Parkinsonism and Related Disorders 20 (2014) 323e327
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Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Short communication
Tremor associated with Klinefelter syndrome e A case series and review of the literature Mariella Koegl-Wallner a, Petra Katschnig-Winter a, Tamara Pendl a, Barbara Melisch a, Martin Trummer b, Etienne Holl b, Ulrike Werner a, Reinhold Schmidt a, Petra Schwingenschuh a, * a b
Department of Neurology, Medical University of Graz, Auenbruggerplatz 22, 8036 Graz, Austria Department of Neurosurgery, Medical University of Graz, Graz, Austria
a r t i c l e i n f o
a b s t r a c t
Article history: Received 4 May 2013 Received in revised form 25 October 2013 Accepted 14 November 2013
Background: Previous case series suggested a link between Klinefelter syndrome (KS) and essential tremor (ET) or an ET-like syndrome. Methods: We investigated three KS-patients with tremor including tremor-analyzes and discuss our data in context to findings from a literature review. The clinical outcome after deep brain stimulation (DBS) is also reviewed. Results: Tremor in KS is predominantly a postural and kinetic tremor that resembles ET. Our patients were further characterized by absent family history for tremor in first degree relatives, lack of subjective alcohol responsiveness inquired by history, and tremor onset in childhood. One of our patients and two cases from literature improved after DBS of the ventral intermediate nucleus (VIM) of the thalamus. Conclusions: Tremor in KS shares several features with ET. If other characteristics such as family history, alcohol responsiveness, and age at tremor onset may serve as discriminating factors from ET, needs to be further investigated. First observations suggest that VIM-DBS may be efficacious. Ó 2013 Elsevier Ltd. All rights reserved.
Keywords: Klinefelter syndrome Essential tremor Deep brain stimulation DBS Tremor analysis
1. Introduction Klinefelter Syndrome (KS) is the most frequent sex chromosome abnormality among males (1:700) and the most common cause of male infertility. Before puberty physical anomalies are discrete. Thereafter the usually tall patients have small firm testes, gynecomastia in about 50%, varying symptoms of androgen deficiency, and a characteristic cognitive and behavioral syndrome. Testosterone replacement therapy should be started as soon as possible [1]. Previous case series suggested a link between KS and essential tremor (ET) or an ET-like syndrome [2]. A questionnaire-based study showed a significantly higher tremor frequency in KS compared to controls with onset at a younger age [3]. The pathophysiology of the tremor is unclear. Two cases with marked improvement from deep brain stimulation (DBS) of the ventral intermediate nucleus (VIM) of the thalamus were reported [4,5]. 2. Methods We present three patients with KS (47XXY) and an ET-like tremor syndrome and a review of the literature. Tremor-analysis was * Corresponding author. Tel.: þ43 316 385 83379. E-mail address: [email protected] (P. Schwingenschuh). 1353-8020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.parkreldis.2013.11.010
performed in our patients. The study was approved by the local ethics committee and was conducted in accordance with the Declaration of Helsinki. All procedures were carried out with the adequate understanding and written consent of the subjects involved. 2.1. Tremor-analysis A triaxial accelerometer transducer was attached to the middle phalanx of the index finger bilaterally. Surface electromyography (EMG) was recorded from wrist flexors and wrist extensors. Tremor was recorded during rest, posture (500 g loading), and action (fingere nose-testing). Data were analyzed as previously described [6]. 3. Results 3.1. Case reports 3.1.1. Patient 1 In 2011 this 51-years-old man presented with disabling arm tremor. Tremor had started at age ten in his arms and head and had increased during the past five years resulting in early retirement. The patient reported a positive family history for tremor (maternal grandfather), exacerbation of tremor by stress, and lack of alcohol
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responsiveness. At age 14 he had reached a height of 195 cm, there were no learning difficulties in school, but mild mood instability and low self-esteem. Because of infertility, KS was diagnosed at age 36, and testosterone replacement therapy was started without tremor improvement. Propranolol (120 mg/day) had only a transient effect on the tremor, all other drugs including topiramate (100 mg/day), clonazepam (1 mg/day), primidone (250 mg/day), gabapentin (1200 mg/day), and nimodipine had no benefit. Neurological examination showed mild head and voice tremor, mild intermittent rest tremor of both hands, and moderate bilateral asymmetric postural and action tremor of the upper limbs (left side more affected). He also had mild postural tremor of both legs. There was slight slowness in repetitive finger tapping tasks without true bradykinesia and a pallhypaesthesia in both legs. The neurological examination was otherwise unremarkable (see Video, segment 1). MRI of the brain and DAT-SPECT were normal. Neuropsychological assessment revealed an impairment of executive functions and language skills. Supplementary data related to this article can be found online at http://dx.doi.org/10.1016/j.parkreldis.2013.11.010. 3.1.2. Patient 2 This 29-years-old man with KS (diagnosed at age 18) was referred in 2009 because of disabling arm tremor. He was treated with testosterone which had no effect on the tremor. Tremor had started in his left arm at age three. During childhood he further developed a tremor in the right arm, head, both legs and an intermittent voice tremor. In school he suffered from attention deficit disorder, mood instability, and short-temperedness. He finished a traineeship as electrician, but was unable to practice this job due to the tremor. Family history for tremor was negative, he reported no alcohol response and propranolol (30 mg/day, side effects with hypotension and bradycardia), clonazepam (2 mg/day), primidone (250 mg/ day), and topiramate (200 mg/day) were tried without benefit. Clinical examination at age 26 showed mild head and rest tremor of both hands, severe asymmetric postural and action tremor of both arms, and mild postural leg tremor. Brain MRI, F-Dopa-PET, and EEG were normal. Cognitive testing revealed mild attention deficit and slight deficits in verbal fluency. Because of the disabling arm tremor, DBS of the VIM was performed in 2009. This led to cessation of the tremor of the right arm and marked improvement on the left side. Due to skin ulcerations around the pacemaker and cranial leads five reoperations were necessary within two years postoperatively. Finally re-implantation and repair by a rotation flap were performed. Since then, stimulation significantly improved his tremor without any further complications. There was no more head or leg tremor, no tremor of the right upper limb and only a slight postural and action tremor on the left side. The patient started a traineeship as design draftsman (also see Video, segments 2 and 3). 3.1.3. Patient 3 This 24-years-old man presented in 2011 to our outpatient clinic because of bilateral upper limb tremor that had started in childhood and was aggravated by stress. Tremor was mild but bothersome, also during activities such as writing. KS was diagnosed in adolescence and testosterone therapy was started without improvement of the tremor. There was no family history of tremor, no clear alcohol effect, and no anti-tremulous drugs had been tried so far. Neurological examination showed a mild postural and action tremor of both arms, predominantly on the left side. There was mild cogwheeling on the left arm, but no rigidity and no bradykinesia. Brain MRI and DAT-SPECT were normal. Propranolol (30 mg/day, side effects with sleepiness) led to mild reduction of the tremor.
