Can Hydroxychloroquine Cause Seizures?
Yes, hydroxychloroquine can cause seizures, though this is a rare adverse effect that appears to be dose-dependent and more likely in predisposed individuals. The FDA label explicitly states that HCQ can lower the seizure threshold and lists seizures as a recognized adverse reaction 1.
Evidence from FDA Drug Labeling
The official FDA prescribing information clearly documents seizure risk:
- Seizures are listed as a recognized nervous system adverse reaction in post-approval surveillance 1
- HCQ can lower the seizure threshold, particularly when co-administered with other antimalarials like mefloquine 1
- The activity of antiepileptic drugs may be impaired when co-administered with HCQ, suggesting interference with seizure control mechanisms 1
Clinical Evidence Quality and Limitations
The systematic review evidence reveals a critical gap: there is no Class I evidence supporting the package insert warning about seizure risk 2. A 2020 systematic review examining seizure risk found:
- Only 11 of 31 studies met criteria for analysis, consisting primarily of case reports and small case series 2
- For chloroquine: one prospective study (n=109), two case series (n=6), and six case reports 2
- For HCQ: one prospective observational study (n=631) and one case report 2
- Clinical trials failed to find any significant relationship between seizures and chloroquine or HCQ 2
Documented Case Reports
Despite limited high-quality evidence, several case reports document temporal associations:
- A 17-year-old with SLE developed tonic-clonic seizures after 2 weeks of HCQ 200 mg/day (5 mg/kg), with no recurrence after drug withdrawal, suggesting causality in predisposed patients 3
- A 68-year-old COVID-19 patient with Fahr's syndrome had generalized tonic-clonic seizures, potentially induced by HCQ treatment 4
- A 41-year-old HIV patient with COVID-19 developed encephalopathy and tonic-clonic seizures while on HCQ and azithromycin 5
Risk Factors and Clinical Context
The risk appears highest in patients with pre-existing seizure disorders or predisposing conditions 3:
- Patients with history of epilepsy or complex partial seizures 3
- Underlying neurological conditions (e.g., Fahr's syndrome) 4
- Concurrent use of other medications that lower seizure threshold 1
- Higher doses, particularly exceeding 5 mg/kg actual body weight 1
Mechanism and Toxicity Profile
HCQ's CNS effects can progress through confusion, convulsions, and coma, particularly with parenteral routes or toxic doses 6. The American College of Chest Physicians guidelines note that chloroquine (structurally similar to HCQ) may cause CNS effects including confusion and convulsions 6.
Clinical Management Recommendations
For patients with epilepsy considering HCQ therapy:
- There is currently no evidence-based need to restrict HCQ prescription in patients with epilepsy history, based on the limited available data 7
- Monitor closely for new-onset seizures or worsening seizure control 1
- Avoid co-administration with other antimalarials that lower seizure threshold (e.g., mefloquine) 1
- Ensure antiepileptic drug levels are optimized, as HCQ may impair their activity 1
- Use the lowest effective dose (≤5 mg/kg actual body weight for chronic use) 1
If seizures occur during HCQ therapy:
- Consider discontinuation if clinically feasible 3
- Evaluate for other contributing factors (infection, metabolic derangements, structural brain lesions) 4
- The short latency after administration and favorable evolution after withdrawal support drug causality 3
Important Caveats
- The package insert warning is not supported by robust clinical trial data 2
- Most evidence comes from case reports with inherent limitations (publication bias, inability to establish causation) 2
- Seizures may be multifactorial in critically ill patients receiving HCQ (e.g., COVID-19 with systemic inflammation, concurrent medications) 4, 5
- The distinction between HCQ-induced seizures and seizures from underlying disease (e.g., SLE with CNS involvement) can be challenging 3