Preserved cardiac 123 I-MIBG uptake and lack of severe autonomic dysfunction in a PARK9 patient

Letters to the Editor Related to New Topics

Novel GFAP Mutation in Patient with

Adult-Onset Alexander Disease Presenting

with Spastic Ataxia

Adult-onset Alexander disease is rare and clinically charac-terized by slowly progressive signs of brainstem and spinalcord involvement.1 Missense mutations in the gene encodingthe glial fibrillary acidic protein (GFAP) have been identifiedas a genetic basis for Alexander disease.2 We here report aJapanese patient with adult-onset Alexander disease with anovel GFAP mutation.

A 36-year-old man of Japanese descent, a child of noncon-sanguineous parents, with a 10-year history of slowly pro-gressive gait disturbance, was referred to us. His early motorand intellectual development were normal. Neurological ex-amination revealed rhythmic ocular nystagmoid movement,dysarthria, truncal and limb ataxia, increased muscle stretchreflex with bilateral Babinski sign, and spasticity in his lowerextremities. Palatal myoclonus was not noted. He was ambu-latory, but his gait was unsteady owing to ataxia and spastic-ity in the lower extremities.

Brain MRI demonstrated a marked atrophy of the medullaoblongata and cervical spinal cord, and a mild atrophy of thecerebellar hemisphere (Fig. 1A). Fluid attenuation inversionrecovery (FLAIR) images revealed abnormal hyperintensitiesin cerebellar dentate nucleus (Fig. 1B) and the periventricularwhite matter (Fig. 1C).

Molecular genetic analysis of GFAP was performed usingthe patient’s genomic DNA after obtaining written informedconsent. Sequence analysis revealed a heterozygous 302T > Csubstitution in exon 1 of GFAP, leading to an L101P substitu-tion. The L101P substitution is located in the C-terminal endof the 1A rod domain of GFAP occurring in a highly con-served amino acid residue across species (Fig. 1D). Thesequence change was confirmed by restriction fragment lengthpolymorphism (RFLP) using enzyme digestion by BcgI in thepatient and 100 normal control subjects (Fig. 1E).

To obtain biochemical evidence of pathogenecity of thenovel GFAP L101P mutant, we transfected wild-type andmutant GFAP, and examined the solubility of the GFAP pro-tein. Samples were sequentially extracted with different strin-gent buffers and subjected to western blot analysis (see Sup-plementary methods). The well-characterized mutant R416WGFAP was largely recovered from the detergent-resistant S2fraction because of the decreased solubility of mutant GFAP(Fig. 1F, lane 8) as previously reported.3,4 In this assay,

wild-type GFAP was predominantly detected in the solubleS1 fraction (Fig. 1F, lane 2). In contrast, the mutant L101PGFAP was largely observed in the detergent-resistant S2fraction (Fig. 1F, lane 7). Transfected cells were further ana-lyzed for GFAP assembly by confocal microscopy (see Sup-plementary methods). Whereas wild-type GFAP displayedcytoplasmic distribution with a filamentous network, theL101P mutant yielded an irregular dot-like structure largelylacking the filamentous structure (Supp. Info. Fig.).

In this study, we identified a novel GFAP mutation in aJapanese patient with adult-onset Alexander disease present-ing with slowly progressive spastic ataxia. The parents of thepatient are unaffected; hence, the mutation seems to arisede novo in the patient as in most cases of Alexander disease.1

Indeed, the mother did not carry the mutation. Unfortunately,DNA sample was unavailable from the father, who hasrecently died of heart disease.

GFAP is a member of the intermediate filament familywith a conserved central helical rod domain flanked bythe head and tail domains (Fig. 1D). The L101P mutationdetected in the patient is located in the coil 1A rod domain,which is considered to play an essential role in filament for-mation. Mutations of the a-helix regions in the rod domainare considered to alter the charge and hydrophobic interac-tions within coiled coils.4 Thus, mutations in the domain mayaffect the solubility of GFAP, which is supported by our bio-chemical experiments using cells expressing mutant GFAP.

To date, more than 10 GFAP missense mutations associatedwith adult-onset Alexander disease have been found, withnearly all occurring in the rod domain.1,5–7 The genotype–phe-notype correlation in Alexander disease has been poorly under-stood particularly in adult-onset cases, probably owing to thevery small number of patients. Alexander disease in our patientis clinically characterized by slowly progressive spastic ataxiawith bulbar signs without palatal myoclonus. In patients withadult-onset Alexander disease, bulbar symptoms, gait ataxia,and spasticity are common clinical features, whereas ocularmotor abnormalities, autonomic dysfunctions, and palatal myo-clonus have been reported with varying frequency.1,5–7

Our patient exhibited atrophy of the medulla and spinalcord, and abnormal hyperintensities of the periventricularwhite matter and cerebellar dentate nucleus on FLAIRimages. The characteristic atrophy of the medulla and spinalcord is invariably present in adult-onset Alexander disease.5–7

In contrast, leukoencephalopathy and abnormal signal inten-sities of the cerebellum are not always observed in adult-onset cases.5–7 The question of why missense mutations inthe same critical domain of GFAP result in such differentclinical phenotypes and MRI findings in Alexander disease isintriguing and deserves further attention and elucidation.

Acknowledgments: This study was supported in part byGrant-in-Aid (18590930) for scientific research from the MEXT,Japan and a grant from the Research Committee for Ataxic Dis-eases, the Ministry of Health, Labor and Welfare, Japan.

Additional Supporting Information may be found in the onlineversion of this article.Hiroyuki Kaneko and Masaki Hirose contributed equally to this

studyPotential conflict of interest: Nothing to report.Published online 1 May 2009 in Wiley InterScience (www.

interscience.wiley.com). DOI: 10.1002/mds.22556

1393

Movement DisordersVol. 24, No. 9, 2009, pp. 1393–1406� 2009 Movement Disorder Society

FIG. 1. Brain MRI of patient. (A) A midsagittal T1-weighted image shows atrophy of the medulla oblongata and the cervical spinal cord. (B)An axial FLAIR scan shows signal abnormality of the cerebellum. (C) White matter hyperintensity in the frontal and occipital portions isobserved in a FLAIR image. (D) Localization of novel L101P mutation. Schematic of GFAP is shown. Boxes indicate the four a-helical subdo-mains within the central rod domain, separated by nonhelical linkers. Amino acid sequences of GFAP among species were compared by multiplesequence alignments using the Clustalw algorithm. The conserved amino acids are indicated by asterisks. (E) The mutation is confirmed by RFLPanalysis. The 330-bp wild-type PCR product (arrow) was not digested with BcgI and generated a single fragment. The mutation resulted in thecleavage of the product into 180 and 150 bp (arrowhead). (F) Solubility of GFAP in culture cells. C6 cells were transiently transfected with theexpression vector encoding wild-type or mutant (L101P or R416W) GFAP. Transfected human GFAP (�50 kDa) was detected with the monoclo-nal anti-human GFAP antibody, which does not react with endogenous rat GFAP (upper panel, lanes 1 and 5). L101P GFAP (lanes 3 and 7)migrates slightly slower than the wild-type or R416W GFAP. The same samples were blotted with the anti-actin antibody to show that compara-ble amounts of proteins were loaded (lower panel).

