Electromyography is a simple and relatively inexpensive technique that can be very useful to support or establish a correct diagnosis (Benaderette et al., 2006). Figure 2 gives an example of an EMG recording in a patient with cortical tremor and a patient with ET.

Tremor frequency determined by EMG can be a discriminator when differentiating ET from PD. Both disorders show an overlap in frequency distributions, particularly in the 5.5–6 Hz range. A tremor frequency below 5.5 Hz suggests PD; a tremor frequency above 6 Hz suggests ET (Burne and Boljevac, 2002). A prospective study by Gironell posed a set of six neurophysiological criteria for ET which give a sensitivity of 97.7%, a specificity of 82.3%, a positive predictive value of 95.1% and a negative predictive value of 91.1% (Gironell et al., 2004), these criteria are summarized in Table 6. With these criteria, postural tremor in ET could successfully be distinguished from postural tremor in PD. Furthermore, in ET, agonist and antagonist muscles usually show synchronous activity, while in contrast, tremor in PD is often caused by alternating contraction of agonist and antagonist muscles (Nistico et al., 2011). Compared to ET, enhanced physiological tremor typically shows a higher frequency and shorter burst duration (Milanov, 2001). Milanov (2001) found cerebellar tremor to have a frequency around 9 Hz during posture and action, decreasing to 6 Hz upon intention. This contradicts with the frequency range stated by the Movement Disorders Society, which addresses cerebellar tremor as mainly intentional tremor below 5 Hz (Deuschl et al., 1998). In the study by Milanov et al., differentiating cerebellar and enhanced physiological tremor with solely EMG is challenging. The frequency of cerebellar tremor is generally lower than enhanced physiological tremor, but more importantly, the bursts are better defined in cerebellar tremor. Usually, the maximum amplitude in cerebellar tremor occurs during intentional movements, while in enhanced physiological tremor, intention tremor is rarely seen (Milanov, 2001).

Distinguishing between ET and dystonic tremor can be difficult. Compared to ET, patients with cervical dystonia and limb tremor showed greater tremor irregularity (up to 50% more) measured by cycle-to-cycle variability (Shaikh et al., 2008).

When orthostatic tremor is suspected, EMG is necessary to confirm the diagnosis, and shows a typical high-frequency (13–18 Hz) EMG pattern which appears after a short period of standing (orthostatism, Figure 3; Yague et al., 2012). Additionally, EMG signals in orthostatic tremor are highly coherent between left and right legs, with coherency values of up to 0.99. These high coherency values are rarely seen in other tremor disorders (Lauk et al., 1999).

Several tremor disorders show a change in frequency and/or amplitude upon loading of the stretched limb. In psychogenic tremor, an increase in amplitude during loading of the limb can be used to support the diagnosis, but its absence should not be used to exclude psychogenic tremor (an increase in amplitude of 130% gives a specificity 92% and a sensitivity of 33%; Schwingenschuh et al., 2011). ET is characterized by a tremor frequency not susceptible to changes upon loading, because of a fixed central oscillating mechanism. One of the proposed ET neurophysiological criteria by Gironell et al. (2004) is that the dominant frequency peak may not decrease by more than 1 Hz after loading. In enhanced physiologic tremor, the tremor frequency peak decreases with more than 1 Hz or a second tremor frequency peak at a lower frequency appears upon loading (Deuschl et al., 2001). No study on specificity and sensitivity for differentiating these patient groups is published. Elble (2003), however, found 8% of the healthy population to have an EMG pattern that is indistinguishable from mild ET.

Schwingenschuh et al. propose a set of EMG and accelerometry markers to be able to establish a positive diagnosis of psychogenic tremor, instead of a diagnosis of exclusion. A score of 3 or more suggests psychogenic tremor. Markers included “incorrect tapping performance at 1, 3, and 5 Hz (maximum three points), entrainment, suppression, or pathological frequency shift at 1, 3, and 5 Hz (maximum three points), pause or 50% reduction in amplitude of tremor with ballistic movements (one point), tonic co-activation before tremor onset (one point), coherence of bilateral tremors (one point), and increase of tremor amplitude with loading (one point)” (Schwingenschuh et al., 2011).

Electromyography in familial cortical tremor is used to confirm that the tremor is actually myoclonus, and shows periodic, irregular muscle bursts with a short burst duration of about 50 ms (van Rootselaar et al., 2005). In the case of suspected neuropathic tremor, nerve conduction studies should be performed with the help of EMG (Bain, 2007).

Using 10-h long continuous EMG recordings, Breit et al. developed a mathematical equation, based on mean tremor frequency, tremor occurrence (percentage of segments, in which tremor occurred), and phase (cross-spectral analysis of extensor and flexor EMG signals) to be able to differentiate ET from PD (Eq. 1).

