Originales

M. Serrano-Dueas

Clonidine versus propranolol in the treatment of essential tremor. A double-blind trial with a one-year follow-up
Neurological Service Carlos Andrade Marn Hospital Quito (Ecuador)

Introduction: To compare the efficacy of clonidine vs propranolol in the control of essential tremor, a double-blind randomized controlled trial with a one year follow-up was designed to obtain 80 % power and 95 % confidence level. Patients and methods: The participants (186 patients with the essential tremor diagnosis) were recruited from the community, 122 (65.6 %) of these patients completed the trial. They were assessed using a Clinical-Evaluation Scale for Tremor and were examined 5 times, once at baseline and 4 times during the treatment phase. We used ANOVA with Bonferroni corrections, a p value of < 0.01 was considered significant. Dropouts due to side effects were compared using the Fishers exact X (2) test for two tails, a p value of < 0.05 was considered statistically significant. Results: Propranolol as well as clonidine (p = 0.005) proved to be statistically efficacious (p = 0.0005). Propranolol was not more efficacious than clonidine (p = 0.4). Dropouts were significantly higher in the clonidine group, 22 patients (p = 0.006) and the most common undesirable side effect in this group was mouth dryness (in 8 patients). Conclusions: Clonidine was useful; when both drugs were compared propranolol was not shown to be superior to clonidine. Based on the results of this study, clonidine appears to be a good option for the treatment of mild to moderate essential tremor.
Key words: Essential tremor. Clonidine. Propranolol. 2 receptors.

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Neurologa 2003;18(5):248-254

mediante un ensayo controlado doble ciego con un ao de seguimiento, diseado para obtener un poder del 80 % y un nivel de confianza del 95 %. Pacientes y mtodos: Los participantes fueron 186 pacientes reclutados de la comunidad, 122 de ellos (65,6 %) completaron el ensayo. Los enfermos fueron valorados utilizando la Escala de Evaluacin Clnica para el Temblor y fueron examinados 5 veces, la evaluacin basal y otras 4 durante la fase de tratamiento. Se realiz el anlisis estadstico con ANOVA y correcciones de Bonferroni para comparaciones mltiples, un valor de p < 0,01 fue considerado significativo. Los abandonos debido a efectos indeseables se compararon empleando el test exacto de Fisher para dos colas; un valor de p < 0,05 se consider significativo. Resultados: El propranolol demostr ser estadsticamente eficaz (p = 0,0005), as como la clonidina (p = 0,005). El propranolol no fue superior a la clonidina (p = 0,4). Los abandonos en el grupo de enfermos que emple clonidina fueron estadsticamente significativos, lo hicieron 22 de ellos (p = 0,006) y el efecto indeseable ms comn fue el de boca seca (en 8 pacientes). Conclusiones: La clonidina result til; cuando se compararon ambos frmacos entre s el propranolol no demostr ser superior a la clonidina. Los resultados del estudio indican que la clonidina es una buena opcin para el tratamiento de formas leves y moderadas de temblor esencial.
Palabras clave: Temblor esencial. Clonidina. Propranolol. Receptores 2.

Clonidina frente a propranolol en el tratamiento del temblor esencial. Estudio doble ciego con un ao de seguimiento
Introduccin: Se compara la eficacia de la clonidina frente al propranolol en el control del temblor esencial,
Correspondencia: Marcos Serrano-Dueas P.O. Box: 17-03-1694 Quito (Ecuador) Correo electrnico: serranom@pi.pro.ec Recibido el 2-9-02 Aceptado el 25-11-02

INTRODUCTION
Essential tremor (ET) is the most common involuntary movement disorder seen in adults. World wide prevalence of this disorder ranges from 4.1 to 39.2 per 1,000 inhabitants. This wide variation in prevalence rates is likely attrib-

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Clonidine versus propranolol in the treatment of essential tremor. A double-blind trial with a one-year follow-up

Elegible patients (n = 186)

Randomized (n = 151) Excluded (n = 35) Randomly assigned to propranolol (n = 75) Randomly assigned to clonidine (n = 76)

Completed the study (n = 68), 90 %

Completed the study (n = 54), 71 %

Withdrew prematurely (n = 7), 9.3 % Lack of efficacy (n = 1) Lost to follow-up (n = 3) Received another therapy: cinarizine (n = 1) fluoxetine (n = 1) Death for another causes (n = 1)