1394 LETTERS TO THE EDITOR

Movement Disorders, Vol. 24, No. 9, 2009

Hiroyuki Kaneko, MMedDepartment of NeurologyBrain Research Institute

Niigata UniversityNiigata, Japan

Department of Molecular NeuroscienceBrain Research Institute


Masaki Hirose, MDDepartment of NeurologyBrain Research Institute


Shinichi Katada, MDDepartment of NeurologyBrain Research Institute


Department of Molecular NeuroscienceBrain Research Institute


Toshiaki Takahashi, MDSchool of Health Science, Faculty of Medicine


Satoshi Naruse, MDDepartment of NeurologyBrain Research Institute


Miyuki Tsuchiya, BSDepartment of Molecular Neuroscience

Brain Research InstituteNiigata University

Niigata, Japan

Tomokatsu Yoshida, MDMasanori Nakagawa, MDDepartment of Neurology

Graduate School of Medical ScienceKyoto Prefectural University of Medicine

Kyoto, Japan

Osamu Onodera, MDDepartment of Molecular Neuroscience


Niigata, Japan

Masatoyo Nishizawa, MDDepartment of NeurologyBrain Research Institute


Takeshi Ikeuchi, MD*Department of Molecular Neuroscience


Niigata, Japan*E-mail: [email protected]

References

1. Li R, Johnson AB, Salomons G, et al. Glial fibrillary acidic pro-tein mutations in infantile, juvenile, and adult forms of Alexanderdisease. Ann Neurol 2005:57;310–326.

2. Brenner M, Johnson AB, Boespflug-Tanguy O, Rodrigues D,Goldman JE, Messing A. Mutations in GFAP, encoding glialfibrillary acidic protein, are associated with Alexander disease.Nat Genet 2001;27:117–120.

3. Yoshida T, Tomozawa Y, Arisato T, Okamoto Y, Hirano H,Nakagawa M. The functional alteration of mutant GFAP dependson the location of the domain: morphological and functional stud-ies using astrocytoma-derived cells. J Hum Genet 2007;52:362–369.

4. Perng MD, Su M, Wen SF, et al. The Alexander disease-causingglial fibrillary acidic protein mutant, R416W, accumulates intoRosenthal fibers by a pathway that involves filament aggregationand the association of aB-crystallin and HSP27. Am J Hum Genet2006;79:197–213.

5. Namekawa M, Takiyama Y, Aoki Y, et al. Identification of GFAPgene mutation in hereditary adult-onset Alexander’s disease. AnnNeurol 2002;52:779–785.

6. Pareyson D, Fancellu R, Mariotti C, et al. Adult-onset Alexanderdisease: a series of eleven unrelated cases with review of the liter-ature. Brain 2008;131:2321–2331.

7. Hinttala R, Karttumen V, Karttumen A, Herva R, Uusimaa J,Remes AM. Alexander disease with occipital predominance and anovel c.799G>C mutation in the GFAP gene. Acta Neuropathol2007;114:543–545.

Early Brain Abscess: A Rare Complication of

Deep Brain Stimulation

Deep brain stimulation (DBS) is successfully used for symp-tomatic treatment of various movement disorders. However,the technique is not without risks for adverse events relatedto surgery, hardware, or stimulation itself. There is a contin-ued need for standardized reporting of adverse events relatedto DBS surgery, especially with respect to serious infections.1

These include the rare complication of intracerebral infec-tions, which if not recognized, may cause serious and long-term morbidity.

A 55-year-old man with tremor-predominant Parkinson’sdisease underwent unilateral DBS surgery. The electrode(3387, Medtronic, Minneapolis, MN) was placed in the right

Published online 1 May 2009 in Wiley InterScience (www.


1395LETTERS TO THE EDITOR


subthalamic nucleus (STN) under microelectrode recordingguidance. Antibiotic prophylaxis was provided. The patienthad no history of diabetes and was not immunocompromised.Postoperative CT scan of the brain showed normal postsurgi-cal changes.

On postoperative day 3, the patient developed confusionand fever (38.68C) and was readmitted. There was no menin-gismus or evidence of scalp infection at the surgical site. Hehad fluctuating inattentiveness, incoherent speech withoutaphasia, and left leg hyperreflexia. White blood cell count(WBC) was 15,000. Cerebrospinal fluid (CSF) contained 135WBCs, 359 RBCs, protein 51 mg/dl, glucose 98 mg/dl. Serialbrain CT scans with and without contrast over the next 4days were normal. Empirical treatment included intravenousvancomycin and meropenem.

Blood and CSF cultures remained negative. RepeatedCSF studies 4 days after readmission showed 46 WBCs,216 RBCs, protein 71 mg/dl, and glucose 71 mg/dl. Tem-perature normalized but alertness continued to fluctuate. Nonew neurological signs developed. Brain CT scan on post-operative day 8 showed a hypodensity surrounding the rightDBS electrode without ring enhancement (Fig. 1A). BrainMRI on postoperative day 10 demonstrated a ring enhanc-ing lesion with surrounding vasogenic edema in the rightfrontal lobe (Fig. 1B,C). MRI was delayed due to institu-tional rules.

Following MRI, right frontal craniotomy showed no evi-dence of scalp or subgaleal infection. Reddish-gray materialwas found subcortically, cultures of which grew Enterobacteraerogenes. The right electrode was removed. Antibiotic treat-ment was changed to intravenous ertapenem and was contin-ued for 6 weeks. Mental status normalized within 2 weeks.Repeat MRI at 6 weeks showed near resolution of the infec-tion (Fig. 1D).

This case is a rare example of early intracerebral infec-tion appearing within several days of DBS electrode im-plantation. Infections following DBS surgery occur in 1.6to 6.1% of patients.1–5 Implantable pulse generator (IPG)related infections are more common than infections of theremaining system (3.7% vs. 2.5%).4 In a series by Sillayet al.2 on DBS hardware related infection that occurredwithin 6 months postoperatively (4.5% of 420 patients),six involved the skull and 13 the IPGs. None was intra-

cranial. Similarly, Hamani and Lozano3 reported infec-tions in 6.1% of DBS patients, none of which was intra-cranial. These extracranial infections are clinically evidentby swelling, erythema, pain, or drainage over the affectedsite. Infections requiring removal of the leads have beenlisted as a rare adverse effect of STN-DBS but withoutsubstantial information regarding location and extent ofinfection.6 We found only one published case report ofintracerebral electrode infection, which contained furtherdetails.7 Similar to our case, there were no signs of local-ized external infection.

DBS hardware related infections have been reported asearly as 7 days following surgery.2 However, the majorityoccurs after weeks2 to months.5 The intracranial infectionreported by Merello et al.7 became clinically apparent 6months postimplantation. This is much later than in ourcase, which may be related to the difference in isolatedpathogens.

Very little data has been made available regardinginvolved pathogens. Extracranial infections usually involveskin flora, including Staphylococcus aureus, Propionibacte-rium acnes, and Staphylococcus epidermidis.2 The intracra-nial infection reported by Merello et al.7 involved Candidaparapsilosus, whereas Enterobacter aerogenes was found inour case. The appearance of these two unexpected pathogensdemonstrates that in addition to starting broad-spectrum anti-biotics when suspecting DBS surgery- or hardware-relatedinfection, isolation and culture of the pathogen is necessaryfor adequate treatment, especially when the infection islocated intracerebrally.

This case illustrates that clinical suspicion of postoperativebrain infection must be maintained even without extracranialsigns of infection. Diagnosis is difficult due to limitations ofCT scanning in detecting vasogenic edema, especially in thesetting of electrode artifact, and may require MRI. Earlydiagnosis and proper treatment, including pathogen isolation,electrode explantation, and high doses of antibiotics, are cru-cial for full recovery.

Veronique G. VanderHorst, MD, PhDDepartment of Neurology

Beth Israel Deaconess Medical CenterBoston, Massachusetts

FIG. 1. CT of the brain on postoperative day 8 demonstrates a hypodense area (arrowheads) surrounding the electrode on the right side (A). TheDBS electrode on the left side (*) was placed into the left thalamic ventral intermediate nucleus 14 months earlier without complication. Gadolin-ium-enhanced axial MPRAGE on postoperative day 10 shows a 2.0 3 1.7 3 2.4 cm3 ring-enhancing lesion (arrow in B), with perilesional edema(arrowheads in C) extending nearly to the level of the lateral ventricle. Nearly 6 weeks after electrode removal, the abscess (arrow) has nearlyresolved (D).