3.2. Tremor-analysis Patients 1 and 2 had a 5e7 Hz asymmetric tremor during rest, posture, and action. Patient 3 had no rest tremor and a smaller amplitude but higher frequency (8e10 Hz) tremor during posture and action. For further details see Table 1. 3.3. Literature review An overview of the literature regarding KS patients with tremor is provided in Table 2. 4. Discussion From a phenomenological point of view, tremor in our patients and in most cases from literature was predominantly a postural and kinetic tremor resembling ET. Previous reports had suggested a potential ET-KS association [2], although epidemiological studies regarding the prevalence of tremor in KS are lacking. A recent questionnaire-based screening study showed a significant increase of tremor frequency in KS patients (63%) versus controls (14%) [3]. However, if patients with KS and tremor truly suffer from ET or an ET-like syndrome remains unknown. We have for the first time performed a detailed tremor analysis using accelerometry and surface EMG, which showed a tremor in concordance, but not specific for ET. For the first time, we report a normal DAT-SPECT or
Table 1 Tremor characteristics in our patients assessed by accelerometry and surface EMG.
Rest right arm Rest left arm Posture right arm Posture left arm Posture with loading right Posture with l oading left Action right arm Action left arm EMG burst duration Phase-analysis Test battery e psychogenic versus organic tremora Corresponding peaks in the frequency power spectra of accelerometry and EMG e “frequency invariantb” with loading
Peak frequency (Hz) Total power (milliG) Peak frequency (Hz) Total power (milliG) Peak frequency (Hz) Total power (milliG) Peak frequency (Hz) Total power (milliG) Peak frequency (Hz) Total power (milliG) Peak frequency (Hz) Total power (milliG) Peak frequency (Hz) Total power (milliG) Peak frequency (Hz) Total power (milliG) Mean SD (milliseconds) degrees Range 0e10 points
Patient 1
Patient 2 (off stim)
Patient 3
5.9 0.46 6.2 0.13 6.2 10.22 5.9 28.50 6.8 30.30 6.2 55.58 6.8 17.11 6.8 34.92 87 2
5.9 0.01 4.9 0.26 6.2 1.25 5.2 8.98 6.5 3.26 5,9 5.20 7.2 4.88 6.2 15.20 86 2
NA NA NA NA 7.8 0.04 9.8 0.11 9.1 0.07 9.1 0.22 8.5 0.31 8.5 1.58 731
44 0
30 1
133 0
Yes
Yes
Yes
Hz, hertz; G, gravity; NA, not applicable (no tremor); off stim, deep brain stimulation turned off. a Test battery (0e10 points): Cut-off score for a diagnosis of laboratory-supported psychogenic tremor was defined as 3 out of 10 points [6]. b Frequency invariant with loading: corresponding EMG peak with the accelerometry power spectrum peak, which does not decrease in frequency by more than 1Hz after loading
Table 2 Characteristics of tremor in Klinefelter syndrome (KS) and KS variants. Literature
Karyotype
Phenomenology
Tremor analysis
Age at tremor onset
FH of tremor
Alcohol response
Response to antitremulous drugs
Testosterone therapy
1
Finley et al. [esupp ref 1]
47XXY/ 48XXXY
NA
15
Negative
NA
NA
No
2
Zuppinger et al. [esupp ref 2]
47XXY
Fine irregular tremor of hands, exacerbated with stress Tremor of both arms Coarse tremor of both hands Unilateral arm tremor Coarse tremor of both hands Tremor Action tremor upper limbs Severe action tremor upper limbs Severe postural and action tremor of arms Mild postural and action tremor of arms Mild postural and action tremor of arms Moderate postural and action tremor of arms Moderate postural and action tremor of arms Mild postural and action tremor of arms Moderate postural and action tremor of arms Moderate postural and action tremor of arms, head tremor Mild rest and marked action tremor
