Paradigms in chronic subdural hematoma pathophysiology: Current treatments and new directions.

ABSTRACT: Chronic subdural hematomas (CSDHs) are an increasingly common pathology encountered in a neurosurgical trauma practice. Although the operative and nonoperative management of CSDH has been studied extensively, the recurrence rate of CSDH remains high, with no significant decrease in recent years. We undertook a detailed assessment of the known pathophysiological mechanisms by which CSDHs recur to improve our ability to treat patients with this disease successfully. In this review of the literature from the PubMed and Scopus databases, we used the search terms "(pathophysiology) AND chronic subdural hematoma [tiab]" to identify pertinent reviews and articles in English. The results demonstrated a complex inflammatory response to subdural blood, which begins with the formation of a collagen neomembrane around the clot itself. Proinflammatory mediators, such as vascular endothelial growth factor, interleukin-6, interleukin-8, tissue necrosis factor α, matrix metalloproteinases, and basic fibroblast growth factor, then contribute to chronic microbleeding by promoting the formation of fragile, leaky blood vessels, and widening of gap junctions of existing vessels. It is evident that the lack of improvement in recurrence rate is due to pathological factors that are not entirely alleviated by simple subdural evacuation. Targeted approaches, such as middle meningeal artery embolization and anti-inflammatory therapies, have become increasingly common and require further prospective analysis to aid in the determination of their efficacy.

Is there an interest in performing a systematic CT scan within the first two months after chronic subdural hematoma evacuation? A ten-year single-center retrospective study.

OBJECTIVES: The aims of the present study were to evaluate the frequency of late recurrence after chronic subdural hematoma (CSDH) evacuation and to examine the interest in the use of a systematic CT scan within the first two months after surgery. PATIENTS AND METHODS: We performed a retrospective study that included all patients who underwent CSDH evacuation between 2007 and 2017. We evaluated the rate of late recurrence, defined as the need to perform a new surgery after the first month of follow-up. All the patients underwent a clinical examination and a systematic CT scan between one and 2 months after the first surgery (delayed systematic CT scan). We evaluated the rate of clinical recurrence, defined as the association between clinical symptoms and radiological abnormalities, and of radiological recurrence, defined only on CT scan data. RESULTS: During the inclusion period, 696 patients underwent CSDH evacuation in our unit. Overall, 54 patients (7.7%) had recurrence, of whom 21 (39%) had recurrence after 4 weeks (late recurrence). Of the 21 patients with late recurrence, 7 (1%) had radiological recurrence, and 14 (2%) had clinical recurrence. There was no difference in the CT scan characteristics between patients with clinical and radiological recurrence. CONCLUSION: The use of a delayed systematic CT scan after CSDH surgery has a marginal impact on patient management, and the indication for reoperation without symptoms seems highly subjective. In patients without neurological symptoms, the use of a delayed cerebral CT scan may not be indicated.

Statistical analysis plan for the Dex-CSDH trial: a randomised, double-blind, placebo-controlled trial of a 2-week course of dexamethasone for adult patients with a symptomatic chronic subdural haematoma.

BACKGROUND: The incidence of chronic subdural haematoma (CSDH) is increasing. Although surgery remains the mainstay of management for symptomatic patients, uncertainty remains regarding the role of steroids. Hence, the Dex-CSDH trial was launched in the UK in 2015 aiming to determine whether, compared to placebo, dexamethasone can improve the 6-month functional outcome of patients with symptomatic CSDH by reducing the rate of surgical intervention and recurrence rate. METHODS AND DESIGN: Dex-CSDH is a multi-centre, pragmatic, parallel group, double-blind, randomised trial assessing the clinical utility of a 2-week course of dexamethasone following a CSDH. Seven hundred fifty patients were randomised to either dexamethasone or placebo. The primary outcome is the modified Rankin Scale at 6 months which is dichotomised to favourable (a score of 0-3) versus unfavourable (a score of 4-6). CONCLUSIONS: This paper and the accompanying additional material describe the statistical analysis plan for the trial. TRIAL REGISTRATION: ISRCTN, ISRCTN80782810. Registered on 7 November 2014. http://www.isrctn.com/ISRCTN80782810. EudraCT, 2014-004948-35. Registered on 20 March 2015.

