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Focal limb dystonia and tremor: Clinical update
Toxicon 176 (2020) 10–14
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Focal limb dystonia and tremor: Clinical update Aditya Ashok Murgai , Mandar Jog * Department of Clinical Neurological Sciences, Western University, London, Canada
A R T I C L E I N F O
A B S T R A C T
Keywords: Dystonia Tremor Electrophysiology
The association between tremor and dystonia has been known for many decades. Dystonic tremor is seen in the body part affected with dystonia. Tremor and dystonia can also co-exist in different body parts. Subtle dystonic posturing can be missed in patients with upper limb tremor and these patients are often misdiagnosed as essential tremor. Careful clinical examination and electrophysiology may help in differentiating classical essential tremor from dystonic tremor. Writer’s cramp, a common focal hand dystonia can mimic primary writing tremor when the dystonic posturing is subtle. Oral medications have limited therapeutic efficacy. Botulinum toxin is considered as first line therapy for focal limb dystonia and is also effective in the treatment of tremor. Surgical options are reserved for cases refractory to medical therapy. In this review, we summarize the current state of knowledge of focal limb dystonia and tremor with a focus on underlying neurophysiology in these conditions.
1. Introduction Tremor is a common motor feature of dystonia. It may occur in same body part as dystonia or a different body part. The terminology ‘dystonic tremor’ is used when tremor is present in the limb having dystonia. When dystonia and tremor occur in different body parts, it is called as ‘dystonia with tremor’ (Deuschl et al., 1998). Dystonic tremor and tremor with dystonia are most likely two different phenomenon, having different underlying pathophysiology (Alexander Münchau et al., 2001). Dystonic tremor commonly occurs during maintenance of posture, on action and is less likely to occur at rest (Defazio et al., 2015). Dystonic tremor is worse when the position of a body part is maintained against the direction of dystonia. Tremor is very prevalent in patients with primary adult-onset dys tonia, most commonly seen in cervical dystonia followed by limb dys tonia (Pandey and Sarma, 2016). Patients with isolated unilateral tremor without obvious dystonic posturing pose a diagnostic challenge as these cases may represent incomplete dystonia phenomenology (‘formes frustes’) (Albanese and Sorbo, 2016, Zeman et al., 1960) It can be challenging to differentiate postural and action tremor with dystonia from essential tremor. Clinical examination by itself is not very reliable in distinguishing these two conditions and misdiagnoses are common. Neurophysiologic features of reduced reciprocal inhibition between agonist and antagonist muscles, lack of brainstem inhibition, and abnormal sensory integration seen in dystonia can differentiate it from essential tremor (ET) (Defazio et al., 2015). Here we present a review on
focal limb dystonia and tremor with current state of evidence to clini cally and electrophysiologically distinguish dystonic tremor and its mimickers. 2. Essential tremor and dystonia Essential tremor is the most common movement disorder and is commonly over diagnosed. It is estimated that 1 in 3 patients with tremor is misdiagnosed as ET and most frequent true diagnosis being dystonia and Parkinson’s disease. (Jain et al., 2006). In a large series of essential tremor patients about 47% patients had associated dystonia of neck, vocal cords, face and upper limbs. (Lou and Jankovic, 1991). Essential tremor is commonly considered as a monosymptomatic disease, but it is not uncommon to find other neurological features like dystonia in patients with ET. A study involving 463 subjects with autosomal dominant, inherited ET or dystonia suggested that familial ET associated with dystonia may represent a distinct subtype of ET. Patients with dystonia associated with ET were clustered in 28% of all included pedigrees, showing a non-random distribution (Hedera et al., 2010). Another study looking at the prevalence and clinical features of unre ported dystonia in subjects with “pure” ET and their first and second degree relatives showed the presence of dystonia in 31% of families. Torticollis was most common (32%), and dystonia was undiagnosed in 93% cases (Louis et al., 2013). These results suggest frequent occurrence of dystonia in patients with ET or their family members, pointing to wards common underlying genetics.
