- Email: [email protected]
Symptomatic therapy of multiple system atrophy
Autonomic Neuroscience: Basic and Clinical xxx (xxxx) xxx–xxx
Contents lists available at ScienceDirect
Autonomic Neuroscience: Basic and Clinical journal homepage: www.elsevier.com/locate/autneu
Review
Symptomatic therapy of multiple system atrophy Guido Rohrera, Günter U. Höglingerb,c,⁎, Johannes Levina,b,⁎⁎ a b c
Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany German Center for Neurodegenerative Diseases (DZNE), Munich, Germany Department of Neurology, Technical University Munich, Munich, Germany
A R T I C L E I N F O
A B S T R A C T
Keywords: Multiple system atrophy Motor symptoms Autonomic failure Alpha-synuclein Parkinson Cerebellum
Multiple system atrophy is a progressive neurodegenerative disease characterized by the association of autonomic failure and a movement disorder that consist of either a hypokinetic movement disorder or a cerebellar syndrome or both. In addition to these core characteristics other movement disorders (e.g. dystonia, myoclonus, spasticity), and neuropsychiatric symptoms (e.g. depression, cognitive dysfunction) may occur in the course of the disease and can severely impair patients' quality of live. To date no causal therapy is available and therefore symptomatic treatment plays a pivotal role in patient care. In this article we provide an overview of frequent clinical symptoms and their symptomatic treatment options.
1. Introduction Multiple system atrophy (MSA) is an adult onset, devastating, progressive neurodegenerative disease with a mean survival of 6 to 10 years from symptom onset (Fanciulli and Wenning, 2015). MSA is a slowly progressive disease characterized by the association of autonomic failure and a variety of movement disorders including parkinsonism and/or cerebellar ataxia as key features, but also dystonic and pyramidal symptoms. According to the predominant motor symptoms two subtypes have been described, characterized by either a hypokinetic-rigid parkinsonian syndrome (MSA-P) or a cerebellar syndrome (MSA-C). In both subtypes, autonomic dysfunction such as orthostatic hypotension, urinary incontinence or erectile dysfunction is required to establish the diagnosis of clinically possible or probable MSA according to current diagnostic criteria (Gilman et al., 2008). Especially autonomic symptoms have been described to severely impact the quality of life of MSA patients (Köllensperger et al., 2010). Another frequent symptom of MSA is occurrence of neuropsychiatric symptoms including depression (Schrag et al., 2006; Schrag et al., 2010). Cognitive impairment and dementia have been described in MSA, although being a non-supporting feature in current diagnostic criteria (Stankovic et al., 2014). At present, no casual treatment for disease modification is available. Therefore, symptomatic treatment is of pivotal importance in patient care along the course of the disease. In this article we provide an overview of the symptomatic treatment
options of the most relevant symptoms in MSA. Treatment options for MSA symptoms are displayed in Table 1. 2. Motor features Motor features in MSA are characterized by a predominant hypokinetic-rigid syndrome in MSA-P, a predominant cerebellar syndrome in MSA-C and other types of movement disorders such as focal dystonia, which can be present both in MSA-C and MSA-P (Levin et al., 2016). 2.1. Parkinsonism Hypokinesia, rigidity and early tendency to fall characterize the core motor features of MSA-P and can be observed at least to some extent in 87% of all cases (Köllensperger et al., 2010). Approximately one third of patients may respond to levodopa although benefit is temporarily limited and often markedly less pronounced than in patients with PD (Constantinescu et al., 2007; Köllensperger et al., 2010; Schrag et al., 2006). A poor levodopa response is one diagnostic feature of possible and probable MSA-P and may therefore be used to differentiate MSA-P from PD (Gilman et al., 2008). Although there is low evidence for the use of levodopa, its use is strongly supported by a broad clinical experience. Levodopa in daily doses up to 1 g is considered as first line therapy (Flabeau et al., 2010). Unresponsiveness to levodopa should only be accepted after a treatment period of at least
⁎ Correspondence to: G. Höglinger, Technical University Munich, Department of Neurology & German Center for Neurodegenerative Diseases (DZNE) e.V., Feodor-Lynen-Straße 17, 81377 Munich, Germany. ⁎⁎ Correspondence to: J. Levin, Ludwig-Maximilians-Universität München, Department of Neurology & German Center for Neurodegenerative Diseases (DZNE) e.V., Marchioninistraße 15, 81377 Munich, Germany. E-mail addresses: [email protected] (G.U. Höglinger), [email protected] (J. Levin).
http://dx.doi.org/10.1016/j.autneu.2017.10.006 Received 26 June 2017; Received in revised form 20 October 2017; Accepted 20 October 2017 1566-0702/ © 2017 Published by Elsevier B.V.
Please cite this article as: Rohrer, G., Autonomic Neuroscience: Basic and Clinical (2017), http://dx.doi.org/10.1016/j.autneu.2017.10.006
Autonomic Neuroscience: Basic and Clinical xxx (xxxx) xxx–xxx
G. Rohrer et al.
Table 1 Symptoms Motor symptoms Parkinsonism
Pharmacological interventions
Nonpharmacological interventions
Levodopa up to 1000 mg/d Amantadine 100–200 mg up to 3 ×/d
Physiotherapy Occupational therapy Speech therapy Physiotherapy Occupational therapy Speech therapy
Cerebellar ataxia
Dystonia Autonomic failure Urinary dysfunction Urge incontinence Incomplete bladder emptying Nycturia Erectile dysfunction Orthostatic hypotension Postprandial hypotension
Neuropsychiatric manifestations Depression Sleep disorders REM-sleep behavior disorder
Botulinum toxin A
Oxybutinin 2.5–5 mg 2–3 ×/d Injections of Botulinum toxin A into the detrusor muscle Moxisylyte 10 mg 3 ×/d Prazosin 1 mg 3 ×/d Desmopressin 10–40 μg intranasal spray once at night Sildenafil 50 mg–100 mg Ephedrine 15–45 × 3mg/d Fludrocortisone 0.1–0.4 mg/d Midodrine 2.5–10 mg 3 ×/d L-threo-DOPS 600 mg 2×/d Octreotide 25–50 μg s.c. 30 min before meals SSRIs
Intermittent or permanent urethral or suprapubic catheterization
Elastic stockings Adequate salt and fluid intake Head-up tilt during night
Psychotherapy
Clonazepam 0.5–2 mg/d Melatonin 2 mg/d Gabapentin 300–800 mg/d Pregabalin 75–100 mg/d Sodium oxybate 4.5–9 g/d
Nocturnal stridor
Non-invasive positive pressure ventilation (NPPV) Continuous positive airway pressure (CPAP) Tracheostomy
In PD, deep brain stimulation has been used very efficiently to improve motor symptoms and quality of daily life (Dams et al., 2013; Deuschl et al., 2006). In contrast, data from case reports and small case series in MSA patients evidence ineffectiveness of deep brain stimulation on motor symptoms in MSA (Chou et al., 2004; Lezcano et al., 2004; Meissner et al., 2016).
3 months without any significant clinical improvement (Gilman et al., 2008). Levodopa response may be objectified by improvement of 30% or more on part II of the Unified Multiple System Atrophy Rating Scale (UMSARS)(Wenning et al., 2004). Withdrawal of medication in patients without apparent clinical benefit may lead to an individual deterioration and justify continuation of treatment (Fanciulli and Wenning, 2015). Results of treatment with dopamine agonists have been disappointing as they show poor efficacy and may involve severe side effects, particularly worsening of orthostatic hypotension. Therefore dopamine agonists are not considered as a therapeutic option (Flabeau et al., 2010; Wenning et al., 1994). Amantadine may be considered as an alternative or additional treatment option for parkinsonism (2–3 × 100–200 mg daily). Amantadine showed a trend towards reduction of motor symptoms in anecdotal reports without providing clinically significant antiparkinsonian benefit in a placebo-controlled trial (Köllensperger et al., 2010; Rajrut et al., 1997; Wenning et al., 2005b). Side effects may include leg edema, livedo reticularis and confusion, especially when doses of more than 300 mg daily are used (Dutra and Vasconcellos, 2014; Hauser et al., 2017). As pharmaceutical strategies are of limited efficacy, non-pharmacological treatment options such as physiotherapy and occupational therapy play important roles in improving symptoms and patients quality of life. A randomized-controlled trial of patients with mild to moderate MSA obtaining occupational therapy showed significant improvement of motor function and activities of daily life (Jain et al., 2004). No controlled trials for physiotherapy are available so far. However, as motor function can be improved by physiotherapy in Parkinson's disease (Tomlinson et al., 2013), patients with MSA-P with predominant Parkinsonism as predominant motor feature may also benefit (Colosimo et al., 2005). Also physical support including canes, walkers or wheelchairs will be an option to support patients with severe movement disorders.
