PERIPHERAL & DIABETIC NEUROPATHY

A FOUR PART SERIES

Charles Laudadio, BSEE, MD, MBA 

Diabetes-Related Amputations on the Rise
-- The number of lower limb amputations in people with diabetes has climbed from 67,000 to 86,000 in just 2 years, according to the latest national health data.

Diabetic Neuropathy is a very serious disease that usually goes undetected until it has progressed to a more serious and painful problem.  Most medical professionals do not have adequate tools to quantify neuropathy.  There are tools currently available but not known that can be used to quickly and easily quantify the severity of neuropathy it becomes a problem. 

This feature will highlight diabetic neuropathy, how to diagnose it and even how to find it before it can be detected with most tests. It will consist of 4 parts and includes studies on a new device to detect sub-clinical neuropathy.

PART 2:

HOW IS PERIPHERAL NEUROPATHY EVALUATED?

The peripheral neuropathies are generally progressive and irreversible. In the advanced stages, they often cause severe pain, ulcerations, amputations and infections that can be difficult to treat. Therefore, early detection is of paramount importance since the earliest stages respond best to preventive measures and treatment. Early detection is difficult since the current diagnostic methods are either insensitive or too sophisticated for primary care applications. The neurological examination can detect only gross clinical neuropathy and not sub-clinical neuropathy.  Thus, unless clear clinical evidence of peripheral neuropathy is present, it is rarely diagnosed.  

Consider this analogy to blood pressure screening.  Before sphygmomanometers were used to screen for high blood pressure, hypertension was not detected until patients developed strokes or other clinical manifestations of hypertension.  Once an association was established between hypertension and these complications and a simple device (the sphygmomanometer) became available to the primary care provider to easily measure blood pressure, screening of patients became a commonplace event. During screening, if hypertension was discovered, patient management of salt intake, weight loss, etc. was instituted.  When medications became available to treat hypertension, the sphygmomanometer allowed the provider to monitor the effects of the drugs and monitor the patient’s response to treatment to allow him/her to titrate the doses, add other drugs or change the medication if no response was seen. 

With peripheral neuropathy, we are at a crossroad reminiscent of hypertension many years ago. If sphygmomanometers were not available to measure blood pressure in the office setting, providers would be required to send their patients to cardiologists (who would have sophisticated, expensive equipment to measure blood pressure) to determine if hypertension was present.  If detected, the primary care provider could institute therapy but could not monitor the treatment effects or progression.  This analogy applies to peripheral neuropathy today!  Unless there is clear clinical evidence of peripheral neuropathy, the primary care provider cannot easily or cost effectively assess neuropathy, requiring neurology consults whenever neuropathy was suspected or in patients who had a high risk of developing neuropathy (e.g. diabetics).  Once neuropathy is quantified by the neurologist, the primary care provider cannot easily monitor the patient for subtle changes in severity so the success or failure of patient management cannot be monitored.  If specific treatments for neuropathy became available, there are no cost effective and sensitive ways to monitor patients nor follow their response to treatment.  Thus, the Tacticon^® is to peripheral neuropathy what the sphygmomanometer is the hypertension.

WHAT ENDPOINTS CAN BE MEASURED?

Comprehensive testing for neuropathy can assess decreased sensation (i.e. increased thresholds) to vibration, proprioception, light touch, circumference discrimination, temperature perception and pain thresholds.  In the past, diabetic neuropathy has been assessed principally based on neuropathic signs and symptoms, including sensorimotor and reflex measures. These clinical measures generally lack precision and reliability, leaving the subtle forms of dysfunction undetected. Often there are wide discrepancies in the findings from one examiner to another or in repeat assessments of a single individual. 

Current sensory testing methods often fail to discriminate between stimulus intensity and perception. All depend on the qualitative assessment of both physician and patient and testing is not well standardized. For example, one common test to assess vibration perception employs an oscillating tuning fork placed over a bony prominence. Results are dependent on the force of the initial strike, the pressure applied to the tested area, the examiner's estimate of decay time, and the patient's perception that the stimulus is no longer present. Negative symptoms, such as numbness, are particularly problematic; they are often insidious in onset, and patients with even moderate to severe involvement may remain unaware of the gradual sensory change. 

