Outpatient Motor Retraining for Functional Movement Disorder: Predictors of a Favorable Short-Term Response.

Background: Treating functional movement disorder (FMD) with motor retraining is effective but resource intensive. Objectives: Identify patient, disease, and program variables associated with favorable treatment outcomes. Methods: Retrospective review of the 1 week intensive outpatient FMD program at Mayo Clinic in Minnesota from February 2019 to August 2021. Outcomes included patient-reported measures (Canadian Occupational Performance Measure-Performance and Satisfaction subscales [COPM-P and COPM-S, range 0-10] and Global Rating of Change [GROC, -7 to +7]) and a retrospective investigator-rated scale (0-3, worse/not improved to significantly improved/resolved). Linear regression models identified variables predicting favorable outcomes. Results: Participants (n = 201, 74% female, mean age = 46) had median FMD duration of 24 months. The commonest FMD subtypes were gait disorder (65%), tremor (41%) and weakness (17%); 53% had ≥2 subtypes. Most patients (88%) completed a therapeutic screening process before program entry. Patient-reported outcomes at the end of the week improved substantially (COPM-P average change 3.8 ± 1.9; GROC post-program average 5.5 ± 1.7). Available investigator-rated outcomes from short-term follow-up were also positive (102/122 [84%] moderately to significantly improved/resolved). Factors predicting greater improvement in COPM-P were completing therapeutic screening, higher number of non-motor symptoms, shorter FMD duration, earlier program entry, lower baseline COPM scores, and (among screened patients) higher GROC between therapeutic screening and program start. Conclusion: Patients with diverse FMD subtypes improved substantially over a 1 week period. Utilization of therapeutic screening and greater improvement between therapeutic screening and program start were novel predictors of favorable outcomes. Non-motor symptoms did not preclude positive responses, although patients with predominant non-motor burden were excluded.

Episodic Ataxias: Primary and Secondary Etiologies, Treatment, and Classification Approaches.

Background: Episodic ataxia (EA), characterized by recurrent attacks of cerebellar dysfunction, is the manifestation of a group of rare autosomal dominant inherited disorders. EA1 and EA2 are most frequently encountered, caused by mutations in KCNA1 and CACNA1A. EA3-8 are reported in rare families. Advances in genetic testing have broadened the KCNA1 and CACNA1A phenotypes, and detected EA as an unusual presentation of several other genetic disorders. Additionally, there are various secondary causes of EA and mimicking disorders. Together, these can pose diagnostic challenges for neurologists. Methods: A systematic literature review was performed in October 2022 for 'episodic ataxia' and 'paroxysmal ataxia', restricted to publications in the last 10 years to focus on recent clinical advances. Clinical, genetic, and treatment characteristics were summarized. Results: EA1 and EA2 phenotypes have further broadened. In particular, EA2 may be accompanied by other paroxysmal disorders of childhood with chronic neuropsychiatric features. New treatments for EA2 include dalfampridine and fampridine, in addition to 4-aminopyridine and acetazolamide. There are recent proposals for EA9-10. EA may also be caused by gene mutations associated with chronic ataxias (SCA-14, SCA-27, SCA-42, AOA2, CAPOS), epilepsy syndromes (KCNA2, SCN2A, PRRT2), GLUT-1, mitochondrial disorders (PDHA1, PDHX, ACO2), metabolic disorders (Maple syrup urine disease, Hartnup disease, type I citrullinemia, thiamine and biotin metabolism defects), and others. Secondary causes of EA are more commonly encountered than primary EA (vascular, inflammatory, toxic-metabolic). EA can be misdiagnosed as migraine, peripheral vestibular disorders, anxiety, and functional symptoms. Primary and secondary EA are frequently treatable which should prompt a search for the cause. Discussion: EA may be overlooked or misdiagnosed for a variety of reasons, including phenotype-genotype variability and clinical overlap between primary and secondary causes. EA is highly treatable, so it is important to consider in the differential diagnosis of paroxysmal disorders. Classical EA1 and EA2 phenotypes prompt single gene test and treatment pathways. For atypical phenotypes, next generation genetic testing can aid diagnosis and guide treatment. Updated classification systems for EA are discussed which may assist diagnosis and management.

