Unusual complication of deep brain stimulation in Parkinson\'s disease

Movement Disorders Vol. 24, No. 8, 2009, pp. 1241–1252 Ó 2009 Movement Disorder Society

Letters to the Editor Related to New Topics

We report the case of an 81-year-old patient with akineticrigid PD with marked sexual disinhibition. According to the proposed diagnostic criteria1 the patient fulfilled the criteria for impulse control disorders. There are several reports stating an association between dopaminergic medication and hypersexuality.1 Therefore, reduction in dopamine agonists leads to an amelioration and remission of compulsive behavior. Because of marked motor fluctuations, a reduction of dopamine agonists was not easily feasible in this patient. Despite their occurrence, treatment options so far are limited.4 Recently, we initiated treatment with CBZ in a patient with sexual disinhibition suffering from Alzheimer’s disease resulting in a remission of the behavior disturbance.3 We found a considerable amelioration of the patient’s symptoms using CBZ without significant increase in motor problems. A similar case report was recently reported with the use of gabapentin in three patients suffering from hypersexuality with a successful outcome.5 Freymann et al.3 speculate that one explanation for the efficacy of CBZ on hypersexual behavior is the reduction of testosterone by CBZ. It is known that CBZ induces enzymes such as the enzyme aromatase, which is responsible for the conversion of free testosterone to estradiol. Bauer et al.6 examined the concentration of various sex hormones in patients suffering from epilepsy, who were treated with different drugs. They found that patients treated with CBZ showed markedly reduced concentrations of free testosterone and hypothesized that enzyme inducing drugs such as CBZ increase the production of sexual hormone binding protein. This in turn lowers free testosterone levels. Furthermore, Voon and Fox2 hypothesize that dopaminergic agonists can alter reward learning and thereby falsely implies reward without an objective reward being present. This effect seems to be mediated by both pulsatile and tonic release of dopamine in the ventral striatum.2 Several groups have found that dopamine release in the central nervous system is influenced by inhibition of voltage-gated ion channels.7,8 Therefore, it is possible that CBZ alters secretion of dopamine and reduces reward seeking behavior in patients with PD, thereby alleviating the patient’s symptoms. Despite the marked decrease of sexual disinhibition following CBZ, the observed reduction in hypersexual behavior could be also due to a spontaneous remission. This is, however, highly unlikely since hypersexual behavior persisted for a substantial period of time and responded quickly and permanently to the treatment with CBZ. We therefore hypothesize that CBZ may alter both dopaminergic release in the CNS and may reduce the concentration of testosterone. This combined effect may cause a marked reduction in hypersexuality in affected patients. It must be kept in mind, however, that additional results from clinical studies are necessary to evaluate the role of CBZ in impulse control behavior before recommendations of its use can be posted.

Treatment of Hypersexuality in Parkinson’s Disease with Carbamazepine—A Case Report We present the clinical case of an 81-year-old patient with marked sexual disinhibition following dopaminergic therapy for idiopathic Parkinson’s disease (PD). Approximately 3% of all patients treated for PD suffer from sexual disinhibition, and this number doubles when treatment involves dopamine agonists.1 No data currently exists regarding sexual behavior in patients with PD without medication. So far, the exact pathophysiological mechanisms have not been elucidated, but there are considerations that persistent dopaminergic stimulation leads to severe dysregulation within the ventral striatum and other areas involved with reward and learning.2 An 81-year-old male person was diagnosed with PD at the age of 69 years. He suffered from rapid on-off and peak-dose dyskinesias following dopaminergic treatment. He received treatment with levodopa every 2.5 hours (total dose: 1050 mg) and tolcapone (qid). He was widowed and lived without any relatives. To cope with the daily problems associated with PD he had a full day and night care with nurses. Following the introduction of dopamine agonists (approximately after 10 months), he developed marked sexual disinhibition. He repeatedly requested sexual actions from the nurses and started compulsive masturbation. His behavior caused major distress for the caregivers and nonpharmacological measures for controlling of his sexual assaults and behavior were unsuccessful. This was pronounced during night-time and was not associated with hypomanic or a manic mood. Neither the caregivers nor the patient himself noted any other disturbance of behavior control. The patient did not tolerate a reduction of dopaminergic medication due to considerable deterioration of his motor function. The clinical examination revealed levodopa responsive PD of the akinetic-rigid type (Hoehn-and Yahr stage 5 in off). In the Mini-Mental Status, he scored 28 points. MRI showed generalized mild brain atrophy and minor vascular lesions. Standard laboratory values were within the normal range. As the patient did not want to be admitted to the hospital, we initiated the treatment with carbamazepine (CBZ).3 We started with 100 mg per day and increased it within 14 days to 200 mg per day, which was well tolerated. Sexual disinhibition returned to acceptable levels within 2 to 3 weeks as judged by the caregivers. Motor function did not deteriorate during the treatment with CBZ and there was no major sedative effect.

Published online 23 March 2009 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.22439

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Author Roles: J.-P. Bach: Conception and design of project, writing first draft of manuscript; F. Jessen: Conception, organization, and execution of the project; W.H. Oertel: Manuscript review and critique; R. Dodel: Conception and organization of the project, review and critique, assisting in first and final draft. Jan-Philipp Bach, MD Wolfgang H. Oertel, MD Richard Dodel, MD* Department of Neurology Philipps-University Marburg Marburg, Germany *E-mail: [email protected] Frank Jessen, MD Department of Psychiatry Friedrich-Wilhelms-University Bonn, Germany

