Blinded placebo crossover study of gabapentin in primary orthostatic tremor.

Primary orthostatic tremor (OT) is a rare but disabling condition characterized by leg tremor and feelings of instability during stance. Previous studies have reported a reduction in OT symptoms with gabapentin treatment. In this study, we report on the benefits of gabapentin treatment in a double-blind placebo-controlled crossover study of 6 OT patients. First, the maximally effective gabapentin dosage (600-2,700 mg/day) for each patient was determined during an initial dose-titration phase. Patients were then studied 7 days after drug withdrawal and again after two 2-week periods of treatment with either gabapentin or placebo, using force platform posturography to quantify postural sway and tremor. Other medications for OT were continued unchanged. Symptomatic response was assessed by a patient-rated severity scale and quality of life (QOL) questionnaire. All patients reported an increase in symptoms during the washout phase and symptom reduction (50%-75%) during gabapentin treatment. Tremor amplitude was reduced to 79% +/- 11% and sway area to 71% +/- 11% of the placebo state. QOL improved in all patients, no adverse drug effects were noted, and symptomatic benefit was maintained at follow-up (mean = 19 months). The findings confirm that gabapentin is an effective treatment for OT, reducing both tremor and postural instability and improving quality of life, and support its use as add-on or first-line therapy for OT.     

Quality of life in patients with orthostatic tremor

We assessed health-related quality of life (QoL) and depression, using the SF-36 and the Beck Depression Inventory (BDI), in 20 orthostatic tremor (OT) patients. All dimensions of the SF-36 were markedly reduced in OT and depression was found in 11 patients. The BDI score correlated significantly with several SF-36 subscores. We conclude that OT strongly impacts on QoL. The results highlight the importance of recognizing and treating depression in patients with OT.     

Sway patterns in orthostatic tremor: impairment of postural control mechanisms.

Sway parameters in orthostatic tremor (OT) patients were compared with age-matched controls. The effects of vision (eyes open or closed), stance width (feet apart or together), and external support (with or without) on sway and 14-18 Hz energy were measured. Sway in OT patients decreased in the presence of each of the stabilizing factors but the extent of benefit obtained by OT patients was significantly less than controls for support for the sagittal plane (22% vs. 42% decrease; P < 0.01) and feet apart in the mediolateral plane (38% vs. 65% decrease; P < 0.01). Three patients with proprioceptive loss also had a reduced response to these factors. Energy in the 14-18 Hz range did not always change in parallel with sway levels. Vision suppresses activity at the OT frequency in patients. Postural control mechanisms in OT remain responsive to postural conditions, but patients differ significantly from normals in the degree of their responsiveness. OT appears to have disruption of the normal generation or processing of proprioceptive signals as one of its important components.     

Isometric features of orthostatic tremor: an electromyographic analysis

A patient is described with "orthostatic" tremor. Electromyography revealed tremor bursts of 15 Hz in the lower extremities while standing and with isometric activation of the muscles, but the bursts disappeared with isotonic activation of muscles. Similar tremor was recorded in the arms with isometric, but not isotonic activation. Review of previously reported cases confirms these findings. The clinical and electrophysiologic features of this tremor distinguish it from other recognized forms of tremor.     

Dopa-responsive pseudo-orthostatic tremor in parkinsonism.

In four patients an inabilitating standing tremor appeared years before that parkinsonian symptoms were evidenced. This tremor was refractory to gabapentin and dramatically responded to Levodopa administration. Its dominant frequency was 6.2 to 6.9 Hz with sporadic subharmonics at 8 to 18 Hz. Three patients were affected by different genetic mutations (Park 2, Park 6, mtDNA deletion) in one no genetic or metabolic alterations could be evidenced. All patients had dopamine transporter abnormalities. We suggest that the term "Pseudo-Orthostatic Tremor" could be used to define this Dopa responsive, 6 to 7 Hz standing tremor.     

Sway patterns in a case of orthostatic tremor responsive to alcohol.

We describe changes in the extent of sway in a man with orthostatic tremor (OT) who reported increased stability after alcohol. He was tested at baseline and again after 40 g (0.5 g/kg) of alcohol. These results were compared to those of 3 age-matched controls (no alcohol). The patient's baseline sway was greater than controls, larger in the lateral than the anteroposterior plane, but retained normal responsiveness to the use of external support, increasing stance width, and vision. Tremor frequency significantly decreased after alcohol, as did low- and high-frequency tremor amplitude and the extent of body sway. Despite these findings, sway remained greater than controls. OT thus may show functionally important alcohol responsiveness.     

