revue neurologique 170 (2014) 26–31
Available online at
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Original article
A clinical study of non-parkinsonian tremor in Moroccan patients Profil clinique de patients Marocains atteints de tremblement non parkinsonien W. Regragui a,b,1, L. Lachhab a,*,b,1, R. Razine c, E.H. Ait benhaddou a, A. Benomar a,d, M. Yahyaoui a a
Department of neurology B and neurogenetics, hoˆpital des spe´cialite´s ONO, avenue Mohammed Belarbi El Alaoui, Souissi, BP 6444, Rabat, Morocco b Movement disorders research group, hoˆpital des spe´cialite´s ONO, avenue Mohammed Belarbi El Alaoui, Souissi, BP 6444, Rabat, Morocco c Laboratory of biostatistics, clinical research and epidemiology, faculty of medicine and pharmacy of Rabat, avenue Mohammed Belarbi El Alaoui, Souissi, BP 6203, Rabat, Morocco d Centre de recherche en e´pide´miologie clinique et essais the´rapeutiques, faculty of medicine and pharmacy of Rabat, avenue Mohammed Belarbi El Alaoui, Souissi, BP 6203, Rabat, Morocco
info article
abstract
Article history:
Objective. – To report the characteristics of the most frequent tremors in a population of
Received 3 December 2012
Moroccan patients.
Received in revised form
Background. – Tremor is the most common movement disorder. It implies a wide variety of
11 June 2013
disorders with Parkinson’s disease and essential tremor being the most frequent.
Accepted 12 June 2013
Methods. – A retrospective study of 148 patients with tremor referred to our movement
Available online 7 December 2013
disorders outpatient clinic was performed. Clinical features and treatment regimens were
Keywords:
Results. – We included 62 patients with non-parkinsonian tremor. The etiologies were as
analyzed. Patients with parkinsonian tremor were excluded. Tremor
follows: essential tremor (54.8%), dystonic tremor (19.4%), tremor associated with dystonia
Essential tremor
(14.5%), enhanced physiological tremor (3.2%), cerebellar tremor (3.2%), psychogenic tremor
Dystonic tremor
(3.2%) and Holmes’ tremor (1.6%). The characteristics of essential tremor patients were
Tremor treatment
analyzed. Female patients accounted for 67.6% of patients. Mean age at the onset of tremor
Mots cle´s :
affected the arms (94.1%), head (52.9%), voice (35.3%) and legs (8.8%). Tremor was bilateral in
Tremblement
87.5% but was asymmetrical in 50% of patients. Patients had postural tremor (76.5%), kinetic
was 52.2 16.4 years. Family history of tremor was reported in 17.6% of cases. Tremor
Tremblement essentiel
tremor (79.4%) and rest tremor (associated in 11.8%). Treatment relied on propranolol
Tremblement dystonique
(88.3%), primidone (14.7%), gabapentin (14.7%), clonazepam (14.7%), alprazolam (11.8%), topiramate (5.9%) and, in one patient, radiosurgery.
* Corresponding author. E-mail address: [email protected], [email protected] (L. Lachhab). 1 Both authors contributed equally for this work. 0035-3787/$ – see front matter # 2013 Published by Elsevier Masson SAS. http://dx.doi.org/10.1016/j.neurol.2013.06.006
27
revue neurologique 170 (2014) 26–31
Conclusions. – Essential tremor was the predominant diagnosis, confirming its high prevalence. There was a predominance of female patients and a peak of age at onset in the fifth and sixth decades. Asymmetry of the disease was noted in half of patients. # 2013 Published by Elsevier Masson SAS.
r e´ s u m e´ Objectif. – Rapporter les caracte´ristiques des tremblements les plus fre´quents dans une population marocaine. Introduction. – Le tremblement est le mouvement anormal le plus fre´quent. Il implique une large varie´te´ de troubles dont la maladie de Parkinson et le tremblement essentiel sont les plus fre´quents. Me´thodes. – Une e´tude re´trospective portant sur 148 patients, ayant e´te´ re´fe´re´s a` notre consultation des mouvements anormaux pour tremblement, a e´te´ re´alise´e. Les caracte´ristiques cliniques et le protocole the´rapeutique ont e´te´ analyse´s. Les patients avec tremblement parkinsonien ont e´te´ exclus. Re´sultats. – Nous avons inclus 62 patients pre´sentant un tremblement non parkinsonien. Les e´tiologies e´taient comme suit : le tremblement essentiel (54,8 %), tremblement dystonique (19,4 %), tremblement associe´ a` une dystonie (14,5 %), tremblement physiologique exage´re´ (3,2 %), tremblement ce´re´belleux (3,2 %), tremblement psychoge`ne (3,2 %) et le tremblement de Holmes (1,6 %). Les caracte´ristiques des patients ayant un tremblement essentiel ont e´te´ analyse´es. Les femmes repre´sentaient 67,6 %. L’aˆge moyen au de´but du tremblement e´tait de 52,2 16,4 ans. Les ante´ce´dents familiaux de tremblement ont e´te´ rapporte´s dans 17,6 % des cas. Le tremblement affectait les bras (94,1 %), la teˆte (52,9 %), la voix (35,3 %) et les jambes (8,8 %). Le tremblement e´tait bilate´ral dans 87,5 % des cas, mais e´tait asyme´trique chez 50 % des patients. Les patients pre´sentaient un tremblement d’attitude dans 76,5 % des cas, un tremblement d’action dans 79,4 % des cas et un tremblement de repos e´tait associe´ dans 11,8 % des cas. Le traitement reposait sur le propranolol (88,3 %), primidone (14,7 %), gabapentin (14,7 %), clonazepam (14,7 %), alprazolam (11,8 %), topiramate (5,9 %) et un patient a be´ne´ficie´ de la radiochirurgie. Conclusion. – Le tremblement essentiel e´tait le diagnostic le plus fre´quent confirmant sa haute pre´valence. Il y avait une pre´dominance fe´minine et un pic d’aˆge de de´but des signes a` la cinquie`me et sixie`me de´cade. L’asyme´trie du trouble a e´te´ note´e chez la moitie´ des patients. # 2013 Publie´ par Elsevier Masson SAS.
