Final Diagnosis -- Multiple Intracranial Tuberculomas.


Multiple intracranial tuberculomas.


Tuberculosis (TB) continues to be one of the important infectious disease worldwide, with more than 2 billion people affected (46, 102). Besides the pulmonary system, TB affects nearly every system in the body, including the lymph nodes, central nervous system (CNS) and others (133). Central nervous system tuberculosis remains one of the most severe manifestations of the disease(117). It can present in many forms, one of which is intracranial tuberculomas (ICT) which develops in 16-40% of affected patients (140, 150, 196).

We searched the PubMed for cases of multiple ICT, using various combinations of keywords including multiple intracranial tuberculomas, disseminated intracranial tuberculomas, multiple intracerebral tuberculomas, disseminated intracerebral tuberculomas, multiple brain tuberculomas, disseminated brain tuberculomas, brain tuberculomas, and trabecular brain abscess. A total of 387 abstracts were collected. Only articles with descriptive cases were filtered and all review articles were excluded. An attempt to retrieve the full-text articles through Google Scholar, King Hussein Cancer Center library, the library at the American University of Beirut and other sources was undertaken. Eventually a total of 162full text articles were collected. Additionally some clinical data could be retrieved from 3abstracts(2-9, 11-15, 17-19, 21-23, 25-27, 29-32, 35-41, 43, 44, 48-53, 56-65, 67-75, 77-99, 101, 103-105, 107-115, 118-127, 129, 135-137, 141, 142, 144, 145, 147-149, 151, 153, 155-157, 159-163, 167, 168, 170-176, 179-195, 198-209). The data then was summarized on an excel spread sheet and collected items included the author(s), publishing journal, the geographic location(based on the address of the corresponding author), age, gender, presenting symptoms and signs, radiological features, involvement of spine, the presence of other potential predisposing medical conditions, the presence of other sites affected by TB including lung, any previous or concurrent TB medications, and the outcome. Additionally the method of confirming the diagnosis such as biopsy, the use of special stains like ZN special stain and/ or polymerase chain reaction (PCR) were all collected.

A total of 291 cases were retrieved including our own case. More than half of the reported cases came from Asia (n=155, 53.2%) (Figure- 2A). The male (n=136) and female (n=140) were affected almost equally with a male to female ratio of 1:1.03. The average age at diagnosis was 30.25 years, and around two thirds of the cases (n=192, 65%) were reported in the first 4 decades. Twenty percent of cases occurred in the 20-29 age group, which was the most common age group affected. Pediatric patients (0-19 years of age) constituted one third of the affected individuals (n=95, 33.8%). Females were more likely to be affected in 2ndand3rddecades, while males were more likely to be affected in later decades (Figure-2B).

Symptoms of increased intracranial pressure were the most common presenting manifestations. Headache was the most common presenting symptom (n=108, 37.1%), followed by fever (n=83, 28.5%). Paresis (n=84, 28.9%) was the most common sign, followed by altered mental status in 64 (21.9%) patients. Many patients however; presented with more than one complaint and the combination of headache, fever, and weakness was the most common. The lesions were mostly seen in the cerebrum involving the frontal lobe in 50(17.2%) cases, the parietal lobe in 41 (14%), the temporal lobe in 34 (11.7%), and the occipital lobe in 22 (7.6%). This was followed by the cerebellum in 97 (33.3%) cases, brain stem in 22 (7%), including the pons in 16 (5%), thalamus in 22 (7%), and the basal ganglia in 12 (4%). Radiologically; enhancing multiple lesions was the most common pattern (n=288, 99%). The enhancement was heterogonous in 2 (0.7%) cases and in one case (0.3%) the lesions were non-enhancing. Edema (n=65, 22%) and hydrocephalus (n=30, 10%) were reported in few cases as well as infarction (n=10, 3%). Leptomeningeal enhancement was seen in 14(5%) cases only. Spinal involvement was reported in only a minority of cases (n=23, 8%).

