Tuesday, 29 July 2014

Chronic Pain: A Modern Problem

Today's very long post from painresearchforum.org (see link below) is worth the space it takes up because it shows the results of a symposium on biological and psychological factors that influence chronic pain. Many neuropathy patients are experts on living with chronic pain and can also tell you a great deal about which factors influence it in their daily lives. Because chronic pain is a hot topic at the moment (mainly because of the health costs required to sustain it), this sort of conference and in-depth discussion means that the authorities are waking up to the fact that people living with chronic pain are not serial fakers or hypochondriacs and that many other factors come into play that affect the seriousness of the condition. Definitely worth a read.

Pain and Depression: A Comorbidity Conundrum
News from the 2014 NIH Pain Consortium Symposium on biological and psychological factors that contribute to chronic pain
by Pat McCaffrey on 9 Jul 2014

Interest in pain is on the rise at the US National Institutes of Health (NIH), said Nora Volkow, chief of the National Institute on Drug Abuse, welcoming participants to the 9th Annual NIH Pain Consortium Symposium, held May 28-29, 2014, in Bethesda, US. Volkow noted a significant increase in research funding at the NIH for chronic pain conditions, which amounted to $400 million in 2014, up from $279 million in 2008. That is still just about 1 percent of the entire NIH pie, but in an era of shrinking budgets overall, that is no small progress.

The increase follows the 2010 Affordable Care Act (aka Obamacare), which mandated a hard look at the state of pain education, care, and research. That legislation led to the 2011 report from the Institutes of Medicine on the public health impact of pain (see PRF related story and commentary).

For those who want to know where that money and other federal funds are going, the NIH recently announced the launch of a database of all the federal grants related to pain (see press release and news coverage). The Interagency Pain Research Portfolio is a publicly accessible, searchable resource that for the first time collects information on all federal research, including efforts by the NIH, the Centers for Disease Control, the Department of Defense, the Food and Drug Administration, and others in one place.The database reflects the Pain Consortium’s mission to enhance pain research and promote collaboration across government agencies.

Volkow also announced that on September 29-30, 2014, the NIH Office of Disease Prevention will sponsor a workshop on the role of opioids in treating chronic pain. Prescription opioid misuse, addiction, and overdose deaths have grabbed the attention of physicians, patients, the media, and policy makers, but data that would support the proper use of these drugs for chronic pain are severely limited. The workshop will tackle the scientific issues around opioid use for chronic pain. Registration will open in June. For more information, see 2014 NIH Pathways to Prevention workshop on The Role of Opioids in the Treatment of Chronic Pain.

The theme of this year’s symposium was biological and psychological factors that contribute to chronic pain. Over one and a half days, speakers discussed comorbid factors including depression, sleep disturbances, and inflammation. Summaries of selected talks on pain and depression are presented here; Part 2 deals with pain and sleep. In addition, an archived webcast of the entire meeting is available on the NIH website (view Day 1 and Day 2). The complete meeting agenda is here.

Pain and depression—what is the relationship?

Pain can certainly be depressing, and some data suggest that depression increases the risk of pain. But in his overview talk on the topic, Dan Clauw, University of Michigan, Ann Arbor, US, said that getting to a precise understanding of how often the two conditions co-occur is actually not easy. One problem is that the clinical instruments designed to identify depression are often “contaminated” by measures, such as sleep disturbances and headaches, that are also present in chronic pain conditions. Clauw said that going forward, studies seeking to measure comorbidity will need to isolate the cognitive and affective aspects of depression from somatic symptoms that are shared with chronic pain.

In people who do have pain and depression, which comes first? Nearly all studies suggest that chronic pain increases the risk of depression, but a fair number of data also suggests the opposite: that people with a history of depression are at a higher risk for chronic pain. Clauw noted that the magnitude of the increased risk for pain is modest (less than a twofold increase), and when measured in similar studies, other factors seem more important: Early life stressors, other psychiatric conditions, prior pain, prior somatic symptoms, and poor sleep are all stronger predictors of subsequent chronic pain. “Depression, although a risk, is not one of the stronger risks for development of subsequent pain,” Clauw said. Nonetheless, depression could be an important absolute risk factor for pain because it is so common.

In considering future directions, Clauw raised what he called “the 800-pound gorilla in the room”—what central nervous system factor or factors should researchers focus on when thinking about chronic pain? “It’s not depression, or catastrophizing. It’s something I don’t have a name for, but I see it over and over,” he said. The “something” manifests in a quartet of symptoms that cut across many diseases and include widespread pain, fatigue, memory and mood problems (including depression), and sleep disturbances.

Clauw, a rheumatologist, said he saw this in people who had consumed contaminated tryptophan in the 1980s. They first developed eosinophilia myalgia syndrome, but when the acute inflammatory phase resolved, these individuals looked like they had a severe form of fibromyalgia. He also saw an epidemic of this in veterans of the first Gulf War, and in a very high proportion of veterans from the Iraq and Afghanistan conflicts who suffer from the “polytrauma triad” of centralized pain, post-traumatic stress disorder, and mild traumatic brain injury.

This disorder goes by several names: fibromyalgia; somatization, or somatoform disorder (which involves pain in multiple areas early in life); and central sensitization, or regional idiopathic pain. This same symptom complex is very common in diseases such as interstitial cystitis, tension headache, irritable bowel, temporomandibular joint disease, vulvodynia, and dry eye. Clauw said that in his tertiary clinic, he sees patients who have had untreated disease for 30 years. These are people who have had pain in many regions over their lives and have been seen by many specialists who have a tendency to focus on where the pain is at that point in the patients' lives rather than on a lifelong history of pain in multiple areas of the body. “These are the people that all subspecialists dislike: They are a huge clinical problem,” Clauw said. “In aggregate, this may be one of the most common clinical diseases known to man, and may be the most disabling.”

This group of symptoms seems to represent some type of centralized pain state. Clauw believes that different chronic pain conditions differ in the proportion of individuals who “centralize” their pain. On the low end of a continuum are primarily nociceptive conditions such as osteoarthritis, where only 15-20 percent of people will clearly exhibit centralization, to the other end of the continuum, where nearly all patients exhibit this (e.g., fibromyalgia). It’s important to tease this out in each patient, he said, because different drugs are effective for each type of pain.

Currently, the best way to approximate this centralized state, Clauw thinks, is the concept of “FM-ness.” The current FM diagnostic criteria involve assessment of pain location and severity, as well as fatigue, depression, and other symptoms, generating an aggregate score that can range from 0 to 31 (Wolfe et al., 2011). The cut-off score for probable fibromyalgia is 13, but Clauw said the scale can also be viewed as a continuous measure of the centralization of pain, with low scores reflecting mainly nociceptive conditions, and higher scores indicating a larger degree of central nervous system involvement.

To support this idea, Clauw showed data from his ongoing study looking at the relationship between FM score and postoperative outcomes of osteoarthritis patients after knee or hip replacement surgery (Brummett et al., 2013). In the study, the researchers assessed patients before surgery for a battery of known risk factors for postoperative pain, but added a new factor—the FM score based on the 2011 revised diagnostic criteria (Wolfe et al., 2011). Only 9 percent of the 519 subjects studied met FM criteria—most subjects had scores between 5 and 10, and when Clauw analyzed outcomes for the patients with scores below 13, he found that the FM score predicted everything bad: post-operative pain, anxiety, and depression. The FM score highly predicted post-operative opioid use—for each one-point increase, patients needed an additional 9 mg opioids per day, and many still had ongoing pain. In terms of predicting six-month pain and global outcomes, the FM score subsumes all other variables they measured, Clauw said.