NA
10
NA
NA
NA
Yes
NA
NA
NA
NA
NA
Yes
NA
NA
NA
NA
NA
Yes
NA
NA
NA
NA
NA
Yes
NA NA
NA 11
NA NA
NA NA
Yes NA
NA
Graduate school
NA Paternal grandfather Negative
NA
NA
NA
NA
Childhood
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
Negative
yes
NA
Mild postural and/ or intention tremor
Mean tremor frequency 8.1Hz
NA
Positive (1) Negative (5)
NA
Improvement to propranolol (120mg/day) NA
Marked intention tremor of both upper limbs, right >left, marked head tremor
NA
4
Positive (one paternal and several
NA
Propranolol and primidone without benefit; modest benefit with
Yes
3
47XXY
4
47XXY
5
47XXY
6 7
Baughmann et al. [esupp ref 3]
8
9
47XXY 47XXY 48XXYY
Baughmann et al. [2]
48XXXY
10
47XXY
11
47XXY
12
48XXXY
13
48XXYY
14 15
47XXY/ 48XXXY 49XXXXY
16
47XXY
17
Boltshauser et al. [esupp ref 4]
47XXY
18
Boisen et al. [esupp ref 5]
47XXY
19 20 21 22 23 24
Telfeian et al. [4]
47XXY 47XXY 47XXY 47XXY 47XXY 47XXY
M. Koegl-Wallner et al. / Parkinsonism and Related Disorders 20 (2014) 323e327
N
NA
325
(continued on next page)
N
Literature
326
Table 2 (continued ) Karyotype
Phenomenology
Tremor analysis
Age at tremor onset
FH of tremor
Alcohol response
maternal great aunts)
Harlow et al. [esupp ref 6]
47XXY
26
Tartaglia et al. [esupp ref 7]
48XXYY
27
48XXYY
28
48XXYY
29
48XXYY
30
48XXYY
31
48XXYY
32
48XXYY
33
48XXYY
34
48XXYY
35 36
Rabin et al. [5]
37
48XXYY 47XXY
47XXY
38
Kinoshita et al. [esupp ref 8]
47XXY
39
Coutinho et al. [esupp ref 9]
47XXY
Moderate head tremor, mild vocal tremor, severe symmetric bilateral upper limb action tremor (kinetic and intention more than postural tremor) Kinetic and postural tremor Kinetic and postural tremor Intention and postural tremor Mild postural and kinetic tremor Mild postural and kinetic tremor Mild kinetic and postural tremor Mild kinetic and postural tremor Unilateral kinetic tremor Mild postural and kinetic tremor Kinetic tremor Severe postural and intention tremor of arms (right more than left), also rest tremor Bilateral rest tremor only Postural tremor of hands, exacerbation with stress Postural and action tremor of both hands, rest tremor
clonazepam; VIM-DBS: 95% tremor reduction right arm and improvement of head tremor Primidone and gabapentin without benefit
Testosterone therapy
Yes (no improvement of tremora)
NA
63
Negative
NA
NA
7
Positive
NA
NA
Yes
NA
4
Positive
NA
NA
NA
NA
10
Negative
NA
NA
Yes
NA
16
Negative
NA
NA
Yes
NA
3
Positive
NA
NA
NA
NA
12
Negative
NA
NA
NA
NA
15
Positive
NA
NA
NA
NA
9
Negative
NA
NA
NA
NA
11
Positive
NA
NA
NA
NA NA
9 7
Negative NA
NA NA
NA NA
NA
55
NA
NA
NA Primidone, propranolol, atenolol and topiramate without benefit; DBS (VIM) at age 18 with marked tremor reduction Topiramate without benefit
NA
61
NA
NA
No antitremor drugs tried
Yes (improvement of tremora)
5e6 Hz rest tremor, 11 Hz postural tremor of all limbs, mainly kinetic and intentional on the left
14
Positive (two sisters, 1 paternal uncle)
NA
Primidone without benefit
NA
N, case number; FH, family history; NA, not applicable (not performed/ information not available). a Effect of testosterone on tremor mentioned in article. Full references are available in the online version.