* Corresponding author. Clinical Neurological Sciences, University Hospital, 339 Windermere Road, London, ON, N6A 5A5, Canada. E-mail address: [email protected] (M. Jog). https://doi.org/10.1016/j.toxicon.2020.01.004 Received 24 August 2019; Received in revised form 4 January 2020; Accepted 13 January 2020 Available online 13 January 2020 0041-0101/© 2020 Elsevier Ltd. All rights reserved.
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3. Differentiating essential tremor from dystonic tremor
the tremor onset) in antagonist muscles is another useful clue for making a diagnosis of dystonic tremor. Patients with cervical dystonia can present with upper limb tremor without obvious dystonic posturing (dystonia with tremor). In these patients, ballistic wrist flexion movements producing a triphasic EMG response shows increased latency of the second agonist EMG burst with co-contraction of agonist1 and the antagonist. ET patients do not show similar co-contractions of agonist and antagonist (Alexander Münchau et al., 2001). Patients with dystonia frequently show increased R2 recovery component of the blink reflex which is normal in patients with ET. ET patients having associated resting tremor have increased R2 response of blink reflex with abnormal R2 recovery index compared to ET patients with no rest tremor (Nistico et al., 2012). Hence, presence of resting tremor in ET patients can be used as a surrogate marker for underlying dystonia. Spiral drawing is another feature that can be used in clinic to
Focal and segmental dystonia is often associated with ET like tremor. Dystonic tremor may precede clear signs of dystonia and hence can cause uncertainty in diagnosis (Deuschl, 2003). Clinical and neuro physiological features may help in differentiating classical ET from dystonic tremor but no neurophysiological test can do this confidently. (Elble, 2013). Features like irregular tremor amplitude, irregular rhythm (Fig. 1), sensory trick, presence of null point and selective responsive ness to anti-dystonic medications may be helpful in diagnosing dystonic tremor (Deuschl, 2003). Irregular or pseudo rhythmic tremor is not a feature essential to dystonic tremor. The dystonic tremor can be regular, high frequency during isometric muscular contraction and irregular, lower frequency during involuntary contractions (Yanagisawa et al., 1972). The pattern of antagonist contractions in dystonic tremor can be alternating or synchronous. The presence of co-contraction (just before
Fig. 1. A 42 years old female with right upper limb dystonic tremor. Gyroscope (x-axis) recording with sensor placed on the dorsal surface of hand shows inconsistent tremor waveform with varying amplitude, figure A. Spectrogram of the same channel (1 s window) showing tremor of variable frequency (4–7hz) and amplitude, figure B. Power spectrum with 5 s window showing multiple frequency peaks suggestive of variability in tremor frequency, figure C. 11
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differentiate ET from dystonia. ET spirals have a single identifiable tremor orientation axis whereas no single predominant axis stands out in dystonic tremor (Michalec et al., 2014). Pen pressure in dystonic tremor is higher and more variable compared to ET patients.
muscle selection for botulinum toxin injections.(Jhunjhunwala et al., 2015, Das et al., 2007, C. Singer et al., 2005). Writer’s cramp patients show high 3–7hz, theta band intermuscular coherence during isometric muscle contraction. This coherence activity is not related to tremor as it can be seen in patients without tremor. This shows the importance of theta band cortical/subcortical rhythm in the pathogenesis of writer’s cramp (Choudhury et al., 2018). Theta band oscillations may in fact play an important role in the pathogenesis of other types of dystonia, as similar oscillations have been described in idiopathic torticollis (Tijssen et al., 2000). Musician’s dystonia (MD) is characterized by involuntary contrac tions in muscles involved in playing a musical instrument (Konczak and Abbruzzese, 2013). It can manifest as embouchure dystonia, affecting the muscles of the lower face, or as limb dystonia affecting the most active digits of the most active hand (Sussman, 2015, Schmidt et al., 2009). An estimate of 1% of professional musicians are affected with MD (Altenmüller, 2003). Musician dystonia like other forms of focal dysto nia is associated with somatosensory deficits and decreased precision of proprioceptive perception (Konczak and Abbruzzese, 2013). Genetics also play an important role in its development with about 10% of pa tients with MD reporting a family history of dystonia (Schmidt et al., 2009 Altenmüller, 2003).
