Adolfo Ramirez-Zamora

Deep brain stimulation of the substantia nigra pars reticulata improves forelimb akinesia in the hemiparkinsonian rat

Deep brain stimulation (DBS) employing high-frequency stimulation (HFS) is commonly used in the globus pallidus interna (GPi) and the subthalamic nucleus (STN) for treating motor symptoms of patients with Parkinsons disease (PD). Although DBS improves motor function in most PD patients, disease progression and stimulation-induced nonmotor complications limit DBS in these areas. In this study, we assessed whether stimulation of the substantia nigra pars reticulata (SNr) improved motor function. Hemiparkinsonian rats predominantly touched with their unimpaired forepaw >90% of the time in the stepping and limb-use asymmetry tests. After SNr-HFS (150 Hz), rats touched equally with both forepaws, similar to naive and sham-lesioned rats. In vivo, SNr-HFS decreased beta oscillations (12-30 Hz) in the SNr of freely moving hemiparkinsonian rats and decreased SNr neuronal spiking activity from 28 ± 1.9 Hz before stimulation to 0.8 ± 1.9 Hz during DBS in anesthetized animals; also, neuronal spiking activity increased from 7 ± 1.6 to 18 ± 1.6 Hz in the ventromedial portion of the thalamus (VM), the primary SNr efferent. In addition, HFS of the SNr in brain slices from normal and reserpine-treated rat pups resulted in a depolarization block of SNr neuronal activity. We demonstrate improvement of forelimb akinesia with SNr-HFS and suggest that this motor effect may have resulted from the attenuation of SNr neuronal activity, decreased SNr beta oscillations, and increased activity of VM thalamic neurons, suggesting that the SNr may be a plausible DBS target for treating motor symptoms of DBS.

Management of neurocysticercosis

Abstract Background: Neurocysticercosis is a parasitic infection of the central nervous system caused by the larval stage of the tapeworm Taenia solium and is the most common parasitic infection involving the human nervous system. Neurocysticercosis represents one of the most common causes of symptomatic epilepsy in developing countries and is an increasing concern in industrialized nations. Methods: We conducted a review of the medical literature regarding the current management of neurocysticercosis in Latin American countries. Results: Mexico and Brazil report the highest incidence of neurocysticercosis in Latin America. However, major obstacles interfere with an accurate determination of the prevalence of neurocysticercosis, including the lack of standardized and comprehensive epidemiological systems, intrinsic limitations of current immunological studies, the high cost of neuroimaging studies in rural communities and the presence of asymptomatic patients with neuroimaging characteristic compatible with neurocysticercosis. As such, the real prevalence of the disease and its burden are likely underestimated in Latin America. There is no universal consensus or guidelines for the management of different forms of the disease, but most experts agree in the use of antihelminthic therapy when viable cysts are encountered and with the use of corticosteroids in patients presenting with encephalitis. Discussion: Neurocysticercosis is a pleomorphic disease, with a broad spectrum of clinical and radiographic features. The medical management of neurocysticercosis is complex and needs to be individualized.

Treatable causes of cerebellar ataxia.

The cerebellar ataxia syndromes are a heterogeneous group of disorders clinically characterized by the presence of cerebellar dysfunction. Initial assessment of patients with progressive cerebellar ataxia is complex because of an extensive list of potential diagnoses. A detailed history and comprehensive examination are required for an accurate diagnosis and hierarchical diagnostic investigations. Although no cure exists for most of these conditions, a small group of metabolic, hereditary, inflammatory, and immune‐mediated etiologies of cerebellar ataxia are amenable to disease‐modifying, targeted therapies. Over the past years, disease‐specific treatments have emerged. Thus, clinicians must become familiar with these disorders because maximal therapeutic benefit is only possible when done early. In this article, we review disorders in which cerebellar ataxia is a prominent clinical feature requiring targeted treatments along with specific management recommendations.

Treatment of motor fluctuations in Parkinson's disease: recent developments and future directions

Parkinson’s disease (PD) is characterized clinically by rest tremor, rigidity, bradykinesia and pathologically by degeneration of nigrostriatal dopamine neurons. Motor fluctuations (wearing off) and motor complications (dyskinesia) are common features of the long-term treatment of PD. Ongoing clinical and preclinical research has led to the discovery of promising new therapeutic targets that might prevent or reduce motor complications. Newer approaches modulating non-dopaminergic systems including adenosine A2A antagonists, monoamine oxidase-B inhibitors, glutamatergic antagonists, adrenergic receptor antagonists and serotonergic agents are encouraging strategies for management of advanced PD. Recent developments in levodopa delivery formulations include duodenal infusion of a levodopa/carbidopa, new extended-release levodopa and oral pro-levodopa forms. Recent clinical trials revealed diverse but promising results raising the possibility of new therapeutic modalities for PD in the near future.