Yes
M. Koegl-Wallner et al. / Parkinsonism and Related Disorders 20 (2014) 323e327
25
Response to antitremulous drugs
M. Koegl-Wallner et al. / Parkinsonism and Related Disorders 20 (2014) 323e327
F-DOPA-PET in all three patients, supporting the integrity of the nigrostriatal system in this disorder. Furthermore we have reported other characteristics relevant in patients with tremor such as alcohol responsiveness, family history, age at tremor onset, and treatment response. Unfortunately these data are lacking in most previous reports. ET shows a positive response to alcohol in two thirds of patients [7]. None of our patients reported a positive alcohol effect. No conclusions regarding alcohol responsiveness can be drawn from the literature review, since this was documented on for one case only (as positive). Only 1/3 patients reported here (maternal grandfather) and 9/39 patients from literature had a positive family history for tremor, while this is reported in up to 80% of young onset cases with ET [8]. While a bimodal age at onset (2nd and 6th decade) has been reported for ET by some authors [7], others have suggested a mean age of onset of 15 years or 40 years in familial, and 50 years in sporadic cases [9]. In contrast, 18/21 cases from the literature, in which the relevant information was available, had a tremor onset in childhood or adolescence, and only three cases had tremor onset after the age of 50 years. All our patients reported tremor onset in childhood. Two of our three patients had a rest tremor in addition to a postural and kinetic tremor, with the rest tremor component having the smallest amplitude (see Table 2). Although rest tremor in ET is a controversial issue and some authors have raised the question if ET patients with rest tremor rather have a dystonic tremor even in the absence of overt dystonia [10], most authors accept ET with rest tremor as an ET subtype occurring in 14e18% of patients [11]. Therefore the presence of a rest tremor in patients with KS does neither support nor refute its link to ET. Propranolol and Primidone are estimated to be effective in 30e 70% of ET patients [12]. Regarding treatment response in KSassociated tremor, patient 1 reported only a transient benefit from propranolol (120 mg/day) and patient 3 (30 mg/day) showed only mild benefit. According to medical records, all other drugs tried in our patients had no effect e at least at the maximum prescribed and tolerated dosage. Drugs tried for tremor are only documented in 6/39 cases from literature, with one patient showing a benefit to propranolol and one to clonazepam. None of our patients noted a tremor reduction with testosterone. Response to oral drug treatment remains inconclusive, since the dosage tried was not appropriate in some cases and length of treatment and objective evaluation of the improvement is not available. Patient 2 underwent VIM-DBS with marked objective tremor reduction. However, recurrent device-related skin ulcerations made reoperation necessary five times. Two KS patients reported in the literature underwent VIM-DBS and showed marked tremor reduction [4,5]. Postoperative complications are not reported. Further studies in a larger patient cohort are warranted to investigate if alcohol responsiveness, family history, and age at tremor onset differ between ET and KS-associated tremor. Among patients with other diagnoses, skin erosions/ulcerations around the DBS-impulse generator, burr hole cap, and along the course of the cables occur in up to 24.7% [13] typically caused by underlying pressure from the leads against the skin or lead migration. Up to 13% of KS patients suffer from wound healing disorders and leg ulcers, often without a history of chronic venous insufficiency or deep venous thrombosis, possibly related to a higher plasma level of plasminogen activator inhibitor-1 (PAI-1)
327
(PAI-1 was not assessed in patient 2) [14]. If KS itself represents a risk factor for DBS-related skin complications needs to be evaluated in future studies. In conclusion, we confirm that tremor in KS clinically and electrophysiologically resembles ET. If other characteristics such as family history, alcohol responsiveness, and age at tremor onset may serve as discriminating factors from ET, needs to be further investigated. VIM-DBS was effective in one patient reported here and in two patients reported in literature and may therefore be considered as a treatment option in KS patients with severe disabling arm tremor. Conflicts of interest The authors declare that they have no conflict of interest related to this study. Acknowledgments The authors thank Dr. Barbara Pendl for referral of patients and thank all patients for their contribution to this research. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.parkreldis.2013.11.010. References [1] Lanfranco F, Kamischke A, Zitzmann M, Nieschlag E. Klinefelter’s syndrome. Lancet 2004;364:273e83. [2] Baughman Jr FA, Higgins JV, Mann JD. Sex chromosome anomalies and essential tremor. Neurology 1973;23:623e5. [3] Harlow TL, Gonzalez-Alegre P. High prevalence of reported tremor in Klinefelter syndrome. Parkinsonism Relat Disord 2009;15:393e5. [4] Telfeian AE, Boockvar JA, Simuni T, Jaggi J, Skolnick B, Baltuch GH. Efficacy of unilateral deep brain stimulation of the thalamic ventralis intermedius nucleus in a patient with bipolar disorder associated with Klinefelter syndrome and essential tremor. Case report. J Neurosurg 2000;93:127e8. [5] Rabin ML, Moghimi N, Jabbari B. Tremor and Klinefelter’s syndrome. Mov Disord 2011;26:S381. [6] Schwingenschuh P, Katschnig P, Seiler S, Saifee TA, Aguirregomozcorta M, Cordivari C, et al. Moving toward “laboratory-supported” criteria for psychogenic tremor. Mov Disord 2011;26:2509e15. [7] Lou JS, Jankovic J. Essential tremor: clinical correlates in 350 patients. Neurology 1991;41:234e8. [8] Deng H, Le W, Jankovic J. Genetics of essential tremor. Brain 2007;130:1456e 64. [9] Koller WC, Busenbark K, Miner K. The relationship of essential tremor to other movement disorders: report on 678 patients. Essential Tremor Study Group. Ann Neurol 1994;35:717e23. [10] Nistico R, Pirritano D, Novellino F, Salsone M, Morelli M, Valentino P, et al. Blink reflex recovery cycle in patients with essential tremor associated with rest tremor. Neurology 2012;79(14):1490e5. [11] Whaley NR, Jd Putzke, Baba Y, Wszolek ZK, Uitti RJ. Essential tremor: phenotypic expression in a clinical cohort. Parkinsoism Relat Disord 2007;13: 333e9. [12] Benito-Leon j, Louis ED. Update on essential tremor. Minerva Med 2011;102: 417e40. [13] Sixel-Doring F, Trenkwalder C, Kappus C, Hellwig D. Skin complications in deep brain stimulation for Parkinson’s disease: frequency, time course, and risk factors. Acta Neurochir (Wien) 2010;152:195e200. [14] Zollner TM, Veraart JC, Wolter M, Hesse S, Villemur B, Wenke A, et al. Leg ulcers in Klinefelter’s syndromeefurther evidence for an involvement of plasminogen activator inhibitor-1. Br J Dermatol 1997;136:341e4.