4. Primary writing tremor The pathophysiology of primary writing tremor is not well under stood. It has been classified as focal form of essential tremor and trem ulous form of writer’s cramp (Modugno et al., 2002). The first case of primary writing tremor was described by Rothwell et al. as a task spe cific upper limb protonation, supination tremor without dystonic posturing. This tremor attenuated after partial motor point anesthesia of Pronator Teres suggesting abnormal muscle spindle input from Pronator Teres in its pathogenesis (Rothwell et al., 1979). About a decade later Elble et al. described electrophysiology in his five primary writing tremor cases, showing a 5–7 hz rhythmic bursts of EMG activity in forearm antagonists, fluctuating between the alternating and synchro nous patterns. Sustained co-contraction, which is a classical feature of dystonia, was seen in all the patients in forearm, arm and shoulder muscles while controls showed co-contraction only in forearm muscle during a writing task (Elble et al., 1990). Co-contraction is believed to be a normal phenomenon seen during rapid, voluntary and rhythmic movements, to control stiffness and reduce unwanted movements (Feldman, 1980). During writing these co-contractions normally occur in forearm and hand muscles (Elble et al., 1990). The subtle dystonic posturing in primary writing tremor can be overshadowed by severe tremor and electromyography can confirm the co-existence of dystonia and tremor. Lobo et al. described a case of primary writing tremor who developed writer’s cramp on the other side 20 years later, suggesting that the two entities share a common patho physiology (Pita Lobo et al., 2013). In another series of 21 primary writing tremor patients, no evidence of an excessive overflow of EMG activity into the proximal musculature was seen, unlike in writer’s cramp (Bain et al., 1995). Rothwell et al. showed normal spinal recip rocal inhibition, and short and long interval intracortical inhibition in seven primary writing tremor patients (Modugno et al., 2002). Similar electrophysiological features have been seen in ET (Romeo et al., 1998, A. Münchau et al., 2001). Writer’s cramp patients on the other hand show reduced spinal reciprocal inhibition and decreased intracortical inhibition compared to healthy subjects (Chen et al., 1995, Ridding et al., 1995). These results suggest differences in underlying patho physiology of writer’s cramp and primary writing tremor. Most studies have shown reduced spinal and cortical inhibition in writer’s cramp producing the phenomenon of co-contractions and overflow of EMG activity, differentiating it from primary writing tremor. Current state of evidence points towards primary writing tremor being a separate clinical entity with different underlying pathophysiology than writer’s cramp. Prominent tremor and lack of overflow of EMG activity into proximal muscles during writing task would suggest the diagnosis of primary writing tremor.