Withdrew prematurely (n = 22), 29 % Lack of efficacy (n = 7) Lost to follow-up (n = 6) Adverse events (n = 8) Received another therapy: clnazepam (n = 1)

Figure 1

Double-blind, propranolol-controlled trial of clonidine for treatment of essential tremor.

utable to the different methods used in epidemiological studies1. Thus far, specific causes of this disorder are unknown. Pathophysiological research has not established the existence of causal lesions or putative neurotransmitters. Current theory suggests that a combination of central and peripheral mechanisms may be involved: a) the reflex-arch loop becomes unstable, and b) central circuits are also unstable and begin to oscillate2. Currently, the drugs of choice used in these cases are primidone and, secondarily, propranolol3. Acute adverse reactions after primidone and disabling side effects after chronic use of propranolol may hamper therapy. In addition, some patients with ET may not respond to these drugs. Contradictory results have been published regarding the efficacy of clonidine in ET treatment; some have found it useful, while others have not. These studies have generally had significant study design flaws and small sample sizes. Studies that have demonstrated positive results include an open non-controlled trial in 10 patients4, a series of 25 patients treated with intravenous clonidine5, and an open, non-controlled, acute pharmacological test performed in 37 patients proved effective6. However, a double-blind test including only 10 patients7 failed to find any benefit to treatment. Clonidine, an imidazole derivative, is a selective agonist of -2 receptors, principally the presynaptic and, to a lesser extent, the post-synaptic. This drug generally acts at the lower brainstem level, causing a decrease in noradrenaline (NA) release at the brainstem projections8. Since no periph-

eral 2 receptors exist, the active mechanism is thought to be a modulation of the unstable arch afferents at the spinal level, with a similar effects on the projections of the noradrenergic system (NAs), both thalamic and cortical9,10. In an attempt to establish the efficacy of treatment with clonidine, we conducted a randomised double-blind clinical trial comparing the efficacy of clonidine to that of propranolol in the control of ET. Patients were followed for one year.

PATIENTS, MATERIALS AND METHODS

A one-year prospective randomised double-blind trial was designed to have 80 % power to determine a differential effect between treatment with propranolol versus clonidine at a 95 % confidence level, with propranolol (PG) and clonidine (CG) groups having equal sample sizes. This design required a minimum of 144 patients, 72 in each treatment group. A one year prospective double-blinded trial aiming to achieve an 80 % power, and 95 % confidence interval, propranolol group (PG)/clonidine group (CG), ratio (PG/CG) of 1.0. This required a minimum of 144 patients divided in two groups of 72 each, PG and CG. We accepted 10 and 30 % desertions respectively.

Patients
Patients with dislypidemia, bronchopulmonary disease, type I and II diabetes, coronary heart disease or known hypersensitivity to the study drugs were ineligible to participate in this study.

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M. Serrano-Dueas

Clonidine versus propranolol in the treatment of essential tremor. A double-blind trial with a one-year follow-up

Table 1

Demographic features of the patient population

Propranolol group Total Number Age (years) Tremor duration (years) Ethnicity Mestizo Blacks Previous Yes treatment No 75 66.1 ( 6.5) 3.5 ( 1.8) 60 13 16 57 Males 36 66.4 ( 7.4) 3.5 ( 1.9) 34 6 8 28 Females 39 65.7 ( 5.6) 3.6 ( 1.6) 26 7 8 29 Total 76 66.9 ( 6.6) 3.1 ( 1.6) 63 15 17 61

Clonidine group Males 36 66.4 ( 7.6) 3.3 ( 1.6) 33 9 9 30 Females 40 67.3 ( 5.7) 3 ( 1.6) 30 6 8 31

Mean age and history of tremor standard deviation .

Patients were recruited from the community (in the city of Quito, Ecuador) over a 4-year period through oral and written announcements made during religious services in five churches in the area of a family-care clinic (the DIFA). The announcement: a) invited any person with hand tremors to come to the DIFA for an evaluation, and b) if found eligible for study participation, patients were offered study, treatment and follow-up appointments free of charge at the DIFA. Patients of all races and religions were eligible to participate in the study. A total of 186 patients with the ET diagnosis were enrolled (diagnostic criteria were based on that described by Elble and Koller11: a) intermittent or constant tremor of the hands, head, or voice; b) tremor is of the postural or kinetic variety (a resting component may be seen in advances cases); c) No other neurological abnormalities related to systemic or neurological disease; d) no other medical explanation for tremor (e.g., not taking drugs that cause tremor); e) positive family history of tremor supports the diagnosis; and f) reduction of tremor with alcoholic beverages supports the diagnosis). Corresponding to the second category proposed by Marsden et al.12: benign pathologic essential tremor.