Kernohan-Woltman Notch Phenomenon ­ Case Report

The Kernohan-Woltman notch phenomenon is a paradoxical neurological manifestation consisting of a motor deficit ipsilateral to a primary brain injury. It has been observed in patients with brain tumors and with supratentorial hematomas. It is considered a false localizing neurological sign. Magnetic resonance imaging (MRI) scan has been the test of choice. The recognition of this phenomenon is important to prevent a surgical procedure on the opposite side of the lesion. The present case report describes a case of chronic subdural hematoma with a probable finding of the Kernohan-Woltman phenomenon, and it discusses its pathophysiology, imaging findings, treatment, and prognosis.

Subdural Tension on the Brain in Patients with Chronic Subdural Hematoma Is Related to Hemiparesis but Not to Headache or Recurrence.

BACKGROUND: Hemiparesis is a major symptom of chronic subdural hematoma (CSDH). Its severity does not always correlate with hematoma size. The authors analyzed hematoma thickness, pressure, and tension to clarify the mechanism of hemiparesis in CSDH patients. METHODS: A burr-hole surgery was performed on 124 CSDHs in 102 patients. Hematoma thickness and midline shift were measured by computed tomography, and hematoma pressure was measured in surgery. According to Laplace law, tension was calculated as follows: (half the hematoma thickness × hematoma pressure)/2. Student t test and Pearson correlation coefficient (r) were applied in statistical analysis of findings. RESULTS: Motor weakness was identified in 76.5% of our cases. Tension was strongly related to hemiparesis (r = -0.747, P < 0.01), whereas hematoma thickness (r = -0.458, P < 0.01) and pressure (r = -0.596, P < 0.01) were moderately correlated. Mean age of 14 patients (13.7%) with headache was much younger than those without headache (P < 0.01). Stronger midline shift (P < 0.01) and greater ratio of midline shift to hematoma thickness (P < 0.01) were statistically correlated with headache. Recurrence was recognized in 8 patients (7.8%), and stronger midline shift (P < 0.05) and greater ratio of midline shift to hematoma thickness (P < 0.05) were statistically associated with recurrence. CONCLUSIONS: Tension is the most influencing factor to hemiparesis in CSDH patients. This study also elucidates the mechanism for quick recovery from hemiparesis after surgery in that tension on the motor cortex is decreased immediately by drainage.

Pathophysiology and Nonsurgical Treatment of Chronic Subdural Hematoma: From Past to Present to Future.

BACKGROUND: Chronic subdural hematoma (CSDH) is one of the more frequent pathologic entities in daily neurosurgical practice. Historically, CSDH was considered progressive recurrent bleeding with a traumatic cause. However, recent evidence has suggested a complex intertwined pathway of inflammation, angiogenesis, local coagulopathy, recurrent microbleeds, and exudates. The aim of the present review is to collect existing data on pathophysiology of CSDH to direct further research questions aiming to optimize treatment for the individual patient. METHODS: We performed a thorough literature search in PubMed, Ovid, EMBASE, CINAHL, and Google scholar, focusing on any aspect of the pathophysiology and nonsurgical treatment of CSDH. RESULTS: After a (minor) traumatic event, the dural border cell layer tears, which leads to the extravasation of cerebrospinal fluid and blood in the subdural space. A cascade of inflammation, impaired coagulation, fibrinolysis, and angiogenesis is set in motion. The most commonly used treatment is surgical drainage. However, because of the pathophysiologic mechanisms, the mortality and high morbidity associated with surgical drainage, drug therapy (dexamethasone, atorvastatin, tranexamic acid, or angiotensin-converting enzyme inhibitors) might be a beneficial alternative in many patients with CSDH. CONCLUSIONS: Based on pathophysiologic mechanisms, animal experiments, and small patient studies, medical treatment may play a role in the treatment of CSDH. There is a lack of level I evidence in the nonsurgical treatment of CSDH. Therefore, randomized controlled trials, currently lacking, are needed to assess which treatment is most effective in each individual patient.

Evaluation of Cortical Brain Parenchyma by Diffusion and Perfusion MRI Before and After Chronic Subdural Hematoma Surgery.