Positive values of F predict the diagnosis of PD whereas negative values predict the diagnosis of ET. This equation was applied on 13 patients in early stages of the disease, and yielded a 100% fit between diagnosis predicted by long-term EMG and the diagnoses inferred by SPECT imaging (Breit et al., 2008).

Little is published on the diagnostic value of coherence analysis in differentiating tremor syndromes. Simultaneous EMG-EEG can be used to look for cortico-muscular coherences at the tremor frequency. Hellwig et al. (2001) found cortico-muscular coherences at the tremor frequency in five out of nine arms in patients with essential tremor and were unable to find this coherence in patients with enhanced physiological tremor. Van Rootselaar et al. used coherence analysis to differentiate cortical tremor from essential tremor. In a group of patients with “Familial Cortical Myoclonic Tremor with Epilepsy” patients, a strong cortico- and intermuscular coherence in the 8- to 30-Hz range was shown with EEG preceding EMG, this coherence was not found in essential tremor and healthy controls (van Rootselaar et al., 2006).

Patients with cortical tremor, presenting with tremulous movements, sometimes resembling ET, and with or without a (family) history of epilepsy, can show a so-called “giant potential” upon median nerve stimulation during a somatosensory evoked potential measurement (Okuma et al., 1997; van Rootselaar et al., 2002). A giant potential is in line with cortical hyperexcitability and a sign of cortical myoclonus.

[¹²³I]-FP-CIT single photon emission computerized tomography, also called (DAT-) SPECT imaging or FP-CIT-SPECT imaging, can be used to assess nigrostriatal denervation, a sign of PD (Benamer et al., 2000). Vlaar et al. (2007) performed a meta-analysis on the diagnostic accuracy of SPECT imaging in parkinsonian syndromes. They found SPECT imaging with presynaptic tracers (such as ¹²³I-ioflupane) to be highly accurate to differentiate between PD and ET (sensitivity 80–100%, specificity 80–100%). One study showing lowest specificity included not only patients with ET, but also patients with isolated postural tremor and postural tremor in combination with rest tremor (Lee et al., 1999). In a more recent study, Coria et al. also used SPECT to differentiate ET and PD. Only patients with an isolated action tremor were included, without resting tremor, bradykinesia, or other hypokinetic parkinsonian symptoms. They found reduced striatal uptake in 68.3% of included patients. The odds ratio of finding reduced striatal uptake was increased three times for patients aged over 50, and increased five times for patients with an asymmetrical action tremor (Coria et al., 2012). However, there are also studies that found reduced striatal uptake in ET compared to controls, but less severely then PD (Isaias et al., 2008). None of these ET patients had clinical signs of PD, which makes the clinical use of these findings questionable. In another study comparing SPECT scans in parkinsonian syndromes with non-parkinsonian syndromes, three patients with atypical asymmetrical postural tremor, initially diagnosed with ET and a fourth patient with a 6-month history of gait ataxia, slight bradykinesia and rigidity, cerebellar tremor, and frequent falls, initially diagnosed with cerebellar tremor had an abnormal SPECT scan. Their diagnosis was altered in subsequently PD and multiple system atrophy. They concluded that SPECT studies may act as an adjunct to diagnosis (Bairactaris et al., 2009). One study looked at nine patients referred with suspected psychogenic parkinsonism. SPECT imaging in this study was successful in differentiating pure psychogenic parkinsonism from psychogenic parkinsonism plus PD, and supported the diagnosis of underlying PD in five of nine patients (Benaderette et al., 2006).

An Italian cost-effectiveness study showed that using SPECT imaging for differentiating unclear cases of ET from PD is cost-effective because of decreasing time on potentially beneficial treatment at a lower overall cost (Antonini et al., 2008). The United Kingdom National Institute for Health and Clinical Excellence guideline also suggests the use of SPECT imaging in patients with tremor where ET cannot be clinically differentiated from PD (Stewart, 2007). SPECT could be used to avoid the costs of treating people who do not suffer from PD. However, they also advise not to use SPECT in all people with PD in place of initial clinical examination.

In the last decade, SPECT imaging has been used as a surrogate marker for disease progression. An unexpected consequence of this was that around 10% of patients, who initially fulfilled the clinical diagnostic criteria of PD, had normal nigrostriatal uptake (Whone et al., 2003). These patients have been referred to as “SWEDDs” (Scans Without Evidence of Dopaminergic Deficit). A study comparing clinical and neurophysiological characteristics of SWEDDs with PD and other tremor disorders by Schwingenschuh et al. suggested that these patients share characteristics with adult-onset dystonic tremor. Furthermore, these SWEDDs patients did not show true bradykinesia (with fatiguing and decrement) and did not respond to levodopa treatment (Schwingenschuh et al., 2010).

