Shaking on Standing: A Critical Review

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Authors: Roberto Erro MD, Kailash P. Bhatia FRCP and Carla Cordivari MD

Article first published online: 12 JUN 2014 | DOI: 10.1002/mdc3.12053


 

In 1970, Pazzaglia et al. described 3 patients with an unusual movement disorder characterized by tremor of the legs, which started with a short latency when they stood and increased to such an extent that patients were unable to stand still.[1] Tremor disappeared when patients were sitting on lying down and there was no additional neurological sign.[1] In 1984, Heilman described a further 3 patients with a similar condition and coined, for the first time, the term “orthostatic tremor” (OT).[2] Since then, the term OT has been widely used in the medical literature, even though it has been referred as “shaky legs syndrome” by other researchers.[3]

Over time, the electrophysiological characteristics of OT have been described and it is generally accepted that classic OT manifests with a high-frequency tremor (>13 Hz) of the legs when standing.[4] However, a number of patients initially reported as having OT (based on the subjective feeling of shaking or unsteadiness on standing) did not actually have such a high-frequency tremor, and this has likely created some confusion in the medical literature. Moreover, a new condition termed “orthostatic myoclonus” (OM) has been recently described.[5] These patients can be clinically indistinguishable from OT patients. There is therefore a clinical spectrum of different conditions presenting as shaking on standing, and this highlights the importance of the electrophysiology to aid the differential diagnosis of these disorders. In the following sections, we provide a current overview of the clinical spectrum of “shaking on standing.” It would appear that current knowledge in this regard is still far from complete and we suggest that the only criterion, which allows a distinction—even though not definitive—between these disorders, is an elctrophysiological one (Table 1).

Table 1. Overview of the main conditions associated with shaking on standing, classified according to the electrophysiological features
  Electrophysiological Features Additional Features
Primary orthostatic tremor
  1. 13- to 18-Hz tremor of the legs upon standing;
  2. Tremor is highly coherent between homologous muscles of right and left leg.
Some patients may have 6- to 7-Hz postural tremor of the arms.
Secondary orthostatic tremor/OT-plus 13- to 18-Hz tremor of the legs upon standing, which can be highly coherent between homologous muscles of right and left leg There is either clinical or imaging evidence of another neurological condition.
Pseudo-orthostatic tremor Tremor of the legs upon standing is below 13 Hz (with low coherence values between homologous muscles of right and left leg) Usually, if not invariably, associated with another neurological condition
Orthostatic myoclonus Irregular bursts (usually of 50–60 ms in duration) of myoclonus of the legs upon standing. Frequency can range from 6 to 18 Hz It can be isolated or associated with another neurological condition.
 

Orthostatic Tremor

OT is considered rare, but (1) it is probably underdiagnosed and (2) there are no available epidemiologic data. One Spanish epidemiologic study has found 1 OT case of 4,000 elderly subjects (unpublished data).[6] The evidence that OT can be associated with or the result of several conditions has led to the broad distinction of patients in two groups: those affected with primary OT (POT) and those affected with secondary OT (SOT) and/or “OT plus.”

Primary OT

POT is supposed to be sporadic, apart from a very few reports of familial cases.[7-9] Women seem to be predominantly affected (sex ratio: 2:1) with disease onset occurring in the sixth decade.

Clinically, POT is associated with an intense and disabling sense of unsteadiness and a fear of falling, which is abolished by sitting, walking, or the use of a support. Besides unsteadiness, patients often complain of a weakness of the legs when standing, and only a few report a tremor. Unsteadiness may lead to stasibasiphobia and patients usually develop strategies through leaning on a support or walking, even if the condition can be progressive and lead to high disability, being that falls are rarely encountered in the course of the disease.[10] On examination, there is not much to see. In fact, such a high-frequency tremor may only be visible as a fine-amplitude rippling of the leg muscles, palpable as a thrill, and heard by muscle auscultation as a thudding sound, similar to that of a distant helicopter.[11, 12] However, in the largest series reported to date, 24 of 31 POT patients (77.4%) had also an associated postural arm tremor[13] and this has been further confirmed.[10] Alcohol benefit is occasionally noted, whereas a majority of these patients may respond, at least partially, to clonazepam.[13] Gabapentin has been proven to improve both tremor and quality of life in a controlled study,[14] whereas levetiracetam,[15] primidone,[13] and botulinum toxin injections into the tibialis anterior muscle[16] failed. However, there are no long-term follow-up studies on OT, and therefore whether or not treatment responses are sustained is unknown.

