Orthostatic tremor as possible presenting sign of progressive supranuclear palsy

Highlights

• •Orthostatic tremor plus syndromes can be a presenting sign of movement disorders. We suggest remaining vigilant for other extrapyramidal symptoms during OT follow-up.
• •Orthostatic tremor is often difficult to treat but can sometimes respond to bilateral thalamic deep brain stimulation (DBS).
• •Diagnosis of PSP can be a challenge during the first years and MRI changes often only become apparent in later stages.

Primary orthostatic tremor is a generalized high frequency (13–18 Hz) isolated tremor syndrome that occurs when standing. Confirmation of the tremor frequency is needed, typically with an electromyography (EMG) [1]. Deuschl describes it as a 13- to 18-Hz tremor in weight-bearing limbs, manifesting as a sensation of instability during standing that attenuates on leaning against an object and disappears on sitting or walking [2].

A classification has been suggested dividing OT into primary OT or OT-plus when associated neurological features are present [3]. The presence of additional neurological features and disorders, such as Parkinson’s disease, vascular parkinsonism, progressive supranuclear palsy (PSP), diffuse Lewy body disease (DLBD) and restless legs syndrome (RLS), have been reported in 25–30 % of OT patients [3], [4].

We present a case of orthostatic tremor as a possible presenting sign of progressive supranuclear palsy (PSP) and provide a short review of literature.

A 73-year-old male presented to our outpatient clinic with postural upper limb tremor for more than 20 years. The last few months he also noticed tremor in his legs during stance. There was a medical history of restless legs syndrome (RLS).

On clinical examination there was a fine action tremor of the hands and a clearly palpable orthostatic tremor of the legs. He did not report any falls or feelings of imbalance. A few months later the tremor also became clinically visible while standing. Gait was slightly impaired due to tremor but there was no gait nor limb ataxia. There was a mild hypokinesia of the hands, especially the left hand. We also noticed some hypomimia. Brain MRI (magnetic resonance imaging) (Fig. 1A) and a [¹²³I]-FP-CIT SPECT (dopamine transporter single-photon emission computed tomography) showed no abnormalities.

Fig. 1.

Sagittal T1-weighted image of a brain MRI performed shortly after the first patient visit shows a normal brainstem without mesencephalic atrophy (A). MRI performed three years later shows mesencephalic atrophy, giving rise to the so-called “hummingbird sign” (B).

Neurophysiological assessment with bilateral surface electromyography of vastus lateralis and tibialis anterior muscles in standing position showed a regular and synchronous 14 Hz tremor. Tremor activity in these both lower limb muscles was absent in sitting position. When the patient was standing and leaning forward on a table with his both arms, a regular and high-frequency synchronous 14 Hz tremor was bilaterally recorded in flexor carpi radialis and extensor carpi radialis muscles.

The following medication was used, all with limited effect or troublesome adverse effects: propranolol, gabapentin, topiramate, primidone, ropinirole, levodopa and clonazepam.

The tremor gradually worsened and impaired stance for longer than a second. It eventually also impaired gait with trembling of the knees when turning, resembling freezing and there were occasional falls. A repeat [¹²³I]-FP-CIT SPECT was again unremarkable. Because of the severe impact of the tremor on his quality of life, we proceeded to bilateral thalamic VIM (ventral intermediate nucleus) deep brain stimulation (DBS).

A few months after surgery, our patient could stand still with his knees extended for several minutes and his gait had markedly improved. Tremor in both hands and legs improved markedly and he reported no more falls. However, there was still some slight balance impairment. Another few months later, he gradually developed increasing balance and gait problems with freezing and daily falls. A (subjective) good response on the orthostatic and action tremor remained, however.

Although freezing is an uncommon side effect of thalamic DBS, this was our first hypothesis. Different stimulation parameters were tried without marked improvement. After DBS was turned off for several days, the clinical picture remained unchanged.

Eventually we performed a new brain MRI which showed a correct placement of both electrodes. However, mesencephalic atrophy and a hummingbird sign were visualized (Fig. 1B). In the following months, the clinical picture became more obvious with the presence of primitive reflexes, axial rigidity, hypometric vertical and horizontal saccades and an upward gaze palsy. A clinical diagnosis of possible PSP with progressive gait freezing (PSP-PGF) was made 4 years after initial presentation, based on the 2017 MDS criteria [5]. At the time of writing our patient is 79y old and the clinical picture has further evolved to both an upward and downward gaze palsy, fulfilling the MDS criteria of probable PSP. His gait has remained stable. On clinical examination we can now also observe the procerus sign and a glabellar tap sign.

Our patient presented with a 14 Hz OT and was classified as an OT-plus syndrome because of the presence of RLS, which is one of the more common movement disorders associated with OT [3], [4]. The initial balance problems were attributed to the invalidating OT, however frequent falls are not typical for OT [6]. After DBS placement, freezing became more evident and a final clinical diagnosis of PSP could be made 4 years after presentation.

To our knowledge, only one other case of OT in PSP has been reported so far. [7] Presence of OT in idiopathic PD is seemingly more common. [8].

Response to dopaminergic medication in primary OT has been reported in a few cases but levodopa does not seem to alleviate OT symptoms in patients with associated parkinsonism [4], [7], [8], as in our case, which suggests a different underlying pathophysiological process.

Many similarities between our case and the previously published case of de Bie et al. [7] exist. There is a similar delay between OT symptoms and PSP symptoms (4 vs. 3 years), both had pre-existent RLS, associated postural arm tremor and a lack of response to levodopa.

The relationship between OT and PSP in our case is uncertain. Mestre et al. suggest that, because of the delayed onset between OT and parkinsonian symptoms, one should consider chance association. [4] However, in our case and the case report of de Bie this delay is much shorter, which makes a pathophysiological association more likely. We should also consider that OT is generally underdiagnosed which may lead to an underestimation of the number of PSP cases with associated OT.

There are still many uncertainties about the pathophysiology of OT and whether dopaminergic systems are involved. Further research on OT in PSP and other parkinsonian syndromes could help gain insight in this matter.

With this case report we want to raise awareness on OT-plus syndromes, and we suggest remaining vigilant for other extrapyramidal symptoms during OT follow-up, especially when other movement disorders such as RLS are already present.

Disclosures

Funding Sources and Conflict of Interest

No specific funding was received for this work.

Financial Disclosures for the previous 12 months

The authors declare that there are no additional disclosures to report.”

Ethical Compliance Statement

Written informed patient consent was obtained We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.