Three people in my circle of acquaintances have recently experienced neuropathies. The cause was different in each instance. Although not equivalent in severity, their symptoms were in many ways quite similar. Their neuropathies were not among the most frequently encountered ones, such as carpal tunnel syndrome and trigeminal neuralgia.
One acquaintance, a woman in her 80s, told me that 6 months previously she was bothered by persistent burning pains, itching, and an exaggerated sensitivity to touch after crusty lesions on her back healed. I will call her Ms. W. Her discomfort was particularly problematic in bed at night when she tried to turn onto her back. Ms. W had chicken pox as a child, and she had ignored advice from her clinician about receiving the shingles vaccine.
I remember seeing quite a few people with comparable concerns during my medical school rotations on neurology. At the time, there was no way to prevent this type of problem which we understood stemmed from the reactivation of latent varicella zoster virus. We did know that shingles was most likely to occur in the elderly and in persons who were immunocompromised, such as children with leukemias. There were no effective ways of providing relief. None of us had a real appreciation of the level of discomfort these patients were experiencing. For a skit we put on at the end of the rotation, I made up an irreverent ditty: “Shingle bells, shingle bells -- the pain can last all day. There is no way to make it stop -- or quickly go away.”
Ms. W’s plight began with three pruritic blistery lesions on her back. She was told that the lesions looked like red, pustular patches. The itching persisted, and pain and allodynia set in 2 weeks later. Her lesions healed, and her pain gradually subsided over the next 4 months. The only treatments she used were acetaminophen and frequent, cold, wet compresses. She was lucky that it did not last longer. Shingles is properly called herpes zoster, and her persistent pain was postherpetic neuralgia (PHN).
Let us look briefly at the pathologic process of PHN. There are virus-induced hemorrhagic, fibrotic, and degenerative changes in the posterior (dorsal) root ganglia of the spinal cord accompanied by the loss of afferent input from sensory nerve endings. These destructive changes lead to discharges from damaged nerves that can be unprovoked or can occur at lower input thresholds. In turn, increased excitability at the level of the dorsal horn leads to altered central nervous system processing.
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As noted, Ms. W’s clinical and pathologic picture is called neuralgia. A simple definition of neuralgia is pain along the path or distribution of a nerve. The term is derived from the Greek words Νεύρο for nerve and Aλγος for pain.
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The French variation is névralgie. Chaussier may have been the first to use this term when, at the beginning of the 19th century, he used it to describe intermittent and intense pain caused by an affected nerve.3
Neuralgia. https://en.wikipedia.org/wiki/Neuralgia. Accessed May 8, 2017.
Ms. X, a second acquaintance, experienced numbness, tingling, and weakness in one foot. She also felt pain in the sole of that foot whenever she put pressure on it. These symptoms began shortly after an epidural injection during a complicated delivery. It took several months before she was free of discomfort. This was an iatrogenic form of neuropathy. Because the symptoms lasted longer than might be caused by the direct effects of the anesthetic agent on the nerve, it is likely that there was physical damage to the nerve from the lumbar epidural. My speculation is that the peroneal nerve was traumatized. In Sheddon’s classification of nerve injuries, I believe this would be called axonotmesis. It seems likely that there was axonal injury without damage to other, nearby tissues.
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GPnotebook. Sheddon classification of nerve injuries. http://www.gpnotebook.co.uk/simplepage.cfm?ID=x20091231010118724280&linkID=72782&cook=no&mentor=1. Accessed May 8, 2017.
I had never learned or heard of the term axonotmesis until I recently looked up the meaning of its related term, neurotmesis. Sheddon coined the word neurotmesis to refer to a condition in which the nerve and the nerve sheath are damaged, such as occurs when a nerve is severed. I first came across the term while reading a delightfully candid and informative memoir called Do No Harm by the English neurosurgeon, Henry Marsh. Greek majors would know that tmesis means to cut or separate into two parts.
Mr. Y, a man in his 60s, developed autoimmune-related demyelinating lesions in his cerebellum and spine. Their cause remains unclear, but there is speculation they were in some way related to his prior use of a tumor necrosis factor-α inhibitor. Fortunately, these lesions gradually diminished over time in conjunction with the use of intermittent cycles of steroids and cyclophosphamide. His symptoms included numbness and tingling in his buttocks and numbness, tingling, weakness, and faulty proprioception in his feet.
I encountered a fourth type of neuropathy in the mid-1980s.