Many patients with PD respond to a single dose of levodopa, and therefore this test is regularly used in clinical practice to differentiate ET from PD. Using levodopa response as a diagnostic test has so far only been studied for differentiating parkinsonian syndromes. One systematic review that included studies with de novo PD and well-established PD found acute levodopa treatment (125–275 mg) to have a positive predictive value of 0.69 (95% CI 0.59 to 0.90; Clarke and Davies, 2000). The acute levodopa challenge consisted of a standard dose of 275 mg levodopa plus decarboxylase inhibitor. Most challenges were performed during a day admission after domperidone pre-treatment. Response to chronic levodopa treatment gave a positive predictive value of 0.76 (95% CI 0.70 to 0.82). A chronic levodopa treatment consisted of a maximum dose of 1000 mg with a duration of treatment varying from 1 to 6 months (Clarke and Davies, 2000). However, this has not been assessed for differentiating ET from PD. Also, the effect of a levodopa trial on tremor has not been assessed separately.

Transcranial sonography can detect increased midbrain echogenicity (Berg et al., 2005). In a study by Bartova, sensitivity and specificity for transcranial sonography in patients with PD, parkinsonian syndromes, ET, and psychogenic movement disorders were evaluated. Transcranial sonography and SPECT findings correlated in 84% of patients (sensitivity 89.7%, specificity 60% for transcranial sonography, sensitivity 96.6%, specificity 70% for SPECT imaging; Bartova et al., 2012). In this study, the diagnostic accuracy of transcranial sonography was comparable to the more expensive SPECT imaging. Gaenslen et al. (2008) found a sensitivity of 90.7% and a specificity of 82.4%. Berg et al. performed a 5-year follow up study of PD cases after transcranial sonography. They found no significant changes in sonography findings across time. It is suggested that the presence of midbrain hyperechogenicity is a trait rather than a state marker for susceptibility to PD (Berg et al., 2005). In a study by Berg et al. (1999), 90% of PD patients exhibited midbrain hyperechogenicity and 8.6% of the healthy population exhibited the same ultrasound signal, associated in more than 60% with a functional deficit of the nigrostriatal system as detected by 18 F-labeled dopa positron emission tomography (PET) examinations. Transcranial sonography, although being much less expensive compared to SPECT imaging, requires high expertise and is to a certain extent, examiner-dependent. Moreover results need to be further investigated. For these reasons, its clinical use remains a subject of debate. However, in settings were SPECT imaging is not available, transcranial sonography can prove to be useful in unclear cases were PD is suspected and where an experienced investigator is available.

Hyperintensities on T2 MRI in the region of the basal ganglia can be seen in Wilson disease. According to the American Association for the Study of Liver Diseases: “MRI should be considered in Wilson disease prior to treatment in all patients with neurological symptoms and be part of the evaluation of any patient presenting with neurological symptoms consistent with Wilson disease” (Roberts and Schilsky, 2008).

Fragile X-associated tremor/ataxia syndrome in symptomatic males shows a characteristic pattern of MRI findings. This pattern includes increased T2 signal intensity in the middle cerebellar peduncle and deep white matter of the cerebellum medial, superior, and inferior to the dentate nuclei (Brunberg et al., 2002).

In patients with spinocerebellar ataxia, three patterns of damage can be seen on conventional MRI: spinal atrophy, olivopontocerebellar atrophy, and cortical cerebellar atrophy (Mascalchi, 2008). There is even a correlation between the specific pattern of changes on the MRI and different diseases underlying the spinocerebellar ataxia (Mascalchi, 2008).

In Holmes’ tremor, data on the relevance of MRI are sparse. In a case series of 10 patients, the structural lesion was due to hemorrhage in six patients and due to cerebral ischemia in four patients. The thalamus was lesioned in five cases, in other cases, involvement of the midbrain tegmentum, superior cerebellar peduncle, substantia nigra, pons, rubro-olivocerebello-rubral loop, rubro-spinal fibers and nigrostriatal fibers was seen (Gajos et al., 2010).

Olfactory dysfunction is found in about 80% of PD cases, regardless of disease stage or duration (Doty et al., 1988; Double et al., 2003). In a study comparing olfactory function of PD with ET using the University of Pennsylvania Smell Identification Test (UPSIT), the olfactory function of PD was significantly worse compared to ET (Shah et al., 2008). Using a cut-off score of 25, the sensitivity of the UPSIT was 83% and the specificity 94%. Raising the cut-off score to 30, improves the sensitivity to 97%, but reduces specificity (87%). In a study comparing olfactory function in ET with healthy controls, ET patients also showed significantly lower UPSIT scores (UPSIT for ET 29.0 ± 6.1 vs. 31.9 ± 4.6 in controls, p = 0.02), the UPSIT scores were not correlated with tremor severity or duration (Louis et al., 2002). In this study, 27% of ET cases had severe olfactory dysfunction (UPSIT cut-off score of 25), compared to 2.7% of controls. At present, olfactory tests can be helpful in the differentiation between PD and ET, but diagnosis should not rely solely on olfactory function. Therefore the clinical relevance of this test remains debatable.