2.2. Cerebellar syndrome To date no efficient drug treatment is available for cerebellar symptoms such as gait ataxia, scanning dysarthria, ataxia of the limbs, intention tremor and oculomotor dysfunction. Intensive physiotherapy as well as resistance training and challengeoriented gait and balance training improve coordination, balance, gait and function in degenerative cerebellar disorders (Giannantoni et al., 2009; Ilg et al., 2014; Ilg et al., 2009; Landers et al., 2009; Wedge, 2008) and is therefore often integrated in the therapeutic concept. Patients with scanning dysarthria and impairment of swallowing may benefit from speech therapy (Colosimo et al., 2005). 2.3. Dystonia Focal dystonia, e.g. cervical dystonia (antecollis), blepharospasm and limb dystonia, is common in MSA-P. Reports on prevalence vary from 12% to 46% (Boesch et al., 2002; Wenning et al., 1997). Botulinum toxin injections may reduce dystonic symptoms and is described to be particularly effective in the treatment of blepharospasm. Furthermore, botulinum toxin may alleviate impaired function of dystonic limb in early disease stages (Müller et al., 2002). Treatment of cervical dystonia with botulinum toxin injections is currently being regarded as potentially harmful, as severe transient dysphagia may occur. For this indication botulinum toxin should therefore be applied with caution (Thobois et al., 2001). 2
Autonomic Neuroscience: Basic and Clinical xxx (xxxx) xxx–xxx
G. Rohrer et al.
3. Autonomic failure
pressure by at least 15 mm Hg after 3 min of standing after rising from the lying position or similar changes in blood pressure during a tilttable test during head-up tilt to at least 60° (Gilman et al., 2008). Nonpharmacologic management should include elastic stockings and abdominal bands (Fanciulli et al., 2016), adequate intake of salt and fluid and avoiding exposure to hot, humid environments (Deguchi et al., 2007; Lahrmann et al., 2006). Postural maneuvers such as head-up tilt during the night might increase intravasal volume and reduce hypotension in the morning (Flabeau et al., 2010; Freeman, 2008; Wenning et al., 2005a). A combination of non-pharmacological options with drug therapy may show better symptom control. The sympathomimetic midodrin (3 × 2.5–10 mg) led to an increase of standing blood pressure and improvement of orthostatic symptoms in a double-blind placebocontrolled study in patients with autonomic failure (Jankovic et al., 1993). No evidence is available for ephedrine (3 × 15–45 mg), another sympathomimetic agent similar to midodrine (Brooks et al., 1989). Fludrocortisone (0.1–0.4 mg/day) hasn't been explicitly studied for MSA but is known to be efficacious in treatment of orthostatic hypotension in PD (Harkel et al., 1992; Schoffer et al., 2007). The effect of the norepinephrine precursor L-threo-3,4-dihydroxyphenylserine (LDOPS, dose range from 200 to 2000 mg daily) was objectified in a double-blind, placebo-controlled, crossover study of patients with neurogenic orthostatic hypotension. An increased blood pressure and improved orthostatic tolerance were shown (Kaufmann et al., 2003). It was recently approved by the FDA for the short-term treatment of neurogenic orthostatic hypotension as it has been shown to significantly improve specific symptoms of neurogenic orthostatic hypotension including dizziness, vision disturbance, weakness and fatigue in two multicenter clinical trials. Yet the durability of the improvement in patients' symptoms beyond 2 weeks has not been demonstrated (Biaggioni et al., 2014; Kaufmann et al., 2014; Kaufmann et al., 2015).
Autonomic symptoms are a mandatory feature in current diagnostic criteria of MSA and therefore affect all patients in a variety of clinical symptoms. Symptomatic treatment is strongly recommended, as patients quality of life is strongly impaired (Schrag et al., 2006). To assure appropriate therapy, autonomic symptoms deserve especial attention during the assessment of the patients. 3.1. Urinary dysfunction The most common feature of autonomic failure is urinary dysfunction including urinary incontinence and incomplete bladder emptying (Fanciulli and Wenning, 2015). 3.1.1. Urinary incontinence Detrusor hyperreflexia and sphincter detrusor dyssynergy causing urge incontinence may be alleviated applying anticholinergic substances like oxybutinine (2–3 × 2.5–5 mg/d) (Colosimo et al., 2005; Wenning et al., 2005a). However, use of this drug leads to an increased risk of worsening urinary retention. In cases with detrusor over activity reports of beneficial effects of botulinum toxin injections into the detrusor muscle in two patients may justify this treatment option for refractory overactive bladder symptoms and detrusor over activity (Giannantoni et al., 2009; Knuepfer and Juenemann, 2014; Marzi et al., 2016). 3.1.1.1. Nycturia. Desmopressine (5 μg intranasal spray at night) has been reported to show therapeutical benefit without any observed side effects in three patients with MSA suffering from nycturia (Sakakibara et al., 2003). Other reports of patients suffering from chronic autonomic failure and consecutive nycturia show comparable results with similar doses (Mathias et al., 1986).
3.4. Postprandial hypotension
3.1.2. Incomplete bladder emptying Neurogenic urinary retention may cause morbidity due to intractable lower urinary tract infections and kidney dysfunction. Clean intermittent self-catheterization is recommended as first-line treatment for urinary retention in MSA (Fowler and O'Malley, 2003). However, permanent suprapubic catheterization may be necessary if motor impairment impedes catheterization advanced disease stages. Urethra oriented alpha-adrenergic antagonists prazosin (1 mg three times daily) and moxisylyte (10 mg three times daily) showed modest benefit in a trial of 49 patients (47% of patients experienced reduced post-micturition residual volumes) with slightly increased risk of worsening of orthostatic hypotension (not significant in moxisylyte)(Sakakibara et al., 2000). Their clinical use should be limited to patients with severe limb ataxia unable to perform self-catheterization.
Postprandial hypotension may be reduced by small and frequent meals with low carbohydrate intake. Octreotide (25–50 μg s.c. 30 min before meals) may have a positive effect on postprandial hypotension with low evidence emerging from case reports (Bordet et al., 1995; Bordet et al., 1994).
3.2. Erectile dysfunction
Non-motor symptoms as depression and anxiety play a major role in MSA. In spite of its frequent occurrence (up to 46% of patients; (Benrud-Larson et al., 2005; Schrag et al., 2006), randomized controlled trials addressing anxiety and depression in MSA are lacking (Strand, 2016). A double-blind placebo-controlled randomized study in 19 patients investigating paroxetine resulted in improvement of motor abilities without influencing depressive symptoms (Friess et al., 2006). Cognitive behavioral therapy as well as selective serotonergic reuptake inhibitors with lower risk of orthostatic hypotension than tricyclic drugs are primarily recommended (Strand, 2016). Alternative treatments with very low evidence may include electroconvulsive therapy (Shioda et al., 2006) in MSA cases fulfilling psychiatric criteria for major depression.
4. Neuropsychiatric manifestations Although neuropsychiatric manifestations such as depression and anxiety are frequent symptoms in MSA, little evidence about their treatment is available. Having a great impact on patient's quality of life, an empirical attempt should be made. 4.1. Depression
Sildenafil citrate (50 mg) has been proven to be efficacious in a randomized, double blind, placebo controlled, crossover study in the treatment of erectile dysfunction in MSA (Hussain et al., 2001; Wenning et al., 2013). Side effects include an increased risk of exacerbation of orthostatic hypotension. Thus performing a Schellong-test and educating the patient about seeking medical advice in the event that they develop symptoms suggestive of orthostatic hypotension are essential prerequisites for the use of sildenafil in MSA. 3.3. Orthostatic hypotension Orthostatic hypotension is a common symptom of autonomic failure, occurring in approximately 75% of MSA patients (Freeman, 2008). Orthostatic hypotension is defined as a sustained reduction of systolic blood pressure by at least 30 mm Hg or of diastolic blood
4.2. Cognitive impairment In contrast to other alpha-synucleinopathies such as Parkinson's 3
Autonomic Neuroscience: Basic and Clinical xxx (xxxx) xxx–xxx
G. Rohrer et al.
have string impact on the patients' quality of life. Aside of drug treatment one should never forget to employ non-pharmacological treatment options, also for autonomic failure and other non-motor symptoms of MSA. Physiotherapy, occupational therapy and speech therapy are also often indicated in hypokinetic and cerebellar syndromes as they can help to maintain the patient's autonomy.
disease and dementia with Lewy bodies, a dementia syndrome is not a supporting feature in the current diagnostic criteria of possible or probable MSA (Gilman et al., 2008). However a recent retrospective study of a cohort of 102 patients (Koga et al., 2017) revealed cognitive impairment (CI) in multiple domains in 32% of the patients, particularly in processing speed and executive functions suggesting a predominant fronto-subcortical pattern of cognitive dysfunction. CI may be linked to neuronal cytoplasmatic inclusions (NCI) in the dentate gyrus, although no regions responsible for specific cognitive deficits could be identified (Saito et al., 2017). To date, no effective treatment of cognitive impairment is available. However, as cognitive impairment affects multiple domains, in cases with marked short term memory disturbance or visuospacial deficits, a therapeutic approach with cholinesterase-inhibitors may be considered.
