Tuberculous meningitis is the most severe form of central nervous system tuberculosis. Mycobacterium tuberculosis reaches the meninges through the bloodstream and sets up a chronic inflammatory process concentrated at the base of the brain, where the basal cisterns become filled with thick, gelatinous exudate. This basal meningitis can compress cranial nerves, obstruct cerebrospinal fluid flow and damage blood vessels, producing hydrocephalus, infarction and a wide range of neurological deficits. Even with modern anti-tuberculous drugs and corticosteroids, mortality and disability remain high, particularly when diagnosis is delayed.

Paradoxical reactions add a cruel twist to this already difficult disease. In a paradoxical reaction, a patient initially improves on anti-tuberculous therapy, then deteriorates neurologically despite the drugs continuing to kill the bacteria. The prevailing explanation is immunological: as anti-tuberculous drugs reduce the bacterial load, they also strip away antigens that had been dampening the immune response, allowing a rebound of cell-mediated immunity directed at residual mycobacterial antigens. Tumor necrosis factor-alpha and other inflammatory mediators surge, granulomatous inflammation flares, and lesions that had been shrinking can enlarge or appear at new sites. Paradoxical worsening is well documented in HIV-negative patients and in HIV-positive patients after starting antiretroviral therapy, a related phenomenon known as immune reconstitution inflammatory syndrome.

The Sri Lankan team, led by Shanindra de Alwis of the University of Sri Jayewardenepura with colleagues from the University of Colombo and the Institute of Neurology at the National Hospital of Sri Lanka, focused on one of the most destructive forms this rebound can take. Optochiasmatic arachnoiditis involves the optic nerves and the chiasmatic cisterns, the fluid-filled spaces surrounding the optic chiasm where fibers from both eyes cross. Inflammation and fibrosis in this region entrap the optic pathways, causing progressive, often irreversible loss of vision. Because the optic chiasm sits directly above the suprasellar cistern and within reach of the basal inflammatory exudate of tuberculous meningitis, it is uniquely vulnerable when paradoxical inflammation flares at the base of the brain.

All three patients in the series followed the same ominous trajectory. Each initially improved after starting anti-tuberculous therapy, consistent with the drugs doing their job. Then, during the course of treatment, they developed new neurological deterioration and radiological changes consistent with a paradoxical reaction. Neuroimaging revealed suprasellar tuberculomas, granulomatous masses in the region above the pituitary fossa, together with basal cisternal involvement affecting the optic pathways in every case. The pattern of optochiasmatic arachnoiditis was thus visible on magnetic resonance imaging as inflammatory disease encasing the structures that carry visual signals from the eyes to the brain.

Managing these patients proved extraordinarily difficult. Treatment required prolonged high-dose corticosteroid therapy to suppress the runaway inflammatory response, an approach that carries its own substantial risks when maintained for months. In selected cases, the team added adjunctive immunomodulatory therapy, including thalidomide, a drug with potent anti-tumor necrosis factor-alpha activity that has been used experimentally in severe central nervous system tuberculosis and in refractory paradoxical reactions. Thalidomide’s mechanism is relevant here: by inhibiting tumor necrosis factor-alpha, it aims to blunt the very cytokine driving the granulomatous flare, offering a targeted way to calm inflammation that corticosteroids alone could not control.

The outcomes were grim. Despite intensive immunosuppressive therapy, two patients died from complications related to prolonged immunosuppression. The surviving patient experienced persistent visual deficits, a lasting reminder that even when life is saved, the optic pathways damaged by optochiasmatic arachnoiditis may never fully recover. The authors emphasize that optochiasmatic arachnoiditis represents a rare but catastrophic paradoxical complication of tuberculous meningitis in HIV-negative patients, a population in whom paradoxical reactions are less commonly anticipated than in patients with HIV who begin antiretroviral therapy.

