Prevalence, Demographic, and Clinical Factors Associated With Cognitive Dysfunction in Patients With Neuromyelitis Optica Spectrum Disorder.

BACKGROUND AND OBJECTIVES: Neuromyelitis optica spectrum disorder (NMOSD) is a chronic CNS demyelinating autoimmune disorder targeting the astrocyte antigen aquaporin-4 (AQP4), typically presenting with optic neuritis, transverse myelitis, and brain syndromes. Cognitive dysfunction (CD) in NMOSD is under-recognized and poorly understood. The purpose of this study was to evaluate the prevalence and clinical variables associated with CD in NMOSD. METHODS: This observational retrospective study with longitudinal follow-up describes a clinical cohort seen in the Collaborative International Research in Clinical and Longitudinal Experience Study in NMOSD. Serial Montreal Cognitive Assessments (MoCAs) were performed upon enrollment and at 6-month intervals to evaluate longitudinal cognitive function relative to demographic and disease-related factors. We used 2-tailed t test, analysis of variance, the χ2 test, linear regression for univariable and adjusted analyses and simultaneous linear regression and mixed-effects model for multivariable analyses. RESULTS: Thirty-four percent (75/219) of patients met criteria for CD (MoCA <26); 29% (64/219) showed mild dysfunction (MoCA 20-26/30), and 5% (11/219) showed moderate (MoCA <20/30) dysfunction. Patients with less neurologic disability and lower pain scores had higher MoCA scores (95% CI 0.24-0.65 and 95% CI 0.09-0.42, respectively). Patients with at least high school education scored higher on the MoCA (95% CI 2.2-5). When comparing patients dichotomized for CD, patients never on rituximab scored higher than patients only treated with rituximab (p < 0.029). There was no significant association between annualized relapse rate, age, sex, disease duration, AQP4 serostatus or brain lesions, and CD. CD was more pronounced among Black than White patients (95% CI -2.7 to -0.7). Multivariable analysis of serial MoCA did not indicate change (p = 0.715). Descriptive analysis of serial MoCA showed 30% (45/150) of patients with worsening MoCA performance had impaired language and verbal recall. DISCUSSION: To our knowledge, this is the largest study of diverse cohort to investigate CD in patients with NMOSD. Our findings demonstrate 34% of patients with NMOSD experience mild-to-moderate CD, while 30% of patients demonstrated decline on serial testing. The substantial prevalence of CD in this pilot report highlights the need for improved and validated screening tools and comprehensive measures to investigate CD in NMOSD.

Three Adult-Onset Autosomal Recessive Ataxias: What Adult Neurologists Need to Know.

PURPOSE OF REVIEW: In this review we seek to raise awareness of 3 autosomal recessive ataxias that look different clinically when presenting in adulthood rather than childhood. RECENT FINDINGS: A study found a high allelic frequency for repeat expansions in the RFC1 gene, a cause of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome, which presents exclusively in adults. This implies that autosomal recessive etiologies of adult-onset cerebellar ataxias may be more common than previously thought. SUMMARY: Adult-onset cerebellar ataxias are commonly caused by mutations inherited in either an autosomal dominant or X-linked pattern, as most autosomal recessive mutations cause disease at earlier ages. However, some autosomal recessive etiologies such as late-onset Tay-Sachs disease, very late-onset Friedreich ataxia, and autosomal recessive spastic ataxia of Charlevoix-Saguenay emerge in adulthood, with age at presentation influencing the progression and clinical signs of the disease. This review will cover the genetics, clinical presentation, and necessary diagnostic steps required to identify 3 causes of autosomal recessive cerebellar ataxia that manifest differently in adults vs children.

Cardiac sympathetic denervation correlates with clinical and pathologic stages of Parkinson's disease.

