A FOUR PART SERIES

Charles Laudadio, MD, MBA, BSEE

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 look for neuropathy with their diabetic patients unless there is a compliant from the patient.  Yet there are tools we can use to detect neuropathy before 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. 

We then will offer our medical professionals the opportunity to participate in a new study that will provide you with a new device to use with your patients that is much more sensitive then the monofilament test and is billable to Medicare and other insurance carriers.

Dr. Laudadio, the inventor of the a new small, hand held, passive medical device that the FDA has recently allowed to be marketed to screen patients for evidence of subclinical peripheral neuropathy of the fingers and toes. The device permits quantitative sensory testing (QST) as recommended by the American Diabetes Association Consensus Panels on Diabetic Peripheral Neuropathy, has degrees in medicine and electrical engineering. He has spent the last 15 years in research related to peripheral neuropathy, diabetes, diabetic neuropathy and diabetic foot ulcers. He has started successful companies including Biotrax Research, Inc., a clinical research organization (CRO) started in 1991 which grew to 35 employees and revenues of 2.5M within 18 months with only $25,000 in funding and no debt. He has invented 2 other devices to assess other modalites of sensory loss associated with peripheral neuropathy which are currently FDA approved and are on the market and available to health care providers. N.J. Dr. Laudadio is a member of the Delaware and Pennsylvania Medical Societies, serves on several advisory committees and boards related to diabetes and peripheral neuropathy including the Delaware Governor's Advisory Board on Diabetes, Board of Directors of the Neurology Institute at Columbian Presbyterian Hospital, and the Neuropathic Pain Advisory Board of Parke Davis Pharmaceutical Co. Dr. Laudadio is an adjunct clinical associate professor at the University of Delaware and is on the research of the Medical Center of Delaware. 

This is a four part weekly feature

Table of Contents:

Part 1:

WHAT IS THE PERIPHERAL NERVOUS SYSTEM?

WHAT IS PERIPHERAL NEUROPATHY?

WHAT DISEASES CAUSE PERIPHERAL NEUROPATHY?

WHAT IS DIABETIC NEUROPATHY?

WHAT‘S THE IMPACT OF NEUROPATHY IN DIABETES?

WHAT ARE THE TYPES OF DIABETIC NEUROPATHY?

WHAT SYMPTOMS DO PATIENTS EXPERIENCE?

CAN POLYNEUROPATHY BE TREATED?

WHAT TREATMENTS ARE AVAILABLE FOR PAIN

Part 2:

HOW IS PERIPHERAL NEUROPATHY EVALUATED?

WHAT ENDPOINTS CAN BE MEASURED?

WHAT IS QUANTITATIVE SENSORY TESTING?

Drugs Associated with Peripheral Neuropathy

Diseases Associated with Peripheral Neuropathy

QUESTIONS PATIENTS OFTEN ASK ABOUT DIABETIC NEUROPATHY

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?

Part 4:

How Do Doctors Diagnose Diabetic Neuropathy?

How Is Diabetic Neuropathy Usually Treated?

Why Is Good Foot Care Important for People with Diabetic Neuropathy?

Are There Any Experimental Treatments for Diabetic Neuropathy?

Overview of new device

Clinical Studies on new device

New study opened for your participation with new device.

PERIPHERAL & DIABETIC NEUROPATHY

A FOUR PART SERIES

Charles Laudadio, MD, MBA

Part 1:

WHAT IS THE PERIPHERAL NERVOUS SYSTEM?

The body’s nervous system has two components: The central nervous system (CNS) containing the brain and spinal cord and the peripheral nervous system (PNS) containing the cell bodies at the spinal cord (e.g., dorsal root ganglia, motor horn cells, etc.) and their associated axons.  Sensory axons enervate internal organs (via autonomic nerves) plus somatic sensory receptors while the motor axons enervate peripheral muscles. 