Acknowledgements Conflicts of interest: none. References Benrud-Larson, L.M., Sandroni, P., Schrag, A., Low, P.A., 2005. Depressive symptoms and life satisfaction in patients with multiple system atrophy. Mov. Disord. 20, 951–957. Biaggioni, I., Freeman, R., Mathias, C.J., Low, P., Hewitt, L.A., Kaufmann, H., 2014. Randomized withdrawal study of patients with symptomatic neurogenic orthostatic hypotension responsive to droxidopa. Hypertension 114.04035 (HYPERTENSIONAHA). Boesch, S., Wenning, G., Ransmayr, G., Poewe, W., 2002. Dystonia in multiple system atrophy. J. Neurol. Neurosurg. Psychiatry 72, 300–303. Bordet, R., Benhadjali, J., Libersa, C., Destee, A., 1994. Octreotide in the management of orthostatic hypotension in multiple system atrophy: pilot trial of chronic administration. Clin. Neuropharmacol. 17, 384. Bordet, R., Benhadjali, J., Destee, A., Belabbas, A., Libersa, C., 1995. Octreotide effects on orthostatic hypotension in patients with multiple system atrophy: a controlled study of acute administration. Clin. Neuropharmacol. 18, 83–89. Brooks, D., Redmond, S., Mathias, C., Bannister, R., Symon, L., 1989. The effect of orthostatic hypotension on cerebral blood flow and middle cerebral artery velocity in autonomic failure, with observations on the action of ephedrine. J. Neurol. Neurosurg. Psychiatry 52, 962–966. Chou, K.L., Forman, M.S., Trojanowski, J.Q., Hurtig, H.I., Baltuch, G.H., 2004. Subthalamic nucleus deep brain stimulation in a patient with levodopa-responsive multiple system atrophy: case report. J. Neurosurg. 100, 553–556. Colosimo, C., Tiple, D., Wenning, G., 2005. Management of multiple system atrophy: state of the art. J. Neural Transm. 112, 1695–1704. Constantinescu, R., Richard, I., Kurlan, R., 2007. Levodopa responsiveness in disorders with parkinsonism: a review of the literature. Mov. Disord. 22, 2141–2148. Dams, J., Siebert, U., Bornschein, B., Volkmann, J., Deuschl, G., Oertel, W.H., Dodel, R., Reese, J.P., 2013. Cost-effectiveness of deep brain stimulation in patients with Parkinson's disease. Mov. Disord. 28, 763–771. Deguchi, K., Ikeda, K., Sasaki, I., Shimamura, M., Urai, Y., Tsukaguchi, M., Touge, T., Takeuchi, H., Kuriyama, S., 2007. Effects of daily water drinking on orthostatic and postprandial hypotension in patients with multiple system atrophy. J. Neurol. 254, 735. Deuschl, G., Schade-Brittinger, C., Krack, P., Volkmann, J., Schäfer, H., Bötzel, K., Daniels, C., Deutschländer, A., Dillmann, U., Eisner, W., 2006. A randomized trial of deep-brain stimulation for Parkinson's disease. N. Engl. J. Med. 355, 896–908. Dutra, J.R., Vasconcellos, L.F.R., 2014. Livedo reticularis in multiple system atrophy: case report. Rev. Bras. Neurol. 50. Escriba, J., Hoyo, B., 2016. Alternatives to clonazepam in REM behavior disorder treatment. J. Clin. Sleep Med. 12, 1193. Fanciulli, A., Wenning, G.K., 2015. Multiple-system atrophy. N. Engl. J. Med. 372, 249–263. Fanciulli, A., Goebel, G., Metzler, B., Sprenger, F., Poewe, W., Wenning, G.K., Seppi, K., 2016. Elastic abdominal binders attenuate orthostatic hypotension in Parkinson's disease. Mov. Disord. Clin. Pract. 3, 156–160. Flabeau, O., Meissner, W.G., Tison, F., 2010. Multiple system atrophy: current and future approaches to management. Ther. Adv. Neurol. Disord. 3, 249–263. Fowler, C., O'Malley, K., 2003. Investigation and management of neurogenic bladder dysfunction. J. Neurol. Neurosurg. Psychiatry 74, iv27–iv31. Freeman, R., 2008. Neurogenic orthostatic hypotension. N. Engl. J. Med. 358, 615–624. Friess, E., Kuempfel, T., Modell, S., Winkelmann, J., Holsboer, F., Ising, M., Trenkwalder, C., 2006. Paroxetine treatment improves motor symptoms in patients with multiple system atrophy. Parkinsonism Relat. Disord. 12, 432–437. Garcia-Sanchez, A., Fernandez-Navarro, I., Garcia-Rio, F., 2016. Central apneas and REM sleep behavior disorder as an initial presentation of multiple system atrophy. J. Clin. Sleep Med. 12, 267. Ghorayeb, I., Yekhlef, F., Bioulac, B., Tison, F., 2005. Continuous positive airway pressure for sleep-related breathing disorders in multiple system atrophy: long-term acceptance. Sleep Med. 6, 359–362. Giannantoni, A., Rossi, A., Mearini, E., Del Zingaro, M., Porena, M., Berardelli, A., 2009. Botulinum toxin A for overactive bladder and detrusor muscle overactivity in patients with Parkinson's disease and multiple system atrophy. J. Urol. 182, 1453–1457. Gilman, S., Wenning, G., Low, P.A., Brooks, D., Mathias, C., Trojanowski, J., Wood, N.W., Colosimo, C., Dürr, A., Fowler, C., 2008. Second consensus statement on the diagnosis of multiple system atrophy. Neurology 71, 670–676. Harkel, A.T., Lieshout, J., Wieling, W., 1992. Treatment of orthostatic hypotension with sleeping in the head-up tilt position, alone and in combination with fludrocortisone. J. Intern. Med. 232, 139–145. Hauser, R.A., Pahwa, R., Tanner, C.M., Oertel, W., Isaacson, S.H., Johnson, R., Felt, L., Stempien, M.J., 2017. ADS-5102 (amantadine) extended-release capsules for
5. Sleep disorders in MSA 5.1. REM sleep behavior disorder REM sleep behavior disorder (RBD) (Schenck et al., 2013) has been described to affect 90–100% of MSA patients (Fanciulli and Wenning, 2015). In spite of the fact that this is one of the most frequent symptoms of MSA, to our knowledge no treatment trial of RBD in MSA has been performed so far. Therefore, treatment recommendations of RBD in MSA rely on general RBD recommendations. Clonazepam (0.5-2 mg) is considered first-line for the treatment of RBD (St Louis et al., 2017). In the clinical experience of the authors, small doses of 0.5 mg are sufficient in most cases. Potential induction of addiction is in our experience not an issue in MSA patients. In case of additional obstructive sleep apnea, clonazepam should be avoided. Other treatment options mostly rely on the experience of case reports, which reported success in some of the patients reported and include gabapentin (300–800 mg/d), pregabalin (75–150 mg/d), melatonin (2 mg/d) or sodium oxybate (4.5–9 g/d) (Escriba and Hoyo, 2016; Moghadam et al., 2017). In the authors' experience, melatonin is well tolerated even in higher doses than described in the literature rendering melatonin a good second line choice in case clonazepam is not efficient/contraindicated. 5.2. Nocturnal stridor Nocturnal stridor is a frequent symptom in MSA affecting up to 13% of patients (Silber and Levine, 2000). Nocturnal stridor is associated with respiratory failure and sudden death during sleep (Iranzo, 2007). Treatment recommendations emerging from several small studies include home non-invasive positive pressure ventilation (NPPV), which was reported to eliminate nocturnal stridor and oxygen desaturation during natural sleep in all patients studied (Nonaka et al., 2006). Continuous positive airway pressure (CPAP) ventilation has been used with comparable success (Iranzo et al., 2004). Especially patients in relatively early disease stages tolerate treatment well and were reported to continue treatment for more than one year (Ghorayeb et al., 2005). Tracheostomy may be used in advanced MSA to prevent airway obstruction due to bilateral vocal cord paralysis but can fatally exacerbate sleep-disordered breathing in MSA (Garcia-Sanchez et al., 2016). 6. Summary Symptomatic treatment options of MSA are often of limited efficacy but should nevertheless be attempted as patients' quality of life is severely affected during the course of the disease. All potential alleviating treatment options should therefore be exploited. Therapeutic approaches on the hypokinetic-rigid syndrome should primarily focus on levodopa, which has low formal evidence but the best clinical experience. Cerebellar ataxia lacks efficient treatment so far. Autonomic dysfunction affecting all patients fulfilling the current diagnostic criteria, should be in the special focus of our attention as such symptoms 4
