and aneurysmatic SAH. MethodsWe analysed retrospectively 109 consecutive patients with spontaneous, non-traumatic SAH. Patients were divided in three groups (perimesencephalic, non-aneurysmatic and aneurysmatic SAH). All patients received standard-of-care treatment. The occurrence of acute (0–7 days after SAH) and remote symptomatic epileptic seizures (7 days or more after SAH), severity of SAH as well as clinical outcome parameters (modified Rankin scale [mRS]) at discharge and the frequency of in-house complications were assessed. mRS scores were dichotomized in 0–3 vs. 4–6 to stratify for good versus bad outcome. ResultsPerimesencephalic SAH patients did not experience acute seizures whereas non-aneurysmatic and aneurysmatic SAH patients showed acute seizures with similar frequency (9% and 11%, p = 0.23). The frequency of remote symptomatic seizures was similar in all subgroups (12% vs. 9% vs. 7%, p = 0.72). Seizure occurrence was not predictive for a poor outcome (mRS >4; acute seizures: OR 0.35 [95%CI: 0.02–6.96], p = 0.49; remote seizures: OR 1.72 [95%CI: 0.14–20.1], p = 0.67). ConclusionsSeizures are important neurologic complications of SAH of all etiologies. Nevertheless, acute as well as remote symptomatic seizures are unrelated to the short-term outcome. These results should be treated as hypothesis generating and require confirmation.

Mirror writing after perimesencephalic subarachnoid haemorrhage

We report a case of a right-handed Caucasian woman who developed mirror writing following a non-aneurysmal, non-traumatic subarachnoid haemorrhage. The patient was unaware of having this phenomenon, and it was detected by clinical staff when the patient was writing a card to a family member. Serial imaging has ruled out a stroke as well as an underlying vascular abnormality. This phenomenon resolved after two months. Whilst there is a body of literature surrounding mirror writing, to our knowledge, this is the first description of mirror writing in the setting of a perimesencephalic subarachnoid haemorrhage.

Long-term fatigue after perimesencephalic subarachnoid haemorrhage in relation to cognitive functioning, mood and comorbidity

Purpose: To study relationships between fatigue and objective and subjective cognitive functioning, mood and comorbidity in the long term after perimesencephalic subarachnoid haemorrhage (PM-SAH).Methods: Cross-sectional study. Objective cognitive functioning was measured with: Trail Making Test; Symbol Substitution; D2; Verbal and Semantic Fluency; Tower Test; Digit Span; 15-Words Test; Rey Complex Figure. Subjective cognitive functioning: Cognitive Failure Questionnaire. Fatigue: Fatigue Severity Scale. Mood: Hospital Anxiety and Depression Scale.Results: Forty-six patients, mean age 50.4 (SD = 9.4), mean time after PM-SAH 4.7 (SD = 1.6) years participated. Patients with fatigue (33%) had significantly lower scores than patients without fatigue on most objective cognitive functioning tests (p < 0.05). Fatigue score was significantly associated with subjective and objective cognitive functioning, mood and comorbidity. After adjustment for mood and comorbidity, fatigue remained associated with attention and executive functioning.Conclusions: This study supports our previous findings that a third of patients with PM-SAH experience fatigue and problems of cognitive functioning, also in the long term. Future research should investigate whether these patients would benefit from long-term follow-up and/or cognitive rehabilitation programmes.Implications for RehabilitationConsequences for patients with PM-SAH are underestimated.One in every three patients suffered from fatigue in the long term after onset of PM-SAH.Patients with PM-SAH should be screened for problems of cognitive functioning, fatigue and mood in outpatient clinic just as patients with aneurysmal SAH.

Differences in cognitive and emotional outcomes between patients with perimesencephalic and aneurysmal subarachnoid haemorrhage