References 1. Voon V, Hassan K, Zurowski M, et al. Prevalence of repetitive and reward-seeking behaviors in Parkinson disease. Neurology 2006;67: 1254–1257. 2. Voon V, Fox SH. Medication-related impulse control and repetitive behaviors in Parkinson disease. Arch Neurol 2007;64:1089–1096. 3. Freymann N, Michael R, Dodel R, Jessen F. Successful treatment of sexual disinhibition in dementia with carbamazepine—a case report. Pharmacopsychiatry 2005;38:144–145. 4. Stamey W, Jankovic J. Impulse control disorders and pathological gambling in patients with Parkinson disease. Neurologist 2008;14: 89–99. 5. Alkhalil C, Tanvir F, Alkhalil B, Lowenthal DT. Treatment of sexual disinhibition in dementia: case reports and review of the literature. Am J Ther 2004;11:231–235. 6. Bauer J, Blumenthal S, Reuber M, Stoffel-Wagner B. Epilepsy syndrome, focus location, and treatment choice affect testicular function in men with epilepsy. Neurology 2004;62:243–246. 7. Parada A, Soares-da-Silva P. The novel anticonvulsant BIA 2-093 inhibits transmitter release during opening of voltage-gated sodium channels: a comparison with carbamazepine and oxcarbazepine. Neurochem Int 2002;40:435–440. 8. Ichikawa J, Dai J, Meltzer HY. Lithium differs from anticonvulsant mood stabilizers in prefrontal cortical and accumbal dopamine release: role of 5-HT(1A) receptor agonism. Brain Res 2005; 1049:182–190.

Unilateral Rest Tremor in Vascular Parkinsonism Associated with a Contralateral Lesion of the Locus Coeruleus Video We report a 76 year-old man with pathologically proven vascular Parkinsonism who had slowly progressive and asymmetrical Parkinsonism with typical unilateral right upper limb Additional Supporting Information may be found in the online version of this article. Published online 7 April 2009 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.22513

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rest tremor. Postmortem examination revealed severe symmetrical bilateral degeneration of the substantia nigra (SN) but unilateral degeneration of the left locus coeruleus (LC). No Lewy bodies were present. We suggest that the unilateral LC lesion played a role in the pathogenesis of the contralateral rest tremor. In 1983, a 59 year-old man with diabetes presented with a 12 month history of intermittent rest tremor of the right hand and difficulty doing up buttons. He had a rest tremor of the right hand, and mild bilateral upper limb rigidity and akinesia that was worse on the right. CT brain showed mild cerebral atrophy. A clinical diagnosis was made of sporadic Parkinson’s disease (PD). Treatment with levodopa (L-Dopa)/carbidopa 100/10 t.d.s. was commenced 12 months later for increasing rest tremor and muscle aches, and increased over the next 10 years to 100/25 t.d.s. When reviewed in 1996 (video segment 1) he was taking L-Dopa/carbidopa 100/25 seven times a day. He had a narrow based gait with absent right arm swing, intermittent right wrist tremor when walking, and rhythmic tongue movements. There was no history of exposure to antiemetics or neuroleptics. A CT scan was reported as showing periventricular lucencies, and possible lacunes in the right lentiform nucleus. In 1998 (video segment 2), the patient’s parkinsonism remained well controlled. He was able to rise from a chair unassisted and had normal postural reflexes. There was an intermittent rest tremor of the right arm that appeared with mental distraction, a re-emergent right arm postural tremor of low amplitude with a latency to onset of several seconds, and moderate rigidity of the right arm with activation. He had slow facial dyskinesias. In 1999 the patient had a small cerebral infarct causing aphasia without motor deficit. His parkinsonism, however, did not change. The patient died in 2001. The pathological features are detailed in Figure 1A–J. Macroscopically there was bilateral depigmentation of the SN and unilateral depigmentation of the left LC. Lacunes were visible in the external globus pallidus bilaterally and right putamen, involving part of the internal capsule. Microscopically, there was symmetrical bilateral depigmentation and severe neuronal loss in the SN without Lewy bodies.1 In the LC and dorsal motor nucleus of the vagus, depigmentation and significant neuronal loss were seen only on the left. Rare neurofibrillary tangles were observed in the hippocampus and entorhinal cortex, and some neuritic plaque was seen in frontal, parietal and temporal cortices, within normal limits for age. In PD, the widespread neuropathology makes it difficult to attribute a specific symptom or sign to particular neural pathways. Our patient provides a unique opportunity to explore the question of the anatomical substrate of rest tremor because of his vascular parkinsonism with limited discrete lesions. He had persistent, unilateral typical parkinsonian rest tremor for 18 years despite bilateral and symmetrical nigral pathology. We therefore suggest that the unilateral LC lesion contributed to the pathogenesis of his contralateral tremor. Rest tremor resembling following basal ganglia strokes can occur but usually with a delayed onset following hemiparesis.2 Rest tremor can follow internal capsule lesions3 but the lesion in our patient was ipsilateral to the tremor. Hence the basal ganglia and pyramidal tract pathology do not provide an explanation for the unilateral right-sided tremor.

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FIG. 1. There is mild atrophy of the frontal and parietal lobes (A) and hippocampus (G), enlarged ventricles (G,H), and lacunes in the right putamen (G) and bilaterally in the external globus pallidus (left shown in H). The SN is bilaterally depigmented (B) but only the left locus coeruleus is depigmented (B). The lacune in the external globus pallidus (haematoxylin and eosin, I) had isolated regions of rarefaction in the surrounding neuropil, while the lacune in the putamen (haematoxylin and eosin, J) also involved the lateral aspects of the right internal capsule. Depigmentation and cell loss in the left (haematoxylin and eosin, C) and right (haematoxylin and eosin, D) SN, but only the left (a-synuclein immunohistochemistry using 610787 antibody from Transduction Laboratories, Lexington, KY, F) LC (compared with right, E). There were no immunopositive inclusions in any brainstem region, while a Lewy body positive control section (not shown) contained immunopositive cytoplasmic inclusions.

