What is the cause of paradoxical worsening of central nervous system (CNS) tuberculosis?

From the Guidelines

Paradoxical worsening of CNS tuberculosis should be managed by continuing anti-tuberculosis therapy and adding corticosteroids, such as prednisone 1.25 mg/kg/day, for 2-4 weeks, with tapering over 6-12 weeks or longer, as this approach has been shown to be effective in reducing the need for hospitalization or surgical procedures 1. When managing paradoxical worsening of CNS tuberculosis, it is essential to distinguish this condition from treatment failure or other opportunistic diseases, such as non-Hodgkin lymphoma or infection. The development of IRIS in patients with CNS tuberculosis can cause severe or fatal neurological complications, and therefore, ART is not initiated in the first 8 weeks of antituberculosis therapy for patients with HIV infection and tuberculous meningitis (or other CNS tuberculosis) 1. Key considerations in the management of paradoxical worsening of CNS tuberculosis include:

• Continuing the standard anti-TB regimen while adding corticosteroids
• Monitoring for signs of IRIS, such as high fevers, worsening respiratory symptoms, and increasing inflammation of involved lymph nodes
• Evaluating the need for surgical intervention, such as drainage of abscesses or relief of obstructive hydrocephalus
• Close monitoring with serial neuroimaging to evaluate response to treatment The use of corticosteroids, such as prednisone, has been shown to be effective in managing IRIS, and the dose and duration of treatment should be tailored to the individual patient's needs, with a typical dose of 1.25 mg/kg/day for 2-4 weeks, followed by a gradual taper over 6-12 weeks or longer 1.

From the FDA Drug Label

Postmarketing cases of paradoxical drug reaction (recurrence or appearance of new symptoms, physical and radiological signs in a patient who had previously shown improvement with appropriate antimycobacterial treatment, in the absence of disease relapse, poor treatment compliance, drug resistance, side effects of treatment, or secondary infection/diagnosis) have been reported with Rifampin for Injection (see ADVERSE REACTIONS). Paradoxical drug reactions are often transient and should not be misinterpreted as failure to respond to treatment. If worsening of symptoms or signs occurs during antimycobacterial treatment, consider paradoxical drug reaction in the differential diagnosis, monitor, or treat accordingly.

Paradoxical worsening of CNS tuberculosis can occur with rifampicin treatment, as it is a form of paradoxical drug reaction. These reactions are often transient and should not be misinterpreted as failure to respond to treatment. If worsening of symptoms occurs during antimycobacterial treatment, consider paradoxical drug reaction in the differential diagnosis, monitor, or treat accordingly 2.

From the Research

Paradoxical Worsening CNS Tuberculosis

• Paradoxical worsening of CNS tuberculosis refers to the recurrence or appearance of fresh symptoms, physical, and radiological signs in a patient who had previously shown improvement with appropriate anti-tubercular medicines 3.
• This phenomenon can occur during or after treatment, and its management is crucial to prevent further complications.
• Studies have shown that paradoxical reactions can occur in patients with CNS tuberculosis, including those with tuberculous meningitis and intracranial tuberculomas 3, 4.

Clinical Presentation and Diagnosis

• The clinical presentation of paradoxical worsening CNS tuberculosis can vary, but it often includes the recurrence of symptoms such as headache, fever, and neurological deficits 3, 4.
• Diagnosis is based on clinical suspicion, laboratory tests, and imaging studies such as MRI or CT scans 5, 4.
• The CSF formula may show a lymphocytic pleocytosis, low glucose, and high protein concentrations, which can help in diagnosing CNS tuberculosis 5.

Treatment and Management

• Treatment of paradoxical worsening CNS tuberculosis typically involves the addition of second-line therapy or an increase in the dose of prescribed drugs, as well as the introduction or increase in dose of steroids 3, 6.
• The use of corticosteroids has been shown to reduce morbidity and mortality in patients with CNS tuberculosis, particularly in those with paradoxical reactions 5, 6.
• In some cases, prolonged administration of corticosteroids may be necessary to achieve clinical cure and resolution of lesions 6.

Special Considerations

• Patients with HIV-negative status can still experience late-onset paradoxical reactions, even years after completing treatment for tuberculous meningitis 4.
• The use of anti-TNF therapy may increase the risk of developing tuberculosis-associated immune reconstitution inflammatory syndrome (IRIS), which can manifest as paradoxical worsening of CNS tuberculosis 7.
• Careful screening for CNS tuberculosis should be performed prior to initiating anti-TNF therapy, and continuing anti-TNF therapy may be necessary to prevent IRIS in patients who develop TB during treatment 7.