To compare cognitive and emotional outcomes between patients with aneurysmal and perimesencephalic subarachnoid haemorrhage and norm scores. First measurement in prospective cohort study. Sixty-seven patients with subarachnoid haemorrhage, were divided into perimesencephalic (n = 8) and aneurysmal (n = 59) subarachnoid haemorrhage groups. Patients completed several questionnaires within the first year after haemorrhage. Depression was measured with the Center for Epidemiologic Studies Depression scale, fatigue with the Fatigue Severity Scale, and objective cognitive functioning with the Trail Making Test. Glasgow Coma Scale scores were collected at hospital admission. Perimesencephalic patients had lower depression (p = 0.006) and lower fatigue scores (p = 0.029) and were faster on the Trail Making Test A (p = 0.002) than aneurysmal patients. No differences between the groups were found on Trail Making Test B (p = 0.112) and presence of fatigue (p = 0.105). Compared with norm scores, aneurysmal patients scored significantly worse on all outcomes, whereas perimesencephalic patients scored worse on Trail Making Test B (p < 0.008), fatigue (p = 0.073) and presence of fatigue (p = 0.058). Perimesencephalic patients may experience problems in complex cognitive functioning and fatigue. In this respect, they have similar sequelae as aneurysmal patients, which may interfere with daily activities and social participation. These findings are of clinical relevance, as perimesencephalic patients often are discharged from hospital without long-term follow-up.

Subarachnoid haemorrhage associated with an intrathecal catheter

Although 15 to 20 percent of patients with subarachnoid haemorrhage (SAH) do not have a vascular lesion on four-vessel cerebral angiography, venous injury is a potential cause. This case describes an intracranial catheter associated with nonaneurysmal SAH. It suggests that intrathecal catheters can cause vascular injury, and that nonaneurysmal perimesencephalic SAH may be due to injury of small blood vessels.

Headache after substance abuse: A diagnostic dilemma

An 18-year-old man inhaled a substance containing synthetic cannabinoids and 1hour later developed a severe global headache. Imaging revealed a perimesencephalic subarachnoid haemorrhage. An angiogram suggested that a small superior cerebellar artery aneurysm was the culprit. This report discusses the, as yet undefined, relationship between “herbal highs” and intracranial haemorrhage.

Cerebral perfusion heterogeneity and complexity in patients with acute subarachnoid haemorrhage

The pathophysiological mechanisms of impaired perfusion during acute subarachnoid haemorrhage (SAH) are incompletely understood. Cerebral perfusion at the micro vascular level can be assessed by single photon emission computed tomography (SPECT). We used a SPECT approach with 99mTc-ECD to measure the cerebral perfusion heterogeneity and complexity in patients with acute aneurysmal SAH or perimesencephalic non-aneurysmal SAH (PNSAH). The perfusion SPECT data of 61 patients with aneurysmal SAH, 18 patients with PNSAH, and 20 healthy control subjects were analysed by dividing the brain into 384 regions of interest. The magnitude of spatial perfusion heterogeneity was assessed by calculating the relative dispersion (RD=coefficient of variation). The fractal dimension (FD) was used to describe the overall complexity of global cerebral perfusion. Patients with aneurysmal SAH (RD=11.30+/-2.17, P<0.001) and PNSAH (10.38+/-2.27, P=0.023) had a higher perfusion heterogeneity than control subjects (8.69+/-0.80). Patients with aneurysmal SAH tended to have a higher perfusion heterogeneity than patients with PNSAH (P=0.061). Also the overall complexity of cerebral perfusion was decreased in aneurysmal SAH (FD=1.11+/-0.06, P<0.001) and PNSAH (1.11+/-0.06, P=0.004) as compared with control subjects (1.17+/-0.06). Acute SAH causes increased regional cerebral perfusion heterogeneity and decreased overall complexity of global cerebral perfusion. Non-invasive assessment of cerebral perfusion characteristics is feasible with SPECT and fractal analysis in patients with acute SAH and may help evaluating micro vascular function in SAH.

Sudden onset of vomiting as a presentation of perimesencephalic subarachnoid haemorrhage

Subarachnoid haemorrhage (SAH) makes up 1% of all attendances for acute severe headache to emergency departments, but other less common presentations may be seen. A 28-year-old man presented to the ED complaining of a 24-h history of nausea and vomiting of sudden onset, but without headache. The patient also described mild photophobia and neck stiffness. A computed tomography scan revealed perimesencephalic blood, and a subsequent angiogram was negative. This appearance is seen in cases of non-aneurysmal SAH, which often occur in younger, male, normotensive patients, and give rise to few warning symptoms. A high index of suspicion should be maintained for SAH, even in the absence of headache.