1.
Introduction
Tremor, the most common form of abnormal involuntary movement, is a rhythmic oscillation of a body region produced by alternating contractions of reciprocally innervated muscles. It occurs across a wide spectrum of neurological disorders and is easily distinguished from other abnormal involuntary movements such as chorea, tics, and myoclonus by its rhythmic, repetitive and stereotypical appearance. Essential tremor (ET) is the most common (Benito-Le´on and Louis, 2006). It has been described as a postural or kinetic tremor that is bilateral and midline, involving the arms, head and/or voice with occasional involvement of legs, chin, and trunk. It is frequently accompanied by a family history of a similar tremor. However, ET is a heterogeneous disorder that has no universally accepted diagnostic criteria and estimates of incidence, prevalence, and family history status vary considerably. Prevalence estimates vary from 0.008% to 22% (Louis et al., 1998). Adding to that, 30–50% of patients with essential tremor are commonly misdiagnosed with Parkinson’s disease or other tremor disorders such as hyperthyroidism, dystonia, or Wilson’s disease (Benito-Le´on and Louis, 2007).
The aims of this study were to determine the distribution of various types of tremor disorders in patients presenting to the movement disorders clinic of university hospital of Rabat and describe the frequency of appearance and clinical characteristics of our patients.
2.
Patients and methods
We conducted a retrospective study of the records of 148 patients with tremor referred to our movement disorders outpatient clinic of university hospital Ibn Sina in Rabat from January 2006 to December 2011. We analyzed the clinical features of tremor and its management. Patients with parkinsonian tremor were excluded from the study. Characteristics of patients were analyzed by a movement disorders specialized neurologist. It included age, gender, family history of tremor, anatomical distribution and symmetry of tremor as well as cerebral MRI and treatment regimen. Consensus Statement of the Movement Disorder society on tremor was used for syndromic classification of tremor
28
revue neurologique 170 (2014) 26–31
(Deuschl et al., 1998). Diagnosis of essential tremor was made in patients having postural or kinetic tremor of the hands and forearms and/or of the head without evidence of dystonia. Diagnosis of dystonic tremor and tremor associated with dystonia were retained respectively in patients presenting tremor in body region affected by dystonia and in a different region. Enhanced physiologic tremor was defined as highfrequency postural and/or kinetic tremor occurring in the absence of any neurologic disease and typically reversible when cause is removed. Cerebellar tremor criteria were predominant intention tremor other cerebellar signs and Holmes’ tremor combined resting and intention tremor associated with parkinsonian and cerebellar features. Psychogenic tremor diagnosis was made in irregular tremor with decreasing amplitude during distraction. Statistical analysis was performed using the SPSS 13.0. All data are presented as mean standard deviation and frequencies. Comparisons were made using Chi2 test and student’s t-test and statistical significance was considered for P < 0.05.
3.
