Peripheral neuropathy: diagnosis and treatment

This is one of two articles on peripheral neuropathy published in HIV & AIDS treatment in practice in March 2009. Click here for the first article: Peripheral neuropathy in people with HIV in resource-limited settings.

Diagnosis of sensory neuropathies

Peripheral neuropathy remains under-diagnosed in people with HIV – partly because patients don’t report milder signs of nerve damage, but more often because health care workers don’t ask about it.

Early detection and diagnosis of peripheral neuropathy is important in those people not yet on ART who already have the condition because HIV-related DSPN may improve on treatment (provided it doesn’t contain a d-drug - d4T or ddI). Furthermore, “early identification for ART-related peripheral neuropathy is important, since changing antiretrovirals early and assessing for treatable contributory conditions can halt progression of, and in some cases reverse, the signs and symptoms,” Dr John Brooks of the US Centers for Disease Control told HATIP.

The good news for those working in resource-constrained settings is that skin punch biopsies, EMG, nerve conduction studies or other specialised investigations aren’t usually needed to clinically diagnose DSPN or ATN (although if there are asymmetric neuropathies, marked motor problems, and situations where there is clear reason to suspect that some other factor is to blame for the symptoms, further investigations (or referral) for definitive diagnosis can be useful).¹

Diagnosis of HIV-related sensory neuropathy is based on clinically measurable signs and symptoms. One tool that may make this easier in resource-constrained settings is a simple questionnaire and brief examination called the brief peripheral neuropathy screening (BPNS) tool (download here).

The tool is straightforward. A trained healthcare worker asks the patient whether they have had any of the main symptoms of neuropathy (on both sides of the feet/legs), grades the severity of the symptoms, and then uses a reflex hammer to test ankle reflexes and a tuning fork to measure loss of sensitivity to vibrations in the great toe.

A clinical diagnosis of sensory neuropathy can be made when any of the bilateral neuropathic symptoms is present, plus either decreased ankle reflexes or vibration sense. The BPNS was developed and tested within US AIDS Clinical Trial Group studies and found to be nearly as specific (91%) for sensory neuropathy as a more extensive examination using a modified ‘Total Neuropathy Score’ administered by a neurologist, though it was not as sensitive (sensitivity of 46%).²

Subsequently, Dr Catherine Cherry and colleagues conducted a study in 80 people with HIV comparing a diagnosis using the BPNS to a diagnosis facilitated with computer-assisted sensory threshold testing and lower limb epidermal nerve fiber quantification of punch skin biopsies.³

The study excluded anyone with diabetes or any of the other common causes of neuropathy besides HIV and the d-drugs. 57 subjects reported symptoms of neuropathy, though only 40 had both symptoms and one of the two signs on the BPNS (and thus a clinical diagnosis). These 40 also had significantly decreased temperature or vibration sensitivity thresholds and lower nerve fibre densities than those without a sensory neuropathy diagnosis. However, no significant loss in nerve fibre density or changes in sensitivity thresholds could be found in the 17 with symptoms but no signs of neuropathy as defined by the BPNS.

Cherry et al concluded that the BPNS can accurately detect those HIV-infected individuals with the greatest  degree of peripheral nerve dysfunction and pathology, and stressed that it is “is simple enough to be applicable in resource-limited settings."

However, from a patient advocate’s perspective, one has to wonder about those 17 subjects who reported symptoms without loss of reflexes. In a clinical setting, Cherry et al wrote those with “isolated neuropathic symptoms require appropriate follow-up.” Indeed, dismissing complaints of pain simply because there are no signs of neuropathy, may not be the best way to provide compassionate and palliative care, as other studies have noted that even mild pain and symptoms have a negative impact on a person’s quality of life.

The WHO definition of palliative care stresses the “early identification and impeccable assessment and treatment of pain.” Consequently, a variety of other tools have been developed to quantify the type and severity of pain that patients are experiencing. Notably, a study conducted in South Africa by Hitchcock, Meyer and Gwyther used the Neuropathic Pain Diagnostic Questionnaire (DN4) (download 824kb pdf version here) and adapted a scoring system called the Brief Pain Inventory (BPI) (download pdf version here) to gauge how much pain interfered with daily functioning.^{4, 5} 

Talking about pain

With training and support, nurses and other clinicians should be able to administer these simple tools for diagnosis and for characterising pain — without expensive equipment.