AIM: To evaluate microcirculatory changes in neighboring parenchyma as a result of pressure due to chronic subdural hematoma (CSDH) in early and late periods after hematoma drainage. MATERIAL AND METHODS: The subject group consisted of 25 patients who underwent CSDH drainage. Brain diffusion and perfusion magnetic resonance images (MRIs) were obtained preoperatively, and at 48 hours (early period) and 2 months (late period) postoperatively. Measurements were performed on 1 cm2 regions of interest (ROI) in the neighboring parenchymal tissue. RESULTS: The early postoperative diffusion values showed improvement compared to the preoperative values. The late postoperative values showed improvement compared to the preoperative and early postoperative values. The early postoperative perfusion values showed slight decline compared to the preoperative values. However, the late postoperative values showed improvement compared to the preoperative and early postoperative values. CONCLUSION: The fact that there was an increase in diffusion values from early to late postoperative periods, compared with the preoperative period, indicates that the beneficial effects of surgery increase over time. Brain perfusion was found to be slightly decreased in early postoperative period. Following CSDH drainage, neurological deteriorations are observed in some patients in the early postoperative periods; a slight impairment in perfusion may account for this. However, during the late postoperative period, perfusion was seen to recover prominently.

Headache in patients with chronic subdural hematoma: analysis in 1080 patients.

Headache is a major symptom in chronic subdural hematoma (CSDH) patients. However, some CSDH patients do not complain headache although the hematoma is thick with definite midline shift. This clinical study was performed to identify the mechanism of headache in CSDH patients. We compiled clinical data of 1080 surgically treated CSDH patients (711 males and 369 females), and in 54 cases, the pressure of hematoma was measured during burr hole surgery using a glass-stick manometer. Headache was recognized in 22.6% of patients, while nausea or vomit suggesting increased intracranial pressure was detected in only 3.0%. Ophthalmological examination was performed in 238 patients, and papilledema was identified in only one patient (0.4%). The mean age of patients with headache (59.8 ± 16.9 years) was significantly younger than that of those without (75.7 ± 11.2 years) (P < 0.01). In 54 cases, the mean hematoma pressure was not significantly different between patients with (17.1 ± 6.2 mmH2O) and without (18.4 ± 7.2 mmH2O) headache (P > 0.10). Hematoma thickness was significantly greater in patients without headache (P < 0.01), but the ratio of midline shift to hematoma thickness was significantly greater in patients with headache (P < 0.01). In our results, the status of increased intracranial pressure was rare in CSDH patients, and high hematoma pressure was not a cause of headache. Midline shift was the most influenced factor for headache in our study, and based on the results, the authors consider that the potential cause of headache in CSDH might be stretching or twisting of the pain-sensitive meninges and meningeal arteries or veins.

Chronic Subdural Hematoma Spontaneous Resolution

Introduction Chronic subdural hematoma (CSH) is a hemorrhagic brain injury that persists for more than 21 days after its initial formation. The incidence is predominantly among the elderly population (> 65 years), and varies from 58 to 74/100,000 inhabitants. Spontaneous resolution is considered variable; in the literature series, it is < 1­20% of cases. Objectives To expose the CSH pathophysiological mechanisms of spontaneous resolution and some treatments that lead to hematoma volume reduction. Methods Literature review between 1971 to 2016, using the PubMed, Medline, Embase, Scielo, LILACS and Cochrane databases using key-words, with inclusion and exclusion criteria. Discussion Spontaneous resolution of the CSH pathophysiology is controversial; however, it can be attributed to four basic mechanisms: 1) outer capsule membrane maturation; 2) decreased fibrinolysis; 3) bidirectional flow of blood vessels; and 4) platelet plug. Some drugs, such as mannitol, corticosteroids, tranexamic acid and atorvastatin, contribute to CSH resolution, since they change the capsule membrane permeability, and inhibit the fibrinolytic and inflammatory systems. Conclusion Spontaneous resolution is unpredictable; in some cases, it has a large temporal evolution (of up to 6 years). It occurs in small or laminar collections, asymptomatic or with transient neurological symptoms, and the pathophysiology is still controversial to this day. Therefore, surgical treatment should remain the first option, even though the conservative management is adopted for some patients. Rigorous outpatient and radiological follow-up are recommended.