Familial orthostatic tremor and essential tremor in two young brothers: A rare entity

Orthostatic tremor (OT), is usually a disease of old age and is characterized by quivering movements of the legs during quiet standing or in the state of isometric contraction in the lower limbs. This is relieved on walking or on lying down. It is diagnosed by surface electromyography, particularly over the quadriceps femoris muscles which shows a distinctive frequency of 13 to 18 Hz on standing. Some investigators consider it as a variant of essential tremor (ET) and the two conditions often co-exist. The disease is usually non-familial. Two brothers presented with tremor in the lower limbs on standing and on the outstretched hands without any family history. Subsequently, they were proved to be suffering from OT and ET by clinical examination and surface EMG. Simultaneous occurrence of OT and ET in two young brothers without any family history in the previous generation has not been described before and they also appeared at a much earlier age than what is described in the literature.     

Quality of life and personality in essential tremor patients.

The aim of this study was to determine the impact of essential tremor (ET) on quality of life and its relation with tremor severity and the personality profile of ET patients. One hundred and five patients with definite or probable ET from an outpatient population were tested with the Short-Form 36-Item Health Survey (SF36) and the Eysenck Personality Questionnaire (EPQ-R). Compared to controls, the ET patients scored worse in all eight domains of the SF36. The physical component score (PCS) did not differ significantly from the normal population, whereas ET patients older than 40 years were significantly more affected with regard to the mental domains measured by the mental component score (MCS) with their median below the 20th percentile of the German controls. Tremor severity correlated with some of the physical domains and the PCS as well as with social function of the mental domains. ET patients showed significantly lower scores in the psychoticism (P) scale of the EPQ-R, with a median value on the 11th percentile of normal German population, indicating a more tender-minded personality type. The MCS correlated highly significant with the neuroticism (N) scale and extraversion (E) scale of EPQ-R. Multiple regression analysis identified age as the only predictive factor for the PCS and the N-scale as the only predictive factor for the MCS. Although ET is considered a pure movement disorder, the mental components of quality of life are more affected than the physical dimensions. A more controlled personality type may in part contribute to this.     

The central oscillatory network of orthostatic tremor

Orthostatic tremor (OT) is a movement disorder of the legs and trunk that is present in the standing position but typically absent when sitting. The pathological central network involved in orthostatic tremor is still unknown. In this study we analyzed 15 patients with simultaneous high‐resolution electroencephalography and electromyography recording to assess corticomuscular coherence. In 1 patient we were able to simultaneously record the local field potential in the ventrolateral thalamus and electroencephalography. Dynamic imaging of coherent source analysis was used to find the sources in the brain that are coherent with the peripheral tremor signal. When standing, the network for the tremor frequency consisted of unilateral activation in the primary motor leg area, supplementary motor area, primary sensory cortex, two prefrontal/premotor sources, thalamus, and cerebellum for the whole 30‐second segment recorded. The source coherence dynamics for the primary leg area and the thalamic source signals with the tibialis anterior muscle showed that they were highly coherent for the whole 30 seconds for the contralateral side but markedly decreased after 15 seconds for the ipsilateral side. The source signal and the recorded thalamus signal followed the same time frequency dynamics of coherence in 1 patient. The corticomuscular interaction in OT follows a consistent pattern with an initially bilateral pattern and then a segregated unilateral pattern after 15 seconds. This may add to the feeling of unsteadiness. It also makes the thalamus unlikely as the main source of orthostatic tremor. © 2013 International Parkinson and Movement Disorder Society     

Natural history and syndromic associations of orthostatic tremor: a review of 41 patients.

