Vascular complications of tuberculous meningitis: An autopsy study
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.170086
Source of Support: None, Conflict of Interest: None
Aims: Vascular complications have the most serious consequences in patients with tuberculous meningitis (TBM). Although stroke is seen in approximately 20% of patients with TBM, the underlying vascular damage and infarction are much more extensive. This study has been undertaken to study the pathology at different levels of cerebral vessels and their resultant complications in TBM. Materials and Methods: Fifty-one postmortem TBM brains were examined over a period of 16 years (1997–2012). The vascular pathology was studied in detail. Changes in middle cerebral artery (MCA) and basilar artery (BA) and their branches at different levels were analyzed in all cases. Results: The age of the patients ranged from 3 months to 72 years. Infarcts were found in 37 cases, among which they were grossly visible in 27 cases. Macroscopic infarcts were more common in MCA territory whereas microscopic infarction was more in BA distribution—brainstem and cerebellum. Vascular involvement was almost universal, with smaller branches of both MCA (94%) and BA (100%) carrying the brunt of the disease, whereas the larger branches were variably involved. Infiltrative lesions were most common at all levels; necrotizing lesions were more common in smaller branches, whereas proliferative changes were seen more in larger branches. Conclusion: This study showed extensive damage of cerebral vessels in TBM, which was responsible for the presence of widespread infarctions. Microscopic infarctions in the brainstem and cerebellum were much more common than reported by radiological studies. Thus, more aggressive management of TBM is required to combat its vascular complications.
Keywords: Basal exudates; infarction; proliferative lesion; stroke; tuberculous meningitis; vasculitis
Tuberculous meningitis (TBM) is the most feared extrapulmonary complication of tuberculosis and carries nearly a 100% mortality in untreated cases. It is the most common form of bacterial meningitis in all age groups. According to the World Health Organization (WHO, 2012), the annual incidence of tuberculosis is 8.7 million worldwide, with the major burden being borne by the developing countries. Approximately 10% of patients with tuberculosis develop a central nervous system disease, with children being more commonly affected. In India, the estimated mortality due to TBM is 1.5/100,000 population.
Histopathology reveals that TBM is characterized by a thick basal exudate composed of lymphocytes, mononuclear cells, epithelioid histiocytes, and areas of necrosis with granuloma formation. Secondary complications include the development of hydrocephalus, raised intracranial pressure, cerebral infarction, opticochiasmatic arachnoiditis, tuberculous brain abscess, tuberculoma, as well as pituitary, and hypothalamic involvement., Vasculitis of major intracranial arteries and their branches secondary to the meningeal inflammation is thought to be responsible for cerebral infarction. Clinically, approximately 20% patients having TBM present with stroke, whereas infarction can be found in 50% patients by sensitive neuroimaging.,, Magnetic resonance imaging (MRI) and its diffusion weighted imaging are more sensitive in detecting an infarction compared to the computed tomographic (CT) scan. Thus, there is no unanimity in the reported clinical and imaging findings. Among the different regions of the brain, infarction most commonly is known to affect the basal ganglia although it may also involve the cerebral cortex, brainstem, and cerebellum.
Even though vascular complications of TBM are devastating, limited data is available on the cerebral vascular pathology in TBM. Lalitha and Dastur (1974) and Vani et al., (1991) from India have presented their data on the vascular pathology of TBM., Recently, Lammie et al., reviewed the vascular pathology in TBM and categorized it as being of three types; infiltrative, proliferative, and necrotizing. Despite the development of recent advances in the understanding of the pathology and pathogenesis of tuberculosis, its many aspects still remain unknown. This study has been undertaken to study the pathology of cerebral vessels at different levels and to correlate them with the resultant complications in patients with TBM.
In this study, postmortem material from the Department of Histopathology was used. Fifty-one cases of TBM were selected based on gross and microscopic finding over a period of 16 years (1997–2012). Detailed clinical findings including demographic characteristics, and the cerebrospinal fluid (CSF) findings were available in 28 cases. A detailed gross and microscopic examination of the brain was done after fixation in 20% formalin for 2 weeks in all cases. The samples for microscopic examination were taken from the frontoparietal cortex, basal ganglia, hippocampus, pons, medulla, cerebellum, basal meninges, optic chiasma and hypothalamus, and choroid plexus in all cases. Additional sections were taken from the pathological lesions such as infarct, tuberculoma, abscess and hemorrhage, as well as from the shunt tract. Vascular pathology of intracranial arteries was evaluated in detail; however, changes in middle cerebral artery (MCA), basilar artery (BA), and their branches were specifically analyzed in all cases. Arterial changes were evaluated at different levels, namely the main artery, major branches, and smaller arteries and arterioles. The arterial branches (medium sized arteries) were defined as arteries >500 µm (0.5 mm) in size whereas smaller arteries were defined as those with size between 100 and 500 µm, and arterioles were defined as being <100 µm in size. Vascular changes were mainly classified into three types: (1) infiltrative, (2) proliferative, and (3) necrotizing. Infiltrative involvement included periarteritis, panarteritis, endothelitis either as an isolated phenomenon or in different combinations. Necrotizing lesions were exhibiting either fibrinoid necrosis alone or in combination with the spectrum of inflammatory infiltrate. Proliferative lesions include endarteritis obliterans due to fibrointimal proliferation with or without inflammatory infiltrate. Vascular changes were also examined in cortical veins.
