Movement Disorders
Vol. 25, No. 13, 2010, pp. 2253–2259
Ó 2010 Movement Disorder Society
Letters to the Editor Related to Published Articles
Response to: ATP13A2 Mutations (PARK9)
Cause Neurodegeneration with Brain Iron
Accumulation
I read with interest the fascinating article by Schneider
et al describing evidence of brain iron deposition on MRI
scans from a case of Kufor-Rakeb disease (KRD)1. Schneider
et al suggest that KRD should be classified as a member of
the Neurodegenerative disorders with Brain Iron Accumula-
tion group (NBIA). Here I provide a comparison between the
clinical and radiological phenotype of KRD and the other
genetic subtypes of NBIA.
The pattern of brain iron deposition on MRI can distin-
guish between the four genetically defined subtypes of
NBIA2. The imaging features of neuroferritinopathy (domi-
nant, ferritin light chain mutations) are complex. In early dis-
ease there is T2* hypointensity (suggestive of iron) in the
putamen, caudate, and globus pallidus. As disease advances
T2* hypointesity spreads to involve the substantia nigra, den-
tate nucleus, and cerebral cortex.2 Cavitation of the lentiform
nucleus and caudates occurs in end stage disease. In acerulo-
plasminemia (recessive, ceruloplasmin mutations) there is dif-
fuse iron deposition in all basal ganglia nuclei, substantia
nigra, and cerebral and cerebellar cortex.2 The iron deposi-
tion in the paediatric recessive NBIA disorders Pantothenate
Kinase Associated Neurodegeneration (PKAN, pantothenate
kinase-2 mutations) and Infantile Neuroaxonal Dystrophy
(INAD, PLA2G6 mutations) is restricted to the globus pal-
lidus and substantia nigra, with an ‘‘eye-of-the-tiger’’ sign in
PKAN and cerebellar atrophy and gliosis in INAD.2 Schnei-
der et al report T2* hypointensities, suggestive of iron depo-
sition, in the putamen and caudate nucleus of KRD. This
pattern is distinct from that observed in the other NBIA sub-
types, though does overlap with putamen and caudate
involvement in early neuroferritinopathy. T2* MRI may thus
provide a noninvasive method of distinguishing KRD from
other causes of NBIA, but further imaging studies of KRD
are required to validate this.
The clinical phenotype of KRD overlaps with the paediat-
ric NBIA disorders. Both PKAN3 and INAD4 have dystonia
and pyramidal signs as major features, but retinitis pigmen-
tosa is seen in PKAN not KRD and cerebellar signs are pres-
ent in INAD but not KRD. KRD is distinct from neuroferri-
tinopathy,5 which presents in adulthood with chorea or dysto-
nia and preserved cognition, and aceruloplasminemia,5 which
presents with combinations of chorea, ataxia, and dementia.
Potential conflict of interest: None.
Published online 24 August 2010 in Wiley Online Library
(wileyonlinelibrary.com). DOI: 10.1002/mds.23224
2253
Parkinsonism in these NBIA disorders is not levodopa
responsive.
There are clinical and pathological links between NBIA
and Parkinson’s disease (PD). Parkinsonism has been
reported in patients with neuroferritinopathy, INAD, PKAN,
aceruloplasminemia, and KRD. Pathological and radiological
evidence of nigral iron accumulation is reported in both PD
and NBIA,5 whereas a case of INAD had classic nigral Lewy
bodies at autopsy.4 Mitochondrial dysfunction had been
reported in sporadic PD and neuroferritinopathy, and PANK2
and PLA2G6 genes may play a role in mitochondrial func-
tion.5 Thus, a common cellular mechanism linking these
diverse disorders - and explaining their similarities - may be
mitochondrial dysfunction. This hypothesis might be further
examined by investigating a role for ATP13A2 in mitochon-
drial function.
Acknowledgments: Alisdair McNeill – salary paid by UK
National Institute for Healthcare Research (NIHR).
Author Roles: Alisdair McNeill was involved in literature
review and wrote manuscript.
Alisdair McNeill, MRCP (UK)
Clinical Genetics Unit
Birmingham Women’s Hospital
Edgbaston
Birmingham, United Kingdom
E-mail: Amcneill@doctors.org.uk
References
1. Schneider SA, Paisan-Ruiz C, Quinn NP, et al. ATP13A2 muta-
tions (PARK9) cause neurodegeneration with brain iron accumula-
tion. Mov Disord; DOI 10.1002/mds.22947.
