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Mesdames et Messieurs
C'est la première fois de visiter Le l'Algérie et de parler aux Algériens sur quelque chose comme Neuropathie diabétique.
Premièrement Je voudrais remercier le comité d'organisation d'organiser et de m'inviter dans cette conférence importante.
Diabetic Neuropathy (Neuropathie diabétique)Introduction
Diabetes is a growing problem in the whole world, the Center for Disease Control estimates that from 1980 through 2007, the number of Americans with diabetes increased from 5.6 million to 23.6 million. The total prevalence of diabetes increased 13.5% from 2005-2007. Only 24% of diabetes is undiagnosed, down from 30% in 2005 and from 50% ten years ago.The WHO in 2000 estimated diabetics allover the world nearly by 171 million and proposed that by 2030 the number will be 366 million.
Diabetes Mellitus : a metabolic condition that is characterized by abnormal sugar metabolism .Type 1 diabetes ‘Juvenile onset diabetes’
‘Insulin dependent diabetes (IDDM)’Reduced insulin production Caused by autoimmune destruction of insulin-producing cellsTreated with insulin replacement
Type 2 diabetes ‘Late onset diabetes’‘Non-insulin dependent diabetes (NIDDM)’Reduced sensitivity to insulinAssociated with obesity, physical inactivity, poor diet, genetic predispositionMay eventually become IDDM
Gestational diabetes: occurs in 2-5% of all pregnancies and disappear after child birth.
Others:Drug-inducedInfection-relatedDiseases of exocrine pancreas
Introduction
Microvascular damage– Nephropathy (kidneys)
Damage to glomeruliBlood albumin leaks into urine (diagnostic)Loss of filtration capacity (kidney failure)
– Retinopathy (eyes)Proliferation of fragile blood vessels in retinaBlood protein leaks into eyeScar tissue damages retina
– Neuropathy (nerves) Damage to nerve fibers and capillariesMacrovascular damage– Atherosclerosis (deposits in blood vessels)
75 % of early diabetic deaths– Angina (reduced blood flow to heart)
Chest painsHypertension (high blood pressure)– Heart and kidney disease
Long Term Problems
Diabetic Neuropathy (Neuropathie diabétique)
Is it a pain or …..?
It is a family of nerve disorders
Diabetic neuropathies are a family of nerve disorders caused by diabetes.
About 60 to 70 percent of people with diabetes have some form of neuropathy.
People with diabetes can develop nerve problems at any time, but risk rises with age and longer duration of diabetes. The highest rates of neuropathy are among people who have had diabetes for at least 25 years.
Diabetic neuropathies also appear to be more common in people who have problems controlling their blood glucose, as well as those with high levels of blood fat and blood pressure and those who are overweight.
Introduction
Incidence of Diabetic Neuropathyas a proportion of all diabetics 20 years after diagnosis
No neuropathy 10%
Asymptomatic 40%
Symptomatic 50%
0
5
10
15
20
25
1995 2025
Hogan P, et al. Diabetes Care. 2003;26:917-932.King H, et al. Diabetes Care. 1998;21:1414-1431.
Patie
nts
(mill
ions
)
Diabetic NeuropathyDamage to nerve fibers and capillaries (nerve fibres degenerate & Blood vessels supplying the nerves are ‘grossly diseased’).
Symptoms depend on nerves involved– Motor fibers : Muscular weakness– Sensory fibers : Loss of sensation
also prickling, tingling, aching and pain– Autonomic fibers : loss of function
functions not under conscious control such as digestion, bladder, genitals, cardiovascular.
Other Consequences– Diabetic foot (15% of all diabetics)– Fractures due to falling.– Compression neuropathies
eg carpal tunnel syndromeDrop foot.
Pathology and pathogenesis
There are four factors thought to be involved in the development of diabetic neuropathy:
Micro vascular insufficiency.
Advanced Glycation Endproducts (AGEs).
Protien Kinase C (PKC).
Polyol Pathway (Poly hydroxy alcohol).
Micro vascular insufficiency Theory
Advanced Glycated Endproducts (AGEs)
Elevated intracellular levels of glucose cause a non-enzymatic covalent bonding with proteins, which alters their structure and inhibits their function. – Non-enzymic reaction with proteins & DNA
Advanced Glycation End-products (AGEs)– Damage to capillaries and nerve fibers– Specific cellular AGE receptors– Protein cross-linking
Some of these glycosylated proteins have been implicated in the pathology of diabetic neuropathy and other long term complicationsof diabetes.
