Blepharospasm (BSP) is an isolated focal dystonia characterized by excessive orbicularis oculi muscle activity leading to abnormal blinking, involuntary eyelid closure, and difficulty with eye opening [1]. Those with BSP frequently experience spread of dystonia to muscles beyond the orbicularis oculi with approximately half of affected individuals experiencing spread to other muscles such as the lower face, mouth and jaw (oromandibular dystonia) [2–4]. A diagnosis of Meige Syndrome (MeS) is often given when an individual has both BSP and oromandibular dystonia [5, 6].

Intramuscular injection of botulinum neurotoxin (BoNT) into the orbicularis oculi and other affected muscles remains the treatment of choice for both BSP and MeS [7]. While BoNT therapy can effectively relieve symptoms in many patients, it requires chronically repeated intramuscular injections that often only partially relieve symptoms, can be painful, and can induce intolerable weakness or other adverse effects. Additionally, for many patients with BSP, the effects of BoNT injections wear off weeks prior to their next injection. In a study of patients with cervical dystonia, up to third of may discontinue BoNT treatment due to these limitations [8].

Many oral medications have been tried for BSP and MeS given the limitations of BoNT therapy and the significant negative impact these disorders can have on daily functions and quality of life [9]. No current oral medication, however, provides adequate relief. Muscle relaxants including anticholinergics, benzodiazepines and other medications targeting gamma-aminobutyric acid receptors (GABA agonists) are frequently tried based on their history of use in and treatment reviews for dystonia [10–13]. Dopaminergic and antidopaminergic medications (including dopamine depleters) are often tried as they can be effective for a variety of forms of dystonia [14]. Antiepileptic medications are occasionally given to BSP and patients as they may provide some symptomatic relief in dystonias [15]. For example, the sodium (Na) channel blocker, carbamazepine, has shown some potential benefit as an adjunct therapy to BoNT in BSP [16]. Also, the stimulant methylphenidate has also been reported to provide relief in individuals with BSP and MeS [17].

Although treatment patterns of medication use in isolated dystonia have been previously reported using data collected by the international multicenter Dystonia Coalition [18], this study involved a relatively small number individuals with BSP, did not include an analysis of individuals identified as having MeS, and most of the patient data analyzed had been collected at tertiary care medical centers possibly leading to a bias of greater medication use. In the present study we sought to use TriNetX, a federated network of Health Insurance Portability and Accountability Act (HIPAA)–compliant data from a large number of healthcare organizations predominantly across the U.S. ¹ , to assess general patterns of oral medication prescribing in patients with BSP and MeS.

In a cohort of 27,339 BSP and MeS patients identified using the TriNetX database platform, we found that approximately half were treated with at least one medication across nine different classes of medications that are often used to treat dystonia. The most prescribed medication class was benzodiazepines followed by muscle relaxants, gabapentinoids, and anticholinergic medications. This order of medications is consistent with the findings of a prior study of Dystonia Coalition patients [18]. The documented prescription duration of benzodiazepines was the longest in our cohort with a median of 15.8 months. While the prescription patterns were largely consistent between BSP and MeS patients, the frequency of benzodiazepine use was higher in MeS compared to BSP (35.0% vs. 25.2%, respectively), despite the levels of anxiety being similar between these dystonia subtypes (22.5% vs. 20.2, respectively). The reason for this difference is unclear. The use of benzodiazepines in dystonia disorders including BSP and MeS has been well-documented [29–31], but their effectiveness in each disorder has not been thoroughly evaluated in large, controlled studies [14]. Nevertheless, it is possible that the more frequent use in MeS stems from differences in effectiveness or from greater number of cranial regions being affected by dystonia [32].

Anticholinergic medications have good evidence to relieve motor symptoms in dystonia, but their side effect profile likely makes them an infrequently applied treatment option, especially in older populations that tend to develop BSP and MeS [33]. Further supporting poor tolerance of anticholinergics in BSP and MeS patients is the very short median prescription duration, 0.1 months, seen in our study cohort (Table 3). The least commonly prescribed medication classes included dopaminergic and antidopaminergic medications, which have scant evidence in BSP and MeS, and methylphenidate, for which there is some limited evidence reported [17, 34, 35].