The FM score is not an ideal measure, Clauw said. “We hate this measure and are trying to move away from this. We think there are relative weightings of the items on this questionnaire or other questions that could be added that would improve the measure, and that it will be particularly important to validate this against biological measures such as brain imaging. He thinks that they are looking at some kind of central nervous system condition that starts in childhood, persists into adulthood, and "severely challenges the historical notion that most chronic pain is due to a problem in the region of the body where the individual hurts."

Mechanistic clues from animal work

A. Courtney DeVries, Ohio State University, Columbus, US, presented new animal work exploring the physiological mechanisms by which stress and social factors influence the risk of pain and depression after nerve injury. Previously, she had shown that stress (induced by two hours of daily restraint for two weeks) exacerbated allodynia and depressive-like behavior in the forced swim test after spared nerve injury in male mice. Stress alone did not induce allodynia or depressive-like behavior, but it made both worse via a mechanism involving induction of IL1beta expression in the brain (Norman et al., 2010). DeVries noted that while all of this work was done in male mice, she and her colleagues have since looked at females and do not see sex differences.

In more recent work, DeVries looked at the effects of social interaction on pain and depression in the same model. She found a reduction in allodynia and depressive behaviors in animals housed in pairs before injury compared to animals reared alone. In addition, if animals were paired after injury, she could see a significant decrease in allodynia.

Looking at the combined effects of pairing and stress on pain, DeVries showed that pairing in stressed animals improved allodynia, but did not completely eliminate it. Animals reared in isolation and exposed to stress fared worst of all. She has not yet looked at effect of pairing on the depressive behaviors, but predicts that those behaviors will be more amenable than allodynia to improvement with social interaction.

How might pairing improve pain? DeVries thinks that, like stress, the effect of pairing may be mediated by changes in IL1beta, because giving IL1beta to paired animals increased allodynia to the level seen in socially isolated mice. In contrast, treating socially isolated mice with IL1 receptor antagonist reduced allodynia to levels comparable to paired mice. The results may apply to other forms of pain—DeVries said she can demonstrate the effect of social interaction and stress on ischemia-induced allodynia, too.

For treatment, accentuate the positive

In her talk, Mary Davis, Arizona State University, Tempe, US, turned around the question of pain and depression. She asked why the pain field focuses so much on negative mood and emotions when data from other fields suggest that the presence of a positive affect predicts good outcomes better than negative affect predicts bad outcomes (e.g., see Southwick and Charney, 2012). Davis, who works on pain and mood regulation in women with chronic pain, asked whether, rather than focus mainly on diminishing negative moods, clinicians should pay more attention to actively promoting positive mood and emotions to build resilience in the face of chronic pain?

That idea is supported by her recent data (Davis et al., 2014) showing that in depressed women with pain, inducing a positive mood improved the response to stress in terms of pain. In the study, Davis looked at 110 women with fibromyalgia and/or osteoarthritis, of whom 29 percent were depressed. The subjects were subjected to a stress-inducing interview and then randomly shown either a humorous film clip or a neutral film clip. Afterwards, they were queried about their mood and pain.

The stress interview caused both depressed and non-depressed subjects to become more despondent and report more pain. After viewing the film clip, the non-depressed subjects showed a spontaneous rebound to better mood, regardless of whether they saw a positive or neutral clip. However, the depressed women rebounded only if they viewed the funny clip. The changes in mood tracked with clinical pain: The depressed subjects reported that their pain was reduced only in the positive mood induction group. The results suggest that interventions that serve to boost positive mood post-stress in depressed chronic pain patients could help lessen pain.

In a test of the clinical efficacy of mood improvement, Davis and colleagues had previously showed that mindfulness-based therapy, which enhances positive affect, pain coping, and resilience, was more effective than cognitive-behavioral therapy (which focuses on restructuring negative thoughts) or education at reducing joint tenderness in depressed people with rheumatoid arthritis (Zautra et al., 2008). When looking at daily diaries in patients from that study, Davis detected an increase in daily resilience with mindfulness training—on high-pain days, the patients showed less catastrophizing and less emotional reactivity to stress. This was not true for CBT or education.

More recently, the group demonstrated the possibility of delivering mindfulness-based therapies online aimed at boosting positive affect and social engagement. In a randomized trial, Davis and her group compared the effects of mindfulness training to general health tips, delivered online to 79 fibromyalgia patients. The groups showed no changes in pain after completing the short (four-hour total) intervention, but everyone improved on negative affect. Mindfulness was better than health tips at boosting positive affect, enjoyment of family, and pain coping efficacy (Davis and Zautra, 2013). Although the effects were small, the results are promising and highlight the potential of Internet-based delivery of low-cost and widely accessible psychological interventions for improving pain coping skills.

From pain and depression, the NIH Pain Consortium Symposium agenda moved to pain and sleep disorders. Michael Vitiello, University of Washington School of Medicine, Seattle, US, described results of a randomized clinical trial of cognitive-behavioral therapy (CBT) for comorbid insomnia and pain. Vitiello, a sleep researcher, said his move to study pain has been inspired by accumulating evidence that one way to improve chronic pain may be to treat the comorbid sleep disturbances that frequently come along with it.

The relationship between sleep and pain, like the pain-depression relationship, is complex. Previously, most assumed that pain caused sleep disturbance, but new thinking holds that insomnia might actually contribute to pain. As far back as 1924, researchers knew that sleeplessness enhanced pain sensitivity, and a growing body of data suggests that experimental disruptions of sleep can lead to increased pain (Roehrs, 2009). Now, Vitiello and colleagues are producing data suggesting that improving sleep can improve pain.

For people with insomnia, cognitive-behavioral therapy can help. Vitiello said that CBT is “robust for sleep and can improve sleep even in the presence of ongoing pain.” But results of the treatment on pain have been mixed. In a previous study of CBT for insomnia, Vitiello found that people with osteoarthritis experienced improvements in both insomnia and pain (Vitiello et al., 2009). That result led him to devise a study to compare the effect of CBT for pain with a combination of CBT for pain plus insomnia. The study involved 367 older adults, mostly women, who received weekly 90-minute training sessions for six weeks.

The results of that study showed that the intervention reduced insomnia but not pain after nine months. At 18 months, there was no effect on either endpoint, suggesting that the combined therapy not only did not improve pain, but might have actually diluted the effectiveness for insomnia (McCurry et al., 2014).

But a post-hoc analysis reveals more reason for hope. When the researchers broke the subjects into groups based on severity of pain and insomnia, they found that the treatment actually worked for the most severe cases, with significant decreases in pain achieved at 18 months in the 98 most affected subjects.

Next, in additional analysis, the results of which have just been published (Vitiello et al., 2014), the researchers looked at people whose sleep improved at two months (regardless of which study arm they were assigned to) versus non-improvers and found that short-term sleep improvers showed continued improvement in sleep as well as decreases in pain severity and arthritis symptoms at 18 months. From this, Vitiello concluded that successful treatment of sleep disturbances in the short term may reduce pain in the long term. He is now proposing to conduct a larger randomized trial in severely affected people, with delivery of therapy by phone.

Monika Haack, Harvard Medical School, Boston, US, reported on her studies of the effects of sleep deprivation and insomnia on inflammation, pain sensitivity, and pain modulation. Haack has found that people with primary insomnia (sleeplessness with no apparent medical cause) report pain on twice as many days as controls, and report increased pain sensitivity. Many studies on evoked pain show sleep deprivation decreases pain thresholds, and Haack showed the same in the insomnia subjects, along with a reduced ability to modulate pain (Haack et al., 2012).

To study sleep deprivation in the lab, Haack brings subjects into a clinical research center, where for 14 days she can rigorously control sleep times, food and drink, and physical and social activity. In healthy volunteers, she has demonstrated that experimental sleep deprivation causes an increase in spontaneous reporting of pain, and decreases in conditioned pain modulation.

