A Pragmatic Approach to the Perioperative Management of Parkinson's Disease.

Patients with Parkinson's disease (PD) may undergo several elective and emergency surgeries. Motor fluctuations, the presence of a wide range of non-motor symptoms (NMS), and the use of several medications, often not limited to dopaminergic agents, make the perioperative management of PD challenging. However, the literature on perioperative management of PD is sparse. In this descriptive review article, we comprehensively discuss the issues in the pre-, intra-, and postoperative phases which may negatively affect the PD patients and discuss the approach to their prevention and management. The major preoperative challenges include accurate medication reconciliation and administration of the dopaminergic medications during the nil per os (NPO) state. While the former can be addressed with staff education and PD-specific admission protocols, knowledge of non-oral formulations of dopaminergic agents (apomorphine, inhalational levodopa, and rotigotine transdermal patch) is the key to the management of the Parkinsonian symptoms in NPO state. Deep brain stimulation (DBS) devices should be turned off to avert potential electromagnetic interference with surgical appliances. Choosing the appropriate anesthesia and avoiding and managing respiratory issues and dysautonomia are the major intraoperative challenges. Timely reinitiation of dopaminergic medications, adequate management of pain, nausea, and vomiting, and prevention of postoperative infections and delirium are the postoperative challenges. Overall, a multidisciplinary approach is pivotal to prevent and manage the perioperative complications in PD. Administration of anti-Parkinson medications during NPO state, prevention of anesthesia-related complications, and timely rehabilitation remain the key to healthy surgical outcomes.

Brain metastasis in breast cancer: a comprehensive literature review.

This comprehensive review provides information on epidemiology, size, grade, cerebral localization, clinical symptoms, treatments, and factors associated with longer survival in 14,599 patients with brain metastasis from breast cancer; the molecular features of breast cancers most likely to develop brain metastases and the potential use of these predictive molecular alterations for patient management and future therapeutic targets are also addressed. The review covers the data from 106 articles representing this subject in the era of modern neuroimaging (past 35 years). The incidence of brain metastasis from breast cancer (24 % in this review) is increasing due to advances in both imaging technologies leading to earlier detection of the brain metastases and introduction of novel therapies resulting in longer survival from the primary breast cancer. The mean age at the time of breast cancer and brain metastasis diagnoses was 50.3 and 48.8 years respectively. Axillary node metastasis was noted in 32.8 % of the patients who developed brain metastasis. The median time intervals between the diagnosis of breast cancer to identification of brain metastasis and from identification of brain metastasis to death were 34 and 15 months, respectively. The most common symptoms experienced in patients with brain metastasis consisted of headache (35 %), vomiting (26 %), nausea (23 %), hemiparesis (22 %), visual changes (13 %) and seizures (12 %). A majority of the patients had multiple metastases (54.2 %). Cerebellum and frontal lobes were the most common sites of metastasis (33 and 16 %, respectively). Of the primary tumors for which biomarkers were recorded, 37 % were estrogen receptor (ER)+, 41 % ER-, 36 % progesterone receptor (PR)+, 34 % PR-, 35 % human epithelial growth factor receptor 2 (HER2)+, 41 % HER2-, 27 % triple negative and 18 % triple positive (TP). Treatment in most patients consisted of a multimodality approach often with two or more of the following: whole brain radiation therapy (52 %), chemotherapy (51 %), stereotactic radiosurgery (20 %), surgical resection (14 %), trastuzumab (39 %) for HER2 positive tumors, and hormonal therapy (34 %) for ER and/or PR positive tumors. Factors that had an impact on prognosis included grade and size of the tumor, multiple metastases, presence of extra-cranial metastasis, triple negative or HER2+ biomarker status, and high Karnovsky score. Novel therapies such as application of agents to reduce tumor angiogenesis or alter permeability of the blood brain barrier are being explored with preliminary results suggesting a potential to improve survival after brain metastasis. Other potential therapies based on genetic alterations in the tumor and the microenvironment in the brain are being investigated; these are briefly discussed.

Botulinum Toxin Treatment of Neuropathic Pain.