The PNS is made up of a variety of nerve types.  Myelinated fibers, with their insulating layers of myelin surrounding the axon, generally have large cross sectional diameters and conduct impulses rapidly. Myelinated fibers include motor nerves as well as nerves for proprioception (which react to stretch and are heavily myelinated), nerves to the touch sense organs, which are smaller and medium myelinated (vibration, light touch, circumference discrimination). Unmyelinated fibers have Schwann cells wrapped around the axon but do not have myelin layers, are generally small and conduct slowly and are usually associated with sensory nerves such as thermal and pain perception. Somesthetic impulses are either exteroceptive (from the skin) or proprioceptive (from the muscles, tendons, and joints).  The fingers and toes contain free nerve endings, plus specific receptors such as Meissner’s corpuscles, Merkel’s disks, bodies of Vater-Pacini (Pacinian Corpuscles), hair follicle receptors, tactile disks, and Ruffini endings. ). Pulses from motor nerves travel from the spinal cord down the axon to the muscles to cause them to contract.  Pulses from peripheral receptors travel in the opposite direction up the axon to the spinal cord, which are transmitted to the brain, which interprets the input.

WHAT IS PERIPHERAL NEUROPATHY?

When the nerves of the PNS become damaged through a variety of mechanisms, they and/or their associated receptors no longer function normally and begin to manifest clinical abnormalities which may include loss of muscle strength and reflexes, abnormal organ function or the inability to perceive normal sensations such as temperature, touch and vibration. When nerves from cadavers and biopsies from humans with peripheral neuropathy are evaluated under a microscope (neuropathology), a variety of structural abnormalities are identified including disruption of the neurofibrils, axonal degeneration (loss of fiber numbers per fascicle resulting in a decreased fiber density) and/or segmental demyelination (individual fiber pathology).  As the number of fibers and receptors decrease or develop pathology, clinical signs and symptoms of peripheral neuropathy emerge and can manifest as either negative signs (loss of sensation or function) or positive signs (pain, paresthesias) from ectopic firing. 

WHAT DISEASES CAUSE PERIPHERAL NEUROPATHY?

Peripheral neuropathy is associated with a variety of diseases (Appendix I) and drugs (Appendix II) that should be considered as part of the differential diagnosis whenever peripheral neuropathy is detected.  When detected, it should be quantified and monitored for proper patient management.  From a socioeconomic standpoint, peripheral neuropathy due to diabetes is the most problematic. However, peripheral neuropathy can occur due to a number of causes including hereditary neuropathies, toxic or pharmacologically induced neuropathies, mechanical insults, metabolic abnormalities, vascular, inflammatory, alcoholism, AIDS (including drugs which may be neurotoxic such as stavudine), chemotherapy (Taxol), nerve entrapments/compression, immunologic diseases and other medical causes of neuropathy.

WHAT IS DIABETIC NEUROPATHY?

A diagnosis of diabetic peripheral neuropathy is dependent on the criteria used to define neuropathy as well as the methodologies and techniques to quantify its severity.  There are no standardized agreements on grading, scoring or assessment techniques. However, two meetings of the American Diabetes Consensus Panels on peripheral neuropathy in diabetes (1988 and 1992) adopted a definition of diabetic neuropathy as  "a demonstrable disorder, either clinically evident or subclinical, that occurs in the setting of diabetes mellitus without other causes for peripheral neuropathy. The neuropathic disorder includes manifestations in the somatic and/or autonomic parts of the peripheral nervous system."  To fulfill this definition, a complete family and personal history, a comprehensive physical and neurological examination, quantitative clinical testing and laboratory evaluations are needed to rule out non-diabetic nerve disease including the consensus panel’s review of the validity, reproducibility and concordance of the available methodologies for in assessing diabetic peripheral neuropathy identified the following evaluations are the most useful and practical: signs and symptoms; electrophysiology, autonomic nervous system testing and quantitative sensory testing (QST) They recommended that to fully classify neuropathy, at least one measure from each of the above categories should be obtained.  Symptoms of neuropathy include loss of sensation perception, pain, abnormal functioning of internal organs causing indigestion, diarrhea or constipation, dizziness, bladder infections, and impotence. Diabetic neuropathy can be classified as follows:

Symmetrical polyneuropathy (most common form)

      Symmetrical distal sensory distribution (glove & stocking)

