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Primary Care Corner with Geoffrey Modest MD: Diabetic Neuropathy Guidelines

14 Mar, 17 | by EBM

By Dr. Geoffrey Modest

The American Diabetes Association just came out with their position paper on diabetic neuropathy (see DOI: 10.2337/dc16-2042). I will limit my points to type 2 diabetes, though type 1 is covered in this paper

Summary of points:

  • Diabetic neuropathy is a diagnosis of exclusion: diabetic patients may well have non-diabetic causes of neuropathy that should be pursued.
  • 50% of diabetic neuropathies are asymptomatic. It is important to assess for them, for example, to decrease the likelihood of significant foot trauma, improve symptoms and quality of life, and decrease sequelae
  • Prevention of neuropathy:
    • Data are largely for distal symmetric polyneuropathy (DSPN) and for cardiovascular autonomic neuropathy (CAN).
    • Best evidence is for those with type I diabetes where it is important to optimize glucose control as early as possible: 78% relative risk reduction with enhanced diabetes control
    • Risk reduction seems to be less in glucose control with type 2 diabetes, perhaps in part reflecting the different pathophysiology and comorbidities: type 2 diabetes tends to be associated more with overweight, polypharmacy, older age; but also many patients with type 2 diabetes have been prediabetic or diabetic for many years prior to diagnosis. In fact 10-15% of newly diagnosed diabetes already have evidence of DSPN.
  • Distal symmetric polyneuropathy (DSPN)
    • Most common (75% of all neuropathies). Defined clinically by symptoms or signs. Electrophysiologic testing or neurology referral are rarely needed.
    • 50% of people have DSPN after 10 years of disease, and is associated with levels of glycemia, height (perhaps as a proxy of nerve length), smoking, blood pressure, weight, and lipids
    • Those with predominantly small-fiber neuropathy present with pain, burning or tingling feeling, sometimes with a shooting sensation. There may also be hyperalgesia. And this may be found in 10 to 30% of patients just with impaired glucose tolerance. Those with large fiber involvement have numbness, tingling without pain, and loss of protective sensation
    • DSPN is associated with foot ulceration/amputation risk (important to assess regularly and refer to podiatry early), Charcot neuro-arthropathy, unsteadiness and falls (should assess gait/balance, though minimal data to support), and quality of life (DSPN can really affect quality of life, and is associated with depression, anxiety, medication nonadherence)
    • Patient should be assessed annually, those with type I diabetes should be assessed starting 5 years after the diagnosis. Consider assessing those with glucose intolerance as well. Assessment should include temperature or pinprick sensation (small fiber function), vibration sense with a 128 Hz tuning fork, proprioception, ankle reflexes, and 10-g monofilament (large fiber function), and the 10 g monofilament also helps assess risk for ulceration and amputation
    • Important to rule out the myriad of other causes of neuropathy, including vitamin B12 (see blog which notes the overall increased incidence of B12 deficiency in diabetics) as well as infections (HIV, hepatitis B, Lyme), thyroid disease, paraproteinemia, alcohol or medications, heavy metal poisoning/work-related exposures, etc.
    • Symptom management: consider pregabalin or duloxetine as the initial​ approach. Though gabapentin may also be used (they do comment that pregabalin has a more linear, dose-proportional absorption and more rapid onset of action). They also note that tricylcic antidepressants (TCAs) are effective but beware of adverse effects. There seems to be some efficacy for the selective norepinephrine/serotonin reuptake inhibitor venlafaxine (dose 150-225 mg/d), mechanistically similar to duloxetine. Opioids should be avoided, given the risks of addiction, as either first- or second-line agents. However, tapentadolextended release, which has analgesic effects both through the m-receptor and noraderenaline reuptake inhibition, is FDA-approved, though there are systematic reviews/ meta-analyses which challenge its effectiveness. And some patients do seem to respond to adding low doses of these opioids in combo with the above agents).
  • Autonomic Neuropathies
