Neuropathologic Features and Underlying Medical Disease States of Spontaneous Subdural Hematomas in Adults: A Hospital Autopsy Case Series From a Single Tertiary Center Open Access

Institutional guidelines regarding retrospective examination of autopsy records were followed. This study was reviewed and approved by the institutional review board at the Johns Hopkins Hospital (Baltimore, Maryland).

We reviewed autopsy records of adult patients (≥18 years old) who were diagnosed with acute to subacute spontaneous SDHs between January 1985 and September 2022 at the Johns Hopkins Hospital, a tertiary medical center. Patients who met the criteria were included (Figure 1). We excluded cases in which no autopsy findings of SDH were present despite a history of SDH and cases with any history of neurosurgery, spillover from intraparenchymal hemorrhage (IPH), history of falls or recent trauma, and chronic SDHs. Demographics and relevant clinical data were collected, including pertinent underlying medical conditions, premortem brain imaging, use of anticoagulant therapies, and coagulation profile (prothrombin time [PT], activated partial thromboplastin time [APTT], INR, D-dimer, and platelet count) near time of death. Coagulopathy was defined as a prolonged PT (≥16 seconds), prolonged APTT (≥40 seconds), high INR (>1.2), D-dimer 0.5 mg/L or greater, or platelet count less than 150 000 × 10³/μL.

Neuropathologic examination was performed by board-certified neuropathologists at the Johns Hopkins Hospital. The following neuropathologic findings were included in the study: (1) thickness of SDH greater than 1 cm or midline shift greater than 0.5 cm, (2) signs of brain herniation, (3) location of SDH, and (4) concurrent but nonconnecting alternative types of intracranial hemorrhage, such as subarachnoid hemorrhage (SAH) or IPH.

Thirty-two patients met the inclusion criteria for ASSDH (62.5% male [n = 20]; median age of 53.5 years; interquartile range, 30–76 years (Table 1). The majority of the patients with ASSDHs were white (n = 24; 75%). Some patients with ASSDHs presented with preceding symptoms of headache (n = 7; 21.9%) or seizure (n = 4; 12.5%). The most common underlying medical condition associated with ASSDHs was thrombocytopenia (n = 21; 65.6%), followed by immunosuppression (n = 15; 46.9), bloodstream infection or sepsis (n = 12; 37.5%), and cardiovascular disease, including hypertension (n = 13; 40.6%) and coronary artery disease (n = 12; 37.5%). Of note, 4 patients had received a circulatory support device, for example, extracorporeal membrane oxygenation or ventricular assist device, and 5 patients had received hemodialysis. A significant portion of patients with thrombocytopenia or immunosuppression had underlying malignancies. Of the malignancies contributing to ASSDH, leukemia was most common (n = 11; 34.4%) (Figure 2, A). The second most common medical etiology of ASSDH was liver disorders, including liver cirrhosis (n = 5; 15.6%) and hepatocellular carcinoma (n = 1; 3.1%) (Figure 2, B and C). ASSDH was considered a cause of death in 4 of 32 patients (12.5%) based on the finding of severe brain herniation.

Anticoagulant and antiplatelet medication use near the time of SDH were documented in 22 patients (Table 2). In these 22 patients, 10 patients were taking heparin (45.5%), 6 patients were taking warfarin (27.3%), 6 patients were taking aspirin (27.3%), 4 patients were taking clopidogrel (18.2%), and 1 patient was taking abciximab (4.5%). The coagulation profile was available for 12 patients near their time of death. Of these 12 patients with coagulation factor measurements, only 2 had a prolonged PT, 2 had a prolonged APTT, and 6 had an elevated INR. Interestingly, 9 of 12 patients had low platelet counts near time of death. The D-dimer measurements were available for 8 patients, all of whom had abnormally elevated D-dimer levels.

Gross (Figure 3, A through D) and histopathologic (Figure 4, A through F) examinations were performed on 32 patients with ASSDHs (Table 3). The overall mean volume of SDH was 44.2 ± 75.1 mL, with the largest measuring 241.44 mL. The degree of herniation, measured as deviation from normal anatomic contour, was 1.8 ± 0.8 cm (n = 4; 12.5%). Hemorrhage thickness greater than 1 cm or midline shift greater than 0.5 cm was identified in 5 cases (15.6%). Additionally, brain edema was seen in 7 cases (21.9%).

Concerning the location of the 32 ASSDHs, the hematomas were more commonly restricted to one hemisphere (n = 11; 34.4%) with multi-lobe involvement (n = 10; 31.3%). Bilateral SDHs were found in 18.8% (n = 6) of cases. Regardless of the laterality, the parietal lobe was most frequently involved (n = 7; 21.9%), followed by the occipital lobe (n = 3; 9.4%) and frontotemporal lobes (n = 2; 6.3%). SDH restricted to the spinal cord was found in 6 cases (18.8%).

Our cohort of 32 ASSDHs frequently occurred with other types of brain hemorrhage, including SAH (n = 16; 50%) (Figure 4, B), IPH (n = 6; 18.8%) (Figure 4, C), epidural hemorrhage (n = 2; 6.3%), intraventricular hemorrhage (n = 2; 6.3%), and microhemorrhage (n = 4; 12.5%). Global and focal hypoxic-ischemic changes were noted in 9 (28.1%) and 2 (6.3%) cases, respectively (Figure 4, D). Other notable neuropathologic findings included arteriosclerosis (n = 10; 31.3%) (Figure 4, F), infarction (n = 8; 25%), reactive/metabolic astrocytosis (n = 5; 15.6%) (Figure 4, E), and infection (n = 1; 3.1%).