In PD, the severity of rigidity and akinesia, but not tremor, correlate with the degree of nigrostriatal dopaminergic deficit.4 The determinants of rest tremor remain relatively unknown. Anatomical structures implicated in its pathogenesis include the cortico-basal ganglia-thalamo-cortical loop and pyramidal tract.5 Degeneration of the LC is a common feature of PD.6 Existing pathological and biochemical data, primarily from animal studies, suggests that noradrenaline released from the LC may have an inhibitory role on cortical and subcortical

regions involved in the generation of tremor. In a rat model, bilateral electrical stimulation of the LC suppressed, while bilateral lesioning worsened, harmaline-induced tremor.7

Legends to the Video Segment 1. Shows the patient in 1996. The patient turns en bloc, and walks on a relatively narrow base with absent right armswing and slow tremor of the right wrist and tongue.

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Segment 2. Shows the patient in 1998. The patient has a unilateral right arm rest tremor appearing with mental distraction that disappears with action, but reappears in posture with a latency to onset of several seconds. Acknowledgments: Brain donation was made to the Prince of Wales Medical Research Institute Tissue Resource Centre which is supported by the National Health and Medical Research Council of Australia (Enabling Grant No. 282933) and the Prince of Wales Medical Research Institute. We wish to thank Heather McCann and Karen Murphy for research assistance and Heidi Cartwright for the figures. Natasha Mevawalla, BMedSci (Hons) Victor Fung, SC, PhD, FRACP* John Morris, GL, DM(Oxon), FRACP, FRCP Movement Disorders Unit Department of Neurology Westmead Hospital Sydney, Australia *E-mail: [email protected] Glenda Margaret Halliday, PhD Prince of Wales Medical Research Institute University of New South Wales Sydney, Australia

References 1. Zijlmans JC, Daniel SE, Hughes AJ, Revesz T, Lees AJ. Clinicopathological investigation of vascular parkinsonism, including clinical criteria for diagnosis. Mov Disord 2004;19: 630–640. 2. Kim JS. Delayed onset hand tremor caused by cerebral infarction. Stroke 1992;23:292–294. 3. Lee MS, Lee SA, Heo JH, Choi IS. A patient with a resting tremor and a lacunar infarction at the border between the thalamus and the internal capsule. Mov Disord 1993;8:244–246. 4. Vingerhoets FJ, Schulzer M, Calne DB, Snow BJ. Which clinical sign of Parkinson’s disease best reflects the nigrostriatal lesion? Ann Neurol 1997;41:58–64. 5. Elble RJ. Origins of tremor. Lancet 2000;355:1113– 1114. 6. Jellinger KA. Pathology of Parkinson’s disease. Changes other than the nigrostriatal pathway. Mol Chem Neuropathol 1991;14: 153–197. 7. Yamazaki M, Tanaka C, Takaori S. Significance of central noradrenergic system on harmaline induced tremor. Pharmacol Biochem Behav 1979;10:421–427.

Psychogenic Paroxysmal Dyskinesia: The Role of Placebo in the Diagnosis and Management Video Psychogenic movement disorders (PMD) can present with any of the wide variety of motor symptoms seen in patients with movement disorders, such as hyperkinetic or

Published online 7 April 2009 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.22509

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hypokinetic motor symptoms, and it can affect speech and gait. An abrupt onset or ‘‘paroxysmal’’ component is one of the most important clinical presentations of PMD. In most previously reported series of PMD patients, psychogenic paroxysmal disorders were rarely mentioned,1 and usually, they could be categorized as pseudoseizures. Here, we describe a patient who presented with psychogenic paroxysmal kinesigenic dyskinesia (PKD) which was confirmed with placebo treatment. A 29-year-old man, right-handed, visited the movement clinic after the sudden onset of a twisting motion in his right arm and leg during 10 years. His symptoms were triggered by sudden voluntary movements, such as when he began to run from a starting line or upon standing suddenly from a sitting position. Three years ago, he was diagnosed with PKD at a local clinic, but he had taken no medication, because of fluctuating frequency of his symptoms. His family history was not remarkable, and he did not have a psychiatric illness. The frequency of the symptoms was variable, and the duration was less than 10 seconds. His symptoms usually began his right arm and then spread to his right leg and face. In the middle 2 years of the 10-year-period, he did not experience any paroxysmal events. A magnetic resonance imaging (MRI) scan of the brain showed no anomalies, and the findings of routine electroencephalography (EEG) with captured clinical event, were normal. The findings of laboratory studies were not remarkable. Interestingly, the patient could trigger the symptoms at will. When he breathed deeply and concentrated hard on his right arm, he immediately began to exhibit paroxysmal ‘‘dystonic’’ movements, first on the right hand with a clenched fist, and extending to his elbow for 5 to 10 seconds. Meanwhile, he was able to answer questions, smile, and behave normally (see video segment 1). We gave him a placebo as a sort of digestive pill with a suggestion, because several episodes were triggered by mere suggestion. Two weeks after he began taking the placebo, he said that approximately 50% of his symptoms had disappeared, based on comparison to the frequency of symptoms at baseline (see video segment 2). We added another drug for anxiety and increased the dosage of the placebo with a suggestion. After one month, he was very happy because his paroxysmal symptoms had completely resolved. His symptoms no longer occurred when he abruptly changed positions or at will (see video segment 3). He was then diagnosed with psychogenic PKD and referred to a psychiatrist for psychotherapy. He returned to normal function and was symptom free at followup, 1 year later. Informed, written consent was obtained after patient had been given a complete description of using his video clip. The present case had the typical features of PKD, but it was accompanied by several atypical clinical manifestations. The patient’s ability to the trigger the symptoms at will or suggestion and fluctuating frequency of symptoms, including the event-free period were unusual in organic PKD. On the basis of these atypical features, we suspected that his complaints were suggestive of PMD and confirmed him with a documented psychogenic PKD,2 because the dyskinesia triggered by sudden movement or the patient’s will completely resolved after the placebo treatment. The diagnosis of psychogenic PKD is very difficult, because ‘‘paroxysm’’ or ‘‘abrupt onset’’ itself is a major positive clue for diagnosing PMD.3 Therefore, psychogenic