Efstathios Papavassiliou, MDDepartment of Neurosurgery

Beth Israel Deaconess Medical CenterBoston, Massachusetts

Daniel Tarsy, MDLudy C. Shih, MD*

Department of NeurologyBeth Israel Deaconess Medical Center

Boston, Massachusetts*E-mail: [email protected]

References

1. Videnovic A, Verhagen-Metman L. Deep brain stimulation forParkinson’s disease: prevalence of adverse events and need forstandardized reporting. Mov Disord 2008;23:343–349.

2. Sillay KA, Larson PS, Starr PA. Deep brain stimulator hardware-related infections: incidence and management in a large series.Neurosurgery 2008;62:360–366; discussion 366–367.

3. Hamani C, Lozano AM. Hardware-related complications of deepbrain stimulation: a review of the published literature. StereotactFunct Neurosurg 2006;84:248–251.

4. Lyons KE, Wilkinson SB, Overman J, Pahwa R. Surgical andhardware complications of subthalamic stimulation: a series of160 procedures. Neurology 2004;63:612–616.

5. Blomstedt P, Hariz MI. Hardware-related complications of deepbrain stimulation: a ten year experience. Acta Neurochir (Wien)2005;147:1061–1064; discussion 1064.

6. Kleiner-Fisman G, Herzog J, Fisman DN, et al. Subthalamicnucleus deep brain stimulation: summary and meta-analysis ofoutcomes. Mov Disord 2006;21 (Suppl 14):S290–S304.

7. Merello M, Cammarota A, Leiguarda R, Pikielny R. Delayed in-tracerebral electrode infection after bilateral STN implantation forParkinson’s disease. Case report. Mov Disord 2001;16:168–170.

Oromandibular Dystonia as a Complication of

Cerebrotendinous Xanthomatosis

Video

Cerebrotendinous xanthomatosis (CTX, sterol 27-hydroxy-lase deficiency, MIM #213700) is a rare autosomal recessivelipid storage disease caused by a defect in bile acid synthesis.Symptoms develop because of accumulation of lipids, includ-ing cholestanol and cholesterol, in many tissues, most notice-ably in tendons and brain.1 It is important to recognize thedisease because its symptoms can be prevented and poten-tially reversed with treatment with chenodeoxycholic acid(CDCA).2 Although early presentation includes neonatal diar-rhea, failure to thrive, and juvenile cataracts, the disease isusually recognized after the development of neurological def-icits, most often ataxia,3 spasticity, and cognitive dysfunc-tion.1 Diagnosis is made by biochemical studies includingelevated serum cholestanol level and urinary bile alcohols.Mutations in the CYP27A1 gene, located on human chromo-

some 2q31, have been described in almost all of thecases.1,4,5

Here, we report a patient who presented at age 33 withneurological deficits. The history of juvenile cataracts and thepresence of achilles tendon xanthomas led to a diagnosis ofCTX. This also led to the identification of her affectedyounger brother, who also had early signs of ataxia and bilat-eral cataracts. In spite of 4 years of treatment with CDCA,her neurological condition progressed and she developed oro-mandibular dystonia, an unusual complication.

A 33-year-old right-handed woman presented with pro-gressive ataxia since early adulthood, with marked worseningin the past 2 years, culminating in numerous falls. As aninfant, she suffered from chronic diarrhea, which persistedinto adulthood in a milder form. She was diagnosed withbilateral cataracts at age 12, which were subsequentlyremoved at ages 18 and 19. She had mild learning disability.

On examination, she had bilateral tendon xanthomas withbilateral pes cavus foot deformities. Her extraocular move-ments were full. She had ocular dysmetria with overshoot.She had marked dysarthria. Tone in her arms was normal,but her legs were spastic. There was no focal weakness. Herreflexes were brisk in her arms and legs. She had extensorplantar responses. There was severe impairment of vibrationin her toes bilaterally and mild impairment in her fingersbilaterally. There was dysmetria on finger-to-nose and heel-to-shin testing bilaterally. Her gait was wide-based and

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

Published online 16 April 2009 in Wiley InterScience (www.


FIG. 1. FLAIR imaging of the cerebellum demonstraing hyperin-tense signal in the dentate nuclei.



ataxic. Serum cholestanol and bile alcohol levels in urine lev-els were elevated. She tested positive for two gene mutationsin CYP27A1 (exon 5: T306M and exon 6: E359A). Treatmentwith CDCA was initiated at 250 mg three times a day. Shewas able to maintain her independence.

Three years later, she developed acute worsening of preex-isting dysarthria. Nonadherence to CDCA was suspected. Shecould no longer eat solid foods and eventually was admittedto the hospital with dehydration. Repeat serum cholestanollevels were elevated, and the dose of CDCA was increasedto 1 g a day. On examination, there was jaw opening dysto-nia and dystonic tongue movements. These improved with asensory geste (see Supporting Information video). There wasa pseudobulbar affect, with frequent distractible crying spells,which responded to dextromethorphan/quinidine therapy.6

The rest of the neurological exam remained unchanged, withspasticity, mild ataxia, and hyperreflexia.

Magnetic resonance imaging (Figs. 1 and 2) did not showany new changes, but was significant for previously seen T2-weighted imaging hyperintensities in the corticospinal tractsand the cerebellar dentate nuclei. However, there was no ra-diographic correlate to the dystonia. A feeding tube wasplaced for nutrition and CDCA administration. CDCA pro-duced a progressive improvement in general medical condi-tion and cholestanol levels, but the oromandibular dystoniaand dysphagia did not improve. Since the patient’s speechimproved with a sensory geste (see Supporting Information

video) a tooth cap was devised to reproduce this trick withsome symptomatic relief. Botulinum toxin injections and tri-hexyphenidyl have improved speech and swallowing.

Focal dystonia in general and oromandibular dystonia inparticular have been rarely reported in CTX.7,8 This mayreflect that these conditions are under-recognized. The mostcommon neurological complications in CTX include pyrami-dal signs (67%), cerebellar signs (60%), and cognitive dys-function (57%). Epilepsy and peripheral neuropathy can bepresent in up to 24% of cases.1 Psychiatric manifestation andParkinsonism have been described as well. The mechanismof CNS damage in CTX is unknown. Although the cerebel-lum is the most common site of injury, the globus pallidusmay also be involved.9 Focal lesions associated with second-ary dystonia have been described with lesions in the basalganglia or thalamus or, less commonly, in the parietal lobeor cerebellum.10 Cholestanol deposition in one of these loca-tions, in spite of treatment with CDCA, may have causeddystonia in this patient.

The importance of diagnosing CTX has increased sincethe discovery that CDCA can reverse neurological deficits insome patients.2 The dose can be monitored using serum lev-els of cholestanol.11,12 Adding a statin to the treatment is stillcontroversial.11,12 Here, the patient developed a new neuro-logical deficit in spite of reportedly good compliance withthe medication.

Legends to the Video

Cerebrotendinous xanthomatosis patient with jaw openingdystonia, which improves with a sensory geste. Bilteral dys-metria, normal extraocular movements, spastic gait, hyperre-flexia, and upgoing toes are present. Achilles tendon xantho-mas are demonstrated.

Roy N. Alcalay, MD*Department of Neurology

Columbia UniversityNew York, New York, USA

*E-mail: [email protected]

Stacy Wu, MDDepartment of NeurologyUniversity Hospital Basel

Basel, Switzerland

Shailendra Patel, BM, ChB, DPhil, FRCPDivision of EndocrinologyDepartment of Medicine

Metabolism and Clinical NutritionMedical College of Wisconsin

Wisconsin, USADepartment of Medicine

Clement J. Zablocki VA Medical CenterMilwaukee, Wisconsin, USA

Steven Frucht, MDDepartment of Neurology

Columbia UniversityNew York, New York, USA

FIG. 2. FLAIR imaging demonstrating hyperintense signal in thebilateral internal capsules.



