Is Inflammation A Chief Cause Of Chronic Pain

Today's post from ufhealth.org (see link below) talks about the effect of inflammation on older pain patients and this includes people living with nerve damage. The link between neuropathy, auto-immune disease and inflammation is often hinted at but rarely confirmed, yet neuropathy is very often the result of inflammation and damage to the nervous system. This article talks about the fact that older people are more prone to and more often suffer from severe inflammation, leading to more and longer lasting pain. It suggests that anti-inflammatory drugs may be the answer but these are rarely on the list of recommended medications for neuropathy patients. It's a chicken and egg question: does the pain cause the inflammation, or the inflammation cause the pain? Inflammation is more often associated with tissue damage than nerve cells but inflammation in the nervous system most definitely can cause chronic pain (ask any shingles sufferer!) An interesting article requiring more research if you're interested. It may also be worthwhile asking your neurologist whether anti-inflammatory drugs such as diclofenac may be of benefit to you, although they do carry the potential for side-effects of their own.

Study shows pain causes older adults to develop more inflammation over a longer period of time 
Published: May 4, 2016 By: Morgan Sherburne 

When older relatives complain about their pains, show a little empathy, because new research suggests that as we age, we may all become more sensitive to pain. A small, preliminary University of Florida Health study has suggested for the first time that inflammation may occur more quickly and at a higher magnitude — and stays around longer — when older adults experience pain versus when younger adults experience pain.

This could mean that older adults could be at risk for developing chronic pain and may benefit from taking anti-inflammatories soon after an injury or procedure, according to the researchers.

Older adults often have a certain level of chronic inflammation in their bodies. But UF researchers found that when they induced pain in older adults, proteins associated with inflammation increased more than they did in younger participants and stayed in the bodies of older adults longer. The researchers also found that anti-inflammatory cytokines, proteins that soothe inflammation, peaked later for older adults than younger adults. Their results were published in a previous issue of Experimental Gerontology.

“Older people go through painful procedures more often, and we wanted to research whether this accumulation of painful procedures or more acute pain episodes that older people encounter is bad,” said Yenisel Cruz-Almeida, Ph.D., MSPH, an assistant professor in the UF College of Medicine’s department of aging and geriatric research who also is affiliated with the UF Institute on Aging. “If you have enough of those in a shorter period of time, does this predispose you to have chronic pain?”

When older adults have this kind of elevated inflammatory response, they’re more likely to have pain generated in the periphery of the body — their tissue and limbs outside of the spinal cord and brain, said the study’s senior author Joseph Riley, Ph.D., director of the pain clinical research unit in the UF Pain Research and Intervention Center of Excellence.

“If older adults are more likely to have these pain messages sent through the spinal cord to the brain, and the nervous system is being adapted to go through these changes, they may become more pain prone,” said Riley, also a professor in the UF College of Dentistry’s department of community dentistry and the UF College of Public Health and Health Professions’ department of clinical and health psychology.While the study does not establish whether accumulation of acute pain predisposes older adults to chronic pain, the researchers say their findings suggest this is a possibility, and it’s the first step in pain research to further understand the relationship between pain and aging. The researchers said the study’s sample size, though small, was more than adequate to demonstrate large differences between the older and younger adults they tested. The differences in inflammation within each group varied very little compared with the overall difference between the two groups, which suggests the populations they sampled were very different and there was little chance of sampling error, Riley said.

Cruz-Almeida and Riley studied eight healthy older adults, whose average age was 68, and nine healthy younger adults, whose average age was 21. None of the participants had illnesses such as diabetes or hypertension. During an initial visit, researchers induced pain in the participants in two ways, either using heat applied to the feet or a cold ice bath.

The first session determined how sensitive the participants were to pain. Determining a tolerable temperature allowed the researchers to recreate the same amount of pain for each participant in the subsequent sessions.

Participants rated their pain on a scale from 1 to 10. The researchers were aiming to induce pain to a Level 4 — a level that created the painful stimuli the researchers needed, but didn’t dissuade the participants from returning for the other visits required in the study.



With a thermode — a device that looks like a microphone with a copper tip — the UF researchers applied heat to the feet of participants in a study that tested the inflammatory response to pain of older adults versus younger adults.To study inflammation in the blood, the scientists inserted a catheter into each participant before inducing pain. That allowed them to collect the participant’s blood before the pain stimulus and then at three, 15, 30, 45, 60 and 90 minutes after the stimulus. These blood samples allowed the researchers to study inflammatory markers in the blood, finding that older adults had higher levels of inflammation when pain was induced than the younger adults.

Riley said activation of the immune system and increased inflammation are not necessarily harmful, but it’s important to understand how the length of time the immune system is activated affects the body.

“We think that the longer you have the immune system activated, having these elevated inflammatory cytokines, the more this activation can alter the homeostasis of the body. Usually an imbalance like that can be associated with autoimmune disorders, which also increase with age,” Cruz-Almeida said. “But the truth is we don’t know what the direct implications would be. We think low-grade inflammation is related to endocrine abnormalities such as diabetes and the development of heart problems. … We need to keep looking and doing future research.”

Riley said immediate implications of the research for patients could be to attack pain quickly with anti-inflammatory medication.

“Early treatment of an injury even with over-the-counter anti-inflammatories may be a good idea,” Riley said. “It’s those first few days of bombarding the central nervous system with pain signals that has a bigger effect (on the body).”
About the Author

Morgan Sherburne

Science writer for UF Health. Morgan writes about the research of faculty physicians in the College of Medicine. She joined the UF Health staff in 2014. A Michigan native, she...Read More

https://ufhealth.org/news/2016/study-shows-pain-causes-older-adults-develop-more-inflammation-over-longer-period-time

Watch Out For Medications That Actually Cause Neuropathy Themselves!

Today's post from medmerits.com (see link below) is highly technical and mentions many drugs you may never have heard of but is nevertheless a very useful article. If only more experts in the field exposed dangerous drugs in this way, many people might be spared the agonies of neuropathy. However, that is easier said than done and when you think of the complexity of the drugs we use for all other conditions, it's maybe little wonder that, despite their effectiveness in treating the main target problem, one of their side effects can be nerve damage. That said, it's the job of pharmaceutical companies and doctors to protect us (or at least warn us) from hidden side effects but sometimes, the achievement of success in treating one problem can be enough to forgive the emergence of another. Take chemotherapy as one glaring example: without it the cancer may not be tackled but with it comes a significant risk of neuropathy - sometimes it's a question of which is the greater evil/benefit. In war they call it 'collateral damage'. What this detailed article does tell us is that it's always important to check and know the chemical name of the drugs we are taking, because the brand names often hide a multitude of sins, If you use various trustworthy drug interaction check sites, you will need to know the drug's proper name in order to be able to check all its potential interactions and side effects. Unfortunately, most people with neuropathy also have other medical issues and are being treated for those as well, so it's vital to be able to trust any drug combinations and at least be forewarned of any possible problems.

Drug-induced neuropathies
By Louis H Weimer MD Etiology Article section 4 of 11. 

No broad etiology or pathogenic mechanism has been suggested, but isolated cases may be part of an acute hypersensitivity reaction (Glyn and Crofts 1966). Most of the potentially pathogenic mechanisms in this section are speculative.

Specific agents.

Allopurinol. Allopurinol has been used for the treatment of gout since its approval in 1966. Allopurinol inhibits the enzyme xanthine oxidase, which blocks the metabolism of hypoxanthine and xanthine (oxypurines) to uric acid, interfering with the catabolism of purines. A number of cases of neuropathy have been associated with this agent in reports with various strengths of association (Glyn and Crofts 1966; Worth and Hussein 1985; Azulay et al 1993). The initial description included a hypersensitivity reaction with later drug rechallenge with a subsequent repeat allergic reaction, which included symptoms and signs of peripheral neuropathy. The patient also received colchicine after symptom onset with unclear timing related to neuropathy onset. Symptoms improved but persisted after cessation (Glyn and Crofts 1966). Fewer than 10 cases have been noted in the literature with at least 2 cases having complicating issues (uremia). The most recent report included some electrophysiologically and pathologically demyelinating features (Azulay et al 1993). These features were not previously noted, and regression occurred after drug cessation. Most cases occur after several or many years of therapy. No predisposition or ancillary factors are currently known. No experimental evidence supports the association, making this a possible, but not a definite, rare idiosyncratic association. In fact, the agent has been used to preserve nerve and vascular function in streptozotocin-induced diabetic neuropathy in rats (Inkster et al 2007). Inhibition of xanthine oxidase produced reactive oxygen species is the suspected beneficial effect. Blood flow declines caused by the experimental diabetes were also partially corrected.