Non-Aneurysmal Perimesencephalic Subarachnoid Haemorrhage with Associated Pontine Haemorrhagic Infarction

Non-aneurysmal perimesencephalic subarachnoid saemorrhage is characterized by an accumulation of blood in the perimesencephalic and prepontine cisterns identified on sectional imaging together with persistently negative cerebral angiography. Magnetic resonance imaging usually contributes no further information on the possible cause of the bleed but may occasionally show further features including associated parenchymal infarcts such as the pontine haemorrhagic infarct seen in the case described here.

Computed Tomography in the Diagnosis of Subarachnoid Haemorrhage

Early computed tomography (CT) is very useful in detecting subarachnoid haemorrhage (SAH). It offers a lot of information about the origin, the extent of the haemorrhage and the early complications (hydrocephalus, haematoma).Moreover, CT scan can suggest the site of bleeding aneurysm and the risk of severe vasospasm.In some cases, CT shows a perimesencephalic SAH in which often no aneurysm can be detected.The sensitivity of CT in demonstrating SAH decreases as the time between onset of SAH and CT scanning increases.

Cognitive and emotional consequences of perimesencephalic subarachnoid hemorrhage.

Little is known about the long-term cognitive-functional outcome of patients with perimesencephalic subarachnoid haemorrhage (PM SAH). We investigated the neurological, cognitive and emotional consequences of perimesencephalic subarachnoid haemorrhage in eighteen PM SAH patients admitted between November 1990 and July 1997 to the Neurology/Neurosurgery services of a University Hospital. The follow-up study consisted of a face-to-face interview, a neurological examination, an headache questionnaire, a neuropsychological evaluation (Mini-Mental State and a complementary battery to assess specific cognitive domains), the Hamilton Depression Rating Scale (HDRS) and the Blessed Dementia Scale. Thirteen patients performed below the 10th percentile in at least one cognitive domain. Six patients scored more than 12 points on the HDRS. Mini-Mental State and HDRS scores were moderately correlated (r = 0.55). Only three patients left their previous occupation. Minor cognitive deficits and high scores on a depression scale were frequent findings in this cohort of PM SAH patients. Reassurance and treatment of depressive symptoms could be important to improve the long-term outcome of PM SAH patients.

Spinal dural arteriovenous fistula with perimesencephalic subarachnoid haemorrhage

A case is reported of a 66 year old woman presenting with perimesencephalic subarachnoid haemorrhage (SAH) which was caused by a spinal dural arteriovenous fistula at the C1 level. The fistula drained into the venous system of the posterior cranial fossa through a perimedullary vein. The bleeding was thought to result from venous hypertension induced by the fistula. This case may support the hypothesis that perimesencephalic non-aneurysmal SAH can be ascribed to venous bleeding and that venous hypertension is the key to its pathology.

Subarachnoid haemorrhage of unknown cause: Clinical, neuroradiological and evolutive aspects

The clinical and radiological data of 52 patients with subarachnoid haemorrhage (SAH) and a negative panangiography were analysed with an average follow-up period of 3.8 years. Of these 52 patients, only one (1.9%) was subsequently found to have an aneurysm. Second angiography proved to be inconclusive in all 24 cases where it was performed. Of the 51 ‘true’ non-aneurysmal SAH, 80% were in a good clinical grade on admission and 12% developed cerebral ischaemia. The mortality rate following SAH was 4%. There was one rebleeding. At follow-up examination, 87% of the patients had made a good recovery and 6% were left disabled due to SAH. Four patients with an aneurysmal pattern of SAH required a permanent shunt. All of the 22 patients with a perimesencephalic SAH were in a good neurological condition upon admission; one of them developed an angiography-induced transient cerebral ischaemia and another one suffered from a fatal rebleeding. None of the 21 survivors was disabled at follow-up examination. The clinical course of patients with SAH of unknown cause, especially those with a perimesencephalic pattern of haemorrhage, is good. Repeated angiography in this latter group is not useful. In the aneurysmal pattern SAH group, repeat angiography is advised only if there is strong computed tomographic (CT) scan suspicion of an aneurysm.