Autonomic Neuroscience: Basic and Clinical xxx (xxxx) xxx–xxx
G. Rohrer et al.
249, 300–304. Nonaka, M., Imai, T., Shintani, T., Kawamata, M., Chiba, S., Matsumoto, H., 2006. Noninvasive positive pressure ventilation for laryngeal contraction disorder during sleep in multiple system atrophy. J. Neurol. Sci. 247, 53–58. Rajrut, A., Uitti, R.J., Fenton, M., George, D., 1997. Amantadine effectiveness in multiple system atrophy and progressive supranuclear palsy. Parkinsonism Relat. Disord. 3, 211–214. Saito, M., Hara, M., Ebashi, M., Morita, A., Okada, K., Homma, T., Sugitani, M., Endo, K., Uchihara, T., Kamei, S., 2017. Perirhinal accumulation of neuronal alpha-synuclein in a multiple system atrophy patient with dementia. Neuropathology 37, 431–440. Sakakibara, R., Hattori, T., Uchiyama, T., Suenaga, T., Takahashi, H., Yamanishi, T., Egoshi, K.-i., Sekita, N., 2000. Are alpha-blockers involved in lower urinary tract dysfunction in multiple system atrophy?: a comparison of prazosin and moxisylyte. J. Auton. Nerv. Syst. 79, 191–195. Sakakibara, R., Matsuda, S., Uchiyama, T., Yoshiyama, M., Yamanishi, T., Hattori, T., 2003. The effect of intranasal desmopressin on nocturnal waking in urination in multiple system atrophy patients with nocturnal polyuria. Clin. Auton. Res. 13, 106–108. Schenck, C., Montplaisir, J., Frauscher, B., Hogl, B., Gagnon, J.-F., Postuma, R., Sonka, K., Jennum, P., Partinen, M., Arnulf, I., 2013. Rapid eye movement sleep behavior disorder: devising controlled active treatment studies for symptomatic and neuroprotective therapy—a consensus statement from the International Rapid Eye Movement Sleep Behavior Disorder Study Group. Sleep Med. 14, 795–806. Schoffer, K.L., Henderson, R.D., O'maley, K., O'sullivan, J.D., 2007. Nonpharmacological treatment, fludrocortisone, and domperidone for orthostatic hypotension in Parkinson's disease. Mov. Disord. 22, 1543–1549. Schrag, A., Geser, F., Stampfer-Kountchev, M., Seppi, K., Sawires, M., Köllensperger, M., Scherfler, C., Quinn, N., Pellecchia, M.T., Barone, P., 2006. Health-related quality of life in multiple system atrophy. Mov. Disord. 21, 809–815. Schrag, A., Sheikh, S., Quinn, N.P., Lees, A.J., Selai, C., Mathias, C., Litvan, I., Lang, A.E., Bower, J.H., Burn, D.J., 2010. A comparison of depression, anxiety, and health status in patients with progressive supranuclear palsy and multiple system atrophy. Mov. Disord. 25, 1077–1081. Shioda, K., Nisijima, K., Kato, S., 2006. Electroconvulsive therapy for the treatment of multiple system atrophy with major depression. Gen. Hosp. Psychiatry 28, 81–83. Silber, M.H., Levine, S., 2000. Stridor and death in multiple system atrophy. Mov. Disord. 15, 699–704. St Louis, E.K., Boeve, A.R., Boeve, B.F., 2017. REM sleep behavior disorder in Parkinson's disease and other synucleinopathies. Mov. Disord. 32, 645–658. Stankovic, I., Krismer, F., Jesic, A., Antonini, A., Benke, T., Brown, R.G., Burn, D.J., Holton, J.L., Kaufmann, H., Kostic, V.S., 2014. Cognitive impairment in multiple system atrophy: a position statement by the Neuropsychology Task Force of the MDS Multiple System Atrophy (MODIMSA) study group. Mov. Disord. 29, 857–867. Strand, I.B., 2016. Depression and Anxiety in Parkinson's Disease and Multiple System Atrophy-Consequences for Treatment. Thobois, S., Broussolle, E., Toureille, L., Vial, C., 2001. Severe dysphagia after botulinum toxin injection for cervical dystonia in multiple system atrophy. Mov. Disord. 16, 764–765. Tomlinson, C.L., Patel, S., Meek, C., Herd, C.P., Clarke, C.E., Stowe, R., Shah, L., Sackley, C.M., Deane, K.H., Wheatley, K., 2013. Physiotherapy versus placebo or no intervention in Parkinson's disease. Cochrane Libr(9), CD002817. http://dx.doi.org/10. 1002/14651858.CD002817. Wedge, F., 2008. The impact of resistance training on balance and functional ability of a patient with multiple system atrophy. J. Geriatr. Phys. Ther. 31, 79–83. Wenning, G., Shlomo, Y.B., Magalhaes, M., Danie, S., Quinn, N., 1994. Clinical features and natural history of multiple system atrophy. Brain 117, 835–845. Wenning, G., Tison, F., Ben Shlomo, Y., Daniel, S., Quinn, N., 1997. Multiple system atrophy: a review of 203 pathologically proven cases. Mov. Disord. 12, 133–147. Wenning, G.K., Tison, F., Seppi, K., Sampaio, C., Diem, A., Yekhlef, F., Ghorayeb, I., Ory, F., Galitzky, M., Scaravilli, T., 2004. Development and validation of the unified multiple system atrophy rating scale (UMSARS). Mov. Disord. 19, 1391–1402. Wenning, G.K., Geser, F., Poewe, W., 2005a. Therapeutic strategies in multiple system atrophy. Mov. Disord. 20, S67–S76. Wenning, G.K., Society, W.G.o.A.P.o.t.A.P.s, 2005b. Placebo-controlled trial of amantadine in multiple-system atrophy. Clin. Neuropharmacol. 28, 225–227. Wenning, G.K., Geser, F., Krismer, F., Seppi, K., Duerr, S., Boesch, S., Köllensperger, M., Goebel, G., Pfeiffer, K.P., Barone, P., 2013. The natural history of multiple system atrophy: a prospective European cohort study. Lancet Neurol. 12, 264–274.
levodopa-induced dyskinesia in Parkinson's disease (EASE LID 2 study): interim results of an open-label safety study. J. Park. Dis. 7, 511–522. Hussain, I., Brady, C., Swinn, M., Mathias, C., Fowler, C., 2001. Treatment of erectile dysfunction with sildenafil citrate (Viagra) in parkinsonism due to Parkinson's disease or multiple system atrophy with observations on orthostatic hypotension. J. Neurol. Neurosurg. Psychiatry 71, 371–374. Ilg, W., Synofzik, M., Brötz, D., Burkard, S., Giese, M., Schöls, L., 2009. Intensive coordinative training improves motor performance in degenerative cerebellar disease. Neurology 73, 1823–1830. Ilg, W., Bastian, A.J., Boesch, S., Burciu, R., Celnik, P., Claaßen, J., Feil, K., Kalla, R., Miyai, I., Nachbauer, W., 2014. Consensus paper: management of degenerative cerebellar disorders. The. Cerebellum 13, 248–268. Iranzo, A., 2007. Sleep and breathing in multiple system atrophy. Curr. Treat. Options Neurol. 9, 347. Iranzo, A., Santamaria, J., Tolosa, E., Vilaseca, I., Valldeoriola, F., Marti, M., Muñoz, E., 2004. Long-term effect of CPAP in the treatment of nocturnal stridor in multiple system atrophy. Neurology 63, 930–932. Jain, S., Dawson, J., Quinn, N.P., Playford, E.D., 2004. Occupational therapy in multiple system atrophy: a pilot randomized controlled trial. Mov. Disord. 19, 1360–1364. Jankovic, J., Gilden, J.L., Hiner, B.C., Kaufmann, H., Brown, D.C., Coghlan, C.H., Rubin, M., Fouad-Tarazi, F.M., 1993. Neurogenic orthostatic hypotension: a double-blind, placebo-controlled study with midodrine. Am. J. Med. 95, 38–48. Kaufmann, H., Saadia, D., Voustianiouk, A., Goldstein, D.S., Holmes, C., Yahr, M.D., Nardin, R., Freeman, R., 2003. Norepinephrine precursor therapy in neurogenic orthostatic hypotension. Circulation 108, 724–728. Kaufmann, H., Freeman, R., Biaggioni, I., Low, P., Pedder, S., Hewitt, L.A., Mauney, J., Feirtag, M., Mathias, C.J., 2014. Droxidopa for neurogenic orthostatic hypotension a randomized, placebo-controlled, phase 3 trial. Neurology 83, 328–335. Kaufmann, H., Norcliffe-Kaufmann, L., Palma, J.-A., 2015. Droxidopa in neurogenic orthostatic hypotension. Expert. Rev. Cardiovasc. Ther. 13, 875–891. Knuepfer, S., Juenemann, K.-P., 2014. Experience with botulinum toxin type A in the treatment of neurogenic detrusor overactivity in clinical practice. Ther. Adv. Urol. 6, 34–42. Koga, S., Parks, A., Uitti, R.J., van Gerpen, J.A., Cheshire, W.P., Wszolek, Z.K., Dickson, D.W., 2017. Profile of cognitive impairment and underlying pathology in multiple system atrophy. Mov. Disord. 32, 405–413. Köllensperger, M., Geser, F., Ndayisaba, J.P., Boesch, S., Seppi, K., Ostergaard, K., Dupont, E., Cardozo, A., Tolosa, E., Abele, M., 2010. Presentation, diagnosis, and management of multiple system atrophy in Europe: final analysis of the European multiple system atrophy registry. Mov. Disord. 25, 2604–2612. Lahrmann, H., Cortelli, P., Hilz, M., Mathias, C., Struhal, W., Tassinari, M., 2006. EFNS guidelines on the diagnosis and management of orthostatic hypotension. Eur. J. Neurol. 13, 930–936. Landers, M., Adams, M., Acosta, K., Fox, A., 2009. Challenge-oriented gait and balance training in sporadic olivopontocerebellar atrophy: a case study. J. Neurol. Phys. Ther. 33, 160–168. Levin, J., Kurz, A., Arzberger, T., Giese, A., Höglinger, G.U., 2016. The differential diagnosis and treatment of atypical parkinsonism. Dtsch Arztebl Int 113, 61. Lezcano, E., Gómez-Esteban, J.C., Zarranz, J.J., Alcaraz, R., Atarés, B., Bilbao, G., Garibi, J., Lambarri, I., 2004. Parkinson's disease-like presentation of multiple system atrophy with poor response to STN stimulation: a clinicopathological case report. Mov. Disord. 19, 973–977. Marzi, V.L., Frizzi, J., Bonifazi, M., Del Popolo, G., 2016. Botulinum Toxin Bladder Injection in the Treatment of Neurogenic Detrusor Overactivity and Idiopathic OAB, Functional Urologic Surgery in Neurogenic and Oncologic Diseases. Springer, pp. 171–186. Mathias, C.J., Fosbraey, P., Da Costa, D., Thornley, A., Bannister, R., 1986. The effect of desmopressin on nocturnal polyuria, overnight weight loss, and morning postural hypotension in patients with autonomic failure. Br. Med. J. (Clin. Res. Ed.) 293, 353–354. Meissner, W.G., Laurencin, C., Tranchant, C., Witjas, T., Viallet, F., Guehl, D., Damier, P., Houeto, J.-L., Tison, F., Eusebio, A., 2016. Outcome of deep brain stimulation in slowly progressive multiple system atrophy: a clinico-pathological series and review of the literature. Parkinsonism Relat. Disord. 24, 69–75. Moghadam, K.K., Pizza, F., Primavera, A., Ferri, R., Plazzi, G., 2017. Sodium oxybate for idiopathic REM sleep behavior disorder: a report on two patients. Sleep Med. 32, 16–21. Müller, J., Wenning, G., Wissel, J., Seppi, K., Poewe, W., 2002. Botulinum toxin treatment in atypical parkinsonian disorders associated with disabling focal dystonia. J. Neurol.