Deep Brain Stimulator Device Infection: The Mayo Clinic Rochester Experience.

Background: Deep brain stimulator (DBS)-related infection is a recognized complication that may significantly alter the course of DBS therapy. We describe the Mayo Clinic Rochester experience with DBS-related infections. Methods: This was a retrospective study of all adults (≥18 years old) who underwent DBS-related procedures between 2000 and 2020 at the Mayo Clinic Rochester. Results: There were 1087 patients who underwent 1896 procedures. Infection occurred in 57/1112 (5%) primary DBS implantations and 16/784 (2%) revision surgeries. The median time to infection (interquartile range) was 2.1 (0.9-6.9) months. The odds of infection were higher with longer operative length (P = .002), higher body mass index (BMI; P = .006), male sex (P = .041), and diabetes mellitus (P = .002). The association between infection and higher BMI (P = .002), male sex (P = .016), and diabetes mellitus (P = .003) remained significant in a subgroup analysis of primary implantations but not revision surgeries. Infection was superficial in 17 (23%) and deep in 56 (77%) cases. Commonly identified pathogens were Staphylococcus aureus (65%), coagulase-negative staphylococci (43%), and Cutibacterium acnes (45%). Three device management approaches were identified: 39 (53%) had complete device explantation, 20 (27%) had surgical intervention with device retention, and 14 (19%) had medical management alone. Treatment failure occurred in 16 (23%) patients. Time-to-event analysis showed fewer treatment failures with complete device explantation (P = .015). Only 1 individual had complications with brain abscess at failure. Conclusions: Primary DBS implantations had higher rates of infection compared with revision surgeries. Complete device explantation was favored for deep infections. However, device salvage was commonly attempted and is a reasonable approach in select cases given the low rate of complications.

Efficacy and Safety of N-Acetyl-l-Leucine in Children and Adults With GM2 Gangliosidoses.

BACKGROUND AND OBJECTIVES: GM2 gangliosidoses (Tay-Sachs and Sandhoff diseases) are rare, autosomal recessive, neurodegenerative diseases with no available symptomatic or disease-modifying treatments. This clinical trial investigated N-acetyl-l-leucine (NALL), an orally administered, modified amino acid in pediatric (≥6 years) and adult patients with GM2 gangliosidoses. METHODS: In this phase IIb, multinational, open-label, rater-blinded study (IB1001-202), male and female patients aged ≥6 years with a genetically confirmed diagnosis of GM2 gangliosidoses received orally administered NALL for a 6-week treatment period (4 g/d in patients ≥13 years, weight-tiered doses for patients 6-12 years), followed by a 6-week posttreatment washout period. For the primary Clinical Impression of Change in Severity analysis, patient performance on a predetermined primary anchor test (the 8-Meter Walk Test or the 9-Hole Peg Test) at baseline, after 6 weeks on NALL, and again after a 6-week washout period was videoed and evaluated centrally by blinded raters. Secondary outcomes included assessments of ataxia, clinical global impression, and quality of life. RESULTS: Thirty patients between the age of 6 and 55 years were enrolled. Twenty-nine had an on-treatment assessment and were included in the primary modified intention-to-treat analysis. The study met its CI-CS primary end point (mean difference 0.71, SD = 2.09, 90% CI 0.00, 1.50, p = 0.039), as well as secondary measures of ataxia and global impression. NALL was safe and well tolerated, with no serious adverse reactions. DISCUSSION: Treatment with NALL was associated with statistically significant and clinically relevant changes in functioning and quality of life in patients with GM2 gangliosidosis. NALL was safe and well tolerated, contributing to an overall favorable risk:benefit profile. NALL is a promising, easily administered (oral) therapeutic option for these rare, debilitating diseases with immense unmet medical needs. TRIAL REGISTRATION INFORMATION: The trial is registered with ClinicalTrials.gov (NCT03759665; registered on November 30, 2018), EudraCT (2018-004406-25), and DRKS (DRKS00017539). The first patient was enrolled on June 7, 2019. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that NALL improves outcomes for patients with GM2 gangliosidoses.

