turn the following into an interesting podcast script:- The Skin and Parkinson’s Disease: Review of
Clinical, Diagnostic, and Therapeutic Issues
Matej Skorvanek, MD, PhD,1,2,* Kailash P. Bhatia, MD, DM, FRCP3
Abstract: Background: Parkinson’s disease (PD) and the skin are related in a number of ways, including
clinical abnormalities of the disease itself and skin-related side effects of dopaminergic medication, pumps,
and surgical therapies. Recent advances in understanding the role of a-synuclein suggest skin biopsies as a
potential diagnostic or even a premotor marker of PD.
Methods: The PubMed database was searched for publications up to October 2015, and the current evidence
on skin-related issues in PD was comprehensively summarized.
Results: The evidence was summarized on the prevalence, etiology, and management of seborrheic
dermatitis, sweating dysfunctions, bullous pemphigoid, and malignant melanoma, as well as therapy-related
skin disorders, especially those observed in amantadine, rotigotine, apomorphine, and levodopa/carbidopa
intestinal gel therapies and deep-brain stimulation. Skin biopsies evaluating the presence of a-synuclein, the
density and morphology of cutaneous nerves, and skin fibroblast functions also are discussed.
Conclusions: Skin disorders are a common manifestation of PD. However, the exact pathophysiology and
prevalence of these disorders are not well understood, and more systematic research is needed in this
regard. Peripheral tissue biopsies as a diagnostic marker of PD are an exciting avenue in future PD research,
although multiple caveats and pending issues need to be solved before they can be used in routine clinical
practice.
Parkinson’s disease (PD) is a progressive neurodegenerative
disease characterized by the presence of multiple motor and
nonmotor symptoms. Skin disorders, such as seborrheic dermatitis (SD) and hyperhidrosis, are well recognized and frequent
—but often overlooked—nonmotor symptoms of PD; they
have been associated with PD for nearly a century, since the
first reports of seborrheic facies in PD by Krestin.1 Given the
interest in biomarkers that precede the motor features of PD, it
is worth noting that skin affection may precede the onset of
typical motor symptoms by years.2 Other skin disorders, such as
malignant melanoma and bullous pemphigoid (BP), are significantly more prevalent in PD patients compared with the general
population.3,4 Recent advances in the understanding of the role
of a-synuclein (SNCA) in the pathophysiology of PD, its
prion-like mechanism of spreading, and findings of typical Lewy
body pathology in the peripheral nervous system, suggest skin
biopsies as a potential diagnostic marker of PD. Unlike the
peripheral melanins produced in skin melanocytes, neuromelanin is produced in specific populations of catecholaminergic
neurons in the brain. It is believed that neuromelanin interacts
with transition metals, especially iron, and mediates intracellular
oxidative mechanisms. This function seems to be compromised
in PD, thus rendering pigmented neurons vulnerable to oxidative damage.5 The skin can be affected by antiparkinsonian
medication as well. Specific drug-delivery methods, such as skin
patches, subcutaneous application of apomorphine, levodopa
(L-dopa)/carbidopa intestinal gel (LCIG) application via percutaneous endoscopic gastrostomy (PEG), and implantation of
deep-brain stimulation (DBS) hardware, can cause iatrogenic
skin lesions. The aim of this review is to summarize current
1Department of Neurology, P. J. Safarik University, Kosice, Slovakia; 2Department of Neurology, University Hospital L. Pasteur, Kosice, Slovakia;
3Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, University College London, London, United
Kingdom
*Correspondence to: Dr. Matej Skorvanek, Department of Neurology, Safarik University and L. Pasteur University Hospital, Trieda SNP 1, 04066
Kosice, Slovakia; E-mail: <PRESIDIO_ANONYMIZED_EMAIL_ADDRESS>
Keywords: a-synuclein, melanoma, Parkinson’s disease, skin, therapy.
Relevant disclosures and conflicts of interest are listed at the end of this article.
Received 13 April 2016; revised 25 July 2016; accepted 26 July 2016.
Published online 8 September 2016 in Wiley InterScience (www.interscience.wiley.com). DOI:10.1002/mdc3.12425
© 2016 International Parkinson and Movement Disorder Society
21
doi:10.1002/mdc3.12425
REVIEW
CLINICAL PRACTICEevidence on clinical, diagnostic, and therapeutic issues of skin
disorders in PD.
