Tuberculous Meningitis
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《新英格兰医药杂志》
As is vividly illustrated by the report by Thwaites et al. in this issue of the Journal (pages 1741–1751), tuberculous meningitis continues to exact a devastating toll in developed and developing countries, despite the availability of effective chemotherapy. In sub-Saharan Africa, because of the effects of human immunodeficiency virus and AIDS, tuberculosis is now the most common form of bacterial meningitis. In countries with a high incidence of tuberculosis, tuberculous meningitis is typically a disease of young children that develops three to six months after primary infection. In countries with a low incidence of tuberculosis, tuberculous meningitis more commonly affects adults, and although it may follow primary infection, it more frequently arises from the reactivation of a dormant subcortical or meningeal focus.
Our understanding of the pathogenesis of tuberculous meningitis dates from the meticulous studies that Arnold Rich and Howard McCordock conducted at Johns Hopkins Hospital in the 1920s and 1930s.1,2 In experiments in animals, they showed that the meninges could not be directly infected by hematogenous spread; then, in a brilliant series of postmortem examinations, they demonstrated that in nearly every case, there was a subcortical or meningeal focus from which bacilli gained access to the subarachnoid space. After the release of bacilli and granulomatous material into the subarachnoid space, a dense gelatinous exudate forms; it is most florid in the interpeduncular fossa and suprasellar region anteriorly, and it may extend throughout the prepontine cistern and surround the spinal cord. This exudate envelops arteries and cranial nerves, creating a bottleneck in the flow of cerebrospinal fluid at the level of the tentorial opening, which leads to hydrocephalus. The most serious consequence, however, is the development of vasculitis in the vessels of the circle of Willis, the vertebrobasilar system, and the perforating branches of the middle cerebral artery. The resultant infarctions lead to hemiplegia or quadriplegia. Direct contact of the exudate with the brain surface causes a border-zone reaction that damages the underlying brain tissue (see Figure). Rich and McCordock ascribed most of these changes to a hypersensitivity response.
Figure. Axial Section of a Brain from a Patient with Tuberculous Meningitis.
Ventricular dilatation is present (asterisks), as well as inflammatory exudate in the ambient cistern (black arrows) and multiple foci of vasculitis-associated subacute, ischemic necrosis (white arrows). Courtesy of Richard H. Hewlett, Department of Anatomical Pathology, Faculty of Health Sciences, University of Stellenbosch, Tygerberg, South Africa.
Clinically, the discharge of tuberculosis bacilli into the cerebrospinal fluid is followed by an insidious prodromal period, marked by the gradual, fluctuating onset of fever, lassitude, weight loss, behavior changes, headache, and vomiting. A delay in diagnosis will be followed by neurologic deficits, loss of consciousness, or convulsions. Unfortunately, it is often only at this point that the diagnosis of tuberculous meningitis is considered, and often irreversible neurologic damage has already occurred. In a minority of cases, a large amount of material may be released from the "Rich focus," followed by a sudden onset of fever, headache, vomiting, and cerebrospinal fluid findings — such as a predominance of polymorphonuclear cells and a high cerebrospinal fluid count — that are more typical of other bacterial meningitides.
In low-incidence geographic areas, clinicians should suspect tuberculous meningitis in members of immigrant groups from high-incidence areas, as well as in patients who abuse alcohol or drugs and those with immunosuppression from any cause. In approximately 50 percent of cases, the patient has a history of contact with sputum-smear-positive pulmonary tuberculosis. In high-incidence geographic areas, tuberculous meningitis must be distinguished from a plethora of other infectious meningitides. The typical cerebrospinal fluid picture includes a low cell count (<300 per cubic millimeter) with a predominance of lymphocytes, a low glucose concentration (<2.2 mmol per liter), and an elevated protein concentration (>0.8 g per liter), but in 10 to 20 percent of cases, the glucose concentration may be normal and the protein concentration may be less than 0.8 g per liter or even less than 0.45 g per liter. A positive tuberculin test can provide diagnostic support, but test results may be negative in patients with tuberculous meningitis. A chest radiograph shows changes compatible with tuberculosis in 50 to 80 percent of cases.
There are additional diagnostic tests, but they often lack the requisite specificity or sensitivity, are too expensive, or are unavailable precisely in the locations where they are most needed. Cranial tomography and magnetic resonance imaging have revolutionized the diagnosis and management of tuberculous meningitis, but these studies may be normal early in the course of illness.
