RARE DISEASE
Primary orthostatic tremor
Primary orthostatic tremor
Primary orthostatic tremor
Synonyms: POT
Synonyms: POT
Synonyms: POT
Drug discovery
0
drugs
With orphan designations
Overview
Primary orthostatic tremor (POT) is a rare movement disorder characterized by high-frequency (>12 Hz) tremor in weight-bearing muscles during standing, causing instability alleviated by sitting or walking. Diagnosis requires electromyography confirming tremor during stance. Symptoms include fear of falling, leg discomfort, and abnormal gait patterns (e.g., bent knees, broad base). Treatment efficacy varies, with progression often leading to functional disability and reduced quality of life [1][4][5].
Burden
Progressive disability in ~80% of patients, often worsening over decades [4][11].
Severe health-related quality-of-life impairment due to fear of falling, restricted standing tolerance, and social isolation [5][15].
Limited treatment response and high symptom variability contribute to chronic dependence on adaptive strategies [1][17].
Therapies
First-line medications: Clonazepam, gabapentin, and perampanel [1][3][8]. Beta-blockers (e.g., propranolol) show limited efficacy [17].
Surgical options: Deep brain stimulation (variable outcomes) and spinal cord stimulation for refractory cases [1][16].
Non-pharmacologic: Physical aids (stools), muscle-strengthening exercises, and patient education [1][15].
Categories: rare neurological diseases
Research Papers
51 drug discovery papers about Primary orthostatic tremor, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
51 drug discovery papers about Primary orthostatic tremor, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-03-26 | Treatment Continuation and Long-Term Outcomes of Perampanel in Primary Orthostatic Tremor; A Cohort Study.
Primary orthostatic tremor (POT) is a rare hyperkinetic movement disorder with limited and largely ineffective treatment options. Perampanel has been suggested as a therapy, but has so far only been investigated in small studies with short duration. To (1) describe longitudinal perampanel use and its association with key clinical outcomes and baseline characteristics in a well-defined cohort of POT, and (2) evaluate factors possibly associated with treatment continuation. A prospective observational cohort study in POT patients who started perampanel treatment between November 2018 and November 2022, and who completed five self-report scales prior to treatment start and during clinical follow-up were included. Scales assessed daily functioning and well-being, and included the Dutch OT-questionnaire, Hospital Anxiety and Depression Scale, (instrumental) Activities of Daily Living, and the Short Form-36. Thirty one POT patients were included, and followed for 32 months on average. Seventeen patients continued taking perampanel, demonstrating improvements in social functioning, fewer emotional role limitations, better mental health, and reduced pain compared to those who discontinued. Fourteen patients discontinued perampanel due to lack of effect and/or adverse effects, which were also common and persistent in those who continued. Men were more likely to continue treatment. Patients who discontinued had lower baseline functioning and well-being scores than those continuing, which persisted over time. In around half of patients, continued use of perampanel is associated with better clinical outcomes, also on the long term, but adverse effects are common and persistent.
2026-03-11 | Increased susceptibility and volume reduction in deep brain nuclei in primary orthostatic tremor.
Primary orthostatic tremor (POT) is a rare progressive neurological disorder with a high-frequency tremor while standing. The pathophysiology remains uncertain, and imaging studies have been inconclusive. The primary objective was to assess whether neurodegenerative changes are detectable in POT by quantitative susceptibility mapping (QSM) on brain MRI. A second objective was to explore volumetric changes in subcortical grey matter and cerebellum. In this cross-sectional study, 20 participants with POT and 14 age- and sex-matched healthy controls (HCs) were examined using a 3 T Siemens Prisma scanner with a T2*-weighted multiecho gradient-echo sequence for QSM. Regions of interest (ROIs) were automatically and manually segmented. Selected ROIs were the red nucleus, globus pallidus (GP), thalamus, caudatus, putamen, substantia nigra, dentate nucleus and inferior and superior colliculus. There was a significant increase in susceptibility in the red nucleus (mean susceptibility 138.1 parts per billion (ppb) in POT and 113.3 ppb in HC, p=0.015) and GP (mean susceptibility 101.2 ppb in POT and 73.3 ppb in HC, p=0.0015) and a significantly lower volume of the GP in the POT group compared with HC (mean volume 3838 mm3 in POT and 4062 mm3 in HC, p=0.012). Increased susceptibility and decrease of volume indicate the possibility of a neurodegenerative process affecting the red nucleus and GP in POT. The red nucleus and GP are involved in motor control, and a focal dysfunction in these networks may be a part of the cause of orthostatic tremor.