“That being said, why is it that we seem to come to the diagnosis so late too often? I would posit at least two reasons: patients may have a high threshold for reporting signs/symptoms and we do a poor job at routinely assessing, screening and monitoring for peripheral neuropathy,” said Dr John Brooks.

“I have been talking with the clinical officers (COs) here [in western Kenya] about the same issue, sadly all too common,” Dr Ana-Claire Meyer of the University of California San Francisco and Kemri told HATIP.  “I personally think the problem is that the COs do not do a sensory exam, ignore the pain, and base their staging of neuropathy on the motor aspects which generally come later in the progression of the disorder… one thing I was thinking was to convince COs to start using their tuning forks.”

This may be a harder sell than she thinks. This writer knows dedicated HIV doctors in South Africa who would be hard-pressed to find their tuning forks.

But the key problem may be something much simpler. As Dr Julia Downing of the African Palliative Care Association (APCA) said in an earlier HATIP clinical review, healthcare workers may be very good at providing supportive care, but they are often uncomfortable coming out and asking about pain.

“The challenge in Africa is that many clinicians do not look at pain as something they need to look out for from their patients. It is not routine that clinicians will ask about the presence of pain during the clinical assessment and because of this, they do not identify the pain,” Dr Henry Ddungu, also of APCA, recently told HATIP.

This isn’t unique to Africa. In one multicentre study in France, doctors underestimated the severity of pain in 52% of 135 patients with HIV reporting pain — especially when it was moderate or severe or when the source of the pain could not be identified.⁶  85% were under-medicated according to the WHO guidelines.

Nor is this limited to the world of HIV. The following comes from an article on peripheral neuropathy in the journal Diabetes & Metabolism.⁷

“Listening to the patient… is an essential but sometimes neglected aspect. In fact, in the first stages of neuropathy, complaints are moderate, since the symptoms quite often emerge progressively, and are either ignored or initially incorporated by the patient into his/her everyday life. The patient does not complain much and the doctor listens distractedly.”

So the first hurdle is simply getting healthcare workers to routinely ask about/or screen for pain. But although it’s brief, it may be difficult to convince nurses working in packed clinics to routinely administer the BPNS to every patient with HIV.  However, it should be possible to start including at least one targeted question about the symptoms of peripheral neuropathy into the examination.

Of note, Dr Gretchen Birbeck performed a validation study in 77 people with AIDS using a single question on peripheral neuropathy symptoms (“do you have symptoms of tingling, burning, or numbness in the feet or hands?”) and found that even though the question cannot assess for important signs of neuropathy, its findings correlated pretty well with the BPNS.⁸  The single question neuropathy screen (SQNS) was 95.7% sensitive, 80% specific, with 88.2% positive and 92.3% negative predictive value.

One of the strengths of a single question screen is that it can be incorporated into a team approach that addresses the needs of patients and their families. Given the need to respond rapidly to the development of peripheral neuropathy, it might [in fact] be better to have adherence counsellors, peer supporter, or pharmacists who see the patient more often to routinely ask this question — especially soon after people start on d-drug containing ART — and refer those with positive responses for diagnosis with the BPNS by someone who’s good with a tuning fork.

A key benefit of engaging the adherence counsellor or peer supporter, or community caregivers is that they can act as an advocate for the patient in pain — making sure the need for further assessment comes to the attention of the healthcare worker.

Treating HIV-related sensory neuropathy

The first step in treating sensory neuropathy is to treat or remove its cause or causes.

Start or optimise ART: For those with DSPN (not yet on ART or failing on their first line regimen), this means starting effective antiretroviral therapy, which has been shown to reduce symptoms and reverse pathology for at least a while, in at least some cases (though clearly not all).

Manage other causes: The initial assessment should have included a complete history and assessments for co-morbidities and other possible causes of neuropathy such as diabetes and alcoholism and known nutritional deficiencies. If any of these exist, they must be addressed. Of note, a Cochrane meta-analysis of available studies suggests that data supporting the use of B vitamins to treat neuropathy are mostly lacking, except in cases where there is a clear nutritional deficiency, such as thiamine deficiency which is common in alcoholics.⁹

In addition, 50 mg daily pyridoxine (vitamin B6) must be given to people on TB treatment or preventive therapy to prevent isoniazid-induced neuropathy, and the pyridoxine dose should be increased to 100 mg if neuropathies develop at a lower dose. But even though coadministration of pyridoxine is consistently recommended in guidelines whenever isoniazid is used, pyridoxine stock-outs seem surprisingly common.