The negative angiogram in subarachnoid haemorrhage

Our purpose was to review the incidence of negative cerebral panangiography in acute nontraumatic subarachnoid haemorrhage (SAH); to document the amount and distribution of subarachnoid blood on CT and determine its relationship to findings on repeat angiography; and to study the outcome of these patients from the time of presentation to hospital discharge. From 1983 to 1992, 295 patients underwent cerebral angiography for acute SAH at our institution. The CT, angiographic and MRI findings and clinical course of patients with initially negative angiograms were reviewed retrospectively. The overall incidence of negative cerebral panangiography was 31% (92/295). An aneurysm was disclosed on a second angiogram in 4 cases, and on a third angiogram in 1, giving a total false negative rate of 5%. In 55% of cases, only a small amount of SAH was present on CT. The distribution of the subarachnoid blood was nonspecific and resembled the pattern seen in aneurysmal SAH. Ninety-four percent of the patients presented in Hunt-Hess grades I and II. The complications of conservative treatment were few: a rebleed rate of 4%, delayed cerebral ischemia in 4%, cerebral infarcts in 8% and hydrocephalus requiring shunting in 3%. On discharge, 93% of patients had recovered completely and the others were left with moderate disability. There were two deaths related to massive rebleeding. Patients with perimesencephalic SAH (35%) fared particularly well; none developed complications during their hospital stay and repeat angiograms never revealed an underlying aneurysm. In such cases, further angiographic investigations do not seem warranted.

Perimesencephalic and nonperimesencephalic subarachnoid haemorrhages with negative angiograms.

van Gijn and co-workers identified "Perimesencephalic haemorrhage" (PM) as distinct, benign, non-aneurysmal subarachnoid haemorrhage. However, there is only one retrospective series of this entity outside the Netherlands. to confirm (or not) the benign nature of perimesencephalic subarachnoid haemorrhage by evaluating its clinical course and long-term follow-up in a consecutive series of patients admitted to a University Hospital. Patients with subarachnoid haemorrhage and negative cerebral angiography admitted between January 1985 and April 1992 were classified according to the distribution of blood on a CT scan performed within 72 hours after onset, in perimesencephalic and non-perimesencephalic haemorrhages. Demographic and clinical data (collected consecutively), complications and long-term follow-up (obtained by chart review and follow-up by mail) were compared in the two groups. Seventy one cases, 36 perimesencephalic and 35 nonperimesencephalic were included. Sex and age distribution were similar in the two groups. A normal examination on admission was the rule in the perimesencephalic group. Only one patient with perimesencephalic haemorrhage had a complication--transient neurological signs during angiography--and there were no deaths or morbidity during follow-up. In the non-perimesencephalic group three patients rebleed, four developed hydrocephalus and two had delayed cerebral ischaemia. Mean duration of follow-up was 27.6 months for the perimesencephalic and 30.8 months for the non-perimesencephalic group. After discharge there was a fatal rebleed in the latter group. Fifteen percent of the subjects (11% of the perimesencephalic group and 20% of the non-perimesencephalic group) retired from work during the follow-up period. Headaches and depression were found in similar percentages (22-25%) in both groups. This study confirms that perimesencephalic haemorrhage is a distinct entity within the larger group of subarachnoid haemorrhage with negative angiograms, with a good short term and long-term prognosis, and no need for repeated angiographic investigation.

Perimesencephalic subarachnoid haemorrhage: negative angiography and favourable prognosis.

The computed tomography (CT) scans of 110 consecutive patients who presented, over a 4.5-year period, following spontaneous subarachnoid haemorrhage (SAH), were reviewed. All 110 patients also had one or more 4-vessel digital subtraction cerebral angiograms. The CT scans were reviewed in each case without knowledge of the angiographic result. In nine patients (8%), SAH was confined to the perimesencephalic area, interpeduncular cistern and/or prepontine region at CT. All nine patients had at least two, and some as many as four, negative cerebral angiograms. Eighteen of the 110 patients (16%) ultimately had negative angiography. Hence, the patients with isolated perimesencephalic haemorrhage (PMH) accounted for 50% of the negative angiograms. There was a significant association between isolated PMH and negative angiography (chi 2 = 50.1, P < 0.005). The specificity of PMH for negative angiography was 100% (95% confidence interval (CI) = 97-100%) and the sensitivity of PMH for a negative study was 50% (95% CI = 16-84%). Six of the 110 patients had basilar artery aneurysms demonstrated angiographically as the cause of their SAH but none of these six had isolated PMH at CT. All patients with isolated PMH were alive and well at follow up and none had suffered repeat SAH or vasospasm-related ischaemic cerebral injury. Perimesencephalic haemorrhage should be distinguished from SAH in general, because of the good prognosis associated with it and the doubtful need for repeat cerebral angiography after an initial negative study.