Concurrent or previous pulmonary involvement was reported in around a third of cases (n=106, 36%). Predisposing conditions were reported in another quarter of cases (n=64, 22.6%) These conditions included HIV (n =10),use of immunosuppressant agents (n=10), malignancies (n=8), diabetes mellitus (n=4), alcoholism (n=4), systemic lupus erythematosus (SLE) (n=3), liver cirrhosis (n=3), and malnutrition (n=2). Interestingly pregnancy was reported in 6 cases. History of contact with tuberculosis patients (n=21) was also a potential important predisposing condition (Figure 2C).

Diagnosis was confirmed by a tissue biopsy in 41% (n=118) of cases, including postmortem tissue diagnosis (n=3) as well as abscess aspiration(n=12). Granulomatous inflammation either caseating or non-caseating was seen. The ZN special stain was performed in 131 (45%) cases and was positivein70(53%) cases, while it was negative in 61 (47%). The PCR was performed in 57(19%) cases, and was positive in 30 (52.6%)cases, while it was negative in 27 (47.4%). Treatment was documented in only 220 (75.0%). Of these anti-tuberculous medication was used alone in 79% (n=174), medication and surgery in 18% (n=40), and surgical alone in 3% (n=6). The outcome was reported in 212 (72.8%) cases. Most cases (n=192, 91%) were cured either completely or partially. Death was reported in only 7% (n=15) of cases, the rest (n=5, 2%) were lost to follow up (Figure 2D).

We are presenting a case of multiple ICT along with an extensive literature review on the topic. CNS tuberculosis accounts for approximately 1% of all cases of tuberculosis(146), and about 10% of patients with tuberculosis develop CNS disease (47). The presence of an active pulmonary tuberculosis on chest X-ray ranges from 30 to 50% in a recent series (166, 178). CNS involvement is noted in 5 to 10% of extra-pulmonary tuberculosis(143), however, most multiple ICT have extra-CNS tuberculosis(1). CNS involvement by tuberculosis has 3 different forms including meningitis, tuberculomas and spinal arachnoiditis. Intracranial tuberculomas are the least common presentation, reported in 1% of these patients (128), and they are multiple in only 15%-33% of the cases (66). While tuberculous meningitis affects mainly children, tuberculoma and spinal arachnoiditis are seen mainly in adults (10).Intracranial tuberculoma has a low incidence in developed countries (0.15 to 0.18%), but remains a challenging condition in developing countries, as it can reach up to 15 - 30% of brain tumorous lesions (28). Interestingly; around 2/3 (66.0%) of the summarized cases in this cohort presumably originated from Asia and Africa. Multiple ICT affected younger age groups and one third of cases affected the pediatric age groups (0-19 years).

The two main routes of infection in CNS tuberculosis are the hematogenous, which is the most common, and the direct spread. The hematogenous pathway is proposed to be a two-stage process. First tuberculous lesions (Rich's focus) develop in the brain during the stage of bacteremia or shortly afterward. Later on rupture or growth of one or more of these lesions leads to the development of CNS tuberculosis. Eventually, the location of TB lesions is directly related to the pattern of blood flow. It usually spreads to the cerebral hemispheres and basal ganglia in adults and to the cerebellum in children (42).These initial tuberculous lesions may be located in the meninges, the subpial or subependymal surfaces of the brain or in the spinal cord, and may remain dormant for years after initial infection. The causes and the mechanisms that control this distribution are still unknown. The direct spread, on the other hand, usually occurs into the meninges from the middle ear or the calvarial bone(33). It is presumed that multiple IC tuberculomas are mostly secondary to hematogenous spread, while the solitary IC ones evolve from CSF infection into the adjacent parenchyma (1).

When comparing solitary versus multiple ICT several differences become apparent. There is a cleat predominance of solitary ICT with a M:F ratio of 1:3.5(1), in contrast to the almost equal distribution in males and females in multiple ICT. However; other reports show an almost equal distribution between both genders (134). Furthermore; multiple ICT appear to affect younger patients. The median age for solitary IC ranges from 38-42 years (134), while the median age in our review is of 28 years. This has practical implications. The presence of multiple IC lesions in a young patient should warrant consideration of infections over metastatic carcinoma, however, in older age groups the reverse should be considered. Interestingly, most cases with multiple IC tuberculomas lacked a clear predisposing condition that might affect the immunity, as less than a quarter of cases (22.6%)had predisposing conditions. These included HIV infection, malnutrition, alcoholism, other malignancies, the use of immunosuppressant agents(146),systemic lupus erythematosus (SLE)(132), diabetes mellitus (DM)(20), liver cirrhosis (100, 177), and pregnancy (16). History of contact with other tuberculous patients was reported in some patients (24). Once the diagnosis is established the outcome is favorable in both conditions. 75.8% of all cases in the single IC recovered completely, while death was reported in 4% (134). In another study, the cure rate was 40%, partial recovery was 40%, and death was 6% (1) . In our literature review 64% of multiple IC tuberculomas showed complete recovery, 32% showed partial recovery and the reported death rate was 4%.

