Thalidomide induced acute worsening of Parkinson's disease

Letters to the Editor Related to New Topics

Reversible Parkinsonism After Chronic

Cyclosporin Treatment in Renal

Transplantation

Video

Cyclosporin A (CsA)-induced neurotoxicities are common,reported in up to 40% of transplant patients receiving CsA.1

Tremor is the most common abnormal movement, observedin 20% of patients receiving long-term CsA,1 Parkinsonism isvery rare and only 3 cases have been reported.2–4 We describea renal transplant patient who developed disabling parkinson-ism after long-term CsA treatment, despite low trough thera-peutic blood levels. Most of her symptoms were reversible af-ter discontinuing CsA.

A 59-year-old right-handed Thai woman presented with18-month history of progressive bradykinesia, which hadrequired assistance with walking and feeding during thepast 4 months. Despite increasing the dose of levodopa (l-dopa) up to 1 g daily, her Parkinsonism deteriorated. Within10 months of symptom onset, she was stuporous and bedrid-den. At the age of 46 years, the patient was diagnosed withend-stage kidney disease in which the etiology remainedinconclusive, later requiring cadaveric kidney transplanta-tion. Immunosuppressive therapy consisted of CsA, myco-phenolate mofetil, and prednisolone. Graft function wasgood and her serum creatinine levels were consistently nor-mal. Her daily medications when transferred to our hopsitalincluded L-dopa (1 g), levetiracetam (400 mg), quetiapine(25 mg), sertraline (50 mg), CsA (150 mg), mycophenolatemofetil (1 g), prednisolone (2.5 mg), clopidogrel, and folicacid.

On the first day of hospital admission, she was apyrexialand normotensive. She only opened her eyes and withdrewlimbs minimally in response to noxious stimuli. She was aki-netic with severe generalized rigidity and tremor and myoclo-nus of the limbs. Mild cervical dystonia, consisting of antero-collis and right laterocollis was also present. Reflexes werebrisk with bilateral flexor plantar response. Basic laboratoryresults were normal, except for borderline low magnesiumlevel (Mg) (0.75; Ref: 0.75–1.05 mg/dL). Serum CsA levelmeasured immediately before CsA intake (C0) was in the lowtherapeutic range, 61.3 ng/mL (<150 ng/mL). Magnetic reso-nance imaging (MRI) of the brain showed minimal T2-signal

hyperintensities in the periventricular white matter. MRangiogram was normal.

After excluding any potential metabolic or infectiouscauses, CsA was discontinued and tacrolimus was started onday 5 of hospital admission; all other medications remainedunchanged (video). Within 4 days, her mental status andspeech returned to normal. She experienced dramaticimprovement in her Parkinsonism. Two weeks after stoppingCsA, rigidity, and cervical dystonia resolved and she couldwalk independently with moderate ataxia. L-dopa was gradu-ally discontinued. At a 5-month follow-up visit, tremor andmyoclonus had completely resolved except for mild residualataxia. Her renal function remained optimal. In view of thedramatic improvement of symptoms in close proximity todiscontinuation of CsA, the diagnosis of CsA-induced Parkin-sonism was made.

We describe a renal transplant patient who developed rap-idly progressive Parkinsonism in association with otherabnormal movements after long-term CsA treatment. HerParkinsonism was not responsive to L-dopa. Kim et al.3

reported the first renal-transplant patient who developed par-kinsonism 6 weeks after taking CsA while the blood levelsof CsA were normal. Similar to our patient, the symptomswere nonresponsive to L-dopa, but markedly improved afterCsA was switched to tacrolimus.

Our patient remained well in the first 4 years while takingCsA. Prolonged CsA therapy might have led to accumulationof CsA toxicities.2 Nevertheless, certain precipitating factorsmight have played a major role in crossing our patient overthe symptom threshold, including hypomagnesemia and druginteraction.1 Other reported risk factors were fluid retention,hypertension, methylprednisolone, hypocholesterolemia, andaluminium overload.1 Hypomagnesemia can lead to vascular-related adverse effects including vascular damage, accelera-tion of atherosclerosis, vasoconstriction, and thrombocyteaggregation, potentially resulting in cerebral vasospasm andendothelial dysfunction, which in turn increases CsA concen-tration in the brain.5

Serum CsA levels were normal in our patient. Similarfindings were also reported in other cases of CsA-relatedneurotoxicities.1 Therefore, neurotoxicities could be causedby CsA metabolites. A trough CsA measurement, C0, may bea poor indicator of CsA exposure, whereas a 2-hour postdose,C2, and the area-under-the-curve of CsA profile are probablybetter.6

In addition to Parkinsonism, our patient also had actiontremor, myoclonus, ataxia, and cervical dystonia. It seemsthat CsA neurotoxicities can induce a variety of movementdisorders. Tremor induced by CsA is almost exclusivelyaction tremor and is seen in 12 to 21% of patients, mostlyduring first 3 months of treatment and are generally mild.2

There were also other reports of transplanted patients withmyoclonus, chorea, and ataxia with prolonged CsA therapy.Although mild in severity, our patient is the first reportedcase of cervical dystonia caused by CsA.

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

Published online 15 July 2009 in Wiley InterScience (www.

interscience.wiley.com). DOI: 10.1002/mds.22530

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Movement DisordersVol. 24, No. 12, 2009, pp. 1848–1866� 2009 Movement Disorder Society

CsA is highly lipophilic and can easily cross the blood-brain barrier.1 Calcineurin inhibitor could be detected in theCSF during treatment. The reversibility of CsA-related neu-rological symptoms implies direct drug-related functionalinterference with the neuronal circuits, such as neurotrans-mitter function, neuroglial phosphorylation pathways, ortranscription factors.3 CsA modulates dopaminergic trans-mission by stimulating the phosphorylation of dopamine andadenosine-dependent phosphoprotein 3-5-monophosphate instriatal neurons.7 However, it remains unclear why CsA-induced parkinsonism is so much rarer than CsA-inducedtremor.

In patients receiving CsA therapy with new-onset neuro-logical symptoms, CsA-related neurotoxicities should alwaysbe considered because these neurological complications arereversible even in severe cases. A useful diagnostic trialwould be to reduce the dosage despite a normal serum CsAlevel or in patients who are already on low dose therapy,CsA should be switched to an alternative immunosuppres-sant with less liability to produce motor symptoms. Precipi-tating factors should be identified and corrected. Improve-ment of neurological symptoms is expected within days, butcomplete resolutions of symptoms might take severalmonths. The time required for recovery seems to be relatedto the duration of CsA therapy as well as the severity andduration of neurological symptoms. Tacrolimus is an immu-nosuppressant reserved for rescue therapy in renal-transplantrecipients with evidence of organ rejection, or in patientswith CsA-related adverse events.8 Although tacrolimus andCsA are both calcineurin inhibitors, switching from CsA totacrolimus often reverses the side effects without subsequentreturn of symptoms. Different pharmacokinetics mightexplain this interesting observation. Tacrolimus-inducedParkinsonism has been reported.8

LEGEND TO THE VIDEO

Eight months after symptom onset, the patient had akineticrigidity, tremor, action myoclonus and cervical dystonia. Tenmonths after symptom onset, her condition rapidly deterio-rated with akinetic mutism, severe myoclonus and tremor atrest. After cyclosporin was discontinued, her mental statusand speech returned to normal within 4 days. Within 2weeks, parkinsonism and cervical dystonia resolved and shecould walk independently. Within 2 months, mild degree oftremor, myoclonus and ataxia were observed. With 5 months,she only had mild residual ataxia.

Acknowledgment: This case was presented in the VideoOlympics at the 12th International Congress of MovementDisorders in Chicago, USA, and was awarded the bronzemedal prize.

Author Roles: (1) Research project: A: Conception:Roongroj Bhidayasiri; B: Organization: Roongroj Bhidayasiri& Helen Ling; C: Execution: Roongroj Bhidayasiri; (2) Sta-tistical analysis: Not applicable; Review and critique: Roon-groj Bhidayasiri; (3) Manuscript: A: Writing of the first draft:Helen Ling; B: Review and critique: Roongroj Bhidayasiri.

Helen Ling, BMBSRoongroj Bhidayasiri, MD, FRCP*

Division of NeurologyDepartment of Medicine

Chulalongkorn Comprehensive Movement Disorders CentreChulalongkorn University Hospital

Bangkok, Thailand*E-mail: [email protected]

References

1. Gijtenbeek JM, van den Bent MJ, Vecht CJ. Cyclosporine neuro-toxicity: a review. J Neurol 1999;246:339–346.

2. Munhoz RP, Teive HA, Germiniani FM, et al. Movement disor-ders secondary to long-term treatment with cyclosporine A. ArqNeuropsiquiatr 2005;63:592–596.

3. Kim HC, Han SY, Park SB, Suh SJ. Parkinsonism during cyclo-sporine treatment in renal transplantation. Nephrol Dial Transplant2002;17:319–321.

4. Wasserstein PH, Honig LS. Parkinsonism during cyclosporinetreatment. Bone Marrow Transplant 1996;18:649–650.

5. Thompson CB, June CH, Sullivan KM, Thomas ED. Associationbetween cyclosporin neurotoxicity and hypomagnesaemia. Lancet1984;2:1116–1120.

6. Belitsky P, Dunn S, Johnston A, Levy G. Impact of absorptionprofiling on efficacyand safety of cyclosporin therapy in transplantrecipients. Clin Pharmacokinet 2000;39:117–125.

7. Fienberg AA, Hiroi N, Mermelstein PG, et al. DARPP-32: regu-lator of the efficacy of dopaminergic neurotransmission. Science1998;281:838–842.

8. Pirsch JD, Miller J, Deierhoi MH, Vincenti F, Filo RS. A compar-ison of tacrolimus (FK506) and cyclosporine for immunosuppres-sion after cadaveric renal transplantation. FK506 Kidney Trans-plant Study Group. Transplantation 1997;63:977–983.

Cervical Dystonia and Constantin Brancusi

Dystonia has a very recent history in Medicine. Focal dysto-nia was described by Gowers1 and Thompson.2 Generalizeddystonia was described at the turn of the century by Oppen-heim.3 However, besides scientific recognition, several artistsclearly described movement disorders including dystonia, inmany cases centuries before its ‘‘official’’ definition. Artisticrepresentations of dystonia can be tracked back to classic andmedieval times,4,5 not to mention clear definition of charac-ters with dystonia in literature.6

But also, it is possible to find descriptions of dystonia incontemporary art; this is the case of ‘‘suffering’’ from Con-stantin Brancusi (Figs. 1 and 2). Constantin Brancusi (1876–1952) was a Romanian sculptor, who trained initially as acarpenter and stonemason. He settled in Paris under the influ-ence of Auguste Rodin. He was an elegant, enigmatic, highlyoriginal, and profoundly personal sculptor. Probably ‘‘TheKiss’’ is his most famous work. Most of his pieces are almostabstract, including ‘‘Fish,’’ ‘‘Pogany,’’ and ‘‘Bird in space’’and many of his sculptures are devoted to movement. In

Published online 26 June 2009 in Wiley InterScience (www.


