Upper limb tremor

Several features of Robert’s condition are typical of parkinsonian tremor. This type of tremor is characteristically asymmetric and most evident at rest but may also persist (albeit usually at lesser amplitude) when the affected limb is elevated against gravity. Parkinsonian tremor typically diminishes or disappears during limb movement, such as a finger-to-nose test, or on changing posture; it then reappears after a short interval (re-emergent tremor). It is thus known as a rest, postural and re-emergent tremor. Parkinsonian tremor is characteristically evident in the affected arm during walking. An asymmetric rest tremor and good response to levodopa are the most specific diagnostic features of pathologically proven PD, although about 30% of patients with PD do not have tremor at presentation. Patients without tremor usually present with symptoms of bradykinesia.

By contrast, the tremor of ET affects both upper limbs more or less symmetrically and is a postural and action (kinetic) tremor — present when the limb is elevated against gravity and during movement, and absent or diminishing at rest. While the tremor of ET can be asymmetric, it is not unilateral, as is typically the case in early PD. Tremor of the head and voice are common in ET but not in PD; in PD, lip, chin or tongue tremor may be seen.

The distinction between PD and ET is not always straightforward. Patients with the tremor-dominant subtype of PD, which has a coarse resting tremor, are often misdiagnosed as having ET. In tremor-dominant PD, the clinical course is benign; there is little motor disability, rigidity or bradykinesia, and the tremor is relatively unresponsive to levodopa (depriving the clinician of one of the key features that aids accurate diagnosis). Diagnosis of PD is aided by clinical features additional to those described above, such as the presence of facial hypomimia or asymmetric arm swing when walking.

Another cause of upper limb tremor, which is less common than PD and ET, is adult-onset dystonic tremor. As in PD, dystonic tremor may be unilateral or asymmetric, and may occur at rest, during certain postures and during action. Helpful pointers to a diagnosis of dystonic tremor are position specificity or task specificity and other dystonic features such as abnormal posturing of the affected limb. Also, patients with dystonic tremor lack other features of PD, such as decremental bradykinesia, hyposmia and rapid-eye-movement sleep behaviour disorder (RBD).1,2

Clinicians should enquire about symptoms of bradykinesia affecting the limbs, such as difficulty with repetitive or rotatory movements (eg, brushing teeth, washing hair) and with fine, coordinated movements (eg, handwriting, doing up buttons). It is also useful to ask about symptoms suggesting disordered axial movements, such as difficulty rising from a chair, getting out of a car or turning over in bed. These symptoms strongly suggest a parkinsonian disorder. In addition to tremor, the core clinical diagnostic features on examination include reduced spontaneous facial movement and blinking, giving a staring expression. Muscle tone is increased in the limbs and trunk. Bradykinesia is evident as a decrement in the amplitude of repetitive finger-tapping movements. A hypokinetic gait with short steps and reduced arm swing on the affected side may also be seen. Resting tremor may reappear in the affected upper limb during walking.

Certain red flags in the patient history and examination (Box 3) should raise doubt about the diagnosis of PD and suggest an alternative diagnosis such as multiple system atrophy or progressive supranuclear palsy (Box 4). The presence of such red flags should prompt referral to a neurologist for further assessment and investigation.

Non-motor symptoms are important for diagnosing a patient with tremor. It is common for non-motor symptoms — including constipation, sexual dysfunction, RBD, hyposmia, depression and anxiety — to predate the motor symptoms of PD. They may also constitute an important cause of disability in their own right.

RBD is characterised by the loss of normal muscle atonia during rapid-eye-movement sleep, causing the patient to “act out” dreams, which can lead to movements that injure the patient and their bed partner. At least 40% of patients with idiopathic RBD develop a neurodegenerative disorder at a mean interval of 11–12 years after onset of RBD.4,5 This is most commonly PD, multiple system atrophy or dementia with Lewy bodies (synucleinopathies).

All dopaminergic medications can cause dose-dependent nausea, postural hypotension, delirium and drowsiness. These are more common with dopamine agonists than with levodopa and limit the dose that can be used.

Recently, attention has been focused on the behavioural disturbances that occur in up to 15% of patients with PD who are treated with high doses of dopaminergic medications.19,20 The most common are impulse-control disorders, which include pathological gambling, hypersexuality, compulsive buying and binge eating. The risk of these is increased in patients treated with dopamine agonists, either alone or in combination with levodopa.