Results
We included 62 patients with non-parkinsonian tremor. The etiologies were as follows: essential tremor: 34 cases (54.8%), dystonic tremor: 12 cases (19.4%), tremor associated with dystonia: 9 cases (14.5%), enhanced physiological tremor: 2 cases (3.2%), cerebellar tremor: 2 cases (3.2%), psychogenic tremor: 2 cases (3.2%) and Holmes’ tremor: 1 case (1.6%). The characteristics of essential tremor patients are detailed in the Table 1. We performed a gender comparison and noted that rest tremor was present only in females and age at onset was 49 years in men versus 53.7 years in women. However, these differences were not statistically significant. In ET patients, first-line treatment relied on propranolol in 26 cases (76.5%), primidone in 5 cases (14.7%), gabapentin in 1 case (3%), clonazepam in 3 cases (8.9%), alprazolam in 2 cases (5.9%), pregabalin in 1 case (3%). Second-line treatment was propranolol in 4 patients (11.8%), gabapentin in 4 patients (11.8%), topiramate in 2 patients (5.9%), clonazepam in 2 patients (5.9%), alprazolam in 2 patients (5.9%). Levodopa was used initially in 1 patient and one patient underwent radiosurgery. The efficacy of propranolol ranged from 20 to 100% and its side-effects included orthostatic hypotension, bradycardia, dizziness, headache, cough, dyspnea and allergy. Concerning primidone, side-effects were sedation, ataxia and vertigo. L Dopa was only used in one patient with rest tremor and there was no response then treatment was switched to propranolol with good clinical improvement. Dystonic tremor was described in 12 patients: 6 with writer’s cramp and 6 with spasmodic torticollis. Seven were females and 5 males. Mean age was 31 13.9 [range 15–50] years and mean age at onset was 25.7 12.8 [range 10–41] years. Tremor associated with dystonia was found in 9 patients of whom 6 males and 3 females. Mean age was 49.2 19.2 [range 21–71] years and mean age at onset was 39.5 16.4 [range 15–57] years. Tremor affected upper limb in all patients and was associated to dystonia of contralateral upper limb (2 patients), oromandibular dystonia (2 patients),
Table 1 – Clinical characteristics of essential tremor patients. n (%) Age (years)a Age at onset (years)
a
Range
59.5 15.3
17–80
52.2 16.4
16–74
Gender Male Female
11 (32.4) 23 (67.6)
Anatomic distribution Upper limbs Head Voice Lower limbs
32 (94.1) 18 (52.9) 12 (35.3) 3 (8.8)
Family history of tremor
6 (17.6)
Tremor characteristics Postural Kinetic Rest Action
26 (76.5) 27 (79.4) 4 (11.8) 7 (20.6)
Tremor symmetry Bilateral symmetrical Bilateral asymmetrical Unilateral
12 (37.5) 16 (50) 4 (12.5)
Treatment Propranolol Primidone Gabapentine Clonazepam Alprazolam Topiramate Pregabaline
30 (88.3) 5 (14.7) 5 (14.7) 5 (14.7) 4 (11.8) 2 (5.9) 1 (3)
n: number of patients. Quantitative variable expressed in mean standard deviation.
a
spasmodic torticollis (2 patients) and blepharospasm (3 patients). Botulinic toxin was used in 3 patients with spasmodic torticollis with good response of dystonia and tremor. Others drugs were used for tremor with good results such as propranolol, alprazolam and clonazepam. Enhanced physiologic tremor was reported in 2 patients who both were under Beta-adrenergic agonists. Psychogenic etiology of tremor was found in 2 patients. Cerebellar tremor was reported in one patient with post trauma cerebellar hematoma in MRI and one patient with hereditary ataxia whose cerebral MRI showed cerebellar atrophy. Holmes’ tremor was noted in one patient who had a cerebellar stroke in the MRI.
4.
Discussion
In our series, the most common diagnoses for tremor were essential tremor, dystonic tremor and tremor associated with dystonia.
4.1.
Essential tremor
Essential tremor was the predominant diagnosis confirming its high prevalence as it is described as the most commonly occurring movement disorder (Pahwa and Lyons, 2003).
revue neurologique 170 (2014) 26–31
In our series, patients were mainly female (67.6%). The gender predominance reported in ET series is controversial as some studies reported female predominance (Tallo´n-Barranco et al., 1997; Hornabrook and Nagurney, 1976; Scaramelli et al., 1996; Haerer et al., 1982) whereas others found male predominance (Larsson and Sjogren, 1960; Critchley, 1972; Rautakorpi et al., 1982) or non-significant difference between the two genders (Koller et al., 1992, 1994; Martinelli et al., 1987; Bain et al., 1994; Lou and Jankovic, 1991). Mean age at onset was 52.2 16.4 years with a peak of age at onset in the fifth and sixth decades. These findings are in line with most ET studies (Whaley et al., 2007). Several peaks of higher frequency of onset have been reported in sixth, seventh and even second decade (Tallo´n-Barranco et al., 1997; Lou and Jankovic, 1991). The early onset of ET was particularly reported in patients with positive family history (Koller et al., 1994; Lou and Jankovic, 1991). In our patients, family history of tremor was reported in 17.6% concurring with the estimates in literature which range from 17% to 100% (Louis and Ottman, 1996) given the differences in methodology and inclusion criteria and the inaccuracy of self reported history. Genetic aspects of ET are not fully elucidated. It is an inherited disease with mainly autosomal dominant transmission, but other patterns of inheritance as well as influence of environmental factors are not excluded. Genetic studies revealed linkage of familial ET in different chromosome locations: 3q13.3 (ETM1, OMIM 190300), 2p25-p22 (ETM2, OMIM 602134) and 6p32 (ETM3, OMIM 611456), but no gene with causative mutations has been reported (Elble and Deuschl, 2011). A genome-wide association study revealed several sequence variants in the LINGO1 gene to be associated with ET, and this was confirmed in independent cohorts. LINGO1 plays a role in neuronal survival, axonal regeneration, and oligodendrocyte maturation in the central nervous system (Radovica et al., 2012). Recently, rare mutations of the fused in sarcoma (FUS) gene were identified in familial ET and are also known to cause two other neurological disorders; amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (Merner et al., 2012). However, the underlying biological mechanisms implicating FUS variants are thought to be different in ALS and ET (Merner et al., 2012). In terms of clinical characteristics of tremor, the most commonly affected body location by tremor was the arms (94.1%) then the head (52.9%), voice (35.3%) and legs (8.8%). This anatomic distribution of the tremor is quite similar to that described in previous studies (Lou and Jankovic, 1991; Whaley et al., 2007; Massey and Paulson, 1985; Findley, 2000) and the characteristic involvement of the hands with head and voice tremor with relative sparing of legs helps in differentiating severe ET from parkinsonian tremor. Tremor was bilateral in 87.5% but was asymmetrical in 50% of patients. Actually, asymmetry is commonly noted in ET and usually tremor is more severe on the nondominant side (Louis et al., 1998). The asymmetry of tremor, as well as initial unilateral onset of tremor, has been considered as predictor of progression (Putzke et al., 2006). Essential tremor is known to produce a mixed postural and kinetic tremor as it was the case in our patients with proportions of respectively 76.5% and 79.4%. However, rest tremor was associated in 11.8% of cases and this statement