Almitrine. Almitrine bismesylate is not FDA approved for use in the United States, but it is available in many other countries for treatment of chronic obstructive pulmonary disease and some vascular disorders including stroke prophylaxis. Almitrine acts as a peripheral chemoreceptor agonist. The component is noteworthy because it appears to commonly induce a predominantly sensory neuropathy. In 1 small placebo controlled study of 7 controls and 5 treated chronic obstructive pulmonary disease patients, 3 of 5 treated patients and none of the controls developed significant neuropathy (Allen and Prowse 1989). Bouche and colleagues reported 46 cases of almitrine-associated neuropathy in one series (Bouche et al 1989). The range of onset described is 9 to 25 months after medication onset. Sensory symptoms restricted to distal legs involving all modalities are typical. Electrophysiology and nerve biopsy findings were consistent with sensory axonopathy (Gherardi and Baudrimont 1987; Petit et al 1987). Improvement is described in most cases and is usually complete after a year (Bouche et al 1989). Numerous other reports have been made that support the high incidence of neurotoxicity with this agent (Louarn 1985; Blondel et al 1986; Petit et al 1987; Allen 1988; Wouters et al 1988; Allen and Prowse 1989; Gherardi et al 1989). Small placebo control studies have reported variable, but significant, percentages of patients stopping trials because of neuropathic symptoms. Gherardi and colleagues have reported nerve biopsy and ultrastructural studies of 8 cases. The primary finding is axonal loss of large myelinated fibers with signs of regeneration in 1 delayed biopsy. In addition, signs including segmental demyelination on teased fiber preparations suggested a demyelinating component in a variable percentage of fibers. No animal studies are available for consideration. No predisposing conditions are known. Moreover, the severity of hypoxemia from the pulmonary disease does not appear to correlate with the appearance of neuropathy or subsequent improvement after cessation. One series did describe a shorter latency to neuropathy onset in chronic obstructive pulmonary disease versus vascular patients, but most were receiving higher doses. However, some additional neuropathological signs seen in isolated cases (microangiopathy) could be secondary to chronic hypoxemia. Weight loss is commonly associated with the appearance of neuropathy. Some studies using a lower dosage (< 100 mg/day) have shown no significant neuropathy, including electrophysiologic changes (Weitzenblum et al 1992). Recent series have reported no dropout due to neuropathy of patients who used similar dosages, but these series are without specific methods to detect sensory loss.

Amitriptyline. Amitriptyline is a useful drug in the treatment of painful conditions including peripheral neuropathy, especially conditions with marked small fiber mediated pain involvement. However, several reports have associated this agent and, even more rarely, other tricyclic antidepressants including imipramine with inducing peripheral neuropathy (LeWitt and Forno 1985; Leys et al 1987). Many of the cases described are in the setting of overdose with other complications including rhabdomyolysis and cholinergic effects on the CNS and periphery; however, a small number have described suspected neuropathy on conventional amitriptyline dosages with improvement after cessation (Isaacs and Carlish 1963; Nimmo Smith and Grieve 1963; Zampollo et al 1988). There is limited experimental evidence of ultrastructural lesions in cultured neurons and astrocytes, but this relation to human toxicity is speculative at best and has not altered use in patients with neuropathy.

Chloroquine. Chloroquine is an agent used to treat malaria prophylaxis and some autoimmune conditions. The primary neuromuscular complication is a vacuolar myopathy, which can be fulminant (Siddiqui 2007); however, rare cases of neuropathy with demyelinating features and axonal loss have been described (Wasay et al 1998; Stein et al 2000). Onset is typically 1 to 2 years after starting medication and involves both sensory and motor fibers. Severity is not typically marked. Schwann cells have shown dense and laminar cytoplasmic inclusions similar to those seen with amiodarone and perhexiline, notable other causes of demyelinating toxic neuropathy. Sural biopsies have shown axonal loss and segmental demyelination and remyelination (Tegner et al 1988). Electrodiagnostic studies have also suggested a neurogenic component superimposed on the predominant myopathy. Some have noted the pattern could mimic a polyradiculopathy. This effect has been reproduced in rats.

Cyclosporin. Cyclosporin A has been used as an immunosuppressive agent in numerous conditions including organ transplantation and even some cases of immune mediated neuropathy. Limited information has associated cyclosporin A with otherwise unexplained peripheral neuropathy. The evidence rates this agent at best as a possible, but not probable, causative agent at present (Blin et al 1989; Chan et al 1996).

Dichloroacetate. Dichloroacetate is used experimentally to treat chronic lactic acidemia from mitochondrial diseases. Peripheral neuropathy is common with chronic dichloroacetate treatment. Clinical and electrophysiologic signs of sensorimotor neuropathy are found (Spruijt et al 2001; Anselm and Darras 2006; Kaufmann et al 2006). The neuropathy is significant but can be reversible over months if the drug is stopped. Neuropathy also develops in younger children with lactic acidosis but was said to be tolerated by most in one trial of 36 impaired children (Stacpoole et al 2008). The neurotoxic mechanism is not fully known, but the agent causes reversible demyelination in cultured rat Schwann cells and dorsal root ganglia neurons exposed to dichloroacetate for up to 12 days (Felitsyn et al 2007). The heme precursor delta-aminolevulinate is implicated in neurologic complications associated with porphyria and tyrosinemia type I. The compound is elevated in the urine of animals and humans on dichloroacetate and appears to damage Schwann cells in part by reducing the levels of myelin-associated lipids and proteins, including myelin protein zero and peripheral myelin protein 22 (Felitsyn et al 2008). It is currently unclear but suspected that patients with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) may be at increased risk of developing the toxic neuropathy. The drug is also under investigation in the treatment of glioblastoma multiforme. Dichloroacetate may help minimize treatment resistance mediated by changes in mitochondria that reduce cancer cell apoptosis in part by a switch from mitochondrial oxidative phosphorylation to cytoplasmic glycolysis. However, studies in humans have been limited by dose-dependent peripheral neuropathy (Michelakis et al 2010).

Glutethimide. Glutethimide is a sedative-hypnotic agent originally used as an ethanol substitute, but it proved to be highly addictive in its own right. The compound was reclassified as schedule II and withdrawn from general availability in 1991. Chemically, the compound is structurally similar to thalidomide, an agent that more commonly induces sensory neuropathy. Rarely, neuropathy has been associated with chronic glutethimide use at high doses (Nover 1967; Haas and Marasigan 1968). Cerebellar ataxia is also described and may be marked and persistent. Manifestations are predominantly but not exclusively sensory and are supported by limited electrodiagnostic data. Improvement or resolution over ensuing months is described. No experimental evidence or nerve biopsy data are available for correlation.

Ixabepilone. The epothilones are a new class of chemotherapeutic agent with currently low tumor resistance. The class includes the natural agents, epothilone B (patupilone) and epothilone D, which are not yet FDA approved as well as the semisynthetic analog, ixabepilone (Bhushan and Walko 2008; Swain and Arezzo 2008); ixabepilone was FDA approved in October 2007. Breast cancer is the primary indication, but phase II studies are completed or are ongoing for a variety of cancer types. The group binds to tubulin similarly to certain other chemotherapeutic agents, such as vinca alkaloids and taxanes, but at differing binding sites. Similar to taxanes, the drugs promote dysfunctional stabilization of microtubules but with a differing mechanism, in contrast to microtubular destabilizing agents such as vincristine, colchicine, and podophyllotoxin (Cortes and Baselga 2007). Peripheral neuropathy from ixabepilone is a major dose-limiting side effect. Mild-to-moderate (grade 1 to 2), predominately sensory neuropathy that improves or resolves is most common, but more severe grades (grade 3) occur rarely in monotherapy and at rates of 10% to 15% with combination therapy or in patients previously exposed to taxanes or capecitabine; grade 4 neuropathy appears to be very rare (Denduluri et al 2007; Perez et al 2007; Roche et al 2007; Thomas et al 2007a). Dose reduction may be adequate in many, but treatment discontinuation occurs as well; more dispersed treatment protocols may have lesser toxicity (Thomas et al 2007b). Twenty-one percent of patients treated with ixabepilone plus capecitabine discontinued treatment because of sensory neuropathy in one large phase III trial (Thomas et al 2007b). Severity increases with cumulative dosing, especially after an average of 4 treatment cycles. The overall neuropathy incidence varies depending on dose and coincident treatments but is as high as 67%. The reported reversibility of sensory neuropathy is surprising considering the experience with other microtubule targeting agents such as vincristine and taxanes. One patient is reported who developed significant weakness associated with neuropathy after 1 treatment cycle (Bosch-Barrera et al 2009). Review of all phase 2 and phase 3 clinical trials found a 1% incidence of severe neuropathy in patients previously untreated and up to 24% of breast cancer patients treated with other agents (Vahdat et al 2012). Carefully monitoring for neuropathy and timely dose adjustment or treatment discontinuation is advocated depending on the neuropathy severity (Swain and Arezzo 2008). Neuropathy is increasingly recognized as a dose-limiting side effect and 20% dose reduction is one proposed strategy (Valero 2013). This entity is also discussed in the section on chemotherapy-induced neuropathy.