The series carries important lessons for clinicians worldwide. First, deterioration during anti-tuberculous therapy is not always treatment failure. Distinguishing paradoxical reactions from drug resistance, inadequate dosing or alternative diagnoses is essential, because the management strategies differ fundamentally: paradoxical worsening calls for intensified immunosuppression, not for changing anti-tuberculous drugs. Second, new visual symptoms in a patient being treated for tuberculous meningitis should prompt urgent neuroimaging of the suprasellar and chiasmatic regions, because early recognition of optochiasmatic arachnoiditis may allow intervention before irreversible fibrosis entombs the optic nerves. Third, the fatal complications of prolonged immunosuppression in two patients highlight the double-edged nature of the available therapies, which must suppress a destructive immune flare without leaving the patient defenseless against infection and other steroid-related harms.

The immunopathology underlying paradoxical reactions remains incompletely understood, and the authors argue that improved understanding is essential to guide targeted adjunctive therapies and improve outcomes. The interplay between mycobacterial antigen load, cell-mediated immunity, tumor necrosis factor-alpha and other cytokines determines whether residual disease smolders quietly or erupts into granulomatous inflammation around the optic chiasm. Better biomarkers to predict which patients will flare, and immunomodulatory agents that can be deployed with precision rather than through prolonged blunt immunosuppression, are the goals the field must pursue. For now, this Sri Lankan case series stands as a stark warning: the very success of anti-tuberculous therapy can ignite an inflammatory backlash capable of stealing a patient’s sight, and in the most severe cases, their life.

Published as an open access case report in BMC Infectious Diseases, the study adds to the growing recognition that central nervous system tuberculosis is not merely an infectious disease but an immunological battleground. As tuberculosis continues to affect millions globally, and as drug-resistant strains prolong treatment courses and expand the window for paradoxical events, awareness of optochiasmatic arachnoiditis among neurologists, infectious disease specialists and ophthalmologists could make the difference between timely intervention and permanent blindness. The Sri Lankan experience shows that vigilance during the treatment of tuberculous meningitis must extend beyond bacterial cure to the immune consequences of that cure itself.

Subject of Research: Health & Medicine

Article Title: Optochiasmatic arachnoiditis as a paradoxical reaction in tuberculous meningitis: a case series from Sri Lanka

Article References: de Alwis, S., Chandrasiri, D., Ruwanpathirana, P., Fernando, A., & Senanayake, B. (2026). Optochiasmatic arachnoiditis as a paradoxical reaction in tuberculous meningitis: a case series from Sri Lanka. BMC Infectious Diseases. https://doi.org/10.1186/s12879-026-14471-4

Image Credits: AI Generated

DOI: 10.1186/s12879-026-14471-4

Keywords: tuberculous meningitis, optochiasmatic arachnoiditis, paradoxical reaction, central nervous system tuberculosis, thalidomide, corticosteroids, Sri Lanka, BMC Infectious Diseases, Optochiasmatic, arachnoiditis, paradoxical, reaction

Hereditary hemorrhagic telangiectasia is an autosomal dominant condition affecting roughly one in five to eight thousand people, in which mutations in genes governing blood vessel development produce clusters of dilated, fragile capillaries called telangiectases. These malformed vessels sit directly beneath the skin and mucosal surfaces, most abundantly in the nasal lining, and rupture with minimal provocation. The result is recurrent epistaxis, or nosebleed, which is the most common manifestation of the disease and, in severe cases, leads to chronic iron deficiency and anemia so profound that patients require regular red blood cell transfusions simply to survive. Beyond the nose, the disorder can seed arteriovenous malformations in the lungs, liver, and brain, making it a multisystem disease that demands lifelong surveillance.

Treatment options for severe epistaxis in HHT have long been frustratingly limited. Local measures such as nasal packing, laser ablation, and septodermoplasty offer temporary relief but rarely alter the underlying vascular pathology. Systemic anti-angiogenic therapies, including bevacizumab and thalidomide, have shown clinical benefit in studies and case series by targeting the abnormal vessel growth itself, yet no oral agent has emerged as a reliably effective and well-tolerated standard of care. It is against this backdrop that the Japanese team’s observation carries weight, because it suggests that a newer member of the thalidomide drug family may succeed where its predecessor failed.