2026-01-27 | Orthostatic tremor and its subtypes: a single centre cohort of 74 patients.
Orthostatic tremor (OT) is a rare, heterogenous disorder, recently sub-classified into primary OT (isolated 13-18 Hz tremor), OT-plus (OT with additional neurological features) and pseudo-OT (OT with frequencies < 13 Hz). However, to our knowledge no study to date has compared clinical characteristics between all three subgroups. We aim to further define and compare the clinical characteristics of the three different OT subgroups, utilising one of the largest described single centre cohorts to date. A retrospective analysis was undertaken of clinical records from 74 OT patients at Charing Cross Hospital between 1999 and 2023, enabling categorisation into subgroups. Clinical characteristics, including treatment efficacy and overall disability, were subsequently described and compared between subgroups. 61 primary OT, 5 OT-plus and 8 pseudo-OT patients were identified. Baseline demographics were comparable between subgroups. Logistic regression suggested age of onset (OR = 1.02, p = 0.229), symptom duration (OR = 1.05, p = 0.083), tremor frequency (OR = 1.02, p = 0.826) and subgroup (OT-plus (OR = 1.86, p = 0.565) and pseudo-OT (OR = 1.41, p = 0.683)) were not significant predictors of disability. Treatment response varied between subgroup, with primary OT and pseudo-OT patients more frequently reporting symptomatic improvement with clonazepam, gabapentin and/or alprazolam than OT-plus patients. We provide further insight into the clinical phenotypes of the OT subgroups and encourage future studies to validate these findings with larger sample sizes and establish reliable tools to measure OT severity to better assess disease progression and treatment response.
2025-03-29 | Systematic review of pharmacological treatment options for orthostatic tremor in prospective patient cohorts and randomized controlled trials.
Orthostatic tremor is an infrequent movement disorder characterized by a high-frequency tremor manifesting primarily in the standing position. This condition can lead to relevant restrictions of mobility in everyday life and adversely affect the quality of life. The etiology has not been conclusively clarified. To date, there are few therapy studies of sufficient quality. The aim of the present literature analysis is to systematically evaluate the existing evidence of pharmacological therapies for orthostatic tremor. This study searched for publications via PubMed and Google Scholar using the terms "orthostatic tremor" AND "therapy" and "shaky legs syndrome" AND "therapy". The main inclusion criteria were a subject number ≥ 5, pharmacological treatment approaches and the presence of a prospective experimental design. The evaluation of the results indicated the most positive evidence for therapy with gabapentin. Additionally, other drugs such as perampanel and levodopa also showed positive outcomes regarding specific endpoints. In contrast, there is a lack of evidence supporting the efficacy of levetiracetam and botulinum toxin in the context of primary orthostatic tremor. According to current evidence, gabapentin is the drug with the most robust data. However, further studies are needed to support the evidence for different pharmacological therapeutic approaches for orthostatic tremor. Future investigations should emphasize larger sample sizes, placebo-controlled, double-blinded methodologies and a longer follow-up to be able to make more precise recommendations with greater generalizability.
2022-01-25 | Primary orthostatic tremor and orthostatic tremor-plus in dogs: 60 cases (2003-2020).
Orthostatic tremor (OT) is a rare movement disorder characterized by high-frequency (>12 Hz) involuntary, rhythmic, sinusoidal movements affecting predominantly the limbs while standing. To describe the signalment, presenting complaints, phenotype, diagnostic findings, treatment, and outcome of a large sample of dogs with OT. Sixty dogs diagnosed with OT based on conscious electromyography. Multicenter retrospective case series study. Dogs were included if they had a conscious electromyography consistent with muscle discharge frequency >12 Hz while standing. Fifty-three cases were diagnosed with primary OT (POT). Giant breed dogs represented most cases (83%; 44/53). Most dogs (79%; 42/53) were younger than 2 years of age at onset of signs, except for Retrievers which were all older than 3.5 years of age. The most common presenting complaints were pelvic limb tremors while standing (85%; 45/53) and difficulty when rising or sitting down (45%; 24/53). Improvement of clinical signs occurred in most dogs (85%; 45/53) treated medically with phenobarbital, primidone, gabapentin, pregabalin or clonazepam, but it was mostly partial rather than complete. Orthostatic tremor-plus was seen in 7 dogs that had concurrent neurological diseases. Primary OT is a progressive disease of young, purebred, giant/large-breed dogs, which appears to begin later in life in Retrievers. Primary OT apparently responds partially to medications. Orthostatic tremor-plus exists in dogs and can be concomitant or associated with other neurological diseases.