    • Cardiovascular autonomic neuropathy (CAN)
      • May be present prior to a formal diagnosis of diabetes, ​is found in up to 60% of patients after 15 years, and is an independent risk factor for cardiovascular mortality (2+ fold increased risk, controlling for other risk factors), arrhythmia, silent ischemia, any major cardiovascular event, and myocardial dysfunction.
      • May be asymptomatic early and detected only by decreased heart rate variability with deep breathing, esp with EKG monitoring (see which discusses ways to measure CAN), but can include symptoms of light-headedness, weakness, palpitations, fainting/syncope. Exam may show resting tachycardia, or orthostatic hypotension without compensatory increase in pulse.
      • Symptom management:
        • Optimize glucose control (to prevent or delay CAN, though this is most evident in type 1 diabetes, but some benefit in studies with type 2), reinforcing lifestyle interventions both in prediabetics and diabetics prior to developing CAN. For those with orthostatic hypotension, can use both nonpharmacologic treatments (exercise, assuring adequate fluid intake/volume repletion) and meds (fludrocortisone, midodrine)
      • Gastrointestinal neuropathies can be anywhere in GI tract, from esophageal dysmotility to gastroparesis to lower GI symptomsof diarrhea, constipation, incontinence
        • Gastroparesis
          • ​May be present in 1% of type 2 diabetics, from a community-based study (higher in type 1 diabetes). Can affect glucose variability and unexplained hypoglycemia because of changes in food absorption. [my experience suggests that gastroparesis may well be more common than this]
          • ​Consider checking for symptoms in those with other microvascular complications  (“C” recommendation), exclude other causes (g. opiates, GLP-1 agonists (grade “C” recommendation”) [and, I would add, considering decreasing dose of metformin, esp since 500mg once a day or even 250mg seems to add substantial clinical benefit], and can do gastric emptying studies to document (grade “B” recommendation”) [I would also add that gastroparesis is usually evident by history, and that it is probably useful just to try the nonpharmacologic and even pharmacologic therapies empirically]
          • Treatment includes eating multiple small meals/d, decreasing dietary fat (which also causes gastroparesis), decreasing other drugs than those mentioned above which can make it worse (g. anticholinergics, pramlintide and ? DPP-4 inhibitors), and one can prescribe metoclopramide, the only FDA-approved agent, though it is associated with extrapyramidal symptoms, acute dystonic reactions, akathisia, tardive dyskinesia, acute dystonic reactions) and is recommended to use for only 5 days (which is problematic for such a chronic condition, and I have patients on this agent for much longer, with frequent assessments by me for the above adverse reactions)
        • Urogenital neuropathies includes bladder and sexual dysfunction, the latter including erectile dysfunction (3x more common in diabetics, may involve combo of autonomic neuropathy, vascular disease, and I would add psych issues, such as depression, stress, etc.) and/or retrograde ejaculation in men and sexual dysfunction in women (decreased sexual desire, increased pain with intercourse, decreased sexual arousal, inadequate lubrication).
          • Bladder dysfunction should be assessed in those with recurrent urinary tract infections, pyelonephritis, incontinence, palpable bladder
          • Recommendations: consider screening men with other forms of neuropathy for ED (grade C) and women with other forms of neuropathy for lower urinary tract symptoms and sexual dysfunction (grade E)
        • ​Sudomotor dysfunction includes dry skin, anhidrosis, or heat intolerance, and occasionally gustatory sweating (food consumption, and occasionally just the smell of food, leading to sweating of head and neck area)
        • Other neuropathies:
          • Mononeuropathies: especially of median, ulnar, radial and common peroneal nerves. cranial neuropathies are rare but include cranial nerves III, IV, VI, VII and usually resolve spontaneously over months
          • Diabetic radiculoplexus neuropathy (also called diabetic amyotrophy): unilateral thigh pain, weight loss, followed by motor weakness. self-limited (though I have a type 1 diabetic patient with this in one of his shoulders)