The patient at the center of the report carried a double diagnosis. In addition to HHT, he had smoldering multiple myeloma, an early, typically asymptomatic stage of a plasma cell malignancy marked by an IgG-kappa monoclonal protein in his blood. He initially received thalidomide for the hematological condition, a choice that also raised hopes of easing his nosebleeds, since thalidomide’s anti-angiogenic properties had been reported to help some HHT patients. Those hopes were not realized: the nosebleeds continued unabated, and his transfusion requirements persisted, leaving him dependent on repeated red blood cell infusions despite the therapy.

Facing limited efficacy, his physicians switched treatment to pomalidomide, a second-generation immunomodulatory derivative of thalidomide that is more potent against abnormal blood vessel formation and is approved for relapsed multiple myeloma. The dose was a modest 2 milligrams per day, taken orally. What followed was rapid and clinically dramatic. Within three weeks of starting the drug, the frequency and severity of the epistaxis decreased markedly, and the patient no longer needed red blood cell transfusions. For a man whose life had been organized around recurring hemorrhage and hospital visits for infusions, the change represented a fundamental restoration of ordinary daily function.

The story then took a turn that, paradoxically, strengthened the case for the drug’s efficacy. Pomalidomide had to be temporarily discontinued because the patient developed a worsening pleural effusion, an accumulation of fluid around the lungs. Subsequent evaluation attributed the effusion to heart failure rather than to the medication itself, but the interruption created an unplanned experiment. During the treatment pause, the nosebleeds gradually returned, and the patient slid back into transfusion dependence, losing the gains that the drug had delivered. The relapse pattern mirrored the treatment status with uncomfortable precision.

When pomalidomide was reintroduced, the response was again swift. The epistaxis improved rapidly, transfusion independence was restored, and, notably, the pleural effusion did not recur, supporting the conclusion that the fluid accumulation had been driven by the patient’s cardiac condition rather than by the drug. This on-off-on sequence, in which bleeding worsened when the drug was withdrawn and abated when it was resumed, is what epidemiologists describe as a dechallenge-rechallenge pattern, and it is one of the strongest forms of evidence obtainable from a single-patient observation. The authors state that this clinical course strongly suggests a genuine therapeutic effect of pomalidomide on HHT-associated bleeding rather than a coincidental fluctuation in disease severity.

The mechanistic rationale for the observation is grounded in the biology of both the disease and the drug. HHT arises from disrupted signaling in the transforming growth factor beta family, particularly through the endoglin and activin receptor-like kinase pathways, which leads to excessive vessel formation and structural instability of the microvasculature. Thalidomide and its derivatives suppress angiogenesis through multiple routes, including inhibition of vascular endothelial growth factor signaling and modulation of immune and stromal cells in the bone marrow microenvironment. Pomalidomide, as a more potent analog, appears to exert a stronger anti-angiogenic effect at lower doses, which may explain why it succeeded in this patient where thalidomide had failed. Cerebrovascular and systemic effects of the drug class on endothelial cells remain an active area of laboratory investigation, and the Japanese team’s case adds a compelling clinical data point to that basic science literature.

Caution is essential in interpreting a single case. The patient’s smoldering myeloma introduces a second disease process that could theoretically influence bleeding tendencies or vascular health, and the authors themselves note that thalidomide and pomalidomide were administered as an individualized therapeutic approach for the HHT-associated epistaxis rather than as established standard treatment for the plasma cell disorder. The report was conducted in accordance with the Declaration of Helsinki, and informed consent for publication was obtained from the patient. The authors declare no competing interests and received no external funding for the work, and they acknowledge using language-editing tools in preparing the manuscript. None of these details diminish the observation, but they underscore that pomalidomide cannot yet be considered a proven therapy for HHT without controlled studies.

Nevertheless, the implications for patients are significant. Severe transfusion-dependent epistaxis is one of the most debilitating faces of HHT, and the authors conclude that pomalidomide may represent a promising oral therapeutic option for patients with severe disease, particularly when conventional treatments prove insufficient. If the finding is reproduced in larger cohorts or formal trials, it could reshape the therapeutic algorithm for a condition that has long lacked effective systemic options, offering patients a simple daily pill in place of chronic transfusion. For now, the case stands as a vivid example of how careful observation of an individual patient, even one treated for an unrelated condition, can illuminate an unexpected path forward for an entire rare disease community.

