DefinitionThis section has been translated automatically.
Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by the appearance of numerous motor and non-motor symptoms.
The concept of the skin as a mirror of Parkinsonism dates back to the beginning of the last century. Since then, a great deal of evidence has been gathered for a causal relationship between the neurological disorder and changes in the areas of the skin with the richest supply of sebaceous glands (seborrhea/seborrheic dermatitis). However, the many lingering uncertainties regarding some general aspects of the skin condition itself (lack of standardized diagnostic criteria, high variability in prevalence estimates and controversies about etiology and pathomechanisms) have so far made it difficult to assess the true nature and significance (if any) of the observed associations (Mastrolonardo M et al. 2003).
ClassificationThis section has been translated automatically.
Basically, skin symptoms in patients with Parkinson's disease can be divided into two groups:
Non-iatrogenic symptoms in PD:
- Disorders of sweat and sebaceous gland functions (hyper/hypohidrosis/seborrhea/sialorrhea, rhinorrhea)
- Dermatological diseases such as seborrheic dermatitis, rosacea, bullous pemphigoid.
- Increased incidence of melanoma in PD patients.
Iatrogenic dermatological diseases in PD (ADRs in therapy modalities)
- Livedo reticularis with amandatin therapy)
- Allergic skin reactions to dopaminergic therapy (very rare).
- Erythromelalgia in connection with ergoline as a dopamine agonist (ergoline derivatives are derived in their structure from the basic structure of ergot alkaloids) (Eisler T et al. 1981; Monk BE et al. 1984).
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ClinicThis section has been translated automatically.
Sialorrhea (salivation), an excessive accumulation or leakage of saliva from the oral cavity, is one of the common non-motor symptoms in PD patients. The pathophysiology of salivation in PD is not yet fully understood. Minimally invasive treatments (local injections into the salivary glands) with botulinum toxin serotypes A and B are therapeutically successful. Both are approved as first-line therapy for the treatment of chronic sialorrhea (Isaacson J et al. 2020).
Seborrhea: Sebaceous gland secretion is quantitatively significantly increased in men and women with Parkinson's compared to healthy individuals of the same age (Kohn SR et al. 1973). The cause of this increased sebaceous gland activity is not known. Treatment with L-dopa leads to a significant quantitative reduction in sebum production in PD patients.
Rhinorrhea: Rhinorrhea is a common symptom in PD patients. The pathophysiology of this symptom has not yet been clarified. In a cross-sectional study (n= 451 patients with PD and 233 control subjects), the prevalence of rhinorrhea in PD patients was 45.0 %. It differed significantly from the control subjects (p < 0.001). The average age of patients with PD and rhinorrhea was higher than that of patients with PD without rhinorrhea (Chen T et al. 2022)
Hyperhidrosis/hypohidrosis: In studies that determined the prevalence of both problems separately in PD populations, hyperhidrosis was found in 10 - 100 % (average about 40 %) and hypohidrosis in 10 - 40 % (average about 15 %) of PD patients (Swinn L et al. 2003). Hyperhidrosis can already occur in the premotor phase of Parkinson's disease (2 to 10 years before the onset of typical motor PD symptoms) (Sunyer C et al. 2015). The symptoms appear to occur more frequently as the disease progresses (Antonini A et al. 2012). Hyperhidrosis can be associated with orthostatic hypotension, sialorrhea and urinary symptoms. The head and trunk are preferentially affected. Other correlates with increased sweating are camptocormia (camptocormia is an involuntary, forward flexion of the trunk up to 45°; camptocormia can occur when standing, walking or sitting, although the flexion is usually more pronounced in these active positions than at rest) and gait freezing (gait freezing is a sudden, unpredictable faltering or freezing of movement when walking. Affected individuals may feel that their feet are stuck to the ground and have difficulty resuming movement).
The pathophysiology of sweating disorders in Parkinson's is unclear. It is likely that both central dysfunction, including sympathetic neurons in the intermediolateral cell column of the spinal cord, and peripheral autonomic denervation are involved. Therapeutically, there are no evidence-based recommendations for the treatment of sweating disorders in Parkinson's disease. However, it has been found that increased sweating can be improved by increased dopaminergic therapy and more continuous medication (reduction of OFF time). Focal increased sweating can be effectively treated with intradermal botulinum toxin injections.