1849LETTERS TO THE EDITOR

Movement Disorders, Vol. 24, No. 12, 2009

addition, he made naturalistic representations such as ‘‘Suf-fering’’ (1907, Museum of Fine Arts, Chicago), which repre-sents a boy with a very notorious painful cervical deviationincluding laterocollis, retrocollis, and shoulder elevation.Brancusi was interested in capturing human deformity andsome of his work has striking similarity to cervical dystonia.

Author Roles: Pedro J. Garcia Ruiz: Research project,organization, execution, writing of first draft; Juan CarlosMartinez Castrillo: Research project, execution, review andcritique.

Pedro J. Garcia Ruiz, MD, PhD*Department of NeurologyFundacion Jimenez Diaz

Madrid, Spain*E-mail: [email protected]

Juan Carlos Martinez Castrillo, MD, PhDDepartment of NeurologyHospital Ramon y Cajal

Madrid, Spain

References

1. Gowers WR, editor. A manual of diseases of the nervous system.Philadelphia: P. Blakiston; 1888. p 1357.

2. Thompson JH. A wry-necked family. Lancet 1896;2:24.3. Oppenheim H. Dysbasia lordotica progressiva, dystonia musculu-

rum deformans. Neurologie Centralblatt 1911;30:1090–1107.4. Lascaratos J, Damanakis A. Torticollis in ancient Macedonians.

Lancet 1996;348:346.5. Garcıa Ruız P, Ruız Ezquerro JJ, Garcıa Torres A, Fanjul S. An-

cient descriptions of movement disorders: Cathedral el Burgo deOsma (Soria, Spain). J Neurol 2006;253:731–734.

6. Brain R. Dickensian diagnoses. Br Med J 1955;2:1553–1556.

Ataxia and Dementia Due to Thinner Abuse

Video

Drug abuse and dependence are major public health problemsworldwide. Inhalants are among the most prevalent andharmful drugs abused by adolescents and young adults withimportant neuropsychiatric burdens, including movementdisorders.

We report the case of a 23-year-old man, who was broughtto a psychiatric emergency unit with psychomotor agitationand movement disorder. The onset of his drug abuse was atthe age of 7 years. He was mainly addicted to thinner, an or-ganic solvent inhalant, but throughout his life, he sporadicallyused marijuana, crack, and cocaine. His motor symptomsstarted at age of 20 years. Initially he developed isolated nys-tagmus, later followed by trunk oscillation and upper limbstremor. Even aware of the possible causal relationship tothinner abuse, he still inhaled 1 L of this drug a day. Twoyears later, he was unable to walk unassisted, crawling out-side his house to search for thinner. He also developed cogni-tive impairment, no longer being able to work as candy streetseller and to handle his finances. At this time, he also devel-oped withdrawal symptoms, especially diaphoresis and diar-rhea, if decreased the use of the drug. Because of theseabnormalities, the patient has required assistance for evensome of the basic activities of the daily living. On examina-tion, his general condition was poor, he was severely anxiousand euphoric, complaining of craving and threatening aggres-sion. Formal cognitive assessment was not possible due tolack of cooperation. He was continuously disoriented in

FIG. 2. Lateral cervical deviation with painful expression. Probably rep-resents a real patient with cervical dystonia. [Color figure can be viewedin the online issue, which is available at www.interscience.wiley.com.]

FIG. 1. ‘‘Suffering,’’ a masterpiece of Brancusi. Lateral cervicaldeviation with painful expression. Probably represents a real patientwith cervical dystonia. [Color figure can be viewed in the onlineissue, which is available at www.interscience.wiley.com.]

Additional Supporting Information may be found in the onlineversion of this article.Potential conflict of interest: Nothing to report.Published online 16 July 2009 in Wiley InterScience (www.



1850 LETTER TO THE EDITOR1850 LETTER TO THE EDITOR


space and time; there were memory and executive functionimpairments, including a moderate decrease of verbal flu-ency. He was not able to recall the name of his doctor andnurses, nor the food served in the meals. There were no opticdisk atrophy or retina abnormalities on fundoscopy, and vis-ual fields were normal. He had spontaneousnystagmus,scanned dysarthria, severe dysmetria and dysdiadocokynesia,kinetic tremor, and wide base gait, which was only possiblewith assistance (Video Segment 1). The patient was diag-nosed with inhalant dependence, inhalant-induced persistentdementia and inhalant-related cerebellar ataxia. The MRIshowed diffuse brain, including cerebellum, atrophy, andwhite matter hyperintensities (Fig. 1). He was treated withabstinence program and carbamazepine 1,200 mg/day withmoderate improvement of his movement disorder (VideoSegment 2) and behavioral symptoms.

Inhalants, also known as solvents or volatile substances,are classified pharmacologically in three groups: (1) volatilesolvents, fuels, and anesthetics; (2) the nitrous oxide group;(3) the volatile alkyl nitrites group.1 Thinner, an organichydrocarbon mixture belonging to Group 1, is a componentof glues, cleaning agents, and other products.2 Inhalantabuse is the self-deliberate use for psychoactive effect bysniffing, huffing, snorting, or bagging.1 It produces euphoriaand pleasurable experience with a rapid onset and minimal‘‘hangover’’ symptoms.1 Tolerance may develop,1 but withmild withdrawal symptoms. Its low price, easy and legalaccess makes it a largely misused substance.1,3 The onset ofabuse is usually at the age of 5 or 6 years, with peak prev-alence at 14 to 15 years.1 One in 10 adults had used inhal-ant at least once in their lives and 0.5% used it a past yearin the United States, from whom 6.6% met the criteria forabuse and 1.1% for dependence.3 It is prevalent in all de-mographic, socioeconomic, and ethnic groups in the UnitedStates.1

Our patient is one of the first video documented cases ofmovement disorder associated to thinner abuse. Reportedcentral nervous system complications of this drug includecerebellar syndrome, decreased visual acuity, behavioralchanges, and dementia.1,2,4 Postural or intentional tremors areusually found in the upper limbs with a frequency of 4–5Hz5; however, without resting tremors.6 Organic solvents ingeneral are related to 6.6–9.9 Hz tremors whereas toluene

induces faster (10.0–13.9 Hz) frequencies.6 Less than 10% ofchronic thinner abusers present with MRI changes: diffusewhite matter hyperintensity of both pyramidal and ponto-cer-ebellar tracts, hypointense thalami and basal ganglia, and dif-fuse brain atrophy.4 In contrast, cerebellar ataxia anddecreased visual acuity are associated with imaging changesin 75% of subjects, whereas just 4% of abusers with normalMRI have mild neurological symptoms, including tremor.4

The pathogenesis of neurological complications of inhalantabuse is likely related to white matter dysfunction.7 Inhalantsare highly lipophilic and have rapid access to the brain.7 Ani-mal imaging studies report high uptake and slower clearanceof these compounds in white matter compared with otherbrain regions.7 Furthermore, there is evidence of induction ofgliosis and astrocytes activation in white matter, as opposedto neuronal death.7

Legends to the Video

Segment 1. Patient 2 weeks after hospital admission, withsevere spontaneous nystagmus, kinetic tremor, and cerebellarsyndrome.

Segment 2. Patient 3 months later, after withdrawal ofdrugs and use of 1,200 mg daily of carbamazepine. There isclear improvement of the movement disorder.

Bernardo de Mattos Viana, MDPsychiatry Service, Hospital das Clınicas

UFMG, Belo HorizonteMinas Gerais, Brazil

Andre de Souza Moura, MDEmergency Unit, UAI Jardim Alterosa

Secretaria de Saude de BetimBetim, Minas Gerais, Brazil

Janaina Matos Moreira, MDPsychiatry Service, Hospital das Clınicas, UFMG

Belo Horizonte, Minas Gerais, Brazil

Hospital Galba VellosoFundacao Hospitalar de Minas GeraisBelo Horizonte, Minas Gerais, Brazil

Hugo Alejandro Cano Prais, MD, MScDepartment of Medical Sciences

UFOP, Ouro Preto, Minas Gerais, Brazil

Francisco Cardoso, MD, PhD**Departamento de Clınica Medica, Neurology Service

Faculdade de Medicina, UFMGBelo Horizonte, Minas Gerais, Brazil

*E-mail: [email protected]

References

1. Williams JF, Storck M. The Committee on Substance Abuse, TheCommittee on Native American Child Health. Inhalant abuse.Pediatrics 2007;119:1009–1017.

FIG. 1. T1 weighted axial image of the cerebellar atrophy (A). Flairaxial image with diffuse brain atrophy; thalami and basal gangliahypointensities; and white matter hyperintensities (B).

1851LETTER TO THE EDITOR


2. White RF, Proctor SP. Solvents and neurotoxicity. Lancet1997;349:1239–1243.

3. Wu LT, Ringwalt CL. Inhalant use and disorders among adults inthe United States. Drug Alcohol Depend 2006;85:1–11.

4. Uchino A, Kato A, Yuzuriha T, et al. Comparison between patientcharacteristics and cranial MR findings in chronic thinner intoxica-tion. Eur Radiol 2002;12:1338–1341.

5. Miyagi Y, Shima F, Ishido K, Yasutake T, Kamikaseda K.Tremor induced by toluene misuse successfully treated by aVim thalamotomy. J Neurol Neurosurg Psychiatry 1999;66:794–796.

6. Iwata T, Mori H, Dakeishi M, Onozaki I, Murata K. Effects ofmixed organic solvents on neuromotor functions among workersin Buddhist altar manufacturing factories. J Occup Health 2005;47:143–148.

7. Lubman DI, Yucel M, Lawrence AJ. Inhalant abuse amongadolescents: neurobiological considerations. Br J Pharmacol 2008;154:316–326.

Clonazepam Is an Effective Treatment for

Hyperekplexia Due to a SLC6A5 (GlyT2)

Mutation

Video

The hyperekplexia major form phenotype (stiffness in theneonatal period, excessive startle, and startle-induced stiff-ness) is associated with mutations in the GLRA1 gene.1

However, a recent report described a second important hyper-ekplexia gene, the GLYT2 gene (SLC6A5).2 We describe theeffect of clonazepam in a SLC6A5 positive patient (casenumber 5, Ref. 2) with electrophysiological and psychiatricassessments before and during treatment.

