Lamotrigine and Anti-Epileptic Medications in HLH: A Systematic Review
Bibliographic record
Abstract
Background: Hemophagocytic Lymphohistiocytosis (HLH) is a rare life-threatening hyper-inflammatory disorder characterized by over-activation of the immune system. Medication induced HLH is a topic of growing scrutiny, particularly with increasing use of immunomodulatory therapies such as immune checkpoint inhibitors. Lamotrigine, a common anti-epileptic medication, has become a commonly reported cause of medication-associated HLH. Unlike other medications implicated in causing HLH, lamotrigine is not traditionally considered as immunosuppressive in nature. Lamotrigine and other aromatic anti-epileptic agents (carbamazepine, phenytoin etc.) are also known to trigger severe immune-mediated adverse drug reactions including drug rash with eosinophilia and systemic symptoms (DRESS) and Stevens-Johnson syndrome or SJS/TEN. Aims: Our primary objective was to conduct a systematic review of reported cases of lamotrigine associated HLH. The secondary objective was to examine these cases in the context of other immune-mediated complications of aromatic anti-epileptics such as DRESS. Methods: We completed a systematic literature search for lamotrigine and twenty-eight other anti-epileptic medications (including aromatic and non-aromatic) and HLH in the EMBASE & MEDLINE databases and the FDA Adverse Event Reporting System (FAERS) to identify English language-published and gray-literature cases. We excluded cases without sufficiently reported clinical and laboratory data/outcomes and included all cases where authors had a clinical suspicion for HLH in the context of recently initiated or titrated anti-epileptic medications. We used the HLH-2004 diagnostic criteria to score reported cases as confirmed (five of eight criteria met) or suspected (four of eight criteria) cases of HLH. We also calculated the H-score, a validated scoring system, which uses various laboratory and clinical features to assess the likelihood of secondary HLH, to classify cases as confirmed (meeting a cut-off of 169) or suspected (≥ 138 in adults and ≥ 120 in pediatric cases). We subsequently used the REGIScar scoring scale for DRESS to characterize the features and overlap with DRESS syndrome (scoring ≤1 - no case, 2-3 - possible, 4-5 - probable, ≥ 6 - definite). Results: We identified thirty one case reports of confirmed (24) or suspected (7) anti-epileptic associated HLH, of which, 20 cases were attributed to lamotrigine as the sole medication or as a new agent added to a prior multi-drug regimen. Furthermore, there were nine cases solely attributable to another anti-epileptic agent (including the aromatic agents of carbamazepine, oxcarbazepine, phenytoin and phenobarbital and the non-aromatic valproic acid) and two multi-drug cases. Treatment regimens employed included HLH-2004 guideline directed chemotherapy with etoposide and dexamethasone (8), high dose corticosteroids (19) and intravenous immunoglobulin (7) or other immunomodulatory agents (anakinra (1) and emapalumab (1)). The clinical prognosis of anti-epileptic associated HLH was favourable in general, with 26 of 31 cases achieving complete clinical resolution, 2 cases of chronic relapsing course and 3 deaths. Furthermore, there was high overlap with DRESS with 8 definite or probable cases of DRESS and 13 possible cases: the most common overlapping features being fever, diffuse skin rash and liver involvement. Discussion: This study confirms an association between lamotrigine and HLH. The overlap between HLH and DRESS in a subset of cases suggests that lamotrigine and other aromatic anti-epileptics may have more significant immunomodulatory properties than currently appreciated. Most patients responded well to discontinuation of anti-epileptics and HLH-directed therapy. Further research into immunological mechanisms of these complications is warranted.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.011 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.005 | 0.004 |
| Bibliometrics | 0.010 | 0.011 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.002 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".