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BACKGROUND: Primary orthostatic tremor (OT) can affect patients' life. Treatment of OT with deep brain stimulation (DBS) of the thalamic ventral intermediate nucleus (Vim) is described in a limited number of patients. The Vim and posterior subthalamic area (PSA) can be targeted in a single trajectory, allowing both stimulation of the Vim and/or dentatorubrothalamic tract (DRT). In essential tremor this is currently often used with positive effects. OBJECTIVE: To evaluate the efficacy of Vim/DRT-DBS in OT-patients, based on standing time and Quality of Life (QoL), also on the long-term. Furthermore, to relate stimulation of the Vim and DRT, medial lemniscus (ML) and pyramidal tract (PT) to beneficial clinical and side-effects. METHODS: Nine severely affected OT-patients received bilateral Vim/DRT-DBS. Primary outcome measure was standing time; secondary measures included self-reported measures, neurophysiological measures, structural analyses, surgical complications, stimulation-induced side-effects, and QoL up to 56 months. Stimulation of volume of tissue activated (VTA) were related to outcome measures. RESULTS: Average maximum standing time increased from 41.0 s ± 51.0 s to 109.3 s ± 65.0 s after 18 months, with improvements measured in seven of nine patients. VTA (n = 7) overlapped with the DRT in six patients and with the ML and/or PT in six patients. All patients experienced side-effects and QoL worsened during the first year after surgery, which improved again during long-term follow-up, although remaining below age-related normal values. Most patients reported a positive effect of DBS. CONCLUSION: Vim/DRT-DBS improved standing time in patients with severe OT. Observed side-effects are possibly related to stimulation of the ML and PT.

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A ponto-cerebello-thalamo-cortical network is the pathophysiological correlate of primary orthostatic tremor. Affected patients often do not respond satisfactorily to pharmacological treatment. Consequently, the objective of the current study was to examine the effects of a non-invasive neuromodulation by theta burst repetitive transcranial magnetic stimulation (rTMS) of the left primary motor cortex (M1) and dorsal medial frontal cortex (dMFC) on tremor frequency, intensity, sway path and subjective postural stability in primary orthostatic tremor. In a cross-over design, eight patients (mean age 70.2 ± 5.4 years, 4 female) with a primary orthostatic tremor received either rTMS of the left M1 leg area or the dMFC at the first study session, followed by the other condition (dMFC or M1 respectively) at the second study session 30 days later. Tremor frequency and intensity were quantified by surface electromyography of lower leg muscles and total sway path by posturography (foam rubber with eyes open) before and after each rTMS session. Patients subjectively rated postural stability on the posturography platform following each rTMS treatment. We found that tremor frequency did not change significantly with M1- or dMFC-stimulation. However, tremor intensity was lower after M1- but not dMFC-stimulation (p = 0.033/ p = 0.339). The sway path decreased markedly after M1-stimulation (p = 0.0005) and dMFC-stimulation (p = 0.023) compared to baseline. Accordingly, patients indicated a better subjective feeling of postural stability both with M1-rTMS (p = 0.007) and dMFC-rTMS (p = 0.01). In conclusion, non-invasive neuromodulation particularly of the M1 area can improve postural control and tremor intensity in primary orthostatic tremor by interference with the tremor network.

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Orthostatic tremor is a rare movement disorder characterized by a sensation of unsteadiness and leg tremor while standing. It has been hypothesized that the disorder is attributable to dysregulation of a central oscillatory network in the brain. This putative network includes primary motor cortex, supplementary motor area, cerebellum, thalamus, and pontine tegmentum. We studied this brain network by recording resting-state functional MRI data from individuals with orthostatic tremor. For each participant, we measured resting-state functional connectivity using a seed-based approach. Regions of interest included were components of the putative central oscillatory network and a primary motor thumb region (identified via transcranial magnetic stimulation). A non-central oscillatory network region of interest-posterior cingulate cortex-was included for comparative analysis of a well-characterized intrinsic network, the default mode network. Demographic information, medical history, and tremor characteristics were collected to test associations with functional connectivity. For normative context, data from the 1000 Functional Connectomes Project were analyzed using an identical approach. We observed that tremor and demographic variables were correlated with functional connectivity of central oscillatory network components. Furthermore, relative to healthy comparison participants, patients with orthostatic tremor exhibited qualitatively different patterns of cerebellar resting state functional connectivity. Our study enhances the current understanding of brain network differences related to orthostatic tremor and is consistent with a hypothesized selective decoupling of cerebellum. Additionally, associations observed between functional connectivity and factors including medical history and tremor features may suggest targets for treatment of orthostatic tremor.

