The Hidden Connection Between a Common Biologic and Tuberculosis of the Brain
Imagine a medication that successfully manages your chronic inflammatory disease, giving you back your quality of life, only to unexpectedly trigger a life-threatening infection in your brain. This isn't a plot from a medical thriller—it's a real scenario facing patients treated with a widely prescribed biologic drug called adalimumab.
In recent years, doctors have documented numerous cases of a rare but dangerous condition: neurotuberculosis, or tuberculosis of the brain and nervous system, developing in patients undergoing treatment with this medication 1 2 .
What makes these cases particularly alarming is that they often occur despite negative screening tests for tuberculosis before starting treatment 3 4 . This article explores the hidden connection between adalimumab and neurotuberculosis, the diagnostic challenges doctors face, and how patients and physicians can navigate this complex medical dilemma.
A biologic drug used to treat autoimmune conditions by targeting TNF-α, a protein involved in inflammation.
A severe form of tuberculosis affecting the brain and nervous system, accounting for 1-5% of extrapulmonary TB cases.
Adalimumab belongs to a class of drugs called tumor necrosis factor-alpha (TNF-α) inhibitors. These medications are remarkably effective for managing various autoimmune conditions including rheumatoid arthritis, psoriatic arthritis, hidradenitis suppurativa, and inflammatory bowel disease 1 2 3 . They work by neutralizing TNF-α, a key protein that drives excessive inflammation in these conditions.
However, this therapeutic effect comes with a significant trade-off. TNF-α also plays a crucial role in our immune system's ability to form and maintain granulomas—organized clusters of immune cells that wall off dangerous pathogens 7 . One such pathogen is Mycobacterium tuberculosis, the bacterium that causes tuberculosis. In about one-quarter of the world's population, this bacterium lies dormant within granulomas, contained by our immune systems in a state called latent tuberculosis 6 .
of the global population has latent tuberculosis
When adalimumab disrupts TNF-α function, it can compromise granuloma integrity, allowing previously contained tuberculosis bacteria to escape and cause active disease 7 . This reactivation can occur months or even years after starting treatment 3 6 .
While reactivated tuberculosis can affect any part of the body, neurotuberculosis represents one of the most severe forms. It accounts for approximately 1-5% of all extrapulmonary tuberculosis cases and typically manifests as tuberculous meningitis or multiple brain abscesses called tuberculomas 1 2 . The condition is especially dangerous because it can cause permanent neurological damage or even death if not promptly diagnosed and treated 6 .
| Aspect | Latent Tuberculosis | Reactivated Tuberculosis (especially neurotuberculosis) |
|---|---|---|
| Symptoms | None | Fever, persistent headache, nausea, neurological deficits, confusion |
| Infectiousness | Not infectious | Potentially infectious (though neurotuberculosis itself less so) |
| Diagnosis | Positive skin test or blood test | Requires imaging, spinal fluid analysis, sometimes brain biopsy |
| Treatment | Usually one antibiotic | Multiple antibiotics for extended period |
| Risks | 5-10% lifetime risk of reactivation | High risk of permanent complications or death if untreated |
A 23-year-old medical student in Portugal had been taking adalimumab for hidradenitis suppurativa for two years when she developed severe occipital headaches, constant nausea, and persistent fever 2 . Initially diagnosed with post-herpetic neuritis, her symptoms persisted despite treatment.
When she finally received a brain MRI, it revealed a lesion in the superior vermis of her cerebellum. Though her cerebrospinal fluid showed no signs of tuberculosis bacteria, her doctors initiated empiric anti-tuberculosis treatment alongside corticosteroids. Her symptoms improved dramatically within a week, and follow-up MRIs showed regression of the lesion, confirming the diagnosis of neurotuberculosis 2 .
A 19-year-old Middle Eastern woman being treated for rheumatoid arthritis with adalimumab developed severe neurological symptoms including agitation, delirium, peri-orbital headaches, and projectile vomiting 1 . Her brain MRI revealed multiple ring-enhancing lesions characteristic of cerebral tuberculomas.
Despite negative tuberculosis tests in her cerebrospinal fluid, she responded favorably to the standard four-drug anti-tuberculosis regimen, with follow-up scans showing significant regression of the brain lesions 1 .
Perhaps most concerning are cases where patients developed neurotuberculosis despite rigorous screening. A 62-year-old man with psoriatic arthritis had negative interferon gamma release assays (a test for latent tuberculosis) both before starting adalimumab and four years into treatment 3 . Nevertheless, he eventually presented with disseminated tuberculosis affecting his brain, lungs, and abdomen.