Introdução O hematoma subdural crônico (HSDC) é uma lesão cerebral hemorrágica que persiste por mais de 21 dias após o começo de sua formação. A sua incidência é predominantemente na população idosa (> 65 anos), e varia de 58­74 /100.000 habitantes, e sua resolução espontânea é considerada rara e variável nas séries da literatura em < 1­20% dos casos. Objetivos Expor os mecanismos fisiopatológicos que favorecem a resolução espontânea do HSDC e alguns tratamentos que favorecem a redução do volume do hematoma. Métodos Revisão bibliográfica entre 1971 e 2016, utilizando as bases de dados PubMed, Medline, Embase, Scielo, LILACS e Cochrane, por meio de palavras-chave, com critérios de inclusão e exclusão. Discussão A fisiopatologia da resolução espontânea dos HSDCs é controversa, porém pode ser atribuída a quatro mecanismos: 1) maturação da membrana externa da cápsula; 2) diminuição da fibrinólise; 3) fluxo bidireccional de vasos sanguíneos; e 4) tampão plaquetário. Alguns medicamentos, tais como manitol, corticoesteroides, ácido tranexâmico e atorvastatina, também podem favorecer a resolução dos HSDCs, uma vez que alteram a permeabilidade da membrana da cápsula e inibem os sistemas fibrinolítico e inflamatório. Conclusão A resolução espontânea é imprevisível; em alguns casos, tem ampla evolução temporal em até 6 anos. Ocorre em coleções pequenas ou laminares, assintomáticas ou com sintomas neurológicos transitórios, e sua fisiopatologia ainda hoje é controversa. Portanto, o tratamento cirúrgico deve continuar sendo a primeira opção, embora se adote uma conduta conservadora para alguns pacientes. O seguimento ambulatorial e radiológico rigoroso é recomendado.

Chronic subdural hematoma pathophysiology: a unifying theory for a dynamic process.

Chronic subdural hematoma pathophysiology has been extensively studied and discussed. In the last decades, optic and electron microscope observations have successfully described its histopathology and the ultrastructure of internal membranes. Moreover, recent biochemical studies have identified a number of important pathways involved in its development and evolution. Our aim was to review recent literature regarding histopathology, ultrastructure and biochemichal pathways and supply a unifying theory about chronic subdural hematoma pathophysiology. The starting point of chronic subdural hematoma is a mechanical injury. The evolution of the pathology is due to the exclusive anatomy of the dura-arachnoid interface. This is a mechanically weak layer. Fibroblasts contained in this region produce an inflammatory reaction with neoangiogenesis and fibrinolysis. Biochemical pathways involved in these reactions is complex and could contain a number of pharmacological targets. The hematoma evolves in different stages thus recent outlooks consider chronic subdural hematoma as a dynamic process. One of the key points for a good outcome and a low recurrence rate may be the timing of the surgical treatment in relation of hematoma natural history. Surgery performed during active inflammatory stages may be less effective in terms of clinical outcome and recurrence rate.

Postural stability in patients with chronic subdural hematoma.

BACKGROUND: Gait disturbances and falls are common in patients with chronic subdural hematoma (cSDH). Postural stability is mainly visually assessed and has not been described using an objective and quantitative measurement tool. The objective of this prospective study was to evaluate postural stability in cSDH patients by measuring trunk sway during stance and gait compared to healthy elderly (HE). It was also to evaluate the relationships among postural stability and age, hematoma size, brain midline shift and hematoma location. METHODS: Using a gyroscopic method, trunk sway was measured in 22 cSDH patients preoperatively, 5 postoperatively and 58 HE during seven standing and walking tasks. Trunk sway amplitude and velocity in the anterior-posterior and medial-lateral directions were assessed. RESULTS: Postural stability was reduced in the cSDH group compared to HE for all standing tasks. During gait, the sway angle was increased while velocity was decreased in the cSDH group. Only 18 % of the patients could perform all tasks without losing their balance. Postoperatively, postural stability was normalized in the medial-lateral direction during standing. There were no correlations among age, hematoma size, brain midline shift or location of the hematoma and trunk sway. CONCLUSIONS: The majority of cSDH patients had reduced postural stability that was partly reversed soon after surgery. It was not correlated to hematoma characteristics, indicating that an increased risk to fall is present regardless of hematoma size and midline shift. This must be accounted for when handling these patients and measures taken to prevent further fall accidents during hospital stays.