Hyperglycemia
Excess glucose converted to Sorbitol
& fructose
Excess Sorbitol & fructose
Diminished nerve myoinositol
Na/K ATPase activity
Impaired axon transp[ort
(structure breakdown)
Abnormal action potential (neuronal dysfunction)
Aldose reductase enzyme
Polyol theory Sorbitol / Aldose Reductase Pathway.
Protein kinase C (PKC )
Increased levels of glucose cause an increase in intracellular diacytylglycerol (DAG), which activates PKC.
Activation of protein kinase C (PKC) via DAG (DiAcytylGlcerol)Damages capillaries (permeability, contractility)Disturbed nerve function.
PKC inhibitors in animal models will increase nerve conduction velocity by increasing neuronal blood flow.
NeuropathiesClinical Classification
Focal ( mononeuritiditis, multifocal and entrapment)Diffuse– Proximal– Distal
large-fiber (ataxia)– Weakness– Wasting– Impaired Vibration– Loss of Position sense– Loss of reflexes– Interferes with QOL and ADL
small-fiber (Autonomic)– Pain– Thermal– Normal strength and reflexes– Electrophysiogically silent– Produces symptoms and leads to morbidity and mortality
Types of diabetic neuropathyPeripheral neuropathy, the most common type of diabetic neuropathy.Autonomic neuropathyProximal neuropathy causes pain in the thighs, hips, or buttocks and leads to weakness in the legs. Focal neuropathy or multifocal.
Peripheral neuropathy affectsToes Feet Legs Hands Arms
Diabetic Peripheral Neuropathy Severity Scale
Adapted from Dyck PJ. Muscle Nerve 1988; 11:21-32.
Rating Description0 No neuropathy
1 Subclinical diabetic peripheral neuropathy
2a Clinical diabetic peripheral neuropathy with symptoms, mild to moderate
2b Clinical diabetic peripheral neuropathy insensate foot, loss of feeling / negative symptoms
3 Disability / late stage
Pupillary– Decreased diameter of dark-adapted pupil– Argyll-Robertson type pupil
Metabolic– Hypoglycemia unawareness– Hypoglycemia unresponsiveness
Cardiovascular– Tachycardia, exercise intolerance– Cardiac denervation– Orthostatic hypotension– Heat intolerance
Neurovascular– Areas of symmetrical anhydrosis– Gustatory sweating– Hyperhidrosis– Alterations in skin blood flow
Gastrointestinal– Constipation– Gastroparesis diabeticorum– Diarrhea and fecal incontinence– Esophageal dysfunction
Genitourinary– Erectile dysfunction– Retrograde ejaculation– Cystopathy– Neurogenic bladder– Defective vaginal lubrication
Autonomic neuropathy affects
Proximal neuropathyIt affects thighs, hips, or buttocks and legs, pain leads to weakness in the legs, (sometimes called lumbosacral plexus neuropathy, femoral neuropathy, or diabetic amyotrophy) usually on one side of the body.
It is more common in those with type 2 diabetes and in older adults with diabetes.
It causes weakness in the legs and the inability to go from a sitting to a standing position without help.
Treatment for weakness :– Strength: Improved handgrip, leg press, knee
extension and foot dorsiflexion and extension– Balance: Improved backward tandem walking– Neurovascular function improved
The length of the recovery period varies, depending on the type of nerve damage.
Peripheral mono neuroapathy– Single nerve damage due to compression or ischemia– Occurs in wrist (carpal tunnel syndrome), elbow, or foot (unilateral foot
drop)– Other nerves susceptible to entrapment may cause pain on the outside
of the shin or the inside of the foot.
– Symptoms:NumbnessEdemaPainPrickling
Focal neuropathy or MononeuropathyIt appears suddenly and affects specific nerves. It is painful and unpredictable and occurs most often in older adults with diabetes.It tends to improve by itself over weeks or months and does not cause long-term damage.Cranial mononeuropathy– Affects the 12 pairs of nerves that are connected with the brain and
control sight, eye movement, hearing and taste– Symptoms:
Eyes: inability to focus the eye - double vision - aching behind one eye. Facial muscles paralysis on one side of the face, called Bell’s palsy.Ears.
DPN is characterized by a stocking and glove distribution:
– Bilateral symmetrical distribution of signs and symptoms
– Affects lower limbs first
– Progresses from distal (toes) to proximal (knee) over time.
