Lateral cerebellothalamic tract activation underlies DBS therapy for Essential Tremor.

BACKGROUND: While deep brain stimulation (DBS) therapy can be effective at suppressing tremor in individuals with medication-refractory Essential Tremor, patient outcome variability remains a significant challenge across centers. Proximity of active electrodes to the cerebellothalamic tract (CTT) is likely important in suppressing tremor, but how tremor control and side effects relate to targeting parcellations within the CTT and other pathways in and around the ventral intermediate (VIM) nucleus of thalamus remain unclear. METHODS: Using ultra-high field (7T) MRI, we developed high-dimensional, subject-specific pathway activation models for 23 directional DBS leads. Modeled pathway activations were compared with post-hoc analysis of clinician-optimized DBS settings, paresthesia thresholds, and dysarthria thresholds. Mixed-effect models were utilized to determine how the six parcellated regions of the CTT and how six other pathways in and around the VIM contributed to tremor suppression and induction of side effects. RESULTS: The lateral portion of the CTT had the highest activation at clinical settings (p < 0.05) and a significant effect on tremor suppression (p < 0.001). Activation of the medial lemniscus and posterior-medial CTT was significantly associated with severity of paresthesias (p < 0.001). Activation of the anterior-medial CTT had a significant association with dysarthria (p < 0.05). CONCLUSIONS: This study provides a detailed understanding of the fiber pathways responsible for therapy and side effects of DBS for Essential Tremor, and suggests a model-based programming approach will enable more selective activation of lateral fibers within the CTT.

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.

Temporomandibular disorder-related characteristics and treatment outcomes in Oromandibular Dystonia patients in two different clinical settings: A cross-sectional study.

INTRODUCTION: Clinical presentation of oromandibular dystonia (OMD) is variable that can be further complicated by the presence of temporomandibular disorder (TMD) symptoms. We sought to evaluate variations in the clinical presentation of OMD patients, particularly TMD-related characteristics, in two clinical settings. METHODS: In a cross-sectional study design, a Web-based data collection survey was provided to eligible patients with OMD from movement disorder (MD) and oro-facial pain (OFP) clinics. The survey questionnaire was designed to collect information on demographic characteristics, clinical presentation particularly related to TMD, quality of life and treatment outcomes. Validated questionnaires were used when available such as the TMD Pain Screener, EuroQol 5-Dimensions 5-Levels (EQ-5D-5L), Jaw Functional Limitation Scale and Global Rating of Change Scale. RESULTS: Of 53 eligible patients, 31 responded to the survey for a 58% response rate. Forty-eight per cent of patients in the MD clinic and 60% of patients in the OFP clinic reported jaw pain along with involuntary movements. Of those, 90% from the MD group and 83% from the OFP group screened positive with the TMD Pain Screener at the onset of symptoms based on recall. Positive TMD Pain Screener response was observed in about 40% of patients in both clinics within 30 days of questionnaire response. No statistically significant differences were observed between two groups for any measured variables. CONCLUSION: Patients with OMD have features of TMD, irrespective of the clinical setting in which they seek and receive care. OMD patients from both clinics were similar in terms of clinical presentation, quality of life and treatment outcomes.

PSP-like syndrome after aortic surgery in adults (Mokri syndrome).

BACKGROUND: A rare progressive supranuclear palsy-like syndrome seemingly triggered by aortic surgery was first described in 2004. This largest case series to date describes the features of this syndrome. METHODS: We searched the Mayo Clinic electronic medical records using the advanced cohort explorer search engine for patients evaluated for neurologic symptoms after cardiac-aortic surgery in the past 30 years. Data were extracted to Microsoft Excel from the identified patients and included clinical and neuroimaging features and outcomes. RESULTS: Twenty-five patients met the inclusion criteria. All surgeries were performed under thoracic aortic bypass and deep hypothermia. Surgery included aortic aneurysm, aortic valve repair, and/or aortic dissection repair. Surgical records were unavailable, although surgery was documented in the Mayo record as uncomplicated in 60% of cases. In the remaining cases, no particular intraoperative or postoperative complications were documented at a high frequency. A typical triad was documented: supranuclear gaze palsy (SNGP; 100%), gait imbalance (80%), and dysarthria (96%). Part or all of the triad was observed before hospital discharge and stabilized over the course of days-weeks. A second phase of symptom worsening plus new symptoms developed up to a year later; this decline continued for up to several years before stabilization. Delayed epileptic seizures occurred in 32% of patients. Brain MRI revealed only nonspecific findings. CONCLUSION: This syndrome following adult thoracic aortic bypass surgery with deep hypothermia remains unexplained. It follows a biphasic course and is characterized by the triad of SNGP, unsteady gait, and a predominantly ataxic dysarthria.