The inability to quantify sensory impairment in an objective fashion makes repeat assessments of individuals or testing by different clinicians unpredictable.  Diabetic neuropathy involves both small and large nerve fibers, however clinical assessment of small-fiber function is limited to examination with a sharp pin and a cold (or hot) object.  Electrophysiology (EMG) measures large-fiber function, and although standardized and objective, cannot fully assess small fiber diabetic neuropathy. 

To properly and sensitively assess the severity, type and change in peripheral neuropathy, various testing methodologies must be employed to cover the scope of the pathologies. These methodologies include electrophysiology, quantitative sensory testing, neurological examination, assessment of patient symptoms and autonomic function testing.

WHAT IS QUANTITATIVE SENSORY TESTING?

Quantitative sensory testing (QST) is a testing procedure designed to facilitate the early diagnosis and accurate assessment of diabetic neuropathy. Current evidence indicates the stabilization or reversal of neuropathy may be possible only in its early stages suggesting that effective pharmacologic treatments will have to be applied during the early stages. The ability to detect subclinical neuropathy and to assess a patient’s response to treatment depends on the availability of tests that are objective, quantitative, quick, easy to obtain, reliable, valid, and inexpensive.  Quantitative sensory testing fulfills many of these requirements by utilizing instruments that control and deliver specific stimuli at specified intensities in order to determine a patient’s sensory threshold, defined as the minimal stimulus energy detectable more than 50% of the time.  QST is non-invasive, requires approximately 10 minutes per testing session, and can be administered by nonprofessional personnel after a brief training period. The hallmark of quantitative sensory testing is its ability to administer stimuli precisely. 

Quantitative sensory testing is not new.  For example, hearing is no longer assessed by clinical impression, but by an audiogram, that precisely quantifies the threshold of hearing in decibels, at specific frequencies. Assessment of somatosensory function, in the past, had been less quantitative, due primarily to the lack of devices capable of delivering stimuli of appropriate characteristics and intensities. The relatively recent development of somatosensory QST methods and instruments has contributed significantly to the assessment of peripheral nerve function. The past decade has seen many new devices become available, many that are driven by computer and require minimal operator interaction.  These devices are being used to assess vibration and thermal thresholds in research studies and special clinics.  Unfortunately, the cost of these devices usually precludes their use in the office setting.  However, the data from these studies confirms the value of quantitative sensory testing as a measure of diabetic neuropathy since elevation of great toe thresholds may be the earliest reliable sign of the onset of diabetic neuropathy. 

Drugs Associated with Peripheral Neuropathy

Listed below are drugs that the PDR indicates may have peripheral neuropathy as a possible side effect.  An asterisk indicates 3% or more. 

Flucytosine, disulfiram, chloroquine HCL, melarsoprol, sulfasalazine, amiodarone, penicillamine, Dapsone USP, phenytoin, Diphtheria and Tetanus Toxoids and Pertussis Vaccine Adsorbed, amitriptyline, levamisole, perphenazine/amitriptyline, metronidazole, cyclobenzaprine, ofloxacin, fludarabine phosphate, foscarnet, amphotericin B, gentamicin sulfate, altretamine*, zalcitabine*, isoniazid*, idarubicin HCL*, indomethacin, nifurtimox, fluvastatin, chlorambucil, maprotiline, leuprolide (Among most frequent)*, nitrofurantoin, lovastatin, gold sodium thiomalate, Netromycin Injection, desipramine HCL, Nydrazid Injection (Among most common)*-isoniazid, iohexol, nortriptyline HCL, Paraplatin for Injection (4-16%)*-carboplatin, ethchlorvynol, cisplatin, pravastatin sodium, Prinivil Tablets (0.3-1.0%)-lisinopril, metronidazole, hepatitis B HBsAg Vaccine, auranofin Gold, rifampin and isoniazid, bamnidazole, Suramin Sodium, stavudine, trimipramine maleate, Taxol (Frequent; 4- 62%)*-paclitaxel, Tirebal-ornidazole, ticlopidine, imipramine HCL, Trimetrexate (with “leucovorin rescue), Tripedia - Diphtheria, Tetanus, Pertussis vaccine, enalapril maleate HCL, enalaprilat, Videx Tablets, Powder for Oral Solution, & Pediatric Powder for Oral Solution (12-51%)*-didanosine, protriptyline HCL, iodoquinol, simvastatin, allopurinol. 