Attention has been drawn to cardiac sympathetic denervation in Parkinson's disease (PD) based on clinical studies using [123I] metaiodobenzylguanidine scintigraphy; however, the histologic correlates and time course of cardiac sympathetic denervation are poorly understood. To address these issues, we used tyrosine hydroxylase (TH) immunohistochemistry to detect cardiac sympathetic nerve fibers in the epicardium of 4 normal controls, 11 cases with incidental Lewy bodies (iLBs), and 14 cases of PD. Cardiac sympathetic innervation was significantly less in PD than in normal controls and cases with iLBs (P < 0.05). There was also a decrease in TH-immunoreactive fibers in iLB cases compared to normal controls (P < 0.01). TH-immunoreactive fibers correlated with the PD stage (r = -0.75, P < 0.001), as well as with Hoehn & Yahr clinical stage (r = -0.61, P < 0.001), and disease duration (r = -0.63, P < 0.001). Immunohistochemistry for alpha-synuclein showed neurites in epicardium in PD and iLB cases, but not in normal controls. The density of alpha-synuclein neurites correlated with Braak PD stage (r = 0.38, P < 0.05), Hoehn & Yahr clinical stage (r = 0.44, P < 0.05), and disease duration (r = 0.42, P < 0.05). This study demonstrates that cardiac sympathetic degeneration and alpha-synuclein pathology is present in presymptomatic phase of PD, and that both increase with disease duration and severity.

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.

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.

Swiss cheese striatum: clinical implications.

IMPORTANCE: Markedly enlarged Virchow-Robin spaces throughout the striatum appear occasionally on magnetic resonance imaging (MRI) scans of the elderly, and this type of striatum is known as the Swiss cheese striatum (SCS); however, its clinical impact is unknown. OBJECTIVE: To determine the clinical features associated with SCS detected on MRI scans. DESIGN, SETTING, AND PARTICIPANTS: A blinded, retrospective case-control study using medical records from 2000 to 2007 obtained from an MRI database at the Mayo Clinic in Rochester, Minnesota, of residents 40 years of age or older of Olmsted County, Minnesota, who had extensive Mayo Clinic medical records and MRI reports suggestive of SCS. Cases with a severe form of SCS (n = 27) were randomly selected for comparison with age-, sex-, and examination year-matched controls (n = 52) with a minimal form of SCS or no SCS. EXPOSURE: Magnetic resonance imaging. MAIN OUTCOMES AND MEASURES: Associations of clinical and imaging features with the presence of a severe form of SCS. Medical records were reviewed for clinical features such as parkinsonism, dementia, and vascular risk factors. The MRI scans were visually scored for degree of leukoaraiosis, central atrophy, and cortical atrophy. RESULTS: No significant differences were found between those with a severe form of SCS and controls in rates of parkinsonism (19% vs 17%; odds ratio, 1.09 [95% CI, 0.28-4.16]) or dementia of any type (30% vs 21%; odds ratio, 1.57 [95% CI, 0.48-5.13]). Vascular risk factors were not significantly different between groups. Swiss cheese striatum correlated with degree of leukoaraiosis (P < .001). Potential associations with visualized cortical atrophy (P = .01), nonobstructive urinary incontinence (18.5% vs 3.9%; P = .04), and syncope (37% vs 9.6%; P = .01) did not hold up after correction for the false discovery rate. CONCLUSIONS AND RELEVANCE: Our study suggests that marked cribriform change in the striatum was not associated with the development of extrapyramidal clinical disorders, including parkinsonism. The association of SCS with leukoaraiosis suggests that it is part of a more generalized cerebrovascular process. Skepticism is called for when attributing clinical symptoms to this MRI finding.

Neuropathology of non-motor features of Parkinson disease.

Non-motor manifestations of Parkinson disease (PD) are common and some may actually antedate motor dysfunction. Extrapyramidal signs in PD are tightly linked to striatonigral dopaminergic denervation associated with neuronal loss and Lewy bodies in the residual neurons of the substantia nigra. Lewy bodies composed of abnormal alpha-synuclein are the histologic hallmark of PD, and their presence beyond midbrain dopaminergic neurons is considered to be the pathologic substrate of many, if not all, of the non-motor manifestations of PD. We review the pathologic correlates of autonomic dysfunction (cardiac and gastrointestinal), hyposmia, depression, rapid eye movement behavior disorder and dementia in PD For each non-motor clinical feature there is strong evidence to suggest a role for alpha-synuclein pathology, lending further support for the notion that PD is a multisystem alpha-synucleinopathy.

Evidence that incidental Lewy body disease is pre-symptomatic Parkinson's disease.

