Exercise dependence induced by pramipexole in Parkinson's Disease-A Case Report

Letters to the Editor Related to New Topics

Stereotypies After Herpetic Encephalitis with

Bitemporal Lesions

Video

Stereotypy is an involuntary, coordinated, patterned,repetitive, rhythmic, purposeless movement.1 Distinguishingstereotypies from other movement disorders is pivotal andat times difficult, particularly with tics and mannerisms, themost likely causes of confusion. Stereotypies may be partof neurodegerative disorders (Rett’s syndrome, Lesh-Nyhansyndrome, and neuroacanthocytosis), psychiatric disorders,Tourette’s syndrome, encephalitis lethargica, and rarely aresponse to focal brain lesions.1 We report on a 34-years-old female who developed an odd motor stereotypies afterherpetic encephalitis with prominent hypersexuality. Thesefeatures plus memory complaints let us to believe in thediagnosis of an incomplete Kluver-Bucy syndrome.

The patient was admitted to the emergency room with ahistory of headache, fever, and somnolence lasting 24 hours.At admission, she was confused and disoriented. CSF analy-ses revealed pleocytosis with lymphocytes predominance(170 cellules/mm3, 94% lymphocytes). Polymerase chainreaction for HSV DNA was positive. She was diagnosedwith herpetic encephalitis and treated with intravenous acy-clovir 10 mg/kg, TID. The patient remained somewhat unre-sponsive and confused. Continuous EEG monitoring demon-strated that such episodes corresponded to complex partialseizures arising independently from both temporal lobes,occurring every 2 to 5 min and defining nonconvulsive statusepilepticus (NCSE). After a phenytoin IV load, her statusworsened leading to entubation and ventilatory support. Fol-lowing recovery from the NCSE, she started with repetitivemovements characterized as face scratching (Video). Thosemovements were triggered by touching the face and were sointense that she developed a skin abrasion on the right sideof her chin. MRI showed bitemporal acute lesions in FLAIR.A month after hospital discharge, her husband reported thatshe developed significant hypersexuality and remained withthe stereotypy. Video-EEG revealed no abnormalities duringthose episodes. She demanded several daily intercourses andallegedly achieved multiple orgasms. She denied dietarychanges, increased appetite, or major emotional changes, butshe did complain of memory difficulties. The stereotypyremained intense in spite of the addition of carbamazepineand haloperidol. At last follow-up morning hygiene, face

makeup and dressing routines were still compromised by thestereotypy.

Neuroanatomical basis of Kluver-Bucy Syndrome remainsunclear. This syndrome was classically reported in monkeysafter bilateral temporal lobectomy, but it also occurs inhumans after herpes encephalitis, brain trauma, status epilep-ticus, Pick or Alzheimer diseases. Patients present withhypersexuality, excessive oral tendencies, dietary changes,loss of normal fear, psychic blindness, and excessive atten-tiveness to visual stimuli, although there are brief reportsaddressing incomplete or partial forms.2–5 Herpes encephalitisis the most frequently reported etiology of this syndrome, asit seems to be the case in our patient. Hypersexuality, mem-ory impairment, and hypermetamorphosis maybe the basisfor the diagnosis of incomplete Kluver-Bucy syndrome. How-ever, motor stereotypies was never reported as a componentof that syndrome. Common stereotypies examples includearm flapping, hand waving/rotating, finger wiggling, headnodding, and body rocking. They occur in association withseveral diseases like autism, mental retardation, sensory de-privation, and a variety of syndromes, as well as in otherwisehealthy individuals. We have found no published report of apatient manifesting such curious stereotypy following acuteencephalitis. Self-injurious behavior is viewed by some ascontinuum on the spectrum of sterotypic behavior. It most of-ten occurs in the setting of autism and retardation, but alsowith some genetic disorders.1 Our patients was indeed hurt-ing herself with almost continuous face scratching. It was thefirst stereotypic movement with self-injurious behavior thatwe have noticed after herpetic encephalitis. There is a gen-eral belief that stereotypy in higher animals is a form of self-stimulation. It seems like the concept of deprivation is thecause of stereotypy. Once a critical period has passed, thesebehaviors are not reversible.1 Other experimental manipula-tions to induce stereotypies are pharmacological and targetedinsults to the central nervous system. In animal models, ster-eotypic behaviors can be induced in response to both directlyand indirectly acting dopamine receptor agonists and mayrequire a combination of both D1 and D2 receptors.6 Nigraland thalamic output pathways plays a significant role in theexpression of these behavioral responses. Thus, we couldhypothesize that those subcortical structures were compro-mised in some way during the encephalitic process in ourpatient. Moreover, there is some evidence that targetedinsults to nonstriatal structures within the medial temporallobe result in locomotor stereotypies in both rodents and non-human primates.7 Although the pathophysiology of repetitivebehaviors is unknown, it seems like the mesial structures ofthe temporal lobe, amygdala, and hippocampus, also couldplay a important role in the development of such movements.

Author Roles: Concepcion/design: CT, LP, and CS; dataacquisition/analysis: CT, LP, and CS; drafting: CT, LP, CS,and HT; editing: CT, LP, CS, and HT; revising: CT, LP, CS,and HT.

Additional Supporting Information may be found in the onlineversion of this article.

Potential conflict of interest: Nothing to report.Published online 29 September 2010 in Wiley Online Library

(wileyonlinelibrary.com). DOI: 10.1002/mds.22803

2888

Movement DisordersVol. 25, No. 16, 2010, pp. 2888–2898� 2010 Movement Disorder Society

Carlos Alexandre Twardowschy, MD

Luciano De Paola, MD, MSc

Helio A.G. Teive, MD, PhD

Carlos Silvado, MD, PhD*Epilepsy Surgery Program

Hospital de ClınicasUniversidade Federal do Parana

Brazil*E-mail: [email protected]

References

1. Jankovic JJ, Tolosa E. Parkinon’s disease and movement disor-ders. Fourth ed. Lippincott Williams & Wilkins: Philadelphia, PA:2002.

2. Anson JA, Kuhlman DT. Post-ictal Kluver-Bucy syndrome aftertemporal lobectomy. J Neurol Neurosurg Psychiatry 1993;56:311–313.

