Faculty Bibliography

Oral medications for the treatment of dystonia are not established. Currently, symptoms of focal dystonia are managed with botulinum toxin injections into the affected muscles. However, the injection effects are short-lived and not beneficial for all patients. We recently reported significant clinical improvement of symptoms with novel investigational oral drug, sodium oxybate, in patients with the alcohol-responsive form of laryngeal focal dystonia. Understanding the mechanism of action of this promising oral agent holds a strong potential for the development of a scientific rationale for its use in dystonia. Therefore, to determine the neural markers of sodium oxybate effects, which may underlie dystonic symptom improvement, we examined brain activity during symptomatic speech production before and after drug intake in patients with laryngeal dystonia and compared to healthy subjects. We found that sodium oxybate significantly attenuated hyperfunctional activity of cerebellar, thalamic and primary/secondary sensorimotor cortical regions. Drug-induced symptom improvement was correlated with decreased-to-normal levels of activity in the right cerebellum. These findings suggest that sodium oxybate shows direct modulatory effects on disorder pathophysiology by acting upon abnormal neural activity within the dystonic network.

Background/UNASSIGNED:Myoclonus and tremor are common movement disorder phenomenologies in steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT). Pure ataxia without encephalopathy has rarely been reported. Case report/UNASSIGNED:We report 21- and 40-year-old females who presented with subacute pure ataxia without encephalopathy. After immunotherapies, both exhibited initial improvement of ataxia, and subsequently remained in plateau phase. Discussion/UNASSIGNED:This treatable disorder should be added to the differential diagnoses of progressive cerebellar ataxia, and anti-thyroid peroxidase and anti-thyroglobulin should be considered as part of the workup. It is crucial not to misdiagnose SREAT presenting with pure cerebellar ataxia as degenerative or spinocerebellar ataxia.

INTRODUCTION/BACKGROUND:This study aimed to assess the outcomes of mirabegron for the treatment of overactive bladder (OAB) symptoms in patients with Parkinson disease (PD). METHODS:A retrospective study was conducted including patients with PD who received mirabegron 50 mg once daily for OAB symptoms between 2012 and 2017. The primary endpoint was clinical success defined as any improvement in overactive bladder symptoms self-assessed by the patients 6 weeks after mirabegron initiation. Secondary endpoints included number of pads per day, number of nocturia episodes and adverse events. RESULTS:Fifty patients (mean 74 years old) were included. Before being treated with mirabegron, 56% had failed prior anticholinergic therapy. After 6 weeks of mirabegron 50 mg, five patients (11.4%) had a complete resolution of their OAB symptoms; 25 patients (50%) reported improvement, 23 (46%) reported no change and 2(4%) reported worsening of their OAB symptoms. The number of pads per day decreased from 1.5 to 0.9 (p = 0.01) and so did the number of nocturia episodes (from 3 to 2.6/night; p = 0.02). Only 2 adverse events were reported during mirabegron treatment (4%): one dizziness and one diaphoresis, that disappeared after mirabegron discontinuation. After a median follow-up of 19 months, 23 patients (46%) persisted on mirabegron. Persistence rates were 51.5%, 44.6% and 36.4% at 1, 2 and 3 years respectively. CONCLUSION/CONCLUSIONS:Mirabegron has an excellent safety profile and appears to be an effective treatment for overactive bladder symptoms in patients with PD. Further prospective randomized trials are needed to properly assess mirabegron in PD patients.

OBJECTIVE:To assess the safety and efficacy of intradetrusor onabotulinum toxin A injections for the treatment of overactive bladder (OAB) in patients with Parkinson's disease (PD). METHODS:All PD patients who underwent intradetrusor injections of onabotulinum toxin A (BoNT-A) for storage symptoms between 2010 and 2017 were included in a retrospective study. A 100 U dose of BoNT-A (Botox®, Allergan Irvine, CA) was used for the first injection in all patients. The primary endpoint was clinical success defined as any subjective improvement in OAB symptoms self-assessed by the patients 4 weeks after the injections. RESULTS:Out of 24 patients analyzed, 19 reported improvement of their OAB symptoms 4 weeks after the first injection (79.2%) with complete resolution of urgency urinary incontinence in seven patients (29.1%; P < 0.001). The average post-void residual (PVR) increased significantly after the first injection from 17.6 to 125.3 mL (P < 0.001). Three of the patients had to start clean intermittent catheterization (CIC) after the first injection (12.5%). Out of 49 injections in total, only five caused incomplete bladder emptying requiring the use of CIC (10.2%). Higher pre-injection PVR was significantly associated with both a lower chance of symptomatic improvement (P = 0.04) and a higher risk of incomplete bladder emptying with institution of CIC (P = 0.047). CONCLUSION/CONCLUSIONS:Intradetrusor injections of BoNT-A 100 U appeared as a safe and effective option in PD patients with OAB symptoms and a low PVR before the injection. Higher preoperative PVR was the strongest predictor of both treatment failure and postoperative urinary retention requiring CIC.