References

1. Verrips A, Hoefsloot LH, Steenbergen GC, et al. Clinical andmolecular genetic characteristics of patients with cerebrotendi-nous xanthomatosis. Brain 2000;123 (Part 5):908–919.

2. Berginer VM, Salen G, Shefer S. Long-term treatment of cere-brotendinous xanthomatosis with chenodeoxycholic acid. N EnglJ Med 1984;311:1649–1652.

3. Okuma H, Kitagawa Y, Tokuoka K, Takagi S. Cerebrotendinousxanthomatosis with cerebellar ataxia as the chief symptom. InternMed 2007;46:1259–1261.

4. Leitersdorf E, Reshef A, Meiner V, et al. Frameshift and splice-junction mutations in the sterol 27-hydroxylase gene cause cere-brotendinous xanthomatosis in Jews or Moroccan origin. J ClinInvest 1993;91:2488–2496.

5. Lee MH, Hazard S, Carpten JD, et al. Fine-mapping, mutationanalyses, and structural mapping of cerebrotendinous xanthomato-sis in U.S. pedigrees. J Lipid Res 2001;42:159–169.

6. Brooks BR, Thisted RA, Appel SH, et al. Treatment of pseudo-bulbar affect in ALS with dextromethorphan/quinidine: a random-ized trial. Neurology 2004;63:1364–1370.

7. Bordia S, Saifee AA. Cerebrotendinous xanthomatosis with oro-mandibular dyskinesia. Neurol India 2003;51:556–558.

8. Szlago M, Gallus GN, Schenone A, et al. The first cerebrotendi-nous xanthomatosis family from Argentina: a new mutation inCYP27A1 gene. Neurology 2008;70:402–404.

9. Pilo de la Fuente B, Ruiz I, Lopez de Munain A, Jimenez-EscrigA. Cerebrotendinous xanthomatosis: neuropathological findings.J Neurol 2008;255:839–842.

10. Geyer HL, Bressman SB. The diagnosis of dystonia. Lancet Neu-rol 2006;5:780–790.

11. Kuriyama M, Tokimura Y, Fujiyama J, Utatsu Y, Osame M. Treat-ment of cerebrotendinous xanthomatosis: effects of chenodeoxycholicacid, pravastatin, and combined use. J Neurol Sci 1994;125:22–28.

12. Verrips A, Wevers RA, Van Engelen BG, et al. Effect of simvastatinin addition to chenodeoxycholic acid in patients with cerebrotendi-nous xanthomatosis. Metabolism 1999;48:233–238.

Benign Tremulous Parkinsonism in a

Patient with Dardarin Mutation

Benign tremulous parkinsonism (BTP) is a rare mostly fami-lial condition characterized by resting and action tremoronset, persistent tremor predominance plus minimal progres-sion of other aspects of parkinsonism, unpredictable responseto medication, and a better prognosis than idiopathic Parkin-son’s disease (PD).1 Given the remarkable frequency of posi-tive family history in BTP and the clinical similarity betweenpatients and leucine-rich repeat kinase 2 (LRRK2) mutationcarriers, screening for Dardarin mutations might be impor-tant.2 We describe the clinical and genetic features and longi-tudinal course of a patient with benign tremulous parkinson-ism encountered in our movement disorders practice.

The patient was an 81-year-old man with a positive familyhistory for an undefined upper limb tremor in a maternalgreat-aunt. Age at onset was 58 years, with a resting tremorassociated with a light postural tremor involving the left armand that became bilateral within a few months, remainingasymmetric. One year later the tremor involved the lower

limbs, with prevalence on the right side. The patient reporteda sleep benefit tremor appearing in fifteen minutes afterawakening. A good levodopa response was evident, althoughover the years the responses to the single administrations hadgradually subsided and moderate dyskinesias involving trunkand limbs appeared at age 70 after 12 years of therapy. Inaddition to tremor, examination at age 75 in the off-state dis-closed a clinically irrelevant mild rigidity and bradykinesiaof the extremities, prevalent on the right side. At age 78, thepatient complained of nocturnal episodes resembling a REMsleep behavior disorder and a video-polysomnographic studydisclosed REM sleep without atonia. Repeated CT scans andMRIs ruled out cerebral lesions except for mild cortical atro-phy and rare T2-hyperintense lesions in the white matter.DaTSCAN (123I-Ioflupane) SPECT was compatible withParkinson’s disease, detecting a reduced striatal uptake, espe-cially in the putamen at age 72, and an absent putaminaluptake at age 81. At this time the Parkinsonian symptomsremained unchanged with the exception of a worsening ofthe resting tremor. Genetic analysis disclosed the G2019Smutation in the LRRK2 gene.

The clinical picture and clinical follow-up of our patientwere compatible with the syndromic diagnosis of benigntremulous Parkinsonism. After genetic analysis the definitediagnosis was genetic PD.

BTP is not yet well clarified and refers to a disease char-acterized by prominent resting tremor, the first or among thefirst signs and persistently overshadowing other aspects ofparkinsonism throughout the course; nontremor componentsof parkinsonism that remain mild; absence of gait disorderapart from reduced arm swing or mild stooping; no morethan mild progression, except for tremor, despite at least8 years of parkinsonism; absence of disability apart fromtremor; high percentage of positive family history of tremor(around 60%).1,2 Whether BTP represents a subtype of PD isa matter of ongoing debate. In clinical practice PD is com-monly divided into at least two subtypes, i.e. tremor-domi-nant vs. akinetic-rigid type3 or tremor-dominant vs. posturalinstability and gait difficulty type.4 Tremor onset and tremordominance is generally considered to confer benignity andare associated with a less rapid and debilitating disease. Thequestion is whether BTP could be a sub-subtype of tremor-dominant PD. Some aspects do not support this view in allpatients with BTP. Firstly, only some of these patientsrespond to L-DOPA.1,2 Secondly, some of these patientshave a normal DaTSCAN SPECT2 and could be the same asthose who have been referred to as Scans Without Evidenceof Dopaminergic Deficits,5 unlike our patient in whom theSPECT was altered. Moreover, a clinicopathologic study of aBTP patient performed by Rajput et al.6 disclosed an autopticdiagnosis of essential tremor. On the other hand, one patient ina series of 26 patients with clinical features of BTP studied byClarimon et al.2 had a new LRRK2 (V2390M) mutation. Muta-tions in the LRRK2 are the commonest genetic cause of PDand are linked to heterogenic phenotypes, ranging from typicalPD, PD with a significantly slower disease progression, earlyonset PD but also PD associated with dementia and psychosis,corticobasal syndrome, and primary progressive aphasia.7,8

Our patient was a c.6055G>A (p.G2019S) substitution carrier.This is the most frequent LRRK2 mutation that accounts forapproximately 1% of patients with sporadic PD and 4% ofpatients with hereditary PD.7

Published online 16 April 2009 in Wiley InterScience (www.




In conclusion, BTP may be a heterogeneous clinical syn-drome comprising different diseases, and further studies areneeded to define its full spectrum. However, some patientscould be LRRK2 mutation carriers and screening for Dar-darin mutations is indicated in BTP.

Author Roles: Giovanni Rizzo: Research project: A.Conception, B. Organization, C. Execution; Manuscript: A.Writing of the first draft. Sara Marconi: Research project: B.Organization, C. Execution; Manuscript: A. Writing of thefirst draft. Sabina Capellari: Research project: C. Execution;Manuscript: B. Review and Critique. Cesa Scaglione:Research project: B. Organization; Manuscript: B. Reviewand Critique. Paolo Martinelli: Research project: A. Concep-tion; Manuscript: B. Review and Critique.

