INTRODUCTION

 

Leptomeningitis is by far the most common form of intracranial tuberculosis¹. Tuberculous meningitis (TBM), remains a challenging illness for clinicians because of the difficulties involved in diagnosis and its high morbidity and mortality.² The early diagnosis of tuberculous meningitis, however, remains difficult³, and delays in diagnosis and treatment are directly related to a poor outcome⁴. Complications of TB meningitis includes tuberculoma, hydrocephalus, encephalomyelopathy, radiculomyelitis, and cranial nerve palsies.²

Cerebral infarction secondary to infection has also been reported as a complication of TB meningitis. Little information concerning the clinical characteristics of patients with cerebral infarction secondary to TB meningitis has been collected.⁵

The aim of the present study is to assess predictive factors for development of cerebral infarction in patients with TB meningitis.

 

PATIENTS AND METHODS

 

Between November 2009 and November 2011, we prospectively collected 22 patients with TB meningitis from neurology and internal medicine departments in Zagazig university hospitals. Their ages

ranged from 22 to 60 years (Mean±SD = 50±2.3). 22 Patients (12 males, 10 females) were subjected to the following:

1-        Urgent brain CT scans before lumbar puncture.

2-         Lumber puncture and cerebrospinal fluid (CSF) analysis.

3-        Urgent brain CT studies were repeated when neurological deterioration occurred.

 

Exclusion criteria: A previous history of cerebrovascular disease, hypertension ,diabetes mellitus, hyperlipidemia, structural heart disease, coagulation disorder. All patients provided informed consent for the study.

 

We graded the severity of meningitis at the time of admission according to medical research council ⁶:

*       Stage I for meningeal signs only, no focal neurological findings and normal mental state.

*       Stage II for confusion or focal neurological findings.

*       Stage III for stupor or coma with hemiplegia or paraplegia.

 

Therapeutic regimens for TB meningitis were initiated within 24 hours after admission. The regimen for TB meningitis treatment consisted of:

0-      Standardized antituberculous medications (isoniazid, rifampicin, pyrazinamide, and ethambutol).

2-      Systemic steroids (6-week course) for all patients (dexamethasone 16 mg daily) (8 mg iv BID) for 1 week, gradually tapering off over 5 weeks.⁷

 

Diagnosis of TB meningitis was based on either: (a) isolation of Mycobacterium tuberculosis in one or more CSF cultures or positive polymerase chain reaction (PCR) test with clinical features of chronic meningitis.  OR (b) isolation of M. tuberculosis from outside the CNS, with a clinical presentation of chronic meningitis, and typical CSF features.⁸

 

Patients were classified into two groups:

0-        Patients who developed stroke. 

2-            Patients who did not develop stroke.

 

All patients with cerebral infarction secondary to TB meningitis were diagnosed by development of new-onset focal neurological signs and consistent follow-up neuroimaging findings. All patients with stroke risk factors were excluded from the study. We compared the clinical and laboratory findings of the patients who did and did not develop stroke. Clinical findings included age, sex, time between meningitis onset and treatment initiation. Laboratory findings included complete blood cell count, CSF findings (pressure, white blood cell (WBC) count, neutrophil percentage, protein, and glucose) were reported.  Meningeal enhancement on the initial brain CT scan was also reported.

 

Statistical Analysis:

T-test and Fisher exact test were performed using SPSS software (version 10.0; SPSS, Chicago, IL, USA). We took p value at or below 0.05 to indicate significance.

 

RESULTS

 

-        CSF polymorphic pleocytosis was found more in patients with stroke than patients without stroke. The difference was statistically significant (P-value=0.00). No statistically significant differences in other CSF findings (Table 1).    

-        Patients with more advanced stage of the disease developed stroke more frequently than patients with earlier stage of disease, and this difference was statistically significant (P value=0.02) (Table 2).

-        Patients with positive meningeal enhancement on initial CT brain developed stroke more frequently than patients with negative enhancement, and this difference was statistically significant (P-value=0.05) (Table 3).

 

Table 1. Clinical and laboratory data in stroke and non-stroke group.

 

	Patients with  stroke	Patients without stroke	P-value
Time between meningitis onset and treatment initiation (days)	9±5.4	10±6.3	0.72
Peripheral blood WBCs count (cells/mm3)	11458±948.7	10688±890.1	0.08
CSF pressure(cm H2O)	22.50±7.74	21.23±7.1	0.71
CSF WBCs (cells/mm3)	263±20.1	255±22.3	0.42
CSF neutrophil %	69±12.2	32±10.1	0.00*
CSF protein (mg/dL)	123±28.3	102±26.5	0.1
CSF glucose (mg/dL)	47±17.3	42±14.1	0.47

* Significant at P<0.01

 

Table 2. Relationship between stage of the disease and development of tuberculous infarction.

 

Stage of disease	Total (N=22)	Patients with stroke (N=7)	Patients without stroke (N=15)	P-value
Stage 1	10(100%)	2(20%)	8(80%)	0.38
Stage2	9(100%)	2(22.2%)	7 (77.7%)	0.64
Stage3	3(100%)	3(100%)	0 (0%)	0.02*

* Significant at P<0.05

 

Table 3. Relationship of meningeal enhancement to development of tuberculosis infarction.