Excrcise often relives pain.hyperalgesia allodynia hyperpathia
DPN affects the limbs symmetrically and progresses from distal to proximal over time.
Signs and symptoms progress
from distal to proximal over time
Diabetic Neuropathy (Boulton), 2001
Clinical Manifestations
A Simplified View of The PNS
Progress Over Time
Symptoms (numbness, prickling, pain)
Reflexes
Pressure Sensation (Monofilament)
Vibratory Sensation
Nerve Conduction Abnormalities
Subclinical Clinical
Time
Sig
ns
Onset ofClinical Diseases
Adapted from ADA. Diabetes Care. 2003;26:S33-S50; Abbott CA, et al. Diabetes Care. 1998;21:1071-1075; Armstrong DG, et al. Arch Intern Med. 1998;158:289-292; Armstrong DG, et al. Ostomy Wound Manage. 1998;44:70-76; Carrington AL, et al. Diabetes Care. 2002;25:2010-2015; Feldman EL, et al. Diabetes Care. 1994;17:1281-1289; Shearer A, et al. Diabetes Care. 2003;26:2305-2310; Veves A, et al. Diabet Med. 1991;8:917-921.
Symptoms may occur any time and intermittently
Patients may or may not have symptoms of diabetic peripheral neuropathy
Patients frequently do not report symptoms to their physicians until the symptoms are severe
The majority of signs of diabetic peripheral neuropathy are not evident at the onset of diabetes
Diabetic Peripheral Neuropathy Severity Scale
Adapted from Dyck PJ. Muscle Nerve 1988; 11:21-32.
Rating Description0 No neuropathy
1 Subclinical diabetic peripheral neuropathy
2a Clinical diabetic peripheral neuropathy with symptoms, mild to moderate
2b Clinical diabetic peripheral neuropathy insensate foot, loss of feeling / negative symptoms
3 Disability / late stage
Clinical Guidelines for Early Detection of Diabetic Peripheral Neuropathy
Adapted from Boulton AJM, et al. Diabet Med. 1998; 15(6):508-514.Adapted from Dyck PJ. Muscle Nerve 1988; 11:21-32
Stages CharacteristicsStages 0/1:No clinical neuropathy No symptoms or signs
Stage 2a: Clinical neuropathy
Positive symptomology (increasing pains at night): burning, shooting, stabbing pains, “pins & needles”; absent sensation to several modalities and reduced or absent reflexes
Less common–diabetes poorly controlled, weight loss; diffuse (trunk); minor sensory signs
Stage 2b: Clinical neuropathy
No symptoms or numbness of feet; reduced thermal sensitivity; painless injury
Stage 3:Disability/late stage
Foot lesions (eg, ulcers); neuropathic deformity (eg, Charcot joint); non-traumatic amputation
History Distal, symmetric, more severe at night Drugs-vitamin excess, toxins, amiodarone, INH, chemotherapy Family history
Exam Neurological exam including sensory testing Evaluation for signs of different neuropathy
Lab Vitamin B12/folate, TSH, fasting blood glucose, serum/urine electrophoresis
Special EMGNCVUltrasound
How to assess diabetic neuropathies?
Components of a Diabetes Treatment Plan
Mission:– Improve the health of people with diabetes
Goals:– Lengthen life– Reduce illness and disability
Objectives:– Diagnose diabetes prior to onset of complications– Control glucose, blood pressure, and lipids to target levels
How are diabetic neuropathies treated?Cornerstone Tight control Treatment of Diabetes (tight glycemic control).Treatment of complications of diabetes.Patient education (achieve optiomal body weight, regular excercise & tight sugar level control).
Stages Objectives Referral
Stage 0/1: No clinical neuropathy
Education to reduce risk of progression; glycemic control; annual assessment
As required
Stage 2a:Clinical neuropathy
Stable glycemic control; symptomatic treatment Diabetologist, neurologist
Stage 2b: Clinical neuropathy
Education, especially foot care; glycemic control according to needs
Foot care team
Stage 3:Disability/late stage
Prevention or new/ recurrent lesions and amputation; emergency referral if lesions present; otherwise referral within 4 weeks
Diabetologist, neurologist, chiropodist, podiatrist, diabetes specialist nurse, diabetic foot clinic if available
Adapted from Boulton AJM, et al. Diabet Med. 1998; 15(6):508-514.Adapted from Dyck PJ. Muscle Nerve 1988; 11:21-32
Treatment of complications of diabetes.
