Efficacy of cranial electrotherapy stimulation in patients with burning mouth syndrome: a randomized, controlled, double-blind pilot study.

Background: The Burning mouth syndrome (BMS) is a chronic pain syndrome characterized by a burning sensation in the oral mucous membranes. The etiology and pathophysiology of BMS is largely unexplained. To date, there is no evidence-based treatment strategy for BMS. Cranial electrical stimulation (CES) represents a non-invasive treatment option with a low side effect profile that is approved for the treatment of pain, depression, anxiety disorder and insomnia. It has shown efficacy in studies for chronic pain such as fibromyalgia and neuropathic pain after spinal cord injury. This study aimed to investigate the therapeutic effectiveness of CES in combination with local transcutaneous electrical nerve stimulation (TENS) as an adjunct therapy in patients with BMS compared to sham stimulation. Methods: This randomized, double-blind, sham-controlled pilot study enrolled 22 patients, aged 18 years and over, with the diagnosis of BMS meeting the ICHD-3 criteria from August 2020 to June 2021. The study duration was 4 weeks (28 days) per participant. After randomization, the active group participants (n = 11) received a 100 µA CES treatment for 60 min a day whereas the devices in the Sham group did not emit electricity. Simple linear regression was used to determine whether the interventions promoted significant differences in pain intensity. Results: The linear regression showed that the period of stimulation significantly predicted decrease in the intensity of pain in the active group [ß = -0.036; t(26) = -7.219; p < 0.001] as in the sham group [ß = -0.026; t(26) = -2.56; p < 0.017]. With the applied cutoff of 30% pain reduction within the stimulation period, both the active and sham groups had 36% responders (n = 4) (Fisher's exact test, p = 1.00). In both groups (active stimulation and sham group), a significant decrease in the intensity of pain, somatic symptoms and an improvement in sleep quality over the study period was observed. Subjects reported no adverse events during the study. Conclusion: Although CES is an easily applicable and safe therapeutic option for chronic facial pain, active stimulation was not superior to sham stimulation. Among other reasons, this could be due to the short double-blinded treatment period, duration of the daily stimulation session or the small sample size.

[Interdisciplinary multimodal pain therapy in headache disorders]. / Interdisziplinäre multimodale Schmerztherapie bei Kopfschmerzerkrankungen.

Primary headaches are among the most common pain disorders. They include migraines (prevalence 15%), tension headaches (up to 80%), and others, including trigeminal autonomic headaches (about 0.2%). Migraine, in particular, leads to significant impairment of personal life and high societal costs. Therefore, the need for effective and sustainable therapeutic procedures is high. This article provides an overview of psychological procedures in headache therapy and critically summarizes the empirical evidence for the effectiveness of interdisciplinary multimodal pain therapy (IMST) consisting of psychotherapy and pharmacotherapy. It can be shown that psychoeducation, relaxation procedures, cognitive behavioral therapy, and biofeedback are psychological procedures from which headache patients can benefit. In the synopsis of multimodal approaches in the treatment of headache, consistently greater effects can be observed when both pharmacological treatment and psychotherapeutic procedures are used. This added value should be regularly taken into account in the treatment of headache disorders. This requires close cooperation between headache specialists and psychotherapists who specialize in the treatment of pain.

Perception of typical migraine images on the internet: Comparison between a metropolis and a smaller rural city in Germany.

The medial portrayal of migraine is often stereotypical and inaccurate but reflects how society perceives migraine. The discrepancy between others' views and the reality of affected individuals may negatively affect access to treatment and the disease course of patients with migraine. This study aimed to investigate whether images presented in the media as typical migraine attacks are perceived as realistic and representative by migraine patients in Rostock, a smaller town in rural Germany, and compare the results to those from Berlin, a large metropolis. We performed an online survey in Rostock. Migraine patients were shown ten images of migraine attacks, which were among the most downloaded stock pictures on the internet under the search term "migraine". They rated on a scale of 0-100 to what extent the pictures were realistic for migraine attacks (realism score), representative of their own migraine (representation score), or the society's view of migraine (society score). In addition, we compared our results with a recently published study from the metropolitan region of Berlin. A total of 174 migraine patients completed our survey. Mean (SD) realism, representation, and society scores were 59.9 (17.5), 56.7 (18.3), and 58.4 (17.1) respectively. Images of older patients were perceived as significantly more realistic and representative than those of younger patients (P < .001). Patients in Rostock (rural region) rated the images as significantly more realistic and representative than survey participants in Berlin (metropolis). Migraine patients in a rural region found typical migraine images only moderately realistic and representative but to a higher degree than their counterparts from a metropolis.