 

Meningeal enhancement on  initial CT Brain	Total (N=22)	Patients with stroke (N=7)	Patients without stroke (N=15)
Positive enhancement	8(100%)	5(62.5%)	3(37.5%)
Negative enhancement	14(100%)	2(14.3%)	12(85.7%)

P-value = 0.05 (significant)

DISCUSSION

 

The incidence of cerebral infarction secondary to TB meningitis is reportedly 6–47%.^8,9 In the present study we found that 32% of TB meningitis patients developed stroke, which falls within the previously reported range. There was no significant difference with respect to age or sex between the non-stroke and stroke groups.

We found that polymorphonuclear leukocytosis in the CSF, meningeal enhancement on initial CT brain , and the initial clinical stage had the strongest relationships with the development of cerebral infarction.

It is difficult to explain the link between a high percentage of polymorphonuclear leukocytes in the CSF and stroke. In atherothrombotic infarction, it is common to have a small number of polymorphonuclear leukocytes (3–8/mm³) in the CSF in the first few days infarction.¹⁰ Significant polymorphonuclear leukocytosis during the initial period of TB  meningitis may be a warning of occult vascular thrombosis.⁵

               Regarding meningeal enhancement, some authors¹¹ suggested that the severity of TB meningitis was not related to the degree of meningeal enhancement. They found that enhancement occurred with the same frequency at each clinical stage. Whereas, others reported that meningeal enhancement was present in approximately 38% of TB meningitis patients at admission, and suggested that meningeal enhancement was not a good indicator of disease stage.

Conversely, some other authors have suggested that basal enhancement is a feature of advanced TB meningitis, and that contrast enhancement of the basal cisterns is frequently associated with development of basal ganglia infarction. ¹³ Our study results support that meningeal enhancement is a predictive factor for poor prognosis, including the development of fatal complications such as stroke, in patients with TB meningitis.

Basal meningeal enhancement in TB meningitis is typically homogeneous ¹⁴and enhancement is uniform and intense after contrast administration ¹⁵. Enhancement over the convexities is rare¹⁶.One study¹⁷ showed that basal meningeal enhancement was demonstrated in (73.1%) of the patients in the study group. 8.5% of patients demonstrated focal basal meningeal enhancement whereas 64.6% had classic basal meningeal enhancement. Localized/focal enhancement of the sylvian fissure was the commonest.

When comparing of the initial clinical presentation and development of cerebral infarction, we found that individuals who were more severely affected on presentation had increased chances of subsequent stroke. In our study, 20% of patients with stage I disease developed stroke, but 100% of patients with stage III disease experienced stroke.

The neuroradiological findings for our patients suggest a possible mechanism of ischemic stroke. Two strokes were caused by large artery occlusion and five were induced by small artery occlusion.

The mechanisms of ischemic stroke in patients with TB meningitis are not well understood, but several mechanisms have been proposed.¹⁸ Vascular narrowing is considered to be caused by: (a) infringement by inflammatory exudate¹⁹ (b) vasculitis¹⁹ (c) vasospasm mediated by vasoconstricting substances, such as platelet-activating factor²⁰ or (d) any combination of these.

Since transcranial Doppler became available as a diagnostic tool in 1982²⁰, several groups have studied the hemodynamic consequences of vasculopathy in purulent bacterial meningitis.^21,22 Some authors reported different prognoses for TB meningitis patients depending on mean blood flow velocity and pulsatility index, and suggested transcranial Doppler as a valuable tool not only in the diagnosis of TB meningitis-related vasculopathy, but also as a potential aid for decision making.

The sites that are susceptible to cerebral infarction in patients with TB meningitis are the basal ganglia, internal capsule, thalamus, cerebral cortex, pons, and cerebellum.²⁴ The locations of cerebral infarction in our patients were the basal ganglia, internal capsule, and cerebellar hemisphere. Inflammatory exudates settle by gravity on the base of the brain, and intense inflammation at the base of the brain induces vasculitis in adjacent vessels. Small penetrating arteries are particularly susceptible, including the lenticulostriate arteries. The middle cerebral artery in the Sylvian fissure and vertebrobasilar system are also involved.

Although the use of steroids for the treatment of TB meningitis is controversial, some authors have proposed that steroids might benefit patients with severe TB meningitis.^25,26 Although the value of steroids in TB meningitis has been demonstrated for reduction of cerebral edema and inflammation, thus preventing hydrocephalus, the role of steroids in preventing cerebral infarction is questionable. In our patients, ischemic stroke complicated TB meningitis within the first week after meningitis symptom onset, despite prompt treatment with a regimen including a steroid.

Our observations indicate that ischemic strokes complicating TB meningitis are most probably due to arterial involvement. The possibility of ischemic stroke should be considered in the treatment of TB meningitis when patients with more advanced disease at presentation have sustained polymorphic CSF pleocytosis (CSF neutrophil count >70%) or meningeal enhancement on their initial CT scans. It may be possible to consider therapeutic interventions such as anti-platelet drugs in patients with these predictive factors.

 

[Disclosure: Authors report no conflict of interest]

 

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