To look for physiological changes that accompany sleep deficits, Haack focused on changes in inflammatory markers in people subjected to sleep restriction and recovery in a pattern that mimicked the common experience of sleep restriction on work or school days and catch-up sleep over the weekend. When subjects were put through repeated cycles of restriction and recovery, she saw increases in the cytokine interleukin 6 (IL6) that became progressively worse with each cycle. Even though subjects felt refreshed after the recovery sleep phase, IL6 levels did not return to normal. This suggests that the subjective feeling of recovery from sleep deprivation may not be reflected by resetting of biological systems, Haack said. In addition, an increase in spontaneous pain with sleep deprivation correlated with IL6 levels and with an increase in urine prostaglandins. Together, the results suggest that inflammation induced by sleep deprivation may contribute to the excess pain reported by sleep-deprived people.

A clean sweep with sleep

What is sleep for, anyway? That question has long puzzled neurobiologists. In her talk, Maiken Nedergaard, University of Rochester, US, outlined recent findings pointing to sleep as a crucial interlude that allows the brain to clean house metabolically by flushing out toxic metabolites through the cerebrospinal fluid (CSF). Nedergaard recently discovered that the flushing process occurs mainly during sleep: In her talk, she presented some new data about how pain can have a significant impact on the brain’s hygiene.

The brain makes up just a fraction of total body weight, but it uses almost 25 percent of the body’s glucose, which means it must produce a lot of waste. The brain lacks a lymphatic system like the one that drains interstitial fluid, and waste, from other tissues, so just how it keeps clean has been unclear. It has been known for some time that CSF flows through the brain in channels alongside the vasculature, its movement driven by the pulsing of the large arteries (Rennels et al., 1985). Nedergaard developed a method to directly visualize that flow in living animals using florescent tracers and in-vivo two-photon video microscopy. In mice, the tracer can be seen moving first along the vasculature and then into the brain tissue spaces before being cleared with the exiting CSF, which drains alongside large veins. Astrocytes facilitate the exchange of substances between CSF and brain interstitial fluid, so Nedergaard coined the term glymphatic system (a combination of glia and lymphatic) to describe this brain-cleaning mechanism.

In a high-profile study published last year, Nedergaard and colleagues showed that glymphatic flow is most active during sleep. When they compared tracer flow in mice anesthetized with ketamine, or naturally asleep, or just waking up, they saw an active transfer of tracer in anesthetized or sleeping mice, but not in awake mice (Xie et al., 2013).

Nedergaard wanted to know how pain might affect glymphatic function. She did a spinal nerve ligation in mice and looked at tracer distribution after three days. In normal, awake mice, little or no tracer enters the brain. After spinal nerve ligation, when the mice were in pain, there was even less tracer than in normal awake mice. In anesthetized, injured mice, there was a slight increase in tracer in CSF, but Nedergaard said she was not yet sure if this was real because the results with ketamine are always more variable.

Because glymphatic function runs opposite to excitation and alertness, Nedergaard speculated that pain might reflect a state of high alert, and thus low waste clearance. The study, while preliminary, raises several interesting questions: Do people in pain need more sleep? Does glymphatic flow contribute to the clearance of inflammatory cytokines, and if so, could increasing clearance reduce pain? And finally, could imaging of clearance provide a novel diagnostic measure of pain?

Crowd sourcing for better treatments

The symposium was also a chance to unveil a new resource for pain treatment and research. Sean Mackey, Stanford University, Palo Alto, US, introduced a new registry designed for gathering clinical data, now in use at his Stanford pain clinic. The goal, he said, is to capture outcome and other data on patients who visit the pain clinic, and to then take advantage of that mass of data to improve patient care and research.

To do that, Mackey and colleagues at Stanford collaborated with the NIH to develop the Stanford-NIH Health Electronic Registry of Outcomes (HERO), an open-source, open-standard, highly flexible and free health and treatment registry. The system allows the collection of, and easy access to, outcome and other data on large numbers of pain patients. Having the data on hand will enable physicians to make better decisions for individual patients based on the patient’s own history and the accumulated data of all patients. The data will also allow comparative effectiveness research as well as “pragmatic” or “practice-based evidence” trials, which analyze outcomes of different treatments in clinical populations (see PRF related news story).

Mackey said he has been collecting these kinds of data at the Stanford pain management center for the last 15 years, starting with a pen and paper, and then using software programs, but he needed more. HERO incorporates easy data import from electronic medical records and collection of patient outcomes based on the NIH Patient Reported Outcomes Measurement Information System (PROMIS).

In HERO, patients enter data using electronic questionnaires. Because of the electronic format, the questionnaires are adaptive, which means that, depending on the answers to initial questions, subsequent questions are tailored mid-test. Mackey said this allows for questionnaires that cover a wide range of situations with many fewer questions, so patients take less time and provide more useful information than older pen-and-paper instruments. PROMIS data are also normative—scores are compared to population norms, allowing pooling and data comparison. Patients enter data at home or in the office on phones and other mobile devices.

The system was rolled out in August 2012, Mackey said, and currently has roughly 10,000 data points on 3,500 patients. The adoption has occurred with minimal complaints from staff or patients. Mackey said the system “has changed the culture of how we practice pain management. Providers use this all the time for teaching and for providing care.”

Mackey showed one example of a woman with chronic regional pain syndrome (CRPS). She had scored above normal on measures of depression and anxiety, and was in the lowest 10 percent of the population on measures of physical function. After initial pharmacological treatment, questionnaire data revealed evidence of improvement in mood and less pain interference, but no change in her physical function. So Mackey gave her a health educator, and by the next visit the patient did show an improvement in physical function. “We can watch what happens over time on multiple measures and adjust treatment accordingly,” Mackey explained. “For some patients, there seems to be some kind of barrier to improvement that shows up early. If they can get over that, they continue to improve,” he said. “We can use this system to ask what that barrier is and how to get people over it. “

Another useful output of the system is the generation of population-based information on the clinical population of pain patients. Comparing the Stanford clinic population to US norms, Mackey showed that his patients skew to the top percentiles for measures of pain, anxiety, fatigue, pain interference, depression, and physical function. But some patients are different—they appear happy and calm, and the system allows Mackey and colleagues to easily identity these interesting outliers with severe pain and dysfunction, but no anxiety, depression, and anger. “What can we learn from them?” he asked.

HERO started as a pain registry, but has morphed into a general health registry, and the group is now working on other versions including Headache HERO, Orthopedic HERO, and GI HERO. Built on industry-standard, non-proprietary tools, the system can accommodate any kind of survey. Mackey has plans for future enhancement and is looking for partners who want to add in features.

Junior investigators highlighted

Each year at the symposium, a junior investigator is recognized with the Mitchell Max Award, given for the best poster presentation. The award honors the late Max, a visionary pain researcher at the NIH and the University of Pittsburgh, US. The 2014 prize went to Fadel Zeidan, a postdoctoral fellow at Wake Forest School of Medicine, North Carolina, US, for work investigating the analgesic mechanisms of mindfulness meditation. Zeidan compared the effect of mindfulness meditation, sham mindfulness meditation, a placebo-conditioning regimen, or a neutral intervention on thermal pain sensitivity and brain activity (measured by arterial spin labeling MRI) in a total of 75 healthy volunteers (17-20 per intervention). In the study, the mindfulness intervention was most effective, reducing pain intensity by 26 percent and unpleasantness by 44 percent. Placebo and sham meditation also reduced pain intensity and unpleasantness significantly (by 19 and 24 percent), but to a lesser extent. In the imaging arm of the study, meditation was found to significantly deactivate the thalamus and the periaqueductal grey matter more than placebo, sham meditation, or control conditions. These results, together with Zeidan’s previous work, suggest that mindfulness meditation probably attenuates pain through multiple mechanisms, while placebo and sham meditation likely engage the expected descending control processes. In his presentation, Zeidan stated that mindfulness-based studies employing robust comparison conditions may better help attract insurers to pay for mindfulness and other psychological interventions that are known to work for pain.