Special histochemical stains such as Luxol fast blue/periodic acid Schiff stain, Elastic van Gieson stain, and Ziehl–Neelsen (ZN) stains were performed on the representative sections.
This study was approved by the Institutional Ethics Committee.
The age of the patients ranged from 3 months to 72 years, and 13 patients were below 14 years of age. Fever was the most common presentation (97%) followed by headache and vomiting (75%). Hemiparesis was seen in 21.4% of cases either at presentation or during the course of the disease. TBM was diagnosed on clinical grounds in 41 cases. Five cases were diagnosed as pyogenic meningitis, four cases as viral meningoencephalitis and one case presented as parietal lobe space occupying lesion. Eleven patients had co-morbidities such as HIV infection (2 cases), pregnancy (3 cases), prior renal transplant (2 cases), protein energy malnutrition (2 cases), and systemic lupus erythematosus and type 2 diabetes mellitus (1 case each, respectively). The details of the cerebrospinal fluid (CSF) findings are shown in [Table 1].
The major pathological findings are summarized in [Table 2]. Basal exudate was present in all cases except one. It was thick, plastic-like in 32 cases covering the anterior surface of the brainstem and interpeduncular fossa [Figure 1]a. Microscopically, 33 cases (64.7%) had a lymphohistiocytic exudate, 8 cases (15.7%) had a neutrophil-rich exudate, and the remaining 10 cases (19.6%) had a mixed exudate. Tuberculomas were seen in 13 (25.5%) cases and were common in the cortical and subcortical locations (10 cases) as well as in the brainstem (4 cases) [Figure 1]c. The ZN stain demonstrated acid fast Bacilli (AFB) in 40 (78.4%) cases. In all the cases, the diagnosis was confirmed by multiplex polymerase chain reaction using primers specific for Mycobacteria from formalin fixed, paraffin embedded tissue.
The arterial tree demonstrated a variable vascular pathology. The frequency and pattern of involvement were dependent on the size of the blood vessels. The findings were similar in both anterior (MCA) and posterior circulation (BA). Whereas the BA involvement was found in 59% cases, the MCA was involved in 46% of cases. However, smaller branches of all arteries were almost universally affected—100% of BA branches and 94% of MCA branches. The vascular involvement was more prominent in branches of MCA and BA embedded within the exudate; however, smaller intraparenchymal vessels also showed similar changes but in lesser intensity.
The type of vascular lesions varied according to the size of the vessels [Figure 2] and [Figure 3]. The proliferative lesions more commonly affected larger arteries [Figure 4]a,[Figure 4]b,[Figure 4]c. Proliferative changes were seen in BA in 22% cases and in MCA in 12% cases, whereas necrotizing lesions were rare in the main arteries (6% in BA and 4% in MCA). On the contrary, necrotizing lesions [Figure 4]e were much more common in smaller arteries (39% in BA branches and 33% in MCA branches). There was complete destruction of the internal elastic lamina by the necrotizing inflammation. Infiltrative lesions were the most common and affected arteries of all sizes; periarteritis and panarteritis were the predominant findings [Figure 4]d. Other infiltrative changes included isolated endotheliitis that was seen more in large and medium sized arteries. The nature of vascular involvement correlated with the course of the disease. Patients with TBM with an acute, fulminant course showed more necrotizing changes, whereas patients with a prolonged course showed more proliferative vascular changes. Perforating arteries of the diencephalon and hypothalamus showed similar changes as seen in medium and small sized arteries. Forty-three cases showed a combination of different types of lesions indicating the progressive nature of the inflammatory pathology. Arterial aneurysms were noted in 2 cases whereas fresh fibrin thrombi [Figure 4]f were noted in medium and small sized arteries in 6 cases. The vascular changes in the anterior cerebral and posterior cerebral arteries (PCA), and their branches, wherever available in tissue sections, were similar to those seen in MCA and BA; however, they were not uniformly sampled in all cases. Thrombophlebitis affecting medium sized meningeal cortical veins had a relatively infrequent presence and was seen in only 9 cases that had a predominantly acute inflammatory infiltrate. Dural sinus or cortical venous thrombosis was seen in these cases.