3. Yilmaz C, Cemek F, Guven AS, Caksen H, Atas B, Tuncer O. Achild with incomplete Kluver-Bucy syndrome developed duringacute encephalitis. J Emerg Med 2008;35:210–211.

4. Janszky J, Fogarasi A, Magalova V, Tuxhorn I, Ebner A. Hyperoral-ity in epileptic seizures: periictal incomplete Kluver-Bucy syn-drome. Epilepsia 2005;46:1235–1240.

5. Naito K, Hashimoto T, Ikeda S. Kluver-Bucy syndrome followingstatus epilepticus associated with hepatic encephalopathy. EpilepsyBehav 2008;12:337–339.

6. Dickson PR, Lang CG, Hinton SC, Kelley AE. Oral stereotypyinduced by amphetamine microinjection into striatum: an anatomicalmapping study. Neuroscience 1994;61:81–91.

7. Bauman MD, Toscano J E, Babineau BA, Mason WA, Amaral DG.Emergence of stereotypies in juvenile monkeys (Macaca mulatta)with neonatal amygdala or hippocampus lesions. Behav Neurosci2008;122:1005–1015.

‘‘Progressive Delayed-Onset Postanoxic

Dystonia’’ Diagnosed with PANK2 Mutations

26 Years After Onset—An Update

Video

In 2002, we reported 2 adults with a progressive dystonicsyndrome after anoxia.1 We here report further follow-up ofCase 1. Genetic testing has now revealed that this patientcarries PANK2 gene mutations. This report highlights that aseparate cause must always be considered in subjects with aprogressive dystonia even if there was a clear and well-docu-mented preceding anoxic event.

This 46-year-old woman suffered a cardiac arrest in 1983during induction of general anesthesia for a routine wisdomteeth extraction. After resuscitation, she was comatose for 48hours but recovered to be discharged home a week later

without residual deficit. Two months later, she developedwriter’s cramp, micrographia, and dysarthria and after 2years, right foot dystonia. She was diagnosed with postanoxicgeneralized dystonia and a medicolegal settlement was madeon the assumption that further progression was unlikely.

However, she continued to progress, and 5 years into theillness had developed severe dysarthria and dysphagia, andfurther worsening of her gait with frequent falls. By 1999, agastrostomy tube was inserted. Following recurrent episodesof stridor, an emergency tracheotomy was done in 2007, 24years after initial symptoms (For neurological findings in2009 see Supporting Information Video).

Over these years, because of her disease progression shewas repeatedly investigated to exclude other secondarycauses of dystonia or predisposition to the severity of theconsequences of her hypoxia.1 The first brain MRI scan done5 years after onset showed bilateral hypointensity in the in-ternal capsules but the basal ganglia were reported as normal.A second MRI (1998) done 15 years after the event showedisolated bilateral T2 hypointensities in globus pallidus, sug-gestive of mineral accumulation. A CT scan to exclude calci-fication was normal and the overall appearance was thoughtto be in keeping with anoxic injury, possibly related to hem-orrhagic transformation associated with anoxia. However, thecontinuing progression of her dystonia led to the third MRIscan in 2007, which showed bilaterally abnormal low signalin globus pallidus with some foci of increased signal on T2sequences, interpreted as an ‘‘eye of the tiger’’ sign (Fig. 1).In retrospect, even the 1998 MRI scan reproduced in our2002 article1 does in fact show the ‘‘eye of the tiger’’ sign.

Additional Supporting Information may be found in the onlineversion of this article.

Potential conflict of interest: Nothing to report.Published online 5 October 2010 in Wiley Online Library


FIG. 1. T2 weighted axial MRI done in 2007 (24 years after symp-tom onset) shows typical ‘‘eye of the tiger’’ sign bilaterally.

2889LETTERS TO THE EDITOR

Movement Disorders, Vol. 25, No. 16, 2010

In 2009, direct DNA sequencing for PANK2 gene muta-tions revealed that the patient was a compound heterozygotefor mutations in exon 2 with c.498_499delITG and c.563T>A(p.Met188Lys) mutations.

Pantothenate kinase–associated neurodegeneration (PKAN)(MIM234200), formerly known as Hallervorden-Spatz dis-ease, is an autosomal recessive disorder caused by mutationsin the PANK2 gene2 that were first reported in 2001. Itaccounts for the majority of neurodegeneration with brainiron accumulation (NBIA) cases.3 Clinically, it is character-ized by dystonia with prominent bulbar involvement and par-kinsonism.2 Since the recognition of PANK2 gene mutations,two main phenotypes have been described.2 Classic PKANhas an early onset (first decade) of gait and balance prob-lems, rapid progression, and loss of ambulation over 10 to 15years. Atypical PKAN usually starts in the second or thirddecade with speech difficulties and has slower progressionwith loss of mobility after 15 to 40 years. Basal ganglia ironaccumulation giving the characteristic ‘‘eye of the tiger’’ signis invariably present on MRI T2 sequences in both groups.2

Our patient clinically falls into the group of atypical PKAN.One interesting aspect of this case is the role of environ-

mental factors in triggering clinical onset of genetic disease,as there was a clear temporal relationship between the anoxicevent and symptom onset here. A possible role of environ-mental factors in genesis of dystonic symptoms has beenreported in DYT1 mutation carriers who developed dystoniaafter exposure to neuroleptics or peripheral trauma.4 How-ever, autosomal recessive diseases generally do not showreduced penetrance. There is no literature concerning homo-zygote or compound heterozygote PANK2 mutation carrierswho do not manifest disease. It is likely that our patientwould have developed the disease even in the absence ofanoxic event, but it is possible that the anoxia somehow trig-gered the earlier expression of the underlying genetic defect.