  • They do promote pregabalinand duloxetine as their primary go-to’s. I personally do not use them till much later in the pyramid of meds, partly because they are relatively new agents (and the older ones have stood the test of time), partly because there are mechanistically similar drugs available (gabapentin and venlafaxine), partly because these are non-generic and quite expensive, and partly (e., a lot) because they require prior approvals from many insurers.​
  • In the vast majority of cases, I have prescribed tricyclic antidepressants with great success. Although amitriptyline is the one used the most overall, it has the most adverse effects. I prescribe either desipramine or nortriptyline, which work as well and with many fewer adverse effects (desipramine has the fewest, but nortriptyline is helpful to take at night if the patient has trouble sleeping). The usually effective doses are desipramine 25-50mg (occasionally 75), or nortriptyline 10-50mg. Not sure why, but the 2012 ADA guidelines (see Diabetes Care 35:2451–2458, 2012) found that there was no significant difference between amitriptyline, duloxetine and pregabalin, though the current guidelines seems to have booted TCAs off the top tier (they are generic with long history of use and knowledge of long-term adverse effects, both plusses, which does raise the question to me of adverse drug-company induced bias….)
  • Gabapentin is used a lot for neuropathy, though the studies have been mixed (and the drug company has been taken to task for withholding large, unpublished negative studies).  And in my limited experience, is associated with many adverse effects and requires a very slow titration up.

So, a pretty useful compilation of diabetic neuropathies, along with reasonable approaches (though there are no medications which actually treat the neuropathies, only ameliorate the symptoms). My own approach is that anyone with any mono or polyneuropathy should be checked for diabetes (for example, they limit the cranial nerve neuropathies to the facial and extraocular movement nerves, though I have seen a couple of diabetic patients with anosmia.) Also, they do not comment that it is not so uncommon in diabetics to have radiculopathies typically on the trunk which simulating zoster clinically and respond to the above meds.

See for a meta-analysis of the meds used for DSPN, finding that SNRIs, capsaicin, tricyclics and anticonvulsants work for short-term pain control (seemed that SNRIs and TCAs were best). Opiates were last by a fair margin.

Primary Care Corner with Geoffrey Modest MD: vitamin B12 and diabetic autonomic neuropathy

23 Feb, 17 | by EBM

By Dr. Geoffrey Modest

A recent Danish study found that vitamin B12 deficiency was associated with diabetic cardiovascular autonomic neuropathy, CAN (see Hansen CS. J Diabetes Complic. 2017; 31(1); 202)


  • 469 type II diabetic patients were screened for CAN by several measures, as well as for peripheral neuropathy.
  • Mean age 59, 60% male, diabetes duration 10 years, 5% excessive alcohol consumption, 12% smokers, BMI 32, blood pressure 132/82, 6% on vitamin B12 supplementation (though 16% in those in the highest B12 quartile), 80% on lipid-lowering drugs, 75% on metformin, 4% on PPIs alone and 10% on the combination with metformin, 40% on insulin
  • CAN was measured after a 5-minute supine resting period:
    • Heart rate variability (HRV)
    • 3 tests assessing cardiovascular autonomic reflexes:
      • Lying-to-standing test
      • Deep breathing test (E/I ratio), a measure of heart rate variation during deep breathing [which is affected by an abnormality in the parasympathetic nervous system]
      • Valsalva
    • Peripheral neuropathy was measured electronically by vibration sensation


  • B12 level varied from the lowest quartile mean of 190 to the highest quartile of 486 pmol/l
  • Serum levels of B12 were significantly lower in those on metformin or proton pump inhibitors, p <0.001.
  • Higher level of B12 were significantly associated with a lower odds ratio of CAN, p=0.04
  • A 25 pmol/l higher level of vitamin B12, adjusted for age, sex, diabetes duration, and alcohol consumption, was associated with:
    • 6% lower level of CAN diagnosis, odds ratio 0.94 (0.88-1.00, p= 0.034)
    • An increase of E/I ratio of 0.21% (p= 0.038)
    • A decrease in resting heart rate of 0.25 bpm (p= 0 .025)
  • No association between B12 levels and decreased vibration/peripheral neuropathy