Both clonidine and propranolol were prepared for administration in jars of 90 tablets per month to be taken in sets of three tablets a day (each jar included 21 extra tablets). The maximum dose of propranolol was 240 mg/day; clonidine was given at the rate of 0.45 mg/day. Medication was purchased for use in this study in regular drugstores and DIFA volunteers prepared the monthly doses for patients, keeping both the patient and physicians blind. Before commencement of the trial, the 33 (21.9 %) patients who were already receiving medication, including propranolol in some cases, underwent a 30-day period off all ET drugs. Other long-term medications with no effect on tremor were not discontinued. All patients were given a 1/4tablet starting dose with another 1/4-tablet added every 72 hours, such that it took 33 days to reach the full dosage of three pills a day. Ninety days after reaching full dosage, the first clinical evaluation was conducted. Follow-up evaluations were then conducted every 3 months after first assessment, and a total of 4 evaluations were completed for each patient.

Table 2

Methods
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Of 186 patients who expressed interest in participating in the trial, 35 were excluded because they had arterial hypertension (fig. 1). Thus 151 patients (72 males and 79 females) who were enrolled in the study. We randomly assigned 75 to the PG and 76 to the CG. The 75 patients in the PG had a mean age of 66.1 years and a mean tremor history of 3.5 years, while the mean figures for CG patients were 66.9 years and 3.1 years. One hundred and eighteen of the patients (78.1 %) had received no previous treatment of any kind. The racial differentiation was 81.4 % mestizo and 18.6 % black (table 1).

Variance-comparison results of clinical-rating scale for tremor (ref. 13) (basal compared to the mean of 4 post-treatment variances)
Basal Post-treatment 85.2 99.7 F 2.25 1.19 p (two-tailed) p = 0.0005 p = 0.005

Propranolol group Clonidine group

192 190

p < 0.01 was considered significant.

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M. Serrano-Dueas

Clonidine versus propranolol in the treatment of essential tremor. A double-blind trial with a one-year follow-up

Table 3

Variance-comparison results of clinical-rating scale for tremor (ref. 13) propranolol vs. clonidine (compared to the mean of 4 post-treatment variances)
Variance F
p (two-tailed)

All patients were examined a total of 5 times with a mean interval of 90 days (81 to 97 days) between visits. The patients received telephone calls 7 and 21 days after each visit from volunteer personnel to encourage treatment compliance and remind them of their next appointment. Every examination included blood pressure (BP), heart rate (HR) and respiratory rate (RR) measurements and a questionnaire on undesirable effects related to propranolol or clonidine. Patients were dropped from the study if they missed one visit, had to stop the medication or were subsequently prescribed other drugs that would potentially affect tremor. For the statistical evaluation we used Analysis of Variance (ANOVA) with planned a priori comparisons, searching for adjustment at the descendent level Bonferroni corrections for multiple comparisons14 with a value of 0.05 divided by 4 (number of comparison evaluations). A p- value of < 0.01 was considered statistically significant. The mean variance results from the 4 evaluations during the treatment phase was compared to the basal evaluation for each treatment group (GP and GC) and these results were then compared. Side effects were compared to one another by the 2 test with Yates correction. Dropout due to side effects or poor response was compared using the Fishers exact 2 test for two tails. A p- value of < 0.05 was considered statistically significant. This study protocol was approved by the DIFA management. Informed consent was obtained for all patients participating in the study. In addition, patients underwent cardiac and haematological evaluations for eligibility.

Propranolol Clonidine

85.2 1.17 99.7

p = 0.4

p < 0.01 was considered significant.