2. McNeill A, Birchall D, Hayflick SJ, et al. T2* and FSE MRI dis-
tinguishes four subtypes of neurodegeneration with brain iron
accumulation. Neurology 2008;70:1614–1619.
3. Hayflick SJ, Westaway SK, Levinson B, et al. Genetic, clinical,
and radiographic delineation of Hallervordern-Spatz syndrome.
N Engl J Med Engl 2003;348:33–40.
4. Gregory A, Westaway SK, Holm IE, et al. Neurodegeneration
associated with genetic defects in phospholipase A2. Neurology
2008;71:1–8.
5. McNeill A, Chinnery PF. Neurodegeneration with brain iron accu-
mulation. In: Weiner & Tolosa, editors. Handbook Clin Neurology
(3rd Series) – Hyperkinetic Movement Disorders. Amsterdam:
Elsevier; 2009.
2254 LETTERS TO THE EDITOR
Backpack Treatment for Camptocormia
In their article, Gerton et al. report of an unusual case of
camptocormia in a 69-year-old man with Parkinson’s dis-
ease.1 The camptocormia was completely relieved by system-
atically wearing a backpack.
Dystonia can occasionally be found in idiopathic Parkin-
son’s disease; it is uncommon in untreated patients and is
more frequently seen as a complication of levodopa treat-
ment. Typically, camptocormia associated with Parkinson’s
disease occurs in severe forms of the disease with axial pre-
dominance, motor fluctuations, and dysautonomic symptoms,
unlike the one described in the report by Gerton et al.2 This
particular case of camptocormia, as presented in the report, is
very reminiscent of our published cases of camptocormia and
camptocephalia (head drop) of pure dystonic origin.3,4 We
postulate that it represents a rare form of dystonia, not neces-
sarily associated with the motor axial abnormalities typically
seen in Parkinson’s disease. Moreover, the presence of a sen-
sory trick in this case—as in our cases—and the fact that the
symptoms of camptocormia were alleviated by the systematic
use of a backpack support the latest view on the pathophysi-
ology of dystonia as a sensorymotor dysfunction and high-
light the role of cortical and subcortical plasticity both in the
development and treatment of dystonia.5
We have experienced striking improvement with GPi-DBS
in our two cases of camptocormia, with a 100% reduction in
the BFMDRS. For both our patients, this benefit remains
unchanged after 81 and 76 moths of follow-up, respectively.
We postulate that camptocormia as a form of axial dystonia
is an excellent candidate for pallidal DBS.4
Author Roles: Damianos Sakas was involved in manu-
script conception and review of final version. Efstathios
Boviatsis was involved in manuscript conception and review
and critique. Lampis Stavrinou was involved in writing of
the first draft.
Financial Disclosures: Prof. Sakas and Dr. Stavrinou are
participating in a single-centre study for the evaluation of
constant-current deep brain stimulation leads in dystonia as
of September 2009. This study is been sponsored by ANS-St.
Jude Medical. This research is irrelevant to the data and
opinions presented in this article.
Damianos E. Sakas, MD
Efstathios J. Boviatsis, MD
Lampis C. Stavrinou, MD*
Department of Neurosurgery
Evangelismos General Hospital
University of Athens
Petros Kokkalis Hellenic Centre
for Neurosurgical Research
*E-mail: mplam@hotmail.com
Potential conflict of interest: Nothing to report.
Published online 28 July 2010 in Wiley Online Library
(wileyonlinelibrary.com). DOI: 10.1002/mds.23252
Movement Disorders, Vol. 25, No. 13, 2010
References
1. Gerton BK, Theeler B, Samii A. Backpack treatment for campto-
cormia. Mov Disord 2010;25:247–248.
2. Lepoutre AC, Devos D, Blanchard-Dauphin A, et al. A specific
clinical pattern of camptocormia in Parkinson’s disease. J Neurol
Neurosurg Psychiatry 2006;77:1229–1234.
3. Sakas DE, Panourias IG, Boviatsis EJ, et al. Treatment of idio-
pathic head drop (camptocephalia) by deep brain stimulation of
the globus pallidus internus. J Neurosurg 2009;110:1271–1273.