“Why on earth is pyridoxine so hard to find in resource-poor settings?” asked Dr Liz Corbett of the London School of Hygiene and Tropical Medicine, who is based in Harare, Zimbabwe. “It should be dirt cheap and given with TB treatment as standard practice in HIV prevalent settings, but somehow peripheral neuropathy doesn’t seem to make it high enough up the list to hit the radar screen.”

Consider alternative medications for d-drug related ATN: Acute ATN may reverse with discontinuation of the causative drug. However, there can be a ‘coasting effect,’ where symptoms may even get worse for 4-8 weeks after stopping the drug.¹⁰

“We keep a close eye on potential neuropathy by asking patients about it, and we change them off stavudine if they do. In the majority of people the neuropathy goes away or stabilises, though for a small percentage it gets worse,” said Dr Jonathan Mermin, of the CDC in Kenya.

Dr Ana-Claire Meyer, who is also in Kenya, told HATIP that this is indeed what some of the most expert clinicians do, and what the national guidelines recommend. But giving up d4T is something many clinicians do not want to do. 

“What I have found through chatting and anecdotal observation is that no one wants to change therapy for mild peripheral neuropathy, which makes sense when you have limited alternatives and it is [occurring in] nearly half of your population. But they often miss switching their patients for moderate neuropathy and don't really notice a problem until they end up with someone with severe neuropathy that they can't do much about.”

“One of my missions while I am here is to come up with a way to identify those people who have a progressing neuropathy before it gets so severe that they cannot walk and are functionally impaired, [to develop] a simple way to test when we should change therapy. [If we could] convince COs to start using their tuning forks: once there is no vibratory sensation at the toes, you have tried one month of multivitamins (B6 and B12 if you have it), and checked a fasting glucose, add in a pain/functional assessment scale... then switch therapy to be off d4T.”

While this is an interesting algorithm to evaluate in a clinical study, clinicians and patient advocates should also remember that sensory neuropathy can be irreversible if left for too long. In many settings, the only real alternative is to switch to AZT, as tenofovir and abacavir are still considered to be too expensive for more widespread use.

“In Malawi we have a protocol to deal with the problem that includes dose reduction of stavudine (now obsolete as all patients now receive 30mg twice daily), amitryptiline and NSAIDs,” said Dr Anthony Harries, who is now with the International Union Against Tuberculosis and Lung Disease. “ If very severe, we then have the option of changing to AZT. Stavudine is the culprit, but at the moment in Malawi we have no real alternative for our first line regimen.”

This is one of the most glaring disparities between the standard of HIV care in industrialised world, which has largely abandoned d4T, and what is given to those who can afford little else.

The World Health Organization has already attempted to limit the burden of toxicity associated with d4T by recommending that the dose be reduced to 30mg twice daily where no alternative to d4T is available, but some countries continue to use stocks of d4T-containing fixed dose combinations containing a 40mg dose of d4T.

"d4T toxicity is a critical aspect of ART scale up and even if countries continue to phase out its use - which seems to me will be a slow process in a majority of them, particularly in rural areas - the demand for peripheral neuropathy treatment will remain," Dr Marco Vitória of the World Health Organization told HATIP.

Symptomatic treatments

Perhaps the most contentious issue is whether any pharmacological treatment can help relieve painful symptoms of neuropathy.

The WHO pain analgesic ladder is a stepwise approach to pain management related to pain severity — beginning with simple analgesics (paracetamol or NSAIDS), then adding a weak opiate, such as codeine, moving onto stronger opiates if that doesn’t work. But, these seem to be ineffective for neuropathic pain, at least when given on their own. This may even be true of the more potent opiates.

“In our experience morphine is not very good for neuropathic pain,” said Dr Harries.

So many neurologists and palliative experts recommend adding a variety of adjuvants, including topical analgesics (lidocaine, low dose capsaicin cream, 0.075%, topical chloroform), but especially the tricyclic antidepressants (amitriptyline, desipramine, etc), and the anticonvulsant agents (including carbamazepine but especially the new drugs, gabapentin and lamotrigine). Some of these drugs have proven to be effective in treating other neuropathic pain, such as diabetic peripheral neuropathy, which has led to the development of the Analgesic Ladder for Neuropathic Pain.