Delayed onset of dystonia after hypoxic–ischemic events isa well-known phenomenon,5,6 especially in children and youngadults. However, there are very few data concerning the dura-tion of disease progression. Bhatt et al.5 described 10 cases ofpostanoxic generalized dystonia with latency to symptomsonset of between 1 week and 3 years and progression lasting upto 8 years. However, Case 6 from their series is the patient weherein describe—if she is excluded, then the longest period ofprogression in that series was 3 years. Similarly, in Burke’s se-ries, the progression was no longer than 3 years.6

Apart from being the first example of PKAN symptomonset possibly provoked by an environmental trigger, this il-lustrative case offers three important teaching points. First,although periods of clinical worsening lasting up to severalyears are well recognized, postanoxic dystonia should ulti-mately be a static condition. Second, even in the presence ofa clear precipitating factor, other causes of dystonia shouldbe kept in mind and the patient should be thoroughly investi-gated. Finally, in patients with progressive dystonia and MRIshowing bilateral T2 hypointensities in globus pallidus, evenwithout the classical ‘‘eye of the tiger’’ sign, NBIA should besuspected and genetic testing should be considered.7

Legends to the Video

Twenty-six years after symptom onset: facial expression ishypomimic with dystonic features, tongue movements are

slow, and there is prominent oromandibular dystonia of‘‘jaw-opening’’ type. She has a tracheostomy and due tosevere dysarthria, she uses a communicator. There is a milddystonic posturing of both arms. Rapid alternating move-ments of the hands are slower, however, lower limbs aremuch more affected by bradykinesia. There are no cerebellarsigns. Eye movements are full range and normal, but there isevidence of blepharoclonus. Gait is dystonic and posturalreflexes are completely lost.

Financial Disclosures: Maja Kojovic receives Lady AstorPhD grant, received EFNS scientific fellowship grant for2008/2009 and received funding to attend congresses fromIpsen and UCB Pharma. MikkoKuoppamaki: Is an employeeof Orion Pharma. Niall Quinn: Receives honoraria fromUCB, Orion Pharma, and Oxford BioMedica. Kailash Bhatia:Advisor/honoraria/financial support to speak/attend meetingsfrom GSK, Boehringer-Ingelheim, Ipsen, Merz, and Orionpharma companies. Grants by the Dystonia Society UK andthe Halley Stewart Trust.

Author Roles: Kojovic—writing of the first draft of themanuscript, review and critique of the manuscript. Kouppa-maki—review and critique of the manuscript. Quinn—writingof the first draft of the manuscript, review and critique of themanuscript. Bhatia—writing of the first draft of the manu-script, review and critique of the manuscript.

Maja Kojovic, MDSobell Department of Motor

Neuroscience and Movement DisordersInstitute of Neurology, Queen Square

London, United Kingdom

Mikko Kuoppamaki, MDOrion Pharma

CNS Development, R&DTurku, Finland

Department of NeurologyTurku University Hospital

University of TurkuTurku, Finland

Niall Quinn, MDKailash P. Bhatia, MD*

Sobell Department of MotorNeuroscience and Movement DisordersInstitute of Neurology, Queen Square

London, United Kingdom*E-mail: [email protected]

References

1. Kuoppamaki M, Bhatia KP, Quinn N. Progressive delayed-onsetdystonia after cerebral anoxic insult in adults. Mov Disord 2002;17:1345–1349.

2. Hayflick SJ, Westaway SK, Levinson B, et al. Genetic, clinical,and radiographic delineation of Hallervorden-Spatz syndrome. NEngl J Med 2003;348:33–40.

3. Gregory A, Polster BJ, Hayflick SJ. Clinical and genetic delinea-tion of neurodegeneration with brain iron accumulation. J MedGenet 2009;46:73–80.


2890 LETTERS TO THE EDITOR

4. Edwards M, Wood N, Bhatia K. Unusual phenotypes in DYT1dystonia: a report of five cases and a review of the literature. MovDisord 2003;18:706–711.

5. Bhatt MH, Obeso JA, Marsden CD. Time course of postanoxicakinetic-rigid and dystonic syndromes. Neurology 1993;43:314–317.

6. Burke RE, Fahn S, Gold AP. Delayed-onset dystonia in patientswith ‘‘static’’ encephalopathy. J Neurol Neurosurg Psychiatry 1980;43:789–797.

7. McNeill A, Birchall D, Hayflick SJ, et al. T2* and FSE MRI dis-tinguishes four subtypes of neurodegeneration with brain ironaccumulation. Neurology 2008;70:1614–1619.

Factors Influencing the Cognitive Function in

Patients with Multiple System Atrophy

Patients with multiple system atrophy (MSA) may developcognitive impairment and the severity of cognitive impair-ment may vary.1,2 However, limited information is availableabout the factors influencing cognitive impairment. Wehypothesized that cognitive impairment may be influenced byeither cerebral hypoperfusion associated with orthostatic hy-potension (OH) or nocturnal hypoxemia caused by sleep-dis-ordered breathing (SDB), both of which are important clini-cal symptoms observed in MSA patients. Our aim was toinvestigate the factors influencing cognitive impairment byfocusing mainly on OH or SDB.

We performed this study on Japanese patients with proba-ble MSA according to the Consensus Criteria (1999), whowere admitted to our hospital between 2005 and 2008. Thepatients were assessed on the basis of the scores of unifiedMSA rating scale (UMSARS), mini-mental state examination(MMSE), and frontal assessment battery (FAB). The cutoffscores for MMSE and FAB were defined as 24 and 10,respectively. The associations between the MMSE or FABscores and disease severity-related variables, namely, OH andSDB were determined by Spearman’s rank correlation test.Statistical significance was defined as P < 0.05.

In this study, we enrolled 17 patients with probable MSA;13 were cerebellar-predominant MSA (MSA-C) and fourwere parkinsonism-predominant MSA (MSA-P). The clinicalfeatures of these patients are summarized in Table 1. Cogni-tive impairment was observed in five patients (31.3%) andfrontal-lobe impairment was observed in four patients(26.7%). Among the five patients showing cognitive impair-ment, three also showed frontal-lobe impairment. Disease du-ration and UMSARS scores were correlated (R2 5 0.497, P5 0.002). Although no correlation was observed between thedisease duration and MMSE or FAB scores (Table 2), theMMSE and the UMSARS scores (R2 5 0.345, P 5 0.021)and the MMSE and FAB scores were correlated (R2 50.628, P < 0.001). The MMSE or FAB scores were not cor-related with the reduction in the blood pressure or parametersof polysomnography, including the values for oxygen satura-tion, apnea index, and apnea-hypopnea index (Table 2).

