Central nervous system (CNS) tuberculosis is a severe manifestation of disseminated tuberculosis in children. The disease begins with the dissemination of organisms from the lungs via the blood and lymphatic system, resulting in development of caseating vascular foci (Rich foci) that allows bacilli to enter the subarachnoid space and brain parenchyma.1 Which form of CNS tuberculosis develops—focal tuberculomas or diffuse tuberculous meningitis—depends in part on the location of the original Rich foci and the immune system’s capacity to contain the organisms within these lesions.
Diagnosis of CNS tuberculomas in children is challenging as symptoms and imaging findings are nonspecific. Large tuberculomas often produce focal neurologic symptoms associated with intracranial mass lesions; however, small tuberculomas, which are more commonly found with disseminated tuberculosis, are often clinically silent.2,3 These asymptomatic tuberculomas are likely to be missed in young children resulting in inadequate treatment.4 We describe 2 recent cases of miliary childhood tuberculosis with multiple tuberculomas in which patients did not present with clinical or laboratory evidence of CNS tuberculosis.
A 3-month-old male presented in December, 2016 with a 1-month history of intermittent fever, cough and poor oral intake. The chest radiograph revealed lobar pneumonia that was treated with a 10-day course of amoxicillin, followed by a course of cefdinir when the fever returned. The child continued to have fever, cough and mild respiratory distress. Upon admission to Texas Children’s Hospital, he had a temperature of 102.9°F and exhibited retractions consistent with pneumonia. The neurologic examination was normal. Laboratory findings included a white blood cell count of 23.78 × 103/µL with 29.8% bands. A chest radiograph (Fig. 1A) showed bilateral diffuse nodular opacities with confluent opacity in the right middle lobe suggestive of atelectasis and pneumonia. Computed tomography scan of the chest demonstrated miliary nodules, collapse of the right middle lobe and mass effect on the bronchus intermedius caused by hilar lymphadenopathy. Gastric aspirate cultures were positive for Mycobacterium tuberculosis susceptible to all first-line antituberculosis drugs. Analysis of the cerebrospinal fluid (CSF) showed: 5 white blood cells, 4 red blood cells, protein of 36 mg/dL, glucose of 53 mg/dL, and the acid-fast bacillus stain was negative. HIV testing was negative. Treatment was initiated with rifampin, isoniazid, pyrazinamide and ethambutol with a preliminary diagnosis of miliary tuberculosis without CNS involvement. The Infectious Disease team recommended obtaining a magnetic resonance imaging (MRI) of the brain with and without contrast which demonstrated numerous 2–4 mm enhancing lesions without edema throughout the supratentorial and infratentorial brain, and 2 similar lesions in the upper cervical spinal cord (Fig. 1B). Based on these findings, a diagnosis was made of disseminated tuberculosis with CNS tuberculomas; ethambutol was replaced with ethionamide and prednisolone 1 mg/kg daily was added. All drugs were administered via directly observed therapy and the prednisolone was weaned after 4 weeks.
The initial history was negative for known exposures to a person with tuberculosis or severe respiratory illness. Both parents had normal chest radiographs and 0 mm reactions to a tuberculin skin test. However, 2 months later the patient’s paternal great uncle, whose house the child had visited several times, died following uncontrollable pulmonary hemoptysis caused by previously undiagnosed tuberculosis. Many paternal family members were subsequently found to have positive tuberculin skin tests.
After 5 months of treatment the chest radiograph showed almost complete resolution of the miliary nodules and bronchial compression, and MRI of the brain showed complete resolution of most of the abnormal enhancing foci both above and below the tentorium. The child completed a 9-month course of antituberculosis therapy and has normal growth and neurologic development 3 years later.