      Predominantly sensory, sensory-motor polyneuropathy

   Distal to proximal progression

   Small fiber involvement with pain and 9 temperature perception

   Large fiber involvement with paresthesias and  9 or absent ankle reflexes

   Slow progression

   Occurs in both Type I and Type II diabetes

   Progression may be slowed with aggressive blood sugar control

Autonomic neuropathies

      Cardiovascular with impaired cardiovascular reflexes and silent ischemia

   Genitourinary with impotence and reduced of bladder emptying

   Gastrointestinal with constipation, nocturnal diarrhea, gastroparesis

Acute painful neuropathy

      Rapid weight loss, burning & hypersensitivity of soles of feet, sensory loss

      Often occurs after a sudden improvement of glucose control

Rapidly reversible neuropathies

      Hyperglycemia in newly diagnosed, untreated diabetes with asymptomatic 9 in NCV

      Seen after hypoglycemic treatment with transitory distal lower limb paresthesias

Chronic immune demyelinating polyneuropathy

Asymmetric neuropathies

      Diabetic amyotrophy

·         Asymmetric pain in hip, buttock, or thigh with little sensory involvement and weight loss

·         Proximal weakness in the quadriceps, thigh adductors and psoas muscles

·         Localized to lumbosacral plexus or upper lumbar roots

·         May be seen with poor diabetic control or rapid glucose reduction

·         Slow recovery over 1-2 years after diabetic control

Mononeuropathies

      Cranial nerve

·         Sudden onset of 3^rd nerve in older diabetics

·         Retro-orbital pain with sparing of pupil involvement

·         Recovery usually seen within weeks

·         7th nerve may be involved

Limb

·         Abrupt & painful onset in major limb nerves possibly due to vascular events

·         Common at compression sites with recovery best with distal lesions

Trunk

·         Acute, unilateral non-radicular pain in distribution of thoracic nerves

·         Hypersensitive skin region

·         Common in patients > 50 years with accompanying weight loss & difficult to manage

·         Spontaneous improvement over 1 to 2 years

WHAT‘S THE IMPACT OF NEUROPATHY IN DIABETES?

Of the more than 16 million people in the United States, peripheral neuropathy may be present in up to 90% of patients with 25% having clinical signs or symptoms. The precise prevalence and incidence of diabetic neuropathy are often difficult to decipher due to the: 1) presence of intercurrent peripheral nerve disorders in the diabetic that may mimic diabetic neuropathy; 2) lack of agreement on the definition of diabetic peripheral neuropathy; 3) lack of instrumentation and methodologies available to detect and quantify the severity of neuropathy; and 4) demographic factors which influence neuropathy such as age, sex, body mass indexes (BMI), height, weight, type and duration of diabetes, level of glucose control, and duration of neuropathy.   

WHAT ARE THE TYPES OF DIABETIC NEUROPATHY?

DN can presently be classified into two distinct types; the diffuse neuropathies (distal symmetrical sensorimotor polyneuropathy and autonomic neuropathy) and the focal neuropathies (entrapments, mononeuropathy, plexopathy, amyotrophy, radiculopathy, and cranial neuropathy).  The pathogenesis of the neuropathies is complex and may involve the interaction of multiple factors, including vascular, metabolic, mechanical, and environmental disturbances.

Symmetric polyneuropathies. The insidious onset and clinical features (burning pain, numbness, and tingling) of these syndromes suggest a metabolic basis.  Several metabolic abnormalities have been demonstrated in the peripheral nerve cells including defects in neuronal protein synthesis, axonal transport, myo-inositol and inositol depletion, accumulation of nerve sorbitol and altered lipid and protein synthesis in the Schwann cell.  This is the most common type and is often referred to as a glove & stocking neuropathy since it is associated with early degeneration of the distal sensory axons (distal axonopathy) which progresses in retrograde direction (dying back) towards the dorsal root ganglia. Sensory abnormalities in the lower extremities are more common since the distal ends of longest myelinated and unmyelinated axons are the first to undergo degeneration.  Loss of neuronal function may lead to sensory deficits to vibration, thermal discrimination, thermal pain, proprioception, circumference discrimination, light touch, etc. Spontaneous, ectopic impulses from A-delta and c-fibers in these degenerating axons may cause unpleasant symptoms of paresthesia ("pins-and-needles"), pain, allodynia, or hyperesthesia.  

Mononeuropathies.  These present as an abrupt onset with frequent spontaneous improvement and may have a vascular basis. They typically occur in elderly patients and can be very debilitating when they occur. 

WHAT SYMPTOMS DO PATIENTS EXPERIENCE?