Medication adherence in patients with cluster headache and migraine: an online survey.

To examine factors for adherent and non-adherent behavior in patients with cluster headache and migraine. Adults with cluster headache or migraine were included in this anonymous online survey using a questionnaire accessed via homepages of headache support groups. Medication adherence in preventive treatment was measured with the Medication Adherence Report Scale (MARS-D). Factors for non-adherent behavior were examined (subjective socioeconomic status, psychological comorbidities, self-efficacy, coping, side effects, expectations of treatment, information on medical treatment, and trust in the physician/treatment concept). 200 participants (n = 58 with cluster headache, n = 142 with migraine) were included. The rate of medication adherence in preventive treatment was 32.8% for participants with cluster headache and 20.4% for migraine. The most common reasons for low adherence in participants with cluster headache were altering the prescribed medication dose (34%) or taking less than instructed (14%), which was mostly due to insufficient benefit from the medication or side effects. Positive expectations of medical treatment (p ≤ 0.05) correlated significantly with adherent behavior in cluster headache. Furthermore, the adherence-promoting factors coping and self-efficacy were more pronounced in patients with cluster headache than in those with migraine (p < 0.05). This study is the first to comprehensively investigate medication adherence and factors influencing adherent/non-adherent behavior in patients with cluster headache. Patients with cluster headache had similar adherence levels to patients with migraine, but had higher resources of adherence-promoting factors.

Reduced midbrain raphe echogenicity in patients with fibromyalgia syndrome.

OBJECTIVES: The pathogenesis of fibromyalgia syndrome (FMS) is unclear. Transcranial ultrasonography revealed anechoic alteration of midbrain raphe in depression and anxiety disorders, suggesting affection of the central serotonergic system. Here, we assessed midbrain raphe echogenicity in FMS. METHODS: Sixty-six patients underwent transcranial sonography, of whom 53 were patients with FMS (27 women, 26 men), 13 patients with major depression and physical pain (all women), and 14 healthy controls (11 women, 3 men). Raphe echogenicity was graded visually as normal or hypoechogenic, and quantified by digitized image analysis, each by investigators blinded to the clinical diagnosis. RESULTS: Quantitative midbrain raphe echogenicity was lower in patients with FMS compared to healthy controls (p<0.05), but not different from that of patients with depression and accompanying physical pain. Pain and FMS symptom burden did not correlate with midbrain raphe echogenicity as well as the presence and severity of depressive symptoms. CONCLUSION: We found reduced echogenicity of the midbrain raphe area in patients with FMS and in patients with depression and physical pain, independent of the presence or severity of pain, FMS, and depressive symptoms. Further exploration of this sonographic finding is necessary before this objective technique may enter diagnostic algorithms in FMS and depression.

Study Design and Protocol of a Randomized Controlled Trial of the Efficacy of a Smartphone-Based Therapy of Migraine (SMARTGEM).

Background: Digitalization and electronic health (eHealth) offer new treatment approaches for patients with migraine. Current smartphone applications (apps) for migraine patients include a wide spectrum of functions ranging from digital headache diaries to app-based headache treatment by, among others, analysis of the possible triggers, behavioral therapy approaches and prophylactic non-drug treatment methods with relaxation therapy or endurance sport. Additional possibilities arise through the use of modern, location-independent communication methods, such as online consultations. However, there is currently insufficient evidence regarding the benefits and/or risks of these electronic tools for patients. To date, only few randomized controlled trials have assessed eHealth applications. Methods: SMARTGEM is a randomized controlled trial assessing whether the provision of a new digital integrated form of care consisting of the migraine app M-sense in combination with a communication platform (with online consultations and medically moderated patient forum) leads to a reduction in headache frequency in migraine patients, improving quality of life, reducing medical costs and work absenteeism (DRKS-ID: DRKS00016328). Discussion: SMARTGEM constitutes a new integrated approach for migraine treatment, which aims to offer an effective, location-independent, time-saving and cost-saving treatment. The design of the study is an example of how to gather high quality evidence in eHealth. Results are expected to provide insightful information on the efficacy of the use of electronic health technology in improving the quality of life in patients suffering from migraine and reducing resource consumption.

Headache in the Neurological Emergency Department-High Degree of Inadequate Documentation Calls for Structured Assessments.