As a neonate, the patient (Turkish, male, consanguineousparents) suffered from generalized tonic clonic seizures withapnoea and difficulty swallowing. Electroencephalographyshowed bilateral synchronous epileptic activity and he wastreated with phenobarbital. The following seven EEG’s dur-ing his first year of life were all normal and the phenobarbi-tal was discontinued. At the age of 1.5 years, the head-retrac-tion reflex and a subtle general stiffness were present (firstvideo fragments) and an extensor plantar response on the leftside. Because no GLRA1 mutation was detected, the patientwas diagnosed with symptomatic excessive startle reflexes.As parents did not approve medication, the patient was nottreated with clonazepam. At the age of 3.5 years, the patientcould walk, but frequently fell forwards ‘‘as stiff as a stick,’’and suffered multiple clavicula fractures and facial bruises.At the age of 6 years, the patient was able to bend his kneesduring the falls and slide down to the floor. At the age of 8years, genetic analysis revealed a homozygous single mis-sense mutation (C1274T) in the SLC6A5 gene.2

When the patient was examined at the age of 9 years, hehad developed considerable anxiety related to his excessive

startle reflexes. He did not ride a bike, climb the stairs, run,nor participate with gymnastics. During walking, falling couldbe reduced in frequency by holding something like keys or acoat. Additionally, his parents reported nocturnal myoclonus.EMG responses following binaural auditory stimulation byheadphones (104 dB SPL, interstimulus 6 2 min) presented tothe patient were measured in the orbicularis oculi, sternoclei-domastoid, masseter, deltoid, abductor pollicis brevis, andquadriceps muscles. The patient did not want to be videoed atthis stage. The averaged (n 5 8) EMG startle reflex was com-pared with an age and sex-matched control (Fig. 1). The reflexof the patient was clearly enlarged. The patient met criteria forDSM-IV diagnoses3 of social phobia, generalized anxiety dis-order, and height phobia.4 Psychiatric questionnaires showedthat both child and parent report of anxiety symptoms5 werein the clinical range. Behavioral problems6 (parent report)showed major internalizing symptoms (i.e., anxiety and affec-tive problems) of the patient (93th percentile). Clonazepam(1 mg dd) was started after the EMG recordings.

At follow up, 3 months after the initiation of clonazepam,a reduced number of startle-induced falls and notably lessimpairment by his symptoms was reported by the parents.The patient now played outside, practised karate, rode hisbike, and walked alone to school. The auditory startle reflexof the patient and the matched control was assessed again.Now the patient gave his permission to make a video (secondvideo fragments). The magnitude of the EMG signal at fol-low up was clearly reduced when compared with baseline inthe patient but not in the control (Fig. 1). At follow up, theanxiety disorders3,4 were still present. However, the psychiat-ric questionnaires revealed that anxiety symptoms5 reportedby the child and his parents were reduced by, respectively,45% and 31%. Internalizing symptoms6 (65th percentile)were reduced by 28 percentiles. The anxiety disorders3,4

were considered in remission after another 6 months.For the first time, the effect of clonazepam on the clinical

symptoms, the electrophysiologically assessed startle reflexand the typical comorbid anxiety symptoms7 of a patientwith a SLC6A5 mutation were described. Not only the exces-sive startle reflex diminished but also the anxiety symptomsclearly decreased during treatment with clonazepam. Clona-zepam has anxiolytic properties, but the improvement of theanxiety symptoms are most likely related to the reducednumber of startle-induced falls and the major reduction ofthe startle reflex. This study confirms that clonazepam can beeffective in SLC6A5 positive patients. As such screening ofthe second hyperekplexia gene SLC6A5 should be consideredin patients with the hyperekplexia major form phenotype1

without a GLRA1 mutation.


The patient is shown as at age 19 months and at age of 9years. The latter fragment is taken after he started taking clona-zepam. No fragment are available before treatment as thepatient did not want to be videoed. In the first video fragments(age 19 months) the head-retraction reflex of the patient is dem-onstrated. Further, it is shown that he is not able to walk by him-self. In the second video fragments (age 9 years), it is shownthat the patient is very jittery, startles from sudden movementof the investigator, and subsequently by the presented auditorystimuli. The patient is very nervous and insists on holding theinvestigator’s hand and wants to keep on talking.

Additional Supporting Information may be found in the onlineversion of this article.Potential conflict of interest: Nothing to report.Published online 26 June 2009 in Wiley InterScience (www.


1852 LETTERS TO THE EDITOR


Acknowledgment: All financial and material support forthis research and work, plus all other support covering thepast year from date of submission are the salaries from theAcademical Medical Centre (Bakker & Tijssen) and JulianaChildren’s Hospital (Peeters).

Mirte J. Bakker, MSc*Department of Neurology and Clinical Neurophysiology,

Academic Medical CentreUniversity of Amsterdam

Amsterdam, The Netherlands

FIG. 1. Averaged EMG of eight auditory startle reflexes elicited by 104 dB tones at baseline (A) and follow up (B) of SLC6A5 positive patientand matched control. OO, orbicularis oculi; MA, masseter; SC, sternocleidomastoid; DE, deltoid; AP, abuctor policis brevis; QU, quadriceps.Black line: Patient (A) before treatment clonazepam, (B) during treatment clonazepam three months later. Gray line: Matched control, (A) base-line (B) follow up 3 months later.



Department of Child and Adolescent PsychiatryAcademic Medical CentreUniversity of Amsterdam

Amsterdam, The Netherlands*[email protected]

Els A.J. Peeters, MDDepartment of Neurology

Juliana Children’s HospitalThe Hague, The Netherlands

Marina A.J. Tijssen, MD, PhDDepartment of Neurology and Clinical Neurophysiology

Academic Medical CentreUniversity of Amsterdam

Amsterdam, The Netherlands

References

1. Bakker MJ, Van Dijk JG, van den Maagdenberg AM, TijssenMA. Startle syndromes. Lancet Neurol 2006;5:513–524.

2. Rees MI, Harvey K, Pearce BR, et al. Mutations in the geneencoding GlyT2 (SLC6A5) define a presynaptic component ofhuman startle disease. Nat Genet 2006;38:801–806.

3. American Psychiatric Association. American psychiatric associa-tion diagnostic and statisical manual of mental disorders, 4th ed.Washington DC: American Psychiatric Association; 1994.

4. Silverman WK, Nelles WB. The anxiety disorders interviewschedule for children. Am Acad Child Adolesc Psychiatry 1988;27:772–778.

5. Spence SH. A measure of anxiety symptoms among children.Behav Res Ther 1998;36:545–566.

6. Achenbach TM, Rescorla LA. Manual for ASEBA school-ageforms & profiles. Burlington, VT: University of Vermont,Research Center for Children, Youth, & Families; 2001.

7. Ozel-Kizil ET, Akbostanci MC, Ozguven HD, Atbasoglu EC. Second-ary social anxiety in hyperkinesias. Mov Disord 2008;23:641–645.

Paraneoplastic Cataplexy: Clinical Presentation

and Imaging Findings in a Case

Symptomatic cataplexy, a rare disorder, can occur during thecourse of some neurological conditions such as encephalopa-thies or brain tumors.1 We present a case of symptomatic cat-aplexy related to diencephalon and brainstem paraneoplasticencephalitis (PE) associated with testicular cancer.

A 36-year-old male was admitted for recurrent cataplexyfor the previous 10 days. One month before, he had 15 daysof excessive daytime sleepiness. Episodes were characterizedby sudden loss of muscle tone of the face, neck and upperand lower limbs, which were responsible for recurrent falls.They were triggered by emotional situations during which

the patient remained conscious. Each episode lasted about 10min. Between the episodes, neurological and general statuswere normal. EEG did not reveal any paroxysms during theattacks. Polysomnography and multiple sleep latency testsdid not demonstrate narcolepsy. Brain-MRI demonstratedhyperintensities within the diencephalon on FLAIR sequencesand post-gadolinium enhancement. CSF showed 26 lympho-cytes/mm3, no malignant cells, and protein 0.45 g/L. Human-leukocyte-antigen (HLA) typing for HLA-DR15-DQB1*0602was negative. Anti-Ma2 antibodies were found after immuno-histochemical and western blot analysis of the serum andCSF. Pelvis MRI demonstrated a left testicular nodule. Nometastases were detected on whole-body contrast-enhancedCT-scan. Left orchidectomy demonstrated teratoma and anunclassified intratubular germ cell neoplasia.

After surgery, the patient progressively worsened and thefrequency of the cataplectic attacks increased. He reported di-plopia without clinically evident ophthalmoplegia. There wasdisinhibition, euphoria and irritability associated to attentiondeficiency and perseverations, suggesting a frontal syndrome.Several days later, the patient developed a pseudo-bulbarsyndrome characterized by recurrent episodes of unmotivatedlaughter, dysphagia, and dysarthria. Cranial nerve examina-tion was normal. Intravenous methylprednisolone and plas-mapheresis were administered without any clinical benefit. Asecond brain-MRI showed the persistence of diencephalonand brainstem lesions (Fig. 1A). Anti-Ma2 antibodies werestill detectable in the serum. Brain 18F-FDG-PET demon-strated diencephalon and brainstem hypermetabolism andbilateral frontal hypometabolism (Fig. 1B). Whole-body 18F-FDG-PET revealed the presence of lymph node metastases.Chemotherapy was started and led to initial clinical stabiliza-tion. Two months later, brain-MRI FLAIR revealed slightbrainstem atrophy (Fig. 1C) and 18F-FDG-PET demonstratednormal diencephalon and brainstem metabolism (Fig. 1D),bilateral frontal hypometabolism, and disappearance of themetastatic lymph nodes. During the following month, the fron-tal and pseudo-bulbar syndromes and cataplexy worsened.Intravenous methylprednisolone was started but did not pro-vide any clinical benefit. Three months later, 18F-FDG-PETfound diencephalon and brainstem hypometabolism and per-sistent bilateral frontal hypometabolism (Fig. 1F). Anti-Ma2antibodies were still detectable in the serum. Intravenouscyclophosphamide treatment was started and led to the disap-pearance of the cataplectic attacks and improvement of thepseudo-bulbar syndrome. One year later, anti-Ma2 antibodieswere still present and MRI demonstrated brainstem atrophywithout gadolinium enhancement (Fig. 1E).

Cataplexy is a rare clinical presentation of PE.2,3 To ourknowledge, previously reported cases were always associatedwith narcolepsy, which was the main clinical symptom.4 Inthe present case, the patient experienced a 15-day period ofexcessive sleepiness suggesting transient narcolepsy. Thispreceded the cataplectic attacks but had disappeared at thetime of diagnosis. Anti-Ma2 is one of the onconeuronal anti-bodies that reacts with antigens common to the central nerv-ous system and cancer, mainly testis in young males.5

Although the pathophysiological mechanisms underlying thisrare syndrome are speculative, the wide expression of Ma2antigens in normal limbic and diencephalic structuresstrongly supports a relationship between anti-Ma2 antibodiesand cataplexy.1 Therefore, an inflammatory immune reaction

Farid Karim and Jeannin Severine contributed equally and shouldbe considered as first authors.





between anti-Ma2 antibodies and diencephalon hypocretinneurons could be hypothesized as a central mechanism.1

Brain 18F-FDG-PET identified different steps of the diseaseprocess. Initially, we observed well-described hypermetabo-lism within brain areas affected by inflammation.6 After chem-otherapy, while the patient was still deteriorating, we observeda progressive decrease in diencephalon metabolism with tran-sient pseudo-normalization and secondary hypometabolism.Therefore, this case confirms previous studies showing thatbrain 18F-FDG-PET adds weight to the diagnosis of PE whenhypermetabolism is observed.2,7 It also suggests that brain 18F-FDG-PET can be used to evaluate potential sequela whenhypometabolism is found, as it might predict atrophy. How-ever, the observation of clinical deterioration and goodresponse to immunosuppression while brain 18F-FDG-PETdemonstrates hypometabolism suggests that brain 18F-FDG-PET is not helpful for ruling out a diagnosis of paraneoplasticsyndrome or for deciding on treatment strategies.