6. Focal leg dystonia Focal leg dystonia is rare compared to focal upper limb dystonia in adults. In children leg dystonia can be seen in conditions causing iso lated dystonia like DYT1(TOR1A) and complicated dystonia like DYT5a, DYT5b. In adults, it is usually structural, sporadic or associated with repetitive activities such running marathons. Leg dystonia could be a presenting manifestation of Parkinson’s disease, before manifesting other cardinal signs of like tremor, rigidity and bradykinesia. The dys tonia in Parkinson’s disease is usually action induced or task specific and responsive to levodopa (McKeon et al., 2008). 7. Complex regional pain syndrome Complex regional pain syndrome (CRPS) is characterized by severe pain, swelling, sensory, autonomic, motor and trophic changes in ex tremities, with or without peripheral nerve injury (Goh et al., 2017). Prevalence of movement disorders in CRPS range from 25 to 65%, dystonia being the most prevalent (91%) (van Hilten, 2010, van Rijn et al., 2007).Dystonia can occur as early as one week from the onset of CRPS or may present even a year later. Delay in onset and progression of dystonia in CRPS probably indicates maladaptive neuroplasticity (van Rijn et al., 2007). Tremor, spasm, bradykinesia and myoclonus are other movement disorders commonly seen in CRPS (Schwartzman and Kerri gan, 1990, van Hilten, 2010). 8. Treatment of focal limb dystonia and tremor 8.1. Medical treatment
5. Focal task specific tremor: Writer’s cramp and musician dystonia
Oral medications like anticholinergics, dopamine modulators, bac lofen and muscle relaxants have been used in the treatment of dystonia. These medications have limited efficacy in focal limb dystonia but are often tried as initial therapy. Botulinum toxin is considered as the most effective treatment for focal dystonia (Jankovic, 2013) Efficacy of Bot ulinum toxin type-A in writer’s cramp has been shown in a randomized controlled trial (Kruisdijk et al., 2007). Botulinum toxin is also effective in the treatment of MD with improvement seen in more than two third of the cases. . Botulinum toxin in dystonia works by dampening muscle activity and has shown to cause motor cortex reorganization, measured by reduction in the paired associative plasticity (Kojovic et al., 2011). Whether the change in motor cortex plasticity is a direct effect of toxin
Writer’s cramp is a common focal hand dystonia which manifests as involuntary and sustained posturing in upper limb during writing (Epidemiological Study of Dystonia in Europe (ESDE) Collaborative Group, 2000). Prevalence of writer’s cramp has been estimated to be around 14 per million (95% confidence interval 11–17) with a higher prevalence in men. Age of onset is usually in the second or third decade (Jhunjhunwala et al., 2015). Forearm pain (56%) is the most common presenting symptom followed by tremulousness of hand (28.8%) and abnormal posturing (15.2%) (Jhunjhunwala et al., 2015). Mirror movements are observed in 35–50% of cases in the hand affected with dystonia, while using the other hand for writing and can guide the 12
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References
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8.2. Surgical treatment Unilateral Ventral Oral Nucleus (Vo) and Ventral Intermediate Nu cleus (Vim) thalamotomy have been safely and effectively performed in patients with writer’s cramp for many years (Asahi et al., 2014). MR-guided focused ultrasound tandem ablation of the ventral interme diate and Ventralis Oralis Posterior nuclei has shown persistent (6-month) improvement in a patient with writer’s cramp (Meng et al., 2018).Globus pallidus interna Deep Brain Stimulation is mainly reserved for primary generalized dystonia, but can be effective in writer’s cramp (Doshi et al., 2017). Surgical treatment for focal dystonia is usually reserved for medically refractory cases. 9. Conclusions Focal limb dystonia with tremor have a wide differential diagnosis including task-specific dystonia like writer’s cramp, musician dystonia, primary writing tremor, ET and CRPS. Literature shows that upper limb dystonia with tremor has been frequently misdiagnosed as ET. Evidence also suggests that dystonia with tremor represents a distinct subtype of ET, especially in familial cases. Dystonic tremor has characteristic neurophysiological features like irregular frequency and amplitude and clinical features like presence of sensory trick and null point. Oral medications have limited role in treatment of focal dystonia. Botulinum toxin is the mainstay of treatment for focal dystonia and may be of use in dystonic tremor. Surgical interventions including thalamotomy and deep brain stimulation are reserved for refractory cases. Ethical statement Ethics clearance was not required for this work. Funding This review did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Declaration of competing interest Aditya Murgai: None. Mandar Jog receives research grants from Allergan, Merz Pharma ceuticals, Abbvie, and Medtronic. Dr. Jog also receives speaker hono raria fees from the same companies and serves on advisory boards of these companies from time to time. CRediT authorship contribution statement Aditya Ashok Murgai: Conceptualization, Writing - original draft. Mandar Jog: Conceptualization, Writing - review & editing. Acknowledgements None. 13
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Toxicon journal homepage: http://www.elsevier.com/locate/toxicon
Focal limb dystonia and tremor: Clinical update Aditya Ashok Murgai , Mandar Jog * Department of Clinical Neurological Sciences, Western University, London, Canada
A R T I C L E I N F O
A B S T R A C T
Keywords: Dystonia Tremor Electrophysiology
The association between tremor and dystonia has been known for many decades. Dystonic tremor is seen in the body part affected with dystonia. Tremor and dystonia can also co-exist in different body parts. Subtle dystonic posturing can be missed in patients with upper limb tremor and these patients are often misdiagnosed as essential tremor. Careful clinical examination and electrophysiology may help in differentiating classical essential tremor from dystonic tremor. Writer’s cramp, a common focal hand dystonia can mimic primary writing tremor when the dystonic posturing is subtle. Oral medications have limited therapeutic efficacy. Botulinum toxin is considered as first line therapy for focal limb dystonia and is also effective in the treatment of tremor. Surgical options are reserved for cases refractory to medical therapy. In this review, we summarize the current state of knowledge of focal limb dystonia and tremor with a focus on underlying neurophysiology in these conditions.