Patients and Methods
We searched the PubMed database for all relevant articles until
October 2015 using the main search terms “Parkinson’s disease”
or “parkinsonism” combined with the following terms: “skin,”
“seborrhea,” “dermatitis,” “hyperhidrosis,” “sweating,” “pemphygoid,” “melanoma,” “sensory,” “autonomic,” “a-synuclein,”
“skin biopsy,” “fibroblasts,” “iPSC” (induced pluripotent stem
cells), “livedo reticularis,” “amantadine,” “dopamine agonist,”
“rotigotine,” “skin patches,” “apomorphine,” “nodules,” “skin
necrosis,” “Duodopa,” “LCIG,” “PEG,” “DBS,” “skin erosion,” and their combinations. The references from relevant articles were also checked. Only articles in English that were related
to human studies were included. Relevant articles were related
to clinical and therapeutic issues, including seborrhea, hyperhidrosis, BP, malignant melanoma, sensory and autonomic skin
functions, skin SNCA as a potential biomarker of PD, amantadine-related livedo reticularis (LR), skin reactions related to
rotigotine patches, apomorphine-related skin nodules, PEG
issues related to LCIG therapy, and skin erosions caused by DBS
therapy. Due to the complexity of the issue, fibroblast enzymatic
and metabolic activity evaluations, as well as fibroblast-derived
iPSCs, are mentioned only briefly in this review.
Seborrheic Dermatitis
SD is a chronic skin disease that affects approximately 3% to 5%
of the general population.6 Seborrheic facies was first described
as a manifestation of PD in 1927.1 It presents as typical sharply
demarcated red patches and plaques with greasy scales in areas
that have an increased density of sebaceous glands, namely, the
scalp, face, hairline, eyebrow, glabella, nasolabial folds, ears,
upper trunk, and flexures. It usually affects multiple body areas,
occurring on the face in 88% of patients with SD, on the scalp
in 70%, on the chest in 27%, on the arms and legs in 1% to
2%.7
With the discovery of L-dopa, several authors noticed an
improvement of SD in patients with PD; and, in the small studies published, this seemed to correlate with the overall dose of
L-dopa administered.8,9 Kohn et al.10 demonstrated a statistically
significant decrease in the amount of sebum on the foreheads of
21 patients with PD during L-dopa treatment, although considerable variation in responsiveness was observed. No correlation
between the dose of L-dopa or the duration of treatment and
the degree of sebaceous gland inhibition could be established.
The quantitative reduction of sebum could not be related to
the degree of neurologic improvement. Also, in a later report,
Martignoni et al.11 found no correlation of sebum excretion
rates with the duration of L-dopa treatment, the presence
of dopamine agonists, or the severity of disease. The prevalence
of SD in PD has been reported previously in 18.6% to 59% of
patients,12 and it is common in early and even premotor stages
of PD. In a retrospective study in this regard, Tanner et al.13
observed that SD was associated with an increased risk of PD
development, suggesting that it may represent a premotor feature of PD related to the autonomic nervous system. SD is
more common in male parkinsonian patients.11,12 However,
there are multiple caveats in estimations of SD prevalence, and
more systematic studies are needed; because the absence of standardized diagnostic criteria, coupled with variability of disease
expressiveness, is likely to introduce significant variation into
the estimates of SD prevalence. Moreover, some of the prevalence studies included only patients who had “significant skin
pathologies,” e.g., conditions that were judged significant
enough to warrant at least 1 physician visit.14,15 There has been
only a single report of SD in atypical parkinsonism, in a patient
who had pathologically confirmed corticobasal degeneration.16
However, no further prevalence data on SD in atypical parkinsonian syndromes were found in the literature.