Leflunomide. The immunosuppressive prodrug leflunomide was FDA approved in late 1998 as a disease-modifying rheumatoid arthritis treatment. It was subsequently recognized that an axonal, sometimes painful, sensorimotor polyneuropathy is associated with leflunomide (Carulli and Davies 2002; Bonnel and Graham 2004; Metzler et al 2005). Eighty cases reported to the FDA were uncovered and described (Bonnel and Graham 2004). After this report, additional series have been reported identifying numerous additional probable cases (Bharadwaj and Haroon 2004; Martin et al 2005; Kho and Kermode 2007). Bharadwaj and Haroon describe 150 prospectively tracked rheumatoid arthritis patients in India. Fifty received leflunomide either as monotherapy or in combination with other drugs. Five developed new neuropathy (10%) in contrast to 2 of 100 receiving other treatments (2%). Nerve biopsy in 3 demonstrated epineural perivascular inflammation around small and medium-sized arterioles patchily affecting large and small myelinated nerve fibers suggesting a predominant axonopathy with features of vasculitis. All showed clinical improvement and were said to become asymptomatic within 3 months, but residual nerve conduction abnormalities remained (Bharadwaj and Haroon 2004). Kopp and colleagues describe a case and suggest a potential interaction between 5-FU and leflunomide and include the possible mechanism (Kopp et al 2005). Onset is usually after 3 to 6 months of drug use, although symptoms may appear sooner. Another study compared 16 rheumatoid arthritis patients treated with leflunomide with 16 others receiving alternative disease-modifying therapies. Neuropathy symptoms scores increased in 54% of the leflunomide group compared with 8% of the others; however, electrophysiology did not correlate with clinical symptoms (Richards et al 2007). Stopping therapy within 30 days of symptom onset gives a better chance of improvement, though recovery is typically slow. Sural nerve biopsies have shown nonspecific axonal loss in most, but signs of perivascular inflammation have been described. Primary rheumatoid arthritis is an independent neuropathy risk factor often associated with vasculitis, but leflunomide reports have not generally described this type of pattern. Neuropathy incidence is higher than with rheumatoid arthritis alone or with other rheumatoid arthritis medications. One retrospective analysis found increased associated neuropathy risk with increasing age, diabetes, and the use of other potentially neurotoxic medication (Martin et al 2007). The mechanism of neurotoxicity is not known; neuropathy cases were not detected in clinical trials. The drug remains an effective treatment and efficacy appears to be similar to methotrexate and better than sulfasalazine. However, withdrawal rates are higher than methotrexate because of toxicity; peripheral neuropathy is one of several forms of toxicity (Alcorn et al 2009). Comparison of 94 rheumatoid arthritis patients treated with either leflunomide or other disease modifying agents found significant differences in quantitative cold but not vibration perception measures; leflunomide-treated patients were roughly twice as likely to have increased cold perception measures (Kim et al 2012).

A similar agent, teriflunomide, is now approved in the United States to treat multiple sclerosis. Paresthesia and peripheral neuropathy are associated with this agent as well but the neuropathy risk and incidence are not yet known. Clinical trial data suggest an incidence of 1% to 2%, but no aftermarket reports of significant neuropathy cases are known.

Lipid-lowering agents. The statin-class of cholesterol medications acts by inhibiting the rate-limiting step in cholesterol synthesis, hydroxymethylglutaryl coenzyme A (HMG CoA). The predominant neuromuscular complication with these agents is a toxic myopathy referred to as cholesterol-lowering agent myopathy, which is well appreciated by physicians and patients. An increasingly recognized acute necrotizing myositis with rhabdomyolysis associated with antibodies against the HMG CoA enzyme can develop. However, a number of cases of peripheral neuropathy temporally associated with conventional doses of simvastatin and other agents in the class have been reported (Jacobs 1994; Ahmad 1995; Phan et al 1995; Ziajka and Wehmeier 1998; Jeppesen et al 1999; Lo et al 2003). Partial or complete recovery after drug cessation is described. One report described sural biopsy data demonstrating small and large fiber axonal loss (Phan et al 1995). Several cases have serial electrophysiological studies showing sensorimotor axonal neuropathy with variable levels of subsequent improvement. No experimental model to support the effect is known. Symptom onset has been described within days to as long as several years after onset. One case described neuropathy onset after several years of treatment with lovastatin; when treatment stopped, the condition improved (Ziajka and Wehmeier 1998). Rechallenge with pravastatin, simvastatin, and later atorvastatin each caused a subacute recurrence of burning dysesthesias that improved with cessation. Similar rapid worsening with rechallenge has been noted in other reports. One speculative mechanism proposed is that inhibition of mitochondrial hydroxymethylglutaryl coenzyme A reductase causes a subsequent decrease of ubiquinone synthesis, which potentially may disturb neuronal energy utilization (Walravens et al 1989).

Thus, only the temporal association with the neuropathy development and subsequent improvement was available to support a causative link until a case control study reported by Gaist and colleagues (Gaist et al 2002). Gaist and colleagues suspected a possible link between these agents and cases of idiopathic neuropathy, despite an earlier negative United Kingdom study (Gaist et al 2001). They then conducted a much larger population-based study in 1 Danish county (465,000 inhabitants) and cross referenced a prescription registry to a national patient diagnosis registry from 1994 to 1998, when statin use in Denmark increased from 11,547 to 50,318 nationwide. Gaist and colleagues identified 1084 registered patients with a diagnosis of polyneuropathy. They excluded 492 with onset prior to 1994 or concurrent cause of neuropathy (diabetes, renal failure, monoclonal gammopathy, etc.). Only cases with clinical signs of distal, symmetric neuropathy and an adequate workup including electrodiagnostic studies were analyzed and categorized as definite, probable, or possible idiopathic neuropathy. Twenty-five controls were randomly chosen per index case. Thirty-five definite, 54 probable, and 77 possible neuropathy cases from the registry (166 total) were found. Nine had been exposed to statins including simvastatin, pravastatin, lovastatin, and fluvastatin. Odds ratios were calculated as 4.6% overall with current users of statins compared to controls and 16.1% with definite neuropathy cases compared to controls. The researchers also calculated an interesting number needed to harm measure and found, based on their odds ratios, 1 excess case of idiopathic peripheral neuropathy for every 2,200 person-years of statin use. Considered in this way, neuropathy was suggested as a more important public health concern than myopathy in patients taking statins. However, potential pitfalls complicate the study, such as whether all symptomatic neuropathy causes were in fact excluded. Examples of complicating disorders include conditions associated with statin use, such as occult diabetes, glucose intolerance, or metabolic syndrome. (Donaghy 2002); however, not all series found a clear association with statins and idiopathic neuropathy (Anderson et al 2005). Despite the rarity of the association, the large number of patients who take these medications makes the association potentially clinically relevant. Further uncertainty was raised in 2007 by the announcement at the meeting of the American Diabetes Association of the large 8-year long Australian Fremantle study of nearly 1300 diabetic patients that demonstrated significantly decreased risk of developing neuropathy in patients treated with statins or fibrates compared to untreated patients. The reduction was 35% and 48%, respectively (Davis et al 2008). Experimental evidence suggests that the statin rosuvastatin improves a mouse model of diabetic neuropathy through improved microcirculation independent of cholesterol lowering effects (Ii et al 2005). The combination of studies and evidence challenges the importance of the earlier Gaist results; statin neuropathy likely occurs but may be much less frequent than recently thought and appears to be neuroprotective in some settings.

One possible case following initiation of simvastatin rapidly developed into neuropathy mimicking Guillain-Barré syndrome; a pravastatin challenge 6 months earlier had led to milder symptoms. The combination suggested a possible hypersensitivity reaction (Rajabally et al 2004). In contrast, lovastatin attenuated nerve injury in an experimental model of experimental allergic neuritis. The effect was blocked by mevalonate (Sarkey et al 2007).

There is no supportive experimental model of the potentially toxic effects, but alteration of membrane function though inhibition of cholesterol synthesis, reduction of axon transport, and inhibition of mitochondrial function have been suggested as possible factors. Interference with selenoprotein synthesis, a well-established pathway also implicated in some hereditary muscle disorders, has been postulated to be causative but probably relates better to myotoxicity. Myopathy from severe selenium deficiency shares some features with statin-induced myopathy (Moosmann and Behl 2004).

Lithium. Lithium has been associated with neuropathy in rare cases. Isolated reports describe the onset of typical toxic neuropathy manifestations after prolonged exposure (Tomasina et al 1990); however, most reports are after acute intoxication or overdose (Brust et al 1979; Uchigata et al 1981; Pamphlett and Mackenzie 1982; Chang et al 1988; Vanhooren et al 1990; Johnston et al 1991; Merwick et al 2011; Chan et al 2012). Excessive levels can occur due, in part, to the narrow therapeutic range of the drug; moreover, neuropathic findings may be underrecognized. Some reported cases are complicated by more generalized toxicity including cerebral impairment with the neuropathy becoming evident only with subsequent recovery. Secondary infections are also problematic, raising the issue of critical illness neuromyopathy in some instances. No convincing experimental evidence is known other than an isolated report suggesting a tendency toward reduced nerve fiber area in rats chronically given lithium over control animals (Licht et al 1997). In fact, in a small series, lithium has been reported to blunt the symptoms of vincristine-associated neuropathy in both mice and humans (Petrini et al 1999). More recently, lithium pretreatment was found to attenuate neuropathy in paclitaxel-treated mice possibly by interacting with paclitaxel-related intracellular calcium signaling pathways (Mo et al 2012).

Phenelzine. Phenelzine is a rarely used monoamine oxidase inhibitor for atypical or refractory depression. Side effects such as hypertensive crises and serious reactions with other agents are well known. Rarely, this agent (but not other MAOIs) has been implicated in inducing peripheral neuropathy. Phenelzine has been shown to affect pyridoxine metabolism and reduce measurable active pyridoxal phosphate levels in humans (Malcolm et al 1994). The compound is in the same chemical class as hydralazine and isoniazid, which both reduce pyridoxal phosphate levels and can cause peripheral neuropathy. Whether this effect is clinically relevant remains to be seen. Malcolm and colleagues demonstrated pyridoxal phosphate levels reduced, on average, by half in 19 patients on phenelzine, but none developed clinical symptoms (Malcolm et al 1994). Several reports of neuropathy associated with phenelzine have been published (Heller and Friedman 1983; Goodheart et al 1991). The neuropathy is described as a typical toxic neuropathy with sensorimotor axonal involvement with predominantly sensory manifestations.

