Diego Torres-Russotto

CD4+ Regulatory and Effector/Memory T Cell Subsets Profile Motor Dysfunction in Parkinson’s Disease

Animal models and clinical studies have linked the innate and adaptive immune system to the pathology of Parkinson’s disease (PD). Despite such progress, the specific immune responses that influence disease progression have eluded investigators. Herein, we assessed relationships between T cell phenotype and function with PD progression. Peripheral blood lymphocytes from two separate cohorts, a discovery cohort and a validation cohort, totaling 113 PD patients and 96 age- and environment-matched caregivers were examined by flow cytometric analysis and T cell proliferation assays. Increased effector/memory T cells (Tem), defined as CD45RO+ and FAS+ CD4+ T cells and decreased CD31+ and α4β7+ CD4+ T cells were associated with progressive Unified Parkinson’s Disease Rating Scale III scores. However, no associations were seen between immune biomarkers and increased age or disease duration. Impaired abilities of regulatory T cells (Treg) from PD patients to suppress effector T cell function was observed. These data support the concept that chronic immune stimulation, notably Tem activation and Treg dysfunction is linked to PD pathobiology and disease severity, but not disease duration. The association of T cell phenotypes with motor symptoms provides fresh avenues for novel biomarkers and therapeutic designs.

Neuromagnetic Evidence of Abnormal Movement-Related Beta Desynchronization in Parkinson's Disease

Parkinsons disease (PD) is a neurodegenerative disorder associated with debilitating motor, posture, and gait abnormalities. Human studies recording local field potentials within the subthalamic nucleus and scalp-based electroencephalography have shown pathological beta synchronization throughout the cortical–basal ganglia motor network in PD. Suppression of such pathological beta synchronization has been associated with improved motor function, which may explain the effectiveness of deep-brain stimulation. We used magnetoencephalography (MEG) to investigate neural population-level beta responses, and other oscillatory activity, during a motor task in unmedicated patients with PD and a matched group of healthy adults. MEG is a noninvasive neurophysiological technique that permits the recording of oscillatory activity during movement planning, execution, and termination phases. Each of these phases was independently examined using beamforming to distinguish the brain areas and movement phases, where pathological oscillations exist during motor control. Patients with PD exhibited significantly diminished beta desynchronization compared with controls prior to and during movement, which paralleled reduced alpha desynchronization. This study is the first to systematically investigate neural oscillatory responses in PD during distinct stages of motor control (e.g. planning, execution, and termination) and indicates that these patients have significant difficulty suppressing cortical beta synchronization during movement planning, which may contribute to their diminished movement capacities.

Systemic Weakness After Therapeutic Injections of Botulinum Toxin A: A Case Series and Review of the Literature

The use of intramuscular injections of Botulinum neurotoxin A (BoNT-A) is common in the treatment of hypertonicity and movement disorders. Although most side effects are mild, systemic effects, manifested by generalized weakness distant from the site of injection, have been reported. Previously reported occurrences are discussed, and 3 new cases of patients, who developed systemic weakness after administration of BoNT-A (Botox), despite having tolerated similar injections on several previous occasions, are presented. A review of the literature and reported cases indicate that risk of developing systemic effects does not seem to be related to dose based on body weight. It may be more likely that risk for systemic effects is related to total injection dose and injection frequency. The results of our 3 patients would indicate that injections of greater than 600 units of Botox with follow-up injections occurring every 3 months may lead to an increased risk. We would recommend careful consideration of reinjection frequency if injections of greater than 600 units of Botox are given. Reduction in systemic side effects may occur if reinjection frequency occurs in intervals of 4 months or greater in these individuals.

Bilateral Deep Brain Stimulation of the Ventral Intermediate Nucleus of the Thalamus for Posttraumatic Midbrain Tremor

Posttraumatic movement disorders are common sequelae of brain injury, occurring in as many as 66% of people suffering traumatic brain injury. Approximately 5% of patients with severe traumatic brain injury have persistent movement disorders, most commonly tremor (1). Posttraumatic midbrain tremor (also known as Holmes or rubral tremor) is particularly disabling because it typically affects the upper extremities and its combination of rest, action, and postural components results in severe functional impairment (1,2). Midbrain tremor is generally refractory to pharmacologic therapy and does not resolve spontaneously (2), so surgical therapies have been offered to some individuals (1). Ablative therapies such as thalamotomy have not been beneficial uniformly (3), and the incidence of neurological complication is relatively high (1). This has led to application of deep brain stimulation (DBS) for the treatment of posttraumatic tremor. DBS for treatment of midbrain tremor has been described in the literature only in limited fashion and with limited follow-up. DBS of the ventral intermediate nucleus (Vim) can reduce posttraumatic tremor, but the frequent occurrence of speech impairment with bilateral DBS has led some authors to conclude that best results are achieved with unilateral DBS (4). We report here the long-term outcome of a patient who underwent bilateral Vim DBS to treat posttraumatic midbrain tremor, in whom durable improvement of tremor and functional status has been achieved without associated speech dysfunction. We provide video and graphic documentation of tremor in the onand off-stimulation conditions.