Giovanni Rizzo, MD*Sara Marconi, MD

Sabina Capellari, MDCesa Scaglione, MDPaolo Martinelli, MD

Department of Neurological SciencesUniversity of Bologna

Bologna, Italy*E-mail: [email protected]

References

1. Josephs KA, Matsumoto JY, Ahlskog JE. Benign tremulous Par-kinsonism. Arch Neurol 2006;63:354–357.

2. Clarimon J, Pagonabarraga J, Paisan-Ruız C, et al. Tremor domi-nant Parkinsonism: Clinical description and LRRK2 mutationscreening. Mov Disord 2008;23:518–523.

3. Schiess MC, Zheng H, Soukup VM, Bonnen JG, Nauta HJ. Par-kinson’s disease subtypes: clinical classification and ventricularcerebrospinal fluid analysis. Parkinsonism Relat Disord 2000;6:69–76.

4. Jankovic J, McDermott M, Carter J, et al. Variable expressionof Parkinson’s disease: a base-line analysis of the DATATOPcohort. The Parkinson Study Group. Neurology 1990;40:1529–1534.

5. Schneider SA, Edwards MJ, Mir P, et al. Patients with adult-onset dystonic tremor resembling parkinsonian tremor havescans without evidence of dopaminergic deficit (SWEDDs).Mov Disord 2007;22:2210–2215.

6. Rajput AH, Robinson CA, Rajput AH. Benign tremulous Par-kinsonism: a clinicopathological study. Mov Disord 2008;23:311–312.

7. Healy DG, Falchi M, O’Sullivan SS, et al. Phenotype, geno-type, and worldwide genetic penetrance of LRRK2-associatedParkinson’s disease: a case-control study. Lancet Neurol 2008;7:583–590.

8. Chen-Plotkin AS, Yuan W, Anderson C, et al. Corticobasalsyndrome and primary progressive aphasia as manifestations ofLRRK2 gene mutations. Neurology 2008;70:521–527.

Botulinum Toxin Injections to Treat Belly

Dancer’s Dyskinesia

Video

‘‘Belly dancer’s dyskinesia’’ (BDD), first described in 1990,is characterised by focal, sometimes painful, involuntarywrithing movements and contractions of the abdominal wall,producing a slow multidirectional displacement of the umbili-cus.1 These focal abdominal movements are distinct fromthose of spinal myoclonus, epilepsy, torsion dystonia or tar-dive dyskinesia.1 BDD has been described after pregnancy,abdominal surgery,1 local trauma,2 spinal cord pathology,3

central pontine and extrapontine myelinolysis.4 BDD is diffi-cult to treat,2 though anticholinergic agents, benzodiaze-pines,1 transcutaneous electrical stimulation2 and anticonvul-sants5 have been reported to ameliorate the condition. Injec-tions of botulinum toxin (BTX) have been used to treat painsyndromes6,7 and conditions involving overactive contractionof the rectus abdominis (RA), such as tics,8 and camptocor-mia in Parkinson’s disease,9 but have not, to our knowledge,been used in the treatment of BDD. We describe a case ofBDD, which was successfully treated with BTX injections tothe RA under electromyographic guidance.

A 50-year-old woman presented with 6-month history ofinvoluntary abdominal wall movements associated with‘‘pulling’’ abdominal pain, which she rated 4 to 5 on a painscale of 0 to 10. These movements, which were voluntarilysuppressible, did not persist when she slept, and she was notaware of any sensory tricks that lessened them. She had nosignificant medical history, but revealed that the abnormalabdominal wall movements had been preceded by a 10-yearhistory of abdominal pain, initially attributed to ovariancysts. Oophorectomy performed a year later did not resolveher pain. She consulted a pain specialist, who had prescribedtramadol 50 mg twice daily and pregabalin 75 mg once daily,with no relief of pain. One year prior to the development ofabdominal wall movements, she underwent laparoscopic pel-vic and abdominal cavitary examination to investigate thecause of her persistent pain, which did not reveal significantpathology. She had no family history of movement disorders,previous history of epilepsy, abdominal trauma, psychiatricillness, and had not been prescribed neuroleptic medications.Clinical examination was unremarkable, save for involuntary,writhing movements of the abdominal wall, due to asynchro-nous contractions (video 1) of the RA. She was able to standerect without truncal flexion, and she did not manifest abnor-mal movements in her limbs, head or neck. These move-ments did not vary in pattern throughout multiple clinicalconsultations, and she did not demonstrate distractibility orany neuropsychiatric manifestations to suggest a psychogenicmovement disorder. Neuroimaging of the brain and spine

Additional Supporting Information may be found in the onlineversion of this article.Financial disclosures: The authors have nothing to declare.Potential conflict of interest: Nothing to report.Published online 16 April 2009 in Wiley InterScience (www.




were normal (excluding cortical and spinal myoclonus), aswas work-up to exclude Wilson’s disease. Thyroid hormones,liver and renal function tests were normal, and examinationof a peripheral blood film did not reveal acanthocytosis. Shewas diagnosed to have BDD, and was prescribed clonazepam1.5 mg daily in addition to pregabalin, which was increasedto 225 mg daily, but this failed to ameliorate her dyskinesiaor abdominal pain. She initially refused injections of BTX.The further addition of carbamazepine 600 mg daily did notlessen the abdominal movements. Instead, it caused unaccept-able sedation that necessitated its withdrawal, although sheremained on pregabalin and clonazepam.

‘‘One year after presentation to our movement disordersclinic, she agreed to low-dose injections of BTX to her RA.This was performed using aseptic technique under electro-myographic (EMG) guidance,6 to lessen the likelihood ofcomplications such as penetration of the abdominal cavity,perforation of adominal viscera or peritonitis. The diagnosisof BDD and involvement of the RA were confirmed byinserting the combination electrode/EMG needle into the RAand noting the presence of end-plate noise during voluntarycontraction of the RA (by asking the patient to flex her neckand lift her head above the examination couch) and spontane-ous abdominal wall movements, during which abdominalwall movements were confirmed visually.6 A total of 90 unitsof BTX (Botox�, Allergan, Irvine, CA) was injected, i.e. 15units into each of six different sites (indicated by X in figure 1)of the RA. At review 4 weeks later, she reported that therewas no amelioration of either the BDD or abdominal pain,although she had no untoward effects such as weakness. She

received a second injection (total 240 units) 3 months later,with 40 units of BTX into each of 6 sites. She was reviewed4 weeks later, at which time it was noted that she had mini-mal, if any, twitching of the abdominal wall (video 2), withno weakness of truncal flexion or other untoward effects. Shereported 80% improvement in abdominal movements, but anoverall satisfaction rating of 40% owing to the residual ab-dominal pain, which had only been partially ameliorated de-spite the near-complete abatement of the BDD.

We have shown that 240 units of BTX to the RA was suf-ficient to overcome abdominal wall contractions but notlessen the painful component of BDD. We postulate that thedose injected was sufficient only to lessen the involuntarycontractions of the RA, but not to ameliorate pain. Alterna-tively, it is possible that the pain generators in our patientwere located remote from the injection sites. Further studies,comparing the effects of different doses of BTX on abdomi-nal dyskinesia and pain in BDD, are warranted.

Legend to the Video 1

Anterior and lateral views showing asynchronous contrac-tions of the rectus abdominis (RA), producing focal abdomi-nal wall movements but not truncal flexion.

Legend to the Video 2

Anterior and lateral views taken 4 weeks after injection of240 units of BTX to the RA in 6 sites. There is occasionalminimal contraction of the RA, but the abdominal wallmovements have essentially abated.

Acknowledgments: Assoc Prof. Erle CH Lim was primaryphysician in charge of the patient and wrote the manuscript;Dr. Raymond CS Seet assisted in the care of the patient, andco-wrote the manuscript.