5
Contents lists available at ScienceDirect
Autonomic Neuroscience: Basic and Clinical journal homepage: www.elsevier.com/locate/autneu
Review
Symptomatic therapy of multiple system atrophy Guido Rohrera, Günter U. Höglingerb,c,⁎, Johannes Levina,b,⁎⁎ a b c
Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany German Center for Neurodegenerative Diseases (DZNE), Munich, Germany Department of Neurology, Technical University Munich, Munich, Germany
A R T I C L E I N F O
A B S T R A C T
Keywords: Multiple system atrophy Motor symptoms Autonomic failure Alpha-synuclein Parkinson Cerebellum
Multiple system atrophy is a progressive neurodegenerative disease characterized by the association of autonomic failure and a movement disorder that consist of either a hypokinetic movement disorder or a cerebellar syndrome or both. In addition to these core characteristics other movement disorders (e.g. dystonia, myoclonus, spasticity), and neuropsychiatric symptoms (e.g. depression, cognitive dysfunction) may occur in the course of the disease and can severely impair patients' quality of live. To date no causal therapy is available and therefore symptomatic treatment plays a pivotal role in patient care. In this article we provide an overview of frequent clinical symptoms and their symptomatic treatment options.
1. Introduction Multiple system atrophy (MSA) is an adult onset, devastating, progressive neurodegenerative disease with a mean survival of 6 to 10 years from symptom onset (Fanciulli and Wenning, 2015). MSA is a slowly progressive disease characterized by the association of autonomic failure and a variety of movement disorders including parkinsonism and/or cerebellar ataxia as key features, but also dystonic and pyramidal symptoms. According to the predominant motor symptoms two subtypes have been described, characterized by either a hypokinetic-rigid parkinsonian syndrome (MSA-P) or a cerebellar syndrome (MSA-C). In both subtypes, autonomic dysfunction such as orthostatic hypotension, urinary incontinence or erectile dysfunction is required to establish the diagnosis of clinically possible or probable MSA according to current diagnostic criteria (Gilman et al., 2008). Especially autonomic symptoms have been described to severely impact the quality of life of MSA patients (Köllensperger et al., 2010). Another frequent symptom of MSA is occurrence of neuropsychiatric symptoms including depression (Schrag et al., 2006; Schrag et al., 2010). Cognitive impairment and dementia have been described in MSA, although being a non-supporting feature in current diagnostic criteria (Stankovic et al., 2014). At present, no casual treatment for disease modification is available. Therefore, symptomatic treatment is of pivotal importance in patient care along the course of the disease. In this article we provide an overview of the symptomatic treatment
options of the most relevant symptoms in MSA. Treatment options for MSA symptoms are displayed in Table 1. 2. Motor features Motor features in MSA are characterized by a predominant hypokinetic-rigid syndrome in MSA-P, a predominant cerebellar syndrome in MSA-C and other types of movement disorders such as focal dystonia, which can be present both in MSA-C and MSA-P (Levin et al., 2016). 2.1. Parkinsonism Hypokinesia, rigidity and early tendency to fall characterize the core motor features of MSA-P and can be observed at least to some extent in 87% of all cases (Köllensperger et al., 2010). Approximately one third of patients may respond to levodopa although benefit is temporarily limited and often markedly less pronounced than in patients with PD (Constantinescu et al., 2007; Köllensperger et al., 2010; Schrag et al., 2006). A poor levodopa response is one diagnostic feature of possible and probable MSA-P and may therefore be used to differentiate MSA-P from PD (Gilman et al., 2008). Although there is low evidence for the use of levodopa, its use is strongly supported by a broad clinical experience. Levodopa in daily doses up to 1 g is considered as first line therapy (Flabeau et al., 2010). Unresponsiveness to levodopa should only be accepted after a treatment period of at least
⁎ Correspondence to: G. Höglinger, Technical University Munich, Department of Neurology & German Center for Neurodegenerative Diseases (DZNE) e.V., Feodor-Lynen-Straße 17, 81377 Munich, Germany. ⁎⁎ Correspondence to: J. Levin, Ludwig-Maximilians-Universität München, Department of Neurology & German Center for Neurodegenerative Diseases (DZNE) e.V., Marchioninistraße 15, 81377 Munich, Germany. E-mail addresses: [email protected] (G.U. Höglinger), [email protected] (J. Levin).
http://dx.doi.org/10.1016/j.autneu.2017.10.006 Received 26 June 2017; Received in revised form 20 October 2017; Accepted 20 October 2017 1566-0702/ © 2017 Published by Elsevier B.V.
Please cite this article as: Rohrer, G., Autonomic Neuroscience: Basic and Clinical (2017), http://dx.doi.org/10.1016/j.autneu.2017.10.006
Autonomic Neuroscience: Basic and Clinical xxx (xxxx) xxx–xxx
G. Rohrer et al.
Table 1 Symptoms Motor symptoms Parkinsonism
Pharmacological interventions
Nonpharmacological interventions
Levodopa up to 1000 mg/d Amantadine 100–200 mg up to 3 ×/d
Physiotherapy Occupational therapy Speech therapy Physiotherapy Occupational therapy Speech therapy
Cerebellar ataxia
Dystonia Autonomic failure Urinary dysfunction Urge incontinence Incomplete bladder emptying Nycturia Erectile dysfunction Orthostatic hypotension Postprandial hypotension
Neuropsychiatric manifestations Depression Sleep disorders REM-sleep behavior disorder
Botulinum toxin A
Oxybutinin 2.5–5 mg 2–3 ×/d Injections of Botulinum toxin A into the detrusor muscle Moxisylyte 10 mg 3 ×/d Prazosin 1 mg 3 ×/d Desmopressin 10–40 μg intranasal spray once at night Sildenafil 50 mg–100 mg Ephedrine 15–45 × 3mg/d Fludrocortisone 0.1–0.4 mg/d Midodrine 2.5–10 mg 3 ×/d L-threo-DOPS 600 mg 2×/d Octreotide 25–50 μg s.c. 30 min before meals SSRIs
Intermittent or permanent urethral or suprapubic catheterization
Elastic stockings Adequate salt and fluid intake Head-up tilt during night
Psychotherapy
Clonazepam 0.5–2 mg/d Melatonin 2 mg/d Gabapentin 300–800 mg/d Pregabalin 75–100 mg/d Sodium oxybate 4.5–9 g/d
Nocturnal stridor
Non-invasive positive pressure ventilation (NPPV) Continuous positive airway pressure (CPAP) Tracheostomy
In PD, deep brain stimulation has been used very efficiently to improve motor symptoms and quality of daily life (Dams et al., 2013; Deuschl et al., 2006). In contrast, data from case reports and small case series in MSA patients evidence ineffectiveness of deep brain stimulation on motor symptoms in MSA (Chou et al., 2004; Lezcano et al., 2004; Meissner et al., 2016).
3 months without any significant clinical improvement (Gilman et al., 2008). Levodopa response may be objectified by improvement of 30% or more on part II of the Unified Multiple System Atrophy Rating Scale (UMSARS)(Wenning et al., 2004). Withdrawal of medication in patients without apparent clinical benefit may lead to an individual deterioration and justify continuation of treatment (Fanciulli and Wenning, 2015). Results of treatment with dopamine agonists have been disappointing as they show poor efficacy and may involve severe side effects, particularly worsening of orthostatic hypotension. Therefore dopamine agonists are not considered as a therapeutic option (Flabeau et al., 2010; Wenning et al., 1994). Amantadine may be considered as an alternative or additional treatment option for parkinsonism (2–3 × 100–200 mg daily). Amantadine showed a trend towards reduction of motor symptoms in anecdotal reports without providing clinically significant antiparkinsonian benefit in a placebo-controlled trial (Köllensperger et al., 2010; Rajrut et al., 1997; Wenning et al., 2005b). Side effects may include leg edema, livedo reticularis and confusion, especially when doses of more than 300 mg daily are used (Dutra and Vasconcellos, 2014; Hauser et al., 2017). As pharmaceutical strategies are of limited efficacy, non-pharmacological treatment options such as physiotherapy and occupational therapy play important roles in improving symptoms and patients quality of life. A randomized-controlled trial of patients with mild to moderate MSA obtaining occupational therapy showed significant improvement of motor function and activities of daily life (Jain et al., 2004). No controlled trials for physiotherapy are available so far. However, as motor function can be improved by physiotherapy in Parkinson's disease (Tomlinson et al., 2013), patients with MSA-P with predominant Parkinsonism as predominant motor feature may also benefit (Colosimo et al., 2005). Also physical support including canes, walkers or wheelchairs will be an option to support patients with severe movement disorders.