Phenytoin. Peripheral neuropathy from chronic phenytoin use has been long recognized and generally accepted. However, despite many reported patient series, the phenomenon is based on relatively few uncomplicated prospective studies. Most likely, there is a probable effect of protracted use, especially with serum levels chronically higher than 20 µg/ml (in excess of the standard therapeutic range). Peripheral neuropathy was more commonly seen early in the history of phenytoin use when doses of 500 mg/day or higher were not uncommon. However, many of the earlier series had relatively few patients on phenytoin monotherapy, and the contributions of acute reversible phenomena were not taken into account. At current dosages with monitored serum levels, peripheral neuropathy is rare and typically produces only asymptomatic examination findings or minimally discernible neuropathy after many years of therapy. The incidence of neuropathy in epileptics on phenytoin varies considerably depending on patient populations and criteria employed (Lovelace and Horwitz 1968; Eisen et al 1974; Swift et al 1981; Shorvon and Reynolds 1982; Taylor et al 1985). Several variables have been proposed as risk factors for neuropathy development, including supra-therapeutic serum levels (greater than 20 µg/ml), protracted use (less than 10 years), and low folate levels (Lovelace and Horwitz 1968; Eisen et al 1974; Chokroverty and Sayeed 1975; Shorvon and Reynolds 1982). Other series have not found any significant association with phenytoin use compared with other anticonvulsants or these risk factors (Swift et al 1981; Taylor et al 1985). Swift and colleagues found signs of neuropathy in epileptic patients on various therapies and showed a higher incidence among patients on phenobarbital (Swift et al 1981). One case with long-term chronically elevated serum levels (31 to 38.5 µg/ml) had clinically symptomatic neuropathy, and sural nerve biopsy demonstrated mild decreases in large diameter axonal number, axonal shrinkage, and secondary demyelination (Ramirez et al 1986). This patient improved clinically and on electrophysiologic studies subsequent to phenytoin cessation.

In addition, there appears to be separate acute effects on nerve function. Acute exposure to high-dose phenytoin causes reversible slowing of nerve conduction velocity. Phenytoin affects sodium permeability across neuronal membranes by stabilizing inactive sodium channels (Macdonald 1994). Phenytoin in myelinated nerve preparations produces a voltage-dependent block of sodium channels, a shift of the sodium channel inactivation curve to more negative voltages, and a reduced rate of sodium channel recovery from inactivation (Schwarz 1989). However, carbamazepine produced some of these effects as well. Several animal studies have examined the effects of phenytoin on peripheral nerve function. Acute reversible effects have been produced with reduced conduction velocity and compound motor action potentials with acute high dose phenytoin administration in rats (Marcus et al 1981) and slow velocity after several days in guinea pigs (LeQuesne et al 1976). Serum levels were higher than 50 µg/ml. This reversible phenomenon likely represents a physiologic effect but is not a model of long-term toxicity. Some degree of acute reversible effects may have complicated some prior studies that examined chronic toxicity on high dose therapy. A human report has described similar reversible symptomatic effects 3 hours after a phenytoin loading dose (Yoshikawa et al 1999). This may represent an additional acute or subacute idiosyncratic syndrome, but a separate syndrome is not well established. The acute reversible effects on nerve function are well established, but the chronic neuropathy is considered a probable association (Mann et al 2000).

Proton pump inhibitors. A rare effect of commonly used medications can be particularly problematic to resolve and substantiate. One example is the proton pump inhibitors omeprazole and lansoprazole. Rajabally and Jacob reported a 42-year-old woman who developed predominantly sensory neuropathy after 3 months of lansoprazole use (Rajabally and Jacob 2005). Some partial improvement was noted after later stopping the medication, and no worsening was seen after switching to rabeprazole and then to ranitidine. Three other cases are reported with omeprazole, 2 of which have adequate electrophysiology and clinical information (Faucheux et al 1998). Additional carefully studied examples are needed to further substantiate this possible link with medication-induced neuropathy in this widely used class of medications. No new cases have been published as of the most recent literature search since these reports despite continued widespread use of these agents. However, these agents and histamine-2 blockers may affect vitamin B12 absorption and lead to secondary neurologic complications (Lam et al 2013).

Slaughterhouse workers progressive inflammatory neuropathy. Although not technically a medication-induced neuropathy, this local toxic epidemic at several pork processing plants in Minnesota and surrounding states produced considerable activity and investigation by numerous researchers, mostly at the Centers for Disease Control (Centers for Disease Control and Prevention (CDC) 2008). Twelve workers in a swine slaughterhouse in Minnesota developed a progressive inflammatory neuropathy with symptoms ranging from acute paralysis to gradually progressive symmetric weakness predominantly in the legs from 8 to 213 days with varying severity between November 2006 and 2007. Eleven patients had evidence of axonal or demyelinating features by electrodiagnostic testing. Spinal fluid from 7 patients showed elevated protein (mean 120 mg/dl) with no or minimal pleocytosis. Ten patients had evidence of inflammation on spinal magnetic resonance imaging (9 patients in peripheral nerves or roots and 1 patient in the anterior spinal cord). Three patients with sural nerve biopsy showed mild perivascular inflammation. In summary, patients were characterized with a sensory greater than motor polyradiculopathy, predominantly at the root or distal nerve level. The CDC researchers identified that all patients were working in close proximity to swine heads. A compressed air device used to liquefy porcine brain material may have generated aerosolized brain material, which may have induced an immune neurotoxic response. Ultimately work at the Mayo Clinic led by Vanda Lennon found a complex autoantibody profile dominated by neural cation channel IgGs that most significantly affected voltage-gated potassium channels (Meeusen et al 2012).

Tacrolimus. Prograf, previously known as FK-506, is a novel immunosuppressant that is widely used in transplant medicine and for suppression of some inflammatory disorders. The agent is a macrolide antibiotic that suppresses both cellular and humoral mediated immune responses. Neurotoxicity is common in treated patients, in part, because of the relatively high doses usually given. Central toxicity is more common with a variety of findings including leukoencephalopathy, seizures, behavioral changes, headache, or other cortical signs, many of which are dose dependent. Peripheral neuropathy appears to take the form of a severe multifocal demyelinating neuropathy that resembles chronic inflammatory demyelinating neuropathy (Wilson et al 1994; Bronster et al 1995; Labate et al 2010). Patients have responded to IVIG or plasmapheresis as well.

Both cyclosporin A and tacrolimus act through inhibition of calcineurin, though by different means (tacrolimus binding protein: FKBP-12) (Snyder et al 1998). The calcineurin inhibition, through several steps, decreases IL-2 and eventually T-cell proliferation. This pathway is also the likely cause of much of the central neurotoxicity and possibly the peripheral effects. Tacrolimus also has an additional separate function through a different binding protein, FKBP-52, that acts as a nerve stimulator, increases growth associated protein (GAP-43), and is beneficial to nerve regeneration in nerve axotomy and ischemia models (Gold et al 1998; Kihara et al 2001). FKBP-52 is part of a steroid receptor complex and may represent a target for future regenerative therapies separate from the growth factor and Trk pathways. The mechanism of why, in some patients, an immune attack that resembles chronic inflammatory demyelinating neuropathy or other autoimmune neuropathy is unclear; however, the number of reported examples is small. Interestingly, tacrolimus has also been shown to have significant and potentially therapeutic neuroregenerative activity, possibly derived from a separate pathway from the immunosuppressive calcineurin inhibition--FKBP-52 binding protein (Kvist et al 2003; Gold et al 2004). Schwann cells may play an important intermediary role (Birge et al 2004). A similar agent, sirolimus, appears to have less risk of this reaction but at least 1 case is reported (Bilodeau et al 2008).

Tumor necrosis factor-alpha blockers. Tumor necrosis factor-alpha (TNF-alpha) blockers are used in the treatment of various forms of inflammatory arthritis and inflammatory bowel diseases but are also associated with inducing or worsening other autoimmune disorders including multiple sclerosis (Stubgen 2008). One agent (etanercept) has been reported to improve chronic inflammatory demyelinating neuropathy (CIDP) (Latov and Sherman 2000; Chin et al 2003). Postmarketing reporting identified 15 patients diagnosed with Guillain-Barré syndrome or Miller Fisher syndrome from 6 weeks to 2 years after starting a TNF-alpha blocker, although associated infection may be a more important risk factor (Robinson et al 2001; Shin et al 2006). One case developed acute sensorimotor neuropathy and concomitant encephalopathy (Faivre et al 2010). Richez and colleagues reported 2 cases that developed a CIDP-like illness (Richez et al 2005). One treated with etanercept for rheumatoid arthritis developed a demyelinating neuropathy 17 months later. The other received infliximab for ankylosing spondylitis and developed CIDP 3 months later. Both incompletely improved after drug cessation without specific treatment for CIDP. Infliximab is also associated with several other CIDP-like cases with underlying rheumatoid arthritis (Jarand et al 2006; Tektonidou et al 2007; Alshekhlee et al 2010) and 3 cases with underlying psoriatic arthritis, a condition which is much less likely to induce spontaneous or vasculitic neuropathy (Stubgen 2008; Eguren et al 2009). Numerous cases resembling multifocal motor neuropathy are also reported in association with infliximab (Singer 2004; Cocito et al 2005; Rodriguez-Escalera et al 2005; Paolazzi et al 2009). However, others question whether some of these cases were actually a form of vasculitic mononeuritis multiplex triggered by the infliximab (Birnbaum 2007). One case of proposed infliximab-associated immune-mediated sensory polyradiculopathy was successfully treated with intravenous gammaglobulin (Naruse et al 2013). There are additional less clear associations with mononeuropathy and axonal sensory or sensorimotor neuropathy (Jarand et al 2006). In any event, it seems that infliximab and etanercept can contribute to or trigger an immune-mediated neuropathy in some possibly susceptible patients (Kotyla et al 2007). Adalimumab is not clearly associated with chronic neuropathy but was associated with one possible Guillain-Barré syndrome case. Ipilimumab, a monoclonal antibody that is not a TNF alpha antagonist but instead blocks a natural inhibitor of cytotoxic T-cell response to cancer cells, is approved to treat melanoma and is undergoing trials for other cancer types. A case of acute neuropathy mimicking Guillain-Barré syndrome is reported; acute enteric neuropathy is also recognized (Gaudy et al 2013).