LETTERS TO THE EDITOR PKDs are mentioned rarely in most reported series of PMD patients, and the prevalence is not clear. Another reason for the rarity of psychogenic PKD is that paroxysmal disorders are by definition brief and reversible, superimposed on normal motor behavior, and not distressing enough to be classified as a severe medical condition.4 There has been some controversy regarding the use of placebos in the management of PMD, because placebos can affect the trust component of the doctor–patient relationship. However, placebos have been used effectively in the diagnosis of pseudoseizures,5,6 although they have not been systematically studied in PMD. We used a placebo as both a diagnostic and therapeutic tool in our patient. On the basis of previous reports and our experience, placebo treatment can serve as a good diagnostic and therapeutic tool in PMD, especially in psychogenic PKD, like pseudoseizure.

Legends to the Video Segment 1. The patient is shown doing a twisting motion suddenly on his right arm and spreads to his right leg and face, when he tries to trigger symptoms at will. Segment 2. Although he can trigger his symptom after two weeks of placebo treatment, he experienced that approximately 50% of his symptoms have disappeared, based on comparison to the frequency of symptoms at baseline. Segment 3. One month after placebo treatment, in spite of his effort to trigger his symptoms several times, his symptoms do not appeared. Jong Sam Baik, MD, PhD* Sang Won Han, MD Jae Hyeon Park, MD, PhD Department of Neurology, Sanggye Paik Hospital Inje University College of Medicine Seoul, Korea *E-mail: [email protected] Myung Sik Lee, MD, PhD Department of Neurology, Youngdong Severance Hospital Yonsei University College of Medicine Seoul, Korea

References 1. Factor SA, Podskalny GD, Molho ES. Psychogenic movement disorders: frequency, clinical profile, and characteristics. J Neurol Neurosurg Psychiatry 1995;59:406–412. 2. Williams DT, Ford B, Fahn S. Phenomenology and psychopathology related to psychogenic movement disorders. Adv Neurol 1995; 65:231–257. 3. Fahn S, Williams DT. Psychogenic dystonia. Adv Neurol 1988;50: 431–455. 4. Vidailhet M, Bourdain F, Nuss P, Trocello J. Paroxysmal psychogenic movement disorders. In: Hallett M, Fahn S, editors. Psychogenic movement disorders. Philadelphia: Lippincott Williams & Wilkins; 2006. p 76–81. 5. Devinsky O, Fisher R. Ethical use of placebos and provocative testing in diagnosing nonepileptic seizures. Neurology 1996;47:866–870. 6. Bhatia M, Sinja PK, Jain S, et al. Usefulness of short-term video EEG recording with saline induction in pseudoseizures. Acta Neurol Scand 1997;95:363–366.

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Evidence for Pre and Postsynaptic Nigrostriatal Dysfunction in the Fragile X Tremor–Ataxia Syndrome Video The fragile X tremor–ataxia syndrome (FXTAS) is caused by premutations in the fragile X mental retardation (FMR1) gene.1 Premutations (55–200 CGG repeats) lead to the production of toxic FMR1 mRNA and intranuclear inclusions. A tremor and cerebellar ataxia form the core features of FXTAS, and the associated features include parkinsonism, neuropsychiatric deficits, autonomic dysfunction, and peripheral neuropathy. The in vivo neurochemical alterations and functional connectivity underlying FXTAS-associated parkinsonism is unclear. Three studies provide contradicting data. In support of a postsynaptic or neurochemical process is the data from Ceravolo et al., which reported normal presynaptic nigrostriatal function using [123I] FP-CIT SPECT in 4 patients with FXTAS-associated parkinsonism.2 On the other hand, 2 other studies show presynaptic and postsynaptic abnormality in a small number of patients.3,4 We report a new patient with FXTAS-associated parkinsonism, providing additional evidence of abnormalities on both dopamine transporter (DAT) [123I] FP-CIT SPECT and D2 receptor [123I] IBZM SPECT scans. The patient was examined by four of the authors (DGH, SB, NWW, AJL), and the clinical data presented is a consensus of the findings. MRI and genetic studies were performed using standard methodology. Presynaptic dopamine transporter integrity was assessed using iodine-123 FP-CIT (DaTSCAN) (GE Healthcare, Amersham, UK). Imaging was performed 3 hours after the intravenous injection of 185 MBq of DaTSCAN on an Elscint Helix (Haifa, Israel) double-headed gamma camera with a total acquisition time of 40 minutes. The assessment of postsynaptic dopamine transporter integrity was determined with iodine-123 iodobenzamide (IBZM; GE Healthcare). For this tracer, imaging was commenced 2 hours following the injection of 185 MBq of IBZM on a triple-headed Philips Prism 3000XP gamma camera (Cleveland, Ohio). Following data acquisition for both tracers, transverse slices through the basal ganglia along the orbitomeatal line were created. The patient was a 68-year-old man who had presented 10 years earlier with rest and kinetic tremor of his right hand. He was initially diagnosed with ‘‘tremor-dominant’’ Parkinson’s disease (PD), a diagnosis which was later revised to multiple system atrophy (MSA). By the time the correct diagnosis of FXTAS was made, based on the presence of 87 CGG repeats in the FMR1 gene, the patient had a severe bilateral rest, postural, and intentional tremor. The tremor was worse on the right side and had characteristics similar to the midbrain tremor of

Additional Supporting Information may be found in the online version of this article. Published online 3 March 2009 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.22267

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FIG. 1. T2-weighted MRI of brain demonstrating prominent signal change in the middle cerebellar peduncles. This is a characteristic radiological feature of FXTAS.