Other young investigators who were runners up for the Max prize were Eric Bair, University of North Carolina, Chapel Hill, US, who described his work identifying patient subtypes in the OPPERA study, and Lisa Kilpatrick, University of California, Los Angeles, US, who described the first study looking at changes in resting-state brain connectivity in 82 women with interstitial cystitis/painful bladder syndrome compared to 85 healthy controls. Overall, her results so far suggest that women with this disease may have altered attention to visceral input and changes in sensorimotor functional connectivity to areas normally linked to pelvic floor function that are different from healthy women.

In addition to these talks there was a comprehensive overview of the TRPV1 channel structure from keynote speaker David Julius, University of California, San Francisco, US, and additional presentations from Linda Watkins, University of Colorado at Boulder, US, and Clifford Woolf, Boston Children’s Hospital, US. An archived webcast of the entire meeting is available on the NIH website (view Day 1 and Day 2). The complete meeting agenda is here.


Monday, 28 July 2014

How Important Is Endostatin To The Nervous System?

Endo...what? Today's post from www.ucsf.edu/news (see link below) talks about a protein called endostatin and its potential value in the workings of the nervous system. Sometimes discoveries are made by accident and endostatin which was previously thought to be able to cut off the blood supply to cancers, has been found to be a key protein in maintaining healthy synapses, which are places where nerves communicate. Now I can't pretend to understand how this works, or what benefits may result form this discovery but congratulations if you can after reading this article. In short, it seems that this protein may be able to stabilise nerve pathways and one thing neuropathy patients do not have, are stable neural pathways. Maybe we'll be hearing the word 'endostatin' much more in the future.

UCSF Researchers Uncover an Unexpected Role for Endostatin in the Nervous System
Protein Once Seen as a Promising Anti-Cancer Compound Helps to Stabilize Neural Circuits
By Pete Farley on July 24, 2014

Researchers at UC San Francisco have discovered that endostatin, a protein that once aroused intense interest as a possible cancer treatment, plays a key role in the stable functioning of the nervous system.

A substance that occurs naturally in the body, endostatin potently blocks the formation of new blood vessels. In studies in mice in the late 1990s, endostatin treatment virtually eliminated cancer by shutting down the blood supply to tumors, but subsequent human clinical trials proved disappointing.

“It was a very big surprise” to find that endostatin, through some other mechanism, helps to maintain the proper workings of synapses, the sites where communication between nerve cells takes place, said Graeme W. Davis, PhD, Hertzstein Distinguished Professor of Medicine in the Department of Biochemistry and Biophysics at UCSF and senior author of the new study. “Endostatin was not on our radar.”

The findings were reported online July 24 in the journal Neuron.

Synapses are continually shaped and reshaped by experience, a phenomenon known as plasticity. But for those changes to be meaningful, said Davis, they must take place against a stable background, which paradoxically requires another form of change that he and colleagues call “homeostatic plasticity.” Just as we change our pace, slowing down or speeding up, to keep abreast of a running partner, neurons adjust aspects of their function at synapses to compensate for changes in their synaptic partners brought on by aging, illness, or other factors.

In an example of homeostatic plasticity, in the neuromuscular disease myasthenia gravis, as muscle cells become less responsive to the neurotransmitter acetylcholine, nerve cells ramp up their secretion of the neurotransmitter to keep the system in balance for as long as possible. Some researchers believe that in other disorders, including autism and schizophrenia, a failure in such homeostatic mechanisms keeps synapses from functioning properly.

In previous research Davis noticed that applying a toxin to a muscle cell in the fruit fly Drosophila melanogaster triggers homeostatic plasticity in the neuron that forms a synapse on that muscle cell: the neuron--which is called presynaptic, because it is “before” the synapse with the muscle cell--reliably releases more neurotransmitter, just as happens when muscle cells begin to malfunction in myasthenia gravis.

Davis has since built on this model of homeostatic plasticity by painstakingly knocking out Drosophila genes one by one and recording from presynaptic neurons to see which genes are necessary for the homeostatic response, because it is these genes that may be compromised in diseases affecting the process.

“So far we’ve tested about 1,000 genes this way, which has entailed close to 10,000 recordings,” Davis said.

Using this technique Davis and colleagues observed at one point that knocking out a gene called multiplexin significantly hampered homeostatic plasticity in presynaptic neurons. But because that gene helps to form a structural protein known as collagen—which in humans is a component of ligaments, tendons, and cartilage—the finding wasn’t immediately considered relevant to synaptic function.

The team learned that the multiplexin protein can be snipped by an enzyme to produce endostatin, so in experiments led by postdoctoral fellow Tingting Wang, PhD, they tested whether endostatin might play a role in homeostatic plasticity.

“Nobody picked up multiplexin to work on for a couple of years, because we didn’t think a collagen could be that interesting,” Davis said. “Then, when a new postdoc, Tingting Wang, came to the lab, we started thinking about it harder.”

When the group genetically deleted the portion of Drosophila multiplexin that forms endostatin, presynaptic neurons behaved normally, but homeostatic plasticity was severely compromised when toxin was applied to postsynaptic muscle cells. On the opposite side of the coin, when the team overexpressed endostatin at Drosophila synapses lacking multiplexin, homeostasis was restored, whether endostatin was expressed in muscle cells or presynaptic neurons.

The research team is unsure precisely how and where endostatin exerts its effects on homeostatic plasticity, but they believe that multiplexin is cleaved at the postsynaptic site to form endostatin, and that the endostatin signal is conveyed to the presynaptic neuron to alter its function. “Because so many people in the cancer world have studied endostatin, there is a great set of tools available” to study the protein, Davis said, so he expects his group to make rapid progress in addressing these questions.

“Despite its checkered history in cancer, we know endostatin is a signaling molecule and we know that the brain has a great deal of collagen—we just haven’t known what it does, and we certainly don’t know what endostatin’s receptors in the brain might be.” Davis said. “But it’s pretty exciting to think about a new signaling molecule with a profound role in the stabilization of the function of neural circuits.”

In addition to Davis and Wang, the research team also included Anna G. Hauswirth, a student in UCSF’s Medical Scientist Training Program; research specialist Amy Tong; and postdoctoral fellow Dion Dickman, PhD. The research was supported by grants from the National Institutes of Health.

UCSF is the nation’s leading university exclusively focused on health. Now celebrating the 150th anniversary of its founding as a medical college, UCSF is dedicated to transforming health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy; a graduate division with world-renowned programs in the biological sciences, a preeminent biomedical research enterprise and two top-tier hospitals, UCSF Medical Center and UCSF Benioff Children’s Hospital San Francisco.


Sunday, 27 July 2014

How To Cope With An Invisible Illness

Today's post from huffingtonpost.com (see link below) looks at the frustrations encountered when you're faced with vague symptoms, sometimes linked with chronic pain, that have not been properly diagnosed and identified. Many people with neuropathy are in exactly this position and feel that they're invisible to the rest of the world. This can lead to isolation and a feeling that it's not only others who think that it's all sitting between your ears. Very often neuropathy patients are having to deal with problematic, autonomic symptoms (autonomic means the involuntary functions of the body - breathing, digestion, sexual function, sweating etc etc) and this can be both alarming and virtually impossible to explain to family and friends, never mind doctors. This article gives some useful support for those in that situation. Autonomic disorders are some of the worst side effects of nerve damage in your body. Don't give up and listen to your body - the doctors and people in your circles will catch up in the end.