2.2. Cerebellar syndrome To date no efficient drug treatment is available for cerebellar symptoms such as gait ataxia, scanning dysarthria, ataxia of the limbs, intention tremor and oculomotor dysfunction. Intensive physiotherapy as well as resistance training and challengeoriented gait and balance training improve coordination, balance, gait and function in degenerative cerebellar disorders (Giannantoni et al., 2009; Ilg et al., 2014; Ilg et al., 2009; Landers et al., 2009; Wedge, 2008) and is therefore often integrated in the therapeutic concept. Patients with scanning dysarthria and impairment of swallowing may benefit from speech therapy (Colosimo et al., 2005). 2.3. Dystonia Focal dystonia, e.g. cervical dystonia (antecollis), blepharospasm and limb dystonia, is common in MSA-P. Reports on prevalence vary from 12% to 46% (Boesch et al., 2002; Wenning et al., 1997). Botulinum toxin injections may reduce dystonic symptoms and is described to be particularly effective in the treatment of blepharospasm. Furthermore, botulinum toxin may alleviate impaired function of dystonic limb in early disease stages (Müller et al., 2002). Treatment of cervical dystonia with botulinum toxin injections is currently being regarded as potentially harmful, as severe transient dysphagia may occur. For this indication botulinum toxin should therefore be applied with caution (Thobois et al., 2001). 2
Autonomic Neuroscience: Basic and Clinical xxx (xxxx) xxx–xxx
G. Rohrer et al.
3. Autonomic failure
pressure by at least 15 mm Hg after 3 min of standing after rising from the lying position or similar changes in blood pressure during a tilttable test during head-up tilt to at least 60° (Gilman et al., 2008). Nonpharmacologic management should include elastic stockings and abdominal bands (Fanciulli et al., 2016), adequate intake of salt and fluid and avoiding exposure to hot, humid environments (Deguchi et al., 2007; Lahrmann et al., 2006). Postural maneuvers such as head-up tilt during the night might increase intravasal volume and reduce hypotension in the morning (Flabeau et al., 2010; Freeman, 2008; Wenning et al., 2005a). A combination of non-pharmacological options with drug therapy may show better symptom control. The sympathomimetic midodrin (3 × 2.5–10 mg) led to an increase of standing blood pressure and improvement of orthostatic symptoms in a double-blind placebocontrolled study in patients with autonomic failure (Jankovic et al., 1993). No evidence is available for ephedrine (3 × 15–45 mg), another sympathomimetic agent similar to midodrine (Brooks et al., 1989). Fludrocortisone (0.1–0.4 mg/day) hasn't been explicitly studied for MSA but is known to be efficacious in treatment of orthostatic hypotension in PD (Harkel et al., 1992; Schoffer et al., 2007). The effect of the norepinephrine precursor L-threo-3,4-dihydroxyphenylserine (LDOPS, dose range from 200 to 2000 mg daily) was objectified in a double-blind, placebo-controlled, crossover study of patients with neurogenic orthostatic hypotension. An increased blood pressure and improved orthostatic tolerance were shown (Kaufmann et al., 2003). It was recently approved by the FDA for the short-term treatment of neurogenic orthostatic hypotension as it has been shown to significantly improve specific symptoms of neurogenic orthostatic hypotension including dizziness, vision disturbance, weakness and fatigue in two multicenter clinical trials. Yet the durability of the improvement in patients' symptoms beyond 2 weeks has not been demonstrated (Biaggioni et al., 2014; Kaufmann et al., 2014; Kaufmann et al., 2015).
Autonomic symptoms are a mandatory feature in current diagnostic criteria of MSA and therefore affect all patients in a variety of clinical symptoms. Symptomatic treatment is strongly recommended, as patients quality of life is strongly impaired (Schrag et al., 2006). To assure appropriate therapy, autonomic symptoms deserve especial attention during the assessment of the patients. 3.1. Urinary dysfunction The most common feature of autonomic failure is urinary dysfunction including urinary incontinence and incomplete bladder emptying (Fanciulli and Wenning, 2015). 3.1.1. Urinary incontinence Detrusor hyperreflexia and sphincter detrusor dyssynergy causing urge incontinence may be alleviated applying anticholinergic substances like oxybutinine (2–3 × 2.5–5 mg/d) (Colosimo et al., 2005; Wenning et al., 2005a). However, use of this drug leads to an increased risk of worsening urinary retention. In cases with detrusor over activity reports of beneficial effects of botulinum toxin injections into the detrusor muscle in two patients may justify this treatment option for refractory overactive bladder symptoms and detrusor over activity (Giannantoni et al., 2009; Knuepfer and Juenemann, 2014; Marzi et al., 2016). 3.1.1.1. Nycturia. Desmopressine (5 μg intranasal spray at night) has been reported to show therapeutical benefit without any observed side effects in three patients with MSA suffering from nycturia (Sakakibara et al., 2003). Other reports of patients suffering from chronic autonomic failure and consecutive nycturia show comparable results with similar doses (Mathias et al., 1986).
3.4. Postprandial hypotension
3.1.2. Incomplete bladder emptying Neurogenic urinary retention may cause morbidity due to intractable lower urinary tract infections and kidney dysfunction. Clean intermittent self-catheterization is recommended as first-line treatment for urinary retention in MSA (Fowler and O'Malley, 2003). However, permanent suprapubic catheterization may be necessary if motor impairment impedes catheterization advanced disease stages. Urethra oriented alpha-adrenergic antagonists prazosin (1 mg three times daily) and moxisylyte (10 mg three times daily) showed modest benefit in a trial of 49 patients (47% of patients experienced reduced post-micturition residual volumes) with slightly increased risk of worsening of orthostatic hypotension (not significant in moxisylyte)(Sakakibara et al., 2000). Their clinical use should be limited to patients with severe limb ataxia unable to perform self-catheterization.
Postprandial hypotension may be reduced by small and frequent meals with low carbohydrate intake. Octreotide (25–50 μg s.c. 30 min before meals) may have a positive effect on postprandial hypotension with low evidence emerging from case reports (Bordet et al., 1995; Bordet et al., 1994).
3.2. Erectile dysfunction
Non-motor symptoms as depression and anxiety play a major role in MSA. In spite of its frequent occurrence (up to 46% of patients; (Benrud-Larson et al., 2005; Schrag et al., 2006), randomized controlled trials addressing anxiety and depression in MSA are lacking (Strand, 2016). A double-blind placebo-controlled randomized study in 19 patients investigating paroxetine resulted in improvement of motor abilities without influencing depressive symptoms (Friess et al., 2006). Cognitive behavioral therapy as well as selective serotonergic reuptake inhibitors with lower risk of orthostatic hypotension than tricyclic drugs are primarily recommended (Strand, 2016). Alternative treatments with very low evidence may include electroconvulsive therapy (Shioda et al., 2006) in MSA cases fulfilling psychiatric criteria for major depression.
4. Neuropsychiatric manifestations Although neuropsychiatric manifestations such as depression and anxiety are frequent symptoms in MSA, little evidence about their treatment is available. Having a great impact on patient's quality of life, an empirical attempt should be made. 4.1. Depression
Sildenafil citrate (50 mg) has been proven to be efficacious in a randomized, double blind, placebo controlled, crossover study in the treatment of erectile dysfunction in MSA (Hussain et al., 2001; Wenning et al., 2013). Side effects include an increased risk of exacerbation of orthostatic hypotension. Thus performing a Schellong-test and educating the patient about seeking medical advice in the event that they develop symptoms suggestive of orthostatic hypotension are essential prerequisites for the use of sildenafil in MSA. 3.3. Orthostatic hypotension Orthostatic hypotension is a common symptom of autonomic failure, occurring in approximately 75% of MSA patients (Freeman, 2008). Orthostatic hypotension is defined as a sustained reduction of systolic blood pressure by at least 30 mm Hg or of diastolic blood
4.2. Cognitive impairment In contrast to other alpha-synucleinopathies such as Parkinson's 3
Autonomic Neuroscience: Basic and Clinical xxx (xxxx) xxx–xxx
G. Rohrer et al.
have string impact on the patients' quality of life. Aside of drug treatment one should never forget to employ non-pharmacological treatment options, also for autonomic failure and other non-motor symptoms of MSA. Physiotherapy, occupational therapy and speech therapy are also often indicated in hypokinetic and cerebellar syndromes as they can help to maintain the patient's autonomy.
disease and dementia with Lewy bodies, a dementia syndrome is not a supporting feature in the current diagnostic criteria of possible or probable MSA (Gilman et al., 2008). However a recent retrospective study of a cohort of 102 patients (Koga et al., 2017) revealed cognitive impairment (CI) in multiple domains in 32% of the patients, particularly in processing speed and executive functions suggesting a predominant fronto-subcortical pattern of cognitive dysfunction. CI may be linked to neuronal cytoplasmatic inclusions (NCI) in the dentate gyrus, although no regions responsible for specific cognitive deficits could be identified (Saito et al., 2017). To date, no effective treatment of cognitive impairment is available. However, as cognitive impairment affects multiple domains, in cases with marked short term memory disturbance or visuospacial deficits, a therapeutic approach with cholinesterase-inhibitors may be considered.