HOW IS PERIPHERAL NEUROPATHY EVALUATED?

The peripheral neuropathies are generally progressive and irreversible. In the advanced stages, they often cause severe pain, ulcerations, amputations and infections that can be difficult to treat. Therefore, early detection is of paramount importance since the earliest stages respond best to preventive measures and treatment. Early detection is difficult since the current diagnostic methods are either insensitive or too sophisticated for primary care applications. The neurological examination can detect only gross clinical neuropathy and not sub-clinical neuropathy.  Thus, unless clear clinical evidence of peripheral neuropathy is present, it is rarely diagnosed.  

Consider this analogy to blood pressure screening.  Before sphygmomanometers were used to screen for high blood pressure, hypertension was not detected until patients developed strokes or other clinical manifestations of hypertension.  Once an association was established between hypertension and these complications and a simple device (the sphygmomanometer) became available to the primary care provider to easily measure blood pressure, screening of patients became a commonplace event. During screening, if hypertension was discovered, patient management of salt intake, weight loss, etc. was instituted.  When medications became available to treat hypertension, the sphygmomanometer allowed the provider to monitor the effects of the drugs and monitor the patient’s response to treatment to allow him/her to titrate the doses, add other drugs or change the medication if no response was seen. 

With peripheral neuropathy, we are at a crossroad reminiscent of hypertension many years ago. If sphygmomanometers were not available to measure blood pressure in the office setting, providers would be required to send their patients to cardiologists (who would have sophisticated, expensive equipment to measure blood pressure) to determine if hypertension was present.  If detected, the primary care provider could institute therapy but could not monitor the treatment effects or progression.  This analogy applies to peripheral neuropathy today!  Unless there is clear clinical evidence of peripheral neuropathy, the primary care provider cannot easily or cost effectively assess neuropathy, requiring neurology consults whenever neuropathy was suspected or in patients who had a high risk of developing neuropathy (e.g. diabetics).  Once neuropathy is quantified by the neurologist, the primary care provider cannot easily monitor the patient for subtle changes in severity so the success or failure of patient management cannot be monitored.  If specific treatments for neuropathy became available, there are no cost effective and sensitive ways to monitor patients nor follow their response to treatment.  Thus, the Tacticon^® is to peripheral neuropathy what the sphygmomanometer is the hypertension.

(Information on the Tacticon will be available in part 4)

WHAT ENDPOINTS CAN BE MEASURED?

Comprehensive testing for neuropathy can assess decreased sensation (i.e. increased thresholds) to vibration, proprioception, light touch, circumference discrimination, temperature perception and pain thresholds.  In the past, diabetic neuropathy has been assessed principally based on neuropathic signs and symptoms, including sensorimotor and reflex measures. These clinical measures generally lack precision and reliability, leaving the subtle forms of dysfunction undetected. Often there are wide discrepancies in the findings from one examiner to another or in repeat assessments of a single individual. 

Current sensory testing methods often fail to discriminate between stimulus intensity and perception. All depend on the qualitative assessment of both physician and patient and testing is not well standardized. For example, one common test to assess vibration perception employs an oscillating tuning fork placed over a bony prominence. Results are dependent on the force of the initial strike, the pressure applied to the tested area, the examiner's estimate of decay time, and the patient's perception that the stimulus is no longer present. Negative symptoms, such as numbness, are particularly problematic; they are often insidious in onset, and patients with even moderate to severe involvement may remain unaware of the gradual sensory change. 