The etiology of SD in PD is not fully understood. Some of
the contradictory causes include autonomic dysfunction,17
although this was not confirmed in other studies11; the role of
androgens or testosterone relating to higher incidence of SD in
male populations11; and the systemic effect of melanocytestimulating hormone.18 SD appears to result from a combination of the 3 following factors: sebaceous gland secretion, the
presence of Malassezia yeast, and the host-immune response.19
In a recent study, Arsenijevic et al.20 observed a positive correlation between SD, PD, Malassezia globosa incidence, high yeast
density, and high skin phosphatase and lipase activity. Treatment options for nonscalp and scalp SD include topical agents
and shampoos that contain antifungal agents (such as ketokonazol), anti-inflammatory agents, keratolytic agents, and calcineurin inhibitors.21
Other types of dermatitis related to PD are transient acantholytic dermatitis,22 and especially debilitating perioral dermatitis, associated with severe and intractable drooling.23 Various
symptomatic treatments are available for drooling that aim
either to reduce saliva production (botulinum toxin injections
into the salivary glands, anticholinergics, or radiotherapy over
the salivary glands) or to improve the quality and frequency of
swallowing.23
Sweating Dysfunction
Dyshidrosis, including hyperhidrosis and hypohidrosis, is a common feature of PD and affects from 30% to 60% of patients. In
7 studies in which the prevalence of hyperhidrosis and hypohidrosis was reported separately, hyperhidrosis was identified in
from 10% to 100% of patients, whereas hypohidrosis was identified in from 0% to 40% of patients.24–30 However, only 2 of
those studies reported a higher prevalence of hyperhidrosis
compared with hypohidrosis.27,30 Dyshidrosis is considered as
part of the spectrum of autonomic dysfunction in PD and is
often associated with other autonomic symptoms, especially
orthostatic hypotension, sialorrhea, and urinary symptoms.28,30,31
Sweating may have a considerable impact on a patient’s physical, psychological, and social well-being.28 It may already be
22 MOVEMENT DISORDERS CLINICAL PRACTICE
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23301619, 2017, 1, Downloaded from https://movementdisorders.onlinelibrary.wiley.com/doi/10.1002/mdc3.12425 by National Health And Medical Research Council, Wiley Online Library on [27/09/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons Licensepresent in the premotor PD period, and results from the recent
ONSET-PD study indicated that excessive sweating preceded
the onset of typical motor symptoms usually by 2 to 10 years.2
Sweating can be often asymmetrical27 and is not necessarily correlated with the side of worse motor symptoms. “Drenching
sweats” also have been described.32,33 The areas predominantly
affected by localized sweating include the head and trunk, and
it is believed that such sweating is a compensatory thermoregulatory mechanism for loss of sweating in the extremities.28,34,35
Sweating was reported more commonly in younger onset versus
to late-onset patients.36 It was also more commonly reported in
patients with camptocormia.37 Hyperhidrosis seems to be more
prevalent with progression of the disease.38
Most of the studies published to date indicate a higher occurrence of sweating during off-medication (off) periods and dyskinesias.28,32,39 Off period sweating may result from insufficient
central dopaminergic stimulation,32 whereas sweating associated
with dyskinesias may be related to the associated excess physical
activity.28 In some studies, sweating has been reported among
the most frequent nonmotor off symptoms.40 On the other
hand, a study by Storch et al.41 identified excessive sweating,
dysphagia, and bladder urgency as the only 3 of 10 nonmotor
symptoms studied that were not associated with motor fluctuations.
There are no randomized controlled studies targeting excessive sweating specifically in patients with PD. However, the use
of botulinum toxin therapy for the treatment of axillary essential
hyperhidrosis did receive a Level A recommendation.42 Future
research is needed to validate the efficacy and safety of botulinum toxin therapy for PD-related hyperhidrosis. Multiple studies suggest that an improvement in motor fluctuations may
alleviate sweating. These include apomorphine pump therapy,43
LCIG,44 and DBS.30,33,45
Bullous Pemphigoid
BP is the most common autoimmune blistering disease (Fig. 1).
BP occurs especially in the elderly and predominantly on the
flexural aspects of limbs and on the trunk.46 Multiple previous
studies have reported increased prevalence of neurological diseases, including stroke, dementia, PD, multiple sclerosis, and
amyotrophic lateral sclerosis, among patients with BP. The
prevalence of PD in 13 identified cohorts of patients with BP
ranged from 2.2% to 17.9%.3,47–58 Four of 9 studies identified
demonstrated a statistically significant association between BP
and PD (odds ratio [OR], 2.16; 95% confidence interval [CI],
1.09–4.27) and PD (OR, 5.0; 95% CI, 1.57–15.94),3,47,50,55
whereas the 5 remaining studies did not find a statistically significant correlation.48,52,54,57,58 Only in a single study was PD
associated significantly with mortality in BP patients (OR, 1.85;
95% CI, 1.11–2.95), whereas this association was not observed
in other neurological diseases, including stroke and dementia.49