Acknowledgements Conflicts of interest: none. References Benrud-Larson, L.M., Sandroni, P., Schrag, A., Low, P.A., 2005. Depressive symptoms and life satisfaction in patients with multiple system atrophy. Mov. Disord. 20, 951–957. Biaggioni, I., Freeman, R., Mathias, C.J., Low, P., Hewitt, L.A., Kaufmann, H., 2014. Randomized withdrawal study of patients with symptomatic neurogenic orthostatic hypotension responsive to droxidopa. Hypertension 114.04035 (HYPERTENSIONAHA). Boesch, S., Wenning, G., Ransmayr, G., Poewe, W., 2002. Dystonia in multiple system atrophy. J. Neurol. Neurosurg. Psychiatry 72, 300–303. Bordet, R., Benhadjali, J., Libersa, C., Destee, A., 1994. Octreotide in the management of orthostatic hypotension in multiple system atrophy: pilot trial of chronic administration. Clin. Neuropharmacol. 17, 384. Bordet, R., Benhadjali, J., Destee, A., Belabbas, A., Libersa, C., 1995. Octreotide effects on orthostatic hypotension in patients with multiple system atrophy: a controlled study of acute administration. Clin. Neuropharmacol. 18, 83–89. Brooks, D., Redmond, S., Mathias, C., Bannister, R., Symon, L., 1989. The effect of orthostatic hypotension on cerebral blood flow and middle cerebral artery velocity in autonomic failure, with observations on the action of ephedrine. J. Neurol. Neurosurg. Psychiatry 52, 962–966. Chou, K.L., Forman, M.S., Trojanowski, J.Q., Hurtig, H.I., Baltuch, G.H., 2004. Subthalamic nucleus deep brain stimulation in a patient with levodopa-responsive multiple system atrophy: case report. J. Neurosurg. 100, 553–556. Colosimo, C., Tiple, D., Wenning, G., 2005. Management of multiple system atrophy: state of the art. J. Neural Transm. 112, 1695–1704. Constantinescu, R., Richard, I., Kurlan, R., 2007. Levodopa responsiveness in disorders with parkinsonism: a review of the literature. Mov. Disord. 22, 2141–2148. Dams, J., Siebert, U., Bornschein, B., Volkmann, J., Deuschl, G., Oertel, W.H., Dodel, R., Reese, J.P., 2013. Cost-effectiveness of deep brain stimulation in patients with Parkinson's disease. Mov. Disord. 28, 763–771. Deguchi, K., Ikeda, K., Sasaki, I., Shimamura, M., Urai, Y., Tsukaguchi, M., Touge, T., Takeuchi, H., Kuriyama, S., 2007. Effects of daily water drinking on orthostatic and postprandial hypotension in patients with multiple system atrophy. J. Neurol. 254, 735. Deuschl, G., Schade-Brittinger, C., Krack, P., Volkmann, J., Schäfer, H., Bötzel, K., Daniels, C., Deutschländer, A., Dillmann, U., Eisner, W., 2006. A randomized trial of deep-brain stimulation for Parkinson's disease. N. Engl. J. Med. 355, 896–908. Dutra, J.R., Vasconcellos, L.F.R., 2014. Livedo reticularis in multiple system atrophy: case report. Rev. Bras. Neurol. 50. Escriba, J., Hoyo, B., 2016. Alternatives to clonazepam in REM behavior disorder treatment. J. Clin. Sleep Med. 12, 1193. Fanciulli, A., Wenning, G.K., 2015. Multiple-system atrophy. N. Engl. J. Med. 372, 249–263. Fanciulli, A., Goebel, G., Metzler, B., Sprenger, F., Poewe, W., Wenning, G.K., Seppi, K., 2016. Elastic abdominal binders attenuate orthostatic hypotension in Parkinson's disease. Mov. Disord. Clin. Pract. 3, 156–160. Flabeau, O., Meissner, W.G., Tison, F., 2010. Multiple system atrophy: current and future approaches to management. Ther. Adv. Neurol. Disord. 3, 249–263. Fowler, C., O'Malley, K., 2003. Investigation and management of neurogenic bladder dysfunction. J. Neurol. Neurosurg. Psychiatry 74, iv27–iv31. Freeman, R., 2008. Neurogenic orthostatic hypotension. N. Engl. J. Med. 358, 615–624. Friess, E., Kuempfel, T., Modell, S., Winkelmann, J., Holsboer, F., Ising, M., Trenkwalder, C., 2006. Paroxetine treatment improves motor symptoms in patients with multiple system atrophy. Parkinsonism Relat. Disord. 12, 432–437. Garcia-Sanchez, A., Fernandez-Navarro, I., Garcia-Rio, F., 2016. Central apneas and REM sleep behavior disorder as an initial presentation of multiple system atrophy. J. Clin. Sleep Med. 12, 267. Ghorayeb, I., Yekhlef, F., Bioulac, B., Tison, F., 2005. Continuous positive airway pressure for sleep-related breathing disorders in multiple system atrophy: long-term acceptance. Sleep Med. 6, 359–362. Giannantoni, A., Rossi, A., Mearini, E., Del Zingaro, M., Porena, M., Berardelli, A., 2009. Botulinum toxin A for overactive bladder and detrusor muscle overactivity in patients with Parkinson's disease and multiple system atrophy. J. Urol. 182, 1453–1457. Gilman, S., Wenning, G., Low, P.A., Brooks, D., Mathias, C., Trojanowski, J., Wood, N.W., Colosimo, C., Dürr, A., Fowler, C., 2008. Second consensus statement on the diagnosis of multiple system atrophy. Neurology 71, 670–676. Harkel, A.T., Lieshout, J., Wieling, W., 1992. Treatment of orthostatic hypotension with sleeping in the head-up tilt position, alone and in combination with fludrocortisone. J. Intern. Med. 232, 139–145. Hauser, R.A., Pahwa, R., Tanner, C.M., Oertel, W., Isaacson, S.H., Johnson, R., Felt, L., Stempien, M.J., 2017. ADS-5102 (amantadine) extended-release capsules for
5. Sleep disorders in MSA 5.1. REM sleep behavior disorder REM sleep behavior disorder (RBD) (Schenck et al., 2013) has been described to affect 90–100% of MSA patients (Fanciulli and Wenning, 2015). In spite of the fact that this is one of the most frequent symptoms of MSA, to our knowledge no treatment trial of RBD in MSA has been performed so far. Therefore, treatment recommendations of RBD in MSA rely on general RBD recommendations. Clonazepam (0.5-2 mg) is considered first-line for the treatment of RBD (St Louis et al., 2017). In the clinical experience of the authors, small doses of 0.5 mg are sufficient in most cases. Potential induction of addiction is in our experience not an issue in MSA patients. In case of additional obstructive sleep apnea, clonazepam should be avoided. Other treatment options mostly rely on the experience of case reports, which reported success in some of the patients reported and include gabapentin (300–800 mg/d), pregabalin (75–150 mg/d), melatonin (2 mg/d) or sodium oxybate (4.5–9 g/d) (Escriba and Hoyo, 2016; Moghadam et al., 2017). In the authors' experience, melatonin is well tolerated even in higher doses than described in the literature rendering melatonin a good second line choice in case clonazepam is not efficient/contraindicated. 5.2. Nocturnal stridor Nocturnal stridor is a frequent symptom in MSA affecting up to 13% of patients (Silber and Levine, 2000). Nocturnal stridor is associated with respiratory failure and sudden death during sleep (Iranzo, 2007). Treatment recommendations emerging from several small studies include home non-invasive positive pressure ventilation (NPPV), which was reported to eliminate nocturnal stridor and oxygen desaturation during natural sleep in all patients studied (Nonaka et al., 2006). Continuous positive airway pressure (CPAP) ventilation has been used with comparable success (Iranzo et al., 2004). Especially patients in relatively early disease stages tolerate treatment well and were reported to continue treatment for more than one year (Ghorayeb et al., 2005). Tracheostomy may be used in advanced MSA to prevent airway obstruction due to bilateral vocal cord paralysis but can fatally exacerbate sleep-disordered breathing in MSA (Garcia-Sanchez et al., 2016). 6. Summary Symptomatic treatment options of MSA are often of limited efficacy but should nevertheless be attempted as patients' quality of life is severely affected during the course of the disease. All potential alleviating treatment options should therefore be exploited. Therapeutic approaches on the hypokinetic-rigid syndrome should primarily focus on levodopa, which has low formal evidence but the best clinical experience. Cerebellar ataxia lacks efficient treatment so far. Autonomic dysfunction affecting all patients fulfilling the current diagnostic criteria, should be in the special focus of our attention as such symptoms 4