Metastatic malignancy remains the most common cause for multiple IC ring-enhancing lesions (154). However, in developing countries infectious diseases appear to be encountered more frequently(55), and remains an important consideration, especially in young individuals. While tuberculosis remains the most common infectious pathology, neurocysticercosis and toxoplasmosis should be ruled out (55) . Neurocysticercosis (NCC) is caused by the larval stage of Taenia solium, is the most common and serious parasitic disease of the CNS in many developing countries (76).The usual mode of presentation is focal seizures with or without secondary generalization, in a previously healthy individual (164), reported in up to 79% of neurocysticercosis cases (197). Other complaints are related to space occupying lesions including headache, vomiting (169) and features of raised intracranial pressure(165). This contrasts with the mode of presentation of IC tuberculomas in which complaints related to increased IC pressure predominate. Seizure was reported in only 19.8% of our cases. The presence of subcutaneous nodules in neurocysticercosis usually confirms the diagnosis (54) . The characteristic appearance of neurocysticercosis in MRI include single, which is more common, or multiple enhancing lesions with diameter range between 5-20mm in any part of cerebral hemispheres. 44% of patients have punctuated eccentric high density structure suggestive of scolex. Another minor characteristic finding of neurocysticercosis is rounded hypotense non-enhancing lesions (123) . The radiological appearance of IC tuberculoma in MRI is hypointensity with ring-shaped contrast enhancement on T1-weighted images, and hyperintensity with a central hypointensity on T2-weighted images(196) .

Toxoplasmosis, on the other hand, is a protozoan infection and is one of the most common causes of focal brain lesions in patients with Human Immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) particularly in developing countries (152, 158) . CT and MR images usually show multiple ring-enhancing lesions (139) which is similar to multiple intracranial tuberculosis. The characteristic imaging pattern in toxoplasmosis lesions however, is a ring-enhancing lesion made up of an eccentric nodule. In around 30% of the lesions, this enhancing nodule is found within and adjacent to the enhancing rim (138) Most lesions in toxoplasmosis occur in basal ganglia (130, 131) and in frontal and parietal lobes(116, 130), which is different from the distribution of the cases in multiple IC tuberculomas.

Another important consideration in multiple IC tuberculomasis differentiating it from metastatic malignancy. Besides clinical history, radiology remains an important techniques that can be used nowadays, through measuring the regional cerebral blood flow (rCBV) which is typically elevated in malignancies but not in tuberculomas(34) . The definitive diagnostic modality however remains to obtain a tissue diagnosis. This is a risky procedure that might be associated with complications, especially brain hemorrhage, which occur in 1.3% to 5% of cases (106). In the absence of a history of malignant tumor, a presumptive anti-tuberculous therapy may be proposed as a diagnostic and therapeutic test (45). In conclusion, we present a case of multiple ICT in a young female patient, with a previous history of pulmonary TB. Multiple ICT remain diagnostically challenging and sorting out the differential diagnosis with other conditions including other infections and metastatic malignancy is crucial. Multiple ICT predominates in less developed countries, and although males and females are affected almost equally, females predominate in younger age groups. Around one third of all reported cases affected children. Spinal involvement is rare and the presence of predisposing conditions can be seen in around a quarter of cases. Establishing the correct diagnosis is of utmost importance since the outcome is favorable with the appropriate management.


The authors would like to thank Dr. Nader Hermas for his help in getting the articles from the medical library of the American University of Beirut.


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Contributed by Maysa Al-Hussaini, MD, Ghassan Al-Shbool, MD, Mohammed Samaha, MD

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