29
was frequently reported with rates of 14% and 18.8% (Whaley et al., 2007; Cohen et al., 2003) and attributed to co-morbid Parkinson’s disease or misclassification (Whaley et al., 2007). However, the duration of disease, the absence of bradykinesia and rigidity, and the association of resting tremor with action or postural tremor argue against a diagnosis of concurrent or otherwise Parkinson’s disease (Whaley et al., 2007). Some authors have considered it as a possible late-stage feature of ET and addressed the significance of rest tremor in individuals with ET (Cohen et al., 2003; Rajput et al., 2004). In the study by Cohen et al., rest tremor was associated with disease that was more severe, more disseminated and of longer duration (Cohen et al., 2003). Some of these patients had electrophysiologic features consistent with parkinsonism. DAT scan is a useful tool for differential diagnosis but it is unfortunately unavailable in Morocco. The basis for the rest tremor could be basal ganglia involvement, raising the possibility that the pathologic process responsible for ET may extend to these structures (Cohen et al., 2003). Actually, the main findings concerning the pathology of essential tremor include cerebellar degenerative changes and Lewy bodies in the locus ceruleus (Benito-Le´on and Louis, 2006). Some studies suggest that an olivocerebello-bulbospinal pathway mediates essential tremor and others that thalamocortical pathways may also be involved but they are still controversial (Benito-Le´on and Louis, 2006). Concerning treatment, propranolol and primidone are first-line agents and are effective for 30–70% of patients (Benito-Le´on and Louis, 2007). Efficacy does not differ significantly between the two, although primidone might be more tolerable in the long term than propranolol (Louis, 2001). In our patients, propranolol was the most used medication as primidone is not available in our country. Despite their efficacy on tremor, side-effects limited the use of propranolol and primidone in some patients and imposed changing the treatment. Topiramate, gabapentin, alprazolam and clonazepam were used as second-line treatments with a good clinical response but antitremor effect often came at a dose that is associated with sedation in most patients. In these particular cases of drug intolerance or inefficacy, surgery is often the best option for patients with resistant and disabling hand tremor. Thalamic deep brain stimulation is the surgery of choice that has fewer adverse events than surgical thalamotomy and results in greater functional improvement (Zesiewicz et al., 2005). However, gamma knife thalamotomy is an interesting alternative in case of contraindications for thalamic deep brain stimulation. Several studies have assessed gamma knife thalamotomy and found favorable results (Zesiewicz et al., 2005).
4.2.
Dystonia and tremor
The coexistence of postural and/or kinetic tremor with dystonia is relatively common and is present in 4–55% patients with focal dystonia (Hedera et al., 2010). Tremor is described in patients with focal, segmental or generalized dystonia in both idiopathic and symptomatic dystonia (Ferraz et al., 1994). Dystonic tremor occurs in an extremity or body part which is affected by dystonia. Typical examples are head tremor in torticollis, hand tremor in writer’s cramp and jaw tremor in
30
revue neurologique 170 (2014) 26–31
orofacial dystonias. It is usually focal tremor with irregular amplitudes and variable frequencies (Deuschl, 2003). In dystonic tremor, sensory trick lead to a reduction of the tremor amplitude, which could be a differential diagnostic hint in unclear head tremors in which the dystonic posture is not obvious. Typically, the commonest type of dystonia seen with tremor in previous studies is cervical dystonia and writer cramp (Lou and Jankovic, 1991; Shukla and Behari, 2004; Dubinsky et al., 1993) as it was the case in our series. Tremor associated with dystonia is a more generalized form of tremor in extremities that are not affected by the dystonia. This is relatively symmetrical, postural and kinetic tremor often seen in the upper limbs in patients with spasmodic torticollis. In our patients with tremor associated with dystonia, tremor affected upper limb and was associated with spasmodic torticollis, writer’s cramp, blepharospasm or oromandibular dystonia. Tremor associated with dystonia is more difficult to separate from ET because it remains controversial whether tremor in limbs not affected by dystonia represents ET or a different movement disorder. Another differential diagnosis of tremor associated with dystonia is psychogenic tremor that could be differentiated by the mode of onset, psychogenic cocontraction of the trembling extremity, distractibility and incongruent tremor expression between tasks. In ours series, psychogenic accounted for only 2 patients. Our study confirmed that ET is the most common cause of non-parkinsonian tremor in our Moroccan population and that this diagnosis should be considered whenever postural and/or kinetic tremor is observed predominantly in upper limbs.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
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Available online at
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Original article
A clinical study of non-parkinsonian tremor in Moroccan patients Profil clinique de patients Marocains atteints de tremblement non parkinsonien W. Regragui a,b,1, L. Lachhab a,*,b,1, R. Razine c, E.H. Ait benhaddou a, A. Benomar a,d, M. Yahyaoui a a
Department of neurology B and neurogenetics, hoˆpital des spe´cialite´s ONO, avenue Mohammed Belarbi El Alaoui, Souissi, BP 6444, Rabat, Morocco b Movement disorders research group, hoˆpital des spe´cialite´s ONO, avenue Mohammed Belarbi El Alaoui, Souissi, BP 6444, Rabat, Morocco c Laboratory of biostatistics, clinical research and epidemiology, faculty of medicine and pharmacy of Rabat, avenue Mohammed Belarbi El Alaoui, Souissi, BP 6203, Rabat, Morocco d Centre de recherche en e´pide´miologie clinique et essais the´rapeutiques, faculty of medicine and pharmacy of Rabat, avenue Mohammed Belarbi El Alaoui, Souissi, BP 6203, Rabat, Morocco
info article
abstract
Article history:
Objective. – To report the characteristics of the most frequent tremors in a population of
Received 3 December 2012
Moroccan patients.