The inability to quantify sensory impairment in an objective fashion makes repeat assessments of individuals or testing by different clinicians unpredictable.  Diabetic neuropathy involves both small and large nerve fibers, however clinical assessment of small-fiber function is limited to examination with a sharp pin and a cold (or hot) object.  Electrophysiology (EMG) measures large-fiber function, and although standardized and objective, cannot fully assess small fiber diabetic neuropathy. 

To properly and sensitively assess the severity, type and change in peripheral neuropathy, various testing methodologies must be employed to cover the scope of the pathologies. These methodologies include electrophysiology, quantitative sensory testing, neurological examination, assessment of patient symptoms and autonomic function testing. 

WHAT IS QUANTITATIVE SENSORY TESTING?

Quantitative sensory testing (QST) is a testing procedure designed to facilitate the early diagnosis and accurate assessment of diabetic neuropathy. Current evidence indicates the stabilization or reversal of neuropathy may be possible only in its early stages suggesting that effective pharmacologic treatments will have to be applied during the early stages. The ability to detect subclinical neuropathy and to assess a patient’s response to treatment depends on the availability of tests that are objective, quantitative, quick, easy to obtain, reliable, valid, and inexpensive.  Quantitative sensory testing fulfills many of these requirements by utilizing instruments that control and deliver specific stimuli at specified intensities in order to determine a patient’s sensory threshold, defined as the minimal stimulus energy detectable more than 50% of the time.  QST is non-invasive, requires approximately 10 minutes per testing session, and can be administered by nonprofessional personnel after a brief training period. The hallmark of quantitative sensory testing is its ability to administer stimuli precisely. 

Quantitative sensory testing is not new.  For example, hearing is no longer assessed by clinical impression, but by an audiogram, that precisely quantifies the threshold of hearing in decibels, at specific frequencies. Assessment of somatosensory function, in the past, had been less quantitative, due primarily to the lack of devices capable of delivering stimuli of appropriate characteristics and intensities. The relatively recent development of somatosensory QST methods and instruments has contributed significantly to the assessment of peripheral nerve function. The past decade has seen many new devices become available, many that are driven by computer and require minimal operator interaction.  These devices are being used to assess vibration and thermal thresholds in research studies and special clinics.  Unfortunately, the cost of these devices usually precludes their use in the office setting.  However, the data from these studies confirms the value of quantitative sensory testing as a measure of diabetic neuropathy since elevation of great toe thresholds may be the earliest reliable sign of the onset of diabetic neuropathy.  Further information on the Tacticon, a new device to measure sub-clinical neuropathy will be available in Part 4 of this feature. 

Drugs Associated with Peripheral Neuropathy

Listed below are drugs that the PDR indicates may have peripheral neuropathy as a possible side effect.  An asterisk indicates 3% or more. 

Flucytosine, disulfiram, chloroquine HCL, melarsoprol, sulfasalazine, amiodarone, penicillamine, Dapsone USP, phenytoin, Diphtheria and Tetanus Toxoids and Pertussis Vaccine Adsorbed, amitriptyline, levamisole, perphenazine/amitriptyline, metronidazole, cyclobenzaprine, ofloxacin, fludarabine phosphate, foscarnet, amphotericin B, gentamicin sulfate, altretamine*, zalcitabine*, isoniazid*, idarubicin HCL*, indomethacin, nifurtimox, fluvastatin, chlorambucil, maprotiline, leuprolide (Among most frequent)*, nitrofurantoin, lovastatin, gold sodium thiomalate, Netromycin Injection, desipramine HCL, Nydrazid Injection (Among most common)*-isoniazid, iohexol, nortriptyline HCL, Paraplatin for Injection (4-16%)*-carboplatin, ethchlorvynol, cisplatin, pravastatin sodium, Prinivil Tablets (0.3-1.0%)-lisinopril, metronidazole, hepatitis B HBsAg Vaccine, auranofin Gold, rifampin and isoniazid, bamnidazole, Suramin Sodium, stavudine, trimipramine maleate, Taxol (Frequent; 4- 62%)*-paclitaxel, Tirebal-ornidazole, ticlopidine, imipramine HCL, Trimetrexate (with “leucovorin rescue), Tripedia - Diphtheria, Tetanus, Pertussis vaccine, enalapril maleate HCL, enalaprilat, Videx Tablets, Powder for Oral Solution, & Pediatric Powder for Oral Solution (12-51%)*-didanosine, protriptyline HCL, iodoquinol, simvastatin, allopurinol. 