Invisible Illness: How to Sustain Hope?
Deborah J. Cornwall Become a fan Author, 'Things I Wish I’d Known: Cancer Caregivers Speak Out' Posted: 07/11/2014 1

Think about your everyday life -- how taking a run, or walking your dog on the beach, or socializing with friends are just part of a normal day. How you share daily responsibilities with others. How you set long-term goals and arrange your life to pursue them.

Then imagine never knowing each morning whether today you'll be able to do those things you take for granted, or if today you'll be unable to get out of bed. Today it might be vertigo and stomach pain. A couple of days ago, it could have been crippling fatigue and muscle pain, or almost fainting. Tomorrow or the day after, it could be a migraine, or a racing heartbeat, or severe insomnia, or all of these at once.

Imagine not knowing which symptoms will hit, and when, and never being able to plan for tomorrow, let alone for your whole future. And imagine a world in which it's extremely hard to find doctors who take seriously that your discomfort is really physiological, a world in which the right treatment for you is elusive.

That's the world of autonomic disorders, like POTS (Postural Orthostatic Tachycardia Syndrome, sometimes called simply Postural Tachycardia Syndrome) and Neurocardiogenic Syncope. In these conditions, body systems that are supposed to work automatically -- controlling your heartbeat, blood pressure, breathing, thinking, temperature, digestion, vision, and more -- don't work as they should and create a plethora of potentially disabling symptoms. This world could force you to give up your career dreams, narrowing your total focus to just getting through today. Such conditions are called "invisible" because you may not actually look sick when you are most displaced from normal living.

Diagnosis and Treatment Planning Can Take Years

Researchers and clinicians don't yet understand the causes for the wide variety of autonomic disorders, why symptoms present differently for every patient, or why each patient's condition varies so greatly from day to day. As a result, treatment for each patient focuses on managing symptoms and may involve a process of trial and error.

A prior article on this topic, "5 Things to Do When Symptoms Are Not 'All in Your Head,'" described Val's multi-year effort to figure out what was wrong with her body. She is not alone in her struggle. Clare's husband described that 18 different physicians took them through nine different diagnoses over 15 years before concluding that she too had POTS. He says it was an unpleasant process:

The treatment that Clare has received has been so degrading and appalling that when we actually found a doctor who was willing to listen to the full story and believe that there was something physically wrong, we were overjoyed. Previously, when blood work and tests kept coming back as normal, many doctors would actually ask me if she was "that fragile type of woman who gets hysterical or over-reacts." Some would ask me that right in front of her, as though she couldn't hear us or her opinion didn't matter.

Kelly's mother described another example of what that kind of interaction with a doctor looks like:

I watched Kelly evolve from being an executive powerhouse and "super Mom" to experiencing severe physical crashes that required emergency hospitalization. When five days of tests all came in as normal, the doctor in charge announced, "We can't find anything wrong with you. You have panic attacks, so I'm sending you home with anti-anxiety drugs and a recommendation to see a counselor." I tried to explain that her heart is jumping out of her body, with a sky-high heart rate one minute and a blood pressure so low that she nearly faints, and then it goes back down when she lies down. When I insisted that those symptoms were real and not psychological, he actually said, "You're not helping your daughter one bit," and stormed out of the room.

Val, Clare, and Kelly represent only the tip of the iceberg.

Patients Are Frustrated, PCPs Are Challenged

Dr. Satish R. Raj, M.D., MSCI, FACC, is a clinician, researcher, and associate professor of cardiovascular sciences at the University of Calgary and an adjunct associate professor of medicine and pharmacology at Vanderbilt University. He is one of the world's experts in the research and clinical aspects of autonomic disorders. He explained that diagnostic delays, especially at the PCP gateway, may occur because symptoms like lightheadedness, chest pains, shortness of breath, and GI upset can be caused by many other medical conditions.

"When you have vague and nebulous but real and sometimes disabling physical symptoms, like crushing fatigue," he says, "and your tests come back negative, it may be hard for a PCP to determine what's wrong. Multiple simultaneous symptoms make it difficult to predict a single course of investigation to reach a definitive diagnosis." As a result, physicians gravitate toward the more prevalent conditions first as the possible causes and look for factual data in test results to rule those in or out.

A Web-based survey implemented by Dysautonomia International in December of 2013 and released on July 11, 2014, reveals stunning statistics about the proportion of such patients who spend years trying to learn why they can no longer function "normally." Nearly 700 respondents with POTS told a shocking story:
Almost six years: The average time from first symptoms to diagnosis. For over 20 percent, it took more than 10 years. This didn't include time to determine (by trial and error) what treatments might relieve symptoms.
83 percent: Proportion of respondents who received a psychological diagnosis before eventually being diagnosed with POTS: In fact, research has shown that POTS patients are actually less anxious than the general population.
12 percent: Proportion diagnosed by a pediatrician or primary care physician.
27 percent: Proportion who saw more than 10 different doctors before being diagnosed. Some 8 percent saw more than 20 doctors.

Given prevailing estimates that these conditions affect between 500,000 and 3,000,000 individuals (disproportionately young women) in the United States, perhaps these patients deserve more timely support from the medical community.


Saturday, 26 July 2014

Dealing With Neuropathy

Looking at the title from today's post from diabetesdigest.com (see link below) may suggest that it has nothing to do with you and you shouldn't read on (unless you also have diabetes of course). However, because diabetes is by far the most common cause of neuropathy, you tend to find many more articles related to that disease than anything else. If you have neuropathy, the cause is just one element in the puzzle; once you have it, you share the same symptoms (generally) with everybody with neuropathy and therefore all articles can be useful and maybe teach you something you didn't know. This particular article is fairly general and many people will recognise the content and already be aware of it but for people just trying to establish the basics of what's happening to them, it may be helpful.

Dealing with Diabetic Neuropathy
Posted on February 7, 2014 by DiabetesDigest.com Staff in Diabetes Basics

According to a recent national survey by the American Diabetes Association (ADA), the majority of people with diabetes have symptoms of diabetic neuropathy (nerve damage). But, only a small minority has been diagnosed with this condition. Diabetic neuropathy is a complication of diabetes that leads to sensations of pain and/or numbness, tingling or “pins and needles” in the feet and hands. According to study findings, a staggering 56 percent of people with diabetes have never even heard of the condition.

This lack of awareness is unfortunate for the 18.2 million people in the United States living with diabetes. The symptoms can make it hard to function, and because the pain of diabetic neuropathy usually is worse at night, many have difficulty sleeping. The nerve damage can make a person extremely sensitive to even the lightest touch, and simply wearing socks or having a foot touch a bed sheet can cause pain. People with this condition may have difficulty walking, working or socializing. And diabetic neuropathy is a major risk factor for foot injury, infection and amputation. Left untreated, diabetic neuropathy always progresses.


With attention, management and treatment, diabetic neuropathy can be prevented or delayed. Awareness is the first, critical step in taking care of yourself and preventing serious problems in the future.

That’s why the ADA has embarked on an awareness campaign to educate people with diabetes about diabetic neuropathy. The campaign focuses on the seriousness of this complication, recognizing the symptoms and most important, the things people can do to prevent, reduce or manage these symptoms. There is a patient “pocket checklist” so that you can review a list of symptoms. If any of these symptoms apply to you, take this list to your health care provider; ask if you have neuropathy and what you can do about it. For more information or to get your free copy of All About Nerve Damage & Diabetes, call the ADA at 1-800-DIABETES (1-800-342-2383), or visit http://www.diabetes.org/living-with-diabetes/complications/neuropathy/.