Symptoms of diabetic neuropathy can be grouped into two distinct classes - positive symptoms (unpleasant symptoms which patients complain about) and negative symptoms (loss of feeling which patients rarely complain about). The positive symptoms include severe dysesthetic burning (most often in the feet and ankles and to a lesser extent in the upper extremities) with nocturnal worsening, cutaneous contact discomfort (allodynia) where the weight of the bed sheets or wind blowing on leg hairs may cause excruciating pain, thermal hyperalgesia, paresthesia, insomnia, weight loss, anxiety, depression, and absenteeism from work.  Painful neuropathy symptoms can accompany either the diffuse or focal neuropathies. The prevalence of painful neuropathy in Type II diabetic patients is 32.1% and in Type I diabetics 11.6%.  The specific descriptors patients may use to describe pain is varied and include burning sensation, tingling, prickling, pins & needles, electric, sharp, shooting, cutting, broken glass, dull or deep aching, cramps or spasms, band like feeling, squeezing, jabbing, crushing, numbness, and coldness.

CAN POLYNEUROPATHY BE TREATED?

Some polyneuropathies can be treated once a diagnosis is established.  However, diabetic neuropathy currently has no approved treatment.  The following measures may be beneficial: maximize glucose control; examination of the feet; fitting of foot orthoses; patient education and awareness; cessation of smoking; weight reduction; and annual neuropathy and vascular testing.  Studies are currently underway to evaluate an aldose reductase inhibitor as a treatment for diabetic neuropathy.  Some nutritional supplements such as evening primrose oil (GLA-Gamma Linolenic Acid), L-carnitine, inositol, lipoic acid and B-vitamins may be of some value.

WHAT TREATMENTS ARE AVAILABLE FOR PAIN

Although there is no specific treatment approved for diabetic neuropathy, the pain associated with it can be treated using a variety of “off-label” medications.  Painful diabetic neuropathy has been reported to respond palliatively to a number of drugs including topical lidocaine (LidoDerm^Ò Patch, Lidocaine Gel, topical capsaicin; NSAIDs; antiepileptic drugs (anticonvulsants are used to manage neuropathic pain, especially when the pain is lancinating or burning. Phenytoin, carbamazepine, valproate, and clonazepam suppress spontaneous neuron A1firing and are used to control lancinating pain complicating nerve injury (Swerdlow, 1984). Dose-related transient bone marrow suppression, which is associated with carbamazepine therapy (Horowitz, Patwardhan, Marcus, 1988; Pellock, 1987), requires that it be used with caution in cancer patients undergoing other marrow-suppressant therapies, such as chemotherapy and radiation therapy. Toxicity often correlates with high concentrations in serum, and levels in serum of phenytoin, valproate, carbamazepine,  gabapentin, clonazepam, ethosuximide, lamotrigine, primidone, divalproex should be monitored routinely (for example, monthly in the stable patient). Systemically administered local anesthetic (intravenous lidocaine, oral mexilitine, and tocanide) and antiarrhythmic agents have been used clinically to treat neuropathic pain (Brose and Cousins, 1991; Dejgard, Petersen, and Kastrup, 1988), although this is not currently an FDA-approved indication for these drugs.); antidepressants (doxepin, amitriptyline, trazodone, imipramine; phenothiazine, fluphenazine, trifluoperazine, venlafaxine); opioids (hydromorphone, codeine, oxycodone, hydrocodone, methadone, levorphanol, fentanyl, meperidine), NMDA inhibitors (Dextromethorphan, Memantidine).  Painful neuropathy is one of the most distressing symptoms of diabetic neuropathy and spontaneous remission may be due to resolution of the neuropathy or progression to anesthesia, putting the patient at risk of developing foot ulcers. When neuropathic pain persists for >12 months, the pain usually does not resolve spontaneously and may last for many years.  Some of the newer anti-epileptic drugs have demonstrated significant beneficial effects in reducing pain and clinical studies are underway to evaluate them further.

Next week Part 2

HOW IS PERIPHERAL NEUROPATHY EVALUATED?

WHAT ENDPOINTS CAN BE MEASURED?

WHAT IS QUANTITATIVE SENSORY TESTING?

Drugs Associated with Peripheral Neuropathy

Diseases Associated with Peripheral Neuropathy

QUESTIONS PATIENTS OFTEN ASK ABOUT DIABETIC NEUROPATHY

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