Seborrheic dermatitis: Seborrheic dermatitis (SD) was first described in 1927 by D. Krestin as a manifestation of PD (Krestin D 1927). The prevalence of SD in PD patients is reported to be between 19-59% (Fischer M et al. 2001). Male PD patients are more frequently affected than women (Martignoni E et al. 1997; Fischer M et al. 2001). Seborrheic dermatitis often occurs in the early and even premotor stages of PD. It can therefore be concluded that patients with SD are at increased risk of developing PD. This constellation suggests that it may be a premotor feature of PD that is related to autonomic nervous system dysfunction (Tanner CM et al. 2012). The symptoms manifest as centrofacial, sharply demarcated, greasy-scaly erythema and plaques. There are also scaly plaques on the hairline, eyebrows, glabella, nasolabial folds, ears and trunk (Peyri J et al. 2007). Treatment with L-dopa often leads to an improvement in SD symptoms in PD patients, although this effect does not correlate with the level or duration of L-dopa therapy, nor with the severity of SD (Burton JL et al. 1970). The etiology of Parkinson-associated seborrheic dermatitis is not clear. A positive correlation between SD and the occurrence of Malassezia globosa as well as high phosphatase and lipase activity of the skin has been demonstrated in PD patients (Arsenijevic VSA et al. 2014).
Transient acantholytic dermatosis (Grover's disease/Pranteda G et al. 2009) and perioral dermatitis have also been described in connection with PD.
Bullous pemphigoid: BP is the most common autoimmune blistering disease. BP patients have an increased prevalence of neurological diseases, including stroke, dementia, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis. The prevalence of bullous pemphigoid in PD patients is between 2 and 18 % (Niemann N et al. 2021). Etiopathogenesis: BP is mediated by antibody formation against the hemidesmosome proteins BPAg1/230 k) and BPAg2/180 kD. The two isoforms of BPAg1 - the endothelial isoform (BPAg1-e) and the neuronal isoform (BPAg1-n) show a high degree of homology. It can be assumed that the neurodegenerative processes in the context of Parkinson's pathogenicities lead to the decoupling of the neuronal isoform of BPAg1 (these proteins are physiologically protected against autoaggression), which leads to antoimmune subepithelial blister formation due to cross-reactivity (Behlim T et al. 2014; Li L et al. 2009).
Melanoma: Several population-based studies have confirmed a reduced risk in patients with PD for most cancers, with the exception of melanoma, which is significantly more common in patients with PD than in the general population (Bertoni JM et al. 2010; Walter U et al. 2016). In a larger meta-analysis (n= 292,275 patients), an OR of 1.83 (95% CI, 1.46-2.30) was calculated (Huang P et al. 2015). The risk of melanoma was increased in both European PD patients (OR, 1.44; 95% CI, 1.22-1.70) and US patients (OR, 2.64; 95% CI, 1.63-4.28). No significant differences were found between the incidences of men and women. The common embryonic origin of melanocytes and neurons in the neural crest was listed as a possible cause for the increased risk of melanoma in PD patients (Pan T et al. 2011). Polymorphisms in the MC1R gene have been cited. However, other genome-wide association studies on single nucleotide polymorphisms in pigmentary disorders or melanoma did not confirm an increased risk of PD (Dong J et al. 2014;Puig-Butille JA et al. 2014; Tell-Marti G et al. 2015).An interesting finding comes from a recent study in which somatic mutations in metastatic cutaneous melanoma (CM) detected by whole-exome sequencing were compared with the 15 Parkinson's-associated genes (PARK- PARK1, PARK2, PARK6, etc.) (genes whose mutations can lead to the development of a familial/monogenetic form of PD). 48% of melanoma samples had ≥1 PARK mutation and 25% had multiple PARK mutations, which was significantly increased compared to a lung cancer group. The overrepresentation of somatic PARK mutations in melanoma of the skin at least indicates common dysregulation pathways for both diseases (Inzelberg R et al. 2016).The EU guidelines, which state that the presence of malignant melanoma is a contraindication for L-dopa therapy, must also be evaluated in this context.