proteins
2022-09-14 | Orthostatic tremor after knee contusion without head trauma: A rare case report
Orthostatic tremor (OT) is an uncommon progressive movement disorder that involves a leg tremor when standing or weight bearing. Additionally, OT can accompany other medical or neurodegenerative disorders. In this article, we report an unusual case of OT after trauma in an 18-year-old male patient whose symptoms of OT have been resolved after a multimodal therapeutic approach, including botulinum toxin injection. Surface electromyography, including a tremor recording, was used for the diagnosis of OT. The patient completely recovered after the rehabilitation. A comprehensive rehabilitative treatment is required in the management of OT as the patient's quality of life is greatly affected.
2013-08-06 | Safety and efficacy of botulinum toxin in primary orthostatic tremor
Primary orthostatic tremor (POT) is a rapid 13-18 Hertz tremor that produces a subjective feeling of unsteadiness when standing, and is absent when seated or supine. It predominantly affects the legs during isometric contraction though a similar tremor can be seen in the arms and jaw. When present in the jaw this rapid tremor has been successfully treated with botulinum toxin. We sought to test whether symptoms of POT improved following injection of abobotulinumtoxinA to muscles in the legs. This randomised, double blind, placebo controlled cross-over design study enrolled eight patients with electrophysiologically confirmed POT. Each patient received injections of either 200 mU abobotulinumtoxinA or 0.9% saline in the tibialis anterior bilaterally, with cross-over after 20 weeks. Electrophysiological and clinical assessments were performed before and 6 weeks after each injection. Seven patients completed the study. No significant differences were seen in the primary outcome measures of time from standing to unsteadiness or symptom diary scores. Electrophysiological characteristics of POT remained remarkably constant throughout the study in all patients with variability of less than 1 Hertz in the frequency recorded. Falls were common, with one patient experiencing a fall with upper limb fracture whilst on the placebo. The frequency of falls correlated with both the severity of the self-rated symptoms and a shorter time to feeling unsteady with eyes closed. In conclusion, treatment with 200 mU of abobotulinumtoxinA in the tibialis anterior does not alter subjective experience of unsteadiness in POT. Postural instability and falls are common.
small molecules
2026-03-26 | Treatment Continuation and Long-Term Outcomes of Perampanel in Primary Orthostatic Tremor; A Cohort Study.
Primary orthostatic tremor (POT) is a rare hyperkinetic movement disorder with limited and largely ineffective treatment options. Perampanel has been suggested as a therapy, but has so far only been investigated in small studies with short duration. To (1) describe longitudinal perampanel use and its association with key clinical outcomes and baseline characteristics in a well-defined cohort of POT, and (2) evaluate factors possibly associated with treatment continuation. A prospective observational cohort study in POT patients who started perampanel treatment between November 2018 and November 2022, and who completed five self-report scales prior to treatment start and during clinical follow-up were included. Scales assessed daily functioning and well-being, and included the Dutch OT-questionnaire, Hospital Anxiety and Depression Scale, (instrumental) Activities of Daily Living, and the Short Form-36. Thirty one POT patients were included, and followed for 32 months on average. Seventeen patients continued taking perampanel, demonstrating improvements in social functioning, fewer emotional role limitations, better mental health, and reduced pain compared to those who discontinued. Fourteen patients discontinued perampanel due to lack of effect and/or adverse effects, which were also common and persistent in those who continued. Men were more likely to continue treatment. Patients who discontinued had lower baseline functioning and well-being scores than those continuing, which persisted over time. In around half of patients, continued use of perampanel is associated with better clinical outcomes, also on the long term, but adverse effects are common and persistent.