Evolving Concepts in Posterior Subthalamic Area Deep Brain Stimulation for Treatment of Tremor: Surgical Neuroanatomy and Practical Considerations.

Background: Although thalamic deep brain stimulation (DBS) has been established as an effective therapy for refractory tremor in Parkinsons disease and essential tremor, reports investigating the efficacy of posterior subthalamic area (PSA) DBS for severe, debilitating tremors continue to emerge. However, questions regarding the optimal anatomical target, surgical approach, programming paradigms and effectiveness compared to other targets remain. Objectives: In this report, we aimed to review the current literature to assess different stereotactic techniques, anatomical considerations, adverse effects and stimulation settings in PSA DBS. Methods: A comprehensive literature review was performed searching for articles discussing tremors and PSA stimulation. We performed a quantitative analysis comparing different DBS tremor targets. Results: Tremor improvement is consistently documented in most reports with an average reduction in tremor of 79% depending on the specific tremor syndrome. Tremor benefit in patients with multiple sclerosis (MS) tremor was significantly higher than for other stimulation targets. Transient paresthesias, imbalance, dizziness and dysarthria are the most common side effects with PSA DBS. Conclusions: PSA DBS is an effective and safe treatment for tremor control and should be considered in patients with refractory tremors with associated cerebellar or dystonic features, proximal tremors and MS tremor.

Deep brain stimulation for the treatment of uncommon tremor syndromes

ABSTRACT Introduction: Deep brain stimulation (DBS) has become a standard therapy for the treatment of select cases of medication refractory essential tremor and Parkinson’s disease however the effectiveness and long-term outcomes of DBS in other uncommon and complex tremor syndromes has not been well established. Traditionally, the ventralis intermedius nucleus (VIM) of the thalamus has been considered the main target for medically intractable tremors; however alternative brain regions and improvements in stereotactic techniques and hardware may soon change the horizon for treatment of complex tremors. Areas covered: In this article, we conducted a PubMed search using different combinations between the terms ‘Uncommon tremors’, ‘Dystonic tremor’, ‘Holmes tremor’ ‘Midbrain tremor’, ‘Rubral tremor’, ‘Cerebellar tremor’, ‘outflow tremor’, ‘Multiple Sclerosis tremor’, ‘Post-traumatic tremor’, ‘Neuropathic tremor’, and ‘Deep Brain Stimulation/DBS’. Additionally, we examined and summarized the current state of evolving interventions for treatment of complex tremor syndromes. Expert commentary: Recently reported interventions for rare tremors include stimulation of the posterior subthalamic area, globus pallidus internus, ventralis oralis anterior/posterior thalamic subnuclei, and the use of dual lead stimulation in one or more of these targets. Treatment should be individualized and dictated by tremor phenomenology and associated clinical features.

Unusual complications of deep brain stimulation

Deep brain stimulation (DBS) has emerged as a successful therapy for the treatment of several neurological disorders with potential implications in management of psychiatric disease. A variety of well-characterized hardware and surgical complications have been reported after the procedure, including postoperative hardware infection, system failure, and intracranial hemorrhage. Fortunately, serious surgical complications are rare, but they can lead to immediate or long-term disability. As the number of patients undergoing DBS continues to increase, newer and less common complications continue to emerge. It is imperative that clinicians become familiar with these complications in order to promptly recognize them and institute adequate early treatment. In this report, we examine the occurrence of unusual complications after DBS with emphasis on surgical, hardware, and stimulation-related complications.

