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 One Spanish epidemiologic study has found 1 OT case of 4,000 elderly subjects (unpublished data). 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.”
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. 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 and this has been further confirmed. Alcohol benefit is occasionally noted, whereas a majority of these patients may respond, at least partially, to clonazepam. Gabapentin has been proven to improve both tremor and quality of life in a controlled study, whereas levetiracetam, primidone, and botulinum toxin injections into the tibialis anterior muscle 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. 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). 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, 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 or the spinal cord. 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, 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. 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). 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, and the two conditions can be frequently associated (see below).
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. 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.
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.” 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. 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, cerebellar degeneration, hydrocephalus, and with spinal lesions. 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.