Unfortunately, clinical evidence in support of using these adjuvants in HIV disease is quite weak.

“This is one of the areas of HIV and treatment which abounds with myths and legends with regards to its treatment. And most of the commonly used treatments, in fact, work not at all,” said Dr Steven Miller of the Innovir Institute in Johannesburg, South Africa, speaking about management of peripheral neuropathies at the International HIV Conference in Botswana in 2006.

Case in point: the tricyclic antidepressants, including desipramine, doxepin, imipramine, nortriptyline, but especially amitryptiline, are widely used for peripheral neuropathy with other causes. Doses usually start at around 25-75mg at night, and titrated up (if side-effects are tolerated) to a maximum dose of 300 mg/day.

But at least two randomised controlled studies show that amitryptiline is no better than placebo in people with HIV and sensory neuropathy.^{11, 12}  

In the first study, Kieburtz et al compared amitriptyline, mexiletine and placebo in 145 patients. The second study, by Shlay et al was also a three-way comparison between amitriptyline, acupuncture and control point (feigned acupuncture) in 250 people with HIV-associated peripheral neuropathy. All groups improved somewhat, but there were no significant differences between them. The authors speculated that the control point did have some beneficial effect and thus was not a true placebo. But there may have been other problems with these studies which render their conclusions suspect.

“The amitriptyline trials were not well designed: they were stopped early and underpowered,” Professor Brew told HATIP. However, those studies took place over 10 years ago, and no one’s bothered to re-examine the drug’s usefulness for this indication.

Meanwhile, other drugs used for other causes of neuropathic pain, the anticonvulsants carbamazepine and phenytoin, cannot be given to patients who are taking antiretroviral therapy because they reduce blood concentrations of efavirenz/nevirapine, and protease inhibitors.¹³

When he was speaking in Botswana, the only symptomatic treatment that Dr Miller showed any hope for were the newer anticonvulsants.  “Consistently in the clinic we see that the only compounds which consistently give relief are the newer anti-convulsants: lamotrigine, gabapentin, topiramate for some people,” he said. He added that there are generic preparations of lamotrigine, making it more affordable.

Data on these drugs since that time have been rather mixed.

Early data were promising for lamotrigine (25 mg alternate days for two weeks then dose escalation over seven weeks to a target dose of 400 mg/day), though there was a very high drop-out rate in the study drug arm.¹⁴  A subsequent randomised study went up to 400 mg per day (600 mg if another medication which might lower lamotrigine concentrations was used, such as rifampicin), followed by a maintenance phase for HIV-associated painful sensory neuropathies.¹⁵ But it could find no clear benefit over placebo in pain scores at the end of the maintenance phase of the study. The authors did report a significant difference in some indicators, such as the slope of improvement for people with ATN and perception of improvement.

However, a recent Cochrane review of the performance of lamotrigine for neuropathic pain (from various causes) in a large number of studies concluded that the routine use of the drug “is unlikely to be of benefit in chronic pain conditions included in this review, or neuropathic pain (pain due to nerve damage).”¹⁶  Furthermore, the authors noted that the incidence of rash on the drug was “not trivial.”

Gabapentin looked good in a small randomised, double-blind placebo-controlled study in 26 patients with HIV sensory neuropathy.¹⁷ Fifteen patients received gabapentin at 400mg per day before being increased to 1200mg per day over 2 weeks. This dose was maintained or increased to 2400mg per day if not beneficial. There was a significant decrease in pain score in the gabapentin group (-44%) but not the placebo group (n = 11; -30%) — initially at least. It also helped people sleep, in fact, somnolescence was reported in 80% of the gabapentin group. A review in 2003 concluded that the drug was effective for a number of types of neuropathic pain, though doses up to 3600 mg/d may be needed in some patients.¹⁸

Unfortunately, at the World AIDS Conference in Mexico City in 2008, Dr David Simpson of Mount Sinai Hospital in New York presented a large randomised, double-blind, placebo-controlled, multicentre trial of the very closely related pregabalin for HIV related peripheral neuropathy, which proved rather disappointing.¹⁹

151 subjects were randomised to each arm. Pregabalin doses were titrated from 150 mg to 600 mg/d BID over the course of two weeks, and then continued at their dose (average 385.7 md/d) for 12 weeks. Surprisingly a large proportion of study participants in both arms felt better. 82.8% of pregabalin recipients rated themselves in one of 3 “improved” categories. So did 66.7% of placebo patients. This difference was not significant. Nor were there any difference in mean pain scores after the first couple of weeks on treatment.

