An 80-year-old man, without an agricultural background and with a history of fully remitted prostate cancer, hypernephroma 15 years before and a coronary artery bypass graft 6 years previously, was admitted to a tertiary care hospital for a subacute gait disorder suspicious for non-pressure hydrocephalus, and slight disorientation. Two non-contrast MRI brain scans were incomplete because of psychomotor unsteadiness. However, they revealed brain atrophy, an internal hydrocephalus and relevant cerebral microangiopathy (fig. 1). CSF revealed a lymphomonocytic pleocytosis [high leukocyte count of 1,089/mm3 (reference value 0-3), and elevated protein of 1,040 mg/dl (reference value <50)]. Serology, microscopy and CSF culture did not reveal bacteria, thus excluding more rare pathogens like Listeria, Brucella, Leptospira, Rickettsia and Tropheryma, fungi such as cryptococci, and neurotropic viruses including HIV. Having diagnosed meningitis of unknown origin, standard first-line antibiotic treatment with ceftriaxone and ampicillin was introduced. As the patient failed to improve within 22 days, he was transferred to our hospital because of a progressive loss of consciousness together with meningeal signs.
Brain CT did not reveal new information. CSF again showed a high cell count of 1,080/mm3, with 31% neutrophils and 56% lymphocytes (fig. 2a), low glucose (48 mg/dl, with serum glucose 180 mg/dl), high protein content (339 mg/dl), and high lactate [.1 mmol/l (reference value 1.2-2.1)]. CSF pressure was elevated to 25 cm H2O. Again, no bacteria were detected, and Ziehl-Neelsen's stain was negative for Mycobacterium. Antibiotics were switched to meropenem plus ampicillin and, with TM included in the differential diagnosis, to a combination of rifampicin (450 mg i.v./day), isoniazid (300 mg p.o./day), pyrazinamide (3 g p.o. 2 times/week) and ciprofloxacin (500 mg p.o./day). PCR detected no DNA of MC. During the days thereafter, triple analysis of bronchial secretions, urine and gastric lavage were all negative for Mycobacterium. Chest X-ray and abdominal sonography were also unremarkable.
For the next 3 days, CSF pressure dropped to 19 cm H2O as a result of daily spinal taps. The patient's condition improved. On the fifth day, he developed Lyell's syndrome with a generalized rash and bullous exanthema leading to allergic shock which had to be treated with catecholamines (time course of C-reactive protein (CRP) and leukocyte cell count data in serum, fig. 2b). As antituberculotics may often cause such an event, and TM was not definitive, these drugs were stopped, and fosfomycin was initiated as a broad-spectrum antibiotic therapy for bacterial meningitis (3 x 3 g i.v./day). Additionally, glucosteroids and antihistamines were given for a total of 10 days. Within 2 weeks of treatment accompanied by several lumbar punctures to reduce CSF pressure, which indeed did not exceed 20 cm H2O, the patient recovered to cooperativeness. He refused a leptomeningeal biopsy to look for tuberculous granulomas. Within 14 days, the CSF leukocyte cell count dropped to 68/mm3 as revealed by a lymphocytic cell picture, and the protein content fell to 55.9 mg/dl; CRP and serum white cell count decreased to reference values (fig. 2b).
After 29 days, the patient was transferred to a rehabilitation center, where fosfomycin was discontinued. Over the next 2 weeks, his condition deteriorated, presenting progressive immobility, headache and somnolence. Due to his recently completed advance directive, neither a spinal tap nor antibiotic therapy was provided. Unfortunately, the patient died suddenly from an acute myocardial infarction. Autopsy was refused.
Two weeks after death, CSF cultures for mycobacteria demonstrated growth in the broth-based MGIT 960 system (Becton Dickinson Microbiology System, Heidelberg, Germany). The isolated acid-fast organism was identified as MTBC by MTBC-specific PCR (16S rDNA-PCR). Species-specific identification of the isolate was performed by gyrB PCR-restriction fragment length polymorphism (RFLP) analysis of a part of gyrB DNA. This method consists of gyrB DNA amplification of the isolated MTBC, subsequent to the electrophoretic separation of the amplified products and finally of the 16S rDNA sequencing of a specific DNA 1,020-bp fragment. Differences in the gyrB sequences allow accurate discrimination of the MTBC and the species-specific identification of M. tuberculosis, M. microti, M. africanum I, MB and last, but not least, MC. Colony morphology of the isolated MC strain showed dysgonic growth on Lowenstein-Jensen (LJ) medium. The strain was susceptible to pyrazinamide (PZA) (100 mug/ml).