The first electrophysiological description of POT dates back to 1986 when Thompson et al. described 1 such patient, noting a fast 16-Hz tremor of the legs when standing, which was not influenced by peripheral feedback.[17] The fast frequency (13–18 Hz) of POT has been subsequently confirmed[18-20] and represents the electrophysiological hallmark of the condition (Fig. 1A). Another distinctive feature is that the tremor is highly synchronous in homologous muscles of the two legs (Fig. 1B).[21] These characteristics are in contrast to all other tremulous disorders, including essential tremor (ET), where tremor frequency very rarely exceeds 10 Hz and usually shows low coherence values in homologous muscles of the right and left side. However, as mentioned before, many of the published POT patients show a postural arm tremor,[13] which usually occurs at lower frequency (5–10 Hz) and this has led to the speculation that POT is a variant of ET. Nevertheless, the results of coherence and bispectral analyses suggest that the lower-frequency postural arm tremor, and similar lower-frequency components in the legs, may be a subharmonic of the high-frequency OT observed in the legs and hence not generated independently.[10, 22] Overall, there are a number of clinical and electrophysiological differences between POT and ET to arguably consider them as distinct disorders.[21, 23-25]

Figure 1. (A) EMG recording showing high-frequency tremor of legs muscles on standing. (B) Coherence analysis between the right and left tibialis anterior muscles, disclosing a tremor peak at 17 Hz (R-RF, right rectus femoris muscle; L-RF, left rectus femoris muscle; R-TA, right tibialis anterior muscle; L-TA, left tibialis anterior muscle).


Because of the highly coherent oscillations throughout the body, a central origin of OT has been suggested.[21, 26] However, the pathophysiological underpinnings of OT are not yet clear. Evidence from SOT cases has led to the notion of a contribution from either the posterior fossa[25] or the spinal cord.[27] The focus has subsequently shifted to supratentorial areas, namely, to the thalamocortical loop, mainly because of the suggestion that high-frequency stimulation of the ventrolateral thalamus can be effective in POT.[28, 29] However, the involvement of thalamus in OT has been recently questioned,[30] and, in fact, thalamic stimulation in POT is far less effective than in ET or other types of tremor.

Involvement of the dopaminergic system has been suggested on the basis of a significant, although modest, reduction of dopamine transporter binding, as measured with 123I-FP-CIT single-photon emission CT.[31] Those patients did not have any neurological sign apart from OT and had a normal olfactory function, supporting the idea that they did not have Parkinson's disease (PD).[31] However, evidence of dopaminergic deficits has not been found in other imaging studies.[32-34] Moreover, there was no follow-up on the patients reported by Katzenschlager et al., and it is unknown whether they further developed frank PD. It has been, in fact, speculated that OT might herald the onset of PD,[33] and the two conditions can be frequently associated (see below).[13]

Regardless of where the tremor generator is, most of the researchers believe that OT is primarily pathological and itself leads to a sense of unsteadiness.[35, 36] On the other hand, Sharott et al. speculated on the existence of a physiological system involved in organizing postural responses under circumstances of imbalance.[37] Such a system would be characterized by a highly synchronized output at approximately 16 Hz. Their findings 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.[37]

OT Plus/Secondary OT

In the previously mentioned article by Gerschlager et al., 10 of 41 patients (24.4%) with an electrophysiological-confirmed OT had additional neurological features and therefore were defined as having “OT plus.”[13] To avoid confusion in the literature, we thought it reasonable to consider in the same rubric “OT plus” and SOT patients. PD is the most common condition associated with SOT.[13] Besides PD, it should be noted that the spectrum of neurological syndromes associated with OT is remarkably heterogeneous and includes progressive supranuclear palsy, dementia with Lewy bodies, ET, task-specific focal dystonia, tardive dyskinesia, restless leg syndrome, SPG31, and stiff-person syndrome.[13, 38-40] Moreover, OT has been reported in patients with pontine and pontocerebellar angle lesions,[41] cerebellar degeneration,[42] hydrocephalus,[20] and with spinal lesions.[27] Although the co-occurrence by chance of these conditions with OT seems to be unlikely, the true association between them remains speculative. From time to time, these reports have provided arguments to postulate on the generator of OT, but, as mentioned above, there is not yet a conclusive model to explain the pathophysiology of OT, with regard of both primary and secondary cases. Electrophysiologically, patients with SOT are indistinguishable from those with POT, and therefore the diagnostic workup should be pursued according to the (additional) clinical features. Treatment with benzodiazepine and other drugs seems to be ineffective.[13, 38] A good response to levodopa (with regard of the OT) has been reported in some, but not all, SOT patients with PD.