Calibrated finger rub auditory screening test (CALFRAST)

Background: Determination of auditory function is a fundamental part of a complete neurologic examination. Disability from permanent hearing loss is common in the general population. Current bedside auditory tests are unreliable and cumbersome. We evaluated the calibrated finger rub auditory screening test (CALFRAST) as a routine diagnostic tool. Methods: The sound spectrum and mean peak intensities of standard finger rub were measured, as well as background noise. CALFRAST overlapped the frequency spectrum of normal speech. Patients and companions were recruited from a neurology clinic. With arms extended, two stimulus intensities were presented: strong finger rub (CALFRAST–Strong 70) and the faintest rub that the examiner could hear (CALFRAST–Faint 70). With subjects’ eyes closed, each ear’s CALFRAST threshold was ascertained and then compared with its audiometric measure. The normal threshold was considered to be 25 dB. Validity, reliability, and discrimination abilities were obtained using standard methods. Results: Two hundred twenty-one subjects (442 ears; 58% women) were examined. Ages ranged from 18 to 88 years, with a mean of 46 years. Eighty-five subjects (39%) had some degree of hearing loss. Both specificity and positive predictive value of CALFRAST–Strong 70 were 100%. Both sensitivity and negative predictive value of CALFRAST–Faint 70 were 99%, with a negative likelihood ratio <0.1. Area under the receiver operating characteristic curve was 0.94, consistent with excellent discrimination ability. Both intrarater and interrater reliability were excellent, both κ >0.8. Subjects’ self-assessment of hearing was unreliable. Conclusion: The calibrated finger rub auditory screening test (CALFRAST) is simple, accurate, inexpensive, and reliable. As a routine screening tool, CALFRAST may contribute to more efficient identification of auditory impairment.

Botulinum toxin in the management of blepharospasm: current evidence and recent developments.

Blepharospasm is a focal (although usually bilateral) dystonia of the orbicularis oculi muscles, producing excessive eye closure. This produces significant disability through functional blindness. Botulinum neurotoxins (BoNT) have become the treatment of choice for blepharospasm; the impressive response rate and the tolerable safety profile have been proven through multiple clinical studies. There are currently four BoNT approved in the United States for different indications - we review the data on blepharospasm for each of these drugs. Currently, incobotulinumtoxinA and onabotulinumtoxinA have the most evidence of benefit for patients with blepharospasm. Current evidence, recent development and future directions are discussed.

A novel CABC1/ADCK3 mutation in adult-onset cerebellar ataxia

Objective: Autosomal recessive cerebellar ataxias (ARCAs) are disabling, inherited neurodegenerative diseases linked to a multitude of genes. ARCA2 is a recently identified condition caused by mutations in CABC1/ADCK3 possibly leading to Coenzyme Q10 (CoQ10) deficiency. Only 35 patients have been reported worldwide. ARCA2 clinical course is variable, exhibiting slowly progressive cerebellar ataxia, seizures, stroke-like episodes, cognitive impairment, exercise intolerance, and cerebellar atrophy. Only 3 cases with adult onset ARCA2 have been reported. Background: We report the case of an 81-year-old female who presented at age 75 for progressive ataxia. The patient, her father, and her two daughters have epilepsy. At 65 years of age noticed action and intention tremor, and chronic motor tics of face and neck. By age 70, she noticed unsteady gait with rare falls. Examination revealed mild symmetric generalized weakness (4/5). She has mild ocular ataxia, and bidirectional horizontal nystagmus. Gait was wide-based, with irregular stepping, multi-step-turning, and was unable to tandem. The BARS (brief ataxia rating scale score) was 15 of 30. She also had upper extremity ataxia, characterized by moderate dysynergia, mild dysdiadochokinesia, abnormal finger-to-nose, finger-tapping, finger-following-finger, sequential finger and heel-knee-shin tests. She had normal reflexes, Babinski was absent, and had decreased vibration sense. Brain MRI showed severe global cerebellar atrophy. Design/Methods: Case report Results: Molecular microarray analysis revealed a 2.9Mb duplication at chromosome region 1q42.11q42.13. ADCK3/CABC1 is included in this region (OMIN#12016), a gene in which mutations are associated with autosomal recessive spinocerebellar ataxia. Molecular cytogenetic (FISH test) studies also revealed the tandem duplication. Conclusions: This is the first report of a duplication mutation on ADCK3/CABC1 in a patient with adult-onset progressive ataxia, chronic motor tics and familial seizures. Further studies are needed to elucidate whether the gain of function or a duplication-induced loss of function play a role in the pathophysiology of this condition. Disclosure: Dr. Malgireddy has nothing to disclose. Dr. Thompson has nothing to disclose. Dr. Torres-Russotto has received pesonal compensation for activities with Abbvie, Allergan, the American Parkinson Disease Foundation (APDA), Lundbeck, Teva, Huntington Disease Society of America (HDSA), Parkinson Disease Foundation, Ipsen, and Medtronic as a speaker or consultant.