Holmes.5 There was also voice tremor and subtle jaw tremor. He had bradykinesia, cogwheel rigidity (worse on the patient’s right side), stooped posture, and reduced arm swing. The Pull test was borderline abnormal and he was unable to properly tandem walk. His score was 25/40 in the University of Pennsylvania Smell Identification Test. There was clinical and electrical evidence for a large fiber neuropathy. Response to levodopa (200 mg TDS) was disappointing. A similar poor response was observed with propranolol, clonazepam, and low-dose pramipexole. However, the patient reported consistent temporary benefits to his tremor to small amounts of alcohol. MRI showed marked signal change in both middle cerebellar peduncles as well as cerebellar atrophy (Fig. 1). The rest of the brain showed milder nonspecific atrophy. DaTscan showed reduced tracer uptake in both striata, more in the right than in the left caudate, and more profound in the putamen when compared with the caudate (Fig. 2). The findings on IBZM were more subtle, with reduced transport of tracer in both striata and again more pronounced in the left (Fig. 3). The background was borderline high. Our data suggest mixed pre and postsynaptic degeneration in FXTAS-associated parkinsonism, supporting two other studies and contradicting Ceravolo et al.2–4 The most striking abnormality in our patient was seen on the presynaptic DaTscan. However, the associated uptake reduction on the IBZM

FIG. 2. DaTscan showing reduced tracer uptake in both striata, more in the right than in the left caudate, and more profound in the putamen when compared with the caudate. This indicates degenerative presynaptic nigrostriatal function and is in a pattern similar to that observed in patients with idiopathic PD. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

FIG. 3. IBZM scan showing slightly reduced transport of tracer to both striata and more pronounced in the left putamen when compared with the caudate. In idiopathic PD, the typical finding is normal, or increased, uptake due to D2 receptor upregulation. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

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LETTERS TO THE EDITOR is more compatible with an atypical parkinsonism especially MSA, a factor which may explain some of the clinical similarities between these two disorders.6,7 An alternative explanation is that our patient had dual pathology, i.e., FXTAS and idiopathic PD. This is supported by the low score in the smell test and could explain the observed presynaptic deficits. However, the combination of pre and postsynaptic uptake is rare in PD (characteristically enhanced or normal D2 receptor function)8 and does not explain the poor response to levodopa. Larger studies are required to clarify the extent and nature of dopaminergic abnormalities in FXTAS-associated parkinsonism.

Legends to the Video Segment 1. This demonstrates severe bilateral rest, postural, and intentional tremor. The tremor on the right side has characteristics of a Holmes tremor. Voice tremor is also present. The patient’s bradykinesia or rigidity is not demonstrated by this video; however, he walks with a stooped posture and reduced arm-swing. Pursuit eye movements are mildly broken. Daniel G. Healy, MD* Department of Clinical Neuroscience Institute of Neurology, University College London United Kingdom Department of Molecular Neuroscience Institute of Neurology, Queen Square London, United Kingdom *E-mail: [email protected] Susan Bressman, MD Beth Israel Medical Centre Department of Neurology New York, USA Albert Einstein College of Medicine Department of Neurology Bronx, New York, USA John Dickson, PhD Institute of Nuclear Medicine University College London Hospitals London, United Kingdom Laura Silveira-Moriyama, MD Reta Lila Weston Institute for Neurological Studies University of London, London, United Kingdom Susanne A. Schneider, MD Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology Queen Square, London, United Kingdom

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Kailash P. Bhatia, MD Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology Queen Square, London, United Kingdom Karen Shaw, RSN Reta Lila Weston Institute for Neurological Studies University of London, London, United Kingdom Jamshed Bomanji, MD Institute of Nuclear Medicine University College London Hospitals London, United Kingdom Nicholas W. Wood, MD Department of Molecular Neuroscience Institute of Neurology, Queen Square London, United Kingdom Andrew J. Lees, MD Department of Molecular Neuroscience Institute of Neurology, Queen Square London, United Kingdom Reta Lila Weston Institute for Neurological Studies University of London, London, United Kingdom

References 1. Hagerman RJ, Leehey M, Heinrichs W, et al. Intentional tremor, parkinsonism and generalised brain atrophy in male carriers of the fragile X. Neurology 2001;57:127–130. 2. Ceravolo R, Antonini A, Volterrani D, et al. Dopamine transporter imaging study in parkinsonism occurring in fragile X premutation carriers. Neurology 2005;65:1971–1973. 3. Scaglione C, Ginestroni A, Vella A, et al. MRI and SPECT of midbrain and striatal degeneration in fragile X-associated tremor/ ataxia syndrome. J Neurol 2008;255:144–146. 4. Zu¨hlke CH, Budnik A, Gehlken U, et al. FMR1 premutation as a rare cause of late onset ataxia—evidence for FXTAS in female carriers. J Neurol 2004;251:1418–1419. 5. Holmes G. On certain tremors in organic lesions. Brain 1904;27:327–375. 6. Plotkin M, Amthauer H, Klaffke S, et al. Combined 123I-FP-CIT and 123I-IBZM SPECT for the diagnosis of parkinsonian syndromes: study on 72 patients. J Neural Transm 2005;112:677–692. 7. Kamm C, Healy DG, Quinn NP, et al.; European Multiple System Atrophy Study Group. The fragile X tremor ataxia syndrome in the differential diagnosis of multiple system atrophy: data from the EMSA Study Group. Brain 2005;128:1855–1860. 8. Rinne UK, Laihinen A, Rinne JO, Na˚gren K, Bergman J, Ruotsalainen U. Positron emission tomography demonstrates dopamine D2 receptor supersensitivity in the striatum of patients with early Parkinson’s disease. Mov Disord 1990;5:55–59.