Headaches are a frequent reason for presentation to the emergency department (ED) and can pose a great challenge for the attending physicians. First and foremost, the distinction between a primary and secondary headache with potentially life-threatening implications can be difficult. Moreover, it often occurs that no specific headache diagnosis is made at discharge from the ED. Therefore, in this present retrospective cross-sectional study, all patients who presented to the emergency department of the Department of Neurology at Rostock University Medical Centre with the main symptom of headache between November 2013 and November 2016 underwent a neurological examination and the extent to which warning symptoms ("red flags") for a secondary headache as well as symptoms necessary for a correct headache diagnosis according to the ICHD-3 classification were recorded and documented. We could show that documentation of red flags and clinical characteristics is inadequate and does not allow proper diagnostic categorization. To facilitate concise documentation and rapid decision making we suggest a structured and standardized form for documenting the headache history and red flags in the ED.

[CGRP antibodies in migraine prophylaxis : The new standard in migraine treatment?] / CGRP-Antikörper in der Migräneprophylaxe : Der neue Standard in der Migränetherapie?

Migraine is associated with a high individual level of suffering. Therefore, an effective preventive treatment is highly important. The spectrum of classical prophylactic drugs has now been expanded to include monoclonal antibodies against calcitonin gene-related peptide (CGRP) and its receptor. These antibodies have shown reliable efficacy compared to placebo and a rapid onset of action with a low rate of side effects and negligible interactions in pivotal studies. Recently, the efficacy of the antibody was shown in many studies even on drug-refractory migraine and migraine associated with medication overuse. Comprehensive head to head comparisons with previously established drugs and among the antibodies are not yet available; however, initial studies suggest better tolerability and efficacy compared to conventional drugs and other antibodies. The role of antibodies in established treatment cascades still needs to be clarified.

Headache Characteristics in the Neurological Emergency Department: A Retrospective Study.

Background: The care of patients with headache in the emergency department (ED) represents a diagnostic and clinical challenge. Data on the prevalence and characteristics of headache patients in purely neurological EDs are sparse. The aim of the present study is to examine patient profiles with the cardinal symptom of headache in an academic neurological ED, to analyze correlations between headache characteristics and search for differences compared to the interdisciplinary ED. Methods: This retrospective cross-sectional study assessed all patients who presented to the ED of the Department of Neurology at Rostock University Medical Center between November 2013 and November 2016 with the main symptom of headache. Epidemiological, clinical, diagnostic data as well as key data regarding the care structure were recorded. Correlations between headache characteristics and diagnosis at discharge were analyzed and risk profiles were identified using binary logistic regression analysis. Conclusion: This study comprehensively characterized a large collective of patients with the cardinal symptom of headache presenting to a purely neurology emergency department.

Optimizing telemedical care in neurological outpatients by characterizing the patients' needs in the physician-patient relationship-content analysis of guideline-based interviews.

BACKGROUND: The use of new concepts in patient care, such as video-consultations, reminder systems, and online evaluation portals, is becoming increasingly important in the physician-patient relationship and outpatient care. This study examines the acceptance of these approaches in a neurological setting and determines the patients' preferences. METHODS: We analyzed 16 guideline-based qualitative interviews with neurological patients using qualitative content analysis (inductive category formation). RESULTS: The patients commented on the benefits and challenges of integrating new concepts of medical care. They identified advantages of telemedical care, including time savings (7 of 16; 43,8%) for both the patient and the physician, the prospect of more intensive (4 of 16; 25%) care, and the possibility for a quick response in case of urgent needs (3 of 16; 18.8%). Several challenges were reported, such as the limitations for patients with psychiatric (2 of 16; 12.5%) or complex diseases (4 of 16; 25%) and limited options for diagnostic procedures (such as physical examination (4 of 16; 25%)). For individual neurological patients' needs, telemedical and telecommunication structures could be discussed, which support the patients' specific requirements, such as answering questions while having a recall (2 of 16; 12.5%) and avoiding the journey (8 of 16; 50%). Also, patients are rejecting evaluation portals and are skeptical of telecare in the treatment of neurological diseases. DISCUSSION: The perception of telemedical care and the successful integration of new medical care concepts depend on fulfilling the individual patient's needs. Regardless of the preferred nature of physician-patient interactions, there are specific instruments that can intensify the relationship. These individual needs of the patients must be inquired about and accommodated for. CONCLUSIONS: For the first time, we could characterize the properties of optimal telemedical care for neurological patients. Interviews like the ones we conducted should be repeated during and after the pandemic, referring to our results and compare.