Cognitive impairment and frontal-lobe impairment werefrequently observed in our patients (31.3 and 26.7%, respec-tively). This finding supports the previous observation thatthe impairment in cognitive function or frontal-lobe functionis a distinct clinical presentation of MSA.1,2 Our findingsindicate that the MMSE scores are useful for evaluating cog-nitive impairments in probable MSA patients, in spite thatthe utility of MMSE in evaluating cognitive impairments inMSA patients was a matter of debate.1,2 In addition, theMMSE scores were inversely correlated with the disease se-verity, suggesting that cognitive impairment was observed inpatients with advanced-stage of disease. The FAB scores didnot correlate with disease duration, but they showed correla-tion with the MMSE scores. Because few frontal executivefunctions, such as attention, calculation, subset language, andthree-stage command, are also evaluated in MMSE, we spec-ulate that this association may explain the correlationbetween the MMSE and FAB scores.

We also showed that the MMSE and FAB scores were notinfluenced by the severities of OH and SDB-related nocturnalhypoxemia. Recent studies have reported that OH contributesto the cognitive impairment in patients with pure autonomicfailure3 and that nocturnal hypoxemia contributes to the cogni-tive impairment in patients with amyotrophic lateral sclerosis,4

thereby indicating that cerebral hypoperfusion or nocturnal hy-poxemia may exacerbate cognitive impairment. In contrast,our results indicate that the impairment of cognitive functionor frontal-lobe function in MSA patients was less likely to beexacerbated by these factors. Further, our findings support thehypothesis that this impairment may represent an importantand independent part of the phenotype of MSA.

Our study has a limitation that needs to be addressed.First, the number of MSA-P patients in the study populationwas small because there were less MSA-P patients in the Jap-anese population.5 Further studies are required to clarify thedifferences between the factors influencing cognitive impair-ment in MSA-P and MSA-C patients. Second, we evaluatedcognitive impairment in MSA patients without respect to theeffect of their posture. Because some studies suggested thatOH elicited during tilt may acutely exacerbate attention andexecutive function,6,7 further studies should be performed toevaluate whether effects of OH on cognition is more promi-nent depending on the posture.

Financial Disclosures: Nothing to report.

Author Roles: All authors contributed equally to this work.

Kunio Kawamura, MD

Takayoshi Shimohata, MD, PhD*

Department of NeurologyBrain Research Institute

Niigata UniversityNiigata, Japan

*E-mail: [email protected]

Hideaki Nakayama, MD, PhD

Division of Respiratory MedicineNiigata University Graduate School of Medical and

Dental SciencesNiigata, Japan

Potential conflict of interest: Nothing to report.Published online 5 October 2010 in Wiley Online Library




Masahiko Tomita, MD, PhD

Department of OtolaryngologyNiigata University Graduate School of Medical and

Dental SciencesNiigata, Japan

Tetsutaro Ozawa, MD, PhD

Masatoyo Nishizawa, MD, PhD

Department of NeurologyBrain Research Institute

Niigata UniversityNiigata, Japan

References

1. Chang CC, Chang YY, Chang WN, et al. Cognitive deficits inmultiple system atrophy correlate with frontal atrophy and diseaseduration. Eur J Neurol 2009;16:1144–1150.

2. Kawai Y, Suenaga M, Takeda A, et al. Cognitive impairments inmultiple system atrophy: MSA-C vs MSA-P. Neurology 2008;70:1390–1396.

3. Heims HC, Critchley HD, Martin NH, Jager HR, Mathias CJ,Cipolotti L. Cognitive functioning in orthostatic hypotensiondue to pure autonomic failure. Clin Auton Res 2006;16:113–120.

4. Kim SM, Lee KM, Hong YH, et al. Relation between cogni-tive dysfunction and reduced vital capacity in amyotrophiclateral sclerosis. J Neurol Neurosurg Psychiatry 2007;78:1387–1389.

5. Ozawa T. Pathology and genetics of multiple system atrophy:an approach to determining genetic susceptibility spectrum. ActaNeuropathol 2006;112:531–538.

6. Peralta C, Stampfer-Kountchev M, Karner E, et al. Ortho-static hypotension and attention in Parkinson’s disease withand without dementia. J Neural Transm 2007;114:585–588.

7. Allcock LM, Kenny RA, Mosimann UP, et al. Orthostatic hypo-tension in Parkinson’s disease: association with cognitivedecline? Int J Geriatr Psychiatry 2006;21:778–783.

TABLE 1. Clinical features of MSA patients

MSA (Total) (N 5 17) MSA-P (N 5 4) MSA-C (N 5 13)

Sex (Male/Female) 17 (6:11) 4 (0:4) 13 (6:7)Age at onset (yr) 55.5 6 7.4 ( 46.0–73.0) 51.3 6 2.1 ( 49.0–53.0) 56.5 6 8.0 ( 46.0–73.0)Disease duration (yr) 4.0 6 1.9 (1.0–8.0) 2.5 6 1.6 (1.1–4.4) 4.4 6 1.8 (1.3–8.0)UMSARS 44.6 6 18.9 (17.0–79.0) 41.0 6 12.0 (28.0–57.0) 45.8 6 21.0 (17.0–79.0)MMSE 25.6 6 4.0 (17.0–30.0) 26.8 6 3.4 (22.0–30.0) 25.2 6 4.2 (17.0–30.0)FAB 12.9 6 3.9 (6.0–18.0) 13.8 6 3.9 (8.0–16.0) 12.6 6 4.1 (6.0–18.0)Cognitive impairment (MMSE <24) 5/16 (31.3%) 1/4 (25.0%) 4/11 (36.3%)Frontal lobe impairment (FAB <10) 4/15 (26.7%) 1/4 (25.0%) 3/11 (27.3%)Dsystolic BP (torr) 29.0 6 18.3 (0.0–61.0) 27.3 6 7.2 (23–38) 29.6 6 21.0 (0.0–61.0)Ddiastolic BP (torr) 13.4 6 9.9 (23.0–30.0) 7.8 6 9.2 (23.0–18.0) 15.3 6 9.8 (0.0–30.0)Mean nocturnal SpO2 (%) 94.3 6 2.15 (91.0–97.0) 96.3 6 1.0 (95.0–97.0) 93.7 6 2.1 (91.0–97.0)Minimal nocturnal SpO2 (%) 88.2 6 4.5 (79.0–96.0) 90.5 6 2.4 (89.0–94.0) 87.4 6 4.9 (79.0–96.0)AI (/hr) 25.5 6 25.4 (0.0–80.8) 3.5 6 4.1 (0.0–9.4) 32.8 6 25.9 (0.6–80.8)AHI (/hr) 46.3 6 31.8 (8.0–117.3) 18.5 6 13.7 (8.0–36.9) 55.6 6 33.4 (8.8–117.3)