Irrespective of the results of individual tests, if tuberculous meningitis is seriously suspected, it is far better to begin treatment immediately and reconsider the diagnosis when the dust has settled. Cerebrospinal fluid changes will still be evident 10 to 14 days after treatment begins and may increase despite treatment, so these assist in differentiating tuberculous meningitis from other bacterial meningitides.
Treatment involves chemotherapy to control and eliminate the infection, management of hydrocephalus and elevated intracranial pressure, and immunomodulation. Standard short-course chemotherapy involving a two-month intensive phase of treatment with isoniazid, rifampin, pyrazinamide, and ethambutol and a four-month continuation phase of treatment with isoniazid and rifampin is recommended by the World Health Organization. Other recommendations, including those of the American Thoracic Society, are more conservative and include a continuation phase of six or eight months of treatment with isoniazid and rifampin.
Elevated intracranial pressure can be life-threatening. If the hydrocephalus is noncommunicating — a condition that can be demonstrated on air encephalography — a ventriculoperitoneal shunt should be placed immediately, which may lead to dramatic improvement. If the hydrocephalus is communicating, medical treatment with furosemide and acetazolamide will often normalize the intracranial pressure within one to two weeks. Patients who do not have a response to this treatment may undergo elective placement of a ventriculoperitoneal shunt.
The usefulness of immunomodulation rests on the assumption that the inflammatory process in tuberculous meningitis, and the vasculitis in particular, is a hypersensitivity response. Corticosteroids have a long and checkered history in this disease, as is again illustrated by Thwaites et al. Our own practice in young children is to use prednisone for the first month of treatment at a dose of 2 to 4 mg per kilogram of body weight, up to a maximum of 60 mg, taking into account the fact that rifampin accelerates corticosteroid breakdown.
As long as tuberculosis continues to flourish in developing countries, tuberculous meningitis will remain a constant threat throughout the world. Because early diagnosis is the key to a satisfactory outcome, a high level of suspicion is essential.
Source Information
From the Department of Pediatrics and Child Health, Faculty of Health Sciences, University of Stellenbosch, Tygerberg, South Africa.
References
Rich AR, McCordock HA. An enquiry concerning the role of allergy, immunity and other factors of importance in the pathogenesis of human tuberculosis. Bull Johns Hopkins Hosp 1929;44:273-382.
Rich AR, McCordock HA. The pathogenesis of tuberculous meningitis. Bull Johns Hopkins Hosp 1933;52:5-37.(Peter R. Donald, M.D., an)
Our understanding of the pathogenesis of tuberculous meningitis dates from the meticulous studies that Arnold Rich and Howard McCordock conducted at Johns Hopkins Hospital in the 1920s and 1930s.1,2 In experiments in animals, they showed that the meninges could not be directly infected by hematogenous spread; then, in a brilliant series of postmortem examinations, they demonstrated that in nearly every case, there was a subcortical or meningeal focus from which bacilli gained access to the subarachnoid space. After the release of bacilli and granulomatous material into the subarachnoid space, a dense gelatinous exudate forms; it is most florid in the interpeduncular fossa and suprasellar region anteriorly, and it may extend throughout the prepontine cistern and surround the spinal cord. This exudate envelops arteries and cranial nerves, creating a bottleneck in the flow of cerebrospinal fluid at the level of the tentorial opening, which leads to hydrocephalus. The most serious consequence, however, is the development of vasculitis in the vessels of the circle of Willis, the vertebrobasilar system, and the perforating branches of the middle cerebral artery. The resultant infarctions lead to hemiplegia or quadriplegia. Direct contact of the exudate with the brain surface causes a border-zone reaction that damages the underlying brain tissue (see Figure). Rich and McCordock ascribed most of these changes to a hypersensitivity response.
Figure. Axial Section of a Brain from a Patient with Tuberculous Meningitis.
Ventricular dilatation is present (asterisks), as well as inflammatory exudate in the ambient cistern (black arrows) and multiple foci of vasculitis-associated subacute, ischemic necrosis (white arrows). Courtesy of Richard H. Hewlett, Department of Anatomical Pathology, Faculty of Health Sciences, University of Stellenbosch, Tygerberg, South Africa.