Neuropathic pain (NP), a common form of human pain, often poorly responds to analgesic medications. In this review the authors discuss the pathophysiology and conventional treatment of neuropathic pain and provide evidenced-based statements on the efficacy of botulinum neurotoxins (BoNTs) in this form of pain. The level of efficacy for BoNT treatment in each category of NP is defined according to the published guidelines of the American Academy of Neurology. The data indicate that BoNT treatment (most of the literature is with onabotulinumtoxinA) is effective (level A evidence) in postherpetic neuralgia and trigeminal neuralgia. It is probably effective (level B) in posttraumatic neuralgia and painful diabetic neuropathy. The data on complex regional pain syndrome, carpal tunnel syndrome, occipital neuralgia, and phantom limb pain are preliminary and await conduction of randomized, blinded clinical trials. Much remains to be learned about the most-effective dosage and technique of injection, optimum dilutions, and differences among BoNTs in the treatment of neuropathic pain.

OnabotulinumtoxinA for treatment of focal cancer pain after surgery and/or radiation.

OBJECTIVE: To report the relief from refractory focal post-radiation and/or postsurgical cancer pain after local treatment with onabotulinumtoxinA. SETTING AND DESIGN: We studied the effect of onabotulinumtoxinA in seven cancer patients who suffered from severe focal pain (visual analog scale >5) at the site of local surgery or radiotherapy or both. OnabotulinumtoxinA (20-100 units) was injected into the focal pain areas (skin or muscle or both). Five of seven patients were followed beyond 1 year (1.5-5 years) with repeat treatment. RESULTS: All seven patients reported a significant improvement in pain (mean drop in visual analog scale score of 5.1). They described their response on the patient global assessment as satisfactory (two patients) or very satisfactory (five patients). Six of seven patients found the pain relief associated with significant improvement in quality of life. One patient developed weakness of jaw muscles after bilateral masseter injection that was not observed during second injection (reduced dose). Improvements with treatment persisted with repeat injections during long-term follow-up (five patients). CONCLUSION: Local treatment with onabotulinumtoxinA can significantly reduce pain and improve quality of life in cancer patients suffering from pain in the area of surgery and radiation and was well tolerated in cancer patients.

Botulinum toxin for the treatment of tremor.

Tremor is one of the common movement disorders worldwide. In the recent classification tremor has been classified into two axes (I and II). Based on axis I feature tremor can be classified as isolated and combined tremor syndrome. Common tremor syndromes include Parkinsonism-associated tremors, essential tremor including essential tremor plus, dystonic tremors, and others. Tremor may also occur secondary to demyelinating, infectious and inflammatory diseases, and stroke. Adequate management of tremor has been an unmet need in clinical practice. Most of the anti-tremor medications have limited efficacy and are. associated with undesirable adverse effects, especially in elderly patients. Several studies have reported good outcomes with the use of botulinum neurotoxin for the treatment of tremor and it has emerged as a useful therapeutic option in tremor syndromes refractory to pharmacological agents. This review describes the role of botulinum neurotoxin in different tremor conditions. This article is part of the Special Issue "Tremor" edited by Daniel D. Truong, Mark Hallett, and Aasef Shaikh.

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.

Paraneoplastic neurological syndrome: an evolving story.

Paraneoplastic neurological syndrome (PNS) comprises a group of neurological disorders that result from a misguided immune response to the nervous system triggered by a distant tumor. These disorders frequently manifest before the diagnosis of the underlying neoplasm. Since the first reported case in 1888 by Oppenheim, the knowledge in this area has evolved rapidly. Several classic PNS have been described, such as limbic encephalitis, paraneoplastic cerebellar degeneration, encephalomyelitis, opsoclonus-myoclonus, sensory neuronopathy, Lambert-Eaton Myasthenic syndrome, and chronic gastrointestinal dysmotility. It is now recognized that PNS can have varied nonclassical manifestations that extend beyond the traditional syndromic descriptions. Multiple onconeural antibodies with high specificity for certain tumor types and neurological phenotypes have been discovered over the past 3 decades. Increasing use of immune checkpoint inhibitors (ICIs) has led to increased recognition of neurologic ICI-related adverse events. Some of these resemble PNS. In this article, we review the clinical, oncologic, and immunopathogenic associations of PNS.

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.

Levodopa responsive-generalized dystonic spells and moaning in DNAJC6 related Juvenile Parkinson's disease.