Pseudo-Orthostatic Tremor

A number of patients who complain about shaky legs upon standing do not have the electrophysiological features of OT and have been differently termed as having “slow orthostatic tremor,” “pseudo-orthostatic tremor,” or “tremor in orthostatism.”[43-46] We advocate defining these patients as having pseudo-orthostatic tremor (psOT) to remark on the neurophysiological and etiological differences with POT. In fact, in our view, patients with psOT do not represent a variant of POT and psOT would not exist as a primary entity. Most, if not all, cases with psOT reported to date had another neurological disorder responsible for the psOT, including PD,[43] parkin-related PD,[44] POLG1-related parkinsonism,[45] and SCA3.[46] Interestingly, all SCA3 patients with psOT further developed parkinsonism at follow-up and improved on l-dopa therapy.[46] This would suggest a dopaminergic involvement in the pathophysiology of psOT. Worthy of note, an autoimmune etiology has been proposed in a few other cases of psOT. It has been, in fact, described as a manifestation of Grave's syndrome,[47] anti-Hu antibody (Ab) paraneoplastic syndrome,[48] and in a patient with a novel antineuronal Ab (binding extracellular epitopes on rat hippocampal neurons in vitro), who responded dramatically to intravenous immunoglobulin treatment.[49]

Besides this evidence, a couple of patients with psOT at approximately 10 Hz have been reported on, who were supposed to be primary in origin.[50, 51] However, in 1 patient, the clinical description and diagnostic workup was minimal to exclude a secondary origin of the tremor,[50] whereas in the other, the electrophysiological testing was limited in the way that tremor recording was not performed in homologous leg muscles and without using accelerometers.[51] A diagnosis of ET in the latter patient cannot therefore be entirely dismissed. Wee et al. described 1 patient with a 6- to 7-Hz tremor of the legs upon standing as recorded by an accelerometer, although the electromyographic (EMG) recording revealed 15- to 16-Hz activity.[52] The evidence that ET patients may have a slow “static postural tremor” of the legs has been confirmed by others.[17, 53] As mentioned before, it is our belief that POT and ET are different disorders and therefore the inclusion of “slow OT” cases in the POT group has little merit. Hence, the presence of a slow tremor of the legs upon standing (<13 Hz; Fig. 2) should alert clinicians to look for another disorder responsible for psOT. It is likely that psOT is much more common in clinical practice than currently thought or reported in the literature, given that PD and ET are two very common disorders.

Figure 2. Slow (3- to 4-Hz) tremor of the legs on standing (R-RF, right rectus femoris muscle; L-FR, left rectus femoris muscle).



Orthostatic Myoclonus

A new syndrome termed OM has been recently described.[5] Glass et al. reported on a total of 15 patients with unsteadiness on standing, whose electrophsyological recording disclosed irregular myoclonic EMG bursts with a median duration of 38 to 62 ms and a median frequency of 6 to 12 Hz.[5] Synchrony of the bursts was highly variable between patients (19%–72% of bursts) and could be observed between muscles of the same or opposite limbs and in agonist/antagonist muscle pairs.[5] Though all patients had such myoclonic activities of legs muscles upon standing, approximately half also had action myoclonus of outstretched upper or lower limbs.[5] Similar electrophysiological features have been further confirmed by Leu-Semenescu et al. in 3 PD patients, whose mycolonic frequency ranged between 9.5 and 15 Hz.[54] Interestingly, OM has been subsequently found to be the most frequent cause of unsteadiness on standing among 93 elderly subjects studied (17.2%), followed by OT (13.9%) and psOT (12.9%).[55] It is our experience that OM frequency can exceed 15 Hz (Fig. 3A) and that coherence values between homologous muscles in the right and left legs are not significant (Fig. 3B).

Figure 3. (A) EEE-EMG recording showing irregular, high-frequency (14- to 17-Hz) bursts of myoclonus in the legs when standing (RVM, right vastus medialis muscle; RTA, right tibialias anterior muscle; RGastro, right gastrocnemius muscle). (B) Nonsignificant coherence analysis between the right and left homologous leg muscles. (C) EEG-EMG back averaging shows a cortical correlate of the myoclonic jerks (C4 references).

OM can present isolated from any identifiable neurological disease (and therefore is supposed to be idiopathic) or in association with a different number of neurological or systemic conditions, including atypical parkinsonism, Alzheimer's disease, mild cognitive impairment, normal pressure hydrocephalus, cerebral amyloid angiopathy, systemic necrotizing vasculitis, and chronic renal failure.[5, 55] As to the EMG characteristics, patients with idiopathic or symptomatic OM are indistinguishable. However, jerk-locked back-averaging EEG may show a cortical correlate preceding the myoclonic jerks (Fig. 3C) in a minority of these patients. Distinction as to whether myoclonus is cortical or not in origin can have crucial consequences in terms of management. In general terms, treatment of myoclonus is often challenging and polypharmacy is commonly adopted to achieve reasonable benefit. In cortical myoclonus, levetiracetam and piracetam are recommended as initial therapy, given their demonstrated effectiveness and relatively favorable side-effect profile.[56] Brivaracetam is one of the new derivatives of levetiracetam, which has been shown to be more potent than levetiracetam in an animal model of posthypoxic myoclonus.[56] Valproic acid has been proven effective in cortical myoclonus, usually at doses between 1,200 and 2,000 mg/day, even if it can very rarely worsen the myoclonus.[53] Moreover, clonazepam is a useful adjunct to treatment by levetiracetam or valproic acid, even though it occasionally works as a monotherapy.[56] Zonisamide and primidone can be useful as add-on therapy.[56] In patients with subcortical OM, response to antimyoclonic treatments seem to be poor even if the samples described are very little to draw definitive conclusions. Clonazepam should be considered the initial choice in these patients.[53] The figure by Gasca-Salas et al. suggests that OM is very likely underdiagnosed[55] and further clinical series would be needed to assess its progression and response to treatment.