Autonomic Neuroscience: Basic and Clinical xxx (xxxx) xxx–xxx
G. Rohrer et al.
249, 300–304. Nonaka, M., Imai, T., Shintani, T., Kawamata, M., Chiba, S., Matsumoto, H., 2006. Noninvasive positive pressure ventilation for laryngeal contraction disorder during sleep in multiple system atrophy. J. Neurol. Sci. 247, 53–58. Rajrut, A., Uitti, R.J., Fenton, M., George, D., 1997. Amantadine effectiveness in multiple system atrophy and progressive supranuclear palsy. Parkinsonism Relat. Disord. 3, 211–214. Saito, M., Hara, M., Ebashi, M., Morita, A., Okada, K., Homma, T., Sugitani, M., Endo, K., Uchihara, T., Kamei, S., 2017. Perirhinal accumulation of neuronal alpha-synuclein in a multiple system atrophy patient with dementia. Neuropathology 37, 431–440. Sakakibara, R., Hattori, T., Uchiyama, T., Suenaga, T., Takahashi, H., Yamanishi, T., Egoshi, K.-i., Sekita, N., 2000. Are alpha-blockers involved in lower urinary tract dysfunction in multiple system atrophy?: a comparison of prazosin and moxisylyte. J. Auton. Nerv. Syst. 79, 191–195. Sakakibara, R., Matsuda, S., Uchiyama, T., Yoshiyama, M., Yamanishi, T., Hattori, T., 2003. The effect of intranasal desmopressin on nocturnal waking in urination in multiple system atrophy patients with nocturnal polyuria. Clin. Auton. Res. 13, 106–108. Schenck, C., Montplaisir, J., Frauscher, B., Hogl, B., Gagnon, J.-F., Postuma, R., Sonka, K., Jennum, P., Partinen, M., Arnulf, I., 2013. Rapid eye movement sleep behavior disorder: devising controlled active treatment studies for symptomatic and neuroprotective therapy—a consensus statement from the International Rapid Eye Movement Sleep Behavior Disorder Study Group. Sleep Med. 14, 795–806. Schoffer, K.L., Henderson, R.D., O'maley, K., O'sullivan, J.D., 2007. Nonpharmacological treatment, fludrocortisone, and domperidone for orthostatic hypotension in Parkinson's disease. Mov. Disord. 22, 1543–1549. Schrag, A., Geser, F., Stampfer-Kountchev, M., Seppi, K., Sawires, M., Köllensperger, M., Scherfler, C., Quinn, N., Pellecchia, M.T., Barone, P., 2006. Health-related quality of life in multiple system atrophy. Mov. Disord. 21, 809–815. Schrag, A., Sheikh, S., Quinn, N.P., Lees, A.J., Selai, C., Mathias, C., Litvan, I., Lang, A.E., Bower, J.H., Burn, D.J., 2010. A comparison of depression, anxiety, and health status in patients with progressive supranuclear palsy and multiple system atrophy. Mov. Disord. 25, 1077–1081. Shioda, K., Nisijima, K., Kato, S., 2006. Electroconvulsive therapy for the treatment of multiple system atrophy with major depression. Gen. Hosp. Psychiatry 28, 81–83. Silber, M.H., Levine, S., 2000. Stridor and death in multiple system atrophy. Mov. Disord. 15, 699–704. St Louis, E.K., Boeve, A.R., Boeve, B.F., 2017. REM sleep behavior disorder in Parkinson's disease and other synucleinopathies. Mov. Disord. 32, 645–658. Stankovic, I., Krismer, F., Jesic, A., Antonini, A., Benke, T., Brown, R.G., Burn, D.J., Holton, J.L., Kaufmann, H., Kostic, V.S., 2014. Cognitive impairment in multiple system atrophy: a position statement by the Neuropsychology Task Force of the MDS Multiple System Atrophy (MODIMSA) study group. Mov. Disord. 29, 857–867. Strand, I.B., 2016. Depression and Anxiety in Parkinson's Disease and Multiple System Atrophy-Consequences for Treatment. Thobois, S., Broussolle, E., Toureille, L., Vial, C., 2001. Severe dysphagia after botulinum toxin injection for cervical dystonia in multiple system atrophy. Mov. Disord. 16, 764–765. Tomlinson, C.L., Patel, S., Meek, C., Herd, C.P., Clarke, C.E., Stowe, R., Shah, L., Sackley, C.M., Deane, K.H., Wheatley, K., 2013. Physiotherapy versus placebo or no intervention in Parkinson's disease. Cochrane Libr(9), CD002817. http://dx.doi.org/10. 1002/14651858.CD002817. Wedge, F., 2008. The impact of resistance training on balance and functional ability of a patient with multiple system atrophy. J. Geriatr. Phys. Ther. 31, 79–83. Wenning, G., Shlomo, Y.B., Magalhaes, M., Danie, S., Quinn, N., 1994. Clinical features and natural history of multiple system atrophy. Brain 117, 835–845. Wenning, G., Tison, F., Ben Shlomo, Y., Daniel, S., Quinn, N., 1997. Multiple system atrophy: a review of 203 pathologically proven cases. Mov. Disord. 12, 133–147. Wenning, G.K., Tison, F., Seppi, K., Sampaio, C., Diem, A., Yekhlef, F., Ghorayeb, I., Ory, F., Galitzky, M., Scaravilli, T., 2004. Development and validation of the unified multiple system atrophy rating scale (UMSARS). Mov. Disord. 19, 1391–1402. Wenning, G.K., Geser, F., Poewe, W., 2005a. Therapeutic strategies in multiple system atrophy. Mov. Disord. 20, S67–S76. Wenning, G.K., Society, W.G.o.A.P.o.t.A.P.s, 2005b. Placebo-controlled trial of amantadine in multiple-system atrophy. Clin. Neuropharmacol. 28, 225–227. Wenning, G.K., Geser, F., Krismer, F., Seppi, K., Duerr, S., Boesch, S., Köllensperger, M., Goebel, G., Pfeiffer, K.P., Barone, P., 2013. The natural history of multiple system atrophy: a prospective European cohort study. Lancet Neurol. 12, 264–274.
levodopa-induced dyskinesia in Parkinson's disease (EASE LID 2 study): interim results of an open-label safety study. J. Park. Dis. 7, 511–522. Hussain, I., Brady, C., Swinn, M., Mathias, C., Fowler, C., 2001. Treatment of erectile dysfunction with sildenafil citrate (Viagra) in parkinsonism due to Parkinson's disease or multiple system atrophy with observations on orthostatic hypotension. J. Neurol. Neurosurg. Psychiatry 71, 371–374. Ilg, W., Synofzik, M., Brötz, D., Burkard, S., Giese, M., Schöls, L., 2009. Intensive coordinative training improves motor performance in degenerative cerebellar disease. Neurology 73, 1823–1830. Ilg, W., Bastian, A.J., Boesch, S., Burciu, R., Celnik, P., Claaßen, J., Feil, K., Kalla, R., Miyai, I., Nachbauer, W., 2014. Consensus paper: management of degenerative cerebellar disorders. The. Cerebellum 13, 248–268. Iranzo, A., 2007. Sleep and breathing in multiple system atrophy. Curr. Treat. Options Neurol. 9, 347. Iranzo, A., Santamaria, J., Tolosa, E., Vilaseca, I., Valldeoriola, F., Marti, M., Muñoz, E., 2004. Long-term effect of CPAP in the treatment of nocturnal stridor in multiple system atrophy. Neurology 63, 930–932. Jain, S., Dawson, J., Quinn, N.P., Playford, E.D., 2004. Occupational therapy in multiple system atrophy: a pilot randomized controlled trial. Mov. Disord. 19, 1360–1364. Jankovic, J., Gilden, J.L., Hiner, B.C., Kaufmann, H., Brown, D.C., Coghlan, C.H., Rubin, M., Fouad-Tarazi, F.M., 1993. Neurogenic orthostatic hypotension: a double-blind, placebo-controlled study with midodrine. Am. J. Med. 95, 38–48. Kaufmann, H., Saadia, D., Voustianiouk, A., Goldstein, D.S., Holmes, C., Yahr, M.D., Nardin, R., Freeman, R., 2003. Norepinephrine precursor therapy in neurogenic orthostatic hypotension. Circulation 108, 724–728. Kaufmann, H., Freeman, R., Biaggioni, I., Low, P., Pedder, S., Hewitt, L.A., Mauney, J., Feirtag, M., Mathias, C.J., 2014. Droxidopa for neurogenic orthostatic hypotension a randomized, placebo-controlled, phase 3 trial. Neurology 83, 328–335. Kaufmann, H., Norcliffe-Kaufmann, L., Palma, J.-A., 2015. Droxidopa in neurogenic orthostatic hypotension. Expert. Rev. Cardiovasc. Ther. 13, 875–891. Knuepfer, S., Juenemann, K.-P., 2014. Experience with botulinum toxin type A in the treatment of neurogenic detrusor overactivity in clinical practice. Ther. Adv. Urol. 6, 34–42. Koga, S., Parks, A., Uitti, R.J., van Gerpen, J.A., Cheshire, W.P., Wszolek, Z.K., Dickson, D.W., 2017. Profile of cognitive impairment and underlying pathology in multiple system atrophy. Mov. Disord. 32, 405–413. Köllensperger, M., Geser, F., Ndayisaba, J.P., Boesch, S., Seppi, K., Ostergaard, K., Dupont, E., Cardozo, A., Tolosa, E., Abele, M., 2010. Presentation, diagnosis, and management of multiple system atrophy in Europe: final analysis of the European multiple system atrophy registry. Mov. Disord. 25, 2604–2612. Lahrmann, H., Cortelli, P., Hilz, M., Mathias, C., Struhal, W., Tassinari, M., 2006. EFNS guidelines on the diagnosis and management of orthostatic hypotension. Eur. J. Neurol. 13, 930–936. Landers, M., Adams, M., Acosta, K., Fox, A., 2009. Challenge-oriented gait and balance training in sporadic olivopontocerebellar atrophy: a case study. J. Neurol. Phys. Ther. 33, 160–168. Levin, J., Kurz, A., Arzberger, T., Giese, A., Höglinger, G.U., 2016. The differential diagnosis and treatment of atypical parkinsonism. Dtsch Arztebl Int 113, 61. Lezcano, E., Gómez-Esteban, J.C., Zarranz, J.J., Alcaraz, R., Atarés, B., Bilbao, G., Garibi, J., Lambarri, I., 2004. Parkinson's disease-like presentation of multiple system atrophy with poor response to STN stimulation: a clinicopathological case report. Mov. Disord. 19, 973–977. Marzi, V.L., Frizzi, J., Bonifazi, M., Del Popolo, G., 2016. Botulinum Toxin Bladder Injection in the Treatment of Neurogenic Detrusor Overactivity and Idiopathic OAB, Functional Urologic Surgery in Neurogenic and Oncologic Diseases. Springer, pp. 171–186. Mathias, C.J., Fosbraey, P., Da Costa, D., Thornley, A., Bannister, R., 1986. The effect of desmopressin on nocturnal polyuria, overnight weight loss, and morning postural hypotension in patients with autonomic failure. Br. Med. J. (Clin. Res. Ed.) 293, 353–354. Meissner, W.G., Laurencin, C., Tranchant, C., Witjas, T., Viallet, F., Guehl, D., Damier, P., Houeto, J.-L., Tison, F., Eusebio, A., 2016. Outcome of deep brain stimulation in slowly progressive multiple system atrophy: a clinico-pathological series and review of the literature. Parkinsonism Relat. Disord. 24, 69–75. Moghadam, K.K., Pizza, F., Primavera, A., Ferri, R., Plazzi, G., 2017. Sodium oxybate for idiopathic REM sleep behavior disorder: a report on two patients. Sleep Med. 32, 16–21. Müller, J., Wenning, G., Wissel, J., Seppi, K., Poewe, W., 2002. Botulinum toxin treatment in atypical parkinsonian disorders associated with disabling focal dystonia. J. Neurol.
5