The most common type of nerve damage in people who have diabetes is called peripheral neuropathy, which affects the feet and hands. Reporting symptoms to your health care provider can help prevent future complications, such as amputations. Take this list to your next office visit. Symptoms Place a check mark next to any symptom you have:

My feet tingle.
I feel “pins and needles” in my feet.
I have burning, stabbing or shooting pains in my feet.
My feet are very sensitive to touch. For example, sometimes it hurts to have the bed covers touch my feet.
My feet hurt at night.
My feet and hands get very cold or very hot.
My feet are numb and feel dead.
I don’t feel pain in my feet, even when I have blisters or injuries.
I can’t feel my feet when I’m walking.
The muscles in my feet and legs are weak.
I ’m unsteady when I stand or walk.
I have trouble feeling heat or cold in my feet or hands.
I have open sores (also called ulcers) on my feet and legs. These sores heal very slowly.
It seems like the muscles and bones in my feet have changed shape.
Other symptoms I have include: ____________________________


Talk with your health care provider about treatments available to relieve pain and reduce burning, tingling and numbness.


Friday, 25 July 2014

Exercise Can Help Neuropathy (Vid)

Today's post from blog.dana-farber.org (see link below) is primarily aimed at people who are living with neuropathy as a result of cancer treatment but it applies to all neuropathy patients and is worth looking at to see if there is anything that may help you personally. It's another post offering exercise as an option for reducing the impact of symptoms and most neuropathy patients will run screaming to the hills at the very idea. However, it proposes low-impact routines which are designed to help with blood flow, sensation, strength and balance and these can be very useful. You need to listen to your own body and not go too far but pushing yourself just a little will reap benefits. Browse through the slides and see what you think.

How Exercise Can Help Neuropathy
Dana-Farber July 23, 2014

For many patients treated with chemotherapy, peripheral neuropathy can be an uncomfortable and sometimes dangerous side effect. The condition, which includes tingling or loss of sensation in the arms or legs, can increase risk for falls and fall-related injuries.

To help prevent and ease these problems, Dana-Farber exercise physiologist Nancy Campbell, MS, recommends patients use low-impact exercise routines like finger taps, calf stretches, and ankle rolls. These exercises help increase blood flow to the peripheral nerves, restoring feeling in the extremities. The routines also build strength and improve balance, which can lead to fewer falls.

View Campbell’s presentation below for more information on how exercise may help ease or prevent neuropathy, including step-by-step instructions for helpful exercises:

How Exercise Can Help Neuropathy from Dana-Farber Cancer Institute


Thursday, 24 July 2014

Nerve Damage: What's Going On?

Very short and simple but very useful for people new to neuropathy, todays post from interohealthcare.com (see link below) sums up nerve damage and which nerves are involved in a nutshell. Thanks to the complex nature of neuropathy, it's so easy to forget the basic details of what's happening to your body. This short article is a useful refresher for everybody living with neuropathy.

Neuropathy and Nerve Damage 
Info from WebMD: Never Damage
Your nervous system is involved in everything your body does, from regulating your breathing to controlling your muscles and sensing heat and cold.
There are three types of nerves, or neurons, in the body: 

Autonomic nerves.
These nerves control the involuntary or partially voluntary activities of your body, including heart rate, blood pressure, digestion, and temperature regulation.

Motor nerves. These nerves control your movements and actions by passing information from your brain and spinal cord to your muscles.

Sensory nerves.
These nerves relay information from your skin and muscles back to your spinal cord and brain. The information is then processed to let you feel pain and other sensations.

Nerve pain and nerve damage can be mild. But, because nerves are essential to all you do, nerve pain and damage can seriously affect your quality of life.
What Are the Symptoms of Nerve Pain and Nerve Damage?

With nerve damage there can be a wide array of symptoms. Which ones you may have depends on the location and type of nerves that are affected. Damage can occur to nerves in your brain and spinal cord. It can also occur in the peripheral nerves, which are located throughout the rest of your body.

Autonomic nerve damage may produce the following symptoms:

inability to sense chest pain, such as angina or heart attack
too much sweating (known as hyperhidrosis) or too little sweating (known as anhidrosis)
dry eyes and mouth
bladder dysfunction
sexual dysfunction

Damage to motor nerves may produce the following symptoms: 

muscle atrophy
twitching, also known as fasciculation

Sensory nerve damage may produce the following symptoms:

tingling or prickling
problems with positional awareness

In some instances, people with nerve damage will have symptoms that indicate damage to two, or even three, different types of nerves. For instance, you might experience weakness and burning of your legs at the same time.


Wednesday, 23 July 2014

How Do You Describe Your Neuropathy Self?

Today's post from paincommunity.org (see link below) is a sort of self-help article, the like of which many neuropathy patients are used to and generally find that 'it's easy for them to say!' However, there are some good points here and it does show how easy it is to talk yourself into feeling worse than you actually do by your choice of words. When you describe your symptoms to your doctor, or others, do you immediately go for the worst case scenario and use language to try to convince the listener that you're not faking it? It may be perfectly understandable (we face enough disbelief and incomprehension as it is) but you may not be doing yourself any favours because you may end up believing your own descriptive language. Talking your pain and discomfort down a bit may help to reduce the impact psychologically. After all, what you're feeling is bad enough without exaggeration of any sort. Certainly something to think about.

The Words You Choose Make a Difference  
Posted by Dionetta Hudzinski | July 16, 2014

Words are the building blocks of language. We use words to communicate our thoughts, ideas, beliefs and emotions. Words can have specific meaning or a variety of meanings depending how they are used in conversation. Words can convey a clear message or a confusing message. Some words are gentle and comforting while others are harsh and distressing to hear. It is HOW we use words that matters most.

Words can explain, define, label, clarify or confuse. Words can influence (positively or negatively) our beliefs about us and our beliefs about others. Words can influence how we think; how we think can influence how we feel.

So what does this have to do with pain management, you might ask? Lots! First our self-talk and the words that we use can either build us up or tear us down. I know, I was the worst offender in this area. The words I chose to speak to myself were harsh, condemning and not nice at all. I would never use those same words to talk to friends or family but I was using them on myself. Words like lazy, worthless, failure, you’re not enough, you’ll never succeed at that…these and so many others; no wonder I was feeling less than everyone else, feeling like a failure with no motivation to change. Why change? My self-talk told me it was not even worth starting so why bother? At one of my lowest points I decided to take an online course which changed my life…in fact the course was called “Change Your Life In 30 Days” with Rhonda Britten famous TV Life coach of the Starting Over TV reality show. I learned that words carry energy and that I need to choose my words carefully and wisely. Slowly over 30 days I stopped the negative self-talk and replaced it with positive thoughts. I learned how to be gentle with myself and how to practice self-compassion. In fact, I came up with a little affirmation that I say even today when a negative thought pops up…”I forgive myself for having that thought; I choose love instead”. My overall vocabulary changed and with it my attitude and motivation.

Vocabulary matters! Think of words that people use to describe people in pain. Words that make you cringe when you read the latest news article about prescription drug abuse. Words like – narcotic, addict, doctor shopper, pain victim and pain killer- are coated heavily with negativity and prejudice. Words that ought to be used are opioid, substance use disorder, pain relief seeker, person living with pain or pain medication.

For example, the word narcotic is a legal term used to denote illegal drugs such as heroin and cocaine. When used in that context, it is appropriate and clearly states what the issue is at hand. When used in the health care system, it unjustly labels individuals who need to take a class of medication called opioid analgesics. The term “addict” is derogatory in nature, whether referring to someone who is physically dependant on opioids treating their pain as well as when referring to someone with a substance use disorder. Addict inappropriately labels someone to a lower station in life as if they are of lower value as a human being.

Even the word DRUG can carry with it a negative overtone—drug as in street drugs? People with pain take medications not DRUGS. What about if you find yourself calling your Oxycodone “OXY’s”? Oxycodone is the medication and OXY, is a street name. How about choosing to call Percocet (oxycodone with Acetaminophen) “PERCS” which is again, a street name? How does that label you and others who use these medications for the legitimate treatment of pain? How do you feel when you hear those words used when directed at you?