Subject of Research: Treatment of transfusion-dependent epistaxis in hereditary hemorrhagic telangiectasia with pomalidomide

Article Title: Pomalidomide successfully treated transfusion-dependent epistaxis in hereditary hemorrhagic telangiectasia: a case report

Article References: Okamoto, Y., Sakamoto, T., Taya, T., & Komiyama, M. (2026). Pomalidomide successfully treated transfusion-dependent epistaxis in hereditary hemorrhagic telangiectasia: a case report. Annals of Hematology. https://doi.org/10.1007/s00277-026-07313-5

Image Credits: AI Generated

DOI: 10.1007/s00277-026-07313-5

Keywords: hereditary hemorrhagic telangiectasia, HHT, Osler disease, pomalidomide, epistaxis, thalidomide, transfusion dependence, anti-angiogenic therapy, multiple myeloma, hematology, case report, rare disease

The study, led by Maja Louise Arendt of the University of Copenhagen and Jennifer R. S. Meadows of Uppsala University and SciLifeLab, focused on cereblon, the protein that thalidomide binds. Cereblon was only identified as the drug’s primary target in 2010, when researchers showed that thalidomide attaches to this substrate receptor of the cullin-4 E3 ubiquitin ligase complex, known as CUL4-RBX1-DDB1. When thalidomide occupies cereblon, the degradation machinery’s specificity changes: it begins recruiting, ubiquitinating and destroying an unnatural set of proteins called neo-substrates, including transcription factors such as SALL4, p63, Ikaros and Aiolos. These proteins govern critical developmental and immunological processes, which helps explain both the drug’s teratogenic tragedy and its therapeutic benefits. At the same time, native substrates such as MEIS2 are no longer degraded, adding further biological consequences. To date, cereblon remains the only described mammalian target of thalidomide.

The crux of the new findings lies in a single amino acid position within the cereblon protein. The C-terminal region of human cereblon, spanning roughly amino acids 318 to 426, forms the thalidomide-binding CULT domain, and variation within this 109-amino-acid stretch is known to determine how different species respond to the drug. In humans, the amino acid at position 388 is a valine, abbreviated V388. In mice, the equivalent position holds an isoleucine instead. This seemingly minor substitution does not prevent thalidomide from binding to cereblon, but it creates steric hindrance that blocks neo-substrates from entering the binding pocket, preventing their ubiquitination and degradation. The result is that thalidomide and its derivatives are pharmacologically ineffective in mice, a fact that contributed to the drug’s original licensing as a supposedly safe sedative, since rodent tests failed to predict its devastating effects in humans.

When the researchers mined the Dog10K consortium datasets, which include single nucleotide and structural variant calls from 1,929 and 1,879 canids respectively, they found that every single dog examined encodes an isoleucine at the position equivalent to human V388. Across the roughly 30-kilobase CRBN gene region, 384 variable sites were detected, but only three had any potential to alter the protein’s coding sequence, and each of these was extraordinarily rare, with allele frequencies below 0.2 percent. Two structural deletions overlapping the gene were also identified, both at frequencies below 0.5 percent. In other words, the canine cereblon protein is essentially uniform across the species, and it uniformly carries the mouse-like isoleucine that has been shown to abolish thalidomide’s neo-substrate degradation activity.

To place this finding in evolutionary context, the team turned to two massive comparative genomics resources: the Zoonomia alignment of 240 mammalian species and the TOGA alignment covering 344 eutherian mammals. At the nucleotide level, the codon encoding position 388 showed little evolutionary constraint, with phyloP conservation scores of 0.40, 4.66 and -1.74 across its three bases; only the second position showed purifying selection. This wobbling tolerance is mirrored by amino acid variability across the mammalian tree. Among 344 species, 72 percent encode an isoleucine at the equivalent position, including all 55 available species of the order Carnivora, to which dogs belong. Only bats, rodents and rabbits, and the order Primates, which includes humans, were found to encode both valine and isoleucine at this site. Notably, rabbits and guinea pigs carry a valine, consistent with decades of toxicology data showing that rabbits, unlike mice, do develop thalidomide-induced birth defects similar to those seen in humans.