Tranexamic Acid in Chronic Subdural Hematomas (TRACS): study protocol for a randomized controlled trial.

BACKGROUND: Chronic subdural hematoma (CSDH) is one of the most frequent reason for cranial neurosurgical consultation. There is no widely accepted medical treatment for this condition. Herein, we present the protocol for the Tranexamic Acid (TXA) in Chronic Subdural Hematomas (TRACS) trial aiming at determining whether TXA can increase the rate of CSDH resolution following conservative management, lower the number of required surgical procedures and decrease the rate of CSDH recurrence following surgical evacuation. METHODS: TRACS is a multicenter, double-blind, randomized, parallel-design, placebo-controlled, phase IIB study designed to provide preliminary efficacy data as well as feasibility, safety and incidence data required to plan a larger definitive phase III trial. Consecutive patients presenting with a diagnosis of chronic subdural hematoma will be screened for eligibility. Exclusion criteria include: specific risk factors for thromboembolic disease, anticoagulant use or contraindication to TXA. A total of 130 patients will be randomized to receive either 750 mg of TXA daily or placebo until complete radiological resolution of the CSDH or for a maximum of 20 weeks. CSDH volume will be measured on serial computed tomography (CT) scanning. Cognitive function tests, quality of life questionnaires as well as functional autonomy assessments will be performed at enrollment, at 10 weeks following randomization and at 3 months following treatment cessation. During the treatment period, patients will undergo standard CSDH management with surgery being performed at the discretion of the treating physician. If surgery is performed, the CSDH and its outer membrane will be sampled for in vitro analysis. The primary outcome is the rate of CSDH resolution by 20 weeks without intervening unplanned surgical procedure. Secondary outcomes include: CSDH volume, incidence of surgical evacuation procedures, CSDH recurrence, cognitive functions, functional autonomy, quality of life, incidence of complications and length of hospital stay. Planned subgroup analyses will be performed for conservatively versus surgically managed subjects and highly versus poorly vascularized CSDH. DISCUSSION: CSDH is a frequent morbidity for which an effective medical treatment has yet to be discovered. The TRACS trial will be the first prospective study of TXA for CSDH. TRIAL REGISTRATION: NCT ID: NCT02568124 .

Nonsurgical Treatment of Chronic Subdural Hematoma with Steroids.

OBJECTIVE: Some studies demonstrated the role of steroids in medical management of chronic subdural hematoma (CSDH). Aim of our study is to evaluate the role of steroids in medical treatment of CSDH and to evaluate the subgroup of patients who respond to steroids. METHODS: This prospective case study was done for 26 months from April 2013 to May 2015. On admission, the parenteral steroid dexamethasone (4 mg) was given every 8 hours for 72 hours. If the patient improved, the oral tapering doses of steroids were continued for 1 month. Neurological assessment and computed tomography scan done after 6 weeks. If the patient had not improved at 72 hours, a standard burr hole and evacuation was done. RESULTS: Twenty-six consecutive patients were studied (20 men; mean age, 60.25 years). The average thickness of the hematoma was 21.9 mm, the mean midline shift was 10.3 mm, and the average attenuation value of bleed on computed tomography scan was 35.7. Eleven patients were treated successfully with steroid treatment, whereas 15 patients required surgery. The female gender, less midline shift, less density (Hounsfield units) were noted to be associated with successful medical treatment. We propose a grading based on the total score given to the midline shift and density. Complications noted were hyperglycemia (1 patient), gastritis (1), and recurrence (1 patient). There was no mortality. CONCLUSIONS: Steroids appear to play a role in the nonsurgical medical treatment of CSDH. Patients with lower grades of CSDH can be treated successfully with steroids. Female patients seem to do better with steroids.

Spontaneous Resolution of Chronic Subdural Haematoma in a Patient Receiving Anticoagulant Therapy.

Significant chronic subdural hematoma (CSDH) is usually a surgical emergency. Spontaneous resolution of CSDH has rarely been reported in the literature. We are reporting a case of spontaneous resolution of CSDH in a patient receiving anticoagulant therapy who had undergone mitral valve replacement surgery.

Spontaneous resolution of nontraumatic chronic subdural hematoma associated with anti-aggregation therapy.