4. Sakas DE, Panourias IG, Stavrinou LC, et al. Restoration of erect
posture in idiopathic camptocormia by electrical stimulation of the
globus pallidus internus. J Neurosurg (in press).
5. Tisch S, Rothwell JC, Limousin P, Hariz MI, Corcos DM. The
physiological effects of pallidal deep brain stimulation in dystonia.
IEEE Trans Neural Syst Rehabil Eng 2007;15:166–172.
Reply: An Exploration of the Burden
Experienced by Spousal Caregivers of
Individuals with Parkinson’s Disease
We read with great interest the report by Roland et al.1
examining the burden on spousal caregivers of individuals
with Parkinson’s disease (PD). Despite the continued focus
on the physical demands of caregiving, their research demon-
strates a greater burden associated with the ‘‘mental stress’’
of caring for individuals with PD and suggests a necessary
shift in focus to improve quality of care and quality of life
for individuals with PD and their caregivers.
In a practice-based cohort of patients with PD and their care-
givers, we recently explored the factors associated with care-
giver burden in this population. We collected demographic in-
formation, disease-specific features, and behavioral assessments
from patients, and demographics and caregiver burden scores
(as measured by the Zarit Burden Interview2) from correspond-
ing caregivers. Multiple linear regression methods were used to
evaluate the factors associated with greater caregiver burden.
In total, 36 individuals with PD and their caregivers partici-
pated in this study. All caregivers, with the exception of one,
were spouses of the patients. Twenty-four (66.7%) of the care-
givers were female, and the mean caregiver age was 64.1
(10.1) years. The corresponding patients had a mean age of
65.4 (10.2) and a mean Hoehn and Yahr disability score of 2.4
(0.7). The greatest contributors to burden, as cited by the care-
givers themselves, were fears for the patients’ futures and feel-
ings that the patients were dependent upon them. Additionally,
caregivers noted most frequently that transporting patients to
appointments or other outings was their most time consuming
task (reported by 36.1% of all caregivers; Table 1). In the mul-
tiple linear regression model, both greater duration of caregiv-
ing (P < 0.0001) and caregiver depressive symptoms (P 5
0.06) were associated with greater caregiver burden.
Potential conflict of interest: Nothing to report.
Published online 27 August 2010 in Wiley Online Library
(wileyonlinelibrary.com). DOI: 10.1002/mds.23273
 LETTERS TO THE EDITOR
TABLE 1. Most time-consuming tasks, as rated
by PD caregivers
Proportion of caregivers
endorsing as ‘‘most
Caregiver tasks time-consuming’’ [n (%)]*
Transporting to 13 (36.1)
appointments or
other outings
House cleaning work 10 (27.8)
Managing money; 8 (22.2)
bill paying
Grocery shopping 8 (22.2)
Supervision 6 (16.7)
Preparing meals 6 (16.7)
Administering/monitoring 6 (16.7)
medications
*Caregivers were permitted to endorse up to three tasks.
Our study results are congruent with the Roland et al.’s
paper implicating ‘‘mental stress’’ as well as social isolation
as main factors contributing to burden on caregivers of
patients with PD. Caregivers expressed a loss of independ-
ence as a result of their spouses’ overall dependence upon
them and their diminished social contacts, which was ampli-
fied as caregiving duration increased. In a similar study of
123 caregivers of patients with PD, Schrag et al. reported
that more than 40% of caregivers noted a decrease in health,
nearly half had increased depression scores, and two-thirds
felt that their social life was impacted by their caregiving.3
Identifying mental burdens, such as caregiver depression, and
developing spousal-specific support groups may help to
improve caregiver knowledge and coping skills, which may
positively impact both patient and caregiver quality of life.
Furthermore, telemedicine, a form of web-based video con-
ferencing, has previously been piloted as a novel method of
care delivery to patients with PD.4 Implementing this tech-
nology can increase access to specialty providers for PD,
decrease isolation felt by caregivers, and reduce the burden
on caregivers associated with transportation to medical
appointments and the lack of education and support.
Acknowledgments: Dr. Como and Ms. Eason were
employees of the Department of Neurology at the University
of Rochester Medical Center at the time this research was
conducted. This work was supported by a Comprehensive
Care Grant from the National Parkinson Foundation.
