Chronic subdural hematoma (cSDH) is a common neurosurgical disease: Its one-year incidence rate is about 5 per 100,000 in the general population, but increases for those aged 70 years and older (58 per 100,000 per year)
. Because the proportion of people aged 65 years and older is expected to double worldwide between 2000 and 2030
, a large rise in incidence is expected.
Despite its relatively high mortality and morbidity it is often considered to be a rather benign entity
[3, 4]. The main risk defining the outcome is recurrence. Even if operated by skillful neurosurgeons, recurrence rates from 3.8 to 30% are reported
cSDH was first described by JJ Wepfer
 in 1656, followed by Rudolf Virchow,
 who detected an inflammatory element and in 1856 named this condition pachymeningitis haemorrhagica interna. The formation of new membranes and the extravasation of fluid in the cavity between these membranes and layers was seen by Virchow as typical for this disease. Today’s definition of chronic subdural hematoma as a 'chronic, self-perpetuating inflammatory process that involves the dura mater' was given by Frati
 and confirms the inflammatory nature of this disease.
Several causes have been described as mechanisms of origin. Analogous to acute subdural hematoma caused by trauma, the occurrence of chronic subdural hematoma has often been described in conjunction with head injury. Histopathological evidence for the influence of trauma was given by Schachenmayr
 in 1978 describing that after microtrauma a cleavage of the inner dural layer occurs ('tissue torn artifact'). Still today the role of head trauma in the origin of chronic subdural hematoma is not clear. A literature search discloses that at least mild head trauma had occurred in 8%
 to 80%
 of the patients.
An important histopathological mechanism of origin is the high non-specific reaction potential of the capillary network in the inner dural sheet which, coming in contact with blood or fibrin degredation products, leads to the formation of a neomembrane. This mechanism is supported by the inflow of liquids like blood, later plasma and/or cerebrospinal fluid (CSF. Further progression is maintained by tissue activator (TA) exuding from the extremely vascularized membranes into the cavity, perpetuating a fibrin/fibrinogene mechanism leading to continuous microhemorrhages. Furthermore the automembrane developes inflammatory cells, like mastcells, eosinophiles, neutrophiles, monocyts, macrophages, endothelial cells and fibroblasts, being continuously activated and recruited. This constitutes a source of inflammatory angiogenic fibrinolytic and coagulation factors
The symptomatology consists of headache, neurological focal symptoms, aphasia, epilepsy and unconsciousness. After assessment of the symptoms a neurological classification can be made grading the patients from grade 0 to grade 4
. The main diagnosis however, is done by imaging. Computerized tomography (CT) and magnetic resonance imaging (MRI) disclose monolateral or bilateral extracerebral fluid with more or less membranes separating the hematoma into chambers. Different classifications for both imaging tools are available
The primary therapeutic option is surgery. The standard procedure consists of a burr hole above the site of the lesion with or without irrigation. Santarius
 has proved that an insertion of a drain diminishes recurrence and mortality at 6 months after burr hole craniostomy. In cases of separation of the hematoma by thick layers, open craniotomy must be chosen to allow for evacuation of all chambers
. Recurrence of the hematoma is defined as reappearance of the clinical and radiological symptoms and leads to reoperation.
The first remark about a nonsurgical treatment of cSDH was given by Ambrosetto
 in 1962. He described four patients, who received a conservative multimodal therapy in combination with corticosteroids: Their clinical symptoms regressed completely. Frati
 and Labadie
[19, 20] reported that due to the proof of proinflammatory and inflammatory cytogene that anti-inflammatory therapy may be beneficial. However, several national surveys show a controversial use of cortisone in treatment of cSDH: 38% of French neurosurgeons use adjuvant corticosteroid therapy after surgery
. For 13% of Canadian neurosurgeons cortisone plays a role in the treatment of cSDH
, and 55% of surgeons in the UK and Ireland prescribe steroids in conservatively managed patients
. Berghauser Pont
 wrote about a generous use of corticosteroids in a nonsurgical setting and in preparation for surgery respectively, in combination with surgical treatment in the Netherlands.
There are only poor data published about the efficacy of concomitant cortisone medication. Sun
 describes 112 cases treated in a prospective set-up. A systematic review regarding corticosteroids and cSDH
 found that beyond Sun’s trial there are only four retrospective studies and concludes that steroids are beneficial and suggests more prospective data are needed. Berghauser Pont also performed a retrospective cohort study
 of patients with cSDH on preoperative corticosteroid therapy. If there were no signs of recovery patients underwent surgery: 496 patients with burr hole craniostomy were enrolled. Recurrence was stated at 11.9. In spite of preselection the basis of cortisone therapy, the relapse rate is low.
In 2011 Park published a prospective study about cSDH
: 31 patients underwent burr hole irrigation plus external drainage. The objective of this study was to investigate the relationship between fibrinolytic factors and computed tomography findings. We emphasize in this trial the postoperative administration of dexamethasone for one week, because the reoperation rate Park described was only 3.2.
Thus, the DRESH study will be the first randomized controlled trial (RCT) to evaluate the role of a short postoperative cortisone protocol in the operative treatment of cSDH.
Choice of comparator
Dexamethasone has been selected because contrary to methylprednisolone, it is independent of weight, allowing for a simplified randomization and blinding procedure. Other advantages of dexamethasone are the longest biological half-life of all glucocorticoids (36 to 54 hours) and seven times higher potency than prednisolone. The total dosage used in the DRESH study is 68 mg in Austria and 68.25 mg in China, which is equivalent to a two times higher dosage of prednisolone (1 mg/kg/day). The drug concentration in CSF correlates with the peak concentration in plasma. The DRESH study considers these pharmacokinetics by a single dose at a physiological time in the morning.
The primary objective is to demonstrate that dexamethasone reduces the reoperation rate by 50% within 12 weeks after hematoma evacuation.
The secondary objectives of the study are as follows: to measure the effect of dexamethasone on clinical outcome by the Markwalder score during a period of 12 weeks after surgery; the impact on radiologic signs of the hematoma, such as thickness, membranes and mass-demanding effect (midline-shift); to evaluate risk factors of the genesis and recurrence of cSDH in a prospective study design; risk of infectious complications, for example, pneumonia, urinary tract infection, ventriculitis, meningitis and encephalitis; dexamethasone-dependent severe psychiatric reactions; and death.
This is a phase III, prospective, multi-center, double blind, randomized, placebo-controlled study. Eligible participants are randomized in a 1:1 allocation ratio to one of the two arms: an intervention arm, in which the participants receive dexamethasone according to the protocol, and a control arm in which they receive placebo.