Erle CH Lim, FRCP (UK)*Raymond CS Seet, MRCP (UK)

Division of NeurologyNational University Health SystemNational University of Singapore

Singapore*E-mail: [email protected]

References

1. Iliceto G, Thompson PD, Day BL, Rothwell JC, Lees AJ, Mars-den CD. Diaphragmatic flutter, the moving umbilicus syndrome,and ‘‘belly dancer’s’’ dyskinesia. Mov Disord 1990;5:15–22.

2. Linazasoro G, Van Blercom N, Lasa A, Fernandez JM, AranzabalI. Etiological and therapeutical observations in a case of bellydancer’s dyskinesia. Mov Disord 2005;20:251–253.

3. Shamim EA, Hallett M. Intramedullary spinal tumor causing‘‘belly dancer syndrome.’’ Mov Disord 2007;22:1673–1674.

4. Roggendorf J, Burghaus L, Liu WC, et al. Belly dancer’s syn-drome following central pontine and extrapontine myelinolysis.Mov Disord 2007;22:892–894.

5. Inghilleri M, Conte A, Frasca V, Vaudano AE, Meco G. Bellydance syndrome due to spinal myoclonus. Mov Disord 2006;21:394–396.

FIG. 1. Rectus abdominis (RA) with 6 injection sites (indicated byX). The patient was injected with 15 units at each site for the 1stinjection, then 40 units each during the 2nd injection.



6. Lim EC, Seet RC. Botulinum toxin: description of injection tech-niques and examination of controversies surrounding toxin diffu-sion. Acta Neurol Scand 2008;117:73–84.

7. Casale R, Tugnoli V. Botulinum toxin for pain. Drugs R D2008;9:11–27.

8. Kwak CH, Hanna PA, Jankovic J. Botulinum toxin in the treat-ment of tics. Arch Neurol 2000;57:1190–1193.

9. Azher SN, Jankovic J. Camptocormia: pathogenesis, classification,and response to therapy. Neurology 2005;65:355–359.

Moyamoya Disease Precipitating Sydenham’s

Chorea in a 19-Year-Old Caucasian Woman

Video

The term ‘‘hemichorea’’ is used for a hyperkinetic movementdisorder characterized by irregularly timed, spontaneous, andinvoluntary movements restricted to one side of the body.Among the acquired causes of this movement disorder,Sydenham’s chorea, the neurological manifestation of rheu-matic fever, is a common one. Despite the declining inci-dence due to the use of antibiotics, several outbreaks wereregistered recently even in developed countries.1 Moyamoyadisease has been described as another, but very rare cause ofhemichorea with striatal hypoperfusion being suggested asthe underlying pathophysiology.2,3 The few perfusion studiesin patients with Sydenham’s chorea accordingly showed hy-poperfusion of the affected brain areas.4 However, no casehas been reported so far involving a patient presenting withSydenham’s chorea and precipitating moyamoya disease.

A 19-year-old Caucasian woman developed involuntaryspasms in her left leg and then in her left arm, graduallydeteriorating over 24 to 48 hrs. Neither involvement of right-sided body parts nor sensory deficits were reported by thepatient. On admission (see Video), she exhibited choreiformmovements of the distal parts of her left arm and leg alongwith subtle involuntary movements of the left-sided neckmuscles that worsened during voluntary actions. Neurologicalexamination was otherwise normal. Mild neuropsychiatricsymptoms of increased emotional lability and distractibilityas described for Sydenham’s chorea5 were recognized aswell. Because of the recent illness of her brother, streptococ-cal infection was taken into account.

The blood tests conducted to uncover treatable causes ofchorea including ESR, thyroid function tests, protein C, pro-tein S and antithrombin III levels, coeruloplasmin, serumrheumatoid factor, ANA, anticardiolipin, anti-dsDNA, anti-b2-GP antibodies as well as lupus anticoagulant tests werenormal. The patient was not pregnant and did not take oralcontraceptives or any other medication at the time. Antistrep-tolysin O antibodies were not elevated in serum nor in theCSF thus neither confirming nor excluding a preceding strep-tococcal infection due to the fact that the titer may no longerbe elevated at symptom onset.2 However, the screening for

antibasal ganglia antibodies, the most sensitive and specifictest to support the diagnosis of poststreptococcal Sydenham’schorea6 was positive. Considering the patient’s history andclinical picture, we therefore started a 10-day-treatment with1.2 mega units of penicillin and 15 mg of methylpredniso-lone per day.

Magnetic resonance imaging (MRI) of the brain con-ducted to exclude ischemia or bleeding did not show anyabnormalities, especially no signal alterations of the right-sided basal ganglia (Fig. 1B,C). Magnetic resonance angiog-raphy (MRA, Fig. 1A), however, revealed bilateral partialstenoses of the distal intracranial ICA (C1), the proximalparts of the ACA (A1), MCA (M1) and of the right PCAwith dilated basal collateral arteries and a fragile collateralnetwork—radiological findings concordant with the guide-lines for the diagnosis of moyamoya disease.7 Reducedblood flow of the ACA and MCA bilaterally and of the rightPCA could be confirmed by transcranial doppler sonographyand MRI perfusion studies (Fig. 1D,E). Seven days after thepatient’s admission, the choreiform movements remittedgradually (see Video).

Moyamoya disease rarely manifests in western parts of theworld thus limiting studies on diagnosis, treatment, and out-come. Genetic factors may influence the pathogenesis of thedisease which is otherwise poorly understood. Most of thepatients present with a stroke as primary symptom. However,some patients only have rare, intermittent ischemic events, oreven extended periods of clinical stability like in our case.

Being a progressive occlusive disorder of the main cere-bral blood supply, moyamoya disease’s major pathomechan-ism is hypoperfusion of brain tissue. Decreased blood supplyof the basal ganglia has been related to the rare cases ofhemichorea observed in otherwise healthy patients withmoyamoya disease.2,3 Paralleling these findings, temporarystriatal hypoperfusion has also been observed during thesymptomatic period of Sydenham’s chorea and likewise sug-gested as the cause for the observed movement disorder.4 Wetherefore assume that the underlying moyamoya disease inour patient favored and enhanced poststreptococcal autoim-mune disease-derived abnormal blood flow in the basal gan-glia. Our observation is in line with the hypothesis of alteredbasal ganglia blood supply constituting a pathophysiologicalmechanism of hemichoreatic symptomes. We suggest thatmoyamoya disease can be interpreted as a precipitating factorfor the manifestation of Sydenham’s chorea.

Legends to the Video

Segment 1. The hyperkinetic movement disorder of thepatient previous to medical treatment 1 day after admission(observation of the patient’s upper extremities followed byobservation of the patient walking towards the camera).

Segment 2. The patient 7 days after initiation of treatmentwith oral antibiotics and steroids (observation of the patient’supper extremities followed by observation of the patientwalking towards the camera).

Author Roles: (1) Clinical management of the patient,including diagnostics and treatment: M. Schmeisser, A.Unrath, M. Otto, H. Tumani, B. Abler; (2) Manuscript: (2A)Writing of the first draft: M. Schmeisser B. Abler; (2B)Review and critique: A. Unrath, M. Otto, H. Tumani.

Additional Supporting Information may be found in the onlineversion of this article.Financial Disclosures: None of the authors has conflicts of finan-

cial interests to disclose.Published online 1 May 2009 in Wiley InterScience (www.




Michael J. Schmeisser, MD*Department of Neurology

Institute of Anatomy and Cell Biology, Ulm UniversityUlm, Germany


Alexander Unrath, MDMarkus Otto, MD

Hayrettin Tumani, MDDepartment of Neurology

Ulm UniversityUlm, Germany

Birgit Abler, MDDepartment of NeurologyDepartment of Psychiatry

Ulm UniversityUlm, Germany

References

1. Weiner SG, Normandin PA. Sydenham Chorea: a case report andreview of the literature. Pediatr Emerg Care 2007;23:20–24.