Bilateral Choreiform Movements Induced by Excessive Sucrose Ingestion

Sean S.O. Sullivan, MD Reta Lila Weston Institute for Neurological Studies University of London, London, United Kingdom

Nonketotic hyperglycemia is a frequent metabolic derangement which can cause involuntary movement and the patients with hyperglycemia induced choreiform movement can show

Luke Massey, MD Reta Lila Weston Institute for Neurological Studies University of London, London, United Kingdom

Published online 3 March 2009 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.22492

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FIG. 1. Axial T1-weighted MR image reveals increased signal intensity (A) and T2-weighted image shows decreased signal intensity (B) in the both basal ganglia (arrows).

lesions of the basal ganglia.1 On the contrary, numerous studies showed that a high sucrose diet induces insulin resistance in rodents.2 However, there is still controversy over whether excessive sucrose affects insulin sensitivity and development of diabetes in healthy human. We report a patient with bilateral choreiform movements induced by chronic ingestion of excessive sucrose without underlying diabetes. A 79-year-old woman presented with sudden onset of involuntary movements involving both arms and legs lasting for 1 day. At the time of admission, her serum glucose level was high (232 mg/dl) and glycosylated hemoglobin level (HgA1C) was remarkably elevated (12.2%). She had been treated under the diagnosis of congestive heart failure and dilated cardiomyopathy but not diabetic. Her laboratory findings which taken 1 year ago revealed euglycemia and nearupper range of HgbA1C (6.6%). On neurological examination, she showed bilateral choreoathetoid movements which involving both upper and lower extremities. During close observation at neurological intensive care unit, her choreiform movements were so continuous that she hardly initiated sleep but, those ceased during sleep. The power of extremities and muscle tones were normal and deep tendon reflexes were normoactive. Slit lamp revealed no Keyser Flesher ring and her serum osmolarity was high without elevation of ketone. MRI revealed high signal intensities in the bilateral basal ganglia on T1-weighted image (Figure 1). Her son said that she habitually had taken white sugar more than 200 g per day additional to regular dietary supply for a few months due to poor appetite. He noticed that her weight had not increased. She was treated with oral hypoglycemic agent gliquidone 30 mg a day and neuroleptic agent risperidon 1 mg a day as the starting dose. The dose of risperidon had increased up to 2 mg a day. Her abnormal involuntary movements had lasted for a few months after normalizing of the glucose level.

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Chorea-ballism combined with nonketotic hyperglycemia and a high signal lesion of basal ganglia on the T1-weighted brain MRI has been regarded as peculiar syndrome. Although the underlying mechanism is unclear, many cases have been reported especially in Asian women suggesting a genetic predominance or poor control of blood glucose.1 Postulated mechanisms include that underlying chronic focal cerebrovascular diseases in diabetes provide the basis for acute blood– brain barrier dysfunction. Hyperglycemia also produces a global decrease in regional cerebral blood flow with maximal reduction in the basal ganglia.3 Thus, the reduction of cerebral blood flow may contribute to the reduction of local amounts of g-aminobutyric acid. Depletion of corpus striatal g-aminobutyric acid in non-ketotic hyperglycemia may allow increased pallidal activity with resultant dyskinesia.4 However, there is no available report which demonstrates excessive dietary sucrose causing chorea-ballismus in the patient without underlying diabetes. In our patient, laboratory results such as serum glucose and HgA1C levels examined one year prior to developing choreiform movement revealed that she was nondiabetic. Chronic ingestion of excessive sucrose can result in glucose intolerance and, moreover, overt diabetes in nondiabetic healthy individual. The mechanisms by which high sucrose diets cause insulin resistance are not fully understood. Sucrose is a disaccharide that is cleaved to a 50:50 molar mixture of glucose and fructose in the intestine. In rats, there is evidence that feeding sucrose-rich diets impairs insulin action and the effect of sucrose is due to its fructose component.5 In a previous study, feeding 30% of the total calories with sucrose as compared with starch to humans can induce increased fasting serum insulin and glucose level, and decreased insulin sensitivity.6 The daily intake of sucrose in Koreans was 60 g in 2001 and it was much lower than in westerners.7 Our patient had eaten 200 g of additional sucrose a day for a few months and it was

LETTERS TO THE EDITOR nearly 50% of total daily calorie intake. We presume that such excessive ingestion of sucrose caused abnormalities in glucose metabolism and eventually resulted in overt nonketotic diabetes and then involuntary choreiform movements with signal changes in the basal ganglia on the T1-weighted MRI. San Jung, MD, MS* Sung-Hee Hwnag, MD, PhD Suk-Yun Kang, MD Seok-Beom Kwon, MD Department of Neurology Hallym University College of Medicine Seoul, South Korea *E-mail: [email protected]

References 1. Oh SH, Lee KY, Im JH, Lee MS. Chorea associated with nonketotic hyperglycemia and hyperintensity basal ganglia lesion on T1-weighted brain MRI study: a meta-analysis of 53 cases including four present cases. J Neurol Sci 2002;200:57–62. 2. Brenner RR, Rimoldi OJ, Lombardo YB, Gonzalez MS, Bernasconi AM, Chicco A, Basabe JC. Desaturase activities in rat model of insulin resistance induced by a sucrose-rich diet. Lipids 2003; 38:733–742. 3. Lai PH, Tien RD, Chang MH, Teng MM, Yang CF, Pan HB, Chen C, Lirng JF, Kong KW. Chorea-ballismus with nonketotic hyperglycemia in primary diabetes mellitus. AJNR Am J Neuroradiol 1996;17:1057–1064. 4. Guisado R, Arieff AI. Neurologic manifestations of diabetic comas: correlation with biochemical alterations in the brain. Metabolism 1975;24:665–679. 5. Thorburn AW, Storlien LH, Jenkins AB, Khouri S, Kraegen EW. Fructose-induced in vivo insulin resistance and elevated plasma triglyceride levels in rats. Am J Clin Nutr 1989;49:1155– 1163. 6. Reiser S, Handler HB, Gardner LB, Hallfrisch JG, Michaelis OEt, Prather ES. Isocaloric exchange of dietary starch and sucrose in humans. II. Effect on fasting blood insulin, glucose, and glucagon and on insulin and glucose response to a sucrose load. Am J Clin Nutr 1979;32:2206–2216. 7. Kim S, Jung H. Sugar supply and intake of Koreans. Korean J Nutr 2007;40:22–28.

