Archive for the ‘therapy’ tag
Stem cell therapy for neurodegenerative diseases: Progress and prospects
Although neurodegenerative diseases have different causes, the dysfunction and loss of specific groups of neurons is common to all these disorders and may allow the development of similar therapeutic approaches to the treatment of diseases like Alzheimer’s disease (AD) and Parkinson’s disease (PD). The efforts to treat the neurodegenerative diseases by existing methods of cellular therapy are insufficiently effective. The modern methods do not provide correct restoration of cytoarchitecture and pattern of connections (the rewiring of specifically organized long-distance connections), which are essential to achieve a significant functional recovery. This article discusses existing methods of neural stem cell therapy and provides example of new approach to the treatment of various neurodegenerative diseases.
Neurodegenerative diseases are an assortment of central nervous system disorders characterized by neuronal loss and intraneuronal accumulation of fibrillary materials. Abnormal protein-protein interactions may allow the precipitation of these proteins, forming extracellular and intracellular aggregates. These abnormal interactions could play a role in the dysfunction and neuronal death that characterizes several common neurodegenerative diseases, such as Alzheimer’s Disease (AD) and Parkinson’s Disease (PD).
AD is the most common cause of dementia, with aging a major contributor to its onset. Currently, it is estimated that 40% of people over age 80 are afflicted with AD. Autopsy examination of a patient’s brain reveals gross cerebral atrophy, signifying loss of neurons and the presence of large numbers of extracellular neuritic plaques and intracellular neurofibrillary tangles. Plaques and tangles are found predominantly in the frontal and temporal lobes, including the hippocampus. In more advance cases, the pathology extends to other regions of the cortex. Similar plaques and tangles do occur in normal ageing brains.
PD is more common in people 60 years old and older. In the US, PD affects 1.5 million people. The degeneration and loss of dopaminergic neurons in PD causes akinesia, rigidity and tremor. Cell transplantation for the treatment of PD is the promising approach that has received most attention.
Cell therapy for PD
The potential of cell therapy for neurodegenerative diseases was demonstrated on implantation of different types of stem cells in the animals with PD (Kim J-H et al 2002, Parati EA et al 2003). Transplantation of stem cells into rat brain resulted in reinnervation of the striatal neurons and partial recovery of motor deficit associated with dopamine deficiency (Kim J-H et al 2002). The same results were obtained after transplantation of fetal dopaminergic neurons in clinical trials (Piccini P et al 2000, Freed CR et al 2001). It is possible to use different types of stem cells to generate dopaminergic neurons. Today the process of dopaminergic neurons differentiation from embryonic stem cells (ESC) in vitro is most effective and understandable (Kim J-H et al 2002, Isacson O, Ann Neurol 2003, Isacson O, Lancet Neurol 2003, Barberi T et al 2003). Recent progress in human therapeutic cloning (Woo Suk Hwang et al 2004) makes this way to generate neurons more and more attractive. Differentiation of ESC in vitro and transplantation of dopaminergic neurons in the animal models of PD resulted in functional integration of implanted cells into recipient’s brain and partial recovery of motor functions (Kim J-H et al 2002, Barberi T et al 2003).
Although transplantation of neurons into striatum in PD model has a higher effectiveness in comparison with transplantation of neurons in other neurodegenerative disorders, it is too early to speak about full restoration of motor deficit associated with parkinsonism. In case of PD significant functional recovery requires cell replacement with, at least partial repair of original connections with neurons in the striatum. If such connections do not exist the full regress of motor deficit is impossible because dopamine release is under feedback control. This fact emphasizes the importance to develop effective methods to
The method to enhance accuracy of regeneration (Potential therapeutic strategy)
After transplantation stem cells make decisions regarding fate and patterning in response to external signals from extracellular environment and neighboring cells. The effectiveness of neural stem cell therapy may be facilitated by the ability to manipulate these signals in a temporal and spatially appropriate fashion (Liu CY et al 2003). The future methods of therapy could include in vitro processing of stem cells before implantation, supporting and guiding the cells after implantation with the help of nanorobots, as well as the in vivo creation of molecular scaffold (The Samuel I. Stupp Laboratory – sistagirl.ms.northwestern.edu, Silva GA et al 2004) for stimulating their growth in the correct direction.