Karim Farid, MDDepartment of Nuclear Medicine

CHU de BordeauxUniversite Bordeaux 2

CNRS-UMR 5543Bordeaux, France

Severine Jeannin, MDVirginie Lambrecq, MDPierre Philip, MD, PhD

Department of Clinical NeurosciencesCHU de Bordeaux

Universite Bordeaux 2Bordeaux, France

Philippe Fernandez, MD, PhDDepartment of Nuclear Medicine



Sandrine Molinier, MDDepartment of Neuroradiology

CHU BordeauxBordeaux, France

Michele Allard, MD, PhDDepartment of Nuclear Medicine



Igor Sibon, MD, PhD*Department of Clinical Neurosciences




References

1. Nishinoa S, Kanbayashib T. Symptomatic narcolepsy, cataplexyand hypersomnia, and their implications in the hypothalamichypocretin/orexin system. Sleep Med Rev 2005;9:269–310.

FIG. 1. A, C, E: Brain MRI-FLAIR demonstrating progressive evolution of diencephalon and brainstem abnormalities with initial hyperinten-sities (A), slight atrophy at 2 months (C), and atrophy 1 year later (E). B, D, F: Brain 18F-FDG-PET showing diencephalon and brainstem meta-bolic changes during the evolution of the disease with initial hypermetabolism (B), pseudo-normal metabolism at 2 months (D), and hypometabo-lism 3 months later (F). [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]



2. Graus F, Delattre JY, Antoine JC, et al. Recommended diagnosticcriteria for paraneoplastic neurological syndromes. J Neurol Neu-rosurg Psychiatry 2004;75:1135–1140.

3. Gultekin SH, Rosenfeld MR, Voltz R, Eichen J, Posner JB,Dalmau J. Paraneoplastic limbic encephalitis: neurological symp-toms, immunological findings and tumour association in 50patients. Brain 2000;123 (Part 7):1481–1494.

4. Landolfi JC, Nadkarni M. Paraneoplastic limbic encephalitis andpossible narcolepsy in a patient with testicular cancer: case study.Neuro Oncol 2003;5:214–216.

5. Dalmau J, Graus F, Villarejo A, et al. Clinical analysis ofanti-Ma2-associated encephalitis. Brain 2004;127 (Part 8):1831–1844.

6. Scheid R, Lincke T, Voltz R, von Cramon DY, Sabri O. Serial18F-fluoro-2-deoxy-D-glucose positron emission tomography andmagnetic resonance imaging of paraneoplastic limbic encephalitis.Arch Neurol 2004;61:1785–1789.

7. Provenzale JM, Barboriak DP, Coleman RE. Limbic encephalitis:comparison of FDG PET and MR imaging findings. Am J Roent-genol 1998;170:1659–1660.

Cognitive Behavioral Therapy for

Psychogenic Movement Disorder

Video

Psychogenic movement disorders (PMDs) are a subtype ofconversion disorder, classified under Somatoform Disorders.Clinically significant somatization results in an estimated$100 billion annually in the US with excessive health careusage.1 One long term study in patients with PMDs over anaverage of 3 years follow-up revealed persistence of abnor-mal movements in 90% of patients despite various treat-ments.2

Treatment outcome studies for PMD are limited, rangingfrom retrospective case reports to case series. A review ofRCTs for somatoform disorders revealed that cognitivebehavioral therapy (CBT) is the best established treatment3;however, the treatment has not been readily utilized in thePMD population. A Medline review revealed no casereports, open label studies, or RCTs of CBT for PMD. Theonly prospective studies were one open label psychody-namic psychotherapy4 and an open label trial of an SSRIfor PMD.5

One-year sustained benefit of short-term CBT in chronicPMD is presented.

A 22-year-old woman was evaluated for presumed psycho-genic dystonia present for 5 years. In 2002, at age 17, shehad swollen cervical glands and developed blurred vision anddystonic spasms in the face. She was given haloperidol and

developed bilateral extremity and abdominal twitching. BrainCT, routine CSF, toxicology screen, urine pregnancy, and in-fectious workup were unrevealing. EBV titers revealed pastinfection. A psychiatrist diagnosed her with medically unex-plained symptoms and recommended Partial Hospital Pro-gram. Her parents disagreed with a psychiatric diagnosis andtreatment was not instituted.

Because of persistent facial and bodily symptoms, a brainMRI with contrast was obtained in 2002 and revealed a smallT2 weighted foci of hyperintensity involving the para-trigo-nal white matter. With the question of demyelination, shesaw a consultant who diagnosed migraine variants and stress.Another specialist treated her with orphenadrine and diaz-epam rectal, and she took topiramate briefly and oral diaz-epam intermittently. Two routine EEG’s were normal. RepeatMRIs in 2006 and 2007 because of persistent symptomsrevealed no changes from 2002, and were thought to be non-specific.

She was treated with three antibiotics for possible Lymedisease, despite negative serologies. On reevaluation at age22 a wide range of serologic investigations were normalincluding B-vitamins levels, heavy metals, LFTs and sedi-mentation rate. Tests also excluded Lyme Disease and Wil-son’s disease [serum copper-1.71 (0.75–1.45 mcg/mL); ceru-loplasmin-55.4 (22.9–43.1 mg/dL); urine copper-5 (15–60mcg/24 hr).] with a negative slit lamp exam.

After initial gradual spontaneous improvement over8 months, she had an episode free period in 2003 lasting15 months. She attended college for less than a semester in2004, however, because of recurrent symptoms interferingwith classes. She had not worked since autumn 2005because of the movements. At presentation in 2007, onexam she displayed severe dystonic posturing consisting offixed flexion at the abdomen, hips, elbows, proximal inter-phalanges and plantar flexion at both ankles. She displayedlateral- and antero-collis and facial movements consistingof alternating contractions of the risorius, independently.She had full strength without spasticity and normal reflexes.She met Fahn and Williams’ diagnostic criteria for probablePMD.

Treatment: She underwent a 12 session weekly CBT pro-gram and had complete resolution of the abdominal and armdystonia by week 4. Facial movements persisted on an inter-mittent basis, but by week 12 her symptoms resolved. Shehas remained symptom free, now 16 months post-treatment,off all medications and has returned to work.

Evidence against a placebo effect or spontaneous recoveryincludes the refractory persistence of her symptoms despitenumerous mediation trials before the CBT, and the gradedCBT ‘‘dose-related’’ response, with partial and then full re-covery over the course of the treatment. The CBT used totreat this patient was modified from a CBT manual that hasbeen used in a trial of CBT for patients with nonepilepticseizures (NES).6

We modified, tested and implemented a structured CBT,which is a time-limited, short-term, present-oriented psycho-therapy that addresses cognitive distortions and promotesbehavioral changes initially specifically for patients withNES.7 The CBT program was used in this case of PMD bysubstituting monitoring the movements rather than monitor-ing seizures. During the sessions, the manual-based therapy

Additional Supporting Information may be found in the onlineversion of this article.Potential conflict of interest: The authors report no conflicts of

interest. Dr. LaFrance has grants from the NINDS and EpilepsyFoundation for treatments of nonepileptic seizures.





focuses on taking control of movements and includes trainingin healthy communication, understanding medications,conducting a functional behavioral analysis and examiningtriggers. Treatment involves addressing mood-cognition-envi-ronment connections, automatic thoughts (ingrained corethoughts about oneself), and somatic misinterpretations.

Along with complete remission of her chronic symptoms,other significant benefits of the treatment for her includedstopping all medications, returning to work and avoiding fur-ther unnecessary evaluations.


Video 1. Pre-, intra-, and post-treatment, CBT for PMD.Segment 1. Dystonia at initial evaluation; pretreatment.Segment 2. Five weeks into CBT treatment for PMD:

Communication discussion.Segment 3. 16 weeks post-treatment, symptom free.

Acknowledgment: This work is supported by the RhodeIsland Hospital, Departments of Psychiatry and Neurology.The patient consented for use of history and video for publi-cation. Signature is on file. I take responsibility for the integ-rity of the report and the accuracy of the history.

W. Curt LaFrance Jr., MD, MPH*Joseph H. Friedman, MD

Division of Neuropsychiatry and Behavioral NeurologyRhode Island Hospital

Departments of Psychiatry and NeurologyBrown Medical School

Providence, Rhode Island, USA*E-mail: [email protected]

References

1. Barsky AJ, Orav EJ, Bates DW. Somatization increases medicalutilization and costs independent of psychiatric and medicalcomorbidity. Arch Gen Psychiatry 2005;62:903–910.

2. Feinstein A, Stergiopoulos V, Fine J, Lang AE. Psychiatric out-come in patients with a psychogenic movement disorder: a pro-spective study. Neuropsychiatry Neuropsychol Behav Neurol2001;14:169–176.

3. Kroenke K. Efficacy of treatment for somatoform disorders: areview of randomized controlled trials. Psychosom Med 2007;69:881–888.

4. Hinson VK, Weinstein S, Bernard B, Leurgans SE, Goetz CG.Single-blind clinical trial of psychotherapy for treatment of psy-chogenic movement disorders. Parkinsonism Relat Disord2006;12:177–180.

5. Voon V, Lang AE. Antidepressant treatment outcomes of psycho-genic movement disorder. J Clin Psychiatry 2005;66:1529–1534.

6. LaFrance WC, Jr, Miller IW, Ryan CE, et al. Cognitive behavioraltherapy for psychogenic nonepileptic seizures. Epilepsy Behav2009;14:591–596.

7. Reiter J, Andreus D, Janis C. Taking Control of Four Epilepsy. AWorkbook for Patients and Professionals, 1st ed. Santa Rosa, CA:The Basics; 1987.

Smoking Induced Worsening of Dystonia

A Case Report

Video

Several biochemical abnormalities have been observed in thebrain of patients with primary dystonia, mainly involving nor-epinephrine, serotonin and dopamine.1 Another neurotransmit-ter that is also probably involved in dystonia is the cholinergicsystem, as evidenced by the response to treatment with anti-cholinergics. However, it is not clear which of these is patho-physiologically related to the development of dystonia.1 Thereare only three published reports which suggest an associationbetween nicotinic cholinergic system and dystonia, howeverwith conflicting roles.2–4 We report here a patient with multifo-cal dystonia, predominantly cervical, which used to worsen af-ter smoking and later showed improvement with anticholiner-gics and cessation of smoking, thus supporting the role of nico-tinic cholinergic system in dystonia.

Our patient was a 31-years-old man symptomatic for thepast 10 years with difficulty in speaking which had increasedin severity over the past 2 years. It was characterized by diffi-culty in pronouncing the words clearly with nasal quality tovoice and occasionally he also felt that he had to strain morewhile speaking. For the past 2 years he also noted abnormalposturing of the neck in the form of turning towards right side,which was associated with neck pain, and difficulty in movingthe neck sideward. There was no history suggestive of dystoniaaffecting other parts of the body, no sleep benefit or diurnalfluctuation, exposure to any toxins or neuroleptics. He did nothave any significant family history of neurological illness.