1. Introduction Tremor is a common motor feature of dystonia. It may occur in same body part as dystonia or a different body part. The terminology ‘dystonic tremor’ is used when tremor is present in the limb having dystonia. When dystonia and tremor occur in different body parts, it is called as ‘dystonia with tremor’ (Deuschl et al., 1998). Dystonic tremor and tremor with dystonia are most likely two different phenomenon, having different underlying pathophysiology (Alexander Münchau et al., 2001). Dystonic tremor commonly occurs during maintenance of posture, on action and is less likely to occur at rest (Defazio et al., 2015). Dystonic tremor is worse when the position of a body part is maintained against the direction of dystonia. Tremor is very prevalent in patients with primary adult-onset dys tonia, most commonly seen in cervical dystonia followed by limb dys tonia (Pandey and Sarma, 2016). Patients with isolated unilateral tremor without obvious dystonic posturing pose a diagnostic challenge as these cases may represent incomplete dystonia phenomenology (‘formes frustes’) (Albanese and Sorbo, 2016, Zeman et al., 1960) It can be challenging to differentiate postural and action tremor with dystonia from essential tremor. Clinical examination by itself is not very reliable in distinguishing these two conditions and misdiagnoses are common. Neurophysiologic features of reduced reciprocal inhibition between agonist and antagonist muscles, lack of brainstem inhibition, and abnormal sensory integration seen in dystonia can differentiate it from essential tremor (ET) (Defazio et al., 2015). Here we present a review on
focal limb dystonia and tremor with current state of evidence to clini cally and electrophysiologically distinguish dystonic tremor and its mimickers. 2. Essential tremor and dystonia Essential tremor is the most common movement disorder and is commonly over diagnosed. It is estimated that 1 in 3 patients with tremor is misdiagnosed as ET and most frequent true diagnosis being dystonia and Parkinson’s disease. (Jain et al., 2006). In a large series of essential tremor patients about 47% patients had associated dystonia of neck, vocal cords, face and upper limbs. (Lou and Jankovic, 1991). Essential tremor is commonly considered as a monosymptomatic disease, but it is not uncommon to find other neurological features like dystonia in patients with ET. A study involving 463 subjects with autosomal dominant, inherited ET or dystonia suggested that familial ET associated with dystonia may represent a distinct subtype of ET. Patients with dystonia associated with ET were clustered in 28% of all included pedigrees, showing a non-random distribution (Hedera et al., 2010). Another study looking at the prevalence and clinical features of unre ported dystonia in subjects with “pure” ET and their first and second degree relatives showed the presence of dystonia in 31% of families. Torticollis was most common (32%), and dystonia was undiagnosed in 93% cases (Louis et al., 2013). These results suggest frequent occurrence of dystonia in patients with ET or their family members, pointing to wards common underlying genetics.