The effects of subthalamic deep brain stimulation on mechanical and thermal thresholds in 6OHDA-lesioned rats

Chronic pain is a major complaint for up to 85% of Parkinsons disease patients; however, it often not identified as a symptom of Parkinsons disease. Adequate treatment of motor symptoms often provides analgesic effects in Parkinsons patients but how this occurs remains unclear. Studies have shown both Parkinsons patients and 6‐hydroxydopamine‐lesioned rats exhibit decreased sensory thresholds. In humans, some show improvements in these deficits after subthalamic deep brain stimulation, while others report no change. Differing methods of testing and response criteria may explain these varying results. We examined this effect in 6‐hydroxydopamine‐lesioned rats. Sprague–Dawley rats were unilaterally implanted with subthalamic stimulating electrodes in the lesioned right hemisphere and sensory thresholds were tested using von Frey, tail‐flick and hot‐plate tests. Tests were done during and off subthalamic stimulation at 50 and 150 Hz to assess its effects on sensory thresholds. The 6‐hydroxydopamine‐lesioned animals exhibited lower mechanical (left paw, P < 0.01) and thermal thresholds than shams (hot plate, P < 0.05). Both 50 and 150 Hz increased mechanical (left paw; P < 0.01) and thermal thresholds in 6‐hydroxydopamine‐lesioned rats (hot‐plate test: 150 Hz, P < 0.05, 50 Hz, P < 0.01). Interestingly, during von Frey testing, low‐frequency stimulation provided a more robust improvement in some 6OHDA lesioned rats, while in others, the magnitude of improvement on high‐frequency stimulation was greater. This study shows that subthalamic deep brain stimulation improves mechanical allodynia and thermal hyperalgesia in 6‐hydroxydopamine‐lesioned animals at both high and low frequencies. Furthermore, we suggest considering using low‐frequency stimulation when treating Parkinsons patients where pain remains the predominant complaint.

Deep brain stimulation significantly decreases disability from low back pain in patients with advanced Parkinson's disease.

Background: Up to 60% of Parkinsons disease (PD) patients suffer from low back pain (LBP) during the course of their disease. How LBP affects daily functional status and how to manage this aspect of PD has not been adequately explored. Methods: We examined 16 patients undergoing bilateral subthalamic nucleus deep brain stimulation (STN DBS) who met the inclusion criteria for moderate disability from LBP, as classified by the Oswestry Low Back Pain Disability Index (OLBPD). Results: Thirteen of 16 patients had attempted additional treatments for LBP, including medical management, massage, chiropractic, epidural steroid injections and/or surgery, with minimal relief. Following DBS, there was a significant improvement in the OLBPD at both the 6-month and 1-year time points (p < 0.02, p < 0.005, respectively). A mean improvement of 31.7% on the OLBPD score was noted. The Visual Analogue Scale (VAS) similarly decreased significantly at 1 year (p = 0.015). There was no correlation between the OLBPD score and other measures, including the Unified Parkinsons Disease Rating Scale (UPDRS), age and other nonmotor symptoms. Conclusion: Given the prevalent yet undertreated disability associated with LBP in PD, these results are novel in that they show that STN DBS has a significant positive effect on disability associated with LBP.

Effect of low-frequency deep brain stimulation on sensory thresholds in Parkinson's disease

OBJECTIVE Chronic pain is a major distressing symptom of Parkinsons disease (PD) that is often undertreated. Subthalamic nucleus (STN) deep brain stimulation (DBS) delivers high-frequency stimulation (HFS) to patients with PD and has been effective in pain relief in a subset of these patients. However, up to 74% of patients develop new pain concerns while receiving STN DBS. Here the authors explore whether altering the frequency of STN DBS changes pain perception as measured through quantitative sensory testing (QST). METHODS Using QST, the authors measured thermal and mechanical detection and pain thresholds in 19 patients undergoing DBS via HFS, low-frequency stimulation (LFS), and off conditions in a randomized order. Testing was performed in the region of the body with the most pain and in the lower back in patients without chronic pain. RESULTS In the patients with chronic pain, LFS significantly reduced heat detection thresholds as compared with thresholds following HFS (p = 0.029) and in the off state (p = 0.010). Moreover, LFS resulted in increased detection thresholds for mechanical pressure (p = 0.020) and vibration (p = 0.040) compared with these thresholds following HFS. Neither LFS nor HFS led to changes in other mechanical thresholds. In patients without chronic pain, LFS significantly increased mechanical pain thresholds in response to the 40-g pinprick compared with thresholds following HFS (p = 0.032). CONCLUSIONS Recent literature has suggested that STN LFS can be useful in treating nonmotor symptoms of PD. Here the authors demonstrated that LFS modulates thermal and mechanical detection to a greater extent than HFS. Low-frequency stimulation is an innovative means of modulating chronic pain in PD patients receiving STN DBS. The authors suggest that STN LFS may be a future option to consider when treating Parkinsons patients in whom pain remains the predominant complaint.