Brain imaging revealed multiple tuberculomas, confirming neurotuberculosis 3 .
| Patient Profile | Condition Treated | Time to Symptom Onset | Key Diagnostic Findings |
|---|---|---|---|
| 23-year-old female 2 | Hidradenitis suppurativa | 2 years | Cerebellar lesion on MRI, positive IGRA blood test |
| 19-year-old female 1 | Rheumatoid arthritis | 6 months | Multiple ring-enhancing brain lesions on MRI |
| 62-year-old male 3 | Psoriatic arthritis | 5+ years | Multiple cerebral tuberculomas on MRI, positive IGRA |
| 34-year-old female 6 | Ulcerative colitis | 4 years | Cortical lesions in frontal and temporal lobes on MRI |
Diagnosing neurotuberculosis in patients taking adalimumab presents numerous challenges that can delay critical treatment.
Standard tuberculosis screening tests like the tuberculin skin test and interferon-gamma release assays (IGRA) can yield false-negative results in patients taking immunosuppressive medications 3 4 . This occurs because these tests rely on a robust immune response to tuberculosis antigens—precisely what immunosuppressants like adalimumab dampen 4 .
In several documented cases, patients developed active neurotuberculosis despite consistently negative annual screening tests 3 6 .
Even when neurotuberculosis is suspected, confirming the diagnosis remains challenging. Cerebrospinal fluid analysis often fails to detect Mycobacterium tuberculosis 1 2 . In fact, polymerase chain reaction (PCR) testing for the bacteria in cerebrospinal fluid has only 70% sensitivity, meaning it misses 30% of cases 1 .
This low detection rate means doctors often must rely on a combination of clinical suspicion, imaging findings, and response to empirical treatment rather than definitive laboratory confirmation.
Magnetic resonance imaging (MRI) has become the cornerstone for diagnosing neurotuberculosis when laboratory tests fail. Characteristic MRI findings include multiple ring-enhancing lesions at the corticomedullary junction and periventricular regions 1 3 . These lesions represent tuberculomas—localized brain infections filled with tuberculosis bacteria that have spread through the bloodstream 1 .
The regression of these lesions on follow-up scans after starting anti-tuberculosis treatment provides additional confirmation of the diagnosis 1 2 .
>90% for detecting neurotuberculosis
~70% for detecting TB bacteria
Key diagnostic confirmation
| Tool | Function | Limitations |
|---|---|---|
| Interferon-Gamma Release Assay (IGRA) | Blood test detecting immune response to TB bacteria | Can yield false negatives in immunosuppressed patients 3 4 |
| Cerebral MRI with Contrast | Imaging technique revealing characteristic ring-enhancing lesions of tuberculomas | Shows structural changes but doesn't confirm TB etiology 1 2 |
| Cerebrospinal Fluid Analysis | Laboratory examination of spinal fluid for TB bacteria, cells, and biochemical markers | Low sensitivity (around 70% for PCR testing) 1 |
| Mycobacterial Culture | Growing TB bacteria from clinical samples in the laboratory | Takes weeks for results, often negative in neurotuberculosis 2 |
Clinical Suspicion
MRI Brain
CSF Analysis
Monitor Response
Empiric Treatment
Consider Biopsy
The connection between adalimumab and neurotuberculosis represents a classic example of medical trade-offs—a highly effective treatment for chronic inflammatory conditions carrying a rare but serious risk. Several key points emerge from the documented cases:
Both patients and physicians must maintain high suspicion for neurological symptoms that develop during adalimumab treatment, even when initial tuberculosis screening is negative.
Confirming neurotuberculosis often demands multiple diagnostic approaches, with brain MRI playing a pivotal role when cerebrospinal fluid tests are negative.
Early recognition, suspension of adalimumab, and initiation of anti-tuberculosis treatment can lead to complete recovery, as demonstrated by the successful outcomes in the cases discussed 1 2 6 .
Current screening methods cannot completely eliminate the risk of tuberculosis reactivation, necessitating ongoing awareness throughout treatment.
While these cases are concerning, it's important to recognize that they represent rare complications of an otherwise beneficial treatment. The goal isn't to avoid adalimumab when medically indicated, but to promote informed vigilance that allows for early detection and intervention should this rare complication occur.
Through increased awareness and appropriate monitoring, patients and doctors can work together to maximize the benefits of treatment while minimizing its risks.