Another study identified increased incidence of PD after diagnosis of BP (OR, 8.56; 95% CI, 1.55–47.25; P = 0.01).48
The correlation between PD and BP is not clearly understood. BP is mediated by autoimmunity to the hemidesmosomal
proteins BP antigen 1 (BPAg1) (230 kD) and BPAg2 (180 kD;
type XVII collagen). The 2 isoforms of BPAg1—the endothelial
isoform (BPAg1-e), which anchors intermediate filaments to the
hemidesmosomes, and the neuronal isoform (BPAg1-n), which
organizes the neuronal cytoskeleton by binding the neuronal
filament triplet proteins to the microfilaments, share high
homology.59 Because of neurodegeneration, uncovering the
neuronal isoform of BPAg1, which normally is protected from
antibody recognition, may cause cutaneous damage due to
cross-reactivity.60,61
Melanoma
Multiple population-based studies have confirmed a decreased
risk in patients with PD for most types of cancer, except melanomas, which are significantly more common in patients with
PD than in the general population.62–64 A recent meta-analysis,
which included 24 studies and 292,275 patients, reported an
OR of 1.83 (95% CI, 1.46–2.30) in this regard.4 The authors
of the study concluded that the risk of melanoma was significantly higher after a diagnosis of PD (OR, 2.43; 95% CI, 1.77–
3.32) but not before a diagnosis of PD (OR, 1.09; 95% CI,
0.78–1.54). The risk of melanoma was increased among patients
with PD in Europe (OR, 1.44; 95% CI, 1.22–1.70) and in
North America (OR, 2.64; 95% CI, 1.63–4.28), and no significant differences were found when comparing the incidence
between men (OR, 1.64; 95% CI, 1.27–2.13) and women
(OR, 1.38; 95% CI, 1.04–1.82). The authors also observe a
slightly increased risk of nonmelanoma skin cancer in patients
Figure 1 Bullous pemphigoid (courtesy of Dr. Zuzana Hrabovska, Department of Dermatology, University Hospital of L.
Pasteur, Kosice, Slovakia).
MOVEMENT DISORDERS CLINICAL PRACTICE 23
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23301619, 2017, 1, Downloaded from https://movementdisorders.onlinelibrary.wiley.com/doi/10.1002/mdc3.12425 by National Health And Medical Research Council, Wiley Online Library on [27/09/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons Licensewith PD than in the general population (OR, 1.20; 95% CI,
1.11–1.29). In a recent study of patients with malignant melanoma without a definite PD diagnosis, an association was
observed with a higher frequency of ultrasound substantia nigra
hyperechogenicity along with prodromal motor and nonmotor
features of PD, especially asymmetric motor slowing and
apathy.65 Greater substantia nigra hyperechogenicity in patients
with melanoma was correlated with low serum iron levels and
with lighter skin pigmentation. An association between light
skin pigmentation phenotype and increased substantia nigra
hyperechogenicity also was confirmed in another recent
study.66
The association between PD and melanoma is not fully
understood. It has been suggested that shared biochemical pathways between PD and melanoma and L-dopa treatment may
underlie this association.67 The relationship between L-dopa and
the risk of developing malignant melanoma was suggested in
some studies,68 whereas others found no apparent relationship.69,70 Recent epidemiological studies, however, have refuted
a causal association.67,71 Opponents have argued that, given the
relatively long latency between initiation and clinical manifestation of melanoma (generally believed to be greater than
10 years and, in some patients, as long as 40 years),72 it is unlikely that L-dopa stimulated the growth of melanoma in a short
period of a few months or years, as often was described in earlier case reports. Multiple patients with PD and melanoma have
been described in the literature who were safely treated with
L-dopa.73 Moreover, a recent meta-analysis was not able to
evaluate the association between PD and melanoma according
to L-dopa use, because few observational or cohort studies have
focused on it.4 However, according to the current European
Commission’s Summary of Product Characteristics, the presence
of malignant melanoma is considered a contraindication for
L-dopa therapy.74 We suggest that decisions should be made on
a case-by-case basis.
Alterations in melanin and melanin-synthesizing enzymes,
genetic factors, and abnormal autophagy, along with the fact
that both melanocytes and neurons share their embryological
origins from the neural crest, have all been proposed to underlie
the increased risk of melanoma in PD.75 Regarding genetic
associations, a recent investigation did not identify any significant associations between genome-wide association studies in
single nucleotide polymorphisms of pigmentation or melanoma
and the risk for PD.76 Two other genetic studies reported that
the melanocortin-1 receptor (MC1R) gene, which plays a key
role in hair and skin pigmentation as well as malignant melanoma predisposition, was associated with an increased risk of
PD development.77,78 An additional study did not report such
an association.79 Another recent study examined 11 single
nucleotide polymorphisms identified from previous genomewide association studies of pigmentation and melanoma, as well
as colors of hair, eyes, or skin, and melanoma in relation to
PD.80 In that study, no significant associations were identified
between genome-wide association studies in single nucleotide
polymorphisms of pigmentation or melanoma and the risk for
PD.