Patients were assessed using the Clinical-Evaluation Scale for Tremor designed by Fahn et al.13. This scale has three parts (A, B and C), which yield partial scores that can be analysed together or separately. Part A, with a maximum score of 80, quantifies tremor at rest, with a posture and with action/intention for nine body parts: face, tongue, voice, head, each upper limbs, each lower limbs and trunk. Part B, with a maximum score of 36, evaluates action tremor in upper limbs while writing, drawing and pouring liquids. Part C, with a maximum score of 28, involves functional disturbances due to tremor in 7 different areas. The scale also includes an examiners global estimation (EGE) and the patients global estimation (PGE) the scoring form allows assessment of overall severity by both the patient and the examiner and subjective general assessment (SPA) this subjective global severity is based on the assessment of tremor-related disability, which is calculated according to the percent of impairment in carrying out all activities of daily living. EGE, PGE, SPA were not included in our analysis.

RESULTS
One hundred and twenty-two patients completed the trial. A total of 29 patients (19.2 %) failed to complete the

Table 4

Percentage of undesirable effects in patients completing the trial

Dryness of mouth Sleepiness Hypotension Fatigue Body coldness Melancholy-apathy Loss of balance-dizziness

26.47 33.82 57.35 26.47 42.64 36.76 27.94

74.07 55.55 14.81 12.96 12.96 9.25 50

25.47 4.93 21.24 2.59 11.36 10.84 5.33

# # * * * #

0.0000004 0.02 0.000004 0.1 0.0007 0.0009 0.02

p < 0.05 is significant; clonidine = #; propranolol = *.

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Propranolol group 68 patients

Clonidine group 54 patients

p value (Yates correction)

p=

M. Serrano-Dueas

Clonidine versus propranolol in the treatment of essential tremor. A double-blind trial with a one-year follow-up

Table 5

Variance-comparison results of systolic blood pressure (sBP) and diastolic (dBP); heart rate (HR) and respiratory rate (RR). Propranolol vs. clonidine (compared to the mean of 4 post-treatment variances)
Basal 3 months 120.3 (10.5) 125.5 (8) 79.2 (7.6) 82.4 (6.9) 70.3 (3.4) 72.8 (2.6) 15.1 (1.6) 15.1 (0.9) 6 months 120.6 (9.1) 123.7 (6.9) 78.3 (7.1) 81.5 (4.7) 68.4 (4.5) 73.4 (2.6) 15.02 (1.2) 15.1 (1.09) 9 months 117.3 (6.4) 120.4 (5.2) 72.8 (4.5) 76.7 (5.2) 62.7 (2.7) 72.8 (2.5) 15.1 (1.1) 14.9 (1.1) 12 months 110.1 (6.5) 115.7 (4.06) 67.05 (2.7) 77.4 (2.7) 61.5 (2.7) 72.2 (1.6) 15.02 (1.2) 14.9 (1.07) Variance 69.8 39.01 34.6 26.8 11.9 5.38 1.41 1.14 F p (two-tailed) =

Propranolol group Clonidine group Propranolol group Clonidine group Propranolol group Clonidine group Propranolol group Clonidine group

sBP dBP HR RR

127.4 (8.9) 126.9 (8.3) 84 (6.5) 83.8 (5.8) 72.9 (2.7) 72.9 (2.6) 15.1 (1.1) 15.1 (1.1)

1.79 1.29 2.06 1.24

0.001 0.2 0.002 0.3

p < 0.01 was considered significant.

trial, 7 patients (9.3 %) from the PG treatment group and 22 (29 %) from the CG treatment group. Three of the dropouts in the PG treatment group were due to poor response; one missed a control visit; one took cinarizine after entry into the study; one was given fluoxetine after entry into the study, and one patient died of a massive hemorrhagic stroke. In the CG treatment group, dropouts were due to undesirable effects (8 patients); missed visits6; poor drug response7, and commencement of clonazepam treatment1.

Statistical analysis comparing baseline variance to the mean variances obtained during treatment phase demonstrated significant efficacy in the PG treatment group, with a p = 0.0005. In the CG treatment group, the p- value was statistically significant (p = 0.005) (table 2). When we compared the mean PG and CG variances in the post treatment phase, the two-tailed p-value was not statistically significant (p = 0.4) (table 3).