TABLE 2. Factors influencing MMSE or FAB scores

MMSE FAB

R R2 P R R2 P

Age at onset (yr) 0.423 0.179 0.103 0.457 0.205 0.09Disease duration (yr) 0.427 0.182 0.099 0.111 0.012 0.695UMSARS 0.587 0.345 0.021 0.288 0.083 0.317Dsystolic BP (torr) 0.124 0.015 0.659 0.002 <0.001 0.993Ddiastolic BP (torr) 0.115 0.013 0.684 0.38 0.144 0.163Mean nocturnal SpO2 (%) 0.163 0.027 0.571 0.077 0.006 0.794Minimal nocturnal SpO2 (%) 0.047 0.002 0.868 0.097 0.009 0.741AI (/hr) 0.111 0.012 0.671 0.378 0.143 0.111AHI (/hr) 0.194 0.038 0.456 0.17 0.029 0.487



Exercise Dependence Induced by Pramipexole

in Parkinson’s Disease—A Case Report

Although universally acknowledged to be a healthy habit,exercise has also been recognized as having the potential tobecome an unhealthy obsession. This phenomenon is usuallycalled exercise dependence (ED).1,2 ED is physical activitythat is extreme in frequency and duration, relatively resistantto change, and is often associated with an irresistible impulseto continue exercise despite injury, illness, fatigue, and otherpersonal demands.1,2

Dopamine agonists have been implicated in causing a vari-ety of compulsive behaviors in patients affected by Parkin-son’s disease (PD), that is, gambling, hypersexuality, hob-bysm, and other repetitive, purposeless behaviors.3 We reporta man with PD, who developed disabling ED consequent topramipexole therapy.

A 66-year-old man was diagnosed with idiopathic PD,based on a 2-year history of slowing down, unilateral resttremor and micrographia. Pramipexole was started andresulted in improvements in speech, tremor, and walking.Shortly after the pramipexole dose was increased to 3 mg/day, the patient, who previously had a very sedentary life-style, developed an unhealthy obsession with physical exer-cise. He started with a 20 km run each morning, followed inthe afternoon by spinning training and aerobic fitness exer-cises lasting up to 3 hour. He had gradually increased the fre-quency and the time spent in training sessions each day with-out realizing these behaviors were unhealthy and time con-suming. He reported an increasing need to exercise toachieve ‘‘well-being.’’ An attempt to reduce the amount ofexercise was unsuccessful. When exercise levels diminished,the patient experienced withdrawal symptoms: he felt antsy,irritated, and sometimes severely depressed. ED continuedfor 4 months at which time the patient had a severe hyperten-sive crisis during a spinning session that led to hospitaliza-tion. Withdrawal of pramipexole and the introduction of lev-odopa, resulted in complete remission, and the patientreturned to his usual daily activities.

A clinical interview showed that the patient fulfilled theclinical criteria for ED based on the DSM-IV4 criteriafor substance dependence, and on previous research1,2,4

(Table 1).Upon discharge from hospital, the patient underwent a

standardized, comprehensive neuropsychological test batteryto evaluate his global cognitive status.

The patient was not demented according to DSM IV cri-teria and the MMSE score. However, verbal working mem-ory task was severely impaired. In contrast, frontal lobefunctions, spatial short-term memory, verbal long-termmemory, visuospatial, and linguistic abilities were preserved.Our patient was not affected by major depressive disorders,visual hallucinations, or by other psychiatric symptoms.Brain magnetic resonance imaging showed minimal diffuseatrophy.

Several theories have been proposed to explain ED in ani-mal models and humans. Exercise induces changes in mentalstatus, namely, analgesia, sedation, anxiolysis, and a sense ofwell-being. The mechanism underlying these changes remainslargely unknown. ED is often described as a direct conse-quence of alterations in endogenous opioid release. As vigor-ous exercise increases the release of endorphins and opiodsfacilitate addiction, ED might be the consequence of animbalance in opiodergic activity.5

Moreover, exercise increases serum concentrations ofendocannabinoids (CB).6 There is also a close interactionbetween dopamine and the CB system in structures that areimplicated in the brain’s reward system.6 Evidence suggeststhat, both endogenous and exogenous CB induce selectiverelease of dopamine in the shell of accumbens through CB1receptors, which suggest that exercise-induced activation ofendogenous cannabinoids could account for ED.6

Sharing many features with other compulsive behaviors,ED might be proposed as a distinct manifestation of the do-pamine dysregulation syndrome in PD. In our patient, theonset of ED appeared to be related to dopamine replacementtherapy. Indeed, ED worsened during pramipexole treatment,and improved when the drug was discontinued. The basis forthis drug-induced pathologic behavior might be related toalterations of brain’s reward and motor systems. Pramipexolehas a selective affinity for dopamine D3 receptors, which areprimarily confined to the limbic system.7 Conceptually, it canprime the dopamine reward circuits, thus facilitating theoccurrence of ED.

Exercise addiction could be a rare and unrecognized com-plication associated with dopamine agonists use in PD. Toour knowledge, this is the first report of ED in a PD patient.Physicians should be alert to the possibility of ED whenadministering a dopamine agonist in PD patients.

Financial Disclosures: Carmine Vitale has received hono-raria for symposia from Boehringer Ingelheim, Lundbeck,Novartis. He has received salary from IDC Hermitage-Capo-dimonte and the University of Naples ‘‘Parthenope’’, Italy.

Potential conflict of interest: Nothing to report.Published online 4 August 2010 in Wiley Online Library


TABLE 1. Criteria for a diagnosis of exercisedependence1,2,4

(1) Tolerance: Need for increased amounts of exercise to achievedesired effect; diminished effect with continued use of sameamount of exercise.

(2) Withdrawal: Characteristic withdrawal symptoms for exercise(e.g., anxiety, fatigue, etc) or exercise is taken to relieve or avoidsymptoms.