An interesting finding comes from a recent study, which
cross-referenced somatic mutations in metastatic cutaneous melanoma (CM) detected by whole-exome sequencing with the 15
know PD (PARK) genes and applied identical analysis also to
adenocarcinoma and squamous cell carcinoma of lungs as controls.81 Forty-eight percent of CM samples carried ≥1 PARK
mutation and 25% carried multiple PARK mutations, which
was significantly more compared to the lung carcinoma groups.
The overrepresentation of somatic PARK mutations in CM
suggests shared dysregulation pathways for CM and PD.
Therapy-Related Skin Disorders
Amantadine
LR is a rare complication seen with amantadine treatment that
has been reported only in case reports or small case series.82–84
It is characterized by patchy mottling of the skin and can be
described as following a “fishnet pattern.”85 It is caused by
increased prominence of the venous beds in the skin, arising
from impediments to arterial flow, venous dilation, or obstruction of venous flow. The blood supply to the skin is through
arterioles, each of which supplies a cone-shaped area with a base
measuring from 1 to 4 cm across. The vein-rich skin between
these well-perfused areas takes on a reddish-blue reticular pattern whenever slow flow causes increased oxygen extraction
and deepening of the color of venous blood.86 The exact
pathophysiologic mechanism of LR in PD is not fully understood, but it has been suggested that amantadine leads to an
interruption of the peripheral blood redistribution.87 LR is a
rare but well documented side effect of amantadine. It usually
appears in the lower extremities but also may affect the upper
extremities.83–88 Rarely, LR even may develop years after
amantadine is prescribed.83–89 Patient perceptions of this condition may play a significant role in the decision to stop amantadine therapy. In this regard, LR in the upper limbs especially
may lead to discontinuation of therapy.83
Rotigotine
The nonergolinic dopamine agonist rotigotine has been formulated in a once-daily transdermal patch for 24-hour application,
which ensures continuous rotigotine release. An integrated analysis of 3 open-label, randomized, phase I, multiple-dose studies90 demonstrated that the rate of rotigotine released to the
skin was 31% to 62% of the total drug content in the patch.
Furthermore, results from that analysis indicated that the variability of rotigotine exposure was low among participants (15%)
compared with the variability observed between participants
(54%). Plasma concentrations at steady state were stable over
the 24-hour patch-on period. Delivery by a single, large patch,
compared with a combination of smaller patches, did not appear
to influence exposure to rotigotine.
A review of phase II and III trials published between 2003
and 2011 indicated that rotigotine has a similar adverse event
24 MOVEMENT DISORDERS CLINICAL PRACTICE
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other nonergolinic dopamine agonists, such as pramipexole and
ropinirole.91 In addition to these, local skin reactions were the
most common AEs observed in rotigotine treatment. In general,
local skin reactions take the form of localized erythema, edema,
or pruritus limited to the patch area. Generalized skin reactions
(i.e., allergic rash, including erythematous, macular–papular
rash, or pruritus) were reported at lower rates than local skin
reactions during the development of rotigotine.92 Local skin
reactions are generally mild and tolerable and may lead to discontinuation of treatment in up to 8% of patients.91 In another
systematic review, up to 3% of patients had severe skin reactions.93 In a clinical study of 221 healthy participants that was
designed to investigate the cumulative skin irritation of rotigotine, daily rotation of rotigotine application sites reduced local
skin reactions incidence compared with repetitive application to
the same site.94 Thus, daily rotation of the application site may
reduce the incidence of local skin reactions. The same site
should not be used more than once every 14 days. Also, to
reduce the possibility of local skin reactions, patients should
wash the application site with soap and water after patch
removal to remove any drug or adhesive. Baby or mineral oil
may be used to remove any excess residue. Alcohol and other
solvents (such as nail polish remover) may cause skin irritation
and should not be used. Direct sunlight on the area where a
skin rash or irritation develops should be avoided until the skin
heals, because this exposure could lead to a change of skin
color.92,94
Other Oral Medications
Allergic skin reactions to dopaminergic therapy are very rare.95
Erythromelalgia, a rare neurovascular skin disorder characterized
by erythema, swelling, and painful burning sensations, was associated with ergolinic dopamine agonists,96,97 which are used
only rarely today. Skin edema that does not satisfy the criteria
for erythromelalgia, however, is more common, especially with
dopamine agonist therapy, and may lead to its discontinuation.
Other skin disorders, such as bullous eruptions associated with
entacapone,98 are very uncommon.