Interestingly, in light of the fluoroquinolone story discussed earlier, peripheral neuropathy associated with TNF-alpha agents was the most common adverse neurologic event reported to the Food and Drug Administration Adverse Event Reporting System (296 reports, 38.3%), exceeding central nervous system and/or spinal cord demyelination (153 reports, 19.8%) (Deepak et al 2013). The majority of reports (71%) were labeled as “possibly associated” and not higher grades of certainty.

In contrast, these agents may have other protective properties. A mouse model of bortezomib neuropathy found that upregulation of TNF-alpha was neuroprotective, possibly by limiting certain inflammatory cytokines (Ale et al 2014).

Zimeldine. Zimeldine is another agent never approved for use in the United States but available transiently as an antidepressant in Sweden, functioning as a 5-HT reuptake inhibitor with purported fewer side effects. The drug is best known as a probable precipitating factor of an outbreak of Guillain-Barré syndrome in Sweden in 1983. The drug was withdrawn from the market 18 months after introduction because of this outbreak. A subsequent Bayesian analysis concluded that the association was supported by relevant data (Naranjo et al 1990). No additional cases, however, were identified in a retrospective review of 761 patients on zimeldine reported more recently from the same region (Bengtsson et al 1994). Hypersensitivity reactions are relatively common with this agent (1.4% to 13%), raising the question of potential immune-mediated mechanisms in this phenomenon. Zimeldine appears to affect T-cell function and blunt experimental allergic neuritis in a rat model of Guillain-Barré syndrome (Bengtsson et al 1992). The risk of developing Guillain-Barré syndrome from zimeldine was estimated as increased 25-fold compared to natural incidence controls (Fagius et al 1985).

http://www.medmerits.com/index.php/article/drug_induced_neuropathies/P3

Cell Toxins That Cause Neuropathy

Today's post from source.wustl.edu (see link below) attempts (successfully) to put some very complex information into words that we as lay readers can pretty much understand. It talks about the toxins produced by Schwann cells which 'leak' out onto adjacent axons and damage them, causing the nerve pain we feel with neuropathy. However, these toxins have been called into action by the mitochondria (energy generators of the cells) which have been damaged themselves and no longer produce the energy needed to make nerve cells work normally. With me so far? Probably not but this article explains the whole process and teaches us how nerves and their complex structures actually work. Finding drugs to block this toxin production is the aim. Have a read. You might surprise yourself how quickly you form a picture of what's going on with neuropathy.
 

New clues to causes of peripheral nerve damage
By Caroline Arbanas March 6, 2013

Anyone whose hand or foot has “fallen asleep” has an idea of the numbness and tingling often experienced by people with peripheral nerve damage. The condition also can cause a range of other symptoms, including unrelenting pain, stinging, burning, itching and sensitivity to touch.

Although peripheral neuropathies afflict some 20 million Americans, their underlying causes are not completely understood. Much research has focused on the breakdown of cellular energy factories in nerve cells as a contributing factor.

Now, new research at Washington University School of Medicine in St. Louis points to a more central role in damage to energy factories in other cells: Schwann cells, which grow alongside neurons and enable nerve signals to travel from the spinal cord to the tips of the fingers and toes.

The finding may lead to new therapeutic strategies to more effectively treat symptoms of this highly variable disorder, the scientists reported March 6 in the journal Neuron.

“We found that a toxic substance builds up in Schwann cells that have disabled energy factories, leading to the same kind of nerve damage seen in patients with neuropathies,” said senior author Jeffrey Milbrandt, MD, PhD, the James S. McDonnell Professor of Genetics and head of the Department of Genetics. “Now, we’re evaluating whether drugs can block the buildup of that toxin, which could lead to a new treatment for the condition.”

The most common cause of peripheral neuropathy is diabetes, which accounts for about half of all cases. The condition also can occur in cancer patients treated with chemotherapy, which can damage nerves.

In the body, Schwann cells wrap tightly around nerve axons, the fibers that relay nerve signals. Graduate student and first author Andreu Viader and colleagues in Milbrandt’s lab studied Schwann cells in mice with genetically disabled mitochondria, or cellular energy factories. Under normal conditions, these mitochondria produce fuel and intermediates of energy metabolism that allow nerve cells to function.

The researchers showed that the crippled mitochondria activated a stress response in the Schwann cells. Instead of synthesizing fatty acids, a key component of Schwann cells, the cells burned fatty acids for fuel.

Over time, inefficient burning of fatty acids by the crippled mitochondria leads to a build up of acylcarnitines, a toxic substance, in the Schwann cells. The researchers found levels of acylcarnitines up to 100-fold higher in these mutant Schwann cells than in healthy Schwann cells.

And the bad news doesn’t end there. Eventually, the toxin leaks out of the Schwann cells and onto the nerve axons. Studying neurons in petri dishes, the researchers showed that acylcarnitines damage nerve axons and disrupt the ability of nerves to relay signals.

“The toxin leaking out of the Schwann cells and onto the adjacent nerve axons causes damage that results in pain, numbness, tingling and other symptoms,” Milbrandt said. “We think that is a likely mechanism to explain the degeneration of axons that is known to occur in peripheral neuropathies.”

The new research suggests that drugs that inhibit the buildup of acylcarnitines may block axonal degeneration. Milbrandt and his team now are evaluating the drugs in mice with disabled Schwann cells to see if they can slow or alleviate the decay of axons. The research is supported by the National Institutes of Health (NIH) Neuroscience Blueprint Center Core Grant (P30 NS057105), the HOPE Center for Neurological Disorders and the National Institutes of Health (AG13730 and PPG 2P01 HL057278).

Viader A, Sasaki Y, Kim S, Strickland A, Workman CS, Yang K, Cross RW, Milbrandt J. Aberrant Schwann cell lipid metabolism linked to mitochondrial deficits leads to axon degeneration and neuropathy. Neuron. March 6, 2013.

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

https://source.wustl.edu/2013/03/new-clues-to-causes-of-peripheral-nerve-damage/

Suppressed HIV Virus may cause Neuropathy

Another interesting article first published in 2003, from Neurology Today (see link below) discusses what is now an accepted, if uncomfortable truth: that the longer you live with HIV, the more likely it is that you will suffer from neurological problems. It's a frightening thought that even though your viral count may be undetectable, the much-reduced virus may well be hiding in spinal fluid and negatively influencing the nervous system and the brain. The article claims that serious work was being done to investigate how much this has to do with neuropathy and other neurological problems. If any reader knows of articles relating to outcomes of this research, please use the Contact button.

It goes further to look at various treatments for neuropathic pain but these must be seen in the context of an article written in 2003. Similarly, Dr Schifitto and his group's conclusion that rates of nerve damage were dropping thanks to HAART, has been proved to be wrong over the longer term, lending more support to the theory that the virus itself plays an important role. However, even if the virus is proved to be acting as a sniper, it's difficult to see what can be done about it. Neuropathy may end up being one of the prices we have to pay for survival.

Longer Hiv-AIDS Survival Raises Likelihood of Neurological Problems
Samson, Kurt: July 2003

The dramatic impact of combination therapy against HIV/AIDS carries a neurological postscript. Even as the incidence of AIDS-related dementia declines with highly active antiretroviral therapy (HAART), researchers are concerned that longer survival may mean a steadily growing population with neurological complications.

Opportunistic infections, side effects from potent medications, and the ability of the virus - even in a diminished state - to affect the brain and central nervous system (CNS) over time mean that neurologists will be treating more and more HIV-AIDS survivors.

Scientists are gaining insight into the pathology of HIV-AIDS on the brain and CNS, but the uncertainty that marks and propels AIDS research in general also applies to neurological studies.

The growing number of people living with AIDS may be neurologically vulnerable, with the cerebrospinal fluid serving as a sanctuary or reservoir for partially suppressed HIV replication, said Ned Sacktor, MD, Assistant Professor of Neurology at Johns Hopkins University in Baltimore, MD.

In an effort to better understand and treat the neurological aspects of the disease, clinical trials are being conducted under the auspices of the National Institute of Allergy and Infectious Diseases (NIAID) through the Neurologic AIDS Research Consortium (NARC) and the AIDS Clinical Trials Group (ACTG).

HIV COMPLICATIONS

HIV infection can damage the brain and spinal cord, causing encephalitis, meningitis, nerve damage, AIDS dementia complex, painful peripheral neuropathies, behavioral changes, poor circulation, headache, and stroke. Cancers and opportunistic infections frequently seen in HIV-AIDS patients can also affect the nervous system. Neurological symptoms may be mild in the early stages of AIDS, but may become more severe as the disease progresses.