Financial Disclosures: Ms. Deuel receives research support
from the National Parkinson Foundation and the Robert Wood
Johnson Foundation. Ms. Chesire receives research support from
the Huntington Disease Society of America, CHDI, Inc, and the
NINDS. Dr. Biglan has received research support from the federal
government (NINDS) and foundations (Michael J. Fox Founda-
tion and National Parkinson Foundation). Dr. Biglan also has con-
tracts with the Presbyterian Home for Central New York, Inc, and
the Parkinson Support Group for Central New York, and serves
on the Tourette’s Syndrome Association Scientific Advisory
Board. Ms. Eason and Dr. Como have no disclosures to report.
Author Roles: Deuel was involved in the execution of the
research project, execution and review and critique of statisti-
cal analysis, and writing of the first draft of the manuscript.
2255
Chesire was involved in the execution of research project,
review and critique of statistical analysis, and review and cri-
tique of the manuscript. Eason was involved in the execution
of research project, review and critique of statistical analysis,
and review and critique of the manuscript. Como was
involved in the conception and organization of research pro-
ject, design of statistical analysis, and review and critique of
manuscript. Biglan was involved in the conception, organiza-
tion, and execution of research project, design and execution
of manuscript, and review and critique of manuscript.
Lisa M. Deuel, BA*
Amy M. Chesire, LCSW-R, MSG
Department of Neurology
University of Rochester
Rochester, New York
*E-mail: lisa_deuel@urmc.rochester.edu
Sheelah M. Eason, MSW
Lifetime Care
Rochester, New York
Peter G. Como, PhD
United States Food and Drug Administration
Silver Springs, Maryland
Kevin M. Biglan, MD, MPH
Department of Neurology
University of Rochester
Rochester, New York
References
1. Roland KP, Jenkins ME, Johnson AM. An exploration of the
burden experienced by spousal caregivers of individuals with
Parkinson’s Disease. Mov Disord 2010;25:189–193.
2. Zarit SH, Reeves KE, Bach-Peterson J. Relatives of the impaired el-
derly: correlates of feelings of burden. Gerontologist 1980;20:649–655.
3. Schrag A, Hovris A, Morley D, Quinn N, Jahanshahi M. Caregiver-bur-
den in Parkinson’s Disease is closely associated with psychiatric symp-
toms, falls, and disability. Parkinsonism Relat Disord 2006;12:35–41.
4. Dorsey ER, Deuel LM, Voss TS, Finnigan K, George BP, Eason S,
Miller D, Reminick J, Appler A, Polanowicz J, Viti L, Smith S, Jo-
seph A, Biglan KM. Increasing Access to specialty care: a pilot,
randomized, controlled trial of telemedicine for Parkinson disease.
Mov Disord (in press).
Racial Differences in the Diagnosis of
Parkinson’s Disease—Not Just a North
American Issue
We read with interest the article by Dahodwala et al.1
about racial differences in the diagnosis of Parkinson’s dis-
ease (PD). The authors reference two incidence studies from
North America2,3 reporting different conclusions, one with
higher incidence rates of PD in blacks and one with lower
Potential conflict of interest: The prevalence study in Tanzania
was support by a grant from the UK Parkinson’s Disease Society.
Published online 18 August 2010 in Wiley Online Library
(wileyonlinelibrary.com). DOI: 10.1002/mds.23242
Movement Disorders, Vol. 25, No. 13, 2010
2256 LETTERS TO THE EDITOR
rates, and four older epidemiological studies, again from
North America, with differing methodologies.1,4 The older
studies all suggested a reduced rate of PD in African Ameri-
cans compared with whites. Of all the studies that suggest a
lower prevalence or incidence rate in black populations when
compared with white or Hispanic populations, the criticism is
that patients from an African American background may
have differential access to health care, and therefore diagno-
sis. In the Mayeux study from northern Manhattan,2 the only
study to report an increased incidence of PD in African
Americans (but a reduced prevalence rate compared with
whites), it is suggested that the census figures for African
Americans in this area were under represented and may have
inflated the actual incidence figures.