Apomorphine
Subcutaneous application of dopamine agonist apomorphine is a
well-established and effective treatment for PD. Due to its
speed of onset, apomorphine injections are a suitable option for
patients who require rapid and reliable relief from both predictable and unpredictable off periods. Apomorphine infusion is
a suitable option for patients who have advanced PD and more
complex motor fluctuations, which cannot be adequately controlled with standard oral medication.99 The subcutaneous
administration of apomorphine is generally well tolerated.
However, skin nodules at the site of drug infusion are a common and sometimes bothersome complication and typically
develop over time (Fig. 2). Skin nodules were reported in up
to 92% of patients who received treatment with subcutaneous
apomorphine.100 These are usually of mild or moderate severity; in severe cases, the nodules may result in skin abscesses and
necrotic ulcers.101 On a pathologic level, skin nodules were
associated with panniculitis.102 Recent expert consensus recommendations summarize the potential options for managing skin
nodules (Table 1).99 None of these have been proven by means
of formal clinical studies, with the exception of ultrasound,
which has been shown to be effective for the treatment of skin
nodules and can make the treated area suitable for further injections.103
LCIG Therapy
Therapy LCIG (Duodopa; AbbVie Inc., North Chicago, IL)
through a PEG is a efficacious, long-term treatment for patients
in advance stages of PD.104 AEs in LCIG therapy are most
commonly related to the device or surgical procedure. AEs
related to the stoma include secretion from the stoma, infection,
abdominal cellulite, proud flesh around the stoma, and pain
(Fig. 3).104,105 It is estimated in the general literature that, in
the general population, the rate of complications after endoscopic placement of enteral feeding tubes is in the range from
8% to 30%. Serious complications requiring treatment occur in
approximately 1% to 4% of individuals. Acute and severe complications, such as perforation, serious abdominal hemorrhage,
Figure 2 Subcutaneous nodules associated with apomorphine pump therapy.
TABLE 1 Management of apomorphine therapy-related skin
nodules, expert consensus recommendation*
 Rotation of the choice of infusion sites
 Use of Teflon

needles
 Adjusting delivery through the skin to an optimal angle
(i.e., 45–90°)
 Maintaining skin hygiene and using emollients at the
infusion site
 Choosing a lower concentration, e.g., 5 mg/mL; lower
concentrations have been used successfully
 Massaging the infusion site (using a spiky rubber
massage ball or vibrating device)
 Applying ultrasound treatment
 Use of silicone gel dressings
*See Monk et al.97
MOVEMENT DISORDERS CLINICAL PRACTICE 25
doi:10.1002/mdc3.12425
M. Skorvanek and K.P. Bhatia REVIEW
23301619, 2017, 1, Downloaded from https://movementdisorders.onlinelibrary.wiley.com/doi/10.1002/mdc3.12425 by National Health And Medical Research Council, Wiley Online Library on [27/09/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons Licenseor peritonitis requiring surgical intervention, occur in far fewer
than 0.5% of cases.106 In 2 large LCIG studies that included 91
and 72 patients with PD, PEG-related AEs led to 18 (18%) and
7 (9.5%) complications, respectively, with subsequent discontinuation of therapy in 2 patients overall.104,107
General prophylaxis with a single dose of an antibiotic (e.g.,
2 g cephazolin intravenously) before PEG insertion as protection against inflammatory complications is debated.107 The rate
of infectious complications without antibiotic prophylaxis may
be up to 32%, and antibiotic prophylaxis is recommended especially for patients with diabetes, malignancies, and immunosuppression and for the geriatric population.108 After PEG
insertion, the PEG should be under moderate tension for 24 to
72 hours. After that, the tube should be loosened and, for longterm maintenance, should allow 0.5 to 1.0 cm of free movement. If the PEG is pulled too tight, then pressure-related
lesions in the skin area with subsequent ischemia, dermatitis
around the stoma, pressure ulcer, and buried bumper syndrome
may be induced.109 On the other hand, an outer bumper that is
too loose is among the most common reasons for stoma infections.