An 8-month-old male presented in May, 2017 with a several week history of fever and cough. The initial chest radiograph demonstrated diffuse bilateral micronodular infiltrates throughout both lungs and a left upper lobe complex pneumonia with evidence of hilar and mediastinal adenopathy. Because tuberculosis was suspected, a lumbar puncture was performed and the CSF was normal. HIV testing was negative. The patient’s cousin was known to be ill and his sputum culture grew pan-susceptible M. tuberculosis. The child’s gastric aspirate cultures also were positive for pan-susceptible M. tuberculosis. The child took 2 months of rifampin, isoniazid, pyrazinamide and ethambutol therapy under direct observation but, unknown to the field workers, the child had been vomiting the medications after they were administered. He continued to have fevers, weight loss, irritability and worsening respiratory status. A chest radiograph demonstrated worsening left upper lobe consolidation with new cavitation and additional fine nodular pulmonary opacities. Because of concern for worsening tuberculosis, the child was transferred to Texas Children’s Hospital. A second analysis of CSF showed: 1 white blood cell, 0 red blood cells, protein of 23 mg/dL, glucose of 53 mg/dL, and the acid-fast bacillus stain was negative. However, because of his worsening status and chest radiograph, an MRI of the head was performed which demonstrated numerous subcentimeter tuberculomas in the posterior fossa, brainstem, deep gray structures and cerebrum; there was also a 1.6-cm conglomerate lesion in the left pons with pronounced edema and mass effect and a 1-cm lesion in the right cerebellar hemisphere with edema. There was mild-to-moderate mass effect on the fourth ventricle without obstructive hydrocephalus. There was no imaging evidence of tuberculosis meningitis or ependymitis.
With concerns for acquired drug resistance due to his vomiting of medications, the patient was given rifampin, isoniazid, pyrazinamide, ethionamide, amikacin and levofloxacin, and prednisone. After several weeks of treatment, he had remarkable clinical improvement, was tolerating oral drugs well, and repeat cultures of gastric aspirates and CSF were negative. He was discharged on oral rifampin, isoniazid and pyrazinamide and completed 12 total months of treatment. Follow-up radiography demonstrated resolution of the pulmonary disease, resolution of most of the small tuberculomas and significant improvement of the larger brain lesions. His growth and neurologic development are normal for a year after treatment completion.
These cases illustrate the diagnostic complexity of CNS tuberculosis in young children with disseminated disease. The majority of children with multiple tuberculomas also have meningitis with accompanying neurologic signs and symptoms and abnormal CSF results.5 Both of our patients presented without neurologic symptoms, and analysis of CSF was normal even though the second patient had slight edema and mass effect around several tuberculomas. In each case, CNS involvement was only detectable via neuroimaging. Both patients received corticosteroids following diagnosis and both patients responded well to their treatment regimens.
Children less than a year of age are at increased risk for developing tuberculosis with widespread dissemination of the disease. While meningitis is the most common manifestation of CNS tuberculosis in children, infants and young toddlers with disseminated tuberculosis are also at risk for CNS tuberculomas. Tuberculous meningitis in young children causes basilar meningitis, hydrocephalus and vasculitis, resulting in rapid clinical deterioration, from initial fever and irritability to meningismus and stroke. Unlike in our 2 patients, tuberculomas in children most often are associated with tuberculous meningitis, and they can occur as part of the initial presentation or as a manifestation of immune reconstitution inflammatory syndrome during therapy.6 Depending on their exact location and whether significant inflammation and edema develop, small tuberculomas often do not present with obvious signs of CNS infection.3 Children with large tuberculomas often present with focal seizures and neurologic findings but children with small diffuse tuberculomas may have no overt signs or symptoms.7
Because CNS involvement can develop quickly in infants and very young children with severe or disseminated tuberculosis disease, diagnostic evaluation should always include lumbar puncture; however, neuroimaging should be strongly considered even in the absence of neurologic findings and CSF abnormalities when there is a miliary appearance to the chest radiograph. MRI is the most sensitive diagnostic tool available for the evaluation of tuberculosis mass lesions, and should be used when available. Relying only on analysis of CSF and culture may not be adequate to exclude CNS involvement.
Additionally, this case report highlights the importance of considering CNS tuberculosis in children even without a confirmed source of exposure, because the child can become ill before the source case has been correctly diagnosed. With our first patient, the source case was not discovered until two months into treatment. A 10-year retrospective review of children with CNS tuberculosis in Houston demonstrated that the majority of children with CNS tuberculosis initially had a negative exposure history, and the source case was found after the ill child presented.8 This has important implications for contact tracing; because tuberculous disseminates rapidly in young children, it is imperative to identify a source case to help confirm the diagnosis and provide information about drug-susceptibility as quickly as possible.
Ultimately, these cases serve as an important reminder that CNS involvement should be suspected in all infants and young children with miliary tuberculosis, even in the absence of overt meningeal symptoms. Delay in diagnosis of CNS tuberculosis can result in significant and rapid clinical deterioration in young children and should be detected as quickly as possible via lumbar puncture and neuroimaging to institute appropriate treatment.3 This poses a dilemma in low resource settings where tuberculosis is common but neuroimaging often is not available. In these settings, it might be wise to assume that the child with miliary tuberculosis could have neurologic involvement and treat accordingly.
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