Complications include cerebral toxoplasmosis, which is a common opportunistic infection in AIDS and one that can cause ataxia, apraxia, seizures, and sensory loss. Progressive multifocal leukoencephalopathy affects the cerebrum and cerebellum, and may cause visual loss.

Some experimental treatments appear promising for neurological complications. For example, anti-dementia drugs may relieve confusion and slow mental decline while infections may be treated with more powerful antibiotics. Radiation therapy may be necessary for AIDS-related cancers in the brain or spinal cord, while HAART cocktails can reduce dementia and opportunistic infections.

STATE OF HAART

Last year Dr. Sacktor and fellow Hopkins researcher Justin C. McArthur, MPH, MBBS, Professor of Neurology, published the results of one of the largest studies of the impact of HAART on the incidence of AIDS dementia. They compared the incidence of dementia and cognitive impairment in 500 AIDS patients, half of whom developed the disease prior to the advent of HAART (J Neurovirol 2002;8(2):136-142).

We found no difference between the two groups, so it is unclear whether HAART has changed the frequency of specific cognitive abnormalities, said Dr. Sacktor. However, we are seeing patients living longer with less severe dementia, and HIV-associated cognitive impairment continues to be a major clinical problem among people with advanced infection.

Although comprehensive data are sparse, anecdotal reports suggest that HAART protects against dementia just as it does against opportunistic infections, and some studies have charted a gradual drop in dementia since HAART became available (Neurology 2001;56(2):257-260).

Estimates of the incidence of HIV-associated dementia vary, depending on the definition used, noted Dr. Sacktor. The Hopkins scientists estimate that 15 percent of HIV-infected people may develop dementia and that 30 percent may show some signs of neurological impairment (Semin Neuro 1999;19:129-150).

Dr. Sacktor acknowledged that HAART is a major advance because it can reduce the viral load in the CNS, allowing patients to live longer lives. But while cases of severe dementia decline, less advanced cases - those with chronic cognitive deficit - are rising. There is a high prevalence of dementia among patients who have had the disease for years, but we're seeing lesser severity. Where dementia once led to death in AIDS patients in three to nine months, suppression of the viral load lets patients live years longer. Co-author Dr. McArthur added that HAART also may result in metabolic disturbances that can cause nerve damage and peripheral neuropathy.

This is a moving target, he said. We anticipate an increase in neurological problems as patients live longer. There are also the toxic effects of the antiretroviral drugs on the peripheral nervous system, and drugs to treat them can't be used in some patients, notably diabetics.

He added that HAART also raises the risk of atherosclerosis in patients who experience higher cholesterol and triglyceride levels.

Some studies suggest accelerated rates of heart attacks and strokes in patients on HAART, and our techniques for cardiovascular observation and intervention are not what they should be. While patients may be put on statin therapy, and remain on it for their entire lives, these drugs can also cause muscle damage.

Giovanni Schifitto, MD, Associate Professor of Neurology at the University of Rochester Medical Center in Rochester, NY, is principal investigator for a NARC-ACTG clinical trial of transdermal selegiline in treating HIV cognitive impairment.

The trial, which began in the fall of 2001, is evaluating transdermal selegiline for treatment of HIV-related motor cognitive disorder. This study, jointly sponsored by NARC and the ACTG system, is assessing the safety and efficacy of selegiline (Deprenyl) patches, following up on an earlier, smaller study that suggested efficacy in treating AIDS dementia.

PERIPHERAL NEUROPATHIES

Finding treatments for painful peripheral neuropathies is a major research goal for NARC and ACTG. As many as 20 percent of AIDS patients suffer neuropathies, which may be exacerbated by the neurotoxicity of several drugs commonly used to treat HIV, including didanosine (ddI), zalcitabine (ddc), and stavudine (d4T).

Peripheral neuropathy develops primarily in advanced disease in patients with low CD4 counts. The viral infection itself typically causes a symmetric, painful, distal sensory neuropathy, often manifesting with the loss of sensation in the feet, and painful paresthesias in the feet and up the legs.

In a trial by consortium researcher David Simpson, MD, of Mount Sinai Medical Center in New York, the anticonvulsant lamotrigine (Lamictal) has shown promise in treating the pain of the distal sensory neuropathy (DSP).

Lamotrigine blocks voltage-sensitive sodium channels and inhibits the release of glutamate and aspartate. In May, Dr. Simpson's team reported that lamotrigine was well tolerated and effective for HIV-associated neuropathic pain in DSP patients receiving neurotoxic antiretroviral therapy (Neurology 2003;60(9):1508-1514).

In the double-blind study, patients were randomized into two groups, those who were currently using a neurotoxic antiretroviral therapy (ART) and those who were not. Ninety-two patients received ART - (62 lamotrigine, 30 placebo) - and 135 (88 lamotrigine, 47 placebo) did not. While little difference was observed in baseline scores for average pain between lamotrigine and placebo, the drug offered greater improvement in pain intensity and also in the ratings of change by patients and clinicians.

A trial of nerve growth factor (NGF) for painful neuropathy found that NGF relieved pain, even though sensory testing did not demonstrate improved peripheral nerve function at the end of the 18-week study (Neuro-logy 2000;54:1080-1088).

Neuropathic pain is difficult to treat under the best of circumstances, noted Russell Bartt, MD, Assistant Professor of Neurology at Cook County Hospital-Rush Presbyterian St. Luke's Medical Center in Chicago, IL. He is co-chair of a pilot study launched in 2002 to evaluate the safety, toxicity, and tolerability of acetyl-L-carnitine (ALC) in treating peripheral neuropathy. It will include 36 HIV patients with mild to moderate peripheral neuropathy currently taking ddI, ddc, or d4T.

Some studies showed striking improvement in painful AIDS neuropathies, as well as histological improvement, even some nerve regeneration, with ALC, said Dr. Bartt (AIDS 2001;15(16):2207-2208; Neurology 2002;58(1):115-119). We're seeking a number of patients for the trial not only to evaluate their physical response but also to document histological changes in nerve function.

NEUROPATHY RATES DROPPING

Dr. Schifitto is lead investigator for a just-completed study that he said strongly suggests that the incidence of neuropathies has fallen since the advent of HAART. The study, by four leading research hospitals, found a significant decrease in pre- and post-HAART neuropathies among 400 HIV/AIDS patients. The results have been submitted in abstract form to the American Neurological Association for the upcoming meeting in October.

Unlike the data showing an increase in dementia cases as patients live longer on HAART, the neuropathy numbers look encouraging. But these conditions are not going away.

There are two important points, Dr. Schifitto said. First, with increased survival there is a greater incidence of neuropathies in patients receiving HAART. Second, the incidence may be lower now, but it is going to increase, as will the incidence of other chronic neurological disorders, in the next ten to twenty years.

Neurologists must be prepared to see more patients with chronic neuropathies in the future, although I suspect these will be less severe, Dr. Schifitto continued. The number of HIV-AIDS patients with severe, life-threatening dementia will be small, but we're going to see a lot more chronic cognitive impairment that will impact patients in different ways, such as limiting their ability to work at some jobs.

Dr. Schifitto agreed that the reported decrease in the incidence of severe dementia does not mean long-term survivors will not suffer cognitive impairment.

Just the opposite, he said. The longer they survive, I believe, the greater the likelihood of some degree of impairment. They will still be able to function, but they will be impaired to some degree.

In addition, even with aggressive treatment, some patients will gradually become more and more resistant to the current HAART medications, he added. In terms of numbers, it will be a catch-up game until there are alternative treatments available. We can't declare any victory here.

http://journals.lww.com/neurotodayonline/Fulltext/2003/07000/Longer_Hiv_AIDS_Survival_Raises_Likelihood_of.14.aspx

Is Stress A Cause Of Neuropathy Vid

Today's YouTube video (see link below) tries to answer the question as to whether stress can cause neuropathy. In the end, the doctor here suggests that stress can indirectly cause neuropathy but the jury's still out on that one. The point is that many people with neuropathy are desperate to find a cause for their problems when really they should be concentrating on the treatment and living with the disease. Especially if you've left the doctor's appointment with a vague diagnosis of 'idiopathic' neuropathy (cause unidentified), you begin to look at the rest of your life to find explanations and causes. If at that time, you're also under a lot of stress, then it's logical that you may lay the blame there but that's not based on scientific fact. On the other hand, if you've got neuropathy in your life, you can easily become stressed, if only from the symptoms alone. So, does stress cause neuropathy? In all likelihood no but does neuropathy cause stress? You betcha!

Can Peripheral Neuropathy be Caused by Stress? 
Streamed live on 19 May 2016

 

Martin Rutherford

https://www.youtube.com/watch?v=uJ6L74C_2NQ

SCIENTISTS DISCOVER NEW CAUSE OF GLAUCOMA

Scientists have revealed that they have discovered a novel cause of glaucoma in an animal model and are developing an eye drop aimed at curing the disease.

The new study for the first time identifies the molecular building blocks needed to make the 'drainage' vessels, providing the necessary chemical tools to repair the eye's plumbing and restore normal drainage. Up until now, the molecular basis of the disease caused by an absent or defective canal was unknown.