Painful diabetic neuropathyAntidepressantsAnticonvulsantsOpioidsCannabinoids.Topical agentsCombined therapy.
Future therapies:– Antioxidants, eg. alpha lipoic acid.– Aldose reductase inhibitors, eg. Sorbinil, Ponalrestat, Tolrestat– PKC inhibitors
Gastrointestinal Problems: erythromycin; metoclopramide..
Urinary and Sexual Problems: antibiotics for infections;
Foot care
Criteria for choosing an agent for neuropathy pain management
Evidence based Superior pain relief Persistent effect Few / mild side effects Positive effect on QOL Low cost
Drugs for Diabetic Neuropathic Pain
Golden Rule:Start low and go slow and titrate the effect and side effect.
Anticonvulsants Tricyclic antidepressants OpioidsCannabinoids Topical agents
If these don’t work, a systemic local anesthetic Consider corticosteroids
Gabapentin (Neurontin) Dose :300mg/day, safe up to 3600mg/day.Pregablin ( Lyrica) Dose: 75 BID safe up to 600mg/day.Carbamazepine (Tegretol) :200-800 mg/day divided BID –QID.Phenytoin (Dilantin) :(200-600 mg/day BID –TID).Valproic acid (Depakote) (500-1500 mg/day BID -TID).Lamotrigine (Lamictal) (50-400 mg/day BID).
Mechanisms of Action of Anticonvulsants Block / modulate sodium, calcium channels
– Decrease action potential frequency– Decrease excitation or decrease NT release
Increase GABA-ergic transmission– Increase inhibition
Decrease Glutamatergic transmission– Decrease excitation
Anticonvulsants
Antidepressants
Tricyclic antidepressants:(Amitryptyline-Nortriptyline-Desipramine).
Selective Serotonin Reuptake Ihibitors (SSRIs): include fluoxetine, paroxetine, sertraline and citalopram.
Serotonin Noradrenaline Reuptake Ihibitors (SNRIs): (Venlafaxine, Duloxetine..)
Others
Tricyclic antidepressants
Amitryptyline - Nortriptyline - DesipramineDose titration can take a long time Have a narrow therapeutic window May produce intolerable side effects before get benefit: sedation, orthostatic hypotension, urinary retention, rare cardiac conduction problems
What is the effective dose of tricyclic antidepressant?Start with 10-25 mg/day Increase by 10-25 mg every few days Maximum dose 150 mg/day
Tramadol Norepinephrine and serotonin reuptake inhibitor with a major
metabolite that is a mild μ opioid receptor agonist
• Dose 300 mg/day in divided doses (adjusted for elders) – Start with 50 mg BID – Adjust by 50-100 mg/day every 3-7 days
• Adverse effects – Dizziness – Somnolence – Constipation – Nausea –Confusion
• Contraindications – History of seizure – Serotonergic agents, risk of serotonin syndrome
Opioids
Side effects: Constipation, Sedation, Respiratory depression, Nausea/vomiting and Pruritis.
Start low and increase slow
Begin with lower potency short-acting agent – Hydrocodone 5-10 mg q 6 hours – Oxycodone 2.5-10 mg q 6 hours
Convert to extended release form – Oxycodone SR 5-10 mg q hs or q 12 hours – Morphine SR 15-30 mg q hs or q 12 hours
Use short acting agent for breakthrough pain.
Combination Therapy
A tricyclic antidepressant and an opioidAnticonvulsant + opioid :Gilron et al., morphine and gabapentinAn oral and a topical agentTricyclic antidepressant and an strong opioid
NEJM;352; 1324-1334 ( March 31/05)
Gabapentin - Opioid – Superior analgesia at lower doses – Lower tolerated maximal dose – Higher frequency of constipation and dry mouth
Take home messages
Diabetic neuropathy is a painful, debilitating complication of diabetes. Patients have difficulty finding relief.
No single treatment works for all neuropathic pains. Any one approach has about a 50 : 75% change of bringing some relief. Combinations often needed
We treat pain and co-morbidity: sleep disturbances, mood disturbances & quality of life.
Duration of pain treatment as long as necessary (drug holiday after e.g. 1 year). Plan for long term reassessment, titration, and follow-up
There are new drugs on the horizon that have the promise of not only slowing the disease progression but, also causing nerve regeneration (ARIs, AGEs I, PKC I , Antioxidants & Neurotrophic agents).
Merci pour votre attention.Thank you for your attention.
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