During experiments on neonatal rats (Englund U et al 2002) the potential ability of neural stem cells to establish appropriate long-distance axonal projection after region-specific differentiation were shown. Unfortunately, adult brain, as compared to neonatal, has unfavorable conditions for axon growth in the correct direction. It is for this reason the stimulation of new neurons growth, for example along the surface of neurons in the zone of progressive degeneration, is necessary. The reconstruction of dysfunctional neural circuits may be facilitated in the following way . The proposed strategies are designed to increase accuracy of dysfunctional neurons regeneration.
Memantine in MS-Related Cognitive Dysfunction: An Unexpected Outcome
Cognitive dysfunction is a well-recognized feature of multiple sclerosis (MS) that can be detected even in benign and pediatric cases. No evidence-based recommendations are available for the treatment of MS-related cognitive problems. Acetylcholinesterase inhibitors are used off-label in MS, on the basis of positive findings from several small-scale clinical trials reported primarily in abstract form. In the largest published trial (69 patients with MS), donepezil improved verbal learning and memory (J Neurol Sci 2006; 245:127). Intuitively, studying other medications approved for dementia, such as the N-methyl-D-aspartic acid (NMDA) receptor inhibitor memantine, might make sense. Moreover, memantine was proposed as a potential therapy for MS-related oligodendrocyte injury based on experimental data (Trends Pharmacol Sci 2007; 28:561) and was reported effective in MS-related pendular nystagmus (J Neurol1997; 244:9).
Now, researchers have conducted a randomized, double-masked, placebo-controlled, manufacturer-supported study of memantine in patients with MS and cognitive impairment. Doses were titrated up by 10 mg weekly, from 10 mg daily to 30 mg daily. The trial was terminated early, at 9 months, because 9 of 19 patients treated with memantine reported worsening of preexisting neurological symptoms, consistent with pseudoexacerbations. The authors conclude that studying NMDA-receptor inhibitors may help us understand the basic pathophysiology of MS-related pseudoattacks.
Comment: Because the authors do not report outcomes in patients who tolerated memantine, whether the medication improves cognitive outcomes remains unclear. The dose titration was relatively rapid in this study, which may have contributed to the adverse outcomes. As the authors note, a previous study of memantine doses up to 60 mg, with a slower titration schedule, to treat MS-related nystagmus did not demonstrate this problem.
More data are needed on NMDA-receptor inhibitors in MS before we can conclude that this class of medication definitely triggers pseudoattacks in MS. Nonetheless, the current data strongly suggest a true cause-effect relationship when the medication is used with a relatively rapid titration schedule. Therefore, memantine should not be used, or should be used with extreme caution, in patients with MS.
Management of Chronic Pain
Comprehensive treatment for chronic pain must address both physical and psychological aspects.
Pain is a leading reason that people seek medical care. Annually, pain is estimated to burden the U.S. economy with $100 billion in direct costs and $61 billion in productivity losses. These losses, which amount to a mean of 4.6 hours weekly, are largely due to diminished performance at work.1 Perhaps more significant, but more difficult to quantify, is the emotional distress and diminished quality of life that pain inflicts on individuals and their loved ones.
WHAT IS PAIN?
Pain, as defined by the International Association for the Study of Pain is “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.”2 Thus, pain is an experience that comprises a physical sensory component and an affective cognitive component. The physical element involves a nociceptive, neuropathic, or inflammatory stimulus that is transmitted via the spinal cord to the thalamus and then to areas of the cerebral cortex, where it is perceived. Acute pain serves a biological purpose as an alert to potential, immediate, or ongoing injury.
Chronic pain is pathologic, serves no biological purpose, and can result from peripheral sensitization, in which processes (such as changes in gene expression in the dorsal root ganglia) augment the synthesis of various peripheral nociceptors. In turn, inputs to the dorsal horn of the spinal cord are amplified, leading to activation of N-methyl-D-aspartate (NMDA) receptors and subsequent spinal cord hyperexcitability. Destruction of inhibitory interneurons and sprouting of nerve fibers at the level of the dorsal horn also can contribute to central sensitization; in addition, disruption of descending inhibitory neural pathways can trigger central hypersensitivity and chronic pain.3
Chronic pain can persist after an initial injury has healed, or it can result from ongoing pathologic processes. Although specific periods (typically 6 months) often are used to define chronic pain, a more appropriate definition of the condition is simply pain that persists longer than it should. Chronic pain often involves neural activity in specific brain areas that are distinct from those that mediate acute pain; for example, unrelenting back pain is processed by areas that also process negative emotions.4 In addition, chronic pain can have widespread effects on overall brain functioning, thereby causing depression, anxiety, and decision-making difficulties in ways that acute pain does not.