Received in revised form
Background. – Tremor is the most common movement disorder. It implies a wide variety of
11 June 2013
disorders with Parkinson’s disease and essential tremor being the most frequent.
Accepted 12 June 2013
Methods. – A retrospective study of 148 patients with tremor referred to our movement
Available online 7 December 2013
disorders outpatient clinic was performed. Clinical features and treatment regimens were
Keywords:
Results. – We included 62 patients with non-parkinsonian tremor. The etiologies were as
analyzed. Patients with parkinsonian tremor were excluded. Tremor
follows: essential tremor (54.8%), dystonic tremor (19.4%), tremor associated with dystonia
Essential tremor
(14.5%), enhanced physiological tremor (3.2%), cerebellar tremor (3.2%), psychogenic tremor
Dystonic tremor
(3.2%) and Holmes’ tremor (1.6%). The characteristics of essential tremor patients were
Tremor treatment
analyzed. Female patients accounted for 67.6% of patients. Mean age at the onset of tremor
Mots cle´s :
affected the arms (94.1%), head (52.9%), voice (35.3%) and legs (8.8%). Tremor was bilateral in
Tremblement
87.5% but was asymmetrical in 50% of patients. Patients had postural tremor (76.5%), kinetic
was 52.2 16.4 years. Family history of tremor was reported in 17.6% of cases. Tremor
Tremblement essentiel
tremor (79.4%) and rest tremor (associated in 11.8%). Treatment relied on propranolol
Tremblement dystonique
(88.3%), primidone (14.7%), gabapentin (14.7%), clonazepam (14.7%), alprazolam (11.8%), topiramate (5.9%) and, in one patient, radiosurgery.
* Corresponding author. E-mail address: [email protected], [email protected] (L. Lachhab). 1 Both authors contributed equally for this work. 0035-3787/$ – see front matter # 2013 Published by Elsevier Masson SAS. http://dx.doi.org/10.1016/j.neurol.2013.06.006
27
revue neurologique 170 (2014) 26–31
Conclusions. – Essential tremor was the predominant diagnosis, confirming its high prevalence. There was a predominance of female patients and a peak of age at onset in the fifth and sixth decades. Asymmetry of the disease was noted in half of patients. # 2013 Published by Elsevier Masson SAS.
r e´ s u m e´ Objectif. – Rapporter les caracte´ristiques des tremblements les plus fre´quents dans une population marocaine. Introduction. – Le tremblement est le mouvement anormal le plus fre´quent. Il implique une large varie´te´ de troubles dont la maladie de Parkinson et le tremblement essentiel sont les plus fre´quents. Me´thodes. – Une e´tude re´trospective portant sur 148 patients, ayant e´te´ re´fe´re´s a` notre consultation des mouvements anormaux pour tremblement, a e´te´ re´alise´e. Les caracte´ristiques cliniques et le protocole the´rapeutique ont e´te´ analyse´s. Les patients avec tremblement parkinsonien ont e´te´ exclus. Re´sultats. – Nous avons inclus 62 patients pre´sentant un tremblement non parkinsonien. Les e´tiologies e´taient comme suit : le tremblement essentiel (54,8 %), tremblement dystonique (19,4 %), tremblement associe´ a` une dystonie (14,5 %), tremblement physiologique exage´re´ (3,2 %), tremblement ce´re´belleux (3,2 %), tremblement psychoge`ne (3,2 %) et le tremblement de Holmes (1,6 %). Les caracte´ristiques des patients ayant un tremblement essentiel ont e´te´ analyse´es. Les femmes repre´sentaient 67,6 %. L’aˆge moyen au de´but du tremblement e´tait de 52,2 16,4 ans. Les ante´ce´dents familiaux de tremblement ont e´te´ rapporte´s dans 17,6 % des cas. Le tremblement affectait les bras (94,1 %), la teˆte (52,9 %), la voix (35,3 %) et les jambes (8,8 %). Le tremblement e´tait bilate´ral dans 87,5 % des cas, mais e´tait asyme´trique chez 50 % des patients. Les patients pre´sentaient un tremblement d’attitude dans 76,5 % des cas, un tremblement d’action dans 79,4 % des cas et un tremblement de repos e´tait associe´ dans 11,8 % des cas. Le traitement reposait sur le propranolol (88,3 %), primidone (14,7 %), gabapentin (14,7 %), clonazepam (14,7 %), alprazolam (11,8 %), topiramate (5,9 %) et un patient a be´ne´ficie´ de la radiochirurgie. Conclusion. – Le tremblement essentiel e´tait le diagnostic le plus fre´quent confirmant sa haute pre´valence. Il y avait une pre´dominance fe´minine et un pic d’aˆge de de´but des signes a` la cinquie`me et sixie`me de´cade. L’asyme´trie du trouble a e´te´ note´e chez la moitie´ des patients. # 2013 Publie´ par Elsevier Masson SAS.
