To date, cerebrospinal fluid or blood biomarkers, even in combination, are still not specific enough or need further evidence-based studies before they can be employed in routine use for the clinical diagnosis of MSA [Constantinescu 2010; Mollenhauer and Trenkwalder, 2009]

To date, cerebrospinal fluid or blood biomarkers, even in combination, are still not specific enough or need further evidence-based studies before they can be employed in routine use for the clinical diagnosis of MSA [Constantinescu 2010; Mollenhauer and Trenkwalder, 2009]. neuroprotective drugs, and future approaches for the management in MSA. 2006; Tison 2002]. MSA is characterized by a variable combination of poor levodopa responsive Parkinsonism, cerebellar ataxia and autonomic failure [Gilman 2008]. MSA-Parkinsonism type Fusicoccin (MSA-P) predominates in the Western Hemisphere and MSA-cerebellar type (MSA-C) is the major phenotype in the Eastern Hemisphere [Watanabe 2002]. There is no recognized efficient treatment for cerebellar ataxia whereas levodopa may transiently improve Parkinsonism in one third of the patients [Constantinescu 2007; Wenning 1997]. Since autonomic failure strongly correlates with poor quality of life [Schrag 2006], therapeutic management focuses on symptomatic therapy of orthostatic hypotension (OH), constipation, genitourinary and breathing disorders. Mean survival is about 9C10 years after symptom onset [Schrag 2008] with nocturnal sudden death being a major cause of death [Shimohata 2008]. Hitherto, no treatment has been shown to improve survival in MSA, creating a strong need for new therapeutic approaches. Abnormal aggregation of alpha-synuclein in oligodendrocytes is the pathological hallmark of MSA and may trigger the progressive cell loss in widespread brain areas [Jellinger and Lantos, 2010; Wenning 2008, 1997]. Advances in therapeutics have been achieved during the past 10 years through the development of transgenic animal models and experimental strategies against alpha-synuclein accumulation and for neuroprotection [Stefanova 2009]. This progress may provide a testbed for future candidate drugs discovery and multicentric clinical trials. Here we review potential neuroprotective drugs, current symptomatic treatment and future approaches in the management of MSA. Current therapies A list of the currently symptomatic treatment for MSA is given in Table 1. Table 1. Available symptomatic treatment for multiple system atrophy (MSA). Almost all of the therapeutics currently used are based on expert experience and do not meet scientific evidence standards. Double-blind, placebo-controlled trials are indicated in references. 2006]Cerebellar ataxiaPhysiotherapyClonazepam, propanolol, baclofen, amantadine, gabapentin, buspironeOrthostatic hypotension Nonpharmacological measures (custom-fitted elastic stockings, raising the head of the bed when sleeping, water drinking, small meals). Midodrine from 2.5 to 30?mg per day [Wright 1998; Low 1997; Jankovic 1993]aFludrocortisone, pyridostigmine,b Fusicoccin droxidopa [Mathias, 2008],c [Kaufmann 2003], antidiuretic hormone desmopressin at bedtime, ephedrine, octreotideNeurogenic lower urinary tract dysfunctionIf postvoid residual 100?ml, clean intermittent catheterizationBotulinum toxin A in the detrusor muscle or the urethral sphincter, surgery options, permanent catheterizationIf postvoid residual 100?ml, anticholinergic agents for detrusor hyperactivity, -adrenergic antagonists for urethra hypertonyConstipationHigh fluid and fibre intake classical laxative therapy, polycarbophil, mosapride citrate, macrogol 3350Erectile dysfunctionIntracavernosal injection of papaverine or prostaglandin E1, sildenafil [Hussain 2001]Subcutaneous apomorphine injectionsBreathing disordersContinuous positive air pressureTracheostomy (for life-threatening and/or daytime stridor, abnormal vocal cord mobility on laryngoscopy), laryngeal surgery or botulinum toxin injections, adaptive servoventilationDystoniaBotulinum toxin injection, levodopa therapyAnticholinergics, amantadine, dopamine agonists, muscle relaxants, tetrabenazineCamptocormiaPhysiotherapy with specific orthosis, wearing a backpackBotulinum toxin injections, protirelin tartrateRapid eye movement sleep behavior disorderClonazepamSodium oxybate, temazepam, zopiclone, gabapentin, pramipexole, donepezil, melatonineDepressionPsychotherapyElectroconvulsive therapy Selective serotonergic reuptake inhibitors, levodopa therapyRepetitive transcranial magnetic stimulationCognitive impairmentSpeech therapyDroolingAnticholinergic drugsInjection of botulinum toxin into the salivary glands Open in a separate window aAmong all of Mouse monoclonal to EGFR. Protein kinases are enzymes that transfer a phosphate group from a phosphate donor onto an acceptor amino acid in a substrate protein. By this basic mechanism, protein kinases mediate most of the signal transduction in eukaryotic cells, regulating cellular metabolism, transcription, cell cycle progression, cytoskeletal rearrangement and cell movement, apoptosis, and differentiation. The protein kinase family is one of the largest families of proteins in eukaryotes, classified in 8 major groups based on sequence comparison of their tyrosine ,PTK) or serine/threonine ,STK) kinase catalytic domains. Epidermal Growth factor receptor ,EGFR) is the prototype member of the type 1 receptor tyrosine kinases. EGFR overexpression in tumors indicates poor prognosis and is observed in tumors of the head and neck, brain, bladder, stomach, breast, lung, endometrium, cervix, vulva, ovary, esophagus, stomach and in squamous cell carcinoma. the subjects included in these trials, there was a minority of MSA patients: 40/171 subjects [Low 1997], 7/25 [Wright 1998], and 18/97 [Jankovic 1993]. In available subgroup analysis, beneficial effect on orthostatic hypotension (OH) was reported [Low 1997; Jankovic 1993]. bPositive effect on OH regarding subgroup analysis in 17 MSA patients of the 58 subjects included, but there was no placebo group control [Singer 2006]. cPreliminary results. Parkinsonism A poor levodopa response is one of the consensus criteria for the diagnosis of MSA [Gilman 2008] and helps to differentiate MSA from PD [Wenning 2000]. Although there are no controlled clinical trials on the efficacy of levodopa in MSA, about one third of patients may experience Fusicoccin a benefit, more often in the MSA-P subtype than in MSA-C [Constantinescu 2007]. In series with pathological confirmation, the positive levodopa responsiveness is reported in 28C65% of the patients [Colosimo 1995; Wenning 1997, 1995; Hughes 1992; Fearnley and Lees, 1990; Rajput 1990]. However, this effect persists for several years (as in PD) in only 13% of all patients [Wenning 1994]. Although levodopa induces less delirium and hallucinations in MSA than in PD [Wenning 2000], it can lead to adverse effects.