  • Cardiovascular autonomic neuropathy is very common in patients with type II diabetes, ranging in prevalence from 20 to 65% and increasing with length of diabetes. CAN is also an independent predictor of cardiovascular mortality and morbidity. But CAN may well be overlooked clinically until a patient is symptomatic, typically late in its course.
  • Vitamin B12 deficiency is also quite common in diabetics, with estimates from 2-33%, potentially mediated in part by the use of metformin through a not-so-well understood mechanism. This relationship is both metformin dose-dependent and treatment duration dependent, and may be measurable in as little as 4 months after the onset of use. In addition, the frequent use of proton pump inhibitors may decrease vitamin B 12 levels. Another potential and common mechanism for B12 deficiency in older patients is the age-associated decrease in several digestive enzymes, leading to the inability to liberate B12 from foods thereby decreasing its absorption (studies have found b12 deficiency in 10-25% of elderly, typically asymptomatic).
  • This was an observational study, therefore it is difficult to attribute causation. In addition, there is no compelling evidence that correcting B12 deficiency decreases the likelihood of CAN [one Indian population-based study of healthy elderly showed that B12 supplementation in those deficient led to normalization of decreased heart rate variability (see Sucharita S. Autonoom Neurosci 2012; 168 (1-2); 66)].
  • Also, the effect of B12 deficiency on CAN in the study was not particularly large. Part of this is that there were very few patients (0.6% of their population) who they defined as having vitamin B12 deficiency (that being below 125 pmol/l in this study, though many consider the cutpoint to be <148 pmol/l, which translates to <200 pg/ml), so the lowest quartile had lots of patients who were probably not actually B12 deficient. And the likely reason for the low B12 deficiency rates was that the standard clinical practice in that area was to check B12 levels in patients every other year. They did not test for methylmalonic acid or homocysteine, which might have been relevant in those with borderline B12 deficiency (35% had B12 levels between 125 and 250 pmol/l, though others consider borderline to be between 148 and 221 pmol/l​, or 200-300 pg/ml). Also, the fact that the effect was particularly evident for the E/I ratio with deep breathing suggests that a parasympathetic abnormality may predominate, and parasympathetic denervation is in fact typically the first abnormality in CAN, leading to increased sympathetic tone.
  • Of note, several different studies, but not all, show that those with peripheral neuropathy associated with B12 deficiency do improve with B12 supplementation, though the degree of improvement tracks inversely with both the extent and duration of disease.

So, my take on this is that given the clear importance of vitamin B12 for several aspects of health (neurologic, psychiatric, hematologic), and that some of these manifestations may be pretty subtle/very hard to detect early on, I personally think it makes sense to check vitamin B12 levels in the elderly as well as those on metformin and PPIs. And now, perhaps more so in diabetics overall, perhaps when they reach the ripe old age of 50 or so.

Primary Care Corner with Geoffrey Modest MD: Fluoroquinolone Warning

16 Dec, 16 | by EBM

By Dr. Geoffrey Modest

There was another FDA warning recently, this time regarding systemic fluoroquinolones (ciprofloxacin, levofloxacin, etc.), leading to a boxed warning, the FDA’s strongest warning (see for the summary, and for the full report).


  • Fluoroquinolones are associated with disabling and potentially permanent adverse effects on tendons (tendinitis, tendon rupture), muscles (muscle weakness or pain), joints (joint pain or swelling), peripheral nerves (peripheral neuropathy), and the central nervous system (anxiety, depression, hallucinations, suicidal thoughts, psychosis, confusion). Other adverse effects include worsening of myasthenia gravis, skin rash, sunburn (photosensitivity/phototoxicity), irregular heartbeat (including prolonged QT interval), severe diarrhea (they are the leading cause of Clostridium difficile-associated diarrhea). Multiple problems can occur in the same patient. The peripheral neuropathy may be irreversible.
  • Therefore, fluoroquinolones should only be used in patients where no other treatment options are available for acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and uncomplicated urinary tract infections. Also for serious bacterial infections where the benefits outweigh the risks.
  • The prior warnings for tendinitis, tendon rupture, and worsening of myasthenia gravis has been extended by the above problems.
  • Side effects may occur within hours to weeks after starting the fluoroquinolone and continue an average of 14 months to as long as nine years after stopping the medicines. (Though, as noted, some may be irreversible)
  • The majority (74%) of reported cases were in patients 30 to 59 year-olds, some with severe resulting disabilities. Most of the adverse reactions involve the musculoskeletal system, peripheral nervous system, and central nervous system. Long-term pain was most commonly reported symptoms, 97% of all cases reporting pain associated with musculoskeletal adverse effects
  • And one should stop treatment at the first sign of an adverse reaction