* Corresponding author. Clinical Neurological Sciences, University Hospital, 339 Windermere Road, London, ON, N6A 5A5, Canada. E-mail address: [email protected] (M. Jog). https://doi.org/10.1016/j.toxicon.2020.01.004 Received 24 August 2019; Received in revised form 4 January 2020; Accepted 13 January 2020 Available online 13 January 2020 0041-0101/© 2020 Elsevier Ltd. All rights reserved.
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3. Differentiating essential tremor from dystonic tremor
the tremor onset) in antagonist muscles is another useful clue for making a diagnosis of dystonic tremor. Patients with cervical dystonia can present with upper limb tremor without obvious dystonic posturing (dystonia with tremor). In these patients, ballistic wrist flexion movements producing a triphasic EMG response shows increased latency of the second agonist EMG burst with co-contraction of agonist1 and the antagonist. ET patients do not show similar co-contractions of agonist and antagonist (Alexander Münchau et al., 2001). Patients with dystonia frequently show increased R2 recovery component of the blink reflex which is normal in patients with ET. ET patients having associated resting tremor have increased R2 response of blink reflex with abnormal R2 recovery index compared to ET patients with no rest tremor (Nistico et al., 2012). Hence, presence of resting tremor in ET patients can be used as a surrogate marker for underlying dystonia. Spiral drawing is another feature that can be used in clinic to
Focal and segmental dystonia is often associated with ET like tremor. Dystonic tremor may precede clear signs of dystonia and hence can cause uncertainty in diagnosis (Deuschl, 2003). Clinical and neuro physiological features may help in differentiating classical ET from dystonic tremor but no neurophysiological test can do this confidently. (Elble, 2013). Features like irregular tremor amplitude, irregular rhythm (Fig. 1), sensory trick, presence of null point and selective responsive ness to anti-dystonic medications may be helpful in diagnosing dystonic tremor (Deuschl, 2003). Irregular or pseudo rhythmic tremor is not a feature essential to dystonic tremor. The dystonic tremor can be regular, high frequency during isometric muscular contraction and irregular, lower frequency during involuntary contractions (Yanagisawa et al., 1972). The pattern of antagonist contractions in dystonic tremor can be alternating or synchronous. The presence of co-contraction (just before
Fig. 1. A 42 years old female with right upper limb dystonic tremor. Gyroscope (x-axis) recording with sensor placed on the dorsal surface of hand shows inconsistent tremor waveform with varying amplitude, figure A. Spectrogram of the same channel (1 s window) showing tremor of variable frequency (4–7hz) and amplitude, figure B. Power spectrum with 5 s window showing multiple frequency peaks suggestive of variability in tremor frequency, figure C. 11
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differentiate ET from dystonia. ET spirals have a single identifiable tremor orientation axis whereas no single predominant axis stands out in dystonic tremor (Michalec et al., 2014). Pen pressure in dystonic tremor is higher and more variable compared to ET patients.
muscle selection for botulinum toxin injections.(Jhunjhunwala et al., 2015, Das et al., 2007, C. Singer et al., 2005). Writer’s cramp patients show high 3–7hz, theta band intermuscular coherence during isometric muscle contraction. This coherence activity is not related to tremor as it can be seen in patients without tremor. This shows the importance of theta band cortical/subcortical rhythm in the pathogenesis of writer’s cramp (Choudhury et al., 2018). Theta band oscillations may in fact play an important role in the pathogenesis of other types of dystonia, as similar oscillations have been described in idiopathic torticollis (Tijssen et al., 2000). Musician’s dystonia (MD) is characterized by involuntary contrac tions in muscles involved in playing a musical instrument (Konczak and Abbruzzese, 2013). It can manifest as embouchure dystonia, affecting the muscles of the lower face, or as limb dystonia affecting the most active digits of the most active hand (Sussman, 2015, Schmidt et al., 2009). An estimate of 1% of professional musicians are affected with MD (Altenmüller, 2003). Musician dystonia like other forms of focal dysto nia is associated with somatosensory deficits and decreased precision of proprioceptive perception (Konczak and Abbruzzese, 2013). Genetics also play an important role in its development with about 10% of pa tients with MD reporting a family history of dystonia (Schmidt et al., 2009 Altenmüller, 2003).