[Migraine prophylaxis-all just antibodies? : Medical and nonmedical migraine preventive treatment in times of CGRP antibodies]. / Migräneprophylaxe ­ alles nur noch Antikörper? : Medikamentöse und nicht-medikamentöse Migräneprophylaxe in Zeiten der CGRP-Antikörper.

BACKGROUND: Migraine is a frequently underdiagnosed disease that is associated with a high burden on affected patients. There are a variety of prophylactic treatment options available, that have been expanded with the introduction of the CGRP-(receptor-)antibodies. OBJECTIVES: Status of pharmacologic and nonpharmacologic preventive treatment in migraine therapy. METHODS: Analysis and evaluation of internationally published articles concerning preventive treatment of episodic and chronic migraine. RESULTS: There are many approved medications for migraine prophylaxis with different evidence. The possibilities were further expanded with CGRP antibodies. Comparative studies of the new antibodies with previous prophylactic drugs have not yet been published, so it's unclear whether the antibodies are therapeutically superior. What should be emphasized is their rapid onset of action and their good tolerance. Basically, an individual choice of prophylaxis, which is based on affectedness, comorbidities and comedication, makes sense. In addition, a combination with nondrug measures is always mandatory. CONCLUSIONS: A variety of medicinal and non-medicinal measures are available for the treatment of migraine, which should be used multimodally.

Effect of calcitonin gene-related peptide (-receptor) antibodies in chronic cluster headache: Results from a retrospective case series support individual treatment attempts.

OBJECTIVE: To assess the efficacy of monoclonal antibodies targeting calcitonin gene-related peptide (CGRP) or its receptor in chronic cluster headache (CCH) treatment under real world conditions. BACKGROUND: Calcitonin gene-related peptide has an important pathophysiological role in cluster headache. Although the randomised controlled trial with the calcitonin gene-related peptide antibody galcanezumab was negative, chronic cluster headache patients with insufficient response to other preventive treatments have been receiving individual off-label treatment attempts with calcitonin gene-related peptide-(receptor) antibodies. METHODS: Data from 22 chronic cluster headache patients who received at least one dose of a calcitonin gene-related peptide(-receptor) antibody and recorded attack frequency in a headache diary were retrospectively collected at eight headache centres. RESULTS: The number of previous preventive therapies was 6.5 ± 2.4 (mean ± standard deviation, range: 2-11). The average number of attacks per week was 23.3 ± 16.4 at baseline and significantly decreased by -9.2 ± 9.7 in the first month of treatment with a calcitonin gene-related peptide(-receptor) antibody (p < 0.001). Fifty-five percent of the patients were 50% responders and 36% were 75% responders with respect to attack frequency. Significant reduction of attack frequency started at week 1 (-6.8 ± 2.8 attacks, p < 0.01). Results were corroborated by significant decreases in weekly uses of acute headache medication (-9.8 ± 7.6, p < 0.001) and pain intensity during attacks (-1.2 ± 2.0, numerical rating scale (NRS) [0-10], p < 0.01) in the first month. In months 2 (n = 14) and 3 (n = 10), reduction of attack frequency from baseline was -8.0 ± 8.4 (p = 0.004) and -9.1 ± 10.0 (p = 0.024), respectively. CONCLUSION: Under real-world conditions, individual treatment with calcitonin gene-related peptide(-receptor) antibodies was effective in 55% of our chronic cluster headache patients. This finding supports individual off-label treatment attempts with calcitonin gene-related peptide-(receptor) antibodies in chronic cluster headache patients insufficiently responding to other therapies.

Neuromodulation in primary headaches: current evidence and integration into clinical practice.

PURPOSE OF REVIEW: Neuromodulatory approaches add to our armamentarium of therapeutic tools for the treatment of primary headaches. This review provides a comprehensive overview of current controlled studies on the different neuromodulation techniques and recommendations for clinical practice. RECENT FINDINGS: Evidence for efficacy of transcutaneous vagal nerve stimulation (tVNS) is limited to acute use in migraine with ambiguous results and episodic cluster headache as well as chronic cluster headache if applied in addition to conventional treatment. Transcutaneous stimulation of the supraorbital and supratrochlear nerve was effective in both acute and preventive stimulation (the latter with ambiguous results) in episodic migraines. Thus, invasive procedures should be reserved for severe and refractory cases only. Occipital nerve stimulation for chronic refractory cluster headache is the only available invasive approach with a Conformité Européenne mark. SUMMARY: Neuromodulation can complement conventional therapy, with noninvasive procedures being used preferably. Given the limited number of studies for each modality and the lack of head-to-head studies, it is difficult to place neuromodulation techniques in a conventional treatment algorithm.

