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Table of Contents
REVIEW ARTICLES
Year : 2019  |  Volume : 2  |  Issue : 2  |  Page : 39-47

Sweating and other thermoregulatory abnormalities in Parkinson’s disease: A review


1 Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, De Crespigny Park, London, UK; Parkinson’s Foundation Centre of Excellence, King’s College Hospital, Denmark Hill, London, UK
2 Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, De Crespigny Park, London, UK; Parkinson’s Foundation Centre of Excellence, King’s College Hospital, Denmark Hill, London, UK; Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands, UK
3 Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, De Crespigny Park, London, UK; Parkinson’s Foundation Centre of Excellence, King’s College Hospital, Denmark Hill, London, UK; Klinik für Gerontopsychiatrie, Asklepios Klinik Nord–Ochsenzoll, Hamburg, Germany, UK
4 Division of Clinical Neurosciences, University of Turku, Turku, Finland
5 Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, De Crespigny Park, London, UK
6 Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, De Crespigny Park, London, UK; Parkinson’s Foundation Centre of Excellence, King’s College Hospital, Denmark Hill, London, UK; Department of Psychiatry, Ng Teng Fong General Hospital, 1 Jurong East Street 21, Singapore, UK

Date of Web Publication13-Aug-2019

Correspondence Address:
Dr. Valentina Leta
Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, De Crespigny Park, London, SE5 8AF
UK
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/AOMD.AOMD_2_19

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  Abstract 

Thermoregulatory abnormalities, especially sweating disorders, are very common in Parkinson’s disease (PD). The estimated prevalence of sweating abnormalities ranges from 5.5% to 12.9% in de novo, newly diagnosed patients with PD and up to 64% during later stages of the disease. The range of thermoregulatory abnormalities in PD is broad, and includes hyperhidrosis, hypohidrosis, and hypothermia. In addition, the way in which these symptoms present themselves varies between patients and they can be chronic or fluctuating, local or generalized affecting the whole body, and related to motor complications or medication. Often there is a strong link to other autonomic symptoms, yet the exact pathogenesis behind these overlapping symptoms remains largely elusive, although current evidence points toward both central and peripheral involvement. Treatment remains difficult because of the lack of understanding of pathophysiology as well as specific clinical trials needed for evidence base. In this review, we have identified 43 studies in English language assessing sweating disorders in idiopathic PD. Here, we summarize knowledge gleaned from these reports and discuss current understanding of thermoregulatory dysfunction in PD, its phenomenology, pathophysiology, and management options.

Keywords: Hyperhidrosis, hypohidrosis, hypothermia, Parkinson, sweating, thermoregulatory


How to cite this article:
Leta V, van Wamelen DJ, Rukavina K, Jaakkola E, Sportelli C, Wan YM, Podlewska AM, Parry M, Metta V, Chaudhuri KR. Sweating and other thermoregulatory abnormalities in Parkinson’s disease: A review. Ann Mov Disord 2019;2:39-47

How to cite this URL:
Leta V, van Wamelen DJ, Rukavina K, Jaakkola E, Sportelli C, Wan YM, Podlewska AM, Parry M, Metta V, Chaudhuri KR. Sweating and other thermoregulatory abnormalities in Parkinson’s disease: A review. Ann Mov Disord [serial online] 2019 [cited 2019 Oct 23];2:39-47. Available from: http://www.aomd.in/text.asp?2019/2/2/39/264359