2. Hong YH, Ahn TB, Oh CW, Jeon BS. Hemichorea as an initialmanifestation of moyamoya disease: reversible striatal hypoperfu-sion demonstrated on single photon emission computed tomogra-phy. Mov Disord 2002;17:1380–1383.

3. Lyoo CH, Kim DJ, Chang H, Lee MS. Moyamoya disease pre-senting with paroxysmal exercise-induced dyskinesia. Parkinson-ism Relat Disord 2007;13:446–448.

4. Wolf DS, Singer HS. Pediatric movement disorders: an update.Curr Opin Neurol 2008;21:491–496.

5. Mercadante MT, Busatto GF, Lombroso PJ, et al. The psychiatricsymptoms of rheumatic fever. Am J Psychiatry 2000;157:2036–2038.

6. Church AJ, Cardoso F, Dale RC, Lees RJ, Thompson EJ, Giovan-noni G. Anti-basal ganglia antibodies in acute and persistentSydenham’s chorea. Neurology 2002;59:227–231.

7. Kuroda S, Houkin K. Moyamoya disease: current concepts andfuture perspectives. Lancet Neurol 2008;7:1056–1066.

Preserved Cardiac 123I-MIBG Uptake and

Lack of Severe Autonomic Dysfunction in a

PARK9 Patient

PARK9 is an autosomal recessive Parkinsonism, known asKufor–Rakeb syndrome, which is characterized by juvenile-onset levodopa-responsive Parkinsonism, pyramidal signs,and dementia.1 Recently, ATP13A2 was identified as thecausative gene for PARK92; however, the precise functionremains unknown.

Recently, decreased uptake of metaiodobenzylguanidine(MIBG) with 123I-MIBG myocardial scintigraphy wasreported as a new diagnostic tool for differentiating Parkin-son’s Disease (PD) from other Parkinsonism’s that lackLewy body pathology.3 Moreover, the cardiac uptake ofMIBG was reported to be almost normal in PARK2,4,5 themost common type of autosomal recessive early-onset parkin-sonism, wherein Lewy body pathology is usually absent.4

Hence, the normal cardiac uptake of MIBG may be of poten-

FIG. 1. Time-of-flight (tof)-MRA shows narrowed distal ICA and proximal circle of Willis vessels with synangiosis (A). No positive evidence foracute (B) or chronic (C) stroke lesions. Contrast-enhanced T1-weighted imaging: diffuse lenticulostriate collaterals with enhancing ‘‘dots’’ and ‘‘net-like’’ thin vessels (white arrows in D and E). [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

Potential conflict of Interest: The authors report no conflict ofinterest.





tial diagnostic value to indicate the absence of Lewy bodypathology, even in patients with levodopa-responsive parkin-sonism.

Both pathologic findings in PARK9 and the pathophysio-logical roles of ATP13A2 are still unknown. Therefore, 123I-MIBG myocardial scintigraphy would provide importantclues to the prediction of presence or absence of Lewy bodypathology in PARK9 and of pathophysiological roles ofATP13A2.

Recently, we reported a PARK9 patient with an ATP13A2homozygous missense mutation.6 We performed 123I-MIBGmyocardial scintigraphy and autonomic function tests in thispatient to investigate the presence or absence of autonomicdysfunction and Lewy body pathology.

The index patient was a 43-year-old woman with early-onset Parkinsonism and dementia who had a homozygousATP13A2 F182L mutation.6 She developed Parkinsonism atthe age of 22. At 43 years, she showed levodopa-responsiverigidity, dementia, bradykinesia, weakness, and atrophy oflower limb muscles, hyper-reflexia in upper limbs, Babinski’ssign, and fine jerky movements of the face and hands.6 Shewas wheelchair bound, and her score on the Hoehn–Yahr rat-ing scale (H-Y) was 5.0.

We performed 123I-MIBG myocardial scintigraphy in thepatient with an intravenous injection of 111 MBq of 123I-MIBG. Planar images were obtained 15 minutes (early) and3.5 hours (delayed) after the injection. Regions of interest(ROI) were drawn around the whole heart and a part of themediastinum of the anterior image, and the tracer uptake wasmeasured within each ROI to calculate the heart-to-mediasti-num (H/M) ratio.5 The H/M ratio from early and delayedimages was evaluated. The washout rate (WR%) was calcu-lated as follows: WR 5 100 3 {(early cardiac count density)2 (delayed cardiac count density)}/(early cardiac countdensity).

We also performed a 708 head-up tilt test (HUT) to esti-mate cardiovascular autonomic functions. In addition, thecoefficient of variation of R–R interval on an electrocardio-gram (CVR–R) during normal breathing was estimated, andplasma norepinephrine concentration was measured with thepatient in the supine position.

For further estimation of autonomic dysfunction, sympa-thetic sweat response and urodynamic variables were esti-mated.

In 123I-MIBG myocardial scintigraphy, the H/M ratio waswithin normal limits (H/M 5 2.24) in the early phase, butdecreased mildly (H/M 5 1.73) in the delayed phase (normalrange: both >2.00). The WR increased slightly (WR 542.8%; normal range: <40.0%).

The plasma norepinephrine level was normal (436 pg/ml)when the patient was in the supine position (normal range:100–450 pg/ml). No obvious orthostatic hypotension wasobserved in the 708 HUT, and CVR–R was normal (Table 1).Abnormal responses were observed for the sympathetic sweatresponse; however, nearly normal findings were observed inurodynamic studies (Table 1).

This study revealed an almost preserved myocardialuptake of 123I-MIBG and no marked autonomic dysfunctionin the patient with PARK9 despite her long disease historyof disease, severe motor disturbance, and dementia. Thesefindings are in contrast with most patients with Lewy bodypathology. These results were similar to those observed inPARK2 patients with long disease duration who lackedLewy body pathology upon postmortem examination.4

Because previous studies reported that severe autonomicdysfunction is often seen in diffuse Lewy body disease andthat normal cardiac MIBG uptake is associated with the ab-sence of Lewy body pathology, the results of this studyshowed that PARK9 patients may not have diffuse Lewybody pathology although they show multisystemic neurode-generation with dementia.2,6

The putative mechanisms of neurodegeneration in PARK9were proteosomal dysfunction owing to overload withmutated ATP13A2 and/or lysosomal dysfunction by loss ofATP13A2 function,2 both of which would be expected toresult in the accumulation of alpha-synuclein and the forma-tion of Lewy bodies. Indeed, preserved myocardial 123I-MIBG uptake was reported previously in a patient with Par-kinsonism and Gaucher’s disease7 in which diffuse Lewybodies were often observed. For genetic PD, a heterogeneouspattern of cardiac 123I-MIBG uptake in patients with geneticPD has been reported despite identical genetic mutations,5

possibly reflecting pleomorphic neuropathology. In PARK9,heterogeneity or such dissociation between Lewy body pa-thology and the findings in myocardial 123I-MIBG uptakecould occur.

Although we cannot reach definitive conclusions from asingle case, the results of the present study provide importantinsights into the pathogenesis of PARK9. Further studies arenecessary to clarify these clinicopathological aspects and theroles of ATP13A2.