A case report: Numb Chin Syndrome due to thalamic infarction: a rare case.

BACKGROUND: Numb Chin Syndrome (NCS), which is also characterized as sensory neuropathy of the mental nerve, describes a mostly unilateral numbness of the chin and lower lip. Benign and malignant diseases are known to cause this circumscribed symptom, which can easily be overlooked or misdiagnosed. In this article we present the very rare case of a clinical NCS caused by thalamic lacunar infarction. As a pure sensory stroke it is a rare variant of the Cheiro-Oral Syndrome (COS). CASE PRESENTATION: A 63-year-old male patient received an emergency referral to our department after the patient had noticed a feeling of numbness of the left lower lip and chin on the previous day. The neurological examination revealed an approximately 2 × 3 cm area of hypoesthesia in the area of the chin and left lower lip and the cranial MRI an acute ischemia in the right thalamus. CONCLUSIONS: In this case report we introduce a patient who clinically shows an NCS. Various diseases may be responsible for NCS, including malignancies or even central neurological disorders such as multiple sclerosis. A lacunar thalamic ischemia as a cause of NCS is very rare and to our knowledge described in the literature only in the contex of a COS in three cases. We wish to remind the reader, through this case, of the purely descriptive and syndromal character of the NCS and the importance for detecting underlying diseases. Furthermore we give a brief overview of the NCS and causative disorders.

[Neuromodulation in primary headache in the year 2019: is it still up-to-date? : New data on invasive and non-invasive neuromodulation in migraine and cluster headaches]. / Neuromodulation bei primären Kopfschmerzen im Jahr 2019 ­ noch zeitgemäß? : Neue Daten zu invasiven und nichtinvasiven Verfahren bei Migräne und Clusterkopfschmerz.

Neuromodulatory approaches have enlarged the therapeutic armamentarium for the treatment of primary headaches such as migraine and cluster headache. While invasive devices are mainly used in patients with refractory and chronic conditions, non-invasive approaches are increasingly used in less severely affected patients with episodic headaches. This article critically reviews the literature focussing on recent controlled studies, provides recommendations on their use in clinical practice and strives to integrate them into present treatment regimes. As a relevant drawback, the number of controlled studies is limited with small cohorts included and marked methodological constraints, which hampers any direct comparison with pharmacological approaches.

Hereditary spastic paraplegia: Clinicogenetic lessons from 608 patients.

OBJECTIVE: Hereditary spastic paraplegias (HSPs) are genetically driven disorders with the hallmark of progressive spastic gait disturbance. To investigate the phenotypic spectrum, prognostic factors, and genotype-specific differences, we analyzed baseline data from a continuous, prospective cohort. METHODS: We recruited 608 HSP cases from 519 families of mostly German origin. Clinical severity was assessed by the Spastic Paraplegia Rating Scale. Complicating symptoms were recorded by a standardized inventory. RESULTS: Family history indicated dominant (43%), recessive (10%), and simplex (47%) disease. We observed a significant male predominance, particularly in simplex cases without a genetic diagnosis. Disease severity increased with disease duration. Earlier disease onset was associated with less severe disease. Specific complicating features including cognitive impairment, extrapyramidal or peripheral motor involvement, and ataxia were associated with worse disease severity. Disease severity also depended on the genotype. HSP cases maintained the ability to walk independently for a median disease duration of 22 years. Early onset cases were able to maintain free walking significantly longer and were at less risk to become wheelchair dependent. INTERPRETATION: This cross-sectional cohort study provides the first large-scale data on disease manifestation, progression, and modifying factors, with relevance for counseling of HSP families and planning of future cross-sectional and natural history studies. Later age of onset, specific complicating features, and the SPG11 genotype are strongly associated with more severe disease. Future interventional studies will require stratification for modifiers of disease progression identified in this study. Prospective longitudinal studies will verify progression rates calculated in this baseline analysis.

Acute hypothalamo-pituitary-adrenal axis response to LPS-induced endotoxemia: expression pattern of kinin type B1 and B2 receptors.