Diseases Associated with Peripheral Neuropathy

Diabetes Mellitus, Alcoholism, Uremia (Renal Failure), Diphtheria

Dorsal Root Ganglionitis of Cancer (lymphoma, bronchogenic carcinoma, ovarian, testes, penis stomach and oral cavity carcinomas)

Paraproteinemia (monoclonal gammopathy (IgG, IgM, IgA), primary systemic amyloidosis (light chain type), osteosclerotic myeloma, osteolytic multiple       myeloma, Waldenström’s macroglobulinemia, gamma heavy chain disease)

Necrotizing Angiopathy, Leprosy, Sarcoidosis, HIV

Shy-Drager Syndrome, Polycythemia Vera, Multiple Sclerosis

Trauma (occupational or accidental) - (air-hammer operators, engravers, gardeners, joint overextension, cold, radiation, leg injuries with anterior compartment syndromes)

Nerve Entrapments (Carpal Tunnel Syndrome, Tarsal entrapment.)

Collagen vascular disorders (polyarteritis nodosa, systemic lupus erythematosus, scleroderma)

Rheumatoid arthritis, Guillain-Barré Syndrome, Lyme disease

CMV infection, Paralytic rabies, Meningococcal septicemia

Migrant sensory neuritis of Wartenberg,

Disseminated Intravascular Coagulation, Mononeuritis multiplex

Multiple Vascular Occlusions, Mononeuritis multiplex

Toxic agents:

Amiodarone, chloramphenicol, lithium, metronidazole, misonidazole, nitrofurantoin, nitrous oxide, phenytoin, pyridoxine, thalidomide, emetine, hexobarbital, barbital, chlorobutanol, sulfonamides, nitrofurantoin, vinca alkaloids, heavy metals, carbon monoxide, tri-ortho-cresyl-phosphate, ortho dinitrophenol, solvents, industrial poisons, acrylamide, carbon disulfide, inorganic mercury, methyl n-butyl ketone, organophosphate parathion, polychlorinated biphenyl, thallium, triorthocresyl phosphate, vinyl chloride, arsenic, perhexiline maleate.

Vitamin Deficiency:

Pellagra, beriberi, pernicious anemia, isoniazid induced pyridoxine deficiency, malabsorption syndromes, hyperemesis gravidarum, vitamin E deficiency, short bowel syndrome, dysentery.

Primary Biliary Cirrhosis, Hypothyroidism, Porphyria, Amyloidosis 

Inherited Neuropathies

Charcot-Marie-Tooth, HMSN Type I, HMSN Type II, Dejerine-Sottas Disease (HMSN Type III), Refsum’s Disease, Hereditary Ataxic Neuropathy (HMSN Type IV), Spinocerebellar Degeneration with Neuropathy (HMSN Type V), Friedreich’s ataxia, acute intermittent porphyria, cerebral lipidosis, Fabry’s Disease, familial amyloid neuropathy, Hereditary Sensory Neuropathy, Lipoprotein Neuropathies, Giant Axonal Neuropathy, Olivo-pontocerebellar Atrophy, Sialidosis Type I, The cherry-red-spot-myoclonus syndrome, cerebrotendinous xanthomatosis, Cockayne’s Syndrome, congenital hypomyelination polyneuropathy, chorea-acanthocytosis, adrenomyeloneuropathy, metachromatic leukodystrophy. 

QUESTIONS PATIENTS OFTEN ASK ABOUT DIABETIC NEUROPATHY 

How Do You Pronounce Neuropathy?

      Nor-rop-a-thee

What Is Peripheral Neuropathy?

Neuropathy is a general term to describe a problem or pathology of the nervous system.  Peripheral Neuropathy affects only the nerves of the sense organs and to the organs of the body.  It does not affect the Central Nervous System such as the brain.

What Is Diabetic Peripheral Neuropathy?