How do the words “drug seeking” strike you? Wouldn’t you rather hear relief seeking? How about being called fat or obese compared with over-weight? How about crippled vs disabled, impaired or handicapped? I looked up the word disabled – other words with similar meanings are incapacitated, inactivated, deactivated, Immobilized, hindered, or rendered useless. Words are powerful in defining ourselves. Think about how you feel when you read “pain sufferer” vs. a person experiencing or living with pain? One is powerless and helpless while the other is empowering and uplifting. After all, not all people living with pain are pain sufferers especially when they have secured an effective pain treatment plan. Many thrive and show their strength in character every single day. What about the use of the word “victim” compared to survivor—one shows helplessness and the other strength? Which would you prefer?

Words are energy. A Japanese researcher, Dr. Masaru Emoto, who wrote Hidden Messages In Water, says that water and its crystals are influenced by the environment they are in. He has shown through his unique photographic process how certain words shaped beautifully awesome crystals while other words produced ugly and unorganized crystals. Words like “I love you. You are beautiful” form gorgeous well organized crystals while words like “I hate you. You are ugly” form distressing unorganized forms that make you turn away. We are composed of 70% water so what do words do to our water?

Another aspect to consider is that your brain believes what you tell it…and makes no distinction between whether it is a true statement or not. So what words do you use to talk to yourself and others?

Choose wisely. I choose love, gentleness, compassion and patience.

Posted in Communication


Tuesday, 22 July 2014

Has Compassion For Chronic Illness Disappeared? (Vid)

Today's excellent video from dontpunishpain.com (see link below) is a must see for anybody living with chronic neuropathy and feeling somehow 'judged' for being ill. Similarly, friends and family will maybe recognise many of the things said here and be better able to understand and support their loved ones. As Ken McKim says; it's 32 minutes long but not as long as anything with a Kardashian in it but it's never boring, or too technical and is definitely worth a half hour of your time. An important video - don't miss it!

The Slow Death of Compassion for the Chronically Ill
Ken McKim
Published on 3 May 2014  
UPDATE: New video up on my channel, "Feel This Pain!" Check it out.________________________

This video, while 32 minutes long, is shorter than anything with a Kardashian in it, and much more important. Please make the time to watch.

A quick summary:

Society has been programmed to view the chronically ill as lazy and not trying hard enough due to an overwhelming amount of inspiring Internet stories highlighting incredible things a minority of people suffering from disease and/or disability have accomplished.

The media has a bias against pain medications, referring to them as "drugs" instead of "medications" more often than not in a concerted effort to stigmatize the medications and by extension those who take them.

Alcohol killed more people in 10 years than died of opioid overdoses: 139,093 deaths attributed to alcohol from 2000-2010 The CDC number puts opioid overdoses at 125,000 deaths over 10 years

The DEA now wants to reclassify any medications containing hydrocodone as Schedule II instead of Schedule III. This will make them harder to prescribe and harder to obtain; in many cases doctors will require more in-person visits before re-prescribing which costs more money for those patients (not everyone has insurance).

The public is okay with this because they now view the chronically is as people who are somehow lacking in motivation and who abuse drugs.The have this viewpoint because they don't truly understand the kind of pain these people are in, every hour of every day.

Making it harder for those with chronic illnesses such as Crohn's and Fibromyalgia to obtain the pain medications they need to sustain any kind of tolerable quality of life does nothing to prevent accidental overdoses. It increases costs for the sickest of our citizens, and has the effect of stigmatizing both the medications and those who take them. Oxycontin has always been Schedule II and it has done nothing to prevent its abuse. People who want to misuse drugs will do so no matter what their classification; punishing the millions who take these meds responsibly, and who need them to live is abuse. The chronically ill have already been betrayed by their own bodies, and now their government as well. The DEA must not reclassify these medications as Schedule II.

Of course people always want to know "where do you get your stats?" so here are some of the pages I looked at when putting this together:


Monday, 21 July 2014

Neuropathy And High Blood Pressure

Today's post from diabetesincontrol.com (see link below) looks at neuropathy and sleep apnea leading to higher blood pressure for patients at night. Many people with neuropathy suffer from disturbed sleep patterns brought on by sleep apnea (stopping breathing a number of times during the night). According to this short but complex article, this can also cause concurrent high blood pressure. Neuropathy is seen as a stress factor which inhibits the body's normal lowering of blood pressure during sleep. The consequences if true are obvious and the study suggests that more attention should be paid to the patient's cardiovascular system if they are living with severe neuropathy. Changes in blood pressure are a known factor in autonomic neuropathy (where it affects involuntary functions in the body) and maybe this should be taken more seriously than it currently is.

Painful Neuropathy and Increasing Blood Pressure 

This article originally posted 18 July, 2014 and appeared in Cardiovascular, Neuropathy, Issue 738

Painful diabetic neuropathy (PDPN) has been associated with higher nocturnal blood pressure in patients....

PDPN can cause obstructive sleep apnea (OSA) and affect one's quality of life. As this condition is often underdiagnosed, researchers conducted a study focusing on the increasing cardiovascular risk associated with neuropathic pain.

The study included a total of 113 diabetes patients with PDPN (n=34), painless diabetic polyneuropathy (n=33), and without diabetic polyneuropathy (n=46). Neuropathic pain, risk of obstructive sleep apnea, autonomic function, and blood pressure were all assessed in the study with the use of the Douleru Neuropathique en 4 Questions (DN4). Nocturnal systolic blood pressure was significantly higher in patients with PDPN (130.4 ± 15.6 mmHg) than those without diabetic polyneuropathy (119.9 ± 10.6 mmHg; P less than 0.0001) and those with painless polyneuropathy (124.2 ± 12.3 mmHg; P less than 0.05). The PDPN group also experienced less change in systolic and diastolic blood pressure overnight when compared to those without diabetic polyneuropathy (p less than 0.05). The "nondipping" decrease in blood pressure overnight was seen in 8 patients, which was highly correlated to PDPN status (p=0.007).

Researchers concluded that PDPN is associated with higher nocturnal blood pressure that is independent of pain-related sleep problems and other diabetes-related comorbidities. The theory is that neuropathic pain acts as a stressor, which induces sympathetic response during the night and inhibits the blood pressure from falling during the night. This highlights the importance of managing the patient's cardiovascular risk more closely while attempting to treat the neuropathic pain at the same time.

Practice Pearls:
  • The theory is that neuropathic pain acts as a stressor, which induces sympathetic response during the night and inhibits the blood pressure from falling during the night.
  • Nocturnal systolic blood pressure was significantly higher in patients with PDPN than those without diabetic polyneuropathy and those with painless polyneuropathy.
  • The PDPN group also experience less dip in systolic and diastolic blood pressure overnight when compared to those without diabetic polyneuropathy.
D'Amato C, Morganti R, Di Gennaro F, et al. A Novel Association Between Nondipping and Painful Diabetic Polyneuropathy. Diabetes Care. 2014 July 10. 


Sunday, 20 July 2014

Nerve Assessments In The Eye For HIV Neuropathy

Today's post from sciencecodex.com (see link below) looks at a new way of assessing small fibre neuropathy by looking at the density of nerve fibres in the cornea. The cornea is one of the most densely packed areas of nerves in the body and it is relatively easy to see whether that nerve density has been diminished through nerve damage. If your doctor is conscientious enough and funds are available, you may undergo a skin biopsy to establish small fibre neuropathy or not. However, it's often inconclusive as well as being invasive and requires repeat surgery to make comparisons. Investigation of the cornea is non-invasive and by definition much cheaper and may well be the way forward in the future of neuropathy diagnosis. You can read about the relationship with HIV in the article, (which may require some concentration) but is definitely interesting and worth the effort.

