The mystery of shaky legs syndrome : clinical characteristics and pathophysiology in orthostatic tremor

Introduction Primary orthostatic tremor (POT) is a rare neurological disorder with a highly disabling impact on affected patients. Since the condition was first described in 1970, several small case studies and investigational studies, as well as a few larger compilations of patient materials have been conducted. However, there are still questions of why the symptoms appear, and how to treat them. Background POT is defined by a high frequency tremor activity of 13 to 18 Hz, evoked in leg and trunk muscles when standing still in an upright (orthostatic) position, without any other neurological disorder that may induce a tremor movement. The tremor is usually slowly appearing around the age of 55 and affecting both sides of the body. Women are slightly overrepresented, and it often takes many years from symptom onset to diagnosis. The tremor frequency is stable over time and does not change in response to medical treatment even though some medications can reduce the tremor amplitude. Patients are affected by an intense feeling of instability while standing still, eventually forcing them to move or sit down. Walking and leaning onto something for support relieves the feeling of instability, but the imbalance and fear of falling progresses over the years. There are no data on the incidence or prevalence of POT, and no data of potential predisposing risk factors. Previous studies have reported the presence of tremor in the arms and mild Parkinsonian features in some patients, as well as an increased prevalence of depression and anxiety. Brain imaging studies have been inconclusive but indicates a disruption in systems of body control and balance, involving the cerebellum, brainstem, basal ganglia and motor cortex. It has also been suggested that the feeling of instability is caused by a disruption of the integration of proprioceptive information from the legs. Objectives The first objective of this thesis was to compile a systematic examination of both clinical and patient reported symptoms and signs present in a patient population with POT in Sweden. The second objective was to analyse how the tremor responds to weight-load and orthostatic position. The third objective was to investigate whether there is an altered cortical reaction to proprioceptive stimulation. The fourth objective was to investigate whether there are signs of neurodegeneration in the brain related to POT. The fifth objective was to present patient reported outcomes of a potential new treatment alternative. Methods A nationwide, descriptive cross-sectional study, SOTIS, was conducted in Sweden during five years. Patients were neurologically examined and interviewed following standardized rating scales and questionnaires. A group of patients from the SOTIS cohort went through a thorough examination of tremor in different body positions including sitting in a leg press machine. Another group of patients from the SOTIS cohort were invited to participate in a cross-sectional MRI-study where data were analysed with quantitative susceptibility mapping, used to identify iron-accumulation, and volume alterations. These patients were also invited to participate in a cross-sectional MEG-study where proprioceptive stimulation was used to evoke cortical response. The patients in the nationwide study-cohort were welcome to seek advice and report treatment outcome even after the initial stud-inclusion visit. Results Fifty-two patients with orthostatic tremor were included in the final analysis of the descriptive cross-sectional study. Common associated symptoms were depression and anxiety (25%), mild Parkinsonian features (25%), freezing of gait (42%), and arm tremor (58%). Health-related quality of life was decreased even though 65% were still able to do their daily activities without human assistance. Disease duration did not correlate to disease severity. Questionnaires developed especially for orthostatic tremor were found to be suitable to estimating disease severity. Seven patients were examined in the leg press machine, and results showed that the same tremor as when standing could be evoked by muscle load in sitting position. Fifteen patients were included in the MEG-study, results showed that there was no significant difference compared to healthy controls in cortical response to proprioceptive stimulation. Twenty patients were included in the MRI-study. The results showed that there was an increase of susceptibility in the red nucleus and globus pallidus, as well as a reduction in volume of the globus pallidus. During the study period several patients reported a former unknown positive effect of the nutrient supplement Beta-alanine, an amino acid used to improve muscle performance. Discussion In this thesis the phenomenology and pathophysiology of primary orthostatic tremor is thoroughly explored through meticulous examinations of patients and investigational methods like tremor analysis, MRI and MEG. Clinical characteristics were consistent with previous studies while the use of rating scales and questionnaires revealed common presentations of additional signs like mild bradykinesia, mild rigidity, arm tremor, tongue tremor, and freezing of gait. These symptoms may cause diagnostic difficulties why the recognition of their prevalence is of importance. They also support the theory of a disruption of the central networks of control and adjustment of body posture. The normal cortical reaction to proprioceptive stimulation, as well as the finding of how the tremor is modulated by muscle force instead of orthostatic position and the increased susceptibility in the red nucleus and globus pallidus, also strengthen the hypothesis that POT is not a balance disorder but a result of motor control impairment. Even though the severity of the disease is not related to disease duration or any additional neurological signs, patients describe a continuing deterioration of the condition, mainly related to increase of tremor intensity and increasing feeling of unsteadiness when standing. The intense tremor activity is likely to evoke anaerobic muscle activity, and the symptom relief from intake of Beta-alanine may be explained by a reduction of lactic acid as Beta-alanine is as a precursor to Carnosine that acts as an intracellular buffer. Conclusion The data generated for this thesis suggest that POT is not an isolated tremor syndrome, but an isometric weight-bearing tremor disorder that may include axial motor symptoms as well. Disease severity is not related to age or disease duration, instead patients with POT need an individual assessment of difficulties affecting daily activities. The tremor may be generated by a dysfunction in the red nucleus or the globus pallidus and is unlikely to be a disorder of impaired cortical integration of proprioceptive information. Symptoms may be treated through tremor modulation as well as by reduction of muscle exhaustion. List of scientific papers I. Af Edholm K, Sundgren M, Fransén E, Sjöström H, Svenningsson A. Clinical characteristics of Primary Orthostatic tremor - a comprehensive clinical assessment of patients in Sweden. Submitted manuscript. [Submitted] II. Af Edholm K, Uribarri G, Sundgren M, Svenningsson A, Fransén E. Orthostatic Tremor Is Evoked by Muscle Load Without the Need for Orthostatic Position. Mov Disord Clin Pract. 2025 Aug 1. https://doi.org/10.1002/mdc3.70270 III. Af Edholm K, Vinding C M, Pfeiffer C, Svenningsson A, Fransén E, Sundgren M, Sjöström H, Edvall N, Lundqvist D, Waldthaler J. Cortical response to proprioceptive stimulation in primary orthostatic tremor - a magnetoencephalography study. Clin Neurophys Pract. 2025;(10):159-166. https://doi.org/10.1016/j.cnp.2025.04.002 IV. Af Edholm K, Oullette R, Sundgren M, Fransén E, Svenningsson A, Granberg T, Sjöström H. Increased Susceptibility and Volume Reduction in Deep Brain Nuclei in Persons with Primary Orthostatic Tremor. Accepted manuscript. [Accepted] V. Af Edholm K. Beta-Alanine Relieves Symptoms in Primary Orthostatic Tremor. Mov Disord. 2025 Aug;40(8):1730-1731. https://doi.org/10.1002/mds.30262