  Introduction Top


Sweating disorders represent one of the least studied non-motor dysfunctions in Parkinson’s disease (PD) despite the fact that its prevalence is reported by some authors to be as high as 64% compared to 12.5% in healthy controls.[1],[2],[3] Sweating disorders in PD consist of hyperhidrosis, and to a lesser extent, hypohidrosis, which can occur as local or generalized complaints. In addition, sweating disorders can be chronic or fluctuating, the latter frequently related to motor complications, such as dyskinesia and wearing off.[4],[5] Most of these complaints appear not to correlate with disease severity because of conflicting results, but there is a strong correlation with other autonomic dysfunction symptoms.[1] In PD, hyperhidrosis appears to be mainly axial and associated with decreased activation of sweat glands in the palms of the hands, suggesting that axial hyperhidrosis could be a compensatory phenomenon for reduced sympathetic function in the extremities.[6] Sweating disorders may have a profound impact on the quality of life in patients with PD. Indeed, heat intolerance and the need to frequently change clothing or bedding may influence social activity.[1] Also, temperature intolerance or night sweats may impact on sleep.[1]

In this review, we will address the symptomatology of sweating dysfunction in PD, its pathogenesis, related autonomic symptoms, and treatment options.


  Methods Top


We performed a systematic literature search, using the PubMed database, encompassing all articles published between 1966 and 1 January 2019. To identify appropriate studies, we used two terms: term A was “Parkinson” or “Parkinson’s” and Term B was “sweating” or “hyperhidrosis” or “diaphoresis” “hypohidrosis” or “dyshidrosis” or “hypothermia” or “thermoregulatory.” We also used the reference lists of each publication to identify further papers. The following inclusion and exclusion criteria were used for each of the articles identified in the search: (1) original papers, (2) human subjects, (3) studies that address idiopathic PD, and (4) written in the English language (articles with at least an abstract written in English were retained). An initial screen returned 324 results from the PubMed database. After excluding articles not written in English and after revision for relevance, 43 studies were retained for the final review and data extraction [Figure 1].
Figure 1: Flowchart diagram of article selection process

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  Prevalence Top


In de novo PD, sweating abnormalities seem to occur in only a minority of patients, with prevalence figures ranging from 5.5% to 12.9%.[7],[8],[9] These numbers increase rapidly, however, during the first few years after formal PD diagnosis. For example, Giorelli et al.[7] showed that 1 year after diagnosis of PD, the prevalence of sweating problems was 12.9%, which increased to 25.8% after 1-year follow-up. Similarly, Ou et al.[10] reported that at 3.9 years disease duration, the prevalence of sweating disorders was 28.2%, increasing to 35.3% after 2 years of follow-up. After approximately 10 years, almost 40% of patients are affected by sweating disorders.[11] Several older studies have reported more conflicting results with sweating disturbances occurring in 30%–80% of patients[1],[3],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25] [Table 1]. In these patients, hyperhidrosis affected 10%–100%, whereas hypohidrosis was present in 0%–40%.
Table 1: Studies on prevalence of sweating abnormalities in Parkinson’s disease

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  Clinical Phenomenology Top


Thermoregulatory problems, including sweating disorders such as hyperhidrosis and hypohidrosis, have already been described in PD as far back as 1893 by Gower[26] in his Manual of Diseases of the Nervous System: “In a few cases, . . . there is an abnormal sensation of cold; the patient always feels chilly, or there is a special sense of coldness in the affected limbs. Such patients like warmth, and may shake more when cold, as the disease progressed, the occasional sensations of cold gradually yield to an enduring sense of warmth, but the alternation may persist even until late stage; at one time the patient feels cold, and another bursts into perspiration . . . one patient could not dictate the simplest letter, even in winter, without first having his coat taken off, so intense was the perspiration caused. Sometimes sweating is local, corresponding to the sense of heat. In one patient, with left-sided agitation, the left axilla was always wet with perspiration, while the right was always dry.”