The Effects of Deep Brain Stimulation in Patients with Multiple System Atrophy.

The course of patients with multiple system atrophy (MSA) who undergo deep brain stimulation (DBS) is unclear. In a retrospective review of 1,496 patients with MSA evaluated at our institutions from 1998-2021, 12 patients underwent DBS; 9 had a diagnosis of Parkinson's disease at the time of surgery. Nine patients reported initial improvement in at least one symptom and 7 experienced overall worsening following DBS. All patients had at least one red flag sign or symptom suggesting atypical parkinsonism prior to surgery. Considering overall poor outcomes of DBS in MSA, we recommend careful consideration of red flags in patient selection.

Utility of routine surface electrophysiology to screen for functional tremor prior to surgical treatment of essential tremor.

Background: Patients with functional tremor may be clinically misdiagnosed as "medication-refractory" essential tremor (ET) and referred for surgical treatment. Electrophysiology can screen for functional tremor and avoid inappropriate surgery. Objective: To report the utility of surface electrophysiology (SEMG) to screen for functional tremor in patients referred for ET surgery. Methods: Retrospective review of consecutive ET patients referred to the Mayo Clinic DBS clinic over 1.5 years. Included subjects had a clinical diagnosis of medication-refractory ET and completed presurgical workup including routine SEMG tremor study. Results: Of 87 subjects, 9 (10%) were clinically suspected of functional tremor by the DBS neurologist. Electrophysiology confirmed functional tremor features in 7/9 and ET in the other 2/9; and newly identified 5 additional cases of functional tremor. There were 12 total confirmed cases of functional tremor: isolated in 1, and mixed functional tremor and ET in 11. Of 11 mixed patients, 6 with mild functional overlay were approved for surgery. The remaining 5 patients with moderate-severe functional overlay and the single patient with isolated functional tremor were referred to the functional tremor motor retraining program. Of these, 1 patient with mixed tremor had residual disabling organic ET after program completion and was later approved for surgery. Thus, 5/87 patients (6%) avoided unnecessary surgery. Conclusions: Functional tremor may frequently overlay "medication-refractory" ET amongst patients referred for surgery, affecting 1 of 7 patients in our quaternary referral DBS center. Electrophysiology studies are useful to routinely screen patients and prevent unnecessary surgery.

Speech-induced action myoclonus.

BACKGROUND: Speech-induced action myoclonus may occur as a component of a generalized myoclonus syndrome. However, it may also present in isolation, or with a paucity of other findings, and be diagnostically challenging. OBJECTIVES: To report a retrospective case series of restricted speech-induced action myoclonus. METHODS: We reviewed cases of speech-induced action myoclonus evaluated at Mayo Clinic Rochester from 1989 to 2020. We eliminated cases where a more generalized myoclonic disorder was also present. Clinical, imaging, and electrophysiologic data were extracted. RESULTS: Four cases were identified in which speech-induced action myoclonus of craniofacial muscles was the predominant clinical presentation. All described cranial muscle twitching induced by speaking, and two cases also reported speech interruptions. Diagnosis was confirmed by expert speech pathologists in all cases. Diagnostic aids included modulation with different speech tasks and speaking rates, and surface electrophysiology which confirmed craniofacial myoclonus induced by speaking tasks (three cases). Previous misdiagnosis included functional, dystonic, neuromuscular junction pathology, or hemifacial spasm. Two cases had isolated speech-induced myoclonus, and the other two had coexistent upper limb tremor. Potential etiologic factors were identified in three cases - medication (2), epilepsy (1) - while in one patient no cause was identified. One patient partially improved with anti-myoclonic medication and speech therapy. CONCLUSIONS: Speech-induced action myoclonus may occur in isolation and is frequently misdiagnosed. Diagnostic aids include modulation with different speech tasks and speaking rates, and surface electrophysiology.