This is a case of young man who has severe generalized dystonic spells with moaning with severe parkinsonism, which improves with dopaminergic medications. Patient was found to be DNAJC6 related juvenile Parkinson's disease. This case adds to the phenotypic variability of the DNAJC6 juvenile Parkinson's disease as severe dystonic spells and moaning has not been reported previously. Early diagnosis and symptomatic treatment with dopaminergic medications helps significantly to improve the quality of life.

Tics and Tourette's syndrome.

Tics and Tourette's syndrome are common hyperkinetic movement disorders seen mostly in the pediatric age group. Tics are defined as sudden, rapid, recurrent, nonrhythmic motor movements or vocalization, generally preceded by urge. Tourette's syndrome is defined as the presence of both motor and phonic tics for more than 1 year in patients with onset less than 18 years old. Most of these hyperkinetic movement disorders improve in adulthood. This review emphasizes the clinical pearls in the diagnosis and distinguishing it from other movement disorders. The treatment ranges from behavioral therapies, medical management, and also surgical treatment such as deep brain stimulation that is limited to refractory patients.

Botulinum Neurotoxins and Cancer-A Review of the Literature.

Botulinum neurotoxins (BoNT) possess an analgesic effect through several mechanisms including an inhibition of acetylcholine release from the neuromuscular junction as well as an inhibition of specific pain transmitters and mediators. Animal studies have shown that a peripheral injection of BoNTs impairs the release of major pain transmitters such as substance P, calcitonin gene related peptide (CGRP) and glutamate from peripheral nerve endings as well as peripheral and central neurons (dorsal root ganglia and spinal cord). These effects lead to pain relief via the reduction of peripheral and central sensitization both of which reflect important mechanisms of pain chronicity. This review provides updated information about the effect of botulinum toxin injection on local pain caused by cancer, painful muscle spasms from a remote cancer, and pain at the site of cancer surgery and radiation. The data from the literature suggests that the local injection of BoNTs improves muscle spasms caused by cancerous mass lesions and alleviates the post-operative neuropathic pain at the site of surgery and radiation. It also helps repair the parotid damage (fistula, sialocele) caused by facial surgery and radiation and improves post-parotidectomy gustatory hyperhidrosis. The limited literature that suggests adding botulinum toxins to cell culture slows/halts the growth of certain cancer cells is also reviewed and discussed.

Novel Botulinum Toxin Injection Protocols for Parkinson Tremor and Essential Tremor - the Yale Technique and Sensor-Based Kinematics Procedure for Safe and Effective Treatment.

Background: Hand tremor associated with Parkinson disease (PD) and essential tremor (ET) can often become challenging to treat in clinical practice. Local injections of botulinum toxin-A (BoNT-A) for hand tremor is an evolving field with newer injection techniques being utilized in clinical studies. The utility of BoNT-A therapy for ET and PD-tremor however, has been questioned based on the high incidence of finger and hand weakness after treatment. Method: The study includes detailed analysis of the techniques utilized in BoNT injection in ET and PD tremor. Results: There were 4 high-quality investigations which consisted of Class I or II double-blind placebo-controlled trials and one medium-quality study that was a prospective, open label, class III investigation. Discussion: This paper discusses two recently developed technology-based injection methods for BoNT-A therapy of ET and PD tremor, which includes comprehensive EMG screening of forearm and arm muscles with selective injections (Yale method) and the whole arm kinematic tremor assessment developed by Jog et al. In recent years, controlled, blinded studies of these two methods have shown significant post-injection reduction of finger, hand and whole limb tremor compared to the previously published controlled clinical trials not using these methodologies.

Spectrum of Movement Disorders in Patients With Neuroinvasive West Nile Virus Infection.