Senior study author and Northwestern Medicine nephrologist Susan Quaggin said that this is a big step forward in understanding the cause of the disease that steals the eyesight from 60 million people worldwide, which gives them a foothold to develop new treatments.

The findings are based on a new mouse model of glaucoma developed by the researchers is one of the first animal models of the disease and researchers expect the animal findings to be relevant in human glaucoma.

The researchers have developed a highly potent peptide nanostructure that has the capacity to interact with many receptors at the same time, which will amplify the required signaling pathway for an effective therapy. The nanostructure is also being designed to have the necessary half-life to optimize efficacy.

The study was The Journal of Clinical Investigation.

Can a high CD4 cell count cause neuropathic pain

Today's post from EATG: the European Aids Treatment Group, (see link below)is based on a study of 1,539 HIV-patients by the University of California. It reveals much of what most of us already know but interestingly also, the fact that a high CD4 cell count (which we all use as a measure of immune system health) can be a possible cause of neuropathic pain. Not really what we want to hear when we're spending every waking minute trying to boost that very cell count. The article suggests that it may be a consideration when deciding whether to start anti retroviral treatment in the first place. Considering that the current thinking is that it's better all round, to start as soon as possible, the dilemma is obvious. On the other hand, there's not really much of a choice is there? The medication which halts viral development is more or less essential and for some people, the pain may be an unwelcome but necessary by-product.

Debilitating HIV-associated sensory neuropathy remains common
20/05/2010

Debilitating sensory neuropathy remains prevalent in HIV-infected patients, despite a general decline of neurological complications with use of combination antiretroviral therapy.

This finding is from a study in which the researchers tested 1,539 HIV-infected individuals for clinical signs of neuropathy and neuropathic pain.

"We were surprised by the high prevalence," lead author Dr. Ronald Ellis of the University of California, San Diego, told Reuters Health by e-mail.

"Painful neuropathy frequently persists and requires ongoing management," even when antiretroviral therapy has reduced viral load and restored immune function, he said.

In the May Archives of Neurology, Dr. Ellis and colleagues report that 881 patients (57.2%) had HIV-associated sensory neuropathy, and 335 of those 881 (38.0%) had neuropathic pain.

"Neuropathic pain was significantly associated with disability in daily activities, unemployment, and reduced quality of life," the investigators say.

Patients currently taking combination antiretroviral therapy had an adjusted odds ratio of 1.60 for clinical signs of sensory neuropathy, compared to past users or never users of antiretroviral combinations.

Age (aOR 2.13), past use of stavudine, didanosine, or zalcitabine (aOR 1.95), and lower CD4 nadir (aOR 1.16) were also associated with sensory neuropathy.

Paradoxically, neuropathic pain was associated with a higher CD4 nadir, as well as with past use of stavudine, didanosine, or zalcitabine.

In an editorial, Drs. Dennis Kolson and Francisco Gonzalez-Scarano, both of the University of Pennsylvania in Philadelphia, said the "association between neuropathic pain and a higher CD4 nadir suggests that a functional immune system may contribute to the induction of pain." They also suggest considering the risk of neuropathy - and the disability that results -- when deciding whether to start antiretroviral therapy.

Regarding potential for peripheral nerve regeneration and recovery, Dr. Ellis told Reuters Health, "It may be that treatments can be designed to enhance regeneration. Alternatively, we may find that earlier HAART therapy using agents without neurotoxicity can protect individuals from developing neuropathy in the first place."

By Dave Levitan
Medscape Today

http://eatg.org/eatg/Global-HIV-News/Treatment/Debilitating-HIV-associated-sensory-neuropathy-remains-common

ACID REFLUX DRUG MAY CAUSE HEART DISEASE

Drugs that help millions of people cope with acid reflux may also cause cardiovascular disease, report scientists from Houston Methodist Hospital and two other institutions in an upcoming issue of Circulation(now online). It is the first time researchers have shown how proton pump inhibitors, or PPIs, might cause cardiovascular problems

In human tissue and mouse models, the researchers found PPIs caused the constriction of blood vessels. If taken regularly, PPIs could lead to a variety of cardiovascular problems over time, including hypertension and a weakened heart. In the paper, the scientists call for a broad, large-scale study to determine whether PPIs are dangerous.

"The surprising effect that PPIs may impair vascular health needs further investigation," said John Cooke, M.D., Ph.D., the study's principal investigator. "Our work is consistent with previous reports that PPIs may increase the risk of a second heart attack in people that have been hospitalized with an acute coronary syndrome. Patients taking PPIs may wish to speak to their doctors about switching to another drug to protect their stomachs, if they are at risk for a heart attack."

Commonly used proton pump inhibitors in the United States are lansoprazole and omeprazole, and these drugs are purchasable over the counter as brands or generics. The FDA estimates about 1 in 14 Americans has used them. In 2009, PPIs were the third-most taken type of drug in the U.S., accounting for $13 billion in sales. PPIs are used to treat a wide range of disorders, including gastroesophageal reflux disease, or GERD, infection by the ulcer-causing Helicobacter pylori, Zollinger-Ellison syndrome, and Barrett's esophagus.

Recent studies of proton pump inhibitors use by people who've already experienced severe cardiovascular events have raised concern about the anti-reflux drugs, at least for this subgroup of patients, said Cooke, chair of the Department of Cardiovascular Sciences and director of the Center for Cardiovascular Regeneration at Houston Methodist DeBakey Heart & Vascular Center.

PPIs are initially inert. After oral consumption, they are activated by specialized cells in the stomach. Once active, the molecules suppress the movement of protons into the intestine, which reduces the amount of acid present there and in the stomach.

In mouse models and cultures of human endothelial cells, Cooke and lead author Yohannes Ghebramariam, Ph.D., found that PPIs suppressed the enzyme DDAH, dimethylarginine dimethylaminohydrolase. That caused an increase in the blood levels of ADMA (asymmetric dimethylarginine), an important chemical messenger. They found ADMA in turn suppressed the production of another chemical messenger, nitric oxide, or NO, proven by 1998 Nobel Prize winners Furchgott, Ignarro, and Murad to impact cardiovascular function. Quantitative studies in mouse models showed animals fed PPIs were more likely than controls to have tense vascular tissue.

"We found that PPIs interfere with the ability of blood vessels to relax," said Ghebremariam, a Houston Methodist molecular biologist. "PPIs have this adverse effect by reducing the ability of human blood vessels to generate nitric oxide. Nitric oxide generated by the lining of the vessel is known to relax, and to protect, arteries and veins."

The researchers found PPIs led to an approximately 25 percent increase in ADMA in mouse and tissue cultures, and reduced the ability of mouse blood vessels to relax by over 30 percent on average.

Also contributing to this report were Paea LePendu, Ph.D., Jerry Lee, Daniel Erlanson, Ph.D., and Nigam H. Shah, Ph.D. (Stanford University) and Anna Slaviero, Ph.D., and James Leiper, Ph.D. (Imperial College London). Work was funded with grants from the National Institutes of Health, the American Heart Association, the Stanford SPARK program, and the Stanford Translational Research and Applied Medicine (TRAM) program.

Circulation is published by the American Heart Association.

The Methodist Hospital recently changed its name to Houston Methodist Hospital.

SARM1 The Lemmings Of The Nervous System That Cause So Much Pain

Today's interesting post from medicalxpress.com (see link below) explains the way that for some reason, axons go into self-destruct mode when there is evidence of neurodegeneration. This is basically what happens when you get neuropathy (nerve damage). As explained clearly here, axons are the electrical wiring of the nervous system and for that reason, comparing neuropathy to short circuiting in a household wiring system, is a pretty good way of illustrating what happens. Scientists have now discovered the molecule responsible for this self-destructive tendency of axons when threatened or disrupted. The problem is how to find a way of blocking this from happening. The molecular villain is called, SARM1 which doesn't tell us ordinary mortals much but gives it a label. Why the body does this is not clear - it seems illogical but at least they've identified the culprit; let's hope they can find a way of stopping it happening without any further consequences for the rest of the nervous system. Worth a read.

Findings suggest ways to block nerve cell damage in neurodegenerative diseases
March 23, 2017 Washington University School of Medicine in St. Louis

Nerve axons (left) serve as the electrical wiring of the nervous system. Scientists have implicated a specific molecule in triggering a self-destruct program in axons that leads to their degeneration (right). Since axonal degeneration is a …more

In many neurodegenerative conditions—Parkinson's disease, amyotrophic lateral sclerosis (ALS) and peripheral neuropathy among them—an early defect is the loss of axons, the wiring of the nervous system. When axons are lost, nerve cells can't communicate as they should, and nervous system function is impaired. In peripheral neuropathy in particular, and perhaps other diseases, sick axons trigger a self-destruct program.

In new research, scientists at Washington University School of Medicine in St. Louis have implicated a specific molecule in the self-destruction of axons. Understanding just how that damage occurs may help researchers find a way to halt it.

The study is published March 22 in the journal Neuron.

"Axons break down in a lot of neurodegenerative diseases," said senior author Jeffrey D. Milbrandt, MD, PhD, the James S. McDonnell Professor and head of the Department of Genetics. "Despite the fact these diseases have different causes, they are all likely rooted in the same pathway that triggers axon degeneration. If we could find a way to block the pathway, it could be beneficial for many different kinds of patients."