  • Although many of the musculoskeletal and central nervous system effects have been known for many years, the above update includes many other conditions. And some of the newly included conditions (e.g. peripheral neuropathy) can last forever.
  • My sense locally is that fluoroquinolones are still being used quite frequently for uncomplicated urinary tract infections and other relatively minor infections. Hopefully the above warning will further discourage their potentially unnecessary usages.
  • I’m also very concerned about antibiotic resistance overall, as many of you know. Please see for many blogs highlighting in rather scary detail the increasing antibiotic resistance in general, both in the US and worldwide. And I am also concerned about the effect of broad-spectrum antibiotics in particular and fundamental changes in the gut microbiome which can lead to many known, and probably many more unknown, health complications (see many blogs in )

Primary Care Corner with Geoffrey Modest MD: Celiac disease and neuropathy

22 May, 15 | by EBM

By: Dr. Geoffrey Modest 

Peripheral neuropathy has been associated with celiac disease in past studies, typically based in referral centers. The current population-based study in Sweden looked more systematically at the association (see doi:10.1001/jamaneurol.2015.0475​). As background, celiac disease is pretty common, with prevalence of about 1%, and peripheral neuropathy is present in 2-7% of the population. Details of the study:

–Data collected on small intestine biopsies performed at Sweden’s 28 pathology departments from 1969-2008

–They compared the risk of neuropathy in 28,232 patients with celiac disease vs 139,473 age- and sex-matched controls (median age at diagnosis of 29: 42% were 0-19 yo, 18% 20-39, 22% 40-59, 18% >60; 62% female; comorbidity of type 1 diabetes in 3.2 vs 0.4% in controls, alcohol use in 2.7 vs 2.6%). Patients had confirmed celiac disease (CD), with villous atrophy, Marsh 3

–CD was associated with a 2.5-fold (2.1-3.0, p<0.001) increased risk of later neuropathy (0.7% vs 0.3% in controls, absolute risk of 64/100K vs 15/100K)

–CD also associated with increased risk of

–chronic inflammatory demyelinating neuropathy: 2.8-fold (1.6-5.1, p<0.001)

–autonomic neuropathy: 4.2-fold (1.4-12.3, p=0.009)

–mononeuritis multiplex: 7.6-fold (1.8-32.4, p=0.006)

–but not with acute inflammatory demyelinating polyneuropathy: 0.8-fold (0.3-2.1, p=0.68)

–No difference in neuropathy by sex, or age. Overall risk decreased minimally from 2.5 fold to 2.3-fold (1.9-2.7) after controlling for educational level, SES, type 1 or 2 diabetes, autoimmune thyroid disease, rheumatologic diseases, pernicious anemia, vitamin deficiencies, and alcoholic disorders.

–Association with neuropathy was pretty consistent in group with <1 yr of followup vs 1-5 yr, vs >5 yr

–There was a positive association between any neuropathy and CD, even when the diagnosis of neuropathy preceded the diagnosis of CD with an odds ratio of  1.8; 1.4-2.2, p<0.001

So, seems like we really should add an evaluation for CD as part of our neuropathy workup. In small studies, it seems that the association of CD with neuropathy is not necessarily associated with CD-related vitamin deficiencies (one study of 18 patients with confirmed CD and neuropathy found that they all had normal vitamin B12 levels). My sense, given the pretty low absolute association as noted above in Sweden, is that screening questions about GI symptoms seem appropriate. It might also be reasonable to perform serologic studies for CD, since there are some data suggesting that a gluten-free diet may either prevent or ameliorate the neuropathy (this is not very robust data), and on the other hand there are data suggesting that there are many people with “asymptomatic” CD who actually do feel better on a gluten-free diet, they might have significant malabsorption issues that should be detected/addressed, and (data not so robust) asymptomatic patients may still be at higher risk of lymphoma or autoimmune diseases which decreases with a gluten-free diet.


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