Episodic Tongue Hyperkinesias and Alternating Limb Movements Associated with Basilar Artery Ischemia Video Paroxysmal involuntary movements involving the tongue are rare. Several underlying conditions associated with isolated involuntary tongue movements have been reported, such as ischemia, trauma, electrical injury, Arnold-Chiari malformation, or epilepsy.1–3 Repetitive movements of the limbs have also

Published online 7 April 2009 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.22542

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been reported in patients with acute basilar artery infarction.4,5 The brainstem has been considered to be the origin of these involuntary movements, but the pathogenesis is still not clear. Here, we report on a case that developed episodic sideto-side involuntary tongue movements and alternating limb movements due to intermittent brainstem ischemia. A 74-year-old man suffered from sudden onset of dizziness and ataxia and then progressive drowsiness the next day. He had a past history of hearing impairment and hypertension for more than 20 years. The patient had never taken neuroleptic drugs. His general physical examination was unremarkable. After admission, his consciousness improved. On neurological examination, there were dysarthria, dysphagia, and quadriparesis. Deep tendon reflexes were not hyperactive, and plantar reflexes were flexor bilaterally. Eight days later, he developed intermittent involuntary tongue and limb movements. The episodes occurred about seven to eight times per day and lasted about 2 to 3 minutes each. During each episode, he stared to the front, the neck became stiff and the mouth was open. The tongue involuntarily wiggled from side to side nearly rhythmically with a frequency of about two times per second (video, segment 1). He also showed alternating flexion movements of the elbows and knees with hands beating and feet rubbing on the bed. The leg movements disappeared 4 days later. There was no response to verbal prompts or commands, and the Doll’s eye sign could not be elicited. All the involuntary movements of the tongue and limbs disappeared during sleep. Between each episode, he could obey simple orders, such as answering his name, and raising his arms (video, segment 2). Magnetic resonance imaging (MRI) of the brain (Fig. 1A–C) showed infarctions in the bilateral thalamus, cerebellum, right temporo-occipital and left occipital areas. Magnetic resonance angiography (MRA) showed presence of segmental narrowing of the basilar artery (Fig. 1D). CSF study showed normal result. An electroencephalography showed no cortical discharges. Treatment with 1 mg per day clonazepam was tried. The alternating limb movements disappeared 12 days later. The episodic tongue hyperkinesias became progressively less frequent and disappeared after 7 months. A variety of involuntary movements of the tongue have been described, such as fasciculations, tremor, myoclonus, dyskinesia, undulating hyperkinesias, or dystonic spasm.1–3 Episodic involuntary movements involving the tongue and limbs are very rare. Previous reports have described similar isolated tongue hyperkinesias after brainstem ischemia, head trauma and in patients with chronic epilepsy.3 The tongue movements in these cases were characterized by episodic undulation. Our case is distinctive because the tongue movements were mainly side to side hyperkinesias (writhing or undulation) in character and were accompanied by alternating limb movements. The slower frequency of the involuntary movements in our case is similar to myorhythmia, which is characterized by relatively rhythmic muscle contractions in ocular, facial, masticatory, limb, and other muscles, typically seen in Whipple disease, brainstem or cerebellar diseases.6 However, the unique tongue and alternating limb movements are not typical of myorhythmia. Alternating limb movements, mainly in the arms, are unusual. Similar cyclic alternating leg movements, so called

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FIG. 1. Diffusion-weighted MRI of the brain showed infarctions in the bilateral thalamus, cerebellum, right temporo-occipital, and left occipital areas (A, B, and C). MRA revealed presence of segmental narrowing of the basilar artery (D).

automatic stepping mimicking walking have been observed in 2 patients with progressive basilar artery infarcts.5 In another report, alternating leg movements have been described in one patient with acute basilar artery infarction in responsive to painful stimulation.4 The mechanism underlying the involuntary tongue and limb movements in our patient remains elusive. Postert et al.3 suggested that brainstem ischemia with involvement of central tegmental tract at the pontine level may be responsible for episodic undulating hyperkinesias of the tongue. Moreover, the phenomenology in our case is very similar to the semirhythmic repetitive bulbar and limb movements in ovarian teratoma-associated encephalitis described recently.7 Similar to their cases, we suggest the involuntary tongue and limb movements in our case may be related to a release of locomotor-suppressive effects on central pattern generator associated with facilitation of locomotion secondary to the acute brainstem ischemia. In summary, MRI of the brain in our patient showed lesions of posterior circulation without involvement of the

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brainstem. MRA revealed segmental narrowing of the basilar artery. Intermittent brainstem ischemia may therefore be the cause of the involuntary tongue hyperkinesias and alternating limb movements in our patient.

Legends to the Video Segment 1. Showing episodic nearly rhythmic involuntary hyperkinesias with a frequency of 2 Hz involving the whole tongue muscle and alternating limb movements. Segment 2. Showing the patient can obey simple orders between each episode. Acknowledgments: We would like to thank Dr. Anthony E. Lang for providing helpful comments. Author Roles. Jie-Yuan Li: Research project: Conception, Organization, Execution; Manuscript: Writing of the first draft, Review, and Critique; Chieh-Hsun Lee: Research project: Conception, Organization, and Execution.

