The systematic review of evidence for the treatment of orthostatic tremor revealed a lack of high-quality studies, specifically prospective, randomized, double-blind, placebo-controlled trials. Notably, only one study of this kind was conducted comparing gabapentin to placebo, but with a small number of participants. This study showed an improvement after treatment with gabapentin in comparison to placebo [10]. Therefore, the available evidence for the various treatment modalities is deemed to be of low quality. In addition, the variables used to measure therapeutic efficacy differ considerably across the individual studies. Moreover, no established consensus exists for uniformly assessing orthostatic tremor, which complicates the comparability between different studies. One potential solution to address this issue could be the use of a standardized scale for evaluating orthostatic tremor, such as the OT-10 scale for severity and disability assessment [14].

According to the study by Bertram et al. [7], botulinum toxin was ineffective in treating orthostatic tremor, as demonstrated by the lack of improvement following the administration of 200mU of abobotulinumtoxin A into the anterior tibial muscles. However, no additional studies matching the inclusion criteria were found that investigate the use of botulinum toxin in primary orthostatic tremor. Further studies would be necessary to evaluate the efficacy of higher doses or alternative injection sites. Nevertheless, the potential adverse effects and the risk of destabilization resulting from injections into different muscle groups must be critically assessed. Given the etiology of the tremor to be central, a causal therapeutic approach with botulinum toxin seems not feasible.

With three relevant studies that investigated gabapentin, it is the treatment option with the most substantial evidence for orthostatic tremor [8,9,10]. Furthermore, these studies also consistently demonstrate a positive effect of gabapentin. However, it should be noted that the sample sizes of each study were very low, resulting in a limited generalizability. Therefore, future studies should involve larger patient cohorts, as well as double-blind randomization and placebo-control. Given that gabapentin is currently regarded as the pharmacological treatment option of choice for primary orthostatic tremor, it would also be necessary to investigate the efficacy of alternative therapies in comparison to gabapentin and/or placebo.

In the investigation conducted by Hellriegel et al. [11], the use of levetiracetam was found to be ineffective in improving the symptoms of orthostatic tremor. It is important to emphasize that high doses up to 3000 mg per day of levetiracetam were used, suggesting that this lack of efficacy was not caused by insufficient dosing. However, no severe adverse effects were reported in any of the patients.

There is one study conducted by Wills et al. [12], investigating the use of levodopa with eight participants, of whom only five completed the study. This study was published alongside a case report. Some individual endpoints exhibited significant improvements with levodopa. The dropout rate of about 40% i noteworthy. It would be necessary to repeat the study with a larger sample size to obtain more substantial evidence of efficacy. It is also currently unclear to what extent the mechanism of action of levodopa can be helpful in this clinical picture, as a dopamine deficiency has not yet been demonstrated [4, 5, 15]. Some authors also emphasize the importance of monitoring for potential tolerance development [12]. Despite the partially positive results, a formal recommendation for the use of levodopa cannot be made currently, as the study in question involved a very small sample size, which was only partially blinded, lacked control, was not randomized and did not incorporate a crossover design, thereby limiting the ability to draw a meaningful comparison. Notably, in a study by Thomas et al. [16], four cases of parkinsonism were described, each marked by the dramatic onset of debilitating standing tremor, which corresponded to the clinical characteristics of orthostatic tremor. In all four cases, the response to levodopa treatment was striking, leading to the complete resolution of the standing tremor. However, this study did not investigate primary orthostatic tremor and only described four cases and therefore did not meet our inclusion criteria [16].

In the study conducted by Gironell and Marín-Lahoz, 92% of the participants showed symptomatic improvement with perampanel [13]. However, a notable amount of adverse drug reactions was documented, which led to a dropout rate of 40% among the initial cohort. As 17 of the 20 participants were also taking other medications for primary orthostatic tremor, the authors suggest that interactions among these medications may have contributed to the severe adverse effects reported. In addition, a reduction or loss of efficacy was observed over the three-month duration of the study. This pronounced development of tolerance was not previously shown in patients taking perampanel due to epilepsy. Given that the tremor study was neither blinded nor randomized and did not include a crossover design, the conclusions regarding clinical applicability are limited. To achieve more generalizable results, controlled studies with larger cohorts would be necessary.

The seizure-suppressive drug primidone, which is mentioned in textbooks as a treatment option, was not included in any of the studies that met the aforementioned criteria [1]. According to the current German S2K guideline [17], the drug is no longer recommended for use in primary orthostatic tremor. The same applies to pramipexole, which is similarly not recommended in the current guideline, despite reports of positive effects in individual patients documented in case reports [17, 18]. Controlled, prospective clinical studies would be necessary to substantiate these effects. No studies were identified regarding clonazepam meeting the above specified criteria, although it is recommended in the German S2k guideline for use in selected cases [17]. Retrospective data, however, indicate a positive effect, underscoring the need for prospective clinical trials in this context [2, 19, 20]. The existence of numerous studies yielding non-significant results raises the question of whether the rarity of the disease and the naturally resulting limitations of sample sizes would negatively impact the validity of statistical tests. This issue can only be resolved through larger multicenter studies. However, it is essential to ensure that diagnostic criteria are clearly defined in order to strengthen the reliability and validity of any study.

None of the studies found significant electrophysiological differences in patients undergoing therapy compared to their pre-therapy state. However, in a case report using perampanel also electrophysiological improvements were detected [21]. In several instances, the electrophysiological differences were deemed insignificant [7, 8, 10, 11], while in other cases, such measurements were not recorded [10, 12, 13]. However, this is an important criterion and should be examined more closely in future studies, as an improvement in electrophysiological outcomes may indicate a restoration of physiological conditions under therapy rather than a mere reduction in symptoms. Further, such findings could provide valuable insights into the etiology of the condition.

One limitation in the comparison of these studies lies in the inconsistent diagnostic criteria employed. In certain studies, this lack of clarity is particularly pronounced. For instance, in the study by Gironell and Marín-Lahoz, it is merely stated that the diagnosis was established by external neurologists [13]. This inconsistency adversely affects comparability and validity. The impact of comorbidities on both therapy and the disease itself must also be critically considered, especially when patients with conditions such as essential tremor are included, as noted in the work by Evidente et al. [8]. Additionally, the studies lack a common primary endpoint, which makes direct comparability difficult. While the potentially prolonged course of the disease is already known, the maximum follow-up reported in one study is only 19 months [20, 22]. Given the expectation of a much longer disease duration, it is prudent to explore extended follow-up periods to identify resistance developments and loss of efficacy. In addition, literature describes that symptoms may intensify over time, raising the question of whether dosage adjustments and/or changes in medication would be necessary in the long-term management to achieve or maintain symptom reduction [22].