2026-03-11 | Increased susceptibility and volume reduction in deep brain nuclei in primary orthostatic tremor.
Primary orthostatic tremor (POT) is a rare progressive neurological disorder with a high-frequency tremor while standing. The pathophysiology remains uncertain, and imaging studies have been inconclusive. The primary objective was to assess whether neurodegenerative changes are detectable in POT by quantitative susceptibility mapping (QSM) on brain MRI. A second objective was to explore volumetric changes in subcortical grey matter and cerebellum. In this cross-sectional study, 20 participants with POT and 14 age- and sex-matched healthy controls (HCs) were examined using a 3 T Siemens Prisma scanner with a T2*-weighted multiecho gradient-echo sequence for QSM. Regions of interest (ROIs) were automatically and manually segmented. Selected ROIs were the red nucleus, globus pallidus (GP), thalamus, caudatus, putamen, substantia nigra, dentate nucleus and inferior and superior colliculus. There was a significant increase in susceptibility in the red nucleus (mean susceptibility 138.1 parts per billion (ppb) in POT and 113.3 ppb in HC, p=0.015) and GP (mean susceptibility 101.2 ppb in POT and 73.3 ppb in HC, p=0.0015) and a significantly lower volume of the GP in the POT group compared with HC (mean volume 3838 mm3 in POT and 4062 mm3 in HC, p=0.012). Increased susceptibility and decrease of volume indicate the possibility of a neurodegenerative process affecting the red nucleus and GP in POT. The red nucleus and GP are involved in motor control, and a focal dysfunction in these networks may be a part of the cause of orthostatic tremor.
2026-01-27 | Orthostatic tremor and its subtypes: a single centre cohort of 74 patients.
Orthostatic tremor (OT) is a rare, heterogenous disorder, recently sub-classified into primary OT (isolated 13-18 Hz tremor), OT-plus (OT with additional neurological features) and pseudo-OT (OT with frequencies < 13 Hz). However, to our knowledge no study to date has compared clinical characteristics between all three subgroups. We aim to further define and compare the clinical characteristics of the three different OT subgroups, utilising one of the largest described single centre cohorts to date. A retrospective analysis was undertaken of clinical records from 74 OT patients at Charing Cross Hospital between 1999 and 2023, enabling categorisation into subgroups. Clinical characteristics, including treatment efficacy and overall disability, were subsequently described and compared between subgroups. 61 primary OT, 5 OT-plus and 8 pseudo-OT patients were identified. Baseline demographics were comparable between subgroups. Logistic regression suggested age of onset (OR = 1.02, p = 0.229), symptom duration (OR = 1.05, p = 0.083), tremor frequency (OR = 1.02, p = 0.826) and subgroup (OT-plus (OR = 1.86, p = 0.565) and pseudo-OT (OR = 1.41, p = 0.683)) were not significant predictors of disability. Treatment response varied between subgroup, with primary OT and pseudo-OT patients more frequently reporting symptomatic improvement with clonazepam, gabapentin and/or alprazolam than OT-plus patients. We provide further insight into the clinical phenotypes of the OT subgroups and encourage future studies to validate these findings with larger sample sizes and establish reliable tools to measure OT severity to better assess disease progression and treatment response.
2025-03-29 | Systematic review of pharmacological treatment options for orthostatic tremor in prospective patient cohorts and randomized controlled trials.
Orthostatic tremor is an infrequent movement disorder characterized by a high-frequency tremor manifesting primarily in the standing position. This condition can lead to relevant restrictions of mobility in everyday life and adversely affect the quality of life. The etiology has not been conclusively clarified. To date, there are few therapy studies of sufficient quality. The aim of the present literature analysis is to systematically evaluate the existing evidence of pharmacological therapies for orthostatic tremor. This study searched for publications via PubMed and Google Scholar using the terms "orthostatic tremor" AND "therapy" and "shaky legs syndrome" AND "therapy". The main inclusion criteria were a subject number ≥ 5, pharmacological treatment approaches and the presence of a prospective experimental design. The evaluation of the results indicated the most positive evidence for therapy with gabapentin. Additionally, other drugs such as perampanel and levodopa also showed positive outcomes regarding specific endpoints. In contrast, there is a lack of evidence supporting the efficacy of levetiracetam and botulinum toxin in the context of primary orthostatic tremor. According to current evidence, gabapentin is the drug with the most robust data. However, further studies are needed to support the evidence for different pharmacological therapeutic approaches for orthostatic tremor. Future investigations should emphasize larger sample sizes, placebo-controlled, double-blinded methodologies and a longer follow-up to be able to make more precise recommendations with greater generalizability.