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Short communication
Tremor associated with Klinefelter syndrome e A case series and review of the literature Mariella Koegl-Wallner a, Petra Katschnig-Winter a, Tamara Pendl a, Barbara Melisch a, Martin Trummer b, Etienne Holl b, Ulrike Werner a, Reinhold Schmidt a, Petra Schwingenschuh a, * a b
Department of Neurology, Medical University of Graz, Auenbruggerplatz 22, 8036 Graz, Austria Department of Neurosurgery, Medical University of Graz, Graz, Austria
a r t i c l e i n f o
a b s t r a c t
Article history: Received 4 May 2013 Received in revised form 25 October 2013 Accepted 14 November 2013
Background: Previous case series suggested a link between Klinefelter syndrome (KS) and essential tremor (ET) or an ET-like syndrome. Methods: We investigated three KS-patients with tremor including tremor-analyzes and discuss our data in context to findings from a literature review. The clinical outcome after deep brain stimulation (DBS) is also reviewed. Results: Tremor in KS is predominantly a postural and kinetic tremor that resembles ET. Our patients were further characterized by absent family history for tremor in first degree relatives, lack of subjective alcohol responsiveness inquired by history, and tremor onset in childhood. One of our patients and two cases from literature improved after DBS of the ventral intermediate nucleus (VIM) of the thalamus. Conclusions: Tremor in KS shares several features with ET. If other characteristics such as family history, alcohol responsiveness, and age at tremor onset may serve as discriminating factors from ET, needs to be further investigated. First observations suggest that VIM-DBS may be efficacious. Ó 2013 Elsevier Ltd. All rights reserved.
Keywords: Klinefelter syndrome Essential tremor Deep brain stimulation DBS Tremor analysis
1. Introduction Klinefelter Syndrome (KS) is the most frequent sex chromosome abnormality among males (1:700) and the most common cause of male infertility. Before puberty physical anomalies are discrete. Thereafter the usually tall patients have small firm testes, gynecomastia in about 50%, varying symptoms of androgen deficiency, and a characteristic cognitive and behavioral syndrome. Testosterone replacement therapy should be started as soon as possible [1]. Previous case series suggested a link between KS and essential tremor (ET) or an ET-like syndrome [2]. A questionnaire-based study showed a significantly higher tremor frequency in KS compared to controls with onset at a younger age [3]. The pathophysiology of the tremor is unclear. Two cases with marked improvement from deep brain stimulation (DBS) of the ventral intermediate nucleus (VIM) of the thalamus were reported [4,5]. 2. Methods We present three patients with KS (47XXY) and an ET-like tremor syndrome and a review of the literature. Tremor-analysis was * Corresponding author. Tel.: þ43 316 385 83379. E-mail address: [email protected] (P. Schwingenschuh). 1353-8020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.parkreldis.2013.11.010
performed in our patients. The study was approved by the local ethics committee and was conducted in accordance with the Declaration of Helsinki. All procedures were carried out with the adequate understanding and written consent of the subjects involved. 2.1. Tremor-analysis A triaxial accelerometer transducer was attached to the middle phalanx of the index finger bilaterally. Surface electromyography (EMG) was recorded from wrist flexors and wrist extensors. Tremor was recorded during rest, posture (500 g loading), and action (fingere nose-testing). Data were analyzed as previously described [6]. 3. Results 3.1. Case reports 3.1.1. Patient 1 In 2011 this 51-years-old man presented with disabling arm tremor. Tremor had started at age ten in his arms and head and had increased during the past five years resulting in early retirement. The patient reported a positive family history for tremor (maternal grandfather), exacerbation of tremor by stress, and lack of alcohol
324
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responsiveness. At age 14 he had reached a height of 195 cm, there were no learning difficulties in school, but mild mood instability and low self-esteem. Because of infertility, KS was diagnosed at age 36, and testosterone replacement therapy was started without tremor improvement. Propranolol (120 mg/day) had only a transient effect on the tremor, all other drugs including topiramate (100 mg/day), clonazepam (1 mg/day), primidone (250 mg/day), gabapentin (1200 mg/day), and nimodipine had no benefit. Neurological examination showed mild head and voice tremor, mild intermittent rest tremor of both hands, and moderate bilateral asymmetric postural and action tremor of the upper limbs (left side more affected). He also had mild postural tremor of both legs. There was slight slowness in repetitive finger tapping tasks without true bradykinesia and a pallhypaesthesia in both legs. The neurological examination was otherwise unremarkable (see Video, segment 1). MRI of the brain and DAT-SPECT were normal. Neuropsychological assessment revealed an impairment of executive functions and language skills. Supplementary data related to this article can be found online at http://dx.doi.org/10.1016/j.parkreldis.2013.11.010. 