With so much conflicting evidence, the experts don’t always agree on what to recommend. This led to something of a debate on the HATIP panel discussion blog site:

“I have found that amitriptyline does work; so does valproic acid. Opiates also work,” said Professor Bruce Brew of the University of New South Wales.

"I think it is important to consider the principles of pain management, [and] that amitriptyline is an adjuvant drug in managing neuropathic pain. It is not in itself an analgesic. It should be combined with an analgesic to provide pain control, so morphine in severe pain plus amitriptyline in low dose is the combination that we use," said Dr Liz Gwyther of the Hospice Palliative Care Association of South Africa.

“We need to be very careful as the placebo effect is significant with pain treatments. Our anecdotal impressions that drugs work in individuals may be demonstration of placebo action not drug effect. I have stopped prescribing amitriptyline for HIV PN as it was demonstrated by two reasonable quality studies to be no more effective than placebo,” Dr Sarah Cox, of London’s Chelsea and Westminster Hospital told HATIP. “Opioids have not yet been trialled in HIV PN but do have an effect in neuropathic PN and are now my first line.”

“The randomised clinical trials do say that nothing much seems to work for peripheral neuropathy in HIV (whether due to ARVs or HIV itself), but I personally find that it never hurts to try amitriptyline and a multivitamin (all we have here) and switch off offending meds if alternatives exist. Sometimes it works (whether [it’s a] placebo or not),” said Dr Ana-Claire Meyer.

“My 2 cents is that whereas we must respect the evidence in clinical trials as the gold standard, we still must take care of patients and provide the best possible therapy, even if empirically driven. We are working hard on developing and testing better meds,” Dr David Simpson told HATIP.

In fact, Dr Simpson has recently conducted a study that found positive results (a mean 22% reduction in pain scores) for 12 weeks from using a single very high dose capsaicin patch.²⁰  This uses doses much higher (8% capsaicin) than available in creams (0.025% to 0.075% capsaicin). The patch essentially works by desensitising the nerves. The patch itself initially causes pain and is put on following a one-hour application of a topical anaesthetic. This sounds as though it would be a bit difficult to administer in a busy clinic setting, and the patch isn’t available yet.

A number of open label studies have reported subjective reductions in pain using the anti-oxidant acetyl carnitine (L-carnitine). For instance, in an open label study, Hart et al  reported that LAC can reverse the loss of nerve fibres from the skin, and reduce mitochondrial toxicity and improve the symptoms of peripheral neuropathy after six months of treatment.²¹

Howver, in the most recently published study "changes were not observed in objective measures of IENF [nerve fiber] density or mtDNA levels, providing little objective support for use of ALC in this setting," wrote the authors.²² There were improvements in symptoms, but again, this was not a placebo controlled study.

A final approach which is often more readily available — though not legally -  is medical marijuana. Several studies have reported positive results from using smoked cannabis for neuropathic pain.^{23, 24, 25, 26, 27}  For instance, Abrams et al conducted a randomised clinical trial that found that smoked cannabis reduced daily pain by 34% (median reduction; IQR = -71, -16) vs a 17% reduction (IQR = -29, 8) on placebo (p = 0.03). Greater than 30% reduction in pain was reported by 52% in the cannabis group and by 24% in the placebo group (p = 0.04). The first cannabis cigarette reduced chronic pain by a median of 72% vs 15% with placebo (p < 0.001). “Smoked cannabis was well tolerated and effectively relieved chronic neuropathic pain from HIV-associated sensory neuropathy,” wrote the authors.

The approach has its proponents.“I just want to make the case for medical marijuana to sound stronger and clearer,” Dr Zvi Bentwich, of Rosetta Genomics in Israel, told HATIP. “For the last 10 years I have been involved repeatedly with patients in whom this worked quite impressively! So much so that we succeeded in convincing the Ministry of Health, to adopt it as an official policy once each individual case was brought before a special committee that then decided whether to approve it or not.”