We would like to highlight our experience in Tanzania, in
a stable East African population. We carried out a commu-
nity-based, door-to-door study, greatly increasing the possi-
bility that previously undiagnosed patients were included, in
a population of 161,000. In this population, the age-standar-
dized prevalence rate of PD was 40/100,000.5 When we split
these figures by sex, the age-standardized prevalence figure
for men was 64/100,000. This is very similar to the figures
reported from the Manhattan study mentioned above:
61/100,000.2 Only 8 of our 33 patients had been diagnosed
before the study, and only 3 were currently treated.
Previous community-based neurological studies from sub-
Saharan Africa (SSA)5 had not used age standardization of
rates, were not specifically designed to detect PD, and did
not disclose the diagnostic criteria used for PD. Their crude
prevalence rates were even lower (10, 7, and 20/100,000,
respectively). The Nigerian team subsequently reported age-
standardized rates of 67/100,000 using the Mississippi popu-
lation for standardization.4
Researchers have recently looked at the risk of PD in
patients with different hair colors6 to see if populations with
low melanin distribution (i.e., red heads or blondes) have an
increased risk of PD. Gao et al.6 looked at relative risks
(RRs) of developing PD from databases from two large
American studies, the Health Professionals Follow-up Study
and the Nurse’s Health Study. Risk of developing PD was
shown to be highest in those with red hair (RR 5 1.93),
closely followed by blondes (RR 5 1.61). The correlation
was even higher when those who developed PD before the
age of 70 were studied (RR 5 3.83 and 2.73, respectively).
Further exploration of why those with the lowest melanin
expression are at the highest risk of developing PD is war-
ranted. It would be interesting to see if our findings in Tanza-
nia are borne out elsewhere in SSA, thus lending support to the
theory that melanin may be protective. Carrying out such stud-
ies in SSA would also, as Dahodwala et al. state, ‘‘improve
appropriate diagnosis of PD among underserved minorities.’’1
Acknowledgments: Catherine Dotchin; contributor, design,
drafting, editing and revising text. Richard Walker; contribu-
tor, editing and revising text, and design.
Catherine Dotchin, MD, MRCP*
Institute for Ageing and Health, Elderly Care
Newcastle University
Campus for Ageing & Vitality
Newcastle upon Tyne, NE45PL, UK
*E-mail: catherine.dotchin@newcastle.ac.uk
Movement Disorders, Vol. 25, No. 13, 2010
Richard Walker, MD, FRCP, FRACP, DTM&H
Department of Medicine
North Tyneside General Hospital
Northshields, Tyne & Wear, UK
References
1. Dahodwala N, Sideroq A, Xie M, Noll E, Stern M, Mandell DS.
Racial differences in the diagnosis of Parkinson’s disease. Mov
Disord 2009;24:1200–1205.
2. Mayeux R, Marder K, Cote LJ, et al. The frequency of idiopathic
Parkinson’s disease by age, ethnic group and sex in Northern
Manhattan, 1988–1993. Am J Epidemiol 1995;142:820–827.
3. Van den Eeden SK, Tanner CM, Bernstein AL, et al. Incidence of
Parkinson’s disease: variation by age, gender and race/ethnicity.
Am J Epidemiol 2003;157:1015–1022.
4. Schoenberg BS, Osuntokun BO, Adeuja AO, et al. Comparison of
prevalence of Parkinson’s disease in black populations in the rural
United States and in rural Nigeria: door-to-door community stud-
ies. Neurology 1988;38:645–646.
5. Dotchin C, Msuya O, Kissima J, et al. The prevalence of Parkin-
son’s disease in Hai, northern Tanzania. Mov Disord 2008;23:
1567–1672.
6. Gao X, Simon KC, Han J, Schwarzschild MA, Ascherio A.
Genetic determinants of hair color and Parkinson’s disease risk.
Ann Neurol 2009;65:76–82.
Reply: Racial Differences in the Diagnosis of
Parkinson’s Disease—Not Just a North
American Issue
We thank Dr. Dotchin and Dr. Walker for their interest in
our article. Their comments regarding the epidemiology of
Parkinson’s disease (PD) in Africa, especially their own expe-
rience were both informative and complementary to our find-
ings. While determining the true risk of PD among individuals
of different racial backgrounds remains elusive given the fea-
sibility, time, and cost constraints of a population-based door-
to-door study of sufficient size, accuracy, and follow-up, we
can learn several points from the current literature.