Punding is a striking complication of dopaminergic therapy. It refers to the performance of repetitive and purposeless motor behaviour, such as collecting and rearranging objects and dismantling and reassembling equipment. Over-indulgence in hobbies — including internet use for excessive periods and at the expense of sleep, meals and other daily activities — also constitutes a form of punding. The incidence of punding in patients with PD is unclear, but it is thought to be less common than impulse-control disorders.19 Patients who begin dopaminergic therapy (especially dopamine agonist therapy) should be warned about the risk of impulsive and compulsive behaviour, and both they and their families should be asked to report any evidence of such behaviour.

Another complication of dopaminergic therapy is dopamine dysregulation syndrome (DDS), which refers to the habitual use of dopaminergic medications at doses in excess of those prescribed and necessary for the treatment of motor symptoms. It appears to be less common than impulse-control disorders, occurring in about 4% of patients treated for PD.19 In patients with DDS, medication use seems to be dictated more by the mood elevation caused by medication and a desire to avoid the dysphoric effects of declining medication levels in “off” periods (ie, periods when PD symptoms are not adequately controlled) rather than by motor function.

Where possible, non-ergot dopamine agonists (eg, pramipexole, rotigotine) should be prescribed in preference to ergot agents (eg, bromocriptine, pergolide, cabergoline), because of the small risk of fibrotic reactions (eg, pleuropulmonary, retroperitoneal and cardiac valve fibrosis) associated with the latter.

Options for continuous dopaminergic stimulation are apomorphine infusion and levodopa–carbidopa enteral gel infusion. Apomorphine infusion produces a substantial reduction in daily off time and a reduction in severity of dyskinesias (grade C evidence).21 Reduction in dyskinesias is particularly marked in patients for whom levodopa therapy is reduced or ceased.21 In one study, 70% of patients with PD who were commenced on apomorphine infusion were able to have other dopaminergic medications withdrawn and be managed with apomorphine monotherapy long term.21 However, another study reported a much lower rate (3%) of achieving apomorphine monotherapy and a discontinuation rate of 40% (due, in many cases, to adverse effects such as skin reactions, sedation and confusion).22

Infusion of levodopa–carbidopa intestinal gel directly into the jejunum produces more stable plasma levodopa levels than intermittent oral dosing.23 Intestinal levodopa infusion also leads to a significant reduction in off time, with either stable or reduced levels of dyskinesia (grade B evidence).24 Levodopa–carbidopa intestinal gel infusion is commenced in the inpatient setting, with a nasoduodenal tube, and the infusion rate is titrated according to therapeutic need. When the optimal motor response is achieved, a percutaneous gastrostomy tube with an inner jejunal tube is inserted for ongoing infusion. Patients receiving apomorphine and intestinal levodopa–carbidopa infusion need to be managed in a specialist PD clinic by an experienced multidisciplinary team, including a specialist PD nurse.

Deep brain stimulation of either the subthalamic nucleus or globus pallidus interna has an established role in the management of PD. Patients who have an excellent motor benefit from levodopa, but who have developed motor fluctuations and dyskinesias from long-term use of levodopa, are good candidates for deep brain stimulation, as are those with tremor that is refractory to medication. Deep brain stimulation produces a significant reduction in off time and substantially

reduces

The benefits of deep brain stimulation in reducing tremor, off time, motor fluctuation and dyskinesia persist at up to 10 years of follow-up.26,27 However, there is some decline in objective measures of motor function with time. This decline appears to be due primarily to progression in domains of motor function that are not responsive to deep brain stimulation, such as freezing of gait in the on-medication state, postural instability and falls.26-28

Careful patient selection is critical to the success of deep brain stimulation. Patients with significant mood disorders or cognitive dysfunction do poorly. Severe postural instability, falls and freezing of gait in the on-medication state are not typically alleviated following deep brain stimulation and may in fact be made worse.28 Improvement in quality of life following deep brain stimulation is significantly greater in patients who are younger than 65 years compared with older patients, despite a similar motor benefit.29 This seems to be due to the greater incidence in older patients of cognitive dysfunction, postural instability and gait dysfunction.29 These problems are not reduced following deep brain stimulation and are major contributors to poor quality of life.