The finding that half of patients were not actively receiving any of the oral medications for dystonia could be attributed to low efficacy and the lack of oral treatment options for BSP and MeS patients [36]. While benzodiazepines are the most commonly prescribed medication class, the magnitude of improvements from this drug class have been described as modest [5]. Muscle relaxants and gabapentinoids were also commonly prescribed to patients with BSP and MeS, and the most common medications from those classes were cyclobenzaprine and gabapentin, respectively (Figure 3). Cyclobenzaprine is widely used for muscle spasms and though not an effective agent to lessen dystonic spasms it has been found to reduce pain in dystonia [12, 37, 38]. Studies of its effectiveness in BSP and MeS, however, have not been reported. Gabapentin has not been studied in isolated idiopathic BSP and MeS, but there is some evidence it can be helpful in drug-induced BSP [39, 40]. Another reason for the prescription of muscle relaxants and gabapentinoids for these patients may be to relieve pain that is associated with BSP and MeS [5, 41].

Our regression analysis revealed some significant predictors of oral medication treatment in BSP and MeS. We found that patient sex and race may influence rates of oral medications: males and Asian patients were less likely and Black patients were more likely to be prescribed oral medications. Further, individuals with BSP and MeS from the southern U.S. were less likely to be prescribed oral dystonia medications. The sex and race findings possibly reflect gender and cultural differences in taking oral medications, while the regional differences may stem from the lower number of urban medical centers and/or a paucity of neurology specialists available to treat dystonia [42]. Indeed, a 2022 study reported that only 3.1% of neurologists in the U.S. had a practice in a rural county [43].

Finally, polypharmacy was common in our BSP and MeS population, with 38.3% being prescribed 3 or more classes of dystonia medications. One likely reason for this is oral medication across different medication classes are insufficiently effective in treating BSP and MeS [5, 44]. Combining different classes of medication is also recommended if symptom control is incomplete or a patient reaches an optimal dosage of another medication [13]. Another possibility includes the presence of neurologic and psychiatric co-morbidities that are being treated with similar medication classes used for dystonia [12, 23, 41, 45]. Similar to findings from a Dystonia Coalition study [23], our identified BSP and MeS patients frequently had co-occurring psychiatric diagnoses. For example, nearly 20% of our cohort carried an anxiety diagnosis. This is unlikely to account for the majority of individuals taking benzodiazepines, however, as 65.7% of patients receiving benzodiazepines in our cohort did not have a diagnosis of anxiety. This pattern carried across the other psychiatric comorbidities we assessed.

Our study has some strengths and limitations. TriNetX offers a large database of patients both in the US and globally, but most available data are from the U.S. similar to other medical database platforms, we are unable to confirm the BSP and MeS diagnoses, and it is possible to miss instances of a BSP or MeS diagnosis if not included in the patient’s medical record or if the diagnosis was documented outside of the index window and therefore not included in our cohort. Additionally, while we aimed to evaluate only isolated idiopathic dystonia cases, it is possible some of the cases were acquired dystonia cases or cases that stemmed from another neurological disorder such as Parkinson’s disease. We limited the chance of this by excluding patients whose records included a confounding diagnosis (Supplementary Table 1) and by exploring the medication history for patients across a 20-year period which allowed us to capture any prescriptions even prior to a formal diagnosis of BSP or MeS. Also unavailable in our study are data on clinical severity, which could have been explored as possible factor underlying lack of oral medication prescriptions and the rates of polypharmacy. TriNetX additionally does not attribute a diagnosis for the prescription of a given medication. Therefore, we are unable to confirm the reason for prescription is for BSP or MeS. For example, muscle relaxants and gabapentinoids may be prescribed for pain for other comorbid conditions and independent of the patient’s diagnosis of BSP or MeS. Finally, data on BoNT injections, which is the primary treatment for BSP and MeS [46], are not captured by the TriNetX database. This is a limitation of study as a variety of prior studies have shown that most patients who have been diagnosed with BSP or MeS have tried treatment with BoNT injections and the majority (∼65-75%) continue to receive these injections with good response for up to 15–20 years [25–28]. Future studies could benefit from the characterization of co-morbidities to better understand the prescription patterns that were observed in our study population.

Despite the lack of FDA-approved oral medications for BSP and MeS, many different types of treatments may be prescribed. While a handful of evidence-based reviews and small clinical trials have been done on some of the medications explored in our study in dystonia patients, to our knowledge no other work has explored a large cohort’s prescription patterns in the BSP and MeS patient population. Assuming many of the BSP and MeS patients were receiving BoNT injections as the standard of care, our findings provide support that oral medications are often used as adjunctive therapy in these patients. Our findings further support that a customized approach, as highlighted in a recently published current expert opinion [47], is likely needed to most effectively treat patients with BSP and MeS.