The patient was a chronic smoker, smoking cigarette formore than 6 years. However, recently, for the past fewmonths, he noted that after smoking 1 to 2 cigaretteshis abnormal movements of neck as well as the neck painworsened significantly. This used to occur approximately 5 to10 min after smoking and lasted for an hour.

On examination he was found to have involuntary move-ments in the form of rotation of head to right side, elevationof right shoulder, mild retrocollis, facial grimacing, poutingof lips and increased frequency of blinking. When he spokethese abnormal movements worsened and he had predomi-nantly adductor type of dysphonia. In addition he had mildpostural tremors of both hands and minimal dystonia of bothhands was noticed on walking. Rest of the neurological andsystemic examinations was normal. There was no Kayser-Fleischer ring in the cornea and the MRI of brain was normal.

The patient was further evaluated, using the Toronto West-ern Spasmodic Torticollis Rating Scale (TWSTRS) beforeand after smoking to objectively confirm the symptomaticworsening of the cervical dystonia reported by him. TheTWSTRS score was 36 before smoking (baseline) (VideoSegment 1), 45.5 5 minutes after smoking 2 cigarettes (Video

Additional Supporting Information may be found in the onlineversion of this article.Financial Disclosure: None of the authors have any financial dis-

closure to make.Published online 19 June 2009 in Wiley InterScience (www.




Segment 2), and again reduced to 35.5 2 hours after smoking.He also had increased blinking, worsening of facial grimac-ing, and neck pain after smoking, but no evidence of worsen-ing of hand dystonia. The patient was started on trihexyphe-nidyl 2 mg/day and slowly increased to 30 mg/day. He wasalso counseled regarding the benefits of smoking cessation.After 3 weeks of therapy he showed significant improvementin his symptoms both pain and dystonia and the TWSTRSscore was 24.5 (Video Segment 3). During this period patientalso had stopped smoking completely. He continued to main-tain improvement at follow up visit after 4 weeks.

There are three previously published reports which hadshown a possible role of nicotine in the pathophysiology ofdystonia.2–4 These reports had showed that nicotine improvedin dystonia in 2 patients and worsened in another 2patients.2–4 The patients who had worsening with nicotinehad primary dystonia in the form of writer’s cramp.3 On thecontrary, the 2 patients with dystonia who had shownimprovement with smoking and subsequently with nicotinehad dystonia due to underlying secondary causes. One patienthad developed dystonia after an encephalitic illness4 andother had developed dystonia following childhood hemiple-gia.2 It is noteworthy that both these patients had associatedspasticity, thus having secondary dystonia. The differences inthe etiologies of dystonia probably contributed to the differ-ence in the response to nicotine in patients with dystonia.Similar to that reported by Murase et al.3 in writer’s crampwhich is a form of primary dystonia, our patient who had,predominantly cranial dystonia, also worsened with smokingand subsequently showed improvement with smoking cessa-tion and anticholinergics.

The exact mechanism of effect of smoking and nicotine ineither improving or worsening dystonia is unknown, primar-ily because there are only few documented cases. The majorcomponent of cigarette smoke that is responsible for addic-tion and other effects on the central nervous system is nico-tine, which acts through nicotinic cholinergic receptors(nAChR).5 Nicotinic receptor activation after smoking facili-tates the release of neurotransmitters. Most of this release isbelieved to occur via modulation by the presynaptic nAChRs.Other neurotransmitters, including norepinephrine, acetylcho-line, serotonin, g-aminobutyric acid, glutamate, and endor-phins are released as well, mediating various behaviors ofnicotine. There is also evidence of both nicotine and cigarettesmoking improving symptoms of Parkinson’s disease6 andthis may be a result of augmentation of release of dopaminefrom the basal ganglia.7 Finally, dopamine-depleting agentsor blockers have been used in treating dystonias. Therefore,it is not surprising that cigarette smoking or nicotine can ag-gravate primary dystonias as demonstrated in our patient andthat reported by Murase et al.3 Smoking or nicotine inducedworsening of dystonia could be also due to facilitation ofrelease of acetylcholine8 or stimulation of nicotinic acetyl-choline receptors in the brain. Since our patient also had ben-efit from trihexyphenidyl, which is only a muscarinic recep-tor blocker, the former mechanism can at least be implicatedin the worsening of dystonia.

In summary, our case illustrates a rare and interesting ob-servation, which needs to be studied further. Apart from clin-ical documentation, functional imaging in dystonic patientsbefore and after smoking may be useful in elucidating therole of smoking in dystonia. Finally, for evaluation of the ef-

ficacy of any medical or therapeutic interventions in a patientof dystonia who is also a smoker, concomitants effects ofsmoking should also be considered.

Legends for the Video

Segment 1. Dystonia before smoking.Segment 2. Worsening of dystonia after smoking.Segment 3. On treatment with trihexiphenidyl; stopped

smoking.

Author Roles: (1) Research Project: Organization, Concep-tion, Execution, (D.K. Prashantha, P.K. Pal); (2) StatisticalAnalysis: Not applicable; (3) Manuscript: Writing of the firstdraft (D.K. Prashantha), Review and Critique (D.K. Prashan-tha, major contribution by P.K. Pal); (4) Video capturing andediting: (D.K. Prashantha, major contribution by P.K. Pal).

D. K. Prashantha, MDPramod Kumar Pal, MD, DM*

Department of NeurologyNational Institute of Mental Health & Neurosciences

Bangalore, India*E-mail: [email protected]

References

1. Fahn S, Jankovic J. Principles and practice of movement disor-ders. Philadelphia: Elsevier; 2007.

2. Lees AJ. Hemidystonia relieved by nicotine. Lancet 1984;2:871.3. Murase N, Kaji R, Sakamoto T, et al. Nicotine-sensitive writer’s

cramp. Mov Disord 2000;15:1276–1279.4. Vaughan CJ, Delanty N, Harrington H, Murphy MB. Treatment of

spastic dystonia with transdermal nicotine. Lancet 1997;350:565.5. Benowitz NL. Clinical pharmacology of nicotine: implications for

understanding, preventing, and treating tobacco addiction. ClinPharmacol Ther 2008;83:531–541.

6. Jarvik ME. Beneficial effects of nicotine. Br J Addict 1991;86:571–575.

7. Di CG, Imperato A. Drugs abused by humans preferentiallyincrease synaptic dopamine concentrations in the mesolimbic sys-tem of freely moving rats. Proc Natl Acad Sci USA 1988;85:5274–5278.

8. Benowitz NL. Pharmacology of nicotine: addiction and therapeu-tics. Annu Rev Pharmacol Toxicol 1996;36:597–613.

Managing Pathological Gambling in

Parkinson’s Disease with Enteral Levodopa/

Carbidopa Infusions

Patients with Parkinson’s disease (PD) are at risk for devel-oping pathological gambling. Pathological gambling is partof the dopamine dysregulation syndrome (DDS), along with



1858 LETTER TO THE EDITOR


hypersexuality, compulsive shopping, punding, anddopamine addiction.1,2

Several risk factors have been associated with pathologicalgambling in PD, in particular the use of dopamine receptoragonists. Additional factors include a younger age at onset,depression, a personal or family history of alcohol abuse,impulsivity, and ‘‘novelty-seeking behaviour’’.1–3

Overall, gambling in PD is difficult to treat. Potentiallybeneficial strategies include reducing the dose of dopamineagonists, a reduction of all dopaminergic treatments anduse of atypical neuroleptics such as quetiapine.1,2 However,reductions of dopaminergic treatment are often poorlytolerated. Deep brain stimulation (DBS) could be an alter-native approach, but uncontrolled psychiatric disease gener-ally excludes patients from DBS programs because thepsychiatric problems may worsen.4 In selected patientsgambling can improve considerably following DBS of thesubthalamic nucleus,5 but pathological gambling can alsoworsen postoperatively, or develop newly in patients with-out preoperative gambling.2 Many clinicians will thereforebe hesitant to advocate DBS in patients with pathologicalgambling, and alternative strategies remain necessary.

Continuous levodopa (L-dopa) delivery through enteral infu-sion is a novel therapy to control motor fluctuations and dyski-nesias in PD.6 This approach may be preferred over DBS inolder patients with comorbidity or cognitive decline. Here, wepresent a patient with PD whose pathological gambling wascompletely abolished after continuous enteral L-dopa treatment.

A 74-year-old man had a 14-year history of PD. Thepatient had no prior history of mood disorders, substanceabuse, or gambling. He started gambling on slot machines in2004. At that time, the patient had developed complex motorfluctuations, while taking levodopa/carbidopa/entacapone 150mg qdd and pramipexole 0.7 mg tdd. His gambling occurredonly during ‘‘ON’’ periods.

When first seen the patient had a motor UPDRS score of34 while ON, accompanied by moderate to severe choreaticdyskinesias. Pramipexole was stopped, but this was poorlytolerated because of worsening motor disability, necessitatingadding a fifth dose of levodopa/carbidopa/entacapone. Hedeveloped severe mood swings, but gambling did notimprove. The motor UPDRS score when off medication was58. The patient was subsequently treated for a year with 100mg sertralin per day, as well as quetiapine 200 mg per day,but without improvements in gambling. He spent about35,000 Euros on gambling during a period of around 3.5years. He also experienced two episodes of punding (fiddlingwith his computer for hours, involving activities such asstarting and restarting the device), together with severe dyski-nesias.

He was then considered for enteral infusion of L-dopa gel(1 mL containing 20 mg L-dopa and 5 mg carbidopa). HisOFF periods lasted about 3 hours per day. The switch toenteral L-dopa was tolerated well. Within 1 week a stableenteral continuous dose of 4.0 mL/h L-dopa gel wasachieved, administered during the day for about 18 hours andstopped in the evening. Extra boluses of 1.0 mL were usedtwo to three times a day.

Twelve months following start of treatment, gambling hadstopped entirely, and no more episodes of punding had occurred.The patient also had only mild dyskinesias and mild motor fluc-tuations, with a reduction of OFF time to 1 hour per day.

Pathological gambling is a dramatic symptom in PD that isgenerally difficult to treat. Here, we describe a patient with PDwhose pathological gambling completely abolished followingadministration of continuous enteral L-dopa treatment. Thisoccurred despite the fact that the equivalent dose of L-dopadelivered via the intestinal tube (1,500 mg per day) was evenhigher when compared with the oral dose of L-dopa that hadbeen given prior to the procedure (750 mg L-dopa, plus 5 x200 mg entacapone). The improvement of pathological gam-bling was paralleled by substantial improvements in motorabilities, as well as a reduction of dyskinesias.