2022-01-25 | Primary orthostatic tremor and orthostatic tremor-plus in dogs: 60 cases (2003-2020).
Orthostatic tremor (OT) is a rare movement disorder characterized by high-frequency (>12 Hz) involuntary, rhythmic, sinusoidal movements affecting predominantly the limbs while standing. To describe the signalment, presenting complaints, phenotype, diagnostic findings, treatment, and outcome of a large sample of dogs with OT. Sixty dogs diagnosed with OT based on conscious electromyography. Multicenter retrospective case series study. Dogs were included if they had a conscious electromyography consistent with muscle discharge frequency >12 Hz while standing. Fifty-three cases were diagnosed with primary OT (POT). Giant breed dogs represented most cases (83%; 44/53). Most dogs (79%; 42/53) were younger than 2 years of age at onset of signs, except for Retrievers which were all older than 3.5 years of age. The most common presenting complaints were pelvic limb tremors while standing (85%; 45/53) and difficulty when rising or sitting down (45%; 24/53). Improvement of clinical signs occurred in most dogs (85%; 45/53) treated medically with phenobarbital, primidone, gabapentin, pregabalin or clonazepam, but it was mostly partial rather than complete. Orthostatic tremor-plus was seen in 7 dogs that had concurrent neurological diseases. Primary OT is a progressive disease of young, purebred, giant/large-breed dogs, which appears to begin later in life in Retrievers. Primary OT apparently responds partially to medications. Orthostatic tremor-plus exists in dogs and can be concomitant or associated with other neurological diseases.
proteins
2022-09-14 | Orthostatic tremor after knee contusion without head trauma: A rare case report
Orthostatic tremor (OT) is an uncommon progressive movement disorder that involves a leg tremor when standing or weight bearing. Additionally, OT can accompany other medical or neurodegenerative disorders. In this article, we report an unusual case of OT after trauma in an 18-year-old male patient whose symptoms of OT have been resolved after a multimodal therapeutic approach, including botulinum toxin injection. Surface electromyography, including a tremor recording, was used for the diagnosis of OT. The patient completely recovered after the rehabilitation. A comprehensive rehabilitative treatment is required in the management of OT as the patient's quality of life is greatly affected.
2013-08-06 | Safety and efficacy of botulinum toxin in primary orthostatic tremor
Primary orthostatic tremor (POT) is a rapid 13-18 Hertz tremor that produces a subjective feeling of unsteadiness when standing, and is absent when seated or supine. It predominantly affects the legs during isometric contraction though a similar tremor can be seen in the arms and jaw. When present in the jaw this rapid tremor has been successfully treated with botulinum toxin. We sought to test whether symptoms of POT improved following injection of abobotulinumtoxinA to muscles in the legs. This randomised, double blind, placebo controlled cross-over design study enrolled eight patients with electrophysiologically confirmed POT. Each patient received injections of either 200 mU abobotulinumtoxinA or 0.9% saline in the tibialis anterior bilaterally, with cross-over after 20 weeks. Electrophysiological and clinical assessments were performed before and 6 weeks after each injection. Seven patients completed the study. No significant differences were seen in the primary outcome measures of time from standing to unsteadiness or symptom diary scores. Electrophysiological characteristics of POT remained remarkably constant throughout the study in all patients with variability of less than 1 Hertz in the frequency recorded. Falls were common, with one patient experiencing a fall with upper limb fracture whilst on the placebo. The frequency of falls correlated with both the severity of the self-rated symptoms and a shorter time to feeling unsteady with eyes closed. In conclusion, treatment with 200 mU of abobotulinumtoxinA in the tibialis anterior does not alter subjective experience of unsteadiness in POT. Postural instability and falls are common.
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