Infarction was seen in 37 (72.5%) cases. It was obvious on macroscopic examination in 27 cases and was seen as a soft, discolored area surrounded by edematous brain parenchyma [Figure 1]b. One case had a central pontine involvement. Of the remaining 26 cases of cerebral infarction, 50% (13 cases) showed bilateral infarcts. The distribution of macroscopic infarction was confined to the MCA territory in 18 cases, PCA territory in 2 cases (occipital lobe), and BA territory in 3 cases. Multiple infarcts involving the MCA and BA territory were seen in 3 cases, and one case had an infarct involving MCA, PCA, and BA territory [Table 3].
All infarcts noticed on gross inspection were confirmed on microscopic examination. In addition, 10 cases showed microscopic infarcts distributed in different areas of the cortex and brainstem. Microscopically, infarcts were classified into 3 types—acute (<2 days), recent (2–21 days), and old (>21 days). Among the different types of infarcts, acute infarcts were the ones most common (52.9%), followed by recent infarcts (39.2%), and old infarcts (13.7%) [Table 4]. Cases showing only microscopic infarction were predominantly acute infarcts (8 cases) or a combination of acute and recent infarcts (2 cases). The microscopic infarcts were more common in the brainstem and were multiple in number. The majority of the cases revealed a combination of infarcts of different ages. Combined together, the macroscopic and microscopic findings revealed that infarcts were seen in the MCA territory in 47% of the patients, and in the BA territory, in 43.1% of the cases.
TBM is a heterogeneous disease with a wide spectrum of clinical and pathological presentation. In this study of 51 cases, TBM was not clinically suspected in 10 cases due to their acute and fulminant course. In these cases, the meningeal exudates were either neutrophil-rich or mixed neutrophilic-lymphohistiocytic, which explains the errors in diagnosis based on CSF examination. Therefore, the presence of neutrophils in CSF does not necessarily exclude the diagnosis of TBM. It is known that TBM more commonly affects the immunocompromised patients, and HIV co-infection is one of the strongest associations. Lanjewar has reported TBM in 13% AIDS patients in a large autopsy study from India. Hemiparesis was present in 21.4% of the patients in our study. Stroke in TBM occurs in 15–20% patients., However, the number of patients showing gross or microscopic infarction on postmortem examination was much higher (72.5%) in this study. Impaired consciousness may mask the hemiparesis in these patients, and the recent infarcts might have developed late in the course of their disease.
Previous autopsy studies have shown basal exudates in up to 96% cases, which was similar to the findings of our study. These figures are much higher than the reported CT findings showing basal exudates in 65–70% cases. This is because a conventional CT scan is not able to detect scanty amount of exudates., The incidence of tuberculomas in TBM patients varied from 22% to 30% and were seen commonly in children., It mostly affected the posterior fossa with the cerebellum being the most common site. However, supratentorial location is the preferred site for adults., In this study, tuberculomas were mainly cortical and subcortical in location. This can be explained by the predominance of adult patients in our study. Moreover, the above figures about location are based on radiological studies. The incidence of hydrocephalus varies in different studies, ranging from 29% to 89% and the communicating type clearly outnumbers the obstructive type., The cause of communicating hydrocephalus may either be increased production or reduced absorption of CSF due to meningeal fibrosis.
The spectrum of vascular pathology in TBM includes arteritis, arterial spasm, arterial thrombosis, and compression of larger arteries by a thick exudate. These vascular changes reduce cerebral perfusion resulting in cerebral infarction. It has generally been reported that arteritis mainly affects perforating branches of major arteries at the base of the brain resulting in basal ganglia infarction that is commonly seen in TBM.,, The present study has different observations. In this study, both proximal as well as distal arteries were frequently involved in the inflammatory process and demonstrated a wide spectrum of lesions. The larger arteries were variably involved whereas the smaller arteries were affected almost universally in all cases. The most common vascular lesion was the infiltrative type that involved arteries of all calibers. Among proliferative and necrotizing lesions, proliferative changes were more common in larger arteries whereas necrotizing lesions were predominant in arterioles and smaller arteries. Previous autopsy based studies have reported predominantly intimal proliferation and periarteritis in larger cerebral arteries whereas smaller arteries showed panarteritis and necrotizing lesions., We observed that necrotizing lesions were more common in patients showing an acute, fulminant course whereas proliferative lesions were common in subacute cases. Lalitha and Dastur (1972) reported that subacute cases show concentric or eccentric intimal fibrosis. The nature of the inflammatory infiltrate in the vessel wall was mostly lymphohistiocytic in infiltrative lesions whereas it was acute, neutrophilic infiltrate in necrotizing lesions. Rich and McCordock, almost 80 years ago, observed that the inflammation spreads from adventitia inwards. This has been our observation in many cases. Similar vascular changes can be seen in cases of cerebral toxoplasmosis. However, in our study, the patients developed TBM as a part of systemic tuberculosis, and the diagnosis was confirmed by demonstration of acid fast bacilli (AFB) in the meningeal exudates or by molecular methods. No case of cerebral toxoplasmosis was included in this study.