Conjugal multiple system atrophy: Chance, shared risk factors, or evidence of transmissibility?

OBJECTIVE: To describe conjugal multiple system atrophy (MSA) in a couple married for 44 years, and to report environmental risk factors possibly contributing to the occurrence. METHODS: Case description of conjugal MSA with report of shared environmental risk factors and retrospective review of consecutively diagnosed MSA patients between 1998 and 2012 with autonomic reflex screen at Mayo Clinic, Rochester (clinical series). Probability calculation was based on the age-specific point prevalence of MSA. RESULTS: A husband and wife both developed MSA symptoms at age 63. The husband's onset was of imbalance, followed by falls and genitourinary failure; parkinsonism and antecollis was evident on examination. Autonomic testing showed widespread autonomic failure. The patient died 2.25 years after onset. The wife initially developed urinary symptoms progressing to incontinence. Parkinsonism, dysphonia, and falls began within 1 year. Autonomic testing revealed severe autonomic failure. Interview with the surviving wife and son revealed substantial chemical exposure, in particular pesticides. In our clinical series, there were no other cases of conjugal MSA. Assuming an age-specific point prevalence of MSA based on population studies and independence of the two events, the probability of both individuals developing MSA by chance is 6.08 e-9. CONCLUSION: Based on the population point prevalence of MSA, conjugal MSA is rare but possible. We conclude that this case of conjugal MSA likely occurred by chance; however, exposure to shared risk factors (pesticides) may be contributory. Because this is the first reported case of conjugal MSA, to our best knowledge, evidence for transmissibility between spouses is lacking.

Intrathecal administration of autologous mesenchymal stem cells in multiple system atrophy.

OBJECTIVE: This phase I/II study sought to explore intrathecal administration of mesenchymal stem cells (MSCs) as therapeutic approach to multiple system atrophy (MSA). METHODS: Utilizing a dose-escalation design, we delivered between 10 and 200 million adipose-derived autologous MSCs intrathecally to patients with early MSA. Patients were closely followed with clinical, laboratory, and imaging surveillance. Primary endpoints were frequency and type of adverse events; key secondary endpoint was the rate of disease progression assessed by the Unified MSA Rating Scale (UMSARS). RESULTS: Twenty-four patients received treatment. There were no attributable serious adverse events, and injections were generally well-tolerated. At the highest dose tier, 3 of 4 patients developed low back/posterior leg pain, associated with thickening/enhancement of lumbar nerve roots. Although there were no associated neurologic deficits, we decided that dose-limiting toxicity was reached. A total of 6 of 12 patients in the medium dose tier developed similar, but milder and transient discomfort. Rate of progression (UMSARS total) was markedly lower compared to a matched historical control group (0.40 ± 0.59 vs 1.44 ± 1.42 points/month, p = 0.004) with an apparent dose-dependent effect. CONCLUSIONS: Intrathecal MSC administration in MSA is safe and well-tolerated but can be associated with a painful implantation response at high doses. Compelling dose-dependent efficacy signals are the basis for a planned placebo-controlled trial. CLASSIFICATION OF EVIDENCE: This phase I/II study provides Class IV evidence that for patients with early MSA, intrathecal MSC administration is safe, may result in a painful implantation response at high doses, and is associated with dose-dependent efficacy signals.

Camptocormia: Etiology, diagnosis, and treatment response.

BACKGROUND: We sought to determine the etiologies, diagnostic testing, and management of a retrospective cohort of patients with camptocormia evaluated at a single center. METHODS: We reviewed medical records of all adult patients evaluated at Mayo Clinic Rochester with a diagnosis of camptocormia from 2000 to 2014. Demographic and clinical data were abstracted and analyzed. RESULTS: There were 276 patients (58.0% male), with mean age at presentation of 68.6 (±12.7) years. An etiology was identified in 98.2%. The most common etiologies were idiopathic Parkinson disease (22.5%), idiopathic axial myopathy (14.1%), and degenerative joint disease without fixed deformity (13.0%). We also identified several rare causes of camptocormia. Investigations included spine imaging, needle and surface EMG, and muscle biopsy. Most patients received physical therapy and orthotic support with limited benefit. Limited improvement of camptocormia was seen where a treatable etiology was identified. CONCLUSIONS: An etiology can be identified in almost all cases of camptocormia. Most cases are due to 3 common disorders: Parkinson disease, axial myopathy, and degenerative joint disease. A diagnostic and treatment algorithm is proposed.