The researchers also considered whether cancer itself might change the equation. Tumors accumulate mutations that can alter drug sensitivity, so the team searched for non-silent, protein-altering mutations in the CRBN gene within two published canine tumor-normal sequencing datasets, comprising 55 mammary tumors and 43 diffuse large B-cell lymphoma cases, as well as 723 samples from the cBioportal Canine Cancer Genome Atlas. The search yielded almost nothing: a single non-synonymous mutation, p.CRBN A10T, was found in one lymphoma sample, affecting the N-terminal region far from the thalidomide-binding CULT domain. No mutations were identified that would plausibly make canine cancer cells more susceptible to thalidomide than normal cells. In human multiple myeloma, somatic CRBN mutations are likewise reported to be neutral or to confer resistance, never enhanced sensitivity.

These genetic findings cast a revealing light on the veterinary literature. Thalidomide has been tested in dogs with splenic hemangiosarcoma, mammary carcinoma, lung carcinoma, lymphoma and multiple myeloma, usually in combination with other therapies, making efficacy difficult to assess. One recent multicentre retrospective study reported that 71 percent of seven dogs with relapsed multiple myeloma maintained or achieved complete remission on thalidomide as a single-agent rescue therapy, with moderate lethargy in two dogs as the only recorded side effect. Strikingly, a 53-week toxicology study in beagles using doses up to 1,000 milligrams per kilogram daily, roughly fifty times the human clinical dose for a ten-kilogram dog, found no clinically significant adverse effects, no hematological or biochemical changes and no evidence of the peripheral neuropathy that plagues human patients. The authors argue that this remarkable tolerance is itself a warning sign: a drug with no side effects at massive doses may simply have no pharmacological activity.

There are caveats. The sedative effect of thalidomide appears to be independent of cereblon, and one canine study reported reduced vascular endothelial growth factor staining in metastatic tissue from treated dogs, hinting that anti-angiogenic mechanisms independent of the CRBN-CUL4-RBX1-DDB1 complex might operate in dogs. A pharmacokinetic study in tumor-bearing dogs also reported a range of clinical signs, though the authors of the new analysis note these could reflect advanced cancer rather than drug toxicity. The researchers are careful not to claim that thalidomide is definitively useless in dogs; rather, they conclude that the molecular function of the drug in this species must be directly investigated before its therapeutic role in canine cancer can be understood or justified.

Beyond its immediate veterinary implications, the study is a compelling demonstration of how publicly available genomic data can inform clinical pharmacology. Because DNA-damaging chemotherapy agents tend to work comparably across humans and dogs, veterinary oncologists have reasonably borrowed human anticancer drugs. But for targeted agents such as thalidomide, whose action depends on the precise structure of a single protein, species differences in that target can silently nullify the drug’s effect. Given thalidomide’s tragic history and its strict regulation in human medicine, the authors advocate that molecular evidence of function should be established before the drug is used therapeutically in dogs, a lesson that applies equally to the growing arsenal of cereblon-targeting protein degraders now entering human clinical development.

Subject of Research: Genetic variation in the canine cereblon protein and its implications for thalidomide therapy in dogs with cancer

Article Title: Genetic evidence supports that thalidomide should not be used therapeutically in dogs

Article References: Arendt, M. L., & Meadows, J. R. S. (2026). Genetic evidence supports that thalidomide should not be used therapeutically in dogs. Veterinary Oncology, 3(1), Article 14. https://doi.org/10.1186/s44356-026-00067-2

Image Credits: AI Generated

DOI: 10.1186/s44356-026-00067-2

Keywords: thalidomide, cereblon, CRBN, dogs, canine cancer, veterinary oncology, comparative genomics, neo-substrates, ubiquitin ligase, drug repurposing, teratogenicity, Dog10K