Lewy bodies, the histologic hallmark of Parkinson's disease (PD), are detected in the brains of about 10% of clinically normal people over the age of 60 years. When Lewy bodies are found in normal individuals, the process is sometimes referred to as incidental Lewy body disease (iLBD). The distribution of Lewy bodies in iLBD is similar to the distribution in PD, but neuronal populations vulnerable to Lewy bodies do not show significant neuronal loss in iLBD. It remains unknown if Lewy bodies in this setting represent pre-symptomatic PD or an age-related change unrelated to PD. To address this question we identified cases of iLBD and used a marker for dopaminergic and noradrenergic neurons, tyrosine hydroxylase (TH), to determine if there were changes similar to those found in PD. TH immunoreactivity in the striatum and the epicardial nerve fibers was decreased in iLBD compared to normal controls, but not to the same extent as in PD. The findings suggest that iLBD is preclinical PD and that the lack of symptoms is due to subthreshold pathology.

Incidental Lewy body disease and preclinical Parkinson disease.

BACKGROUND: The significance of Lewy bodies detected at autopsy in the brains of clinically normal individuals is uncertain but may represent preclinical Parkinson disease (PD). OBJECTIVE: To determine whether diminished striatal dopaminergic innervation and nigral cell loss are present in incidental Lewy body disease (iLBD), as one might expect if it is a forerunner of PD. DESIGN: Case-control study. SETTING: Medical records and archival brain tissue were obtained from a tertiary medical center for further study. PARTICIPANTS: Brains from clinically healthy individuals older than 60 years with alpha-synuclein-immunoreactive Lewy bodies (iLBD; n = 12) were compared with those from clinically healthy individuals with no alpha-synuclein pathologic findings (n = 31) and patients with PD (n = 25). MAIN OUTCOME MEASURES: Striatal dopaminergic integrity assessed in sections of putamen by immunofluorescence for tyrosine hydroxylase (TH) and vesicular monoamine transporter 2 (VMAT2), neuronal loss score in the substantia nigra, and distribution of Lewy bodies according to PD stage. RESULTS: Among the participants with iLBD, decreased striatal dopaminergic immunoreactivity was documented for both TH (33%) and VMAT2 (42%), compared with the pathologically normal subjects; as expected, the reductions were even greater in PD (73% decrease for TH and 96% decrease for VMAT2). Substantia nigra neuronal loss inversely correlated with both striatal TH (r = -0.84) and VMAT2 (r = -0.77). In addition, PD stage inversely correlated with both striatal VMAT2 (r = -0.85) and TH (r = -0.85). CONCLUSIONS: The results indicate that iLBD has nigrostriatal pathological features that are intermediate between those in pathologically normal persons and those with PD. The findings suggest that iLBD probably represents presymptomatic PD, rather than nonspecific, age-related alpha-synuclein pathological changes.

Bilateral internal carotid artery occlusions resulting in near total acute brain infraction.

INTRODUCTION: Acute bilateral acute carotid arteries occlusion is a very rare condition. We describe a patient with initial right middle cerebral artery syndrome who developed coma and quadriplegia 1 h after thrombolysis with intravenous tPA and was found to have bilateral cervical internal carotid artery occlusion.

Reliability of self-reported ancestry among siblings: implications for genetic association studies.

This study investigated the reliability of self-reported ancestry by comparing the interview responses of probands and their siblings. A total of 546 sibling pairs were ascertained in a family-based study of susceptibility genes for Parkinson's disease and asked to identify maternal and paternal countries of origin. Probands were recruited prospectively from the Department of Neurology of the Mayo Clinic in Rochester, Minnesota, from June 1, 1996, through May 31, 2005. Probands resided within Minnesota or one of the four surrounding states (Wisconsin, Iowa, South Dakota, North Dakota). Only 49 percent of these sibling pairs, primarily Caucasian, agreed completely on the countries of origin of both parents. The agreement increased to 68 percent when named countries were postcoded into six population genetic clusters (as previously defined by microsatellite markers). Self-reported ancestry may not be a reliable method to reduce the possible impact of population stratification in genetic association studies of outbred populations, such as in the United States.