Hyperhidrosis

Hyperhidrosis or diaphoresis is a condition characterized by abnormally increased sweating. Hyperhidrosis can be local or generalized, symmetric or asymmetric, chronic or fluctuating, related or not to motor complications such as wearing off and dyskinesia, and related to medication [Figure 2]. In patients with PD, hyperhidrosis is usually fluctuating in nature, but it can be generalized or even local with an asymmetric distribution,[20],[27] frequently affecting the side of maximal motor deficit.[28],[29] Fluctuating hyperhidrosis is often associated with motor complications including dyskinesia and motor fluctuations.[5],[29]
Figure 2: Sweating abnormalities in Parkinson’s disease. Sweating abnormalities in Parkinson’s disease (PD) include hyperhidrosis and hypohidrosis. These conditions can be classified according to different criteria such as spatial, temporal, and etiological criteria. PD = Parkinson’s disease

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Hyperhidrosis can also be the result of dopamine agonist withdrawal syndrome in PD. Although hyperhidrosis is not an isolated feature of this syndrome,[30] it occurs very commonly. When patients, in whom recent changes in dopaminergic medication have been made, present with excessive sweating the possibility of a withdrawal should be considered. Symptoms, which are often associated with withdrawal syndrome, include anxiety, panic attacks, depression, agitation, nausea, orthostatic hypotension, and insomnia.[30] Similar symptoms in PD, including hyperhidrosis, may occur in serotonin syndrome and neuroleptic malignant syndrome.[31],[32]

Hypohidrosis

Although less common than hyperhidrosis, hypohidrosis (abnormally decreased sweating) is still frequently reported by patients with PD and evidence suggests that it occurs more frequently in them than that in the healthy population.[1] It may be reported by the patient as heat intolerance, and frequently involves the distal extremities, in particular, the lower limbs.[1],[33],[34] Similar to hyperhidrosis, hypohidrosis can be local or generalized, and in the latter, it may be related to treatment with anticholinergic medication.

Hypothermia

Another common thermoregulatory disorder is hypothermia, which refers to a body temperature of 35°C (95°F) or less, although some patients with PD may have a body temperature of as low as 30.9°C. Episodes of hypothermia are often associated with worsening bradykinesia and rigidity and changes in mental state, ranging from somnolence to coma.[35],[36],[37],[38] In addition, other features may be present such as myoclonus[38] and cardiac arrhythmia, requiring cardiac monitoring.[39] These latter changes include bradycardia that resolves after a return of the normal body temperature.[37],[38] Mortality in these cases, on the contrary, appears to be linked to comorbid conditions rather than exact body temperature.[40] Whether or not hypothermia episodes in PD are precipitated by any triggers remained unclear in the aforementioned studies.


  Pathogenesis Top


Sweating has a thermal and mental aspect. Mental sweating, mainly seen in the palms and soles of the feet, develops with psychological stress and it is not associated with disorders in thermoregulation.[24] A variety of other factors may lead to sweating abnormalities in PD.[31] It has been observed that hyperhidrosis episodes frequently occur together with dyskinesia.[5] It is likely that excessive movements may, in part, lead to increased sweating[1]; however, the pathological mechanism underlying dyskinesia-related sweating is still poorly understood. On the contrary, the multiplicity of autonomic symptoms occurring during off periods suggests that “off sweating” may result from sympathetic dysfunction.[28],[30] Indeed, evidence suggests that thermoregulatory dysfunction, and subsequently, thermal sweating, are intrinsic features of PD [Figure 3].
Figure 3: Pathogenesis of sweating disorders in Parkinson’s disease. PD = Parkinson’s disease

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Normal thermoregulatory responses (involving both central and peripheral mechanisms) are crucial in maintaining a set body temperature, which in most individuals is around 37°C. The central regulation is driven by the hypothalamus. Here, heat conservation and production are triggered by temperature-sensing neurons located within the preoptic area in response to heat loss. This system is modulated by several neurotransmitters, for example, stimulation of D2 and 5-HT1 receptors by dopamine and serotonin, respectively, induces hypothermia, whereas stimulation of 5-HT2 receptors induces hyperthermia.[41],[42] The output of the hypothalamic system involved in thermoregulation includes projections to the rostral raphe pallidus area.[41],[43] From here, projections run down to sympathetic and motor neurons in the spinal cord, which when activated, modulate skin vasomotor tone and induce shivering.[42] Dyshidrosis may be explained by alterations in dopaminergic neurotransmission, supported both by the fact that changes in dopaminergic medication may improve dyshidrosis[5] and by the observation that sweating attacks in PD are more prevalent during the motor off-state.[29] It is recognized that the hypothalamus in patients with PD shows Lewy pathology[44] and alpha-synuclein deposits,[45] although in the latter studies, no correlation was reported between the amount of alpha-synuclein and non-motor symptoms (NMS) burden, including autonomic symptoms. This suggests that hypothalamic functional deficits rather than Lewy pathology contribute to NMS, supported by the observation that hypothalamic functional connectivity is disturbed in autonomic dysfunction in PD.[46]