3.1.2. Patient 2 This 29-years-old man with KS (diagnosed at age 18) was referred in 2009 because of disabling arm tremor. He was treated with testosterone which had no effect on the tremor. Tremor had started in his left arm at age three. During childhood he further developed a tremor in the right arm, head, both legs and an intermittent voice tremor. In school he suffered from attention deficit disorder, mood instability, and short-temperedness. He finished a traineeship as electrician, but was unable to practice this job due to the tremor. Family history for tremor was negative, he reported no alcohol response and propranolol (30 mg/day, side effects with hypotension and bradycardia), clonazepam (2 mg/day), primidone (250 mg/ day), and topiramate (200 mg/day) were tried without benefit. Clinical examination at age 26 showed mild head and rest tremor of both hands, severe asymmetric postural and action tremor of both arms, and mild postural leg tremor. Brain MRI, F-Dopa-PET, and EEG were normal. Cognitive testing revealed mild attention deficit and slight deficits in verbal fluency. Because of the disabling arm tremor, DBS of the VIM was performed in 2009. This led to cessation of the tremor of the right arm and marked improvement on the left side. Due to skin ulcerations around the pacemaker and cranial leads five reoperations were necessary within two years postoperatively. Finally re-implantation and repair by a rotation flap were performed. Since then, stimulation significantly improved his tremor without any further complications. There was no more head or leg tremor, no tremor of the right upper limb and only a slight postural and action tremor on the left side. The patient started a traineeship as design draftsman (also see Video, segments 2 and 3). 3.1.3. Patient 3 This 24-years-old man presented in 2011 to our outpatient clinic because of bilateral upper limb tremor that had started in childhood and was aggravated by stress. Tremor was mild but bothersome, also during activities such as writing. KS was diagnosed in adolescence and testosterone therapy was started without improvement of the tremor. There was no family history of tremor, no clear alcohol effect, and no anti-tremulous drugs had been tried so far. Neurological examination showed a mild postural and action tremor of both arms, predominantly on the left side. There was mild cogwheeling on the left arm, but no rigidity and no bradykinesia. Brain MRI and DAT-SPECT were normal. Propranolol (30 mg/day, side effects with sleepiness) led to mild reduction of the tremor.
3.2. Tremor-analysis Patients 1 and 2 had a 5e7 Hz asymmetric tremor during rest, posture, and action. Patient 3 had no rest tremor and a smaller amplitude but higher frequency (8e10 Hz) tremor during posture and action. For further details see Table 1. 3.3. Literature review An overview of the literature regarding KS patients with tremor is provided in Table 2. 4. Discussion From a phenomenological point of view, tremor in our patients and in most cases from literature was predominantly a postural and kinetic tremor resembling ET. Previous reports had suggested a potential ET-KS association [2], although epidemiological studies regarding the prevalence of tremor in KS are lacking. A recent questionnaire-based screening study showed a significant increase of tremor frequency in KS patients (63%) versus controls (14%) [3]. However, if patients with KS and tremor truly suffer from ET or an ET-like syndrome remains unknown. We have for the first time performed a detailed tremor analysis using accelerometry and surface EMG, which showed a tremor in concordance, but not specific for ET. For the first time, we report a normal DAT-SPECT or
Table 1 Tremor characteristics in our patients assessed by accelerometry and surface EMG.
Rest right arm Rest left arm Posture right arm Posture left arm Posture with loading right Posture with l oading left Action right arm Action left arm EMG burst duration Phase-analysis Test battery e psychogenic versus organic tremora Corresponding peaks in the frequency power spectra of accelerometry and EMG e “frequency invariantb” with loading
Peak frequency (Hz) Total power (milliG) Peak frequency (Hz) Total power (milliG) Peak frequency (Hz) Total power (milliG) Peak frequency (Hz) Total power (milliG) Peak frequency (Hz) Total power (milliG) Peak frequency (Hz) Total power (milliG) Peak frequency (Hz) Total power (milliG) Peak frequency (Hz) Total power (milliG) Mean SD (milliseconds) degrees Range 0e10 points