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Shaking upon standing is associated with a spectrum of different conditions. We describe an unusual case with a combination of slow orthostatic tremor, orthostatic myoclonus, and parkinsonism. The case illustrates the utility of electrophysiology for precise characterization of physical findings to establish the diagnosis.

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Introduction: There are currently no effective treatments for primary orthostatic tremor (POT). An adequate disease-specific POT severity scale is a prerequisite to conduct clinical trials and monitor disease severity in clinical practice. Recently, the English OT-10 scale has been developed for this purpose. Here we aimed to obtain a scale to measure the severity of POT in Dutch speaking individuals. Methods: An established translation, adaptation and validation approach was employed to obtain a Dutch version of the OT-10 scale. Validation was performed in a Dutch POT cohort (n = 46). Results: A Dutch OT-10 scale was obtained which showed good internal consistency (Cronbach's alpha > 0.80), total score test-retest reliability (intraclass correlation coefficient > 0.80), and concurrent validity (Pearson correlation > 0.80). Item-to-total correlation was good (weighted kappa > 0.40) for all items, and item test-retest reliability was good (weighted kappa > 0.40) for eight out of ten items. Overall, the Dutch OT-10 scale demonstrated acceptable validity. Conclusions: We obtained and validated a Dutch version of the OT-10 scale, capturing POT severity. Next to its use in clinical practice, translation and validation of the OT-10 scale in more languages will help to find evidence-based treatments for POT.

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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.

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Introduction: Orthostatic tremor (OT) is a rare neurological disorder characterized by a sensation of instability while standing. Very few clinical signs have been described for OT to date. Finding other symptoms and signs could prove valuable for this hard-to-recognized disease. Methods: This protocol is part of the University of Nebraska Medical Center Orthostatic Tremor longitudinal study. It was noted that OT patients flex their toes and sometimes the foot arch while standing (Plantar Grasp). They reported doing this to "grab" the floor and improve stability. This paper analyses the diagnostic test characteristics of the patient-self-reported Plantar Grasp, a new sign in OT. Results: There were 34 OT patients (88% females), and 20 controls (65% females). Eighty-eight percent of patients with OT reported the plantar grasp sign and none of the controls. The Plantar Grasp Sign was found to be very sensitive (88%), and extremely specific (100%) in our cohort. Non-weighted Negative Likelihood Ratio (NLR) was 0.12. And the 3% prevalence-weighted NLR was so low that the negative post-test probability was close to zero. Conclusion: Due to its high sensitivity, specificity, and ideal likelihood ratio, we propose that the Plantar Grasp sign could be considered to screen patients with possible OT. Further studies are needed to determine the specificity of this sign in OT versus other balance disorders.

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Klinefelter's syndrome (KS) is the most common cause of hypogonadism in men. Essential tremor (ET) and parkinsonism have been reported in KS, but ataxia, which has been commonly reported with other causes of hypogonadism, is very rare in KS. Orthostatic tremor has not been reported. We present a case with multiple movement disorders, including gait ataxia, essential-type tremor, rest tremor, orthostatic tremor and parkinsonism.

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@#Vitamin B12 deficiency has long been known to present with various neurological manifestations, but only rarely presents as movement disorders, especially in adults. We present the case of a 30-year-old vegan male presenting with tremors on both legs when standing which was relieved by vitamin B12 supplementation. To the best of our knowledge, this is the first documented case of slow orthostatic tremor or pseudo-orthostatic tremor caused by vitamin B12 deficiency.