(3) Intention Effect: Exercise is often taken in larger amounts orover a longer period than intended.

(4) Lack of Control: A persistent desire or unsuccessful effort to cutdown or control exercise.

(5) Time: A great deal of time is spent in activities necessary toobtain exercise (e.g., physical activity vacations).

(6) Reduction in Other Activities: Social, occupational, orrecreational activities are given up or reduced because ofexercise.

(7) Continuance: Exercise is continued despite knowledge of havinga persisting/recurring physical or psychological problem that islikely to have been caused or exacerbated by the exercise (e.g.,continued running despite injury).

2893LETTER TO THE EDITOR


Gabriella Santangelo has received honoraria for symposiafrom Lundbeck. Francesca Verde has not received honorariaor research support from any pharmaceutical company.Marianna Amboni has received honoraria for symposia fromBoehringer Ingelheim, Lundbeck, Novartis. She has receivedsalary from IDC Hermitage-Capodimonte and the Departmentof Neurological, Sciences-University of Naples ‘‘FedericoII.’’ Dario Grossi has not received honoraria or research sup-port from any pharmaceutical company. He has received sal-ary from the Department of Psychology, Second Universityof Naples, Italy. Giuseppe Sorrentino has not received hono-raria or research support from any pharmaceutical company.He has received salary from the University of Naples ‘‘Par-thenope’’, Italy. Paolo Barone has received honoraria as aConsultant & Advisory Board Memberships for Novartis,Schwarz Pharma/UCB, Merck-Serono, Eisai, Solvay, GeneralElectric and Lundbeck. He has received research supportfrom Boehringer Ingelheim, Novartis, Schwarz Pharma/UCB,Merck-Serono, Solvay, and Lundbeck. He has received salaryfrom the Department of Neurological Sciences-University ofNaples ‘‘Federico II.’’

Authors’ Roles: Carmine Vitale: Conception, interpreta-tion of date, writing the first draft and recruitment of patient;Gabriella Santangelo: Conception, interpretation of date,assessment of patient, rewieving the article. FrancescaVerde:Assessment of patient, rewieving the article. MariannaAmboni: Interpretation of date, rewieving the paper. Giu-seppe Sorrentino: Interpretation of date, rewieving the article.Dario Grossi: interpretation of date, rewieving the article.Paolo Barone: Conception, interpretation of date, rewievingthe article.

Carmine Vitale, MD, PhD

University of Naples ‘‘Parthenope’’, ItalyIstituto di Diagnosi e Cura ‘‘Hermitage Capodimonte’’

Naples, ItalyDepartment of Neurological SciencesUniversity of Naples ‘‘Federico II’’

Naples, Italy

Gabriella Santangelo, PhD

Department of Neurological SciencesUniversity of Naples ‘‘Federico II’’, Naples, Italy

Department of Psychology, Second University of Naples, ItalyIstituto di Diagnosi e Cura ‘‘Hermitage Capodimonte’’

Naples, Italy

Francesca Verde, MPsy


Department of Psychology, Second University of Naples, Italy

Marianna Amboni, MD

Parthenope University of Naples, ItalyIstituto di Diagnosi e Cura ‘‘Hermitage Capodimonte’’

Naples, ItalyDepartment of Neurological Sciences

University of Naples ‘‘Federico II’’, Naples, Italy

Giuseppe Sorrentino, MD, PhD

University of Naples ‘‘Parthenope’’, ItalyIstituto di Diagnosi e Cura ‘‘Hermitage Capodimonte’’

Naples, Italy

Dario Grossi, MD

Department of Psychology, Second University of Naples, Italy

Paolo Barone, MD, PhD*


Istituto di Diagnosi e Cura ‘‘Hermitage Capodimonte’’Naples, Italy


References

1. Hausenblas HA, Symons Downs D. Exercise dependence: asystematic review. Psychol Sport Exerc 2002;3:89–123.

2. Hausenblas HA, Symons Downs D. How much is too much? Thedevelopment and validation of the exercise dependence scale. Psy-chol Health 2002;17:384–404.

3. Voon V, Fox SH. Medication related impulse control and repetitivebehaviors in Parkinson’s disease. Arch Neurol 2007;64:1089–1096

4. American Psychiatric Association. Diagnostic and statistical man-ual of mental disorders, 4th ed (DSM-IV). Washington DC: Ameri-can Psychiatric Association, 1994.

5. Pierce EF, Eastman NW, Tripathi HL, et al. Endorphin response toendurance exercise: relationship to exercise dependence. PerceptMot Skills 1993;77:767–770.

6. Dietrich A, McDaniel WF. Endocannabinoids and exercise. Br JSports Med 2004;38:536–541.

7. Gerlach M, Double K, Arzberger T, et al. Dopamine receptor ago-nists in current clinical use: comparative dopamine receptor bind-ing profiles defined in the human striatum. J Neural Transm2003;110:1119–1127.

Magnetic Resonance Spectroscopy in Two

Siblings with Chorea-Acanthocytosis

Chorea-acanthocytosis (ChAc) (OMIM #200150) is aneurodegenerative disorder characterized by chorea, neuro-psychiatric disturbances, and degeneration of the striatum.1

Common other clinical findings are epilepsy, peripheralneuropathy, myopathy, oral self-mutilation, neuropsychiatricmanifestations, and elevation of creatine kinase (CK), whilethe determination of acanthocytes is less reliable.1,2 Magneticresonance imaging (MRI) suggests that the head of the cau-date nucleus is particularly vulnerable.3 Functional neuroi-maging studies showed a marked decrease in neuronal meta-bolic activity and blood flow in the basal ganglia.4 Magnetic

Potential conflict of interest: Nothing to report.Published online 14 September 2010 in Wiley Online Library




resonance spectroscopy (MRS) recorded from putamen andglobus pallidus showed a significantly higher intensity ofmyo-inositol (mI) and choline (Cho) peaks in neuroacantocy-tosis (NA), which encompasses ChAc but may also includeadditional entities.5 To our knowledge, MRS was not per-formed in confirmed ChAc before. Confirmation of the diag-

nosis of ChAc is possible through Western blot with reducedor absent levels of chorein in erythrocytes.6 Here, we reportthe MRS findings of two molecularly confirmed ChAc sib-lings, based on Western blot, from Turkey as well as theirfindings on single photon emission computed tomography(SPECT).