Bradykinin (BK) and des-Arg9-BK are pro-inflammatory mediators acting via B2 (B2R) and B1 (B1R) receptors, respectively. We investigated the role of B2R and B1R in lipopolysaccharide (LPS)-induced hypothalamo-pituitary-adrenal (HPA) axis activation in SD rats. LPS given intraperitoneally (ip) up-regulated B1R mRNA in the hypothalamus, both B1R and B2R were up-regulated in pituitary and adrenal glands. Receptor localization was performed using immunofluorescence staining. B1R was localized in the endothelial cells, nucleus supraopticus (SON), adenohypophysis and adrenal cortex. B2R was localized nucleus paraventricularis (PVN) and SON, pituitary and adrenal medulla. Blockade of B1R prior to LPS further increased ACTH release and blockade of B1R 1 h after LPS decreased its release. In addition, we evaluated if blockade of central kinin receptors influence the LPS-induced stimulation of hypothalamic neurons. Blockade of both B1R and B2R reduced the LPS-induced c-Fos immunoreactivity in the hypothalamus. Our data demonstrate that a single injection of LPS induced a differential expression pattern of kinin B1R and B2R in the HPA axis. The tissue specific cellular localization of these receptors indicates that they may play a crucial role in the maintenance of body homeostasis during endotoxemia.

Relative acidic compartment volume as a lysosomal storage disorder-associated biomarker.

Lysosomal storage disorders (LSDs) occur at a frequency of 1 in every 5,000 live births and are a common cause of pediatric neurodegenerative disease. The relatively small number of patients with LSDs and lack of validated biomarkers are substantial challenges for clinical trial design. Here, we evaluated the use of a commercially available fluorescent probe, Lysotracker, that can be used to measure the relative acidic compartment volume of circulating B cells as a potentially universal biomarker for LSDs. We validated this metric in a mouse model of the LSD Niemann-Pick type C1 disease (NPC1) and in a prospective 5-year international study of NPC patients. Pediatric NPC subjects had elevated acidic compartment volume that correlated with age-adjusted clinical severity and was reduced in response to therapy with miglustat, a European Medicines Agency­approved drug that has been shown to reduce NPC1-associated neuropathology. Measurement of relative acidic compartment volume was also useful for monitoring therapeutic responses of an NPC2 patient after bone marrow transplantation. Furthermore, this metric identified a potential adverse event in NPC1 patients receiving i.v. cyclodextrin therapy. Our data indicate that relative acidic compartment volume may be a useful biomarker to aid diagnosis, clinical monitoring, and evaluation of therapeutic responses in patients with lysosomal disorders.

Potential impact of self-perceived prodromal symptoms on the early diagnosis of Parkinson's disease.

The detection of Parkinson's disease (PD) at stages earlier than current diagnostic criteria allow for may increase the efficacy of disease-modifying therapies. Here we studied the relationship between retrospectively reported prodromal non-motor and motor features of PD, their pre-diagnostic presentation to physicians, and the extrapolated potential of an earlier diagnosis of PD considering early diagnostic markers detected at presence. One hundred and fifteen PD patients (41 women; age 63.2 ± 8.6 years) underwent a structured face-to-face interview on 22 prediagnostic symptoms. Present olfactory function, motor symptoms, and substantia nigra hyperechogenicity (SN-h) were assessed using standardized tools. Most frequently self-perceived symptoms in the early and very early prediagnostic phase (>2, >7 years prior to diagnosis) were hyposmia (23, 10 %), musculoskeletal pain (21, 9 %), and depression/anxiety (14, 11 %). In the late prediagnostic phase (≤ 2 years) mild motor signs, especially asymmetric bradykinesia and rest tremor, increasingly dominated the self-perception. In the prediagnostic phase, 99 % of patients consulted a physician because of motor symptoms but only 36 % with non-motor symptoms, mostly pain (20 %), depression/anxiety (9 %), constipation, bladder urgency, insomnia, REM sleep behaviour disorder, sexual dysfunction, and malignant melanoma (each, <6 %). Assuming the potential detectability of present hyposmia, asymmetric motor slowing and SN-h, a triad highly specific for PD, as early as 5 years prior to diagnosis, up to 84 (73 %) patients could have been identified in the prediagnostic phase using their or their physicians' awareness of early symptoms. We conclude that educating the general population and physicians on the importance of distinct prodromal features and applying symptom-specific diagnostic programs can improve the early detection of PD.