Deep-Brain Stimulation
DBS is an efficacious treatment for PD. However, it may be
associated with skin complications, such as skin erosions and
infections over the implanted foreign material. Skin erosions are
most commonly seen in the area of the burr hole cap, at the
connection site between the DBS lead and the extensions cable,
and in the area of an implantable pulse generator (IPG)
(Fig. 4).110 They may be commonly associated with infection
of the site of erosion.111 For patients in whom bacteria are not
isolated and who do not respond to antibiotics, foreign-body
reactions should be considered in the differential diagnosis. Skin
complications after DBS have been reported in up to 24.7% of
patients, and this risk seemed to be highest in the first year after
implantation.112 The risk of skin erosions is increased especially
in thin patients, and implanting smaller (e.g., rechargeable) IPGs
may reduce this risk. Surgical techniques, such as sine-wave–
shaped incisions,112 a double C-shaped incision with dual-floor
burr hole technique,113 isolating the hardware from the skin
incision (e.g., burying the lead and the Stimloc below the pericranium), or implanting the IPG within the muscle in thin
patients, also may reduce the risk of skin erosions.111 For skin
erosions that occur on the scalp, free flaps seem to be superior
to scalp rotation flaps.114
Skin Biopsies and SNCA as Diagnostic
Markers of PD
The role of SNCA was first described in 1997, when it was
established that the SNCA gene caused autosomal dominant
PD.115 Subsequently, SNCA was identified as the main component of Lewy bodies.116 Historically, Lewy bodies were considered as a major pathologic hallmark of PD but were not
believed to have a role in the etiology of PD. A major breakthrough came with a publication by Kordower et al.,117 who
identified Lewy body-like inclusions in relatively young grafted
nigral neurons from a patient with PD 14 years after transplantation and raised the possibility of prion-like spreading of
SNCA in PD. SNCA in PD misfolds from an a-helix to a
b-sheet–rich conformation and polymerizes to form toxic fibrils
and aggregates.118 Cell-to-cell spreading of SNCA pathology
has been demonstrated in vitro in cell cultures119 as well as
in vivo in different animal models.120,121 Pan-Montojo et al.122
demonstrated that chronic intragastric administration of low
Figure 3 Local infection and subcutaneous abscess associated with percutaneous endoscopic gastrostomy stoma.
Figure 4 Skin infection and wound dehiscence over a deepbrain stimulation implantable pulse generator.
26 MOVEMENT DISORDERS CLINICAL PRACTICE
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23301619, 2017, 1, Downloaded from https://movementdisorders.onlinelibrary.wiley.com/doi/10.1002/mdc3.12425 by National Health And Medical Research Council, Wiley Online Library on [27/09/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons Licensedoses of rotenone in rodents could induce typical SNCA
pathology in the enteric nervous system, with subsequent timedependent spread to the dorsal motor nucleus of the vagus
nerve and then to the substantia nigra. This spread of SNCA
may be stopped by vagotomy.123 Importantly, SNCA pathology
has been identified in different peripheral human tissues, including the olfactory mucosa/bulb,124 salivary glands,125 gastrointestinal tract,126 and the skin.127 These findings suggest the
potential for peripheral tissue biopsy as a diagnostic marker or
even as a premotor biomarker of PD.
Eleven in vivo studies128–137 and 3 postmortem studies125,138,139 have evaluated skin biopsies as potential diagnostic
markers for PD. Sample sizes in those studies ranged from 16
patients127 to 67 patients,134 and biopsies were performed
especially from the trunk and lower limbs. Phosphorylated
SNCA (pSNCA) was evaluated in 10 of those studies. The
sensitivity of pSNCA examinations was low, because the staining rate ranged from 0% to 100%. The specificity of pSNCA
evaluation was satisfactory, because staining was absent in
healthy controls. Three studies evaluated whether the presence
of pSNCA could differentiate PD from multiple system atrophy and atypical parkinsonism.129,132,135 pSNCA-positive staining was found in 5.3%,131 62%,134 and 100%137 of patients
with PD and in 7%, 0%, and 0% of patients with multiple system atrophy or atypical parkinsonism. Studies of related SNCA
immunoreactivity found positive staining both in patients with
PD and in controls. The frequency of pSNCA deposits seems
to decrease from proximal (trunk, chest, thigh) to distal (distal
leg, finger) sites.129,130,132 Variable sweat gland density may
also contribute to this proximodistal gradient of pSNCA distribution.137
Eight studies have evaluated the morphology and distribution
of different types of cutaneous nerves.128–130,133–137 Loss of dermal nerve fibers and reduced intraepidermal nerve fiber density
were consistent findings. Some studies propose a length-independent loss of intraepidermal nerve fibers associated with the
appearance of pSNCA at proximal sites129 and sweat gland denervation correlating with pSNCA distribution.130 Adjacent to neurodegenerative alterations, Nolano et al.133 reported increased
nerve regeneration evidenced by abnormal nerve fiber sprouting
and altered neurochemical coding. Rodriguez-Leyva et al.134
demonstrated significantly decreased intraepidermal nerve fiber
density in patients who had PD compared with those who had
multiple system atrophy. Autonomic denervation is in line with
several studies that demonstrated autonomic skin dysfunction in
PD. These may include abnormal vasomotor reflex (which is
evaluable using thermography with a cold stress test),140 abnormal
skin wrinkling in response to immersion of the hands in hot
water,141 abnormal sympathetic skin response and R-R interval
variation tests,29 abnormal skin resistance levels, and skin resistance response.142
Skin fibroblasts may play a significant role in future PD diagnosis and therapy. Hoepken et al.143 reported increased SNCA
expression in skin fibroblasts. Mitochondrial dysfunction and
decreased energetic metabolism are consistently observed in skin
fibroblasts from patients with PD.144 This has been
demonstrated in cultures from patients with parkin mutations145,146 and SNCA triplication.147 Enhanced vulnerability of
skin fibroblasts in PARK6 to apoptosis induced by proteosomal
stress has been reported.148 Also, decreased cholesterol biosynthesis in skin fibroblasts has been observed.149 Skin fibroblasts
may have a significant role in future cell-replacement therapies
through the development of induced pluripotent stem cells.150
However, this topic was beyond the scope of the current
review.