In addition to the central mechanisms, peripheral thermoregulatory processes also are involved to maintain body temperature. These pathways are mainly cholinergic (to the sweat glands) and noradrenergic (responsible for vasoconstriction). Furthermore, there are several vasodilator outputs (including nitric oxide).[47] Combined, these systems support the central process of heat conservation. Sudomotor output to sweat glands, resulting in sweating, is the most important way for humans to reduce body temperature. Sweat glands consist of two types: eccrine, which are cholinergic and distributed over almost the entire body, and apocrine glands, mainly in the palms and soles and are activated by emotional responses. The pattern of dyshidrosis in PD appears to differ from the general population, and axial hyperhidrosis in PD is associated with decreased activation of sweat glands in the palms of the hands suggesting that axial hyperhidrosis could be a compensatory phenomenon for reduced sympathetic function in the extremities.[8] Moreover, alpha-synuclein can be found in the cutaneous autonomic nerves innervating sweat glands and arterioles in patients with PD.[48],[49]


  Related Autonomic Symptoms and PD Endophenotypes Top


Sweating abnormalities in PD are frequently linked to other autonomic features. These features often aggregate in patients with PD, and several authors have proposed specific non-motor subtypes in PD, analogs to the better-known motor subtypes. One of these phenotypes is an autonomic phenotype, with adrenergic/cholinergic dysfunctions, such as orthostatic hypotension and gastrointestinal symptoms overlapping with sleep dysfunction and levodopa-induced dyskinesia.[4],[50],[51] In a recent study, it was shown that hyperhidrosis was associated with a dysautonomia dominant subtype in patients with PD, including sleep disorders and a higher rate of dyskinesia. Conditions, which were related to hyperhidrosis in this study, included orthostatic hypotension, fatigue, somnolence, restless legs, apathy, double vision, sialorrhea, constipation, urinary urgency and frequency, and unexplained pain.[52] Others have also shown the link between dyshidrosis and sialorrhea as well as constipation.[1] These symptoms often correlate with disease severity as measured by motor impairment.[53],[54],[55],[56] Whether or not this was related to dopaminergic medication in these studies remains unclear.


  Management Top


Treatment of sweating abnormalities in patients with PD remains challenging because of the lack of validated and evidence-based algorithms.[57] First, it is recommended to adopt non-pharmacological measures, such as avoiding hot and humid environments, as well as food and drinks that may trigger sweating (e.g., alcoholic drinks and spicy food), maintaining a good hydration status, and wearing well-ventilating clothes made of natural fibers.

Pharmacological treatment

A detailed history of thermoregulatory symptoms and particularly their fluctuations, according to the administration of dopaminergic medication, is essential for the management of sweating abnormalities in patients with PD. Indeed, motor complications-related sweating can be managed by optimizing dopaminergic treatment [Figure 4]. Although advanced therapies are not indicated for the treatment of sweating dysfunctions, a few observational studies suggest that infusion therapies, such as subcutaneous apomorphine[58] and intrajejunal levodopa infusion,[59] may have a positive effect on sweating.
Figure 4: Management of motor complications-related sweating in Parkinson’s disease: dopaminergic treatment optimization. COMT = catechol-O-methyltransferase

