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Nbaa Masood, Joohi Jimenez-Shahed Department of Neurology, Icahn School of Medicine at Mount Sinai, Mount Sinai West, New York, NY, USACorrespondence: Joohi Jimenez-Shahed, Associate Professor of Neurology & Neurosurgery, Icahn School of Medicine at Mount Sinai, Bonnie and Tom Strauss Movement Disorders Center, 1000 10th Avenue, Suite 10C, New York, NY, 10019, USA, Tel +1 212-523-8335, Fax +1 212-523-8342, Email Joohi.Jimenez-Shahed@mountsinai.orgAbstract: Motor complications related to the chronic administration of levodopa and failure to prevent the neurodegenerative disease process counterbalance the pivotal discovery of levodopa as the cornerstone of PD treatment. Excellent motor control is offered early during the course of treatment, but this diminishes as pathological changes in the striatum lead to synaptic dopamine levels becoming completely dependent on exogenous dopamine. This non-physiologic stimulation of dopamine receptors eventually manifests as OFF episodes. As no disease modifying therapy exists for PD that can disrupt these pathological changes, most research and treatment focuses on optimization of dopaminergic stimulation of striatal receptors so that they mimic tonic, physiologic stimulation as closely as possible. Strategies focusing on these challenges have included non-pharmacologic approaches, optimizing levodopa pharmacokinetics, using adjunctive treatments including those with non-dopaminergic mechanisms, and implementing rescue therapies. Device aided therapies, including surgery, are also available. In this review, we will focus on effective management of motor symptoms related to OFF periods, including emerging strategies. Unmet clinical needs will be discussed, including non-motor symptoms, targeted molecular therapies and disease modifying therapy.Keywords: continuous dopaminergic stimulation, advanced Parkinson’s Disease, motor complications, nonmotor symptoms, dyskinesias, chronic levodopa complications

Ami B Patel, Joohi Jimenez-Shahed Department of Neurology, Baylor College of Medicine, Houston, TX, USA Abstract: Inhaled levodopa is a newly emerging therapeutic option in the treatment of “off” symptoms associated with Parkinson’s disease (PD). Its mode of delivery offers more rapid absorption of levodopa and shorter onset of clinical benefit compared to oral formulations, and has been shown to be feasible for use in patients with PD experiencing worse motor function due to declining plasma levodopa levels. Clinical development of this compound is supported by preclinical, Phase I–III, long-term-safety studies and studies in special populations, including otherwise-healthy asthmatics and smokers. These investigations demonstrated that the drug is well tolerated without risk of long-term (up to 1 year) changes in pulmonary function or spirometry measures. The most common side effects among PD patients were a mild cough, upper respiratory tract infection, nausea, sputum discoloration, and dyskinesia. Inhaled levodopa offers a different administration method and side-effect profile from the currently available options for rescue therapy for Off periods in PD, though comparative studies have not been performed. The drug is presently under review by the US Food and Drug Administration. Keywords: levodopa, dry-powder inhalation, motor fluctuations, dyskinesia, spirometry

Joohi Jimenez-ShahedDepartment of Neurology, Baylor College of Medicine, Houston, TX, USAAbstract: Dystonia is a movement disorder of uncertain pathogenesis that is characterized by involuntary and inappropriate muscle contractions which cause sustained abnormal postures and movements of multiple or single (focal) body regions. The most common focal dystonias are cervical dystonia (CD) and blepharospasm (BSP). The first-line recommended treatment for CD and BSP is injection with botulinum toxin (BoNT), of which two serotypes are available: BoNT type A (BoNT/A) and BoNT type B (BoNT/B). Conventional BoNT formulations include inactive complexing proteins, which may increase the risk for antigenicity, possibly leading to treatment failure. IncobotulinumtoxinA (Xeomin®; Merz Pharmaceuticals GmbH, Frankfurt, Germany) is a BoNT/A agent that has been recently Food and Drug Administration-approved for the treatment of adults with CD and adults with BSP previously treated with onabotulinumtoxinA (Botox®; Allergen, Inc, Irvine, CA) – a conventional BoNT/A. IncobotulinumtoxinA is the only BoNT product that is free of complexing proteins. The necessity of complexing proteins for the effectiveness of botulinum toxin treatment has been challenged by preclinical and clinical studies with incobotulinumtoxinA. These studies have also suggested that incobotulinumtoxinA is associated with a lower risk for stimulating antibody formation than onabotulinumtoxinA. In phase 3 noninferiority trials, incobotulinumtoxinA demonstrated significant improvements in CD and BSP symptoms in both primary and secondary measures, compared with baseline, and met criteria for noninferiority versus onabotulinumtoxinA. In placebo-controlled trials, incobotulinumtoxinA also significantly improved the symptoms of CD and BSP, with robust outcomes in both primary and secondary measures. The use of incobotulinumtoxinA has been well tolerated in all trials, with an adverse event profile similar to that of onabotulinumtoxinA. Based on these data, incobotulinumtoxinA is a safe and effective BoNT/A for the treatment of CD and BSP, and may pose a lower risk for immunogenicity leading to treatment failure compared with other available BoNT agents. This paper reviews the treatment of focal dystonias with BoNTs, in particular, incobotulinumtoxinA. Controlled trials from the existing incobotulinumtoxinA literature are summarized.Keywords: blepharospasm, botulinum toxin, cervical dystonia, complexing proteins, dystonia, incobotulinumtoxinA (Xeomin®)