Speech‐Induced Atrial Tachycardia: An Unusual Presentation of Supraventricular Tachycardia

A 63‐year‐old male radio announcer was admitted with a narrow complex, long RP tachycardia. While in the awake state, the patient spoke in his radio voice, initiating and maintaining the tachycardia. Three‐dimensional electroanatomic mapping during electrophysiology study localized the tachycardia to the ostium of the right superior pulmonary vein. After single radiofrequency energy application, no further arrhythmias were inducible with speech. At more than 1 year of follow‐up, the patient had no recurrences and continues to work as a radio announcer.

Hyperbaric oxygen for late sequelae of carbon monoxide poisoning enhances neurological recovery: case report

Neuropsychiatric sequelae have been reported in 15%-45% of survivors of carbon monoxide (CO) poisoning. Hyperbaric oxygen (HBO₂) therapy reduces the incidence of cognitive and neurological a dysfunction. The efficacy of providing HBO₂ beyond the first one to two days after initial insult is unknown. However, some evidence exists for the benefit of this treatment. We report on treating a patient 14 months after CO injury, who responded with markedly improved neurologic status. A 27-year-old scholar was found comatose due to CO poisoning (carboxyhemoglobin = 31.7%). He received five acute HBO₂ treatments. After discharge, he developed chorea, Parkinsonism, dystonia, memory loss, slowed processing speed and verbal fluency, leaving him disabled. After the patient reached a clinical plateau, HBO₂ was tried again at 90 minutes at 2.4 ATA plus air breaks. Neuropsychological testing was performed at baseline and after each 20 HBO₂ cycles, five of which were performed during the period from 14-22 months after CO exposure. After the first 20 treatments, Parkinsonism and dystonia improved. After 40 sessions, further improvements were seen on mental speed, verbal fluency, and fine motor movements. The outcome following 100 treatments was that the patient regained independence, including the ability to drive and to become gainfully employed. Our case calls into question the concept that HBO₂ therapy has no role during the chronic phase of CO brain injury. Randomized clinical trials should be considered to evaluate the therapeutic efficacy of HBO₂ in patients with neurological sequelae following CO injury.

Role of the Personal KinetiGraph in the routine clinical assessment of Parkinson’s disease: recommendations from an expert panel

ABSTRACT Introduction: Evaluation of people with Parkinson’s disease (PD) is often complex due to heterogeneity of symptoms and disease course, including the variability of motor fluctuations and dyskinesia. Routine clinical evaluations may be incomplete, may not accurately capture important symptoms, and may not reflect day-to-day variability. While significant advances have been made in wearable ambulatory continuous objective monitoring (COM) technologies, many clinicians remain uncertain of how to incorporate them in clinical practice, including the value to clinical decision-making. The Personal KinetiGraph™ (PKG) has FDA clearance in the United States, and has recently been used in several clinical studies. Areas covered: An expert group of movement disorders neurologists convened to discuss the clinical utility of the PKG in the routine assessment of people with PD. Based on their experience, the group identified clinical scenarios where objective information gained from review of PKG reports can provide useful information to improve clinical management. Expert commentary: PKG provides clinically meaningful data in patients with PD that can aid the clinician in evaluating patients and optimizing their pharmacologic therapy. Early clinical experience and expert opinion suggest that utilization of COM technologies such as the PKG have the potential to improve medical care in people with PD.