Acknowledgments: This work was partially supported byGrants-in-Aid from ‘‘the Research Committee for Ataxic Dis-eases’’ and ‘‘the Research Committee for NeurodegenerativeDiseases’’ of the Research on Measures for Intractable Dis-

TABLE 1. Autonomic Function Tests

70-degree head-up tilt testSupine position

Systolic blood pressure (mm Hg) 96Diastolic blood pressure (mm Hg) 48Heart rate (beat/minute) 77

70-degrees head-up tilt positionSystolic blood pressure (mm Hg) 88Diastolic blood pressure (mm Hg) 39Heart rate (beat/minute) 92

The coefficient of variation of R-R intervalsAt rest (%)a 1.82

Sympathetic sweat responseBasal sweat output DecreasedResponse to stimuli Absent

Urodynamic studyBladder volume at first sensation NormalMaximum bladder capacity NormalResidual urine (ml) 93Detrusor overactivity AbsentDetrusor-sphincter dyssynergia AbsentUninhibited sphincter relaxation AbsentSphincter needle elecromyogram Normal

aAge-dependent normal value > 1.66%



eases from the Ministry of Health, Welfare and Labor, Japan,and Grants-in-Aid for Scientific Research from the Ministryof Education, Culture, Sports, Science and Technology of Ja-pan (18790587, 20591018).

Kazuaki Kanai, MD, PhD*Masato Asahina, MD, PhDDepartment of Neurology

Chiba University Graduate School of MedicineChiba, Japan


Kimihito Arai, MD, PhDDepartment of Neurology

National Hospital OrganizationChiba-East Hospital, Chiba, Japan

Hiroyuki Tomiyama, MDDepartment of Neurology

Juntendo University School of MedicineTokyo, Japan

Yoichi Kuwabara, MD, PhDDepartment of Cardiovascular Science and Medicine


Tomoyuki Uchiyama, MD, PhDYukari Sekiguchi, MD

Department of NeurologyChiba University Graduate School of Medicine

Chiba, Japan

Manabu Funayama, PhDResearch Institute for Diseases of Old Ages

Juntendo University Graduate School of MedicineTokyo, Japan

Satoshi Kuwabara, MD, PhDDepartment of Neurology


Nobutaka Hattori, MD, PhDDepartment of Neurology

Juntendo University School of MedicineTokyo, Japan

Takamichi Hattori, MD, PhDDepartment of Neurology


References

1. Najim al-Din AS, Wriekat A, Mubaidin A, Dasouki M, Hiari M.Pallido-pyramidal degeneration, supranuclear upgaze paresis anddementia: Kufor-Rakeb syndrome. Acta Neurol Scand 1994;89:347–352.

2. Ramirez A, Heimbach A, Grundemann J, et al. Hereditary parkin-sonism with dementia is caused by mutations in ATP13A2, encod-ing a lysosomal type 5 P-type ATPase. Nat Genet 2006;38:1184–1191.

3. Orimo S, Ozawa E, Oka T, et al. Different histopathologyaccounting for a decrease in myocardial MIBG uptake in PD andMSA. Neurology 2001;57:1140–1141.

4. Orimo S, Amino T, Yokochi M, et al. Preserved cardiac sympa-thetic nerve accounts for normal cardiac uptake of MIBG inPARK2. Mov Disord 2005;20:1350–1353.

5. Quattrone A, Bagnato A, Annesi G, et al. Myocardial (123)meta-iodobenzylguanidine uptake in genetic Parkinson’s disease. MovDisord 2007;23:21–27.

6. Ning Y, Kanai K, Tomiyama H, et al. PARK9-linked parkinson-ism in eastern Asia: the distribution and clinical phenotype. Neu-rology 2008;70:1491–1493.

7. Itokawa K, Tamura N, Kawai N, Shimazu K, Ishii K.Parkinsonism in type I Gaucher’s disease. Intern Med 2006;45:1165–1167.

Bilateral Hemichorea–Hemiballism Caused

by Metastatic Lung Cancer

Hemiballism and hemichorea are rare complications ofmetastatic brain tumors to the subthalamus.1,2 Texts empha-size the need for neuroimaging of unilateral hyperkineticmovement disorders to rule out structural lesions.3 Thisreport describes a patient with bilateral chorea-ballism causedby bilateral thalamic metastases.

A 65-year-old woman presented with a 6-month history ofinvoluntary ‘‘jerky’’ movements of both arms and the distalright leg. The movements were continuous during the dayand did not interfere with her functioning, although her hus-band noted it was difficult for her to drive. She claimed to beable to suppress the movements for brief periods of time.Her husband disputed this. He was unsure if the movementspersisted during sleep. She had complained of bony pain for6 months and was treated with prednisone and a fentanylpatch for polymyalgia rheumatica. The week before presenta-tion she complained of shortness of breath. She had a historyof hypothyroidism and hypertension but not rheumatic heartdisease. She had a 30 pack-year history of smoking. Medica-tions included levothyroxine, hydrochlorothiazide/ramipril,paroxetine, indapamide, fentanyl, and vitamin B6. Examina-tion revealed continuous, nonrhythmic, low-frequency writh-ing, jerking, and occasionally flinging movements of the rightarm, right leg, and left leg. She could not suppress the move-ments. The remainder of her neurological exam was normal.She was afebrile, tachypneic, and had markedly reduced airentry over the right chest.

Chest X-ray revealed a right pleural effusion, and analysisof thoracentesis fluid revealed metastatic adenocarcinoma.CT scanning revealed multiple enhancing brain lesions, aswell as lesions in the right upper lobe of her lung, liver, andadrenal gland. A bone scan revealed multiple lesions consist-ent with bone metastases. She was admitted to hospital andgiven dexamethasone. Brain MRI revealed left frontal, rightoccipital, pontine, cerebellar, and bilateral thalamic lesionsconsistent with metastases (Fig. 1). Three days after admis-





sion, her involuntary movements were less prominent, and byday 9 they had essentially ceased. She received palliativeradiation to her brain, right femoral head, and right scapula.She returned 2 months later with worsening shortness ofbreath and a large right pleural effusion, which rapidly reac-cumulated after thoracentesis. She died 2 days later.

Hemiballism and hemichorea are caused by unilaterallesions of the contralateral subthalamic nucleus or thalamiclesions extending into the subthalamic region.4 Brain imag-ing is recommended to rule-out a focal lesion.3 The mostcommon etiology is infarction or hemorrhage,4 whereasmetastatic tumor is a rare cause.1,2 This case is unusualbecause of bilateral thalamic metastases producing bilateralchorea-ballism. Edema from the thalamic lesions may haveaffected the subthalamic nuclei or efferents.4 Prednisonemay have helped control the edema and her symptoms,delaying her presentation. She subsequently responded todexamethasone. In the right clinical context, even patientswith bilateral chorea or ballism should still be suspected ofhaving structural lesions in the thalamus or subthalamicregion.

Acknowledgments: No support was obtained for thiswork. In the past year, FGAM (corresponding author) hasparticipated in multiple sclerosis clinical trials sponsored byEMD Serono and Bayer and received consulting fees fromEMD Serono and Bayer.

Fraser G.A. Moore, MD, FRCPCDepartment of Neurology and Neurosurgery

Member, Centre for Medical Education, McGill UniversityMontreal, Quebec, Canada


References

1. Glass JP, Jankovic J, Borit A. Hemiballism and metastatic braintumor. Neurology 1984;34:204–207.

2. Ziainia T, Resnik E. Hemiballismus and brain metastases fromsquamous cell carcinoma of the cervix. Gynecol Oncol 1999;75:289–292.

3. Jankovic J, Lang AE. Movement disorders, diagnosis and assess-ment. In: Bradley WG, Daroff RB, Fenichel GM, Jankovic J, edi-tors. Neurology in clinical practice. Boston: Butterworth-Heine-mann; 2004. p 319–320.

4. Lee MS, Masrsden CD. Movement disorders following lesions ofthe thalamus or subthalamic region. Mov Disord 1994;9:493–507.

FIG. 1. Axial, gadolinium-enhanced T1-weighted MRI of the brainshowing multiple cerebral metastases, including in both thalami.



Preserved cardiac 123 I-MIBG uptake and lack of severe autonomic dysfunction in a PARK9 patient

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