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BACKGROUND: Orthostatic tremor (OT) is a type of postural tremor of the lower extremities that has not been described in either phenylketonuria (PKU) or hyperphenylalaninemia (HPA). Because little is known about the clinical features and therapeutic responses of OT in mild HPA, we describe a mild HPA patient who presented with OT as an initial symptom. CASE PRESENTATION: A 22-year-old male was admitted for bilateral leg tremor while standing, with symptom onset eight months prior. One month before admission, the tremor disappeared in the left leg but persisted in the right leg. Electromyography recorded from the right gastrocnemius revealed a 6-8 Hz tremor, which appeared when the patient was standing and disappeared when he was resting or walking. Blood screening showed a phenylalanine/tyrosine ratio of 2.06 and a phenylalanine level of 140 µmol/L. Urine metabolic screening was negative. Whole-exome sequencing confirmed the presence of a compound heterozygous mutation, c.158G > A and c.728G > A, in phenylalanine hydroxylase (PAH) gene. After three months of levodopa/benserazide tablets (250 mg, tid) and a low-phenylalanine diet treatment, the tremor disappeared. CONCLUSIONS: Young-onset mild HPA is a relatively rare autosomal recessive metabolic disease, and slow OT is a rare clinical feature. Metabolic screening and genetic testing are the keys to early diagnosis and treatment. For adolescents and young adults, appropriate medication and long-term dietary therapy remain important treatments. This case expanded the disease spectrum of slow OT.

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BACKGROUND: Orthostatic tremor is a rare and debilitating movement disorder. Its first-line treatment is pharmacological. For pharmaco-refractory patients, surgical treatment options such as deep brain stimulation (DBS) and spinal cord stimulation (SCS) have been investigated recently. OBJECTIVES: We conducted a systematic review of all published outcome and safety data on DBS and SCS for orthostatic tremor patients. METHODS: We searched Pubmed and Embase for studies describing orthostatic tremor patients treated with DBS or SCS. We collected all available outcome and safety data and our primary endpoint was the change in unsupported stance duration 1 year postoperatively (±6 months). RESULTS: We included 15 studies, reporting on 32 orthostatic tremor patients who underwent DBS, 4 patients SCS and 2 both. The ventral intermediate nucleus and the zona incerta were targeted in 25/34 and 9/34 DBS cases, respectively. The median stance time at 1 year follow-up was 240 s compared to 30 s pre-operatively (p < 0.001). Stimulation-induced side effects occurred in the majority of patients, but were often transient. Bilateral stimulation appeared more effective than unilateral and stimulation settings were comparable to thalamic DBS for essential tremor. There were insufficient data available to draw meaningful conclusions on the long-term effects of DBS. Due to insufficient data, no conclusions could be drawn on the effects of SCS on orthostatic tremor. CONCLUSION: DBS may be effective to increase stance time in orthostatic tremor patients in the first year, but further research is necessary to evaluate the long-term effects and the role of spinal cord stimulation.

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Slow orthostatic tremor is an extremely rare movement disorder with relatively low-frequency tremor (< 13 Hz) in the legs and trunk, which is evoked by standing. There is still much controversy regarding its precise etiology. Here we present a 57 year-old female patient with a slow orthostatic tremor variant who experienced progressive gait disturbances since six years due to isolated trunk tremor. Potential symptomatic causes of tremor and other neurological co-morbidities were excluded through an exenstive clinical, laboratoy and imaging work-up. Subsequently, a combined treatment with propranolol and primidone was started, which resulted in almost complete resolution of the trunk tremor. Given that the slow trunk tremor in this patient almost completely resolved after therapy with a low-dose propranolol and primidone, considered first line drugs for the treatment of essential tremor, this case illustrates that isolated orthostatic trunk tremor may occur as a rare variant of essential tremor.