Spontaneous resolution of chronic subdural hematoma (CSDH) is rare, especially for the nontraumatic cases. Here, we present 1 case of a 70-year-old female patient with spontaneous resolution of CSDH. She was chronically anticoagulated after percutaneous coronary intervention. Moreover, she denied previous mild head trauma and bleeding episodes. For personal reasons, she declined surgery. Treatment just included mannitol, which was used to alleviate the symptoms. Intermittent computed tomography showed gradually resolution of CSDH. Spontaneous resolution of nontraumatic CSDH is rare, with different mechanisms and computed tomography characteristics compared with that of traumatic CSDH. Dimerized plasmin fragment D in venous blood may be more sensitive in the judgment of types of CSDH.

Cerebral perfusion changes in chronic subdural hematoma.

Abstract Chronic subdural hematoma is a frequent disorder in the elderly. Although intensively investigated, numerous aspects, including the pathophysiology of clinical symptoms, remain unclear. Perfusion deficits are likely to induce the transient neurologic symptoms seen in chronic subdural hematoma (cSDH). The aim of the present study was to quantify cerebral perfusion impairment in cSDH. Before surgery, 34 patients were examined neurologically using the National Institutes of Health Stroke Scale (NIHSS) score and investigated by CT perfusion imaging. Hematoma volume, localization, and hematoma configuration were recorded. Clinical and radiological data were correlated. Mean hematoma volume was 91.8 cm(3) (16.2-241.6 cm(3), standard deviation [SD] 49.5). Whole brain mean transit time (MTT) was slightly elevated (mean 36.6 sec, SD 5.8). Hematoma volume and cerebral blood volume (CBV) in the underlying hemisphere correlated marginally but not significantly (p=0.067). Perfusion parameters determined in the area below the hematoma (ABH) and the corresponding contralateral cortex (MAC) were highly significantly different regarding cerebral blood flow (CBF) (mean 88.8 vs. 70.4, p<0.01) and CBV (mean 29.4 vs. 22.5, p<0.01). On the other hand, MTT and Tmax were almost equal between these areas (MTT means 35.0 vs. 34.8, (p)=0.914; tMax means 16.0 vs. 15.4, p=0.587). We conclude that local brain perfusion autoregulation is active in the cortical area below cSDH. CBV and CBF are significantly upregulated in the cortical area below cSDH indicating the effect of autoregulation in tissue at risk of ischemia. Cerebral autoregulation is intact in cSDH. Neurologic deficits are likely induced by borderline perfusion.

PlGF and sVEGFR-1 in chronic subdural hematoma: implications for hematoma development.

OBJECT: A considerable body of evidence indicates that inflammation and angiogenesis play a significant role in the development and progression of chronic subdural hematoma (CSDH). While various experimental and clinical studies have implicated placental growth factor (PlGF) in the processes that underpin pathological angiogenesis, no study has thus far investigated its expression in CSDH. The actions of PlGF and its related proangiogenic vascular endothelial growth factor (VEGF) are antagonized by a high-affinity soluble receptor, namely soluble VEGF receptor-1 (sVEGFR-1), and thus the ratio between sVEGFR-1 and angiogenic factors provides an index of angiogenic capacity. METHODS: In the present study, using an automated electrochemiluminescence assay, levels of PlGF and sVEGFR-1 were quantified in serum and hematoma fluid obtained in 16 patients with CSDH. RESULTS: Levels of PlGF and sVEGFR-1 were significantly higher in hematoma fluid than in serum (p < 0.0001). In serum, levels of sVEGFR-1 were higher than those of PlGF (p < 0.0001), whereas in hematoma fluid this difference was not apparent. Furthermore, the ratio of sVEGFR-1 to PlGF was significantly lower in hematoma fluid than in serum (p < 0.0001). CONCLUSIONS: Given previous evidence indicating a role for PlGF in promoting angiogenesis, inflammatory cell chemotaxis, and stimulation, as well as its ability to amplify VEGF-driven signaling under conditions favoring pathological angiogenesis, enhanced expression of PlGF in hematoma fluid suggests the involvement of this factor in the mechanisms of inflammation and angiogenesis in CSDH. Furthermore, a reduced ratio of sVEGFR-1 to PlGF in hematoma fluid is consistent with the proangiogenic capacity of CSDH. Future studies are warranted to clarify the precise role of PlGF and sVEGFR-1 in CSDH.