Other Mimics

There are a number of other conditions that should be considered in the differential diagnosis when facing a patient complaining of shaking on standing. Apart from the patients described to have OM, action myoclonus of the legs upon standing (and usually also when walking) has been associated with tryciclic antidepressants and antipsychotic drugs.[57-61] In our experience, we also have encountered a case of myoclonus of the legs upon standing, but not when walking, as a result of clozapine (unpublished case). Remarkably, the EMG recording disclosed positive myoclonic bursts as well as negative lapses of postural tone (negative myoclonus; Fig. 4). A combination of positive myoclonic jerks and negative lapses can be also present in patients with postanoxic myoclonus, who usually have also a peculiar walking, referred as to bouncy gait, and less frequently in patients with hepatic encephalopathy. Isolated “whole-body tremulousness” resulting from generalized polymyolconus has also been described as a clinical entity associated with several etiologies, including paraneoplastic, autoimmune resulting from voltage-gated potassium channel antibodies, and drug induced (most commonly with serotonin reuptake inhibitors).[62] In the original series reported on by McKeon et al., 14 of 19 patients had stance and gait impairment.[62] In general terms, both positive and negative jerks of the legs resulting from myoclonus are clinically detectable (in contrast to what is observed in POT) and more frequently lead to recurrent falls.

Figure 4. Orthostatic myoclonus on standing; negative myoclonus is indicated by red arrows. R-Bic, right biceps muscle; R-ECR, right extensor carpi radlialis muscle; R-FDIO, right first dorsalis interossei muscles; R-VM, right vastus medialis muscle; R-TA, right tibialis anterior muscle; R-Ga, right gastrocnemius muscle.



Moreover, we have also encountered some patients with familial cortical myoclonic tremor with epilepsy (FCMTE) with shaking of the legs when standing. However, tremor in these patients is almost invariably present also in the upper limbs and worsens on action or posture. Moreover, there is usually an autosomal-dominant familial history for either tremor or seizures. Finally, there are often EEG abnormalities, including paroxysmal polyspike and wave activity with a marked photosensitivity, which can help the differential diagnosis.[63] We would also advise including in the differential diagnosis a psychogenic movement disorder, because we have encountered at least a couple of patients complaining of shaking on standing who turned out to be psychogenic. In both, tapping on standing with one foot stopped or entrained the tremor in the other leg. Finally, cerebellar ataxia, multiple sclerosis, and pyramidal trait dysfunction with marked clonus can also produce shaking of the legs and lead to unsteadiness upon standing, but history, examination, and imaging will usually distinguish these conditions.

Conclusions

In summary, there are a number of conditions that can present with shaking on standing. This highlights the need and importance of a rational workup. As mentioned before, it is usually possible to discriminate between patients with OT and OM, because there are usually associated features in the latter group and most commonly these patients fall. However, the differential diagnosis may be challenging in single cases. We would therefore advocate that the electrophysiology is crucial. Initially, it is important to judge whether the abnormal movement disorder upon standing represents in fact tremor or myoclonus. In the first instance, it would be crucial to discriminate between fast (>13 Hz) and slow (<13 Hz) tremor and also whether those patients having fast tremor have POT or SOT. Patients with POT are more likely to benefit from treatment with clonazepam than patients with SOT or psOT, who instead show a less homogenous response to treatment. In both SOT and psOT patients, treatment should be pursued empirically and some of them (especially those with PD) can respond reasonable well to l-dopa treatment. If electrophysiology discloses myoclonus, then it is crucial to establish whether or not it is cortical in origin. Patients with cortical myoclonus can, in fact, benefit from antiepileptics drugs, whereas those with subcortical myoclonus are more likely to respond to clonazepam. If electrophysiological recoding disclosed neither tremor nor myoclonus, then other mimics should be considered and detailed history, examination, and ancillary investigations will usually distinguish these conditions.

 

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