Clinically, the discharge of tuberculosis bacilli into the cerebrospinal fluid is followed by an insidious prodromal period, marked by the gradual, fluctuating onset of fever, lassitude, weight loss, behavior changes, headache, and vomiting. A delay in diagnosis will be followed by neurologic deficits, loss of consciousness, or convulsions. Unfortunately, it is often only at this point that the diagnosis of tuberculous meningitis is considered, and often irreversible neurologic damage has already occurred. In a minority of cases, a large amount of material may be released from the "Rich focus," followed by a sudden onset of fever, headache, vomiting, and cerebrospinal fluid findings — such as a predominance of polymorphonuclear cells and a high cerebrospinal fluid count — that are more typical of other bacterial meningitides.
In low-incidence geographic areas, clinicians should suspect tuberculous meningitis in members of immigrant groups from high-incidence areas, as well as in patients who abuse alcohol or drugs and those with immunosuppression from any cause. In approximately 50 percent of cases, the patient has a history of contact with sputum-smear-positive pulmonary tuberculosis. In high-incidence geographic areas, tuberculous meningitis must be distinguished from a plethora of other infectious meningitides. The typical cerebrospinal fluid picture includes a low cell count (<300 per cubic millimeter) with a predominance of lymphocytes, a low glucose concentration (<2.2 mmol per liter), and an elevated protein concentration (>0.8 g per liter), but in 10 to 20 percent of cases, the glucose concentration may be normal and the protein concentration may be less than 0.8 g per liter or even less than 0.45 g per liter. A positive tuberculin test can provide diagnostic support, but test results may be negative in patients with tuberculous meningitis. A chest radiograph shows changes compatible with tuberculosis in 50 to 80 percent of cases.
There are additional diagnostic tests, but they often lack the requisite specificity or sensitivity, are too expensive, or are unavailable precisely in the locations where they are most needed. Cranial tomography and magnetic resonance imaging have revolutionized the diagnosis and management of tuberculous meningitis, but these studies may be normal early in the course of illness.
Irrespective of the results of individual tests, if tuberculous meningitis is seriously suspected, it is far better to begin treatment immediately and reconsider the diagnosis when the dust has settled. Cerebrospinal fluid changes will still be evident 10 to 14 days after treatment begins and may increase despite treatment, so these assist in differentiating tuberculous meningitis from other bacterial meningitides.
Treatment involves chemotherapy to control and eliminate the infection, management of hydrocephalus and elevated intracranial pressure, and immunomodulation. Standard short-course chemotherapy involving a two-month intensive phase of treatment with isoniazid, rifampin, pyrazinamide, and ethambutol and a four-month continuation phase of treatment with isoniazid and rifampin is recommended by the World Health Organization. Other recommendations, including those of the American Thoracic Society, are more conservative and include a continuation phase of six or eight months of treatment with isoniazid and rifampin.
Elevated intracranial pressure can be life-threatening. If the hydrocephalus is noncommunicating — a condition that can be demonstrated on air encephalography — a ventriculoperitoneal shunt should be placed immediately, which may lead to dramatic improvement. If the hydrocephalus is communicating, medical treatment with furosemide and acetazolamide will often normalize the intracranial pressure within one to two weeks. Patients who do not have a response to this treatment may undergo elective placement of a ventriculoperitoneal shunt.
The usefulness of immunomodulation rests on the assumption that the inflammatory process in tuberculous meningitis, and the vasculitis in particular, is a hypersensitivity response. Corticosteroids have a long and checkered history in this disease, as is again illustrated by Thwaites et al. Our own practice in young children is to use prednisone for the first month of treatment at a dose of 2 to 4 mg per kilogram of body weight, up to a maximum of 60 mg, taking into account the fact that rifampin accelerates corticosteroid breakdown.
As long as tuberculosis continues to flourish in developing countries, tuberculous meningitis will remain a constant threat throughout the world. Because early diagnosis is the key to a satisfactory outcome, a high level of suspicion is essential.
Source Information
From the Department of Pediatrics and Child Health, Faculty of Health Sciences, University of Stellenbosch, Tygerberg, South Africa.
References
Rich AR, McCordock HA. An enquiry concerning the role of allergy, immunity and other factors of importance in the pathogenesis of human tuberculosis. Bull Johns Hopkins Hosp 1929;44:273-382.
Rich AR, McCordock HA. The pathogenesis of tuberculous meningitis. Bull Johns Hopkins Hosp 1933;52:5-37.(Peter R. Donald, M.D., an)