New research sets stage for noninvasive monitoring of HIV-induced peripheral neuropathy
Posted By News On May 12, 2014 - 4:30am

Philadelphia, PA, May 12, 2014 – Corneal nerve fiber assessment has great potential as a tool to diagnose and monitor peripheral neuropathy induced by HIV, say scientists at the Johns Hopkins University School of Medicine. The results of their study are published in The American Journal of Pathology.

Although corneal nerve assessments have shown increasingly valuable as a replacement for epidermal nerve fiber evaluation in diabetic peripheral neuropathy, the evaluation of corneal alterations in tracking HIV-induced neuropathy has yet to be explored.

"The cornea is the most densely innervated tissue in the body, so corneal nerve assessment is extremely sensitive for detecting small sensory nerve fiber damage as compared to other tests including measurement of intra-epidermal nerve fibers in the skin," notes lead investigator Joseph L. Mankowski, DVM, PhD, who is Professor of Molecular and Comparative Pathobiology, Pathology, and Neurology at the Johns Hopkins University School of Medicine, Baltimore, MD.

Although not life threatening, HIV-induced peripheral neuropathy greatly compromises patient quality of life. Currently, skin biopsy is the accepted standard for measuring the loss of small, unmyelinated C fibers in the epidermis, one of the earliest detectable signs of peripheral nerve damage. However, skin biopsy is an invasive procedure, and ongoing assessment requires repeated surgical procedures. Electrophysiological testing to measure peripheral nerve conduction properties is not a viable alternative because current methods lack the sensitivity required to detect damage to small, unmyelinated fibers, especially in early stages of disease. Therefore, new sensitive, noninvasive methods of assessing small fiber nerve damage are urgently needed to detect and monitor peripheral neuropathy in HIV-infected individuals.

To study the pathogenesis of HIV-induced PNS disease, Jamie Dorsey, Research Technologist, and the research team led by Dr. Mankowski developed a simian immunodeficiency virus (SIV)-infected macaque model that closely reflects key peripheral nervous system (PNS) alterations seen in HIV patients with peripheral neuropathy. They sought to determine whether SIV infection leads to decreases in corneal nerve fiber density, and whether corneal nerve fiber density correlates with epidermal nerve fiber length counts, thereby setting the stage for follow-up investigation using corneal confocal microscopy.

"Moving to non-invasive and repeatable methods of nerve fiber measurements such as in vivo corneal confocal microscopy would enhance study of peripheral neuropathy by enabling early detection of damage, progression of nerve fiber deterioration, and enable assessment of therapeutic strategies in the SIV/macaque model," explains Dr. Mankowski. "Furthermore, adapting in vivo corneal confocal microscopy for use in tracking HIV-induced PNS damage in patients may be of great value to identify early PNS damage independent of performing skin biopsies."

To determine whether SIV infection leads to corneal nerve fiber loss, the researchers immunostained corneas for the nerve fiber marker βIII tubulin. They developed and applied both manual and automated methods developed by Jonathan Oakley, PhD, of Voxeleron to measure nerves in the corneal sub-basal plexus. These counting methods independently demonstrated significantly lower sub-basal corneal nerve fiber density among SIV-infected animals that rapidly progressed to AIDS as compared to slow progressors. Corneal nerve fiber density was also directly correlated with epidermal nerve fiber length.

Besides decreased corneal nerve fiber density, rapid SIV progressors had increased levels of SIV RNA, CD68-positive macrophages, and GFAP expression by glial satellite cells in the trigeminal ganglia, the location of the neuronal cell bodies of corneal sensory nerve fibers.

Together, these findings demonstrate that emerging noninvasive techniques to measure corneal nerve fiber alterations such as in vivo corneal confocal microscopy may be useful clinical tools to screen for and monitor progression of peripheral neuropathy in HIV-infected patients.
Source: Elsevier Health Sciences


Saturday, 19 July 2014

It's Like Lightning: Personal Neuropathy Blog

Today's post from finless.blogspot.com (see link below) is another personal story of life with neuropathy and the various diagnoses that this person meets along the way. Personal stories like this are often the most powerful because they remind readers that they're not alone in how they're feeling, regarding the strange things that neuropathy does to their bodies. Well worth a read if you think you've got it bad!

It's Like Thunder...LIGHTNING...in my veins?? 

Posted by Davee Thursday, July 3, 2014

Good morning! I’ve decided to use my blog not only to writing, music, and other facets of entertainment, but, also to share my journey. I’ve had significant health problems for almost two years. Initially, my rheumatologist diagnosed me with systemic lupus (SLE) on June 19, 2013. However, the medication wasn’t working and I kept getting worse and developing new symptoms. So, after second, third, and fourth opinions, my neurologist believes instead I have fibromyalgia.

In April 2014 I visited yet another rheumatologist who I hoped would be familiar with autoimmune disorders. Following an extensive intake during my initial appointment, I found a place where the doctor also listened to me. Based upon my blood work, the doctor believes I have Sjogren’s Syndrome. She also made the diagnosis of Fibromyalgia and pre-lupus. I’ve never heard of pre-lupus, but, hopefully it stays in the “pre” category.

Thank you for listening, each week I will have a new installment chronicling my journey- Which is now more frustrating than ever. I test positive for ANAs in my blood, but, the lupus tests are negative. There are several varieties of autoimmune disorders, with different caveats and health variations. Learning to live with the unknown has become my routine.

It's like LIGHTNING struck my insides...


I also write fiction books and research at least one thing for each of my writings. I want to be as accurate as possible when talking about history, illnesses, dates, geographic areas....etc, but, you get my drift. In one of my recent books, I had characters who were struck by lightning. In order to get an accurate appraisal of the medical symptoms, longer term problems, or delayed symptoms, I turned to the internet.

Lightning is primarily an injury to the central nervous system, often with brain and nerve damage. Including muscle soreness, headaches, nausea, mild confusion, memory slowness, mental fog, and dizziness or balance problems.


How interesting that the majority of the issues occurring with me involve my nervous system. It seems that I was struck by lightning and didn't know it...NAH.

It did get me thinking about why this would happen . What is going on within my body that's causing my nerves to misfire? I had horrible neuropathy all over my body. At times it felt like pin pricks everywhere. My lips and tongue would also go numb. I would occasionally lose feeling in my shins and forearms as well. At one point, I thought I was having a stroke and my doctor even instructed me to go to the emergency room.
(Thankfully, I was not having a stroke.)

The longer term problems are even more ironically similar:
Problems processing new information
Difficulty accessing old information
Slower reaction time
Irritable and possible personality changes
Inattentiveness or forgetfulness
Headaches such as migraines
Chronic pain from nerve injury
Difficulty sleeping - either sleeping excessively or insomnia

I suffer from each item on the longer term problem list. This list further proved to me that maybe studies could combine persons with chronic nerve injuries for treatment possibilities. I'm not sure if this is already occurring, but, it might be a good start. I know I currently take 3 different meds to make life bearable, but, it would be great not to rely on such drugs.

Progressing further in research, I discovered the delayed symptom list:
Personality changes/isolation
Irritability and embarrassment at not remembering people, job responsibilities, and key information
Difficulty carrying on conversation
Chronic pain ad headaches


I can no longer multi-task and I still grieve over it. I used to be the go-to girl. I could juggle several projects at once and it was a piece of cake. Now, I can't even load a dishwasher and keep up with a conversation! no joke
I've experienced depression, anxiety, and anger at the limitations this auto-immune disease has forced upon my life. I'm not the same woman and it hurts, mentally.

I have to take meticulous notes and my co-workers know I will need everything in writing. Sometimes I miss critical elements of a project, and I've asked my team leader to review all my work.

It's debilitating and it worse than sucks.

Maybe I can make it more interesting and say I was struck by lightning.

It's worth a shot.