1.
Introduction
Tremor, the most common form of abnormal involuntary movement, is a rhythmic oscillation of a body region produced by alternating contractions of reciprocally innervated muscles. It occurs across a wide spectrum of neurological disorders and is easily distinguished from other abnormal involuntary movements such as chorea, tics, and myoclonus by its rhythmic, repetitive and stereotypical appearance. Essential tremor (ET) is the most common (Benito-Le´on and Louis, 2006). It has been described as a postural or kinetic tremor that is bilateral and midline, involving the arms, head and/or voice with occasional involvement of legs, chin, and trunk. It is frequently accompanied by a family history of a similar tremor. However, ET is a heterogeneous disorder that has no universally accepted diagnostic criteria and estimates of incidence, prevalence, and family history status vary considerably. Prevalence estimates vary from 0.008% to 22% (Louis et al., 1998). Adding to that, 30–50% of patients with essential tremor are commonly misdiagnosed with Parkinson’s disease or other tremor disorders such as hyperthyroidism, dystonia, or Wilson’s disease (Benito-Le´on and Louis, 2007).
The aims of this study were to determine the distribution of various types of tremor disorders in patients presenting to the movement disorders clinic of university hospital of Rabat and describe the frequency of appearance and clinical characteristics of our patients.
2.
Patients and methods
We conducted a retrospective study of the records of 148 patients with tremor referred to our movement disorders outpatient clinic of university hospital Ibn Sina in Rabat from January 2006 to December 2011. We analyzed the clinical features of tremor and its management. Patients with parkinsonian tremor were excluded from the study. Characteristics of patients were analyzed by a movement disorders specialized neurologist. It included age, gender, family history of tremor, anatomical distribution and symmetry of tremor as well as cerebral MRI and treatment regimen. Consensus Statement of the Movement Disorder society on tremor was used for syndromic classification of tremor
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(Deuschl et al., 1998). Diagnosis of essential tremor was made in patients having postural or kinetic tremor of the hands and forearms and/or of the head without evidence of dystonia. Diagnosis of dystonic tremor and tremor associated with dystonia were retained respectively in patients presenting tremor in body region affected by dystonia and in a different region. Enhanced physiologic tremor was defined as highfrequency postural and/or kinetic tremor occurring in the absence of any neurologic disease and typically reversible when cause is removed. Cerebellar tremor criteria were predominant intention tremor other cerebellar signs and Holmes’ tremor combined resting and intention tremor associated with parkinsonian and cerebellar features. Psychogenic tremor diagnosis was made in irregular tremor with decreasing amplitude during distraction. Statistical analysis was performed using the SPSS 13.0. All data are presented as mean standard deviation and frequencies. Comparisons were made using Chi2 test and student’s t-test and statistical significance was considered for P < 0.05.
3.