4. Primary writing tremor The pathophysiology of primary writing tremor is not well under stood. It has been classified as focal form of essential tremor and trem ulous form of writer’s cramp (Modugno et al., 2002). The first case of primary writing tremor was described by Rothwell et al. as a task spe cific upper limb protonation, supination tremor without dystonic posturing. This tremor attenuated after partial motor point anesthesia of Pronator Teres suggesting abnormal muscle spindle input from Pronator Teres in its pathogenesis (Rothwell et al., 1979). About a decade later Elble et al. described electrophysiology in his five primary writing tremor cases, showing a 5–7 hz rhythmic bursts of EMG activity in forearm antagonists, fluctuating between the alternating and synchro nous patterns. Sustained co-contraction, which is a classical feature of dystonia, was seen in all the patients in forearm, arm and shoulder muscles while controls showed co-contraction only in forearm muscle during a writing task (Elble et al., 1990). Co-contraction is believed to be a normal phenomenon seen during rapid, voluntary and rhythmic movements, to control stiffness and reduce unwanted movements (Feldman, 1980). During writing these co-contractions normally occur in forearm and hand muscles (Elble et al., 1990). The subtle dystonic posturing in primary writing tremor can be overshadowed by severe tremor and electromyography can confirm the co-existence of dystonia and tremor. Lobo et al. described a case of primary writing tremor who developed writer’s cramp on the other side 20 years later, suggesting that the two entities share a common patho physiology (Pita Lobo et al., 2013). In another series of 21 primary writing tremor patients, no evidence of an excessive overflow of EMG activity into the proximal musculature was seen, unlike in writer’s cramp (Bain et al., 1995). Rothwell et al. showed normal spinal recip rocal inhibition, and short and long interval intracortical inhibition in seven primary writing tremor patients (Modugno et al., 2002). Similar electrophysiological features have been seen in ET (Romeo et al., 1998, A. Münchau et al., 2001). Writer’s cramp patients on the other hand show reduced spinal reciprocal inhibition and decreased intracortical inhibition compared to healthy subjects (Chen et al., 1995, Ridding et al., 1995). These results suggest differences in underlying patho physiology of writer’s cramp and primary writing tremor. Most studies have shown reduced spinal and cortical inhibition in writer’s cramp producing the phenomenon of co-contractions and overflow of EMG activity, differentiating it from primary writing tremor. Current state of evidence points towards primary writing tremor being a separate clinical entity with different underlying pathophysiology than writer’s cramp. Prominent tremor and lack of overflow of EMG activity into proximal muscles during writing task would suggest the diagnosis of primary writing tremor.