OBJECTIVE:Laryngeal dystonia (LD) is a functionally specific disorder of the afferent-efferent motor coordination system producing action-induced muscle contraction with a varied phenomenology. This report of long-term studies aims to review and better define the phenomenology and central nervous system abnormalities of this disorder and improve diagnosis and treatment. METHODS:Our studies categorized over 1,400 patients diagnosed with LD over the past 33 years, including demographic and medical history records and their phenomenological presentations. Patients were grouped on clinical phenotype (adductor or abductor) and genotype (sporadic and familial) and with DNA analysis and functional magnetic resonance imaging (fMRI) to investigate brain organization differences and characterize neural markers for genotype/phenotype categorization. A number of patients with alcohol-sensitive dystonia were also studied. RESULTS:A spectrum of LD phenomena evolved: adductor, abductor, mixed, singer's, dystonic tremor, and adductor respiratory dystonia. Patients were genetically screened for DYT (dystonia) 1, DYT4, DYT6, and DYT25 (GNAL)-and several were positive. The functional MRI studies showed distinct alterations within the sensorimotor network, and the LD patients with a family history had distinct cortical and cerebellar abnormalities. A linear discriminant analysis of fMRI findings showed a 71% accuracy in characterizing LD from normal and in characterizing adductor from abductor forms. CONCLUSION/CONCLUSIONS:Continuous studies of LD patients over 30 years has led to an improved understanding of the phenomenological characteristics of this neurological disorder. Genetic and fMRI studies have better characterized the disorder and raise the possibility of making objective rather than subjective diagnoses, potentially leading to new therapeutic approaches. Laryngoscope, 128:S1-S9, 2018.

Mitochondrial aminoacyl-tRNA synthetases (mtARSs) are essential, ubiquitously expressed enzymes that covalently attach amino acids to their corresponding tRNA molecules during translation of mitochondrial genes. Deleterious variants in the mtARS genes cause a diverse array of phenotypes, many of which involve the nervous system. Moreover, distinct mutations in mtARSs often cause different clinical manifestations. Recently, the gene encoding mitochondrial tryptophanyl tRNA synthetase (WARS2) was reported to cause two different neurological phenotypes, a form of autosomal recessive intellectual disability and a syndrome of severe infantile-onset leukoencephalopathy. Here, we present the case of a 17 year-old boy with compound heterozygous mutations in WARS2 (p.Trp13Gly, p.Ser228Trp) who presented with infantile-onset, Levodopa responsive parkinsonism at the age of 2 years. Analysis of patient-derived dermal fibroblasts revealed decreased steady state WARS2 protein and normal OXPHOS content. Muscle mitochondrial studies suggested mitochondrial proliferation without obvious respiratory chain deficiencies at age 9 years. This case expands the phenotypic spectrum of WARS2 deficiency and emphasizes the importance of mitochondrial protein synthesis in the pathogenesis of parkinsonism.

Background/UNASSIGNED:Primary progressive apraxia is a rare form of apraxia in the absence of dementia which develops insidiously and is slowly progressive. Most reports of patients with apraxia also describe coexisting aphasias or involve additional apraxias with affected speech, usually in the setting of neurodegenerative diseases such as corticobasal degeneration, Alzheimer's disease or frontotemporal dementia. The aim of this report is to describe and demonstrate by video two cases of isolated primary progressive ideomotor apraxia seen in our clinic. Case presentation/UNASSIGNED:We describe two patients with 2-5 years of progressive difficulty using their hands, despite having intact cognition and lack of correlating lesions on imaging. Conclusion/UNASSIGNED:We report two cases of primary progressive apraxia that may be early presentations of taupathic disease in both patients. In both cases, there is isolated profound ideomotor apraxia of the hands, with preserved cognition, language skills, muscle power and tone, and gait. There are no correlating lesions on imaging.

Background/UNASSIGNED:Dopa-responsive dystonia (DRD) has largely been associated with autosomal dominant mutations in the GCH1 gene leading to GTP cyclohydrolase 1 deficiency. More recently, a deficiency in tyrosine hydroxylase (TH) has been recognized to cause DRD. This is a rare disorder resulting from genetic mutations in the TH gene on chromosome 11. The phenotype ranges from DRD with complete resolution on levodopa to infantile parkinsonism and encephalopathy only partially responsive to levodopa. Here we discuss an adult with TH deficiency with a history of possible parkinsonism and dystonia responsive to levodopa, notable for a residual dynamic segmental dystonia. Case presentation/UNASSIGNED:Our patient grew up in rural Myanmar with limited medical care. Childhood was normal except for episodic illness with difficulty moving and speaking. At 18 years he developed difficulty writing. At 21 years he could not speak, walk, or write and was taken to a city hospital. Multiple medications were tried without benefit until he received carbidopa/levodopa, to which he had a miraculous response. Since then he has attempted to come off medication, however after several weeks his symptoms returned. On presentation to us at 31 years he was taking 450 mg levodopa/day and 4 mg trihexyphenidyl/day. He had a dynamic dystonia in his neck and trunk, subtle at rest and prominent with walking. He exhibited a sensory trick when touching his hand to his chin; improvement occurred to a lesser degree when he imagined touching his chin, and to an even lesser degree when the examiner touched his chin. He had no parkinsonism. He underwent genetic testing which revealed a homozygous variant mutation in the TH gene (p.Thr494Met) leading to a diagnosis of autosomal recessive tyrosine hydroxylase deficiency. Conclusions/UNASSIGNED:TH deficiency can cause a broad range of clinical symptoms and severity. As more cases are discovered, the phenotype expands. Here we describe a unique case of DRD and possible parkinsonism due to TH deficiency with residual symptoms of dystonia that was task dependent and responded to a sensory trick. In addition, while the history is limited, it is possible he may have had episodes similar to "lethargy-irritability crises" seen in more severe cases. In large part he fits within the milder form of TH hydroxylase deficiency.