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Despite the fact that anticholinergics are often considered in the treatment of sweating disorders, evidence for their use is very limited. In fact, no studies have been performed in PD and only a few studies have investigated the effect of anticholinergics on sweating in other disorders, including the use of topical glycopyrrolate, oral oxybutynin, and oral methantheline bromide. Glycopyrrolate wipes, compared to placebo, appear to have a beneficial effect on axillary and facial sweating.[60],[61] Another study looked at glycopyrrolate spray and compared it to botulinum toxin (BoNT) injections for axillary hyperhidrosis and no effect was noticed.[62] Three placebo-controlled studies evaluated the effectiveness of oral oxybutynin for axillary, plantar, and palmar hyperhidrosis, and generalized hyperhidrosis.[63],[64],[65] Two additional placebo-controlled studies investigated oral methantheline bromide for axillary and palmar hyperhidrosis.[66],[67] None of the studies showed a clear benefit and probably all studies were biased for treatment outcomes.[68] Overall, the use of anticholinergic medication in PD should be approached with caution, especially in older patients, given the high rate of side effects (including cognitive effects).

The efficacy of BoNT injections has not been studied in PD. There is, however, evidence for its efficacy in essential/primary hyperhidrosis.[69],[70] Future research is needed to validate the efficacy and safety of BoNT therapy for hyperhidrosis related to PD.

No studies have yet focused on the drug treatment of hypothermia; however, it is advised to carefully perform external rewarming rather than the use of invasive rewarming methods. Indeed, faster rewarming has not been proven to reduce mortality.[71]

Treatment of medical emergencies, including the treatment of serotonin syndrome, dopamine agonist withdrawal syndrome, and neuroleptic malignant syndrome, is not the merit of these reviews, and as such, the treatment for these syndromes will not be discussed here.

Non-pharmacological treatment

Several authors have reported improvement of (severe) hyperhidrosis after deep brain stimulation (DBS) to the bilateral subthalamic nucleus (STN),[72] and also improvement of sympathetic skin responses in 19 patients who received bilateral STN DBS.[73] In a recent cohort of 67 patients with PD who underwent bilateral STN DBS, a significant improvement of hyperhidrosis was reported as measured by the NMS scale. This improvement was persistent after 24 months of follow-up.[58] In addition, others have reported an improvement on hyperhidrosis using a structured interview with improvement of this symptom in 34 of 35 patients after 1 year of bilateral STN DBS.[74] It may be argued that the reduction in hyperhidrosis may have been due to reduction in the dose of dopaminergic medication; however, a recent publication has shown a differential effect on specific NMS, including hyperhidrosis, based on the exact location of the DBS leads within the STN.[75]


  Conclusion Top


Sweating disorders are one of the many non-motor expressions of PD with a clinical prevalence as high as 64% during later stages of the disease. The range of sweating disorders and thermoregulatory abnormalities in PD is broad, and includes hyperhidrosis, hypohidrosis, and hypothermia. These conditions can be chronic, fluctuating, related to motor complications, and related to medication. Interestingly, these complaints are not always correlated to the severity of the disease but there is a strong link with other autonomic symptoms. The pathogenesis remains largely elusive; however, there is emerging evidence to suggest that several levels of the sympathetic outflow pathways are affected in PD, including the hypothalamus and the sweat glands. Further, the treatment of thermoregulatory abnormalities in PD remains understudied and the available evidence is largely biased. On the basis of mainly essential hyperhidrosis, current treatment options include BoNT injections, anticholinergic drugs, and although not indicated for the treatment of thermoregulatory disorders, advanced treatments may reduce hyperhidrosis.

Financial support and sponsorship

This article represents independent collaborative research part funded by the National Institute for Health Research Biomedical Research Centre at South London and Maudsley National Health Service Foundation Trust and King’s College London.

Conflicts of interest

There are no conflicts of interest.



 
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