First, there is a growing body of evidence that suggests
that the prevalence of PD, particularly the diagnosed preva-
lence, is lower among both sub-Saharan Africans and Afri-
can Americans than Whites.1–3 On the other hand, between
42 and 75% of individuals in door-to-door studies of PD
that included either sub-Saharan Africans or African Ameri-
cans had been previously undiagnosed.1,4 Furthermore, cases
of undiagnosed PD are twice as likely to be African Ameri-
can than White.4 We need to understand why such high rates
of under-diagnosis of PD exist, and why African Americans
are at higher risk for under-diagnosis. Second, current strat-
egies for screening and detection of PD are limited because
they rely on the recognition of parkinsonian signs by
affected individuals, which may be influenced by an individ-
ual’s race, culture, and/or socioeconomic status.5 We need
better methods for population-based screening for PD to
Potential conflict of interest: Nothing to report.
Published online 18 August 2010 in Wiley Online Library
(wileyonlinelibrary.com). DOI: 10.1002/mds.23237
 LETTERS TO THE EDITOR
understand the true prevalence of disease among different
racial and ethnic groups.
The continued dual investigation into both the genetic,
especially the role of melanin, and environmental causes of
PD, and social determinants and barriers to its timely diagno-
sis will indeed improve our understanding of the relationship
between race and PD.
Acknowledgments: Dr. Dahodwala contributed to the con-
ception and drafting of the manuscript. Dr. Siderowf helped
with critical revision of the manuscript for important intellec-
tual content and supervision. Ms. Xie helped with critical revi-
sion of the manuscript. Ms. Noll also aided in critically revising
the manuscript. Dr. Stern contributed to the interpretation of
data and critical revision of the manuscript. Dr. Mandell helped
with the conception and critical revision of the manuscript.
Nabila Dahodwala, MD, MS*
Andrew Siderowf, MD, MSCE
Matthew Stern, MD
Department of Neurology
University of Pennsylvania
Philadelphia, Pennsylvania, USA
*E-mail: nabila.dahodwala@uphs.upenn.edu
Ming Xie, MS
Elizabeth Noll, MS
David Mandell, ScD
Department of Psychiatry
University of Pennsylvania
Philadelphia, Pennsylvania, USA
References
1. Dotchin C, Msuya O, Kissima J, et al. The prevalence of Parkinson’s
disease in rural Tanzania. Mov Disord 2008;23:1567–1572.
2. Okubadejo NU, Bower JH, Rocca WA, Maraganore DM. Parkin-
son’s disease in Africa: a systematic review of epidemiologic and
genetic studies. Mov Disord 2006;21:2150–2156.
3. McInerney-Leo A, Gwinn-Hardy K, Nussbaum RL. Prevalence of
Parkinson’s disease in populations of African ancestry: a review. J
Natl Med Assoc 2004;96:974–979.
4. Schoenberg BS, Anderson DW, Haerer AF. Prevalence of Parkin-
son’s disease in the biracial population of Copiah County, Missis-
sippi. Neurology 1985;35:841–845.
5. Dahodwala N, Siderowf A, Karlawish J, Duda J, Mandell DS. Are
disparities in parkinsonism diagnoses due to underreporting of
symptoms? Neurology 2010;74(Suppl 2):A71–A72.
Reply: Safe and Effective Deep Brain
Stimulation for Parkinson’s Disease
in the Context of HIV
We like to thank Tisch and Brew for their interest in our
article. Tisch and Brew raise the point that HIV and Parkin-
son’s disease may not be coincidental in our patient, and that
Potential conflict of interest: Nothing to report.