The pathogenesis of vascular pathology in TBM is not clearly understood. It may be speculated that the arterial inflammation starts from periarterial location because of the direct effect of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukins secreted by lymphocytes and macrophages. TNF-alpha demonstrated in CSF of TBM patients may induce vasculotoxicity due to its prothrombotic activity. However, it cannot explain the isolated intimitis and intimal proliferation without the involvement of media and adventitia as seen in some of our cases. Therefore, it may be related to an immune-mediated process that may be related to host immunity and pathogen virulence. Vascular lesions occuring due to the direct inoculation of tuberculous Bacilli into the vessel wall causing vascular inflammation may be possible since we found isolated tuberculous Bacilli in the arterial walls and some arteries also showed granulomatous inflammation in their wall. However, it does not appear likely because these lesions were only few and affected a small number of vessels. Thus, direct involvement of cerebral vessels by tuberculous Bacilli cannot explain the florid and exuberant vasculitis seen in TBM.
The occurrence of overlapping acute and chronic vascular pathology in TBM patients in this study supports the previous observations by Lalitha and Dastur (1972) that cerebral arteries develop progressive and recurrent inflammation. The arterial pathology has its own implications and complications. Infiltrative lesions may lead to vascular spasm and impaired blood flow resulting in altered sensorium and seizures, but they cannot be demonstrated at autopsy. Necrotizing lesions can cause destruction of the media and weakening of the vessel wall. These vessels are more susceptible to aneurysm formation and its rupture, giving rise to subarachnoid or parenchymal hemorrhage. However, in this study, even if the smaller arteries were weakened by the necrotizing process, subarachnoid hemorrhage was not seen at autopsy suggesting that even necrotic vessels maintained their integrity. They may rupture only when their elastic tissue is replaced by fibrosis. Aneurysm was observed only in two cases in this study including one patient who had congenital tuberculosis with a mycotic aneurysm involving the MCA. The observations in this study substantiate the fact that vascular involvement in TBM is widespread although it is under-reported by clinical or radiological studies.
Infarction was seen in 37 (72.5%) cases. It was identified on gross examination in 27 (52.9%) cases whereas in 10 cases, the infarcts were microscopic in nature and acute in onset (<2 days). Macroscopic infarctions were predominantly in the MCA territory whereas microscopic infarctions were mostly in the BA distribution. Overall, combinations of acute, recent, and old infarctions were seen in the MCA and BA territory in almost similar frequency. Previous autopsy studies have also revealed macroscopic infarction in around 41% cases with the majority of them being in the MCA territory. There is limited data available on the incidence of microscopic infarction; however, it may be as high as 70%. This study highlights that in TBM, there is universal involvement of smaller arteries and arterioles in both anterior and posterior circulation. This often results in extensive microscopic infarcts that might be responsible for the increased mortality and morbidity. These infarcts resulting from the involvement of microvasculature may be difficult to pick up by the currently available imaging modalities. Udani et al., have observed that small vessel occlusion is common in the early stages of TBM resulting in monoplegia whereas middle cerebral or internal carotid arterial territory infarcts are common in the advanced stages resulting in hemiplegia or quadriplegia. The available imaging modalities show a variable sensitivity for the detection of small brainstem infarctions, explaining the discrepancy in the frequency of infarction reported on autopsy and at imaging based studies. The incidence of cerebral infarction, detected in TBM by the conventional CT scan in different studies, ranges between 28.3% to 38.5%, and most of the infarctions are detected in the basal ganglia and cortical locations., MRI showed a much higher sensitivity in detecting small brainstem infarcts and also revealed that 40–46% patients with TBM may have brainstem infarcts., Brainstem infarcts are not usually visible on macroscopic examination and multiple sections from different representative areas are required to identify them. Thus, the overall presence of infarcts in TBM is frequently under-reported, and brainstem infarction is more common than was previously thought. This may be responsible for the poor prognosis in TBM patients.
A major limitation of the study was the inherent selection bias as this was an autopsy based study; it may be representing only severe and complicated cases of TBM. Therefore, the spectrum of vascular pathology seen in uncomplicated early cases of TBM is not represented in this study. However, this study highlights the almost universal involvement of smaller arteries in TBM and a high incidence of cerebral infarction, including microscopic brainstem infarcts, that may indicate a poor prognosis.
The authors are grateful to the faculty and colleagues of the departments of Internal Medicine, Pediatrics and Neurology of PGIMER, Chandigarh for their efforts in getting the autopsies done.
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Conflicts of interest
There are no conflicts of interest.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4]