BACKGROUND: West Nile virus (WNV) is a flavivirus that is recognized as one of the common causes of arboviral neurological disease in the world. WNV infections usually manifest with constitutional symptoms such as fever, fatigue, myalgia, rash, arthralgia, and headache. Neuroinvasive WNV infections are characterized by signs and symptoms suggestive of meningitis, encephalitis, meningoencephalitis, and acute flaccid paralysis. In addition, many patients with neuroinvasive WNV infection develop a wide range of movement disorders. This article aims to comprehensively review the spectrum and natural course of the movement disorders observed in patients with neuroinvasive WNV infections. METHODS: A literature search was performed in March 2019 (in PubMed and EMBASE) to identify articles for this review. RESULTS: Movement disorders observed in the context of WNV infections include tremor, opsoclonus-myoclonus, parkinsonism, myoclonus, ataxia, and chorea. Most often, these movement disorders resolve within a few weeks to months with an indolent course. The commonly observed tremor phenotypes include action tremor of the upper extremities (bilateral > unilateral). Tremor in patients with West Nile meningitis subsides earlier than that in patients with West Nile encephalitis/acute flaccid paralysis. Opsoclonus-myoclonus in WNV infections responds well to intravenous immunoglobulins/plasmapheresis/corticosteroids. Parkinsonism has been reported to be mild in nature and usually lasts for a few weeks to months in the majority of the patients. CONCLUSION: A wide spectrum of movement disorders is observed in neuroinvasive WNV infections. Longitudinal studies are warranted to obtain better insights into the natural course of these movement disorders.

Botulinum toxin for the treatment of tremor.

Tremor is a key clinical feature of several common neurological disorders. Adequate management of tremor has been an unmet need in clinical practice. Most of the anti-tremor medications have limited efficacy and are associated with undesirable adverse effects, especially in elderly patients. Several studies have reported good outcomes with the use of botulinum neurotoxin (BoNT) for the treatment of tremor. This article aims to systematically review these studies and to highlight the role of BoNT in the management of tremor. A PubMed search was performed in August 2018 to identify articles pertinent to this review. Majority of the studies that have assessed the efficacy of BoNT in tremor, enrolled patients with essential tremor (ET), Parkinson's disease (PD), and dystonic tremor. Results of these studies suggest clinically meaningful improvement in hand tremor in both ET and PD and vocal tremor in ET after BoNT therapy. Additionally, BoNT has been reported to be efficacious in alleviating head and palatal tremor, tremor in multiple sclerosis, and proximal positional tremor. It is apparent that BoNT injections tailored to the needs of individual patients yield better efficacy and lower adverse effects compared to fixed-muscle-fixed-dose approach. BoNT individualized approach adds to the armamentarium for patients who have medically refractory tremors or those who are unable to tolerate the anti-tremor medications. The studies are limited and mostly open-label; thus, randomized placebo-controlled studies are needed to prove the efficacy of BoNT in various tremor conditions.

Botulinum Toxin in Restless Legs Syndrome-A Randomized Double-Blind Placebo-Controlled Crossover Study.

BACKGROUND: Restless Legs Syndrome (RLS) is a common movement disorder with an estimated prevalence of up to 12%. Previous small studies with onabotulinumtoxin A (OnaA) for RLS have shown inconsistent results. METHODS: Twenty-four patients with an International RLS score (IRLS) of >11 (moderate-severe) were enrolled in this blinded, placebo-controlled crossover study. Twenty-one patients completed the evaluations at 4, 6, and 8 weeks after each injection. One-hundred units of Incobotulinumtoxin A (IncoA) or normal saline were injected into tibialis anterior, gastrocnemius, and biceps femoris muscles each side. RESULTS: Improvement from a severe (IRLS >21) to a mild/moderate (IRLS ≤20) score was significant at four weeks (p = 0.0036) and six weeks (p = 0.0325) following IncoA administration compared to placebo. Additionally, there was significant improvement in pain score at six weeks as measured by Visual Analogue Scale (p = 0.04) and the Johns Hopkins Quality of Life Questionnaire (p = 0.01) in the IncoA group. Definite or marked improvement on Patient Global Impression of Change was seen in 7 out of 21 patients in the IncoA group vs. 1 out of 21 patients in the placebo group at 4 weeks (p = 0.012). CONCLUSION: IncoA injection lead to a reduction in severity of RLS symptoms, pain score, and quality of life, without any adverse effects.

Botulinum toxin in essential hand tremor - A randomized double-blind placebo-controlled study with customized injection approach.