PG is associated with dopamine agonist use, and has alsobeen attributed to pulsatile L-dopa stimulation.1,7,8 Discontinu-ation of dopamine agonist treatment as well as DBS haveshown improvement in PG.5,8 The improvement of PG symp-toms following DBS surgery may be related to a reduction ofdopaminergic treatment or a decrease of pulsatile dopaminer-gic stimulation.5,8 However, the case history presented heredemonstrates that continuous L-dopa application can in fact al-leviate pathological gambling, in a patient where most other‘‘conventional’’ measures had failed completely, and thatpulsatile dopaminergic stimulation seems to contribute to PGin PD. The total daily dose of L-dopa did not appear to contrib-ute, extending other observations.2,7 Taken together, our ob-servation suggests that continuous L-dopa treatment or lesspulsatile dopaminergic stimulation, as provided by enteralL-dopa or subcutaneous apomorphine delivery, may offer anew therapeutic approach for patients with pathological gam-bling, but randomized studies are obviously needed to confirmour present observation.

Acknowledgment: As corresponding author and principalinvestigator (W Gerschlager), I take full responsibility forthis article. I also want to confirm, that I do have full accessto all of the data and that I have the right to publish any andall data separate and apart from any sponsor. In addition,I have received the patient’s consent form.

Willi Gerschlager, MD*Department of Neurology

Krankenhaus Hietzing, Neurologisches Zentrum RosenhugelPavillon B, Vienna, Austria


Bastiaan R. Bloem, MD, PhDDepartment of Neurology

Donders Center for Brain, Cognition and BehaviourRadboud University Nijmegen Medical Center

Nijmegen, The Netherlands

References

1. Gallagher DA, O’Sullivan SS, Evans AH, Lees AJ, Schrag A.

Pathological gambling in Parkinson’s disease: risk factors and dif-

ferences from dopamine dysregulation. An analysis of published

case series. Mov Disord 2007;22:1757–1763.2. Voon V, Potenza MN, Thomsen T. Medication-related impulse

control and repetitive behaviors in Parkinson’s disease. Curr OpinNeurol 2007;20:484–492.

3. Evans AH, Lawrence AD, Potts J, Appel S, Lees AJ. Factors

influencing susceptibility to compulsive dopaminergic drug use in

Parkinson disease. Neurology 2005;65:1570–1574.



4. Houeto JL, Mesnage V, Mallet L, et al. Behavioural disorders,Parkinson’s disease and subthalamic stimulation. J Neurol Neuro-surg Psychiatry 2002;72:701–707.

5. Ardouin C, Voon V, Worbe Y, et al. Pathological gambling inParkinson’s disease improves on chronic subthalamic nucleusstimulation. Mov Disord 2006;21:1941–1946.

6. Nyholm D, Nilsson Remahl AI, Dizdar N, et al. Duodenal levo-dopa infusion monotherapy vs oral polypharmacy in advancedParkinson disease. Neurology 2005;64:216–223.

7. Voon V, Thomsen T, Miyasaki JM, et al. Factors associated withdopaminergic drug-related pathological gambling in Parkinson dis-ease. Arch Neurol 2007;64:212–216.

8. Weintraub D. Dopamine and impulse control disorders in Parkin-son’s disease. Ann Neurol 2008;64 (suppl):S93–S100.

Neuronal Responses to High-Frequency

Stimulation in Human Subthalamic Nucleus

Attempts to clarify the therapeutic mechanism of deep brainstimulation of the subthalamic nucleus (STN DBS) by inves-tigating the responses of neuronal activity to high-frequencystimulation in the STN have demonstrated conflicting results,i.e., inhibition,1–4 excitation,5 or a dual effect.6 We investi-gated the actual effects of high-frequency stimulation on theactivity of neurons in human STN DBS.

The patient was a 62-year-old man with a 5-year historyof Parkinson’s disease, who underwent bilateral implantationof quadripolar electrodes (DBS 3387 and Kinetra; Medtronic,Minneapolis, MN) into the STN. After a significant numberof trials of stimulation adjustment using monopolar and bipo-lar stimulations, it became clear that the stimulation intensitycould not be sufficiently increased because of the inductionof corticobulbar effects on the right side. Based both on thelower threshold for alleviation of parkinsonian symptomsthan for the induction of corticobulbar effects and on theMRI findings, the DBS electrode location was estimated tobe in the lateral portion in the left STN. Reimplantation ofone DBS electrode in the left STN was performed 7 monthsafter the initial surgery. No sedation was used during surgery,and all medications were withheld overnight. The target loca-tion was set to 2 mm medial to the initial implantation site atthe depth of the center of the STN. Microrecording with aglass-coated elgiloy electrode was performed during left STNbipolar stimulation using the third deepest contact as a cath-ode and the deepest contact as an anode with the formerlyimplanted DBS electrode with 60 microseconds pulse width,4.0 V, 2 Hz, and 136 Hz. This stimulation ameliorated par-kinsonian symptoms on the right side, while producing slightdysarthria by current spread into the internal capsule. Sponta-neous neuronal activity was recorded under the followingconditions: prestimulation, on-stimulation, and poststimula-tion, with a period of 25 to 35 seconds for each condition.Neuronal spikes were detected during stimulation using thetemplate subtraction method.7 A peristimulus time histogram

(PSTH) was constructed, and mean discharge rates weredetermined. The recording procedures were approved by theEthical Committee of Shinshu University School of Medi-cine, and the patient provided informed consent.

Intrasurgical CT scans revealed that the recording trackwent through the point 4 mm (center-to-center distance) ante-romedial to the DBS electrode at 15 mm above the DBSelectrode tip and the point 2 mm posteromedial to the DBSelectrode at 4 mm above the DBS electrode tip. There were20 neurons observed firing, and the responses to stimulationof a total of nine neurons were recorded. The recording sitesalong the track in the patient’s brain were precisely recon-structed, based on the phase reversal of the stimulation arti-facts which is located on the midline between the cathodeand anode (Fig. 1B). Seven neurons showed almost completecessation of firing during 136-Hz stimulation (Fig. 1A,C) andstrong inhibition for a period of �10 milliseconds or longerfollowing the stimulus during 2-Hz stimulation (Fig. 1C).The other two neurons showed a sequence of short-latencyresponses to the stimulus during 136-Hz stimulation: excita-tion at 1.0 to 1.5 milliseconds, inhibition at 2.0 to 4.0 milli-seconds, and excitation at 5.0 to 7.0 milliseconds (Fig.1A,D). Similar short-latency responses were elicited at 2 Hz,and furthermore, the responses were followed by oscillatoryfiring of �16 Hz (Fig. 1D). These two neurons were locatedin an area of 0.5 to 1.0 mm cathodal side to the midplane ofthe cathode and anode along the track. The mean firing ratesof the nine neurons decreased by 69% during 136-Hz stimu-lation (P < 0.001, Student’s t test, two-tailed) and did notchange during 2-Hz stimulation. In the poststimulation peri-ods at 136-Hz stimulation, two neurons showed an increasein firing rate of >50%, one neuron showed a decrease of>50%, and the other seven neurons showed less change.

The strong suppression in the seven STN neurons at 136-Hz stimulation is estimated to be caused mainly by temporalsummation of the short-latency inhibition provoked by 2-Hzstimulation. The short-latency inhibition with a single stimu-lation may occur as the result of activation of the GABAer-gic STN afferent axons and/or their presynaptic terminals,mainly from the GPe. There are also glutamatergic excitatoryafferents to the STN from the cerebral cortex, but higherexcitability and the higher number of GABAergic afferentsto the STN neurons may explain the dominated inhibition.8

On the other hand, a dual effect, suppression of spontaneousspikes and generation of burst spikes, by directly activatingthe neuronal membrane with high-frequency STN stimulationwas found in slices obtained from rats.6 It is probable thatthe strong inhibition with 136-Hz stimulation in our studyoccurred mainly through activation of GABAergic presynap-tic axons and/or their terminals and possibly through directeffects on the cell bodies.

Two neurons showed a sequence of short-latencyresponses during 136-Hz and 2-Hz stimulation. Initiation ofaction potentials later than 0.5 milliseconds to the stimulus,some variant latency, and lack of an all-or-none fashion ofthe earliest excitatory response also do not fit the criteria ofdirect activation of nerve cells. It could be speculated thatthe activated cells have a geometric configuration of excita-tory and inhibitory presynaptic axons with respect to theelectrodes so as to produce an excitation. The inhibition fol-lowing the earliest excitation may be due to inhibitory post-synaptic potentials, direct effects on the cell membranes, and/

Potential conflict of interest: The authors declare that they have nofinancial disclosure.





or postspike hyperpolarization. The second excitation at 5.0to 7.0 milliseconds may be rebound excitation. Furthermore,the 16-Hz oscillatory firing followed the earliest excitation in2-Hz stimulation. This oscillation could be generated by therecruitment of rebound excitation, as was shown in the recip-rocal connection of the STN and GPe,9 or by the intrinsicability of STN neurons to fire rhythmically.10

Recently, a number of data have supported the possibilitythat abnormally synchronized oscillation of the basal gangliamotor circuit is pathogenetically relevant to parkinsonian aki-nesia and bradykinesia.11 Meissner et al.4 observed that STNhigh-frequency stimulation reduced and resets subthalamicfiring in an MPTP monkey, leading to reduction of oscilla-tory activity in the STN. The present study has demonstratedthat high-frequency STN stimulation strongly suppresses neu-ronal activity in a wide area in the STN and changes the fir-ing patterns time-locked to stimulation pulses in a smallnumber of STN neurons in human DBS. These changes blockthe abnormal oscillatory activity transmitting through theSTN in the indirect and hyperdirect pathways.

Acknowledgment: This manuscript was reviewed byDonna Hope, American English School, GA.

Takao Hashimoto, MD, PhD*Center for Neurological Diseases

Aizawa HospitalMatsumoto, Japan


Tetsuya Goto, MD, PhDKazuhiro Hongo, MD, PhDDepartment of Neurosurgery

Shinshu University School of MedicineMatsumoto, Japan

References

1. Filali M, Hutchson WD, Palter VN, et al. Stimulation-induced in-hibition of neuronal firing in human subthalamic nucleus. ExpBrain Res 2004;156:274–281.

FIG. 1. Short-latency responses of STN neurons during 136-Hz stimulation. (A) PSTHs with a bin-width of 0.5 milliseconds reconstructed fromsuccessive 7.0-millisecond time periods in the prestimulation period and from the interstimulus periods in the on-stimulation period. Each binshows firing incidence per 1 second. The first two PSTH bins are omitted in the on-stimulation period because of signal saturation and residualstimulation artifacts. (B) Locations of the electrode lead and recording sites in the frontal view. Stimulation artifacts showed phase reversalbetween recording sites 808 (80.8 mm deep from the referential point) and 810, and the phase reversal was located on the midline between thecathode and anode in the control study (unpublished observation). (C, D) Examples of neuronal responses occurring during 136-Hz (upper PSTH)and 2-Hz (lower PSTH) STN stimulation in STN cells, Cell 810 and Cell 803. The first two PSTH bins are omitted in the on-stimulation periodbecause of signal saturation and residual stimulation artifacts. Arrows indicate the stimulation onset. *Significant increase at P < 0.01;1significant decrease at P < 0.01; Wilcoxon signed rank test.



2. Welter ML, Houeto JL, Bonnet AM, et al. Effects of high-fre-quency stimulation on subthalamic neuronal activity in Parkinso-nian patients. Arch Neurol 2004;61:89–96.