Patient 1
Patient 2 (off stim)
Patient 3
5.9 0.46 6.2 0.13 6.2 10.22 5.9 28.50 6.8 30.30 6.2 55.58 6.8 17.11 6.8 34.92 87 2
5.9 0.01 4.9 0.26 6.2 1.25 5.2 8.98 6.5 3.26 5,9 5.20 7.2 4.88 6.2 15.20 86 2
NA NA NA NA 7.8 0.04 9.8 0.11 9.1 0.07 9.1 0.22 8.5 0.31 8.5 1.58 731
44 0
30 1
133 0
Yes
Yes
Yes
Hz, hertz; G, gravity; NA, not applicable (no tremor); off stim, deep brain stimulation turned off. a Test battery (0e10 points): Cut-off score for a diagnosis of laboratory-supported psychogenic tremor was defined as 3 out of 10 points [6]. b Frequency invariant with loading: corresponding EMG peak with the accelerometry power spectrum peak, which does not decrease in frequency by more than 1Hz after loading
Table 2 Characteristics of tremor in Klinefelter syndrome (KS) and KS variants. Literature
Karyotype
Phenomenology
Tremor analysis
Age at tremor onset
FH of tremor
Alcohol response
Response to antitremulous drugs
Testosterone therapy
1
Finley et al. [esupp ref 1]
47XXY/ 48XXXY
NA
15
Negative
NA
NA
No
2
Zuppinger et al. [esupp ref 2]
47XXY
Fine irregular tremor of hands, exacerbated with stress Tremor of both arms Coarse tremor of both hands Unilateral arm tremor Coarse tremor of both hands Tremor Action tremor upper limbs Severe action tremor upper limbs Severe postural and action tremor of arms Mild postural and action tremor of arms Mild postural and action tremor of arms Moderate postural and action tremor of arms Moderate postural and action tremor of arms Mild postural and action tremor of arms Moderate postural and action tremor of arms Moderate postural and action tremor of arms, head tremor Mild rest and marked action tremor
NA
10
NA
NA
NA
Yes
NA
NA
NA
NA
NA
Yes
NA
NA
NA
NA
NA
Yes
NA
NA
NA
NA
NA
Yes
NA NA
NA 11
NA NA
NA NA
Yes NA
NA
Graduate school
NA Paternal grandfather Negative
NA
NA
NA
NA
Childhood
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
Negative
yes
NA
Mild postural and/ or intention tremor
Mean tremor frequency 8.1Hz
NA
Positive (1) Negative (5)
NA
Improvement to propranolol (120mg/day) NA
Marked intention tremor of both upper limbs, right >left, marked head tremor
NA
4
Positive (one paternal and several
NA
Propranolol and primidone without benefit; modest benefit with
Yes
3
47XXY
4
47XXY
5
47XXY
6 7
Baughmann et al. [esupp ref 3]
8
9
47XXY 47XXY 48XXYY
Baughmann et al. [2]
48XXXY
10
47XXY
11
47XXY
12
48XXXY
13
48XXYY
14 15
47XXY/ 48XXXY 49XXXXY
16
47XXY
17
Boltshauser et al. [esupp ref 4]
47XXY
18
Boisen et al. [esupp ref 5]
47XXY
19 20 21 22 23 24
Telfeian et al. [4]
47XXY 47XXY 47XXY 47XXY 47XXY 47XXY
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N
NA
325
(continued on next page)
N
Literature
326
Table 2 (continued ) Karyotype
Phenomenology
Tremor analysis
Age at tremor onset
FH of tremor
Alcohol response
maternal great aunts)
Harlow et al. [esupp ref 6]
47XXY
26
Tartaglia et al. [esupp ref 7]
48XXYY
27
48XXYY
28
48XXYY
29
48XXYY
30
48XXYY
31
48XXYY
32
48XXYY
33
48XXYY
34
48XXYY
35 36
Rabin et al. [5]
37
48XXYY 47XXY
47XXY
38
Kinoshita et al. [esupp ref 8]
47XXY
39
Coutinho et al. [esupp ref 9]
47XXY
Moderate head tremor, mild vocal tremor, severe symmetric bilateral upper limb action tremor (kinetic and intention more than postural tremor) Kinetic and postural tremor Kinetic and postural tremor Intention and postural tremor Mild postural and kinetic tremor Mild postural and kinetic tremor Mild kinetic and postural tremor Mild kinetic and postural tremor Unilateral kinetic tremor Mild postural and kinetic tremor Kinetic tremor Severe postural and intention tremor of arms (right more than left), also rest tremor Bilateral rest tremor only Postural tremor of hands, exacerbation with stress Postural and action tremor of both hands, rest tremor
clonazepam; VIM-DBS: 95% tremor reduction right arm and improvement of head tremor Primidone and gabapentin without benefit
Testosterone therapy
Yes (no improvement of tremora)
NA
63
Negative
NA
NA
7
Positive
NA
NA
Yes
NA
4
Positive
NA
NA
NA
NA
10
Negative
NA
NA
Yes
NA
16
Negative
NA
NA
Yes
NA
3
Positive
NA
NA
NA
NA
12
Negative
NA
NA
NA
NA
15
Positive
NA
NA
NA
NA
9
Negative
NA
NA
NA
NA
11
Positive
NA
NA
NA
NA NA
9 7
Negative NA
NA NA
NA NA
NA
55
NA
NA
NA Primidone, propranolol, atenolol and topiramate without benefit; DBS (VIM) at age 18 with marked tremor reduction Topiramate without benefit
NA
61
NA
NA
No antitremor drugs tried
Yes (improvement of tremora)
5e6 Hz rest tremor, 11 Hz postural tremor of all limbs, mainly kinetic and intentional on the left
14
Positive (two sisters, 1 paternal uncle)
NA
Primidone without benefit
NA
N, case number; FH, family history; NA, not applicable (not performed/ information not available). a Effect of testosterone on tremor mentioned in article. Full references are available in the online version.