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I would call this a nutritional neuropathy. It developed in a patient of mine who I learned later was pyridoxine (vitamin B6) deficient. She was also taking the hydrazine monoamine oxidase inhibitor phenelzine for her depression. Her burning pains disappeared when she was put on a low dose of pyridoxal phosphate. Similar cases of neuropathy in patients taking phenelzine were also reported at the same time.7
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I soon became aware that B6 supplementation is tricky. Too little does not help; too much can increase the intensity of the burning pain (ie, dosages near or >200 mg/d). Doses of levodopa for Parkinson’s disease can also use up B6 stores and cause burning pains; B6 is a cofactor in the metabolism of dopamine.9
People do not synthesize vitamin B6.
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It is acquired from certain foods or by supplementation through pills. Requirements increase with age, ranging from 0.1 mg/d in newborns to about 1.5 mg/d in older adults; about 2.0 mg/d is recommended during pregnancy or for nursing mothers.11
I have wondered if supplemental B6 would have been beneficial for Ms. W or Ms. X or Mr. Y. Given the current craze for hummus products, one should know that chickpeas (garbanzo beans) are a strong source of B6; a typical can provides about 1 mg. Other sources of B6 are sunflower seeds and certain nuts such as pistachios, walnuts, and peanuts; fish such as tuna and salmon; meats such as turkey, chicken, pork, and beef; dried fruits such as prunes and apricots; bananas; avocados; and spinach.Vitamin B6. http://www.lifescript.com/health/centers/allergies/alternative_treatments/vitamin_b6.aspx#sthash.lbDuisWV.dpuf. Accessed May 8, 2017.
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Cooking may reduce the B6 content from foods.HealthAliciousNess.com. Top 10 foods highest in vitamin B6. https://www.healthaliciousness.com/articles/foods-high-in-vitamin-B6.php. Accessed May 8, 2017.
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It is impossible to estimate by how much, because B6 is water soluble and cooking temperatures vary.Spritzler F. How cooking affects the nutrient content of foods. https://authoritynutrition.com/cooking-nutrient-content. Accessed May 8, 2017.
In a few patients I saw whose neuropathies were related to HIV/AIDS, some degree of relief was afforded by the use of the antidepressants amitriptyline or imipramine. Collins et al
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have written an instructive review covering the use of antidepressants and antipsychotic agents in certain neuropathies. Newer agents are available for the pain of some neuropathies; these include pregabalin, gabapentin, duloxetine, venlafaxine, and tapentadol.15
FDA approves new neuropathy pain drug. https://www.diabeteshealth.com/fda-approves-new-neuropathy-pain-drug. Accessed May 8, 2017.
Yet another neuropathy is diabetic peripheral neuropathy (DPN), which is typically experienced as stabbing and burning pains in the feet or hands. It occurs to a lesser or greater degree in most diabetic patients, especially in those with type 1 diabetes mellitus; in undertreated patients with poor glycemic control, including those with type 2 diabetes mellitus; and in persons with diabetes for an extended number of years. DPN is the underlying cause in most cases of diabetic foot ulcers. Although the exact cause of DPN is unknown, elevated blood sugar (glucose) levels are unquestionably implicated. Here are some additional factors I recall hearing or learning: (1) affected nerves have impaired signaling ability; (2) blood vessels in the microvascular circulation that nourish nerves are damaged; (3) although not clearly causally linked, sorbitol levels increase and myoinositol levels decrease; (4) glucose molecules may attach to vascular proteins, thereby altering their functioning; (5) lowered levels of nitric oxide may also be involved; (6) oxidative stress is present; (7) protein kinase C is activated; and (8) small and large nerve fibers are affected and axonal atrophy occurs. Unfortunately, the precise role and relative importance of these factors has not been established.
I find it useful to differentiate among the various sometimes confusing afflictions of nerves with the following short and admittedly incomplete descriptions. (1) Neuritis means a nerve is affected by an inflammatory process. (2) Neurotmesis means a nerve has been severed or probably irreversibly damaged. (3) Neuralgia means pain from a variety of causes along the path of a nerve. (4) Neuropathy means nerve damage or injury, compromised function, and pain.
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Right Diagnosis. Prevalence and incidence of diabetic neuropathy. http://www.rightdiagnosis.com/d/diabetic_neuropathy/prevalence.htm#prevalence_discussion. Accessed May 8, 2017.
What follows in this issue is a themed Update assembled by Dr. John G. Ryan, our Topic Editor for Endocrinology, Diabetes, and Other Endocrine Disorders. I have shared my observations about neuropathies with you because he has brought together a collection of articles focusing on DPN.
