1. MANAGEMENT OF PAINFUL DIABETIC NEUROPATHY IN THIS MILLENNIUM Prof. A.V. SRINIVASAN, MD, DM, Ph.D, F.A.A.N, F.I.A.N, WALKING THE BEST MEDICINE FOR DIABETES HOTEL HILTON TRIDENT 24-09-2006
2. Diabetic neuropathy Interoduction Pathogenesis Diagnosis & evaluation clinical Electrophysiology Lab investigations Blood investigations- to r/o other causes. Biopsy of nerves. Monitoring and clinical scoring systems Functional disability Rehablitation Vedanta admits realization But defies verbal definition
3. DIABETES MELLITUS 1990 – 2000 – Decade of brain. 2001-2010 - Decade of pain control & research India – Diabetic capital of the world. Every fifth Indian will be a diabetic. Every fifth diabetic in the world will be an Indian. 32 million diabetics at present. 250% rise by 2035 – 100 million Pure love ever gives Never seeks
4. Diabetic neuropathy-definition A demonstrable disorder, either clinically evident or subclinical, that occurs in the setting of diabetes mellitus without other causes for peripheral neuropathy. Manifestation may be somatic and/or autonomic Science is below the mind; Spirituality is beyond the mind
5. Oxidative stress Hyperglycemia ↑ NO↑Aldose reductase activity 3 Anti phospholpid antibody Ab to gangliosides. 1 GLA deficiency 4 Nerve damage 5 ↓PGI2,PG Nerve growth factor deficiency 2Protein kinase C deficiency Microvasculopathy
6. Diabetic polyneuropathy The most common type of diabetic neuropathy. Presents primarily with sensory symptoms & pain May have a prominent autonomic component. Associated with secondary complications of neuropathy Of a burning and unremitting character - F.W.PAVY
7. Prevalence of Polyneuropathy (Variable depending on criteria)All patients Type 1 Type 2withpolyneuropathySymtomatic 54% 45%polyneuropathyNeuropathy 15% 13%impairmentscale.+ 7 (Rochesterabnormal tests study)
8. Classification of diabetic neuropathy Diffuse Focal Distal symmetric Mononeuropathies sensorimotor neuropathy Entrapment neuropathies -large fiber Truncal neuropathy -small fiber Cranial neuropathy Autonomic Focal amyotrophy. Symmetric proximal lower limb motor neuropathy (Amyotrophy) What is mind no matter What is matter never mind
9. Diagnosis of polyneuropathy3 challenges Clinical signs & symptoms are due to polyneuropahy. Categorisation of polyneuropathy Etiology- history, investigations- lab, immunological,histological,genetic. 25 – 30% - cause not identified. Speak obligingly even if you cannot oblige
10. Evaluation of polyneuropathy History Clinical examination. Electrophysiological testing – extension of clinical examination Laboratory investigations. Every thing should be made as simple as possible; but not simpler
11. Clinical characteristics Polyneuropathies of many different etiologies have similar signs & symptoms. Though the features are common the patterns are different. The clinical features result from Lack of function – negative symptoms & signs abnormal function – positive symptoms & signs Knowledge without action is useless; Action without knowledge is foolish
12. Clinical characteristics Clinical course – acute, subacute chronic prgressive, remitting and relapsing forms Distribution of involvement distal Vs proximal symmetrical Vs asymmetrical Upper limb Vs lower limb predominance. Hate screeches, fear squeals; conceits trumpets but love since lullabies
13. Clinical characteristics Types of fiber involvement Motor, large sensory, small sensory, autonomic Inheritance – family history. History of exposure to toxins and drugs, concomittant illness. Learn to adapt, adjust and accommodate Learn to give, not to take and learn to serve not to rule
14. Clinical manifestations Motor - weakness,atrophy, fatigue. Sensory – sensory loss, paresthesias. DTR – diminished or absent Autonomic dysfunction Skeletal deformity.Teachers are reservoirs from which, through the process of education, the students draw the water of life
15. Neurological manifestations negative positiveMotor Weakness, Fasciculations, atrophy,fatigue cramps reduced tone myokymiaReflex Hypo or areflexia _Small fiber Decrease of pain & Spontaneous dull temperature sensation, burning pain Loss of visceral pain hyperesthesia sensation parasthesia Foot ulceration Love is selfishness and selfishness is lovelessness
17. Axonal Vs Demyelination(Clinical) Demyelinating AxonalMuscle atrophy Slight SevereWeakness Severe SevereReflexes Global areflexia Knee & UL preservedSensory signs Motor > sensory Significant
18. Risk factors For Painful neuropathy For painless neuropathy Hyperglycemia Greater height Hypertension Male gender Dysmetabolic syndrome Smoking HT+DM+IHD+DYSLIPIDEMIA Total abstinence from alcohol High HbA1C When they tell you to grow up, they mean stop growing
19. Types of painful neuropathies Acute (< 6 months) Chronic(> 6 months) Truncal neuropathy. Distal symmetrical painful cachectic neuropathy-Acute, sensorimotor painful,wt.loss,poor control of polyneuropathy DM Entrapment neuropathies Insulin neuritis -Acute painful, weight loss, good control of Difficult to treat. DM Painful 3rd cranial nerve palsy. Easy to treat. Speak obligingly even if you cannot oblige
20. Clinical features – Distal symmetrical painful sensorimotor polyneuropathy Burning, superficial pain. Hypoalgesia in later stages. Defective thermal sensation. Impaired vasomotion Defective autonomic function Intact DTR and power till late stages. Progressive with increasing duration of diabetes. Related to glycemic control & complications.