Since the molecular pathway that leads to loss of axons appears to do more harm than good, it's not clear what role this self-destruct mechanism plays in normal life. But scientists suspect that if the pathway that destroys axons could be paused or halted, it would slow or prevent the gradual loss of nervous system function and the debilitating symptoms that result. One such condition, peripheral neuropathy, affects about 20 million people in the United States. It often develops following chemotherapy or from nerve damage associated with diabetes, and can cause persistent pain, burning, stinging, itching, numbness and muscle weakness.

"Peripheral neuropathy is by far the most common neurodegenerative disease," said co-author Aaron DiAntonio, MD, PhD, the Alan A. and Edith L. Wolff Professor of Developmental Biology. "Patients don't die from it, but it has a huge impact on quality of life."

In previous studies, Stefanie Geisler, MD, an assistant professor of neurology, working with DiAntonio and Milbrandt, showed that blocking this axon self-destruction pathway prevented the development of peripheral neuropathy in mice treated with the chemotherapy agent vincristine. The hope is that if methods are developed to block this pathway in people, then it might be possible to slow or prevent the development of neuropathy in patients.

Toward that end, the Milbrandt and DiAntonio labs showed that a molecule called SARM1 is a central player in the self-destruct pathway of axons. In healthy neurons, SARM1 is present but inactive. For reasons that are unclear, injury or disease activate SARM1, which sets off a series of events that drains a key cellular fuel—called nicotinamide adenine dinucleotide (NAD)—and leads to destruction of the axon. Though the researchers previously had shown SARM1 was required for this chain of events to play out, the details of the process were unknown.

SARM1 and similar molecules—those containing what are called TIR domains—most often are studied in the context of immunity, where these domains serve as scaffolds. Essentially, TIR domains provide a haven for the assembly of molecules or proteins to perform their work.

The researchers had assumed that SARM1 acted as a scaffold to provide support for the work of destroying axons, beginning with the rapid loss of cellular fuel that occurs minutes after SARM1 becomes active. The scientists set about searching for the demolition crew—the active molecule or molecules that use the SARM1 scaffold to carry out the demolition. The study's first author, Kow A. Essuman, a Howard Hughes Medical Institute Medical Research Fellow and an MD/PhD student in Milbrandt's lab, performed a litany of cellular and biochemical experiments searching for the demolition crew and came up empty.

"We performed multiple experiments but could not identify molecules that are traditionally known to consume NAD," Essuman said.

But as a last resort, the investigators tested SARM1 itself. To their great surprise, they found it was doing more than simply providing a passive platform. Specifically, the researchers showed SARM1's TIR domain acts as an enzyme, a molecule that carries out biochemical reactions, in this case destroying axons by first burning all their NAD cellular fuel.

"There are more than 1,000 papers describing the function of proteins containing TIR domains," DiAntonio said. "No one had ever shown that this type of molecule could be an enzyme. So we went into our experiments assuming SARM1 was only a scaffold and that there must be some other enzyme responsible for demolition of the axon. We essentially searched for a demolition crew, only to discover that the scaffold itself is destroying the structure. It's the last thing you would expect."

The findings suggest molecules similar to SARM1—those with TIR domains and known to serve as scaffolds in the immune system—may prove to have additional functions that go beyond their structural roles. The research also invites a search for drugs that block the SARM1 enzyme from triggering axonal destruction.


Explore further: Major pathway identified in nerve cell death offers hope for therapies

More information: Kow Essuman et al. The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD +Cleavage Activity that Promotes Pathological Axonal Degeneration, Neuron (2017). DOI: 10.1016/j.neuron.2017.02.022

Journal reference: Neuron

Provided by: Washington University School of Medicine in St. Louis

Read more at: https://medicalxpress.com/news/2017-03-ways-block-nerve-cell-neurodegenerative.html#jCp


https://medicalxpress.com/news/2017-03-ways-block-nerve-cell-neurodegenerative.html

How The HIV Virus Itself Can Cause Neuropathy

Many doctors and HIV specialists still maintain surprise when HIV patients report neuropathy despite their never having used the older, so called 'D'Drugs (Zerit, Videx etc) or having long since stopped using them. The idea that neuropathy for people living with HIV could only stem from those drugs, or other diseases like diabetes, or cancer, is difficult to dislodge from medical specialists who studied the area long ago. The fact is that it has been known for some time now that the HIV virus itself can play an active role in bringing on neuropathic problems. The fact that numbers of neuropathy patients who also have HIV are growing, despite the withdrawal of the old drugs, shows that the cause had to come from somewhere else. The prime suspect then becomes the virus itself and more and more studies are proving exactly that. Today's post comes from reports from the CROI (Conference on Retroviruses and Opportunistic Infections) in 2011 (see link below). It discusses a study which reveals that neuropathy can occur in the first few months of infection. Not an easy read but the message is clear.

Signs of Peripheral Neuropathy Associate with Elevated Inflammatory Biomarkers in Blood and Cerebrospinal Fluid in Primary HIV Infection
Reported by Jules Levin CROI 2012

From Jules: Study reports 35% of ART-naïve patients during early/primary HIV-infection have neuropathy & 65% of these have symptomatic neuropathy, that this study finds appears to be caused by nervous system immune activation that begins during early/primary HIV infection. Since CSF viral load levels were similar in patients with & without neuropathy the investigators feel the neuropathy appears to be due to the immune activation that starts shortly after HIV infection.

Samantha XY Wang1, Marie Grill2, Evelyn Lee2, Julia Peterson2, Emily Ho3, Emilie Jalbert4, Elizabeth Sinclair2, Dietmar Fuchs5, Richard W. Price2, Serena Spudich1
1Yale University, New Haven CT; 2University of California, San Francisco (UCSF), San Francisco, CA; 3University of Washington, Seattle, WA; 4John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii;
5Division of Biological Chemistry, Biocenter, Innsbruck Medical University, Innsbruck, Austria

CONCLUSIONS

· Signs and symptoms of peripheral neuropathy are present at a median of 3.5 months after HIV transmission.

· Pro-inflammatory cytokines MCP-1 and IP-10, and the macrophage activation marker neopterin are elevated in the CSF of PHI subjects with peripheral neuropathy, while HIV RNA levels are not.

· Percent CD8+ T lymphocyte activation in CSF is elevated in PHI subjects with signs of peripheral neuropathy.

· [therefore] Host-derived immune activation in the nervous system during PHI may contribute to development of peripheral neuropathy and neurological dysfunction.

INTRODUCTION

· Peripheral neuropathy (PN) is a frequent complication of chronic HIV infection.

· Systemic and nervous system immune activation begins during primary HIV infection(PHI).

· Immune activation markers associate with the presence of neurological disorders in chronic infection.

· We investigated whether PN presents during PHI and if correlations exist between infectious and inflammatory markers and signs of PN during this stage of infection.

Signs of Peripheral Neuropathy Associate with Elevated Inflammatory Biomarkers in Blood and Cerebrospinal Fluid in Primary HIV-1 Infection

Samantha Wang*1, M Grill2, E Lee2, J Peterson2, E Ho3, E Jalbert2, E Sinclair2, R Price2, and S Spudich1
1Yale Univ Sch of Med, New Haven, CT, US; 2Univ of California, San Francisco, US; and 3Univ of Washington Sch of Med, Seattle, US
Background: Peripheral neuropathy (PN) is a frequent complication of chronic HIV infection, potentially mediated by pathologic effects of systemic and nervous system inflammation. Given that immune activation in the nervous system begins during primary HIV infection (PHI), we hypothesized that PN may be present during PHI, and that correlations may exist between levels of infectious and inflammatory biomarkers and signs of peripheral neuropathy in this setting.

Methods: Subjects within the first 12 months after transmission as confirmed by laboratory testing underwent clinical exams and analysis of blood and cerebrospinal fluid (CSF) including quantification of infectious and inflammatory biomarkers at the baseline visit of a longitudinal study. Subjects were categorized as PN if they had one or more of the following on a standardized clinical (NeuroMacro) exam by a neurologist: decreased position, vibration, pinprick or temperature sense at great toes, distal pain or paresthesia, absent or decreased ankle jerks, or hyporeflexia. Two subjects with diabetes were excluded from the study. Statistical analysis employed the nonparametric Mann-Whitney U test.

Results: Fifty-eight ART-naïve subjects (100% male) were evaluated at a median107 days post estimated HIV transmission; 20 (35%) met criteria for PN, 38 were considered no-PN (NPN). PN tended to be older than NPN subjects (median 39.5 vs 34.0 years, p = 0.054), but the groups did not significantly differ in terms of days post-HIV transmission at evaluation or blood CD4 and CD8 counts. Elevated CSF neopterin (p = 0.003) and MCP-1 (p = 0.006) and blood neopterin (p = 0.006) characterized PN as compared to NPN. There was a trend for CSF IP-10 levels to be elevated in PN (p = 0.09). Evaluation between presence of PN and of cell surface markers of activation in CD8+ T lymphocytes and monocytes in a subset of subjects revealed a higher percentage of activated CSF CD8+ T lymphocytes in PN (p = 0.0035). There were no differences between the 2 groups in levels of CSF and blood HIV RNA, CSF white blood cells, CSF protein, or ratios of CSF:serum albumin.

Conclusions: Signs of PN are present in one third of HIV-infected individuals at a median 3.5 months after viral transmission. Significant correlations between signs of PN and CSF measures of neopterin, MCP-1, and CD8 T cell activation as well blood levels of neopterin support the hypothesis that a component of PN during this early period is mediated by host immune responses to HIV infection

http://www.natap.org/2012/CROI/croi_154.htm