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Background: The presence and prevalence of several neurological signs in patients with primary orthostatic tremor have not been systematically studied. Objectives: To assess the prevalence of clinical features of primary orthostatic tremor. Methods: Video-based assessment by four raters of standardized neurological examination of 11 patients with primary orthostatic tremor. Results: On standing, bent knees (7/11), hem sign (6/10), and a broad base of support (6/11) were the three most prevalent signs. Examination of gait revealed abnormal tandem gait (9/11) and bent knees (6/11) as the most prevalent clinical signs. In the arms, none of the patients displayed bradykinesia, ataxia, or dystonia. In the legs, ataxia was absent in all patients and bradykinesia was present in only one patient. Conclusions: Abnormal tandem gait, bent knees, hem sign, and broad base on standing are the most prevalent clinical signs in primary orthostatic tremor. We did not encounter clear extrapyramidal or unequivocal cerebellar signs.

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Tremor is one of the most common movement disorders, though it can arise in the context of several unrelated neurological disorders whose pharmacology and anatomical origins differ greatly. Treatment of tremors can take advantage of several medications and neurosurgical treatments. Medications useful for treating tremor are discussed in this review, including those for action tremor as seen in essential tremor, the resting tremor of Parkinson's disease, orthostatic tremor, cerebellar tremor, Holmes tremor, dystonic tremor, and drug-induced tremors. A medication that is useful for most types of tremors is the beta-blocker propranolol, though even in essential tremor it can fail to be effective at tremor control. This article is part of the Special Issue "Tremor" edited by Daniel D. Truong, Mark Hallett, and Aasef Shaikh.

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The Consensus Statement on the Classification of Tremors, from the Task Force of the International Parkinson's and Movement Disorder Society was published in 2018 in response to advances in the understanding of essential tremor (ET), tremor associated with dystonia and other monosymptomatic and indeterminate tremors. This was a revision of the previous 1998 Consensus Statement. A number of problems arise from this classification and, in this manuscript, we highlight several of these. These problems relate to the definition of tremor, the definition of ET, the proposal of the term 'essential tremor plus', issues related to orthostatic tremor (OT) including the proposal of the term 'orthostatic tremor plus', and the absence of a hierarchy of terms used to classify tremor. Among the proposals we make is that the definition of tremor should acknowledge that tremor is a symptom, ET should be redefined, severity is an important characteristic for classifying and diagnosing tremor, the terms 'essential tremor plus' and 'orthostatic tremor plus' should be abandoned, and classification of tremor requires rules for creating a hierarchy of terminology. "This article is part of the Special Issue "Tremor" edited by Daniel D. Truong, Mark Hallett, and Aasef Shaikh".

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BACKGROUND AND PURPOSE: Orthostatic tremor and spinal cord melanoma are rare entities and seem unlikely to be associated. Herein, we report a patient diagnosed with orthostatic tremor secondary to primary malignant melanoma of the spinal cord. CASE PRESENTATION: We report the case of a 67-year-old man who experienced tremor when he was standing, which disappeared when he was sitting or walking. He also reported gait disturbance and cognitive dysfunction. Electromyography revealed a regular and symmetric high-frequency tremor in the lower extremities. The patient was admitted to a hospital several times and was diagnosed with primary orthostatic tremor and later hydrocephalus; thus, he received a ventriculoperitoneal shunt. Finally, he showed symptoms of the presence of melanoma in the spinal cord, which was supported by spinal cord magnetic resonance imaging findings. Primary malignant melanoma of the spinal cord was confirmed postoperatively. CONCLUSIONS: Orthostatic tremor is a rare entity that can be characterized by specific high-frequency tremors when the subject is standing. Considering that it remains unknown why this condition appears, some possible associations, such as primary spinal cord melanoma, should be considered. Thus, a comprehensive assessment of these types of patients is required. Our case report may facilitate the understanding of the pathophysiology and clinical symptoms of this disease.