But in settings where governments don’t want to agree to make opiates available, despite their proven benefits for pain, suggesting marijuana is opening a can of worms, to put it mildly. The neurocognitive side-effects of the drug would also be a concern. Still it is hard to begrudge this approach to someone whose pain keeps them awake all night.

But more will need to be done for those patients who must live with pain.

"In contrast to pain management in general, neuropathic pain requires a more rigorous approach, involving a multidimensional bio-psycho-social approach that involves the use of appropriate pharmacological agents, exercise, behavioural therapy, attention to sleep quality, patient education and return to work if possible," wrote Hitchcock, Meyer and Gwyther in their assessment of neuropathic pain in South Africa.²⁶

In industrialised settings, people with peripheral neuropathy that won't heal are referred to physical and occupational therapists. Experts trained at offering people supportive care are rarely if ever available in resource-limited settings. But perhaps countries should begin training more of these cadres of healtchcare workers, as it is evident that the demand for their services will be growing.

Prevention: avoiding the problem in the first place

Given the lack of adequate treatment options for sensory neuropathy, the best approach would be to simply try to avoid the problem altogether.

Both the CHARTER and the ALLRT studies presented at CROI concluded that earlier antiretroviral treatment, at higher CD4 cell counts, would be the best strategy to prevent much of the sensory neuropathy directly related to HIV.

Avoiding drug-related neuropathy in resource-limited settings is more of a challenge given the few therapeutic options available. And yet some countries are doing this.

“We are lucky that the policy here in Indonesia now is to start with AZT, and only change to d4T in case of anaemia. However, once the change has been made, it can be difficult to get doctors to agree to changing back,” Chris Green of the Spiritia Foundation told HATIP.

In settings where first line AZT is not an option, employing an algorithm such as the one suggested by Dr Cherry (age over 40, height over 1.70 cm should start with AZT) seems a prudent prevention approach (see part one). Perhaps advanced disease should be added to this algorithm given that several studies indicate a higher risk of neuropathy in those with lower CD4 cell counts and high viral loads.

“Ideally we should not be using d4T especially in people who have been treated before for TB, where incidence of peripheral neuropathy is huge,” Dr Liz Corbett told HATIP.

Indeed, d4T should be avoided in anyone with major pre-existing comorbidities that may cause neuropathy (such as hepatitis C).

Clearly, there should be a work-up before going onto ART to detect DSPN and make certain that someone with sensory neuropathy is not put on a d-drug containing regimen.

Increasing patient awareness that they should report the first signs of neuropathy should also help. But this can cut both ways. Advocacy and treatment literacy groups could have perhaps done more to educate people to complain earlier, but as Zachie Achmat’s case study in part one suggested, there may be a tendency not to want to scare already reluctant people away from life-saving treatment.

“I did not report my side effects for two reasons. Both of them were wrong. One, I did not want government or AIDS denialists to misuse my side effects. And, I did not want to believe that my medicines could go wrong,” he said in the TAC report.

The TAC report clearly recommends that “because there is no cure for neuropathy yet, the best choice is to stop using d4T and change to another drug if this is possible…. If there are no other treatment choices, and you are otherwise doing well, it may be better to stop your treatment for a period until there are new treatment choices.”

Although TAC recommended this should only be done following a consultation with a doctor, it is clear that if clinicians don’t begin finding ways make certain that people at high risk of neuropathy aren’t being put on d4T (or ddI), patients (and patient advocates) will increasingly make the decision to dump the drug — even when they may not be at much risk of neuropathy.

“We recommend anyone on d4T who experiences any 'pins and needles' to press for a change,” said Green, who is a treatment educator. “And if they have been on d4T for more than six months, have a normal Hb and a CD4 count above 200, we encourage them to press for a change. If the doctor is unsupportive ("you're doing well on that regimen, don't change it") we suggest they report peripheral neuropathy (even if they haven't experienced it) because the doctor can't tell...”

Resources

Where there is no neurologist: download book by following this link (3.94mb pdf) 

World Federation of Neurology:

http://www.wfneurology.org/default.php

WHO & WFN’s Atlas of Country Resources for Neurological Disorders:

http://www.who.int/mental_health/neurology/epidemiology/en/

The Neuropathy Association, an non-profit begun in NYC by people with neuropathy and their families with approximately 120 support groups throughout the US and abroad providing public awareness, patient support, education and advocacy.

http://www.neuropathy.org

The Neuropathy Trust

http://www.neurocentre.com