Yes
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25
Response to antitremulous drugs
M. Koegl-Wallner et al. / Parkinsonism and Related Disorders 20 (2014) 323e327
F-DOPA-PET in all three patients, supporting the integrity of the nigrostriatal system in this disorder. Furthermore we have reported other characteristics relevant in patients with tremor such as alcohol responsiveness, family history, age at tremor onset, and treatment response. Unfortunately these data are lacking in most previous reports. ET shows a positive response to alcohol in two thirds of patients [7]. None of our patients reported a positive alcohol effect. No conclusions regarding alcohol responsiveness can be drawn from the literature review, since this was documented on for one case only (as positive). Only 1/3 patients reported here (maternal grandfather) and 9/39 patients from literature had a positive family history for tremor, while this is reported in up to 80% of young onset cases with ET [8]. While a bimodal age at onset (2nd and 6th decade) has been reported for ET by some authors [7], others have suggested a mean age of onset of 15 years or 40 years in familial, and 50 years in sporadic cases [9]. In contrast, 18/21 cases from the literature, in which the relevant information was available, had a tremor onset in childhood or adolescence, and only three cases had tremor onset after the age of 50 years. All our patients reported tremor onset in childhood. Two of our three patients had a rest tremor in addition to a postural and kinetic tremor, with the rest tremor component having the smallest amplitude (see Table 2). Although rest tremor in ET is a controversial issue and some authors have raised the question if ET patients with rest tremor rather have a dystonic tremor even in the absence of overt dystonia [10], most authors accept ET with rest tremor as an ET subtype occurring in 14e18% of patients [11]. Therefore the presence of a rest tremor in patients with KS does neither support nor refute its link to ET. Propranolol and Primidone are estimated to be effective in 30e 70% of ET patients [12]. Regarding treatment response in KSassociated tremor, patient 1 reported only a transient benefit from propranolol (120 mg/day) and patient 3 (30 mg/day) showed only mild benefit. According to medical records, all other drugs tried in our patients had no effect e at least at the maximum prescribed and tolerated dosage. Drugs tried for tremor are only documented in 6/39 cases from literature, with one patient showing a benefit to propranolol and one to clonazepam. None of our patients noted a tremor reduction with testosterone. Response to oral drug treatment remains inconclusive, since the dosage tried was not appropriate in some cases and length of treatment and objective evaluation of the improvement is not available. Patient 2 underwent VIM-DBS with marked objective tremor reduction. However, recurrent device-related skin ulcerations made reoperation necessary five times. Two KS patients reported in the literature underwent VIM-DBS and showed marked tremor reduction [4,5]. Postoperative complications are not reported. Further studies in a larger patient cohort are warranted to investigate if alcohol responsiveness, family history, and age at tremor onset differ between ET and KS-associated tremor. Among patients with other diagnoses, skin erosions/ulcerations around the DBS-impulse generator, burr hole cap, and along the course of the cables occur in up to 24.7% [13] typically caused by underlying pressure from the leads against the skin or lead migration. Up to 13% of KS patients suffer from wound healing disorders and leg ulcers, often without a history of chronic venous insufficiency or deep venous thrombosis, possibly related to a higher plasma level of plasminogen activator inhibitor-1 (PAI-1)
327
(PAI-1 was not assessed in patient 2) [14]. If KS itself represents a risk factor for DBS-related skin complications needs to be evaluated in future studies. In conclusion, we confirm that tremor in KS clinically and electrophysiologically resembles ET. If other characteristics such as family history, alcohol responsiveness, and age at tremor onset may serve as discriminating factors from ET, needs to be further investigated. VIM-DBS was effective in one patient reported here and in two patients reported in literature and may therefore be considered as a treatment option in KS patients with severe disabling arm tremor. Conflicts of interest The authors declare that they have no conflict of interest related to this study. Acknowledgments The authors thank Dr. Barbara Pendl for referral of patients and thank all patients for their contribution to this research. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.parkreldis.2013.11.010. References [1] Lanfranco F, Kamischke A, Zitzmann M, Nieschlag E. Klinefelter’s syndrome. Lancet 2004;364:273e83. [2] Baughman Jr FA, Higgins JV, Mann JD. Sex chromosome anomalies and essential tremor. Neurology 1973;23:623e5. [3] Harlow TL, Gonzalez-Alegre P. High prevalence of reported tremor in Klinefelter syndrome. Parkinsonism Relat Disord 2009;15:393e5. [4] Telfeian AE, Boockvar JA, Simuni T, Jaggi J, Skolnick B, Baltuch GH. Efficacy of unilateral deep brain stimulation of the thalamic ventralis intermedius nucleus in a patient with bipolar disorder associated with Klinefelter syndrome and essential tremor. Case report. J Neurosurg 2000;93:127e8. [5] Rabin ML, Moghimi N, Jabbari B. Tremor and Klinefelter’s syndrome. Mov Disord 2011;26:S381. [6] Schwingenschuh P, Katschnig P, Seiler S, Saifee TA, Aguirregomozcorta M, Cordivari C, et al. Moving toward “laboratory-supported” criteria for psychogenic tremor. Mov Disord 2011;26:2509e15. [7] Lou JS, Jankovic J. Essential tremor: clinical correlates in 350 patients. Neurology 1991;41:234e8. [8] Deng H, Le W, Jankovic J. Genetics of essential tremor. Brain 2007;130:1456e 64. [9] Koller WC, Busenbark K, Miner K. The relationship of essential tremor to other movement disorders: report on 678 patients. Essential Tremor Study Group. Ann Neurol 1994;35:717e23. [10] Nistico R, Pirritano D, Novellino F, Salsone M, Morelli M, Valentino P, et al. Blink reflex recovery cycle in patients with essential tremor associated with rest tremor. Neurology 2012;79(14):1490e5. [11] Whaley NR, Jd Putzke, Baba Y, Wszolek ZK, Uitti RJ. Essential tremor: phenotypic expression in a clinical cohort. Parkinsoism Relat Disord 2007;13: 333e9. [12] Benito-Leon j, Louis ED. Update on essential tremor. Minerva Med 2011;102: 417e40. [13] Sixel-Doring F, Trenkwalder C, Kappus C, Hellwig D. Skin complications in deep brain stimulation for Parkinson’s disease: frequency, time course, and risk factors. Acta Neurochir (Wien) 2010;152:195e200. [14] Zollner TM, Veraart JC, Wolter M, Hesse S, Villemur B, Wenke A, et al. Leg ulcers in Klinefelter’s syndromeefurther evidence for an involvement of plasminogen activator inhibitor-1. Br J Dermatol 1997;136:341e4.