Glycine receptor modulating antibody predicting treatable stiff-person spectrum disorders.

BACKGROUND: Glycine receptor alpha-1 subunit (GlyRα1)-immunoglobulin G (IgG) is diagnostic of stiff-person syndrome (SPS) spectrum but has been reported detectable in other neurologic diseases for which significance is less certain. METHODS: To assess GlyRα1-IgGs as biomarkers of SPS spectrum among patients and controls, specimens were tested using cell-based assays (binding [4°C] and modulating [antigen endocytosing, 37°C]). Medical records of seropositive patients were reviewed. RESULTS: GlyRα1-IgG (binding antibody) was detected in 21 of 247 patients with suspected SPS spectrum (8.5%) and in 8 of 190 healthy subject sera (4%) but not CSF. Among 21 seropositive patients, 20 had confirmed SPS spectrum clinically, but 1 was later determined to have a functional neurologic disorder. Sera from 9 patients with SPS spectrum , but not 7 controls, nor the functional patient, caused GlyRα1 modulation (100% specificity). SPS spectrum phenotypes included progressive encephalomyelitis with rigidity and myoclonus (PERM) (8), classic SPS (5), stiff limb (5), stiff trunk (1), and isolated exaggerated startle (hyperekplexia, 1). Neuropsychiatric symptoms present in 12 patients (60%) were anxiety (11), depression (6), and delirium (3). Anxiety was particularly severe in 3 patients with PERM. Objective improvements in SPS neurologic symptoms were recorded in 16 of 18 patients who received first-line immunotherapy (89%, 9/10 treated with corticosteroids, 8/10 treated with IVIg, 3/4 treated with plasma exchange, and 1 treated with rituximab). Treatment-sparing maintenance strategies were successful in 4 of 7 patients (rituximab [2/3], azathioprine [1/1], and mycophenolate [1/3]). CONCLUSIONS: GlyRα1-modulating antibody improves diagnostic specificity for immunologically treatable SPS spectrum disorders. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that GlyRα1-modulating antibody accurately identifies patients with treatable SPS spectrum disorders.

Orthostatic myoclonus after brain tumor radiation: Insights from two lesional cases.

INTRODUCTION: Orthostatic myoclonus (OM) is a recognized syndrome of gait unsteadiness accompanied by lower limb myoclonus provoked by the assumption of an upright posture. OM typically affects the elderly and is often associated with neurodegenerative disease. We sought to review the clinical and electrophysiologic characteristics of OM due to brain tumor treatment, the first reported lesional cases of this rare disorder. METHODS: The database of the Mayo Clinic Rochester Movement Disorders Laboratory was searched for all patients diagnosed with OM from January 2007 to December 2016. All available clinical, radiographic, and surface electromyographic data were reviewed, and patients with a history of primary or metastatic brain tumor were analyzed. RESULTS: Two patients with OM and brain tumor were identified; both had undergone tumor resection and targeted brain radiation. Both patients complained of unsteadiness while walking and recurrent falls. Tumor pathology (atypical meningioma, gliosarcoma) was centered in the frontal lobe and extended to the supplementary motor area (SMA), pre-SMA, or prefrontal cortex. Medications did not improve gait. CONCLUSION: Two cases of brain tumor-related OM suggest that degeneration of frontal motor programming circuits underlies the pathophysiology of OM.

Creating three dimensional models of Alzheimer's disease.

BACKGROUND: Alzheimer's disease prevalence will reach epidemic proportions in coming decades. There is a need for impactful educational materials to help patients, families, medical practitioners, and policy makers understand the nature and impact of the disease. Defining an effective workflow to create such models from existing segmentation tools will be a valuable contribution in creating these patient-specific models. RESULTS: A step-by-step workflow was developed and used to take patients' Digital Imaging and Computing in Medicine magnetic resonance brain images through a process resulting in illustrative 3D-printed brain and hippocampus models that clearly demonstrate the progressive degenerative changes caused by Alzheimer's disease. We outline the specific technical steps of auto-segmentation, manual smoothing, Standard Triangle Language file customization, and 3D printing used to create these models. CONCLUSIONS: Our explicated workflow can create effective models of Alzheimer's brains that can be used in patient education, medical education, and policy forums.

Precise stimulation location optimizes speech outcomes in essential tremor.