Orthostatic tremor (OT) is a rare condition characterized by unsteadiness when standing still that is relieved when sitting or walking and is thought to arise from a central generator in the cerebellum or brainstem. OT is considered to be a distinct, discrete condition, and little is known about its demographic characteristics, natural history, associated features, and treatment response. We have reviewed these aspects in 41 OT patients fulfilling current diagnostic criteria, seen at our institution between 1986 and 2001. We classified 31 (75%) as having idiopathic "primary OT" either with (n = 24) or without an associated postural arm tremor. We found that 10 of 41 (25%) cases had additional neurological features, and we defined this group as having "OT plus" syndrome. Of these 10, 6 had parkinsonism; 4 of these had typical Parkinson's disease (PD), 1 had vascular and 1 had drug-induced parkinsonism. Among the remaining 4 patients, 2 had restless legs syndrome (RLS), 1 had tardive dyskinesia, and 1 orofacial dyskinesias of uncertain etiology. One patient with PD and the patient with vascular parkinsonism also had RLS. Age at onset was significantly earlier in the "primary OT" (mean +/- SD, 50.4 +/- 15.1) than in the "OT plus" (61.8 +/- 6.4; z = 2.7; P =.006) group. In 7 of the 10 "OT plus" patients, OT leg symptoms preceded the onset of additional neurological features. OT appeared to be underdiagnosed, and on average, it took 5.7 years from the initial complaints until a diagnosis was made. In general, treatment response to a variety of drugs such as clonazepam, primidone, and levodopa was poor. In most cases, OT symptoms remain relatively unchanged over the years, but in 6 of 41 cases (15%), the condition gradually worsened over the years, and in some of these cases, symptoms spread proximally to involve the trunk and arms. OT may not be a discrete disorder as commonly believed and associated features like parkinsonism present in nearly 25% of cases. Dopaminergic dysfunction may have a role in the pathophysiology of this disorder.     

Is essential tremor predominantly a kinetic or a postural tremor? A clinical and electrophysiological study

Both postural and kinetic tremors may occur in essential tremor (ET), however the relative contribution of each is not clear. ET has been variably defined with respect to kinetic and postural tremors. To examine the relative severity of postural and kinetic tremors in ET, 50 ET cases from a clinic and 55 from a community underwent a videotaped tremor examination. Kinetic and postural tremors were rated using a validated clinical rating scale (score range, 0-3). Thirty-one cases also underwent accelerometry to precisely quantify tremor amplitude. In clinic cases, the mean postural tremor rating was 1.25 (S.D., 0.89). The mean kinetic tremor rating was 52% higher (1.90; S.D., 0.57; P < 0.001). The community cases had similar characteristics. Sixty percent of the 105 cases had postural tremor ratings scoring 0 or 1 (no tremor or low amplitude, intermittent tremor). In clinic cases, the mean amplitude of postural tremor during tremor analysis was 0.51 mm (S.D., 0.66 mm), and the mean amplitude of kinetic tremor was 2.91 mm (S.D., 2.11 mm; P < 0.01). Similar values were obtained for community cases. These quantitative data suggest that kinetic tremor is more severe than postural tremor in ET. The majority of cases had mild or absent postural tremor. Despite this, ET is defined only as a postural tremor in many studies. Our data argue for a more consistent inclusion of kinetic tremor in diagnostic criteria for ET.     

Coupling between limb tremor and postural sway in Parkinson's disease

Increased tremor and postural instability are motor problems commonly associated with Parkinson's disease (PD). Despite the similarity between these oscillatory forms, little is known about the relation between them, especially for individuals with enhanced tremor. This study was designed to examine the nature of any relation between center of pressure (COP) excursions and postural/resting limb tremor of young, older individuals, and Parkinsonian participants in their different medication states. The resting and postural tremor for the PD participants was characterized by a single, prominent peak frequency between 4 and 7 Hz. The postural tremor for young/older participants contained smaller peaks between 1 to 4 and 7 to 12 Hz although no prominent peak was seen in their resting tremor. The AP and ML COP dynamics of all participants was characterized by a major peak between 0.1 and 0.5 Hz. An additional peak was observed in the COP output of the PD participants between 4 and 7 Hz. While no tremor‐COP coupling was observed for the young/old groups, coherence analysis revealed a significant degree of coupling between COP motion and tremor between 4 and 7 Hz for PD participants. These results highlight that the amplified tremor in PD can manifest itself in COP dynamics. This finding may have implications for postural stability for this patient group. © 2007 Movement Disorder Society     

Primary orthostatic tremor associated with a persistent cerebrospinal fluid monoclonal IgG band.

Primary orthostatic tremor is of unknown aetiology and is believed to be a distinct entity rather than a subtype of essential tremor. We describe the first patient with a typical phenotype of primary orthostatic tremor who has a persistent isolated monoclonal immunoglobulin G band in the cerebrospinal fluid.     

Orthostatic tremor during modification of standing.