Results
We included 62 patients with non-parkinsonian tremor. The etiologies were as follows: essential tremor: 34 cases (54.8%), dystonic tremor: 12 cases (19.4%), tremor associated with dystonia: 9 cases (14.5%), enhanced physiological tremor: 2 cases (3.2%), cerebellar tremor: 2 cases (3.2%), psychogenic tremor: 2 cases (3.2%) and Holmes’ tremor: 1 case (1.6%). The characteristics of essential tremor patients are detailed in the Table 1. We performed a gender comparison and noted that rest tremor was present only in females and age at onset was 49 years in men versus 53.7 years in women. However, these differences were not statistically significant. In ET patients, first-line treatment relied on propranolol in 26 cases (76.5%), primidone in 5 cases (14.7%), gabapentin in 1 case (3%), clonazepam in 3 cases (8.9%), alprazolam in 2 cases (5.9%), pregabalin in 1 case (3%). Second-line treatment was propranolol in 4 patients (11.8%), gabapentin in 4 patients (11.8%), topiramate in 2 patients (5.9%), clonazepam in 2 patients (5.9%), alprazolam in 2 patients (5.9%). Levodopa was used initially in 1 patient and one patient underwent radiosurgery. The efficacy of propranolol ranged from 20 to 100% and its side-effects included orthostatic hypotension, bradycardia, dizziness, headache, cough, dyspnea and allergy. Concerning primidone, side-effects were sedation, ataxia and vertigo. L Dopa was only used in one patient with rest tremor and there was no response then treatment was switched to propranolol with good clinical improvement. Dystonic tremor was described in 12 patients: 6 with writer’s cramp and 6 with spasmodic torticollis. Seven were females and 5 males. Mean age was 31 13.9 [range 15–50] years and mean age at onset was 25.7 12.8 [range 10–41] years. Tremor associated with dystonia was found in 9 patients of whom 6 males and 3 females. Mean age was 49.2 19.2 [range 21–71] years and mean age at onset was 39.5 16.4 [range 15–57] years. Tremor affected upper limb in all patients and was associated to dystonia of contralateral upper limb (2 patients), oromandibular dystonia (2 patients),
Table 1 – Clinical characteristics of essential tremor patients. n (%) Age (years)a Age at onset (years)
a
Range
59.5 15.3
17–80
52.2 16.4
16–74
Gender Male Female
11 (32.4) 23 (67.6)
Anatomic distribution Upper limbs Head Voice Lower limbs
32 (94.1) 18 (52.9) 12 (35.3) 3 (8.8)
Family history of tremor
6 (17.6)
Tremor characteristics Postural Kinetic Rest Action
26 (76.5) 27 (79.4) 4 (11.8) 7 (20.6)
Tremor symmetry Bilateral symmetrical Bilateral asymmetrical Unilateral
12 (37.5) 16 (50) 4 (12.5)
Treatment Propranolol Primidone Gabapentine Clonazepam Alprazolam Topiramate Pregabaline
30 (88.3) 5 (14.7) 5 (14.7) 5 (14.7) 4 (11.8) 2 (5.9) 1 (3)
n: number of patients. Quantitative variable expressed in mean standard deviation.
a
spasmodic torticollis (2 patients) and blepharospasm (3 patients). Botulinic toxin was used in 3 patients with spasmodic torticollis with good response of dystonia and tremor. Others drugs were used for tremor with good results such as propranolol, alprazolam and clonazepam. Enhanced physiologic tremor was reported in 2 patients who both were under Beta-adrenergic agonists. Psychogenic etiology of tremor was found in 2 patients. Cerebellar tremor was reported in one patient with post trauma cerebellar hematoma in MRI and one patient with hereditary ataxia whose cerebral MRI showed cerebellar atrophy. Holmes’ tremor was noted in one patient who had a cerebellar stroke in the MRI.
4.
Discussion
In our series, the most common diagnoses for tremor were essential tremor, dystonic tremor and tremor associated with dystonia.
4.1.
Essential tremor
Essential tremor was the predominant diagnosis confirming its high prevalence as it is described as the most commonly occurring movement disorder (Pahwa and Lyons, 2003).
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In our series, patients were mainly female (67.6%). The gender predominance reported in ET series is controversial as some studies reported female predominance (Tallo´n-Barranco et al., 1997; Hornabrook and Nagurney, 1976; Scaramelli et al., 1996; Haerer et al., 1982) whereas others found male predominance (Larsson and Sjogren, 1960; Critchley, 1972; Rautakorpi et al., 1982) or non-significant difference between the two genders (Koller et al., 1992, 1994; Martinelli et al., 1987; Bain et al., 1994; Lou and Jankovic, 1991). Mean age at onset was 52.2 16.4 years with a peak of age at onset in the fifth and sixth decades. These findings are in line with most ET studies (Whaley et al., 2007). Several peaks of higher frequency of onset have been reported in sixth, seventh and even second decade (Tallo´n-Barranco et al., 1997; Lou and Jankovic, 1991). The early onset of ET was particularly reported in patients with positive family history (Koller et al., 1994; Lou and Jankovic, 1991). In our patients, family history of tremor was reported in 17.6% concurring with the estimates in literature which range from 17% to 100% (Louis and Ottman, 1996) given the differences in methodology and inclusion criteria and the inaccuracy of self reported history. Genetic aspects of ET are not fully elucidated. It is an inherited disease with mainly autosomal dominant transmission, but other patterns of inheritance as well as influence of environmental factors are not excluded. Genetic studies revealed linkage of familial ET in different chromosome locations: 3q13.3 (ETM1, OMIM 190300), 2p25-p22 (ETM2, OMIM 602134) and 6p32 (ETM3, OMIM 611456), but no gene with causative mutations has been reported (Elble and Deuschl, 2011). A genome-wide association study revealed several sequence variants in the LINGO1 gene to be associated with ET, and this was confirmed in independent cohorts. LINGO1 plays a role in neuronal survival, axonal regeneration, and oligodendrocyte maturation in the central nervous system (Radovica et al., 2012). Recently, rare mutations of the fused in sarcoma (FUS) gene were identified in familial ET and are also known to cause two other neurological disorders; amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (Merner et al., 2012). However, the underlying biological mechanisms implicating FUS variants are thought to be different in ALS and ET (Merner et al., 2012). In terms of clinical characteristics