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This month’s Endocrinology, Diabetes, and Other Endocrine Disorders Update is a special feature which is available as FREE ACCESS content on the journal’s website. One of the previous Endocrinology, Diabetes, and Other Endocrine Disorders Updates, entitled “Managing Patients with Type 2 Diabetes at Risk for Cardiovascular Disease,” was published in Volume 38, Number 6 of Clinical Therapeutics. To view the previous Update, see the articles below:
- 1.
- 2.Rydén L, Shahin B, Mellbin L. Clinical Implications of Cardiovascular Outcome Trials in Type 2 Diabetes: From DCCT to EMPA-REG.
- 3.Shernthaner G, Shernthaner-Reiter MH, Shernthaner G-H. EMPA-REG and Other Cardiovascular Outcome Trials of Glucose-lowering Agents: Implications for Future Treatment Strategies in Type 2 Diabetes Mellitus.
- 4.Kohler S, Salsali A, Hantel S, et al. Safety and Tolerability of Empagliflozin in Patients with Type 2 Diabetes.
- 5.Weng W, Liang Y, Kimball ES, et al. Longitudinal Changes in Medical Services and Related Costs in a Single Cohort of Patients Newly Diagnosed With Type 2 Diabetes, 2006 to 2012.
- 6.
References
- Postherpetic neuralgia--pathogenesis, treatment, and prevention.N Engl J Med. 1996; 335: 32-42
- The Shorter Oxford English Dictionary.Clarendon Press, Oxford, UK1980: 1398
Neuralgia. https://en.wikipedia.org/wiki/Neuralgia. Accessed May 8, 2017.
GPnotebook. Sheddon classification of nerve injuries. http://www.gpnotebook.co.uk/simplepage.cfm?ID=x20091231010118724280&linkID=72782&cook=no&mentor=1. Accessed May 8, 2017.
- Do No Harm.Thomas Dunne Books/St. Martin’s Press, New York2015
- Phenelzine and the dream machine—ramblings and reflections.J Clin Psychopharmacol. 1985; 5: 65-70
- Pyridoxine-deficiency neuropathy due to hydralazine.N Engl J Med. 1965; 273: 1182-1185
- Pyridoxine deficiency and peripheral neuropathy associated with long-term phenelzine therapy.Am J Med. 1983; 75: 887-888
- Effect of vitamin B-6 nutrition on the levels of dopamine, dopamine metabolites, dopa decarboxylase activity, tyrosine, and GABA in the developing rat corpus striatum.Neurochem Res. 1989; 14: 571-578
- Nutritional neuropathies.Neurol Clin. 2013; 31: 477-489
Vitamin B6. http://www.lifescript.com/health/centers/allergies/alternative_treatments/vitamin_b6.aspx#sthash.lbDuisWV.dpuf. Accessed May 8, 2017.
HealthAliciousNess.com. Top 10 foods highest in vitamin B6. https://www.healthaliciousness.com/articles/foods-high-in-vitamin-B6.php. Accessed May 8, 2017.
Spritzler F. How cooking affects the nutrient content of foods. https://authoritynutrition.com/cooking-nutrient-content. Accessed May 8, 2017.
- Antidepressants and anticonvulsants for diabetic neuropathy and postherpetic neuralgia.J Pain Symptom Manage. 2000; 20: 449-458
FDA approves new neuropathy pain drug. https://www.diabeteshealth.com/fda-approves-new-neuropathy-pain-drug. Accessed May 8, 2017.
Right Diagnosis. Prevalence and incidence of diabetic neuropathy. http://www.rightdiagnosis.com/d/diabetic_neuropathy/prevalence.htm#prevalence_discussion. Accessed May 8, 2017.
- Diabetic peripheral neuropathy and associated pain: emerging and updated research.Clin Ther. 2017; 39: 1082-1084
- Declining skeletal muscle function in diabetic peripheral neuropathy.Clin Ther. 2017; 39: 1085-1103
- Efficacy of venlafaxine in neuropathic pain: a narrative review towards optimized treatment.Clin Ther. 2017; 39: 1104-1122
- Electrical muscle stimulation induces an increase of VEGFR2 on circulating hematopoietic stem cells in diabetes patients.Clin Ther. 2017; 39: 1132-1144
- Real-world clinical outcomes among patients with type 2 diabetes receiving canagliflozin at a specialty diabetes clinic: subgroup analysis by baseline HbA1c and age.Clin Ther. 2017; 39: 1123-1131
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Published online: May 26, 2017
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