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Jie-Yuan Li, MD* Division of Neurology Kaohsiung Veterans General Hospital Kaohsiung City, Taiwan, ROC Faculty of Medicine, School of Medicine National Yang-Ming University Taipei, Taiwan, ROC *E-mail: [email protected] Chieh-Hsun Lee, MD Division of Neurology Kaohsiung Veterans General Hospital Kaohsiung City, Taiwan, ROC

References 1. Lee PH, Yeo SH. Isolated continuous rhythmic involuntary tongue movements following a pontine infarct. Parkinsonism Relat Disord 2005;11:513–516. 2. Lin K, Lin J, Piovesan EJ, Germiniani FM, Teive HA, Werneck LC. Tongue tremor in a patient with coma after electrical injury. Mov Disord 2003;18:834–836. 3. Postert T, Amoiridis G, Pohlau D, Hoffmann V, Przuntek H. Episodic undulating hyperkinesias of the tongue associated with brainstem ischemia. Mov Disord 1997;12:619–621. 4. Lee MS, Oh SH, Lee KR. Transient repetitive movements of the limbs in patients with acute basilar artery infarction. Neurology 2002;59:1116–1117. 5. Lee PH, Lee JS, Yong SW, Huh K. Repetitive involuntary leg movements in patients with brainstem lesions involving the pontine tegmentum: evidence for a pontine inhibitory region in humans. Parkinsonism Relat Disord 2005;11:105–110. 6. Masucci EF, Kurtzke JF, Saini N. Myorhythmia: a widespread movement disorder. Clinicopathological correlations. Brain 1984;107:53–79. 7. Kleinig TJ, Thompson PD, Matar W, et al. The distinctive movement disorder of ovarian teratoma-associated encephalitis. Mov Disord 2008;23:1256–1261.

Unusual Complication of Deep Brain Stimulation in Parkinson’s Disease We report a rare complication of lead malfunction after deep brain stimulation surgery for Parkinson’s disease. In this patient, twisting of both lead cords around each other occurred as a consequence of uncontrolled neck tremor. The mechanism of this complication and the patient’s course after corrective surgery is discussed. A 55-year-old lady, diagnosed with Parkinson’s disease 12 years ago underwent subthalamic (STN) DBS for uncontrolled drug-induced peak dose dyskinesia. DBS surgery was uneventful and the IPG was switched on the next day and her drugs were gradually reduced as the DBS was adjusted. She continued to have left upper limb, left lower limb, and head tremors during periods of waning drug effect. She experienced severe ‘‘NO-NO’’ tremors of the head. Seven days after

Published online 20 March 2009 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.21876

FIG. 1. X-ray chest showing twisted leads. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

implanting the IPG, a serous collection of fluid developed around the IPG implant, which was drained without recurrence. Episodic severe head tremors continued for more than 3 months, during which time she complained of a stretching sensation along the right connecting lead’s subcutaneous course. Her clinical response to DBS was markedly asymmetric with continued parkinsonism on the left side, whereas the right side improved remarkably. An imaging of brain (NCCT) at 3 months showed that the right STN electrode was below the expected level and hence, revision surgery was planned. At reexploration surgery, both connecting lead wires were twisted on each other as shown in the X-ray chest (see Fig. 1). It was very difficult to segregate these leads from each other, and the twisting continued beyond the connector into the extension wires, up to the IPG. Both the leads were disconnected from the extension cable and the extension cable was replaced. The right-sided lead was repositioned and the patient had an uneventful course thereafter with bilateral clinical improvement without severe tremulous episodes. Infections, skin erosions, electrode fracture, or dislocations and hardware failures are complications after DBS.1,2 Hardware complications are well known and occur in 7–65% of cases in various case series of DBS.3–6 We report a rare complication, which has not been reported in the literature to our knowledge. We believe that the repeated and large amplitude ‘‘NONO’’ tremors of the head in this patient led to twisting of the electrodes. Though the implant was fixed to the underlying tissue by nylon sutures to prevent any movement, during exploration, they were found to have cut through the muscles, thereby freeing the implant. Probably the serous collection dissolved the sutures or weakened them. In our view, due to the repeated tremor of the head and left upper limb, the IPG moved and kept rotating inside the subcutaneous pocket so that the leads twisted around each other and resulted in such a rare complication.

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LETTERS TO THE EDITOR Vinay Goyal* Sandeep Vaishya Garima Shukla Sumit Singh Madhuri Behari Department of Neurology, AIIMS New Delhi, India *E-mail: [email protected]

References 1. Oh MY, Kim SH, Lozano AM. Hardware related complication of deep brain stimulation in 100 consecutive electrodes. J Neurosurg 2001;94:412A (abstract).

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2. Hariz MI, Shamsgovara P, Johansson F, Hariz G-M, Fodstad F. Tolerance and tremor-rebound following long-term chronic thalamic stimulation for Parkinsonism and essential tremor. Steriotact Funct Neurosurg 1999;72:208–218. 3. Lyons KE, Koller WC, Wilkinson SB, Pahwa R. Neurol 2001;56 (Suppl):A147. 4. Pahwa R, Lyons KE, Wilkinson SB, Koller WC. One-year followup of bilateral subthalamic stimulation in Parkinson’s disease. Neurol 2001;56 (Suppl):A146. 5. Hariz MI, Johansson F. Hardware failure in Parkinsonian patients with chronic subthalamic nucleus stimulation is a medical emergency. Mov Disord 2001;16:166–168. 6. Oh MY, Abosch A, Kim SH, Lang AE, Lozano AM. Long-term hardware-related complications of deep brain stimulation. Neurosurgery 2002;50:1268–1274.