WOMEN AND PAIN
Conditions such as headache, pelvic pain, rheumatoid arthritis, and facial pain are more common in women than in men; accordingly, women are two to three times more likely than men to suffer from chronic pain. Compared with men, women also tend to perceive pain as more severe and to report lower pain thresholds and higher pain ratings in research studies. Such sex differences could be secondary to the influence of hormones, family history, traditional sex roles, cognitive factors, and how the central nervous system processes pain.5
INTERDISCIPLINARY TREATMENT OF CHRONIC PAIN
Comprehensive treatment of chronic pain must address both physical and psychological aspects; thus, interdisciplinary approaches to pain management involve medical management, physical therapy, occupational therapy, biofeedback, vocational and recreational therapy, and psychological counseling.
Rational polypharmacy (evidence-based use of multiple medications) is a cornerstone of medical management of pain syndromes, which can encompass sleep and mood disorders. Treatment options include nonsteroidal anti-inflammatory agents, antiepileptic drugs such as gabapentin (for neuropathic pain), antidepressants, and opioid drugs. Use of chronic opioid therapy has risen substantially, along with concerns about drug abuse and addiction; accordingly, treatment recommendations have been developed by the American Pain Society and the American Academy of Pain Medicine to provide guidance about patient selection, risk factors for abuse, and opioid management plans.6 Chronic opioid treatment is appropriate if analgesia is achieved, adverse side effects do not occur, activities of daily living improve, and aberrant behavior or signs of abuse are not present (sometimes referred to as the four A’s). In addition to documentation of the four A’s, clinicians’ use of opioid contracts with patients, as well as random urine screens, all help to justify prescribing these agents as part of therapy for patients with chronic pain. Other medical strategies involve steroid injections (epidural or delivered directly to affected joints) to treat pain flares, and, when indicated, surgical approaches.
Physical therapy serves to allay the patient’s fear of movement; to teach the difference between “hurt” and “harm” sensations; to increase endurance, range of motion, and tolerance for sitting, standing, and walking; and to improve posture and strength. Occupational therapy addresses body mechanics, pacing, functional mobility and activities of daily living, and ergonomic modifications in the workplace. Biofeedback helps the patient to master diaphragmatic breathing and progressive muscle relaxation with the goals of alleviating muscle tension, reducing physical and emotional distress, and encouraging mindfulness of pain in an effort to divert attention away from it.
Managing pain largely entails attending to its psychological features and their impingement on overall emotional status. Sleep disturbances, anxiety, and depression can be treated with psychotherapy and, when required, pharmacologic agents. Along with medical management, cognitive-behavioral therapy (CBT) is often a mainstay of treatment.7 CBT is based on the theory that thoughts affect feelings and behaviors, which, in turn, influence how one experiences pain. CBT teaches individuals how to identify negative dysfunctional pain-related thoughts and how to replace them with more-adaptive thoughts. Ideally, one learns coping skills that can be applied to daily situations, including pain flares.
A key goal of CBT — indeed, of all the therapies for chronic pain — is to foster the belief that patients have the power to manage their pain by improving their physical abilities and by learning how to control their thoughts, behaviors, and reactions. Having a healthy sense of command of oneself includes being both physically and socially active and integrated. Unremitting pain leads to lower physical activity levels, resulting in diminished function and greater likelihood of depression; maintaining higher activity levels leads to less pain, thereby breaking the cycle.
Maintaining a sense of control is undeniably challenging for women who are in continual pain. Isolation and depression commonly accompany chronic pain conditions, which makes treatment difficult. Women must learn to maintain direction over their own lives and take time to care for themselves while also meeting the challenges of employment, caring for their families, and remaining socially integrated. Being able to do all of this, in addition to handling a debilitating condition, can be demoralizing and exhausting — physically, emotionally, and financially. Likewise, managing chronic pain conditions can be challenging and potentially draining for clinical pain-care teams. The treating clinician has a responsibility not only to educate the patient that her chronic pain is a disease but also to stop ongoing and unnecessary laboratory and radiologic testing after the diagnosis has been made definitively.
CONCLUSION
Collaboration among therapists, psychologists, and other supportive resources is crucial to delivering effective pain treatments. Helping women with chronic pain to take ownership of their conditions and to actively curb physical and emotional aspects will boost their functional mobility, productivity, and quality of life while also shrinking the associated financial burden.