Table 6
Evaluations Propranolol group Mean SD Range Median Variance F p (two-tailed) = Clonidine group Mean SD Range Median Variance F p (two-tailled) =

Variance-comparison results of Clinical-rating scale for tremor (ref. 13) (Basal compared to each of 4 evaluations post treatment)
Basal 3 months 6 months 9 months 12 months

56 (13.8) 13 to 85 59 192

22.6 (9.1) 8 to 44 21 83.3 2.3 0.0004 24.4 (10.9) 9 to 46 25 118 1.61 0.04

17.2 (8.3) 10 to 34 15 70.3 2.73 0.00002 24.5 (9.3) 8 to 45 25 87.4 2.17 0.0009

20.7 (9.8) 8 to 45 21 96.1 2 0.003 28.7 (10) 9 to 47 31 101 2.32 0.0003

19.4 (9.5) 9 to 40 15 91.1 2.11 0.001 29.3 (9.6) 9 to 50 27 92.5 2.05 0.002

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55.9 (13.8) 13 to 79 58.5 190

p < 0.01 was considered significant.

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Clonidine versus propranolol in the treatment of essential tremor. A double-blind trial with a one-year follow-up

Mouth dryness occurred in 74 % of the patients in the CG treatment group, while 26.4 % of the PG treatment group patients had this reaction. Likewise, drowsiness affected a higher percentage in the CG treatment group (55.5 %) than in the PG treatment group (33.8 %). On the other hand, hypotension, body coldness and feelings of sadness-depression were more noticeable in the PG treatment group (table 4). As regards to the BP, HR and RR, we found that in the PG the systolic pressure, descendent in significant value way in comparison to CG (= 0.01), the same thing happened with HR (= 0.002). This didnt happen with diastolic pressure and RR (= 0.2 and 0.3, respectively) (table 5).

to side effects was significantly higher, statistically, in the CG than in the PG. Our results imply that NA is probably one of the neurotransmitters involved in ET11 (NA is elevated in specific brain regions in essential tremor23). Clonidine, by stimulating 2 central receptors, exerts an inhibitory effect on spinal transmission, blocking long-latency reflexes by preventing descendant NAs9; that is, it may modify the peripheral component of ET11,24, while at the same time acting on the same receptors in the brain cortex, mainly at lamellas I and IV, thus reducing spontaneous discharge25. In conclusion, reduction of peripheral (reflex arch) afferents9 and cortical-center discharge levels25 through 2 receptor clonidine action should reduce tremor, modifying abnormally high excitability levels (spontaneous discharge) in the cortex-thalamus-basal ganglia circuits. In ET, rather than a putative central oscillator, there appears to be higher excitability states in different areas26. Based on the results of this study, clonidine appears to be a good option for the treatment of mild to moderate ET. Further research should be done to evaluate this drug as a potential treatment for more severe ET.

DISCUSSION
Some of the limitations of the current study were that: a) patients coming from a public recruitment had mild to moderate ET level (all within second category proposed by Marsden et al12), and our results thus cannot be extrapolated to patients with more severe and incapacitating ET; and b) due to the trials design, it was impossible to adjust doses for each patients response and undesirable effects. For many, the final dosage, both of propranolol and clonidine, may have been too high. A major part of the long-term compliance of the patients was due to stringent and cumbersome telephone follow-up and surveillance. Demographic and clinical findings were similar to those in other community-based epidemiological trials. We should stress that 78.1 % of our study patients had received no treatment for their illness prior to entry into this study, a phenomenon already reported by other authors15. The efficacy of propranolol in ET treatment observed in our study has been previously reported16-19, and the dose we administered is similar to the recommended optimal dose (240-320 mg/day)20,21. Undesirable effects found in the PG were also similar to previously reported rates3. The efficacy of clonidine in this study was significant (= 0.005) (table 6). A comparison of the outcomes for the two drug treatments, propranolol versus clonidine, showed no statistically significant differences (= 0.4). In addition, the difference in the drop out rates due to poor response to drug for the two treatment groups was not statistically significant (= 0.06 by Fishers two-tailed exact test). On comparing undesirable side effects, hypotension, body coldness, apathy and melancholy were found to occur more frequently in the PG treatment group compared to the CG treatment group. This depressant effect of -blockers has been previously recognised22. However, dropout due

ACKNOWLEDGEMENTS

We wish to thank Luisa Prez, Martha Velasco and Clara Estrella for co-ordinating the preparation of the pharmacological material for these trial. In addition, thanks to Brenfi Arvalo, Josefina Chicaiza and Maritza Fiallos from the volunteer group for their valuable help with the telephone follow-up of the patients. Finally to Elizabeth Kelvin for the statistics an editorial assistance.

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Clonidine versus propranolol in the treatment of essential tremor. A double-blind trial with a one-year follow-up

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