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The various forms of tremor are now classified in two axes: clinical characteristics (axis 1) and etiology (axis 2). Electrophysiology is an extension of the clinical exam. Electrophysiologic tests are diagnostic of physiologic tremor, primary orthostatic tremor, and functional tremor, but they are valuable in the clinical characterization of all forms of tremor. Electrophysiology will likely play an increasing role in axis 1 tremor classification because many features of tremor are not reliably assessed by clinical examination alone. In particular, electrophysiology may be needed to distinguish tremor from tremor mimics, assess tremor frequency, assess tremor rhythmicity or regularity, distinguish mechanical-reflex oscillation from central neurogenic oscillation, determine if tremors in different body parts, muscles, or brain regions are strongly correlated, document tremor suppression or entrainment by voluntary movements of contralateral body parts, and document the effects of voluntary movement on rest tremor. In addition, electrophysiologic brain mapping has been crucial in our understanding of tremor pathophysiology. The electrophysiologic methods of tremor analysis are reviewed in the context of physiologic tremor and pathologic tremors, with a focus on clinical characterization and pathophysiology. Electrophysiology is instrumental in elucidating tremor mechanisms, and the pathophysiology of the different forms of tremor is summarized in this review.

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BACKGROUND: Primary orthostatic tremor (OT) is a rare movement disorder characterized by a 13-18 Hz leg tremor, which arises when standing and is relieved by walking/sitting. Those affected generally do not fall, but experience fear of falling, lessened by ambulation. Because of its low amplitude, the tremor is not readily visible, and diagnosis requires confirmation with surface electromyography (sEMG). Recently, applications using the accelerometer feature of smartphones have been used to detect and quantify tremors, including OT, though the accuracy of smartphone accelerometry (SPA) in diagnosing OT is unknown. METHODS: We completed SPA in consecutive adults (18+ years), who presented to our neurology clinic with either subjective leg shakiness upon standing or unsteadiness when standing that lessened with ambulation, which comprised 59 of 2578 patients. We assessed tremor using the StudyMyTremor application on an iPhone 6 s adhered with tape to the patient's tibialis anterior. Surface electromyography was completed on the same muscle. The primary outcome of this study was to determine SPA's sensitivity and specificity in detecting OT compared with surface electromyography. RESULTS: Fifty-nine patients with the following diagnoses were included: OT (6), Parkinson's disease, Hereditary Spastic Paraplegia, orthostatic hypotension, essential tremor, spinal cerebellar ataxia, sensory ataxia and functional movement disorder. Smartphone accelerometry detected a 13-18 Hz tremor in 5 of 6 patients diagnosed with OT by sEMG with no false positives in other conditions, yielding a sensitivity of 83%, specificity of 100% in the cohort we studied. CONCLUSIONS: Though a larger sample size is desirable, preliminary data suggest that smartphone accelerometry is an alternative to surface electromyography in diagnosing OT.

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Transcranial magnetic stimulation (TMS) is a painless, non-invasive, and established brain stimulation technique to investigate human brain function. Over the last three decades, TMS has shed insight into the pathophysiology of many neurological disorders. Tremor is an involuntary, rhythmic oscillatory movement disorder commonly related to pathological oscillations propagated via the cerebello-thalamo-cortical pathway. Although tremor is the most common movement disorder and recent imaging studies have enhanced our understanding of the critical pathogenic networks, the underlying pathophysiology of different tremor syndromes is complex and still not fully understood. TMS has been used as a tool to further our understanding of tremor pathophysiology. In addition, repetitive TMS (rTMS) that can modulate brain functions through plasticity effects has been targeted to the tremor network to gain potential therapeutic benefits. However, evidence is available for only a few studies that included small patient samples with limited clinical follow-up. This review aims to discuss the role of TMS in advancing the pathophysiological understanding as well as emerging applications of rTMS for treating individual tremor syndromes. The review will focus on essential tremor, Parkinson's disease tremor, dystonic tremor syndrome, orthostatic tremor, and functional tremor.