Conclusions
To our knowledge, this is the first comprehensive review on
skin affections associated with PD. Skin disorders in PD are
common and may result in decreased quality of life23,28; however they are frequently overlooked and underrated. We have
identified several areas in which more systematic research will
be needed:
(1) Although it is a well-recognized manifestation of PD, the
prevalence of SD was studied mostly in small samples of
patients with SD and used varying inclusion criteria. Therefore, more systematic studies on the prevalence of SD in
PD would be needed. Also, the etiology of SD has not
been fully elucidated. Autonomic dysfunction, sebaceous
gland excretion, the presence of Malassezia yeast, and the
host-immune response seem to contribute to the occurrence
of SD; however. This needs to be confirmed.
(2) The prevalence of BP is significantly increased in several
neurological disorders, including PD. It is believed that the
underlying cause of this association is the cross-reactivity of
the endothelial and neuronal isoforms of the hemidesmosomal BPAg1 proteins. This needs further validation.
(3) The prevalence of malignant melanoma is significantly
increased in PD, and this relationship is not fully understood. It is important that physicians are aware of this
increased risk of melanoma, explain the risk to their
patients with PD, and recommend sun protection, self-surveillance, and periodic skin check-ups.151 An interesting
recent finding is the correlation between substantia nigra
hyperechogenicity and light skin pigmentation phenotype;
the underlying cause of this relationship is not well understood and would need further research.
(4) Diagnostic utilization of peripheral tissue biopsies, including
the skin, is an exciting area of current PD research. However, multiple caveats and pending issues are present in this
regard, including optimal tissue selection, site selection,
technique and sample processing, optimal immunohistochemistry marker, sensitivity and specificity of these examinations compared with healthy controls, and patients with
other synucleinopathies.
(5) Skin disorders may be a common side effect of medication
and are often associated with a specific mode of drug delivery, such as skin patches, subcutaneous drug application,
PEG delivery in LCIG therapy, and hardware implantation
in DBS. These iatrogenic skin disorders often may be
MOVEMENT DISORDERS CLINICAL PRACTICE 27
doi:10.1002/mdc3.12425
M. Skorvanek and K.P. Bhatia REVIEW
23301619, 2017, 1, Downloaded from https://movementdisorders.onlinelibrary.wiley.com/doi/10.1002/mdc3.12425 by National Health And Medical Research Council, Wiley Online Library on [27/09/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons Licenseeffectively prevented or managed using the above-mentioned procedures. Many of these recommendations, however, are based on expert opinion only and would need to
be proven in formal clinical studies.
Author Roles
1. Research Project: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C.
Review and Critique; 3. Manuscript Preparation: A. Writing
the First Draft, B. Review and Critique.
M.S.: 1A, 1B, 1C, 3A
K.P.B.: 1A, 1C, 3B
Disclosures
Ethical Compliance Statement: We confirm that we have
read the Journal’s position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.
Funding Sources and Conflicts of Interest: This work was
supported by the Slovak Research and Development Agency
under contract no. APVV-14-0415 and by the Slovak Scientific
Grant Agency under contract no. VEGA 1/0024/14. The
authors report no conflicts of interest.
Financial Disclosures for the previous 12 months: “MS
received grants from the Slovak Research and Development
Agency, the Slovak Scientific Grant Agency, speaker honoraria
and compensations for consultations from Abbvie, Actavis, Egis,
Krka, Lundbeck, Medtronic, TEVA and UCB. Otherwise the
authors declare no conflict of interest.”
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