Iatrogenic dermatological diseases in PD.
ADRs with amantadine should be mentioned in this context. Livedo reticularis (LR) is a rare complication that occurs with amantadine therapy (Quaresma MV et al.2015). The exact pathophysiological mechanism of LR in PD is not clear.
Other oral medications: Allergic skin reactions to dopaminergic therapy are very rare. Erythromelalgia, a rare neurovascular skin disorder characterized by erythema, swelling and painful burning, has been associated with ergoline dopamine agonists (ergoline derivatives are structurally derived from the ergot alkaloid backbone) (Eisler T et al. 1981; Monk BE et al. 1984).
Note(s)This section has been translated automatically.
SNCA as a diagnostic marker for Parkinson's disease:
SNCA is a neuronal protein that plays multiple roles in synaptic activity, such as regulating synaptic vesicle trafficking and subsequent neurotransmitter release (Burré J et al. 2010; Logan T et al. 2017). SNCA also plays a role in the regulation of dopamine neurotransmission by binding to the dopamine transporter (DAT1) and thereby modulating its activity (Butler B et al. 2015). SNCA also acts as a molecular chaperone by supporting the folding of synaptic fusion components, the so-called SNAREs (Soluble NSF Attachment Protein REceptors), at the presynaptic plasma membrane (Logan T et al. 2017).
In Parkinson's disease, SNCA refolds from an α-helix to a β-sheet-rich conformation and polymerizes into toxic fibrils and aggregates (Irwin DJ et al. 2013). The spread of SNCA pathology from cell to cell has been demonstrated in vitro in cell cultures and in vivo in various animal models. Importantly, SNCA pathology has been detected in various peripheral human tissues, including the olfactory mucosa/bulb, salivary glands, gastrointestinal tract and skin (Michell AW et al. 2005). These results suggest that a skin biopsy, for example, could be considered as a diagnostic marker or even a premotor biomarker for PD. Cutaneous pSNCA deposits appear to decrease from proximal (trunk, chest, thighs) to distal (distal legs, fingers) parts of the body (Doppler K et al. 2014; Donadio V et al. 2014).
There is evidence of autonomic skin dysfunction in PD (Rodriguez-Leyva I et al. 2014). Consistent with this are abnormal vasomotor reflexes (which can be assessed by thermography with a cold stress test) evidence of abnormal skin wrinkling in response to hand immersion in warm water, abnormal sympathetic skin responses, abnormal skin resistance values and skin resistance responses (Antonio-Rubio I et al. 2015; Djaldetti R et al. 2001; Esen F et al. 1997).
Studies on the morphology and distribution of cutaneous nerves in PD have shown that dermal nerve fiber loss and decreased intraepidermal nerve fiber density are consistent findings. A length-independent loss of intraepidermal nerve fibers associated with the presence of pSNCA at proximal sites and denervation of sweat glands correlating with pSNCA distribution is suspected (Donadio V et al. 2014). ).
Skin fibroblasts of PD could play an important role in the diagnosis and treatment of PD in the future. There is evidence of increased SNCA expression in PD skin fibroblasts. Furthermore, mitochondrial dysfunction and reduced energy metabolism are observed in skin fibroblasts of patients with PD. This was confirmed in cultures of patients with Parkin mutations and SNCA triplication (Hoepken HH et al. 2008). An increased susceptibility to apoptosis of skin fibroblasts in genetic PD patients with variations in the PARK6 gene has also been demonstrated, as well as reduced cholesterol biosynthesis in skin fibroblasts. It is possible that skin fibroblasts could play an important role in future cell replacement therapies through the development of induced pluripotent stem cells (Jacobs BM 2014).
LiteratureThis section has been translated automatically.
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Outgoing links (10)
Amantadine; Apoptosis; Bullous Pemphigoid ; Chaperones; Erythromelalgia; Livedo reticularis; Melanoma cutaneous; Perioral dermatitis; Seborrheic dermatitis of adults; SNCA gene;Disclaimer
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