21. Clinical features – Truncal neuropathy Truncal polyneuropathy Truncal radiculopathy Rare Acute onset of pain in a Occur in long standing DM radicular pattern “Bandlike” Painful Asymmetrical pain symptoms in thoracic root Patchy sensory loss is a distribution clue to the diagnosis. Motor involvement- muscle herniation – asymmetric bulge in abdominal wall Learn to adapt, adjust and accommodate Learn to give, not to take and learn to serve not to rule
22. Clinical features Insulin neuritis Acute painful, occurs 1 month after insulin /OHA. Due to rapid glycemic control. Nerves in these patients are under general hypoxia and use glucose under anaerobic conditions. Once glucose is normalised in blood and nerves, glucose is no longer available and the nerves undergo degeneration.Reputation is made in a moment; character is built in a life time
23. Insulin neuritis- contd.., Burning pain, paraesthesia, allodynia with nocturnal exacerbation. Depression is a feature. No weight loss. Sensory loss is mild. No motor signs. Complete resolution in 1 year. A good teacher is a perpetual learner
24. Clinical features - Cachectic neuropathy In patients with a poor control of DM. Wt.loss is prominent. Severe burning pain- continuous or intermittent. Subjective feeling of swollen limb. Allodynia is common- nocturnal exacerbation. Sensory loss is mild. No motor signs.The Truth is fear and im oralityare two of the greatest inhibitors of m P erformance to progress
25. Cranial nerve palsy Most common mononeuropathy Acute pain in the orbit, ptosis, opthalmoplegia, pupil spared. Usually unilateral Complete recovery in 3 months. Vascular etiology suggested. 6th & 7th cranial nerve involvement are described. Hate screeches, fear squeals; conceits trumpets but love sings lullabies
26. Electrophysiology (EDX) Confirm presence of PN. Demyelination or Axonal. Motor, sensory or a combination. Assess severity and distribution. Follow the course of the disease.Science is below the mind; Spirituality is beyond the mind
27. Axonal Vs Demyelination(EDX) Demyelinating AxonalMCV/SCV Slowing in 2 or Normal/ slightly more nerves to reduced less than 60%Conduction block Present in one or No more motor nerves.Fibrillation Scanty Generally prominent
28. Axonal Vs Demyelination(EDX) Demyelinating AxonalMotor/sensory Slightly reduced Significantlyamplitude reducedDistal latency Prolonged in 2 or Normal/ slightly more nerves prolongedLate responses Prolonged or Normal/ slightly missing in 2 or prolonged more nerves
29. EDX Conduction block is the sign of focal demyelination Conventional NCS measures distal segments. F latency and penetration measure proximal segments. Temporal dispersion and conduction block occur only in acquired neuropathies Asymmetrical and multifocal lesions distinguish acquired from inherited polyneuropathies. Whatever the Mind can conceive and Believe, the mind can Achieve Napoleon Hill
30. EDX- Recommendations In clinical practice only a few cases fulfill the classic criteria of one group or the other of neuropathies rules- Test several nerves. Both upper & lower extremity should be sampled. Should include sensory & motor nerves. Recording of F responses. Concentric needle examination is an important complementary examination.Many Ideas grow better when transplanted into another mind than in the one where they sprang UP O.W. Holmos
31. EDX- Recommendations Distal and proximal muscles of at least one lower and upper extremity should be sampled. Paraspinal muscles should be sampled in suspected proximal involvement. In Ul – biceps and first dorsal interossei. In LL – anterior tibial and quadriceps. Avoid intrinsic foot muscles – as repeated trauma may show neurogenic abnormalities. Ratio of sural to radial SNAP Incorpotation of anthropometric factors.
32. Diagnosis & monitoring The neuropathies associated with DM represent insidious and progressive processes for which a disconnect exists between pathological severity and the development of symptoms. DSP leads to leg ulceration and amputation. DSP is strongly related to glycemic control. DSP affects motor, sensory, and