FIG. 1. (A1) 1H-MRS (point-resolved spectroscopy sequence; TE, 30 ms, TR, 2,000 ms) with manually placed voxels at the level of the basalganglia of the first 35-year-old male patient. MRS shows normal Cho/Creatine (Cr) ratio, decreased N-acetylaspartate (NAA)/Cr ratio, andincreased myo-inositol (mI)/Cr ratio. (A2) SPECT of the first 35-year-old male patient; hypoperfusion of superior temporal gyrus and insula con-taining basal ganglia. (B1) 1H-MRS (point-resolved spectroscopy sequence; TE, 30 ms, TR, 2,000 ms) with manually placed voxels at the levelof the basal ganglia of the 25-year-old female patient. MRS shows normal Cho/Cr and NAA/Cr ratio and decreased mI/Cr ratio. (B2) SPECT ofthe 25-year-old female patient; slightly decreased perfusion of left basal ganglia and thalamus. [Color figure can be viewed in the online issue,which is available at wileyonlinelibrary.com.]



The proband is a 35-year-old right-handed man with con-sanguineous parents. Symptom onset was at age 22 and wascharacterized by chorea, oral self-mutilation, temporal lobeepilepsy, neuropathy, depression, acanthocytosis, and ele-vated CK. At age 35, neurological examination revealed mildchorea, gait instability, pes cavus, ankle hyporeflexia, anddysarthria. There were lesions due to biting on his lips, oralmucosa, and tongue. Electroencephalography showed milddisorganization with theta rhythms. Wet blood preparations(EDTA) were stained according to May-Grunwald-Giemsa(automated blood stain system Sysnex SP 1000i) and assess-ment with light microscopy revealed 10% acanthocytes.Western blot showed absence of chorein. MRI demonstratedbasal ganglia atrophy, prominent at caudate nucleus and puta-men. MRS at the level of the basal ganglia revealed normalCho/Creatine (Cr) ratio, decreased N-acetylaspartate (NAA)/Cr ratio, and increased mI/Cr (Fig. 1A1). SPECT demon-strated bilateral hypoperfusion of the basal ganglia and insulaas well as the superior temporal gyri (Fig. 1A2). Hippocam-pal MRI showed bilateral atrophy of the hippocampus.

The proband’s 25-year-old sister’s symptom onset was atage 20 and characterized by mild choreic movements in herarms, orobuccal tics, depression, and elevated CK. MRI dem-onstrated basal ganglia atrophy (less severe than in herbrother). MRS at the level of the basal ganglia revealed nor-mal Cho/Cr, and NAA/Cr ratio and decreased mI/Cr ratio(Fig. 1B1). Evaluation with SPECT showed slightlydecreased perfusion of left basal ganglia and thalamus (Fig.1B2). Acanthocytes (40%) were found. Western blot showedabsence of chorein.

Our patients had typical neuroimaging findings with atro-phy of the caudate nucleus on MRI and with decreased bloodflow in the basal ganglia on SPECT. Using MRS, we wereable to demonstrate metabolic alterations in the striatal areasof ChAc patients with prominent chorea. The proband withmore advanced disease had increased mI/Cr and decreasedNAA/Cr ratios at the level of basal ganglia, whereas his sis-ter with relatively recent disease onset had decreased mI/Crand normal NAA/Cr ratios. These MRS findings are consist-ent with the few neuropathological observations in geneti-cally confirmed ChAc, which demonstrate marked atrophyand neuronal loss, with astrocytic gliosis in the caudate nu-cleus, putamen, and globus pallidus.7 NAA levels may repre-sent a marker for neuronal cellular function and mI, primarilyfound in glial cells, can be used as a marker of glial cellfunction, whereas Cho levels may indicate membrane turn-over.8 Molina et al.,5 reported increased mI and Cho peaks,normal NAA/Cr ratios, and increased Cho/Cr and mI/Crratios on MRS from putamen and globus pallidus in two sib-lings with NA. Unfortunately, these NA patients5 werenot specifically diagnosed. NA is a nonspecific term andrefers to any disorder with neurologic abnormalities andacanthocytosis.

The MRS changes in our first patient reflect two neuropa-thologic features of ChAc: neuronal loss (reduction of NAA)and reactive glial activation (increase of mI), in the absenceof increased membrane turnover (normal Cho). However,decreased mI/Cr ratios in the second patient differed fromher brother’s and the Molina’s report of NA,5 and, mayreflect her short disease duration. In accordance with this,basal ganglia atrophy was less severe in her than in herbrother.

In summary, the current report is the first to describe MRSfindings in molecularly confirmed ChAc and may help to es-tablish MRS as a method to elucidate and follow the evolu-tion of pathology in this condition.

Acknowledgments: The molecular analysis was supportedby The Advocacy for Neuroacanthocytosis (www.naadvocacy.org).

Financial Disclosures: Prof. Dr. Adrian Danek serves onthe editorial board of ‘‘Zeitschrift fur Gerontoneurologie’’and ‘‘Translational Neuroscience’’; has received speaker hon-oraria from Merz, Pfizer, Novartis, Janssen-Cilag, and Neuro-Update; receives research support as Principal Investigatorfrom Bayerische Forschungsstiftung, German Federal Minis-try of Research, Munchner Universitatsgesellschaft, Deutsch-Franzosische Hochschulstiftung, and Advocacy for Neuroa-canthocytosis Patients; and has served as an expert witnessfor German courts of justice in medico-legal cases. BenedictBader is supported by the Advocacy for NeuroacanthocytosisPatients; by the Bayerische Forschungsallianz; by the Bayeri-sche Forschungsstiftung; and by the Bundesministerium furBildung und Forschung. Murat Aksu is member of adviserboard of UCB Pharma, lecturer in Novartis and Pfizer.

Author Roles: S. Ismailogullari: research project: concep-tion, organization, and execution; manuscript: writing of thefirst draft, review and critique. A.O. Caglayan: research pro-ject: conception, organization, and execution; manuscript:writing of the first draft, review and critique. B. Bader:research project: conception, organization, and execution;manuscript: review and critique. A. Danek: research project:organization and execution; manuscript: review and critique.S. Korkmaz: research project: conception and organization;manuscript: review and critique. F. Kurnaz: research project:organization; manuscript: review and critique. E. Sharifov:research project: organization; manuscript: review and cri-tique. M. Aksu: research project: conception, organization,and execution; manuscript: review and critique.