BACKGROUND: Deep brain stimulation for essential arm tremor is often complicated by dysarthria and persistent voice tremor. OBJECTIVE: To determine the relationship of stimulation location to speech outcomes following bilateral thalamic deep brain stimulation (DBS) for essential tremor (ET). METHODS: Eighteen patients undergoing bilateral DBS for ET were prospectively studied. Speech pathologists grouped patients by final speech outcome (normal speech, voice tremor, or dysarthria). Locations of the active leads were calculated by normalizing the segmented thalamic volumes to those in the Morel atlas. Stimulation volumes within thalamic nuclei, error distances from target, and measures of accuracy were calculated and differences in measures between outcome groups tested. RESULTS: At optimal stimulation, 8 patients had normal speech, 6 had voice tremor, and 4 had mild dysarthria. Stimulation volumes were statistically concentrated within the ventral lateral posterior nucleus (VLp). The percentage of stimulation volume outside the VLp was higher in patients with dysarthria (60% vs. 24%, p = 0.02) or voice tremor (55% vs. 24%, p = 0.03) compared to patients with normal speech outcomes. The error distance from the center of VLp was greater for patients with dysarthria than those with normal speech (12.6 vs. 7.6 mm, p = 0.02). Electrodes with lower efficiency for VLp stimulation were more frequent with poor speech outcomes and in patients with persistent voice tremor. CONCLUSIONS: Following bilateral DBS for ET, 22% of patients develop a non-disabling dysarthria. Optimal speech outcomes were achieved in 44% of patients and correlated with precise stimulation location within and not outside of the VLp.

The clinical spectrum and natural history of pure akinesia with gait freezing.

Gait freezing as a presenting and relatively restricted condition is uncommon but a distinctive disorder. This entity was initially defined as "pure akinesia with gait freezing", and later a neuropathological substrate of progressive supranuclear palsy has been recognized. Limited studies have reported the clinical evolution after presentation, which is important for patient counseling. The objective of this study was to assess the demographic and clinical features, treatment-response, neuroimaging, and evolution of pure akinesia with gait freezing. A retrospective review of patients with this phenotype as previously defined was performed. Patients included had no or minimal limb rigidity and/or bradykinesia and no resting tremor, and all underwent neuroimaging of the brain after onset. Inclusion criteria were met by 30 patients, who were followed up to 21 years after symptom onset. During their course, 28 patients had falls (93 %), 12 patients had dysarthria (40 %), and 13 had handwriting changes (43 %). All patients had progression of their gait disorder over time, but with a variable interval until falls occurred. None of the patients developed vertical gaze palsy or met diagnostic criteria for an alternative parkinsonian disorder. Pure akinesia with gait freezing is a distinctive disorder that can be recognized in the clinic. Despite the previously reported progressive supranuclear palsy-like neuropathology, the clinical course is much less aggressive and disabling than classic Richardson syndrome, although fall risk eventually develops in nearly all patients. Bradykinesia, tremor, and rigidity do not develop, distinguishing pure akinesia with gait freezing from Parkinson's disease and other parkinsonian disorders.

Highly specific radiographic marker predates clinical diagnosis in progressive supranuclear palsy.

INTRODUCTION: The diagnosis of progressive supranuclear palsy is often challenging early in the course of the disease, when clinical signs of the condition may be less apparent and patients do not clearly meet diagnostic criteria. In this study, we examine a potential radiographic marker in progressive supranuclear palsy, and assess the timing of its presence in relation to diagnosis. METHODS: A retrospective review of patients fulfilling clinical research criteria for multiple system atrophy, Parkinson's disease, and progressive supranuclear palsy (total n = 75) was performed. Midbrain and pontine diameters, and the midbrain to pons ratio were calculated by a neuroradiologist blinded to the clinical diagnosis. The timing of the presence of a midbrain to pons ratio of less than or equal to 0.52 was assessed in the progressive supranuclear palsy group in reference to the time of diagnosis. RESULTS: The midbrain to pons ratio was significantly reduced in the progressive supranuclear palsy cohort (p < 0.0001), and a midbrain to pons ratio of less than or equal to 0.52 was 100% specific for progressive supranuclear palsy. This radiologic sign predated the clinical diagnosis of progressive supranuclear palsy by a mean of 15 months (range 1-47 months) in 14 of 17 (82%) of patients in whom it was found. CONCLUSIONS: The midbrain to pons ratio is an easily applied and highly specific tool in the diagnosis of progressive supranuclear palsy, and is frequently present before the diagnosis is made.

Stimulation-Induced Transient Nonmotor Psychiatric Symptoms following Subthalamic Deep Brain Stimulation in Patients with Parkinson's Disease: Association with Clinical Outcomes and Neuroanatomical Correlates.