Our study demonstrates that ASSDHs can be severe, causing death in 9.4% of our cohort, and are often associated with SAH and/or IPH. The mechanism of death is brain herniation caused by diffuse cerebral edema associated with SDH. Although ASSDH is not necessarily the primary cause of death in some cases, the grave prognosis warrants investigation into its etiology or predisposing factors in order to develop preventative strategies.

In our cohort of ASSDH, we found that thrombocytopenia, immunocompromised states, and leukemia were 3 major contributing factors to coagulopathy. The 3 factors are often correlated. For instance, patients with leukemia after radiation or chemotherapy treatment tend to be thrombocytopenic and immunocompromised. Many leukemic patients have platelet levels low enough to necessitate platelet transfusions. Although platelet transfusions to maintain platelet counts at safe levels have been shown to reduce the risk of hemorrhagic complications, intracranial hemorrhages are still a frequent complication in patients with hematologic malignancies.¹⁵ 

Bloodstream infection or sepsis in our cohort was also a major contributor to coagulopathy. Several patients with sepsis developed disseminated intravascular coagulation, especially at the end of life. In septic patients without disseminated intravascular coagulation, there could be other contributing factors of coagulopathy. For instance, in patients with cancer, bloodstream infections could arise from neutropenia as a complication of chemotherapy treatments. Severe infections, such as septic shock, could cause hemodynamic instability that may eventually lead to ASSDHs. In addition to bacterial infection, HIV infection, which causes AIDS, and infectious mononucleosis with secondary hemophagocytosis can also cause profound pancytopenia, resulting in bleeding tendency.

Cardiovascular diseases, including hypertension, coronary artery disease, atrial fibrillation, and heart failure, were found in a portion of our patients with ASSDHs. In patients on mechanical circulatory support for atrial fibrillation or heart failure, bleeding tendency is common because of side effects of anticoagulant regimens: extracorporeal membrane oxygenation is associated with thrombocytopenia resulting from peripheral destruction of platelets in the device circuit; placement of left ventricular assist devices can cause acquired von Willebrand factor syndrome with defects in platelet aggregation. The mechanism for left ventricular assist device–associated platelet dysfunction appears to be cleavage of large von Willebrand multimers by the high shear stress generated by the device pump.¹⁶ 

Liver disorders may predispose to ASSDHs via various mechanisms. Coagulopathies are common in liver disorders because of thrombolytic therapy for portal vein thrombosis or coagulation factor deficiency from liver cirrhosis, because hepatocytes are normally responsible for synthesizing clotting factors II (prothrombin), V, VII, IX, X, XI, and XII and fibrinogen. In one of our cases with known liver cirrhosis but no history of cancer, postmortem examination revealed moderately differentiated hepatocellular carcinoma with metastasis to the lungs, suggesting a more extensive liver disease than previously known. This case illustrates the importance of autopsy in determining the etiology for ASSDHs, particularly for patients with liver disorders. Although the main goal of this study was to identify medical disease states associated with ASSDHs, it is important to acknowledge the roles of antiplatelet and anticoagulation therapies in the development of ASSDHs. Both of these medications are administered to patients to prevent thrombotic complications but are nevertheless associated with an increased risk of intracranial hemorrhages.^17,18 

We collected data of platelet counts and coagulation factor levels near the time of death to evaluate their values in predicting the occurrence of ASSDHs. Although prolonged PT, APTT, and INR are known risk factors for intracranial hemorrhage,¹⁹  most of our ASSDH patients had normal PT and APTT. This finding suggests that ASSDHs can occur when the coagulation profile is normal. Based on our observations, the parameters that are better for predicting ASSDHs are platelet count and D-dimer levels, which were abnormal in the majority of our patients with these data available. This finding highlights the importance of correcting platelet deficiencies as a preventive measure for ASSDHs.

For de novo autopsy cases presenting with ASSDH, including those in the forensic setting where medical records are lacking and trauma may be under consideration, it may be helpful to use a comprehensive evaluation approach, including a complete postmortem examination of all organs, careful assessment of the extent and severity of the SDH, and review of the medications and coagulation profile if available. This comprehensive approach helps to determine the pathogenic mechanism of the SDH and exclude the possibility that it may result from a traumatic cause.

Our study revealed several underlying medical conditions that are associated with bleeding tendency in ASSDH. It also highlighted the value of autopsies in identifying pathologic features and potential risk factors of ASSDH. The result may facilitate the development of appropriate intervention strategies to prevent the occurrence of severe SDH in patients at risk.

A major limitation of this study is that it did not include live patients with ASSDHs, which is a known limitation of autopsy studies. As this was a long-term retrospective study relying on a review of hospital medical records, not all patients had comprehensive clinical histories or laboratory values, particularly D-dimers, which were only available for some patients (Table 4). Moreover, the autopsies were performed by different autopsy pathologists and neuropathologists over the years, leading to potential variations in documentation and interpretations of the neuropathologic findings. For instance, the size of SDH was reported in 2 different formats in autopsy reports: in greatest dimension (centimeters) or volume (cubic centimeters). The variation in reporting caused difficulty in determining which format should be used for the study, and we ended up having to exclude more than half of the cases for measurement (Table 3).