Effectiveness of Thalamic Ventralis Oralis Anterior and Posterior Nuclei Deep Brain Stimulation for Posttraumatic Dystonia.

Herein we report that the ventralis oralis anterior and posterior (Voa/Vop) nuclei of the thalamus may be effective alternative targets for deep brain stimulation (DBS) to improve posttraumatic dystonia when the globus pallidus interna is traumatically damaged. This patient presented at age 35 years with a clinical diagnosis of posttraumatic cervical and bilateral upper limb acquired dystonia resulting from intracerebral and intraventricular hemorrhage after a motorcycle accident at age 19 years. Due to a right globus pallidus interna traumatic lesion, conventional DBS targeting of the inferior basal ganglia was not possible; thus, the alternative Voa/Vop nuclei target was implanted. The patient realized significant benefit and at last follow-up 3 years postoperatively continued to endorse marked benefit and improvement of dystonia symptoms with minimal adverse effects from bilateral DBS implantation in the alternative targets of the Voa/Vop nuclei of the thalamus.

Does limited EMG denervation in early primary lateral sclerosis predict amyotrophic lateral sclerosis?

Objective: We assessed whether a cohort of patients with primary lateral sclerosis (PLS) and limited electromyography (EMG) motor unit denervation changes evolve into amyotrophic lateral sclerosis (ALS) with prolonged follow-up. Methods: We initially ascertained all PLS patients diagnosed at Mayo Clinic-Rochester (1990-2016). Of 64 total cases, 43 had normal EMGs ("pure" PLS) during the first 4 years after symptom onset and were the focus of a prior publication, documenting absence of evolution to ALS. The remaining 21 patients had limited motor unit changes on EMG needle examination (denervation and most with fibrillation or fasciculation potentials) but insufficient to raise a strong suspicion of ALS; these 21 patients were followed to determine whether they evolved into ALS. Results: Of these 21 patients, the median follow-up was 7 years' disease duration (range: 4-27 years; IQR 5-8.5). They included 11 females (52%) with median onset-age of 57 years (range: 42-72 years). Two patients (10%) subsequently met revised El Escorial criteria for ALS after 7 and 13 years, respectively. The remainder had stable EMG changes with a persistent PLS phenotype. Among these remaining 19 patients, the PLS course was somewhat more aggressive than our previously reported series of 43 patients devoid of EMG denervation. The paraparetic variant was more common than the hemiparetic and bulbar variants, similar to "pure" PLS. Conclusions: Among PLS patients with definite but limited EMG denervation, 2/21 (10%) later developed ALS. The patients in this series had a more progressive clinical course compared to our previously reported pure PLS cases.

The clinical and electrophysiological investigation of tremor.

The various forms of tremor are now classified in two axes: clinical characteristics (axis 1) and etiology (axis 2). Electrophysiology is an extension of the clinical exam. Electrophysiologic tests are diagnostic of physiologic tremor, primary orthostatic tremor, and functional tremor, but they are valuable in the clinical characterization of all forms of tremor. Electrophysiology will likely play an increasing role in axis 1 tremor classification because many features of tremor are not reliably assessed by clinical examination alone. In particular, electrophysiology may be needed to distinguish tremor from tremor mimics, assess tremor frequency, assess tremor rhythmicity or regularity, distinguish mechanical-reflex oscillation from central neurogenic oscillation, determine if tremors in different body parts, muscles, or brain regions are strongly correlated, document tremor suppression or entrainment by voluntary movements of contralateral body parts, and document the effects of voluntary movement on rest tremor. In addition, electrophysiologic brain mapping has been crucial in our understanding of tremor pathophysiology. The electrophysiologic methods of tremor analysis are reviewed in the context of physiologic tremor and pathologic tremors, with a focus on clinical characterization and pathophysiology. Electrophysiology is instrumental in elucidating tremor mechanisms, and the pathophysiology of the different forms of tremor is summarized in this review.

Efficacy and safety of N-acetyl-L-leucine in Niemann-Pick disease type C.

OBJECTIVE: To investigate the safety and efficacy of N-acetyl-L-leucine (NALL) on symptoms, functioning, and quality of life in pediatric (≥ 6 years) and adult Niemann-Pick disease type C (NPC) patients. METHODS: In this multi-national, open-label, rater-blinded Phase II study, patients were assessed during a baseline period, a 6-week treatment period (orally administered NALL 4 g/day in patients ≥ 13 years, weight-tiered doses for patients 6-12 years), and a 6-week post-treatment washout period. The primary Clinical Impression of Change in Severity (CI-CS) endpoint (based on a 7-point Likert scale) was assessed by blinded, centralized raters who compared randomized video pairs of each patient performing a pre-defined primary anchor test (8-Meter Walk Test or 9-Hole Peg Test) during each study periods. Secondary outcomes included cerebellar functional rating scales, clinical global impression, and quality of life assessments. RESULTS: 33 subjects aged 7-64 years with a confirmed diagnosis of NPC were enrolled. 32 patients were included in the primary modified intention-to-treat analysis. NALL met the CI-CS primary endpoint (mean difference 0.86, SD = 2.52, 90% CI 0.25, 1.75, p = 0.029), as well as secondary endpoints. No treatment-related serious adverse events occurred. CONCLUSIONS: NALL demonstrated a statistically significant and clinical meaningfully improvement in symptoms, functioning, and quality of life in 6 weeks, the clinical effect of which was lost after the 6-week washout period. NALL was safe and well-tolerated, informing a favorable benefit-risk profile for the treatment of NPC. CLINICALTRIALS. GOV IDENTIFIER: NCT03759639.

Deep Brain Stimulation and Treatment Outcomes of Young- and Late-Onset (≤55 Years) Parkinson's Disease: A Population-Based Study.

Background: No studies have reported the rate of motor complications (MC) and response to medical and surgical treatment in a population-based cohort of young-onset Parkinson's Disease (YOPD) patients and a cohort of sex-matched late-onset Parkinson's Disease (LOPD). Objective: To assess the outcomes of dopaminergic treatment in YOPD and LOPD, explore treatment-induced MC, medical adjustment, and rate of deep brain stimulation (DBS). Methods: We used the expanded Rochester Epidemiology Project (eREP) to investigate a population-based cohort of YOPD between 2010 and 2015 in 7 counties in Minnesota. Cases with onset ≤55 years of age were included as YOPD. An additional sex-matched cohort of LOPD (onset at ≥56 years of age) was included for comparison. All medical records were reviewed to confirm the diagnoses. Results: In the seven counties 2010-15, there were 28 YOPD patients, which were matched with a LOPD cohort. Sixteen (57%) YOPD had MC, as compared to 9 (32%) LOPD. In YOPD, 9 had motor fluctuations (MF) and Levodopa-induced dyskinesia (LID) together, whereas 3 had LID only and 4 MF only. In LOPD, 3 had MF and LID, 3 MF only, and 3 LID only. Following medical treatment for MC, 6/16 YOPD (38%) and 3/9 (33%) LOPD had symptoms resolution. In YOPD, 11/16 (69%) were considered for DBS implantation, in LOPD they were 2/9 (22%), but only 7 (6 YOPD and 1 LOPD) underwent the procedure. YOPD had significantly higher rates in both DBS candidacy and DBS surgery (respectively, p = 0.03 and p = 0.04). Among DBS-YOPD, 5/6 (83%) had positive motor response to the surgery; the LOPD case had a poor response. We report the population-based incidence of both YOPD with motor complications and YOPD undergoing DBS, which were 1.17 and 0.44 cases per 100,000 person-years, respectively. Conclusion: Fifty-seven percent of our YOPD patients and 32% of the LOPD had motor complications. Roughly half of both YOPD and LOPD were treatment resistant. YOPD had higher rates of DBS candidacy and surgery. Six YOPD and 1 LOPD underwent DBS implantation and most of them had a positive motor response after the surgery.

Clinical Characteristics of Patients with Gait Instability after MR-Guided Focused Ultrasound Thalamotomy.

Background: MRgFUS thalamotomy is an incisionless procedure which effectively treats patients with tremor, although the procedure can result in adverse side effects including gait instability. By determining whether certain pre-existing conditions predispose patients to developing gait instability, we will be able to better counsel patients regarding risk of MRgFUS thalamotomy. Methods: All patients diagnosed with essential tremor, mixed tremor syndrome, or tremor predominant Parkinson disease who underwent MRgFUS thalamotomy at Mayo Clinic, Rochester between 2017 and 2020 were retrospectively reviewed. Baseline demographic and clinical data was extracted, and gait symptoms were compared pre- versus post-operatively. Results: Of 45 patients who underwent MRgFUS thalamotomy, 42 had at least one follow-up visit within twelve months and were included in the study. 39 patients had essential tremor, 1 had tremor predominant Parkinson disease, and 2 had mixed tremor syndrome. 19 out of 42 patients (45%) had gait decline. There were 10 (24%) females, and median age was 77.6 years (IQR 71.5-83.2). Older age was not correlated with gait decline (p = 0.82). Patients with a history of neuropathy and joint replacements were more likely to have gait decline after MRgFUS thalamotomy (p = 0.0099 and p = 0.0376). Patients with pre-existing gait aids were not more likely to have gait instability (p = 0.20). Conclusion: Patients who undergo MRgFUS thalamotomy for each of the tremor conditions, have an increased risk of experiencing gait decline, when there is a pre-procedure history of peripheral neuropathy, or joint replacement surgery. Older age or pre-existing gait aid use is not associated with worsened gait outcomes. Highlights: Patients who undergo MRgFUS thalamotomy for tremor syndromes have a significantly increased risk of experiencing gait decline when there is comorbid peripheral neuropathy or joint replacementOlder age or pre-existing gait aid use is not associated with worsened gait outcomes.

Utility of tremor electrophysiology studies.

OBJECTIVE: To determine the utility of tremor electrophysiology testing in differentiating clinically indeterminate tremor due to organic, functional, and mixed tremor types. BACKGROUND: Prior studies have shown that electrophysiological studies increase diagnostic sensitivity of tremor syndromes; however, few have examined mixed organic and functional tremors. METHODS: Patients referred for tremor to the Mayo Clinic, Rochester movement disorders lab were consecutively selected and retrospectively reviewed. Surface electromyography (EMG) recordings of upper limb muscles were performed at rest, posture, with action and distractibility tasks. RESULTS: Of 116 patients, all were clinically described as having either a resting tremor, postural tremor, action tremor, postural and action tremor, mixed resting, postural, and action tremor, or nonspecific tremulousness. Based on electrophysiological features, patients were diagnosed with organic tremor (parkinsonian, essential, mixed, rubral, cerebellar, non-specific tremulousness), functional tremor, or mixed functional and organic tremors. The median disease duration at electrophysiological confirmation of diagnosis was shorter for functional tremor at 1.5 years (IQR 1-9.3), and organic tremor at 3 years (IQR 1-15), versus mixed organic and functional tremor at 11 years (IQR 2-15) (p = 0.0422). The electrophysiology study clarified the referral/clinical diagnosis in 87 patients (75%), 26 (29.5%) of whom had functional tremor, and 61 (70.1%) had organic tremor or mixed organic/functional tremor. Variability of tremor during electrophysiology testing was associated with a change in diagnosis (p = 0.0286). CONCLUSION: Our findings show that electrophysiological assessment of tremor can be helpful in the clinical diagnosis of patients with both organic and functional tremor.

Cohort Study in Parkinsonism: Delayed Transit, Accelerated Gastric Emptying, and Prodromal Dysmotility.

OBJECTIVE: To evaluate gastric emptying (GE) and colonic transit in a cohort of patients with Parkinson disease and other parkinsonism disorders and to determine whether abnormal gut transit precedes motor onset of parkinsonism. METHODS: Medical record review of 84 patients with parkinsonism who underwent clinically indicated transit studies at Mayo Clinic (2001-2019) and 11 patients with transit studies who subsequently developed parkinsonism. Data are summarized as median (interquartile range). RESULTS: The 84 patients (52% female) with parkinsonism were aged 72 (66-76) years with a disease duration of 5 (2-8) years: Parkinson disease = 70, multiple system atrophy = 7, dementia with Lewy bodies = 4, progressive supranuclear palsy = 2, and parkinsonian syndrome = 1. Ten had delayed GE, 10 slow colonic transit, 16 accelerated GE (14 Parkinson disease, 1 multiple system atrophy, and 1 parkinsonian syndrome), and 49 normal transit. One patient with parkinsonian syndrome had both slow colonic and accelerated gastric transit. Longer disease duration and higher levodopa equivalent daily dose were observed for Parkinson disease compared with other parkinsonisms and with slow compared with normal colonic transit. Of 11 patients (5 female) with transit studies who later developed motor parkinsonism after 4 (3-5) years, 1 had accelerated GE, 1 had delayed GE, and 1 had both delayed GE and colonic transit. CONCLUSIONS: Accelerated GE was newly identified in patients with parkinsonism, in addition to delayed GE or colonic transit. Furthermore, gut dysmotility was objectively identified to precede the motor onset of parkinsonism.

A prospective pilot study of the effects of deep brain stimulation on olfaction and constipation in Parkinson's disease.

BACKGROUND: Previous studies suggest deep brain stimulation of the subthalamic nucleus (STN-DBS) may improve olfaction and constipation in PD, using subjective measures. OBJECTIVE: To utilize objective measures to assess olfaction and constipation in PD following STN-DBS. METHODS: In this prospective pilot study, olfaction (University of Pennsylvania Smell Identification Test [UPSIT]), bowel symptoms (ROME III questionnaires, daily bowel diaries, 100 mm visual analog scales for satisfaction with treatment and bowel habits), and motor manifestations of PD were evaluated before and after STN-DBS. Levodopa equivalent daily dose (LEDD) was calculated. RESULTS: Ten patients (8 men, mean age 67.4 ± 6.0 years) with mean PD duration of 7.5 ± 3.7 years underwent bilateral STN-DBS, with mean follow-up of 3 months for all measures, except 7 months follow-up for bowel diaries. There was improvement in the Unified Parkinson's Disease Rating Scale motor "off" scores (33.7 ± 6.7 before and 16.1 ± 10.8 after, P = 0.001). Mean UPSIT scores (20.0 ± 6.6 versus 17.5 ± 5.7, P = 0.03) worsened from severe to total hyposmia. Seven patients had baseline constipation and completed bowel diaries. There was improvement in number of complete spontaneous bowel motions (CBSM) per week (2.2 ± 1.9 before versus 4.7 ± 2.4 after, P = 0.04), satisfaction with treatment of constipation (44 ± 27 before versus 64 ± 25 after, P = 0.02), and with bowel motions (33 ± 22 before and 48 ± 20 after, P = 0.2). However, laxative use (P = 0.15) and LEDD (P = 0.15) were unchanged. CONCLUSION: Olfaction worsened while symptoms of constipation improved but did not resolve after STN-DBS.

Natural History of "Pure" Primary Lateral Sclerosis.

OBJECTIVE: To assess whether primary lateral sclerosis (PLS), classified as pure when the EMG is normal, converts to amyotrophic lateral sclerosis (ALS) after longitudinal follow-up. METHODS: Retrospective chart review was performed of patients with pure PLS at Mayo Clinic in Rochester, MN (1990-2016). Inclusion criteria required a normal EMG during the first 4 years of symptoms. RESULTS: Forty-three patients had pure PLS (25 female, 58%) with a median onset age of 50 years (range 38-78 years) and median follow-up at 9 years' disease duration (range 4-36 years). The ascending paraparesis phenotype (n = 30, 70%) was most common, followed by hemiparetic onset (n = 9, 21%) and bulbar onset (n = 4, 9%). Among the 30 paraparetic-onset cases, bladder symptoms (n = 18, 60%) and dysarthria (n = 15, 50%) were more common than pseudobulbar affect (n = 9, 30%) and dysphagia (n = 8, 27%). By the last follow-up, 17 of 30 (56%) used a cane and 6 (20%) required a wheelchair. The paraparetic variant, compared with hemiparetic and bulbar onset, had the youngest onset (48 vs 56 vs 60 years, respectively; p = 0.02). Five patients died; 1 patient required a feeding tube; and none required permanent noninvasive ventilation. Two patients developed an idiopathic multisystem neurodegenerative disorder, which surfaced after 19 and 20 years. Two patients developed minor EMG abnormalities. The remainder 39 had persistently normal EMGs. CONCLUSIONS: Pure PLS did not convert to ALS after a median of 9 years' disease duration follow-up in our study population. The ascending paraparetic phenotype was most common, with earlier onset and frequent bladder involvement. After years of pure PLS, <5% develop a more pervasive neurodegenerative disorder.

Frequency of spinocerebellar ataxia mutations in patients with multiple system atrophy.

PURPOSE: Investigate single nucleotide variants and short tandem repeats in 39 genes related to spinocerebellar ataxia in clinical and pathologically defined cohorts of multiple system atrophy. METHODS: Exome sequencing was conducted in 28 clinical multiple system atrophy patients to identify single nucleotide variants in spinocerebellar ataxia-related genes. Novel variants were validated in two independent disease cohorts: 86 clinically diagnosed multiple system atrophy patients and 166 pathological multiple system atrophy cases. Expanded repeat alleles in spinocerebellar ataxia genes were evaluated in 36 clinically diagnosed multiple system atrophy patients, and CAG/CAA repeats in TATA-Box Binding Protein (TBP, causative of SCA17) were screened in 216 clinical and pathological multiple system atrophy patients and 346 controls. RESULTS: No known pathogenic spinocerebellar ataxia single nucleotide variants or pathogenic range expanded repeat alleles of ATXN1, ATXN2, ATXN3, CACNA1A, AXTN7, ATXN8OS, ATXN10, PPP2R2B, and TBP were detected in any clinical multiple system atrophy patients. However, four novel variants were identified in four spinocerebellar ataxia-related genes across three multiple system atrophy patients. Additionally, four multiple system atrophy patients (1.6%) and one control (0.3%) carried an intermediate length 41 TBP CAG/CAA repeat allele (OR = 4.11, P = 0.21). There was a significant association between the occurrence of a repeat length of longer alleles (> 38 repeats) and an increased risk of multiple system atrophy (OR = 1.64, P = 0.03). CONCLUSION: Occurrence of TBP CAG/CAA repeat length of longer alleles (> 38 repeats) is significantly associated with increased multiple system atrophy risk. This discovery warrants further investigation and supports a possible genetic overlap of multiple system atrophy with SCA17.