Peripheral neuropathy found in patients with Diabetes Mellitus in which other causes for their neuropathy has been eliminated.

What Causes Diabetic Neuropathy?

There are many theories for the exact cause of neuropathy in patients with diabetes. High blood sugar levels produce higher levels of some biochemical end products of glucose (e.g. sorbitol) inside the nerve cells, which over time damages the cells.  Blood flow to the nerves is also impaired in the diabetic patient, which may also contribute to the nerve damage. 

Who Gets Diabetic Neuropathy?

Although all patients with diabetes will eventually develop some level of neuropathy, patients with very poor glucose control generally develop neuropathy much earlier and are usually more severe. 

How is peripheral neuropathy detected?

Unless the patient complains of symptoms, neuropathy is often missed since there may be no symptoms in the early stages and the tools primary care providers have available to them to measure neuropathy are not sensitive enough to detect very low levels of neuropathy early in its course. 

Will the Diabetic Neuropathy get worse?

Diabetic neuropathy is a chronic condition that usually progresses over time.  There may be symptoms such as pain which may get worse over time, but sometimes, the pain may disappear when the nerves get so bad they don’t function anymore leading to the mistaken belief the neuropathy is getting better.

What symptoms are associated with neuropathy?

Patients may complain of pain, which has many descriptions such as sharp, lancinating, burning, broken glass, electric, shooting, cutting, dull, aching, cramps, squeezing, jabbing, crushing, etc.  There may also be symptoms of numbness (loss of feeling) or Pins & Needles, or things that cause pain that should not like the bed sheets touching the toes.

Other than the discomfort, are there any complications?

The loss of feeling in the feet combined with poor circulation often leads to damage of the skin and deeper tissues overlying bony structures, resulting in ulcers which often get infected and require special treatments and dressings.  The infection may spread into the bone (osteomyelitis) and be very difficult to treat. If these problems persist, the toes, feet or legs may eventually require amputation.

Is there a treatment for neuropathy?

Patients should consult their doctor for advice on treatment.  There are drugs available which can relieve the painful symptoms of neuropathy.  However, there is yet no approved drug to treat diabetic neuropathy.  Better control of blood sugar has been demonstrated in the DCCT (Diabetes Control and Complications Trial sponsored by the NIH) to slow the progression of neuropathy so it is important to obtain as good a control as possible.  Some vitamin supplements such as evening primrose and borage oil, L-carnitine, inositol, choline, etc. have been studied in animals and humans, but to date have not demonstrated unequivocal efficacy.  Proper foot care is essential to help avoid the ulcers and tissue damage.  Patients should discuss with their doctors obtaining a foot pressure test (Harris Mat) and possible foot orthotics.  Patients should understand they may have lost feeling to temperature and pain and should not walk barefooted since hot sand or sidewalks or sharp nails may not be felt and cause damage. With the help of the Tacticon, physicians will be able to diagnose and manage diabetic neuropathy, which is a complex condition.  By staying aware of the latest treatments and management techniques, diabetic neuropathy may be more manageable.

How is diabetic neuropathy managed?

Management of your condition depends primarily on the kind of problems you are experiencing. No two patients are exactly alike in their condition and symptoms. There is a variety of pain you may experience such as numbness, tingling, jabbing, electric, stabbing, burning or stinging pain.  You can assist your physician by reporting any symptoms as accurately as possible using descriptions like those mentioned above.  There are a number of options available to your physician if you have pain that is best suited to your specific type of condition. Your doctor might prescribe medications that can be taken by mouth or those that are applied directly to the skin. He or she might prescribe a combination of medications or recommend additional, non-medicinal measures. 

For any comments you would like answered from Charles Laudadio, BSEE, MD, MBA  please email me at

diabetesincontrol@home.com 

Next Week Part 3

DCCT:  Can Diabetic Neuropathy Be Prevented?

How Common Is Diabetic Neuropathy?

What Causes Diabetic Neuropathy?

What Are the Symptoms of Diabetic Neuropathy?

Diabetic Neuropathy Can Affect Virtually Every Part of the Body

What Are the Major Types of Neuropathy?

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