3. Tai CH, Boraud T, Bezard E, et al. Electrophysiological and meta-bolic evidence that high-frequency stimulation of the subthalamicnucleus bridles neuronal activity in the subthalamic nucleus and thesubstantia nigra reticulata. FASEB J 2003;17:1820–1830.

4. Meissner W, Leblois A, Hansel D, et al. Subthalamic high fre-quency stimulation resets subthalamic firing and reduces abnormaloscillations. Brain 2005;128:2372–2382.

5. Lee KH, Roberts DW, Kim U. Effect of high-frequency stimulationof the subthalamic nucleus on subthalamic neurons: an intracellularstudy. Stereotact Funct Neurosurg 2003;80:32–36.

6. Garcia L, Audin J, D’Alessandro G, et al. Dual effect of high-fre-quency stimulation on subthalamic neuron activity. J Neurosci2003;23:8743–8751.

7. Hashimoto T, Elder CM, Vitek JL. A template subtraction methodfor stimulus artifact removal in high-frequency deep brain stimula-tion. J Neurosci Methods 2002;113:181–186.

8. Shink E, Smith Y. Differential synaptic innervation of neurons inthe internal and external segments of the globus pallidus by theGABA- and glutamate-containing terminals in the squirrel monkey.J Comp Neurol 1995;358:119–141.

9. Plenz D, Kitai ST. A basal ganglia pacemaker formed by the sub-thalamic nucleus and external globus pallidus. Nature 1999;400:677–682.

10. Bevan MD, Wilson CJ. Mechanisms underlying spontaneous oscil-lation and rhythmic firing in rat subthalamic neurons. J Neurosci1999;19:7617–7628.

11. Brown P. Oscillatory nature of human basal ganglia activity: rela-tionship to the pathophysiology of Parkinson’s disease. Mov Disord2003;18:357–363.

Acute Respiratory Failure due to Vocal

Cord Paralysis in a Patient with

Parkinson’s Disease

Video

Vocal cord paralysis (VCP) is a frequent and important clini-cal feature of multiple system atrophy (MSA) because itleads to obstructive sleep apnea and sudden death. But it hasbeen only rarely reported in Parkinson’s disease (PD).1

Herein, we report a case of acute respiratory failure due tobilateral VCP in a patient with PD.

A 49-year-old woman with a 19-year history of PD wasadmitted because recent antiparkinsonian medication changeshad resulted in visual hallucination and the worsening ofmotor fluctuation and dyskinesia. Her parkinsonism startedwith a right-hand tremor at the age of 30 and had beentreated with antiparkinsonian medications at other hospitals.On presentation in the emergency room, she was febrile. A

chest X-ray revealed mild infiltration in the right lower lungfield. Brain computerized tomography was normal.

Aspiration pneumonia was treated with antibiotics. Percutane-ous endoscopic gastrostomy (PEG) was placed due of continueddysphagia. Antiparkinsonian drugs were adjusted and clozapinewas added. During her stay, severe inspiratory stridor was notedboth when asleep and awake. Her O2 saturation repeatedlydropped and intermittent hypercapnea (up to 65.1 mm Hg by ar-terial blood gas analysis) was observed even when she wasawake. Fiber optic laryngoscopy showed that the vocal cordswere nearly immobile during respiration (Video Segment 2).Subsent tracheostomy resolved this respiratory difficulty.

At the time of discharge, she was taking levodopa (L-dopa)/carbidopa at 250/25 mg qid, pramipexole at 0.125 mgqid, clozapine at 25 mg qid, and amantadine at 200 mg bid.Still, she had mild visual hallucinations. During the ‘‘on’’state, she was fully ambulatory and independent; however,during the ‘‘off’’ state, she was bed-bound.

Two months after discharge, her mini-mental (MMSE) scorewas 28/30. Motor fluctuation still remained but had becomemild. During the ‘‘off’’ state, she felt weak and showed freezingof gait but was able to walk independently. Visual hallucinationgradually disappeared. She had been able to have a meal with-out the use of a feeding tube, thus the PEG tube was removed at8 months after discharge. She did, however, continue to haveintermittent stridor when the T-tube was sealed for 30 to 40minutes, especially during the ‘‘off’’ period. A 12-month fol-low-up of the laryngoscopic examination revealed that hervocal cords were in the more adducted position than normal atrest and showed incomplete abduction worse on the right sidewith inspiration but normal adduction with phonation duringthe ‘‘on’’ period (Video Segment 3). Vocal cords were in a nearfull adducted position at rest and showed only limited abduc-tion with inspiration worse on the right side during the ‘‘off’’period (Video Segment 4). Thus the tracheostomy tube wasmaintained.

Based on her continued excellent response to L-dopa, de-spite having had a 19-year history with the disease, the clini-cal diagnosis of PD is firm. She does not exhibit autonomicfailure, cerebellar dysfunction, or pyramidal tract signs.

There are several differences in VCP between MSA andPD. Pathologically, there were neurogenic atrophy in the pos-terior cricoarytenoid (PCA) muscle, with sparing of theadductor muscles in MSA.2,3 In contrast, there were no sig-nificant abnormalities of the intrinsic laryngeal muscles inPD.1 Clinically, laryngeal obstruction was usually exacer-bated during sleep in MSA,4,5 whereas inspiratory stridor inPD was noted with a similar degree when awake as well asduring the sleep as in our patient.4

Whether the mechanism of such laryngeal stridor in MSAcan be attributed to denervation2,3 or dystonia5,6 of laryngealmuscles remains controversial. Vetrugno et al. suggested thatstridor in MSA was attributed to sleep-related adductor laryn-geal muscle dystonic contraction due to impaired sleep-relatedsupranuclear control.6 Onoue et al. reported a 69-year-oldpatient with PD with paroxysmal laryngeal stridor which wasmainly present during the wearing-off period. They suggestedfocal laryngeal dystonia as a phenomena.7 In our case, laryn-geal stridor gradually improved as control of her parkinsonismimproved. The fact that laryngeal movement visualized by lar-yngoscopic examination was reversed, at least partially, sug-gests that laryngeal paralysis was functional and not caused by






neurogenic degeneration. VCP in our patient showed temporalsynchrony with motor fluctuation suggesting that, dopaminer-gic dysfunction on laryngeal motor control may be the cause offluctuating stridor. Electromyography (EMG) was not done;however, upon laryngoscopic examination, VCP appeared to bedue to hypokinesia rather than dystonia.

Despite the clinical and pathological differences betweenMSA and PD and the underlying mechanism yet to be eluci-dated, our case clearly emphasizes the possibility of life-threatening VCP in PD.


Segment 1. The aryepiglottic folds in a normal subjectshows wide abduction during inspiration, slight adductionduring expiration, and full adduction during phonation.

Segment 2. Bilateral vocal cords lie in a paramedian posi-tion and are apparently immobile on inspiration in thispatient with PD. Adductor activity during phonation is pre-served. There is pooling of the secretion.

Segment 3. A twelve-month follow-up of the laryngo-scopic examination. During the ‘‘on’’ state, bilateral vocalcords show partial abduction on inspiration and normaladduction with phonation.

Segment 4. A twelve-month follow-up of the laryngoscopicexamination. During the ‘‘off’’ state, bilateral vocal cordsare more in the adducted position and show only limited abduc-tion on inspiration. Mobility is more limited in the right vocalcord.

Segment 5. Bilateral VCP in a 59-year-old patient withMSA. She had laryngeal stridor during sleep for severalmonths, which had crept into the awake period for severaldays. Bilateral vocal cords lie in a paramedian position andshow only limited abduction during inspiration. She devel-oped acute respiratory failure 10 hours after this laryngo-scopic examination. Emergency intubation and tracheostomywere performed.

Acknowledgment: H.J.K.: Clinical data collection, draft-ing the manuscript. B.S.J.: review and critical revision of themanuscript, final approval of the manuscript.

Fiancial Disclosure: Beom S Jeon received grants fromKorea Health 21 R&D Project, Ministry of Health & Wel-fare, Republic of Korea and Seoul National University Hospi-tal, and also conducted clinical trials related to the drugs ofNorvartis and Boehringer Ingelheim.

Hee J. Kim, MDBeom S. Jeon, MD, PhD*Departments of Neurology

Seoul National University HospitalSeoul, Korea


References

1. Isozaki E, Shimizu T, Takamoto K, et al. Vocal cord abductor pa-ralysis (VCAP) in Parkinson’s disease: difference from VCAP inmultiple system atrophy. J Neurol Sci 1995;130:197–202.

2. Bannister R, Gibson W, Michaels L, Oppenheimer DR. Laryngealabductor paralysis in multiple system atrophy. A report on three

necropsied cases, with observations on the laryngeal muscles andthe nuclei ambigui. Brain 1981;104:351–368.

3. Hayashi M, Isozaki E, Oda M, Tanabe H, Kimura J. Loss of largemyelinated nerve fibres of the recurrent laryngeal nerve in patientswith multiple system atrophy and vocal cord palsy. J Neurol Neu-rosurg Psychiatry 1997;62:234–238.

4. Isozaki E, Osanai R, Horiguchi S, Hayashida T, Hirose K, TanabeH. Laryngeal electromyography with separated surface electrodesin patients with multiple system atrophy presenting with vocalcord paralysis. J Neurol 1994;241:551–556.

5. Vetrugno R, Liguori R, Cortelli P, et al. Sleep-related stridor dueto dystonic vocal cord motion and neurogenic tachypnea/tachycar-dia in multiple system atrophy. Mov Disord 2007;22:673–678.

6. Merlo IM, Occhini A, Pacchetti C, Alfonsi E. Not paralysis, butdystonia causes stridor in multiple system atrophy. Neurology2002;58:649–652.

7. Onoue H, Yukitake M, Kurohara K, Takasima H, Kuroda Y. Acase report of Parkinson’s disease presenting with recurrent dysp-neic attacks due to focal laryngeal dystonia. Rinsho Shinkeigaku2003;43:192–194.

Thalidomide Induced Acute Worsening

of Parkinson’s Disease

Acute worsening of Parkinson’s disease (PD) can occur dur-ing intervening diseases, particularly infectious and gastroin-testinal illnesses; withdrawal from dopaminergic medications,and as a complication of several medications.1

We report an acute and severe worsening of PD symptomsin a 74-year-old man treated with thalidomide for myelofibro-sis with myeloid metaplasia, which partially resolved within2 weeks of its discontinuation. Thalidomide was not previ-ously known to adversely affect PD, and limited experimen-tal evidence even suggested a beneficial effect on dopaminer-gic and other neuronal cells.2–5

The patient, a 74-year-old radiologist and coauthor of thisreport (J.L.) developed PD at age 66 and he was initiallytreated with ropinirole with good symptom control. Threeyears later, with progression of his disease, carbidopa/levo-dopa (L-dopa) was added, with excellent clinical response.When ‘‘wearing-off’’ phenomena developed 3 years later,entacapone was added, with good control of the fluctuations.