of tremor, the most commonly affected body location by tremor was the arms (94.1%) then the head (52.9%), voice (35.3%) and legs (8.8%). This anatomic distribution of the tremor is quite similar to that described in previous studies (Lou and Jankovic, 1991; Whaley et al., 2007; Massey and Paulson, 1985; Findley, 2000) and the characteristic involvement of the hands with head and voice tremor with relative sparing of legs helps in differentiating severe ET from parkinsonian tremor. Tremor was bilateral in 87.5% but was asymmetrical in 50% of patients. Actually, asymmetry is commonly noted in ET and usually tremor is more severe on the nondominant side (Louis et al., 1998). The asymmetry of tremor, as well as initial unilateral onset of tremor, has been considered as predictor of progression (Putzke et al., 2006). Essential tremor is known to produce a mixed postural and kinetic tremor as it was the case in our patients with proportions of respectively 76.5% and 79.4%. However, rest tremor was associated in 11.8% of cases and this statement
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was frequently reported with rates of 14% and 18.8% (Whaley et al., 2007; Cohen et al., 2003) and attributed to co-morbid Parkinson’s disease or misclassification (Whaley et al., 2007). However, the duration of disease, the absence of bradykinesia and rigidity, and the association of resting tremor with action or postural tremor argue against a diagnosis of concurrent or otherwise Parkinson’s disease (Whaley et al., 2007). Some authors have considered it as a possible late-stage feature of ET and addressed the significance of rest tremor in individuals with ET (Cohen et al., 2003; Rajput et al., 2004). In the study by Cohen et al., rest tremor was associated with disease that was more severe, more disseminated and of longer duration (Cohen et al., 2003). Some of these patients had electrophysiologic features consistent with parkinsonism. DAT scan is a useful tool for differential diagnosis but it is unfortunately unavailable in Morocco. The basis for the rest tremor could be basal ganglia involvement, raising the possibility that the pathologic process responsible for ET may extend to these structures (Cohen et al., 2003). Actually, the main findings concerning the pathology of essential tremor include cerebellar degenerative changes and Lewy bodies in the locus ceruleus (Benito-Le´on and Louis, 2006). Some studies suggest that an olivocerebello-bulbospinal pathway mediates essential tremor and others that thalamocortical pathways may also be involved but they are still controversial (Benito-Le´on and Louis, 2006). Concerning treatment, propranolol and primidone are first-line agents and are effective for 30–70% of patients (Benito-Le´on and Louis, 2007). Efficacy does not differ significantly between the two, although primidone might be more tolerable in the long term than propranolol (Louis, 2001). In our patients, propranolol was the most used medication as primidone is not available in our country. Despite their efficacy on tremor, side-effects limited the use of propranolol and primidone in some patients and imposed changing the treatment. Topiramate, gabapentin, alprazolam and clonazepam were used as second-line treatments with a good clinical response but antitremor effect often came at a dose that is associated with sedation in most patients. In these particular cases of drug intolerance or inefficacy, surgery is often the best option for patients with resistant and disabling hand tremor. Thalamic deep brain stimulation is the surgery of choice that has fewer adverse events than surgical thalamotomy and results in greater functional improvement (Zesiewicz et al., 2005). However, gamma knife thalamotomy is an interesting alternative in case of contraindications for thalamic deep brain stimulation. Several studies have assessed gamma knife thalamotomy and found favorable results (Zesiewicz et al., 2005).
4.2.
Dystonia and tremor
The coexistence of postural and/or kinetic tremor with dystonia is relatively common and is present in 4–55% patients with focal dystonia (Hedera et al., 2010). Tremor is described in patients with focal, segmental or generalized dystonia in both idiopathic and symptomatic dystonia (Ferraz et al., 1994). Dystonic tremor occurs in an extremity or body part which is affected by dystonia. Typical examples are head tremor in torticollis, hand tremor in writer’s cramp and jaw tremor in
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orofacial dystonias. It is usually focal tremor with irregular amplitudes and variable frequencies (Deuschl, 2003). In dystonic tremor, sensory trick lead to a reduction of the tremor amplitude, which could be a differential diagnostic hint in unclear head tremors in which the dystonic posture is not obvious. Typically, the commonest type of dystonia seen with tremor in previous studies is cervical dystonia and writer cramp (Lou and Jankovic, 1991; Shukla and Behari, 2004; Dubinsky et al., 1993) as it was the case in our series. Tremor associated with dystonia is a more generalized form of tremor in extremities that are not affected by the dystonia. This is relatively symmetrical, postural and kinetic tremor often seen in the upper limbs in patients with spasmodic torticollis. In our patients with tremor associated with dystonia, tremor affected upper limb and was associated with spasmodic torticollis, writer’s cramp, blepharospasm or oromandibular dystonia. Tremor associated with dystonia is more difficult to separate from ET because it remains controversial whether tremor in limbs not affected by dystonia represents ET or a different movement disorder. Another differential diagnosis of tremor associated with dystonia is psychogenic tremor that could be differentiated by the mode of onset, psychogenic cocontraction of the trembling extremity, distractibility and incongruent tremor expression between tasks. In ours series, psychogenic accounted for only 2 patients. Our study confirmed that ET is the most common cause of non-parkinsonian tremor in our Moroccan population and that this diagnosis should be considered whenever postural and/or kinetic tremor is observed predominantly in upper limbs.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
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