Habituation After Deep Brain Stimulation in Tremor Syndromes: Prevalence, Risk Factors and Long-Term Outcomes

Abstract

Deep brain stimulation (DBS) of the thalamus is an effective treatment for medically refractory essential, dystonic and Parkinson's tremor. It may also provide benefit in less common tremor syndromes including, post-traumatic, cerebellar, Holmes, neuropathic and orthostatic tremor. The long-term benefit of DBS in essential and dystonic tremor (ET/DT) often wanes over time, a phenomena referred to as stimulation “tolerance” or “habituation”. While habituation is generally accepted to exist, it remains controversial. Attempts to quantify habituation have revealed conflicting reports. Placebo effects, loss of micro-lesional effect, disease related progression, suboptimal stimulation and stimulation related side-effects may all contribute to the loss of sustained long-term therapeutic effect. Habituation often presents as substantial loss of initial DBS benefit occurring as early as a few months after initial stimulation; a complex and feared issue when faced in the setting of optimal electrode placement. Simply increasing stimulation current tends only to propagate tremor severity and induce stimulation related side effects. The report by Paschen and colleagues of worsening tremor scores in the “On” vs. “Off” stimulation state over time, even after accounting for “rebound” tremor, supports the concept of habituation. However, these findings have not been consistent across all studies. Chronic high intensity stimulation has been hypothesized to induce detrimental plastic effects on tremor networks, with some lines of evidence that DT and ET may be more susceptible than Parkinson's tremor to habituation. However, Tsuboi and colleague's recent longitudinal follow-up in dystonic and “pure” essential tremor suggests otherwise. Alternatively, post-mortem findings support a biological adaption to stimulation. The prevalence and etiology of habituation is still not fully understood and management remains difficult. A recent study reported that alternating thalamic stimulation parameters at weekly intervals provided improved stability of tremor control consistent with reduced habituation. In this article the available evidence for habituation after DBS for tremor syndromes is reviewed; including its prevalence, time-course, possible mechanisms; along with expected long-term outcomes for tremor and factors that may assist in predicting, preventing and managing habituation.

Unravelling delayed therapy escape after thalamic deep brain stimulation for essential tremor? – Additional clinical and neuroimaging evidence

“…There is an ongoing scientific debate on the mechanisms involved in delayed therapy escape after Vim DBS mostly focusing on disease progression versus habituation ( Fasano and Helmich, 2019 , Favilla et al, 2012 , Peters and Tisch, 2021 ). We here add a further possibility, namely a direct effect of long term DBS.…”

“…In general, comparability of studies is limited due to their focus on selected aspects of the phenomenon, which moreover lacks a consensus definition ( Fasano and Helmich, 2019 ; cf. Patel et al, 2014 , Peters and Tisch, 2021 ). Fasano and Helmich (2019) defined this phenomenon as “therapy escape” and coined a consistent nomenclature of associated processes.…”

Rescue procedure for isolated dystonia after the secondary failure of globus pallidus internus deep brain stimulation

“…Another reason worth considering is habituation. The term “habituation,” previously known as “tolerance,” is referred to as the vanishing of DBS efficacy despite reprogramming that could not be explained by loss of micro-lesional implant effect or disease progression ( Fasano and Helmich, 2019 ; Peters and Tisch, 2021 ). It is mostly reported in cases of essential tremor cases, but the phenomenon has also been described in dystonia patients receiving GPi DBS ( Shah and Jimenez Shahed, 2014 ).…”

“…Previous studies have shown that GPi-DBS could normalize excessive cortical plasticity and is one of the fundamental factors for its effect ( Tisch et al, 2007 ; Ruge et al, 2011a ; Barow et al, 2014 ). However, it has been suggested that habituation may also be generated from neural reorganization ( Dostrovsky and Lozano, 2002 ; Ruge et al, 2011a; Peters and Tisch , 2021 ). And theoretically, it should be noted that STN DBS may also induce habituation.…”

“…Disease progression can also contribute to the decline of DBS efficacy. However, it is difficult to distinguish natural disease progression from habituation ( Ruge et al, 2011a; Peters and Tisch , 2021 ). The emergence of new symptoms may be an indicator of disease deterioration.…”