Published online 27 August 2010 in Wiley Online Library
(wileyonlinelibrary.com). DOI: 10.1002/mds.23275
2257
Parkinson’s disease may have developed as a consequence of
chronic HIV infection and highly active antiretroviral therapy
(HAART). This is based on their experience of 3 patients
with relatively young age onset Parkinson’s disease treated
with HAART for HIV disease.1 It is true that HAART has sig-
nificantly improved the prognosis of patients with HIV, essen-
tially turning the disease into a chronic one. Thus, patients with
HIV disease live considerably longer than before and, in a simi-
lar manner to the general aging population, are more likely to
be affected by degenerative conditions such as Parkinson’s dis-
ease. The observation that HAART can lead to mitochondrial
dysfunction further strengthens the possible link between HIV
disease and its treatment with Parkinson’s disease.2 Yet, in our
opinion, definite evidence for a causal link is lacking. Further-
more, even if the Parkinson’s disease was directly attributable
to HAART, stopping this treatment would not have been an
option given the negative impact on the HIV control and uncer-
tainty about improvement in the parkinsonian symptoms. Not-
withstanding the pathophysiology, however, the aim of our ar-
ticle remains the same, namely presenting deep brain stimula-
tion as a safe and effective treatment for medically refractory
Parkinson’s disease in the presence of HIV disease.
Financial Disclosures: None.
Author Roles: K. Ashkan: writing of the first draft. S.
Hettige: review and critique of the manuscript. M. Samuel:
review and critique of the manuscript.
Keyoumars Ashkan, MRCP, FRCS
Samantha Hettige, MRCS*
Department of Neurosurgery
King’s College Hospital
Denmark Hill, London
United Kingdom
*E-mail: shettige@doctors.org.uk
Michael Samuel, FRCP
Department of Neurology
King’s College Hospital
Denmark Hill, London
United Kingdom
References
1. Tisch S, Brew B. Parkinsonism in HIV-infected patients on highly
active antiretroviral therapy. Neurology 2009;73:401–403.
2. Vittecoq D, Jardel C, Barthélémy C, et al. Mitochondrial damage
associated with long-term antiretroviral treatment: associated alteration
or causal disorder? J Acquir Immune Defic Syndr 2002;31:299–308.
HIV, HAART, and Parkinson’s Disease:
Co-incidence or Pathogenetic Link?
We read with interest the case of Hettige et al.1 of a 47
year old men with a 27 year history of HIV and antiretroviral
Potential conflict of interest: Nothing to report.
Published online 27 August 2010 in Wiley Online Library
(wileyonlinelibrary.com). DOI: 10.1002/mds.23277
Movement Disorders, Vol. 25, No. 13, 2010
2258 LETTERS TO THE EDITOR
therapy, since 1986 who developed Parkinson’s disease at
age 40. He responded well to dopamine replacement thera-
pies but developed disabling motor fluctuations after several
years. He underwent successful bilateral STN deep brain
stimulation with significant clinical improvement. The
authors consider HIV ‘‘coincidental’’ to Parkinson’s disease
in this case. However, recent data supports a pathogenetic
link between chronic HIV disease and long term antiretrovi-
ral therapies with the development of Parkinson’s disease.
We recently reported three male HIV infected, highly active
antiretroviral therapy (HAART) treated patients who devel-
oped Parkinsonism at a relatively young age (mean 48 years)
all with unilateral upper limb rest tremor and one with good
response to levodopa clinically indistinguishable from idio-
pathic Parkinson’s disease.2 These cases differed from previ-
ous reports of Parkinsonism in HIV because they lacked de-
mentia and developed the movement disorder while virally
suppressed on HAART with minimal systemic or CNS viral
replication. The occurrence of three new cases of Parkinson-
ism in a 2 year period in our HIV cohort exceeded the
expected incidence of Parkinson’s in this age group by 4–8
times. We proposed that chronic HIV disease and HAART
predispose to the development of Parkinsonism by promoting
neurodegeneration via chronic inflammation (despite success-
ful HAART), and interference with the ubiquitin proteosome
and mitochondrial function; some protease inhibitors are
known to disturb proteosome function. Our patients have
only had Parkinsonism for several years and have so far not
developed major motor fluctuations in contrast to the case of
Hettige. It is now well accepted that the neurodegenerative
process in Parkinson’s disease begins years or even decades
before the cardinal clinical motor manifestations appear.3 It
therefore follows that in those patients destined to develop
Parkinson’s disease, HIV, and HAART may hasten its
appearance explaining why cases reported so far have all
been relatively young. In summary, we wish to highlight that
the relationship between chronic HIV disease and HAART
and Parkinson’s disease in this case is likely more than coin-
cidental and instead pathogenetically contributory.