INTRODUCTION: To evaluate the safety and efficacy of incobotulinumtoxinA (IncoA) injection for treatment of essential hand tremor. In essential tremor and Parkinson's disease tremor, administration of onabotulinumtoxinA via a fixed injection approach improves the tremor but a high percentage of patients (30-70%) develop moderate to severe hand weakness which has limited its use in clinical practice. METHODS: This study was performed from July 2013 to July 2016 on 33 subjects. This is a double-blind, placebo-controlled, crossover trial injecting 80-120 units of IncoA into 8-14 hand and forearm muscles using a customized approach. The subjects were followed for 28 weeks. The treatment efficacy was evaluated by the Fahn Tolosa Marin tremor rating score and NIH genetic criteria for tremor severity at 4 and 8 weeks after each of the two sets of treatments. Hand strength was assessed by an ergometer. RESULTS: There was statistically significant improvement in clinical rating score of tremor at 4 and 8 weeks following the IncoA injection. CONCLUSION: In this study, injection of IncoA treatment via a customized approach improved essential tremor on the clinical scales and patient's perception with a low occurrence of significant hand weakness.

Motor and non-motor features of Parkinson's disease in LRRK2 G2019S carriers versus matched controls.

INTRODUCTION: LRRK2 G2019S mutation carriers with Parkinson's disease (PD) have been generally indistinguishable from those with idiopathic PD, with the exception of variable differences in some motor and non-motor domains, including cognition, gait, and balance. LRRK2 G2019S is amongst the most common genetic etiologies for PD, particularly in Ashkenazi Jewish (AJ) populations. METHODS: This cross-sectional data collection study sought to clarify the phenotype of LRRK2 G2019S mutation carriers with PD. Primary endpoints were the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS) and Montreal Cognitive Assessment (MoCA). Other motor and non-motor data were also assessed. The Mann-Whitney U Test was utilized to compare LRRK2 G2019S carriers with PD (LRRK2+) with non-carrier PD controls who were matched for age, gender, education, and PD duration. Survival analyses and log rank tests were utilized to compare interval from onset of PD to development of motor and non-motor complications. RESULTS: We screened 251 subjects and 231 completed the study, of whom 9 were LRRK2+, including 7 AJ subjects. 22.73% of AJ subjects with a family history of PD (FH) and 12.96% of AJ subjects without a FH were LRRK2+. There were no significant differences between the 9 LRRK2+ subjects and 19 matched PD controls in MDS-UPDRS, MoCA, or other motor and non-motor endpoints. CONCLUSION: Prevalence of the LRRK2 G2019S mutation in AJ and non-AJ subjects in our study population in Cleveland, Ohio was comparable to other clinical studies. There were no significant motor or non-motor differences between LRRK2+ PD and matched PD controls.

Abducens nerve palsy due to inferior petrosal sinus thrombosis.

Isolated unilateral abducens nerve palsy is usually due to ischemia, trauma or neoplasm. Dorello's canal is the space between the petrous apex and superolateral portion of the clivus, bound superiorly by Gruber's ligament. The abducens nerve travels with inferior petrosal sinus (IPS) though the Dorello's canal before entering the cavernous sinus. A 31-year-old man presented with neck pain, and binocular horizontal diplopia, worse looking towards left and at distance. He had a history of intravenous drug abuse but no history of hypertension or diabetes. On examination, he had complete left 6th nerve palsy with normal fundi, pupils, and other cranial nerves. Methicillin-resistant Staphylococcus aureus bacteremia was detected with naïve tricuspid valve endocarditis and multiple septic emboli to lungs with infarcts. His cerebrospinal fluid was normal. MRI of the brain was normal. MRV of head and neck showed thrombosis of the left internal jugular vein, left sigmoid sinus and left inferior petrosal sinus with normal cavernous sinus and no evidence of mastoiditis. He was treated with broad spectrum antibiotics. He was not anticoagulated for fear of pulmonary hemorrhage from pulmonary infarcts. Although cerebral venous sinus thrombosis commonly presents with elevated intracranial pressure, isolated ipsilateral 6th nerve palsy from its compression in Dorello's canal due to thrombosis of the ipsilateral inferior petrosal sinus is extremely rare. To our knowledge, only two patients have been reported with isolated abducens palsy due to IPS thrombosis; one caused by septic emboli and the other developed it during IPS cortisol level sampling.