6. Focal leg dystonia Focal leg dystonia is rare compared to focal upper limb dystonia in adults. In children leg dystonia can be seen in conditions causing iso lated dystonia like DYT1(TOR1A) and complicated dystonia like DYT5a, DYT5b. In adults, it is usually structural, sporadic or associated with repetitive activities such running marathons. Leg dystonia could be a presenting manifestation of Parkinson’s disease, before manifesting other cardinal signs of like tremor, rigidity and bradykinesia. The dys tonia in Parkinson’s disease is usually action induced or task specific and responsive to levodopa (McKeon et al., 2008). 7. Complex regional pain syndrome Complex regional pain syndrome (CRPS) is characterized by severe pain, swelling, sensory, autonomic, motor and trophic changes in ex tremities, with or without peripheral nerve injury (Goh et al., 2017). Prevalence of movement disorders in CRPS range from 25 to 65%, dystonia being the most prevalent (91%) (van Hilten, 2010, van Rijn et al., 2007).Dystonia can occur as early as one week from the onset of CRPS or may present even a year later. Delay in onset and progression of dystonia in CRPS probably indicates maladaptive neuroplasticity (van Rijn et al., 2007). Tremor, spasm, bradykinesia and myoclonus are other movement disorders commonly seen in CRPS (Schwartzman and Kerri gan, 1990, van Hilten, 2010). 8. Treatment of focal limb dystonia and tremor 8.1. Medical treatment
5. Focal task specific tremor: Writer’s cramp and musician dystonia
Oral medications like anticholinergics, dopamine modulators, bac lofen and muscle relaxants have been used in the treatment of dystonia. These medications have limited efficacy in focal limb dystonia but are often tried as initial therapy. Botulinum toxin is considered as the most effective treatment for focal dystonia (Jankovic, 2013) Efficacy of Bot ulinum toxin type-A in writer’s cramp has been shown in a randomized controlled trial (Kruisdijk et al., 2007). Botulinum toxin is also effective in the treatment of MD with improvement seen in more than two third of the cases. . Botulinum toxin in dystonia works by dampening muscle activity and has shown to cause motor cortex reorganization, measured by reduction in the paired associative plasticity (Kojovic et al., 2011). Whether the change in motor cortex plasticity is a direct effect of toxin
Writer’s cramp is a common focal hand dystonia which manifests as involuntary and sustained posturing in upper limb during writing (Epidemiological Study of Dystonia in Europe (ESDE) Collaborative Group, 2000). Prevalence of writer’s cramp has been estimated to be around 14 per million (95% confidence interval 11–17) with a higher prevalence in men. Age of onset is usually in the second or third decade (Jhunjhunwala et al., 2015). Forearm pain (56%) is the most common presenting symptom followed by tremulousness of hand (28.8%) and abnormal posturing (15.2%) (Jhunjhunwala et al., 2015). Mirror movements are observed in 35–50% of cases in the hand affected with dystonia, while using the other hand for writing and can guide the 12
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References
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8.2. Surgical treatment Unilateral Ventral Oral Nucleus (Vo) and Ventral Intermediate Nu cleus (Vim) thalamotomy have been safely and effectively performed in patients with writer’s cramp for many years (Asahi et al., 2014). MR-guided focused ultrasound tandem ablation of the ventral interme diate and Ventralis Oralis Posterior nuclei has shown persistent (6-month) improvement in a patient with writer’s cramp (Meng et al., 2018).Globus pallidus interna Deep Brain Stimulation is mainly reserved for primary generalized dystonia, but can be effective in writer’s cramp (Doshi et al., 2017). Surgical treatment for focal dystonia is usually reserved for medically refractory cases. 9. Conclusions Focal limb dystonia with tremor have a wide differential diagnosis including task-specific dystonia like writer’s cramp, musician dystonia, primary writing tremor, ET and CRPS. Literature shows that upper limb dystonia with tremor has been frequently misdiagnosed as ET. Evidence also suggests that dystonia with tremor represents a distinct subtype of ET, especially in familial cases. Dystonic tremor has characteristic neurophysiological features like irregular frequency and amplitude and clinical features like presence of sensory trick and null point. Oral medications have limited role in treatment of focal dystonia. Botulinum toxin is the mainstay of treatment for focal dystonia and may be of use in dystonic tremor. Surgical interventions including thalamotomy and deep brain stimulation are reserved for refractory cases. Ethical statement Ethics clearance was not required for this work. Funding This review did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Declaration of competing interest Aditya Murgai: None. Mandar Jog receives research grants from Allergan, Merz Pharma ceuticals, Abbvie, and Medtronic. Dr. Jog also receives speaker hono raria fees from the same companies and serves on advisory boards of these companies from time to time. CRediT authorship contribution statement Aditya Ashok Murgai: Conceptualization, Writing - original draft. Mandar Jog: Conceptualization, Writing - review & editing. Acknowledgements None. 13
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