Financial Disclosures: Dr. Tisch has been awarded fund-
ing from the Brain Foundation of Australia and Hospira phar-
maceuticals. Prof. Brew is funded by the NHMRC, NIH, and
has served as paid consultant for Biogen Idec, Glaxo, Boeh-
ringer Ingelheim, Gilead, and Abbott pharmaceuticals. None
of these financial disclosures relate to this submitted work
and the authors have no conflicts of interest to declare.
Author Roles: Stephen Tisch: Research project: Concep-
tion, Organization, Execution; Manuscript: Writing of the first
draft, Review and Critique; Bruce J. Brew: Research project:
Conception, Organization; Manuscript: Review and Critique.
Stephen Tisch, MBBS, PhD, FRACP*
Bruce J. Brew, MBBS, MD, FRACP
Department of Neurology
St. Vincent’s Hospital
Darlinghurst, Sydney
New South Wales, Australia
*E-mail: stisch@stvincents.com.au
Movement Disorders, Vol. 25, No. 13, 2010
References
1. Hettige S, Samuel M, Clough C, Hulse N, Ashkan K. Deep brain
stimulation for Parkinson’s disease when HIV coexists. Mov Dis-
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2. Tisch S, Brew B. Parkinsonism in HIV-infected patients on highly
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3. Gaig C, Tolosa E. When does Parkinson’s disease begin? Mov
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Reply: Case Series of Painful Legs and
Moving Toes: Clinical and
Electrophysiological Observations
We wish to thank Dr. João Guimarães for his insights
and comments in relation to our published article on Painful
Legs Moving Toes (PLMT).1 We agree completely that
PLMT cannot only be associated with peripheral nervous
system (PNS) lesions, but also central nervous system
(CNS) disorders. We, in fact, alluded to a variety of CNS
disorders in the introduction portion of our article that have
been reported to be associated with PLMT. We thank Dr.
Guimarães for sharing their report on a patient with PLMT
associated with Hashimoto’s disease,2 where only CNS
white matter lesions were noted with no PNS involvement
electrophysiologically or clinically. Similar to our surface
electromyography (EMG) findings, Dr. Guimarães’ patient’s
surface EMG showed cocontraction of antagonistic muscles
suggestive of dystonia.
We also wish to thank Drs. Argyrious and Papapetro-
poulous for pointing out their positive experience in treat-
ing PLMT with botulinum toxin (BoNT) type A.3,4 The
main reason we have not previously used BoNT for treat-
ment of PLMT is mainly due to costs incurred by the
patients. PLMT is an off-label indication for BoNT, and
is therefore not covered by Medicare in the US or by pri-
vate insurance. However, since the time of writing of our
paper on PLMT,1 we have since utilized BoNT type B to
successfully treat 2 patients with PLMT and significant
pain (unpublished data). The two had relief of pain as
well as toe movements. Thus, we agree with Drs. Argyri-
ous and Papapetropoulous that BoNT can be a viable
option for treating PLMT (and pain from PLMT), though
the issues regarding costs will have to be addressed with
the patients individually.
Virgilio Gerald H.Evidente, MD*
Department of Neurology
Mayo Clinic
Scottsdale, Arizona, USA
*E-mail: evidente.virgilio@mayo.edu
Published online 3 August 2010 in Wiley Online Library
(wileyonlinelibrary.com). DOI: 10.1002/mds.22526
 LETTERS TO THE EDITOR
Maria V.Alvarez, MD
Department of Neurology
Wilford Hall Medical Center
Lackland AFB, Texas, USA
References
1. Alvarez MV, Driver-Dunckley E, Caviness JN, Adler CH, Evi-
dente VGH. Case series of painful legs and moving toes: clinical
2259
and electrophysiologic observations. Mov Disord 2008;23:2062–
2066.
2. Guimarães J, Santos L, Bugalho P. Painful legs and moving toes
syndrome associated with Hashimoto’s disease. Eur J Neurol
2007;14:343–345.
3. Eisa M, Singer C, Sengun C, Russel A, Jabbari B, Papapetropou-
lous S. Treatment of painful limbs/moving extremities with botuli-
num toxin type A injections. Eur Neurol 2008;60:104–106.
4. Singer C, Papapetropoulous S. A case of painless arms/moving
fingers responsive to botulinum toxin A injections. Parkinsonism
Relat Disord 2007;13:55–56.
Movement Disorders, Vol. 25, No. 13, 2010