Primary orthostatic tremor (OT) occurs only during standing. We studied whether modification of the condition standing influences OT. In seven patients with OT, surface EMG was recorded from both tibialis anterior and gastrocnemius muscles during two maneuvers: relief, whereby the patient was gradually lifted by a crane, and tilting, whereby the patient was tilted by a tilting table to positions of 90 degrees (upright standing), 45 degrees (diagonal position), and 0 degrees (lying position). We determined the parameters tremor frequency, tremor intensity, coherence, and phase shift between the different muscles. Relief did not influence OT. In contrast, tilting modified significantly tremor intensity and phase shifts; tremor frequencies and coherences were not influenced. We chose both these maneuvers because of their different impact on the standing condition: relief modifies the factors afferent input and muscle forcing but not the factor postural set, whereas tilting modifies all three factors. The fact that tilting modifies OT, whereas relief does not, suggests an important role of postural set in OT generation. Afferent input and muscle forcing seem to play less important role.     

Corticomuscular coherence is increased in the small postural tremor of Parkinson's disease.

The mechanisms and electrophysiological characteristics of the postural tremor in Parkinson's disease (PD) have not been defined. We hypothesized that PD subjects with small amplitude postural tremor would show increased corticomuscular coherence at certain frequencies compared to PD subjects without visible tremor. Four groups of participants were studied: (1) Control without postural tremor, (2) Control with small amplitude postural tremor, (3) PD without postural tremor, and (4) PD with small amplitude postural tremor. Accelerometry and electroencephalography-electromyography fast-fourier transform and corticomuscular coherence spectra were generated. Findings showed (1) elevated corticomuscular coherence centered at 12-18 Hz in PD with small amplitude postural tremor; (2) 5-12 Hz accelerometer frequency peaks that did not shift with increasing weight loads in some individuals; and (3) 5-8 Hz accelerometer peaks that shifted frequency with increasing weight loads, consistent with a peripheral-mechanical oscillator in all groups. The small amplitude postural tremor in PD arises from heterogeneous oscillator mechanisms. The discovery of increased corticomuscular coupling shows cortical involvement in the small amplitude postural tremor of PD.     

Vascular responses to orthostatic stress in patients with postural tachycardia syndrome (POTS), in patients with low orthostatic tolerance, and in asymptomatic controls

Patients with postural tachycardia syndrome (POTS) are characterized by development of symptoms of orthostatic intolerance during standing that are not because of hypotension but are associated with tachycardia. The goal of this study was to compare the cardiac and vascular responses to orthostatic stress for patients with POTS (n=8) with those for patients with low orthostatic tolerance (n=29) and for healthy control subjects (n=12). Responses of heart rate (ECG), arterial blood pressure, and brachial artery blood velocity (Doppler) were determined during a progressive orthostatic stress test of head-up tilt and lower body suction. Changes in forearm vascular resistance (mean arterial pressure/brachial velocity) were less for patients with POTS than for healthy persons, and also less than for most of the patients with low orthostatic tolerance. However, patients with POTS did not have a low tolerance to orthostatic stress (measured as time to discontinuation of the test). For the patients with POTS, the test was discontinued often because of symptoms associated with tachycardia but not hypotension, whereas for the other two groups, the test was discontinued because of hypotension. This study shows that for patients with POTS, abnormal sympathetic responses exist, with an increased sympathetic drive to the heart but deficient peripheral vascular responses, as measured in the forearm. This supports the hypothesis that patients with POTS may have a selective peripheral neuropathy, with small responses in some regions being compensated by overactivity in other regions.     

Primary orthostatic tremor is an exaggeration of a physiological response to instability.

Primary orthostatic tremor (POT) is a rare disorder characterised by an intense sense of unsteadiness upon standing and a 16-Hz tremor in which the timing between tremor bursts in different muscles (unilateral and bilateral) remains constant. Hitherto, similar EMG activity has not been described in healthy subjects and it has been postulated that the oscillations seen in POT are primarily pathological. In this study, EMG was recorded from tibialis anterior in healthy subjects who were made unsteady through vestibular galvanic stimulation or leaning backwards. Under these conditions, a peak at approximately 16 Hz was seen in the coherence between the left and right tibialis anterior. This bilateral coherence was absent when the subjects activated the same muscles when not unsteady. These data indicate the existence of a physiological system involved in organising postural responses under circumstances of imbalance and characterised by a highly synchronised output at approximately 16 Hz. In addition, the results suggest that the core abnormality in POT may be an exaggerated sense of unsteadiness when standing still, which then elicits activity from a 16-Hz oscillator normally engaged in postural responses.