The patient remained well for >6 months, when he devel-oped severe malaise and fatigue, though his PD symptomsremained well controlled. Although he had a longstandinghistory of intermittent anemia, he had never been completelyevaluated. Medical evaluation demonstrated severe spleno-megaly, and hematologic studies revealed a leukocyte countof 32,000 cells/mm3 and Hgb of 8.1 g/dL. Bone marrowbiopsy led to the diagnosis of myelofibrosis with myeloidmetaplasia. Treatment with growth factors and transfusionsfailed to sustain the patient’s blood counts. Given his ageand general physical condition, splenectomy was deferred.Thalidomide, a selective tumor necrosis factor-alpha (TNF-a)inhibitor, was selected as a chemotherapeutic agent because





of its lack of known adverse effects on PD. Immediatelybefore starting thalidomide, the patient’s PD symptoms werewell controlled, with Unified Parkinson’s Disease RatingScale (UPDRS) subscores of Part III 5 10 and Part IV 5 1,and Hoehn and Yahr (H&Y) stage of III during ‘‘on time.’’Within 2 weeks of starting thalidomide 50 mg and predni-sone 20 mg daily, his PD symptoms worsened dramatically.The patient’s response to medication became less consistent,with longer and less predictable ‘‘off’’ periods, and for thefirst time, he experienced ‘‘sudden-off’’ periods. L-Dopa andentacapone dosage and frequency were increased, resultingin worsening dyskinesias, without adequate control of the‘‘off’’ phenomenon. Prednisone was discontinued after 1week whereas thalidomide was continued, with no improve-ment. Approximately 6 weeks after initiating treatment,UPDRS subscores worsened significantly, with Part III 5 15and Part IV 5 8. The ‘‘on time’’ H&Y stage progressed IIIto IV. A complete medical workup and neurologic examfailed to reveal a cause for the deterioration. Medicationswere reviewed carefully; as no other drugs associated withworsening of Parkinsonism were used, thalidomide was con-sidered the likely culprit. The drug was discontinued �8weeks after it was begun, and within 1 week, the patient’scondition dramatically improved. Four weeks later, his ‘‘ontime’’ H&Y stage had returned to III and he regained hisprior level of function. However, dyskinesias and motor fluc-tuations, although improved, did not completely resolve, de-spite further medication reduction. UPDRS subscores 1month after stopping thalidomide were 7 on Parts III and IV.

Over the following months, the patient’s PD symptomsremained stable, but he became increasingly symptomatic fromhis myeloproliferative disease, eventually requiring splenec-tomy. The UPDRS subscores 6 months after surgery were PartIII 5 7, Part IV 5 5, whereas his H&Y stage remained III. Ayear later his PD continued to remain well controlled.

The acute deterioration of motor function following theinitiation of thalidomide treatment and the prompt, althoughpartial, recovery after its discontinuation suggest the drugcaused the acute worsening of PD. Thalidomide had beencarefully selected among potential chemotherapeutic agentsbecause of its lack of known adverse effects on PD, and ex-perimental evidence even suggested a potential benefit. Tha-lidomide seems to protect nigral dopaminergic cells inMPTP-treated mice,2 and its use has been advocated aspotential neuroprotective agent in other neurodegenerativediseases.3,4

We speculate that thalidomide worsened PD through itsmodulating effect on cytokines. Thalidomide selectivelyinhibits the transcription of TNF-a, a cytokine elevated inPD.3 In neoplastic disease, aberrant release of cytokines mayalter the CNS effects of thalidomide. Interestingly, in ourpatient thalidomide also induced de novo ‘‘sudden-off’’ peri-ods and dyskinesias, leading us to wonder whether cytokinesplay a role in the development of long-term motor complica-tions. Thalidomide may also have altered the gastrointestinalabsorption of PD medications.

This is the first reported case of acute worsening of PDassociated with thalidomide treatment. The complication wasunexpected, given the current understanding of thalidomide’saction in the CNS. The authors believe that the medical com-munity should be informed that thalidomide might causeacute and partially irreversible worsening of PD symptoms.

Sara C. Crystal, MD*Department of Neurology

New York University School of MedicineNew York, New York, USA


John Leonidas, MDLong Island Jewish Hospital

New Hyde Park, New York, USA

Ann Jakubowski, MDClinical Director, Outpatient Services

Memorial Sloan Kettering Cancer CenterNew York, New York, USA

Alessandro Di Rocco, MDDepartment of Neurology

New York University School of MedicineNew York, New York, USA

References

1. Onofrj M, Thomas O. Acute akinesia in Parkinson’s disease. Neu-rology 2005;54:1162–1169.

2. Boireau A, Bordier F, Dubedat P, Peny C, Imperato A. Thalido-mide reduces MPTP-induced decrease in striatal dopamine levelsin mice. Neurosci Lett 1997;234:123–126.

3. Greig NH, Mattson MP, Perry T, et al. New therapeutic strategiesand drug candidates for neurodegenerative diseases: p53 and TNF-alpha inhibitors, and GLP-1 receptor agonists. Ann NY Acad Sci2004;1035:290–315.

4. Ryu JK, McLarnon JG. Thalidomide inhibition of perturbed vas-culature and glial-derived tumor necrosis factor-alpha in an animalmodel of inflamed Alzheimer’s disease brain. Neurobiol Dis2008;29:254–266.

5. Kiaei M, Petri S, Kipiani K, et al. Thalidomide and lenalidomideextend survival in a transgenic mouse model of amyotrophic lat-eral sclerosis. J Neurosci 2006;26:2467–2473.

Movement Disorders as a Manifestation

of Metronidazole-Induced

Encephalopathy in a Patient with

Chronic Liver Disease

Video

Metronidazole (MTZ) is an antibiotic used to treat anaerobic-related infections. It is safe to use, but dosages exceeding 2g/day for prolonged periods can produce peripheral neuropa-thies and, uncommonly, acute encephalopathy.1,2 MTZ neuro-toxicity has been described in patients treated for helico-bacter pylori infection, patients with no previous liver orbrain damage, and patients treated for acute amebic liverabscesses.2


Published online 18 May 2009 in Wiley InterScience (www.




In patients suffering from MTZ toxicity, MRI of the braintypically reveals a pattern of lesions similar to what is seenin metabolic encephalopathy; namely, symmetric and bilat-eral lesions always involving the cerebellar dentate nucleiand variably involving the midbrain, pons, medulla oblon-gata, corpus callosum, and basal ganglia.2 All lesions tend tocompletely resolve after MTZ use is discontinued.

According to a few available publications, none reportingdata on more than 20 patients, MTZ has been implicated inthe induction of acute encephalopathy characterized by con-fusion, dysarthria, and ataxia.2–4 Although magnetic reso-nance imaging (MRI) revealed basal ganglia lesions in asmany as 20% of reported cases,2 we did not find any refer-ence to the presence of movement disorders as a clinicalmanifestation of MTZ neurotoxicity.2 Kim et al. recentlypublished an important report on seven patients with manifes-tations of MTZ-induced encephalopathy. In the patientsincluded in this report, none showed signs of movementdisorders.2

We present a 60-year-old man in stable condition withchronic liver disease secondary to viral hepatitis type C, ironoverload associated with acquired porphyria (most likelyrelated to hepatitis C), and chronic encephalopathy. Manifes-tations of his chronic encephalopathy were a very mild cho-rea and ataxia. Because of suspected worsening of hepaticencephalopathy, the patient received an increased dose ofMTZ, he went from taking 750 mg/day to 1.5 g/day. Thepatient was also receiving a stable regime of spironolactone,lactulose, and vitamin K.

Within a few days of his MTZ dosage increase, the patientexperienced dysarthria, an increase in gait ataxia, chorea ofthe face and limbs, and myoclonus (see video). The patientwas not on any other drugs, such as dopamine receptor antag-onists, that could have potentially induced his movement dis-order. An MRI of the brain showed bilateral hyperintense T2lesions that involved the cerebellar dentate nuclei, inferiorcolliculus, lower medulla, and corpus callosum. The lesionson the dentate nuclei and inferior colliculus produced highsignals in FLAIR and diffusion-weighted images (Fig. 1).

Considering the MRI findings, MTZ was discontinued andthe patient experienced a marked improvement evident dur-ing the first week, with remarkable relief of ataxia andmarked reduction of chorea and myoclonus. The MRI lesionsresolved completely after discontinuation of MTZ (Fig. 1).

The exact mechanism underlying MTZ toxicity remainsunclear, but interactions with neuronal RNA or DNA andmodulation of g-aminobutyric acid receptor have been sug-gested.1,2 Discernible lesions found in MRI diffusion sequen-ces and increased ADC maps (image not shown), suggest thepresence of vasogenic edema.

Our patient developed a marked worsening of his previouschorea and ataxia, which were old manifestations of hischronic hepatic encephalopathy. Myoclonus was a new sign.In spite of the absence of basal ganglia lesions in this case,the involvement of the cerebellum and brainstem, whichform part of the circuitry of the basal ganglia, may havebeen responsible for the observed worsening of movementdisorders in this patient.

FIG. 1. (A, B) Diffusion-weighted images that depict hyperintense lesions on the cerebellar dentate nuclei and inferior colliculus (arrow). (C)FLAIR image that shows hyperintense lesions on cerebellum dentate nuclei. (D–F) T2-weigthed images that show hyperintense T2 lesions involv-ing the bilateral cerebellum dentate nuclei, inferior colliculus, and corpus callosum (arrow). (G, H) Diffusion-weighted and FLAIR images thatshow complete resolution of the hyperintense lesions in the cerebellum and brainstem after 1 month of metronidazole discontinuation (only cere-bellum shown).



Differential diagnosis in this case includes Wernicke’sencephalopathy. Although findings on imaging may be simi-lar, the clinical context is quite different.

In summary, this case suggests that MTZ neurotoxicityshould be considered in patients taking this drug who de-velop acute manifestations of central nervous system dys-function, including movement disorders. MRI findings helpto support the diagnosis.

LEGENDS TO THE VIDEO

Segment 1. In this segment the patient is shown afterstarting the new MTZ dose. He developed increased oro-facial and limb chorea and severe ataxia. Myoclonic jerks inthe limbs can also be observed.

Segment 2. One week after stopping MTZ, the patientreturned to stable condition, with a very mild facial and limbchorea and gait ataxia.

Marcelo Galvez, MDDepartment of Radiology

Clinica Las CondesSantiago, Chile

Javier Brahm, MDDepartment of Gastroenterology


Marcelo Miranda, MD*Department of Neurology



References

1. Freeman CD, Klutman N, Lamp K. Metronidazole a therapeuticreview and update. Drugs 1995;54:679–708.

2. Kim E, Na D, Kim EY, Kim JH, Son KR, Chang KH. MR imagingof Metronidazole-induced encephalopathy: lesion distribution anddiffusion-weighted imaging findings. AJNR 2007;28:1652–1658.

3. Aemed A, Loes D, Bressler E. Reversible resonance imaging find-ings in metronidazole-induced encephalopathy. Neurology 1995;45:588–589.

4. Woodriff BK, Wijdicks EF, Marshall WF. Reversible metronida-zole-induced lesions of the cerebellar dentate nuclei. N Engl J Med2002;346:68–69.



Thalidomide induced acute worsening of Parkinson's disease

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