Sevda Ismailogullari, MD*Department of Neurology

Erciyes University Medical FacultyKayseri, Turkey


Ahmet Okay Caglayan, MDDepartment of Medical Genetics

Kayseri Education and Research HospitalKayseri, Turkey

Benedikt Bader, MDAdrian Danek, MD

Neurologische Klinik und PoliklinikLudwig-Maximilians-Universitat

Munich, Germany

Selda Korkmaz, MDDepartment of Neurology




Elman Sharifov, MDDepartment of Radiology, Erciyes University

Medical Faculty, Kayseri, Turkey

Fatih Kurnaz, MDDepartment of Hematology


Murat Aksu, MDDepartment of Neurology


References

1. Ichiba M, Nakamura M, Kusumoto A, Mizuno E, Kurano Y, Mat-suda M, et al. Clinical and molecular genetic assessment of a cho-rea-acanthocytosis pedigree. J Neurol Sci 2007;263:124–132.

2. Bayreuther C, Borg M, Ferrero-Vacher C, Chaussenot A, LebrunC. Chorea-acanthocytosis without acanthocytes. Rev Neurol(Paris). 2010;166:100–103.

3. Henkel K, Danek A, Grafman J, Butman J, Kassubek J. Head ofthe caudate nucleus is most vulnarable in chorea-acanthocytosis: avoxel based morphometry study. Mov Disord 2006;21;1728–1731.

4. Muller-Vahl KR, Berding G, Emrich HM, Peschel T. Chorea-acanthocytosis in monozygotic twins: clinical findings and neuro-pathological changes as detected by diffusion tensor imaging,FDG-PET and (123)I-beta-CIT-SPECT. J Neurol 2007;254:1081–1088.

5. Antonio Molina J, Manuel Garcia-Segura J, Benito-Leon J, JavierJimenez-Jimenez F, Martinez V, Viano J, Bermejoa F. In vivoproton magnetic resonance spectroscopy in patients with neuroa-canthocytosis. Parkinsonism Relat Disord 1998;4:11–15.

6. Dobson-Stone C, Velayos-Baeza A, Flippone LA, et al. Choreindetection for the diagnosis of chorea-acanthocytosis. Ann Neurol2004;56:299–302.

7. Ishida C, Makifuchi T, Saiki S, Hirose G, Yamada M. A neuro-pathological study of autosomal-dominant chorea-acanthocytosiswith a mutation of VPS13A. Acta Neuropathol 2009;117:85–94.

8. Soares DP, Law M. Magnetic resonance spectroscopy of the brain:review of metabolites and clinical applications. Clin Radiol2009;64:12–21.

Shortness of Breath in a Parkinson’s

Disease Patient

Hydropneumothorax may present with isolated shortness ofbreath (SB).1 Because breath shortness is quite common inneurological diseases, the diagnosis of hydropneumothoraxmight be extremely challenging when this is the only symp-tom in neurological disorders.

Report of a Case

We describe a 64-year-old man who has suffered fromParkinson’s disease (PD) for about 1 year. His medicationwas 8 mg/day of prolonged-release ropinirole. He presentedwith a 2-months history of slight shortness of breath, usuallymanifesting when he climbed the stairs. Because the patienthad no past medical history of heart or lung disease, as PDpresents fluctuating motor and nonmotor symptoms, anddyspnea is a frequent and disabling nonmotor symptom,2

dyspnea was considered PD related. One week later, hereported a slight dyspnea worsening. General examinationrevealed absent breath sounds on the right side. Because ofthis finding and because of the well-known occurrence ofpericardial, valvular and pleuropulmonary fibrosis duringtreatment with of dopamine agonists,3 we decided to performheart and lung instrumental evaluation. Chest radiographyand CT scan showed hydropneumothorax with collapsed rightlung (Fig. 1). Pneumothorax cause remained undeterminedbut the patient remembered a short-lasting severe thoracicpain about 2 months before. Conceivably, the cause wasspontaneous rupture of a small lung bulla. The patient wassuccessfully treated with chest-tube placement.

FIG. 1. Chest radiography (A) and CT scan (B) showing hydropneumothorax with a collapsed right lung and an adjacent thoracic air-liquid level.

Potential conflict of interest: The authors report no conflict of interest.Published online 11 October 2010 in Wiley Online Library




Conclusions

All possible causes should be considered for respiratorysymptoms even when they might be related to PD.

Financial Disclosure: P. Granone, A. Sestito, T. Pirronti,F. Pilato: none. Di Lazzaro has no financial support relatedto this article but has the following unrelated financial sup-port: grant support from Medtronic, Inc. (Minneapolis, MN)sponsor of the study CRYSTAL AF.

Author Roles: Di Lazzaro—writing of the first draft,review, and critique of the manuscript. Granone—review andcritique of the manuscript. Sestito—review and critique of themanuscript. Pirronti—review and critique of the manuscript.Pilato—review and critique of the manuscript.

V. Di Lazzaro, MD*

F. Pilato

Institute of NeurologyUniversita Cattolica, Rome, Italy*E-mail: [email protected]

P. Granone, MDDivision of General Thoracic Surgery

Universita Cattolica, Rome, Italy

A. Sestito, MDInstitute of Cardiology

Universita CattolicaRome, Italy

T. Pirronti, MDInstitute of RadiologyUniversita Cattolica

Rome, Italy

References

1. Chen PH, Lin XZ. Images in clinical medicine. Hydropneumo-

thorax. N Engl J Med 2010;362:e9.2. Witjas T, Kaphan E, Azulay JP, et al. Nonmotor fluctuations in Parkin-

son’s disease: frequent and disabling. Neurology 2002;59:408–413.3. Antonini A, Tolosa E, Mizuno Y, Yamamoto M, PoeweWH. A reas-

sessment of risks and benefits of dopamine agonists in Parkinson’s

disease. Lancet Neurol 2009;8:929–937.



Exercise dependence induced by pramipexole in Parkinson's Disease-A Case Report

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