BACKGROUND: The clinical and neurobiological underpinnings of transient nonmotor (TNM) psychiatric symptoms during the optimization of stimulation parameters in the course of subthalamic nucleus deep brain stimulation (STN-DBS) remain under intense investigation. METHODS: Forty-nine patients with refractory Parkinson's disease underwent bilateral STN-DBS implants and were enrolled in a 24-week prospective, naturalistic follow-up study. Patients who exhibited TNM psychiatric manifestations during DBS parameter optimization were evaluated for potential associations with clinical outcome measures. RESULTS: Twenty-nine TNM+ episodes were reported by 15 patients. No differences between TNM+ and TNM- groups were found in motor outcome. However, unlike the TNM- group, TNM+ patients did not report improvement in subsyndromal depression or quality of life. TNM+ episodes were more likely to emerge during bilateral monopolar stimulation of the medial STN. CONCLUSIONS: The occurrence of TNM psychiatric symptoms during optimization of stimulation parameters was associated with the persistence of subsyndromal depression and with lower quality of life ratings at 6 months. The neurobiological underpinnings of TNM symptoms are investigated yet remain difficult to explain.

Repetitive exercise dystonia: A difficult to treat hazard of runner and non-runner athletes.

INTRODUCTION: Runner's dystonia has previously been described in small series or case reports as a lower limb, task-specific dystonia. We have occasionally encountered this disorder and recognized the same phenomenon in non-runners regularly engaging in lower limb exercise. We wished to characterize the syndrome further, including outcomes, treatment, and the diagnostic usefulness of electrophysiology. METHODS: We conducted a retrospective review and follow-up survey of adults seen at Mayo Clinic (1996-2015) with task-specific dystonia arising after prolonged repetitive lower limb exercise. The findings were compared to all 21 previously reported cases of runner's dystonia. RESULTS: We identified 20 patients with this condition, 13 runners and seven non-runner athletes. Median age at dystonia onset was in mid-adulthood. Correct diagnosis was delayed by a median of 3.5 years in runners and 1.6 years in non-runners, by which time more than one-third of patients had undergone unsuccessful invasive procedures. Most patients had dystonia onset in the distal lower limb. Dystonia was task-specific with exercise at onset but progressed to affect walking in most. Sensory tricks were reported in some. Surface EMG was consistent with task-specific dystonia in nine patients. Botulinum toxin, levodopa, clonazepam, trihexyphenidyl, and physical therapy provided modest benefit to some, but all patients remained substantially symptomatic at last follow up. CONCLUSIONS: Repetitive exercise dystonia is task-specific, confined to the lower limb and occasionally trunk musculature. It tends to be treatment-refractory and limits ability to exercise. Diagnosis is typically delayed, and unnecessary surgical procedures are common. Surface EMG may aid the diagnosis.

Orthostatic tremor: Clinical, electrophysiologic, and treatment findings in 184 patients.

OBJECTIVE: To evaluate the clinical, electrophysiologic, and treatment outcome features of orthostatic tremor (OT) in a large case series. METHODS: We performed medical record review of 184 patients who met clinical and electrodiagnostic criteria for OT from 1976 to 2013 at the Mayo Clinic. Demographic, clinical, electrophysiologic, and treatment data were extracted. RESULTS: The majority of OT cases were female (63.6%) and mean age at onset was 59.3 years (range 13-85 years). Diagnosis was delayed by a mean of 7.2 years (range 0-44 years). The average tremor frequency was 15.7 Hz (range 12.5-20 Hz), and transmitted to the arms on weight-bearing (95.5%). Patients reported a spectrum of progressive orthostatic leg symptoms, relieved by sitting or leaning. Falls were reported in 24.1%. Coexistent neurologic disorders included essential tremor (22.8%), other tremor (4.9%), and parkinsonism (8.7%). Family history of OT was noted in 4.9%. Of 46 medications trialed, 24 failed to provide any benefit. Benzodiazepines provided at least mild benefit in 55.9%, and moderate to marked benefit in 31.5%; ß-blockers (31.0%) and anticonvulsants (25.0%) provided mild benefit, and the remainder were largely ineffective. Medication benefit waned over time. Deep brain stimulation (DBS) was effective in 2 cases. CONCLUSION: OT predominantly affects female seniors, and the diagnosis should be considered with any orthostatic-induced leg symptoms, and confirmed by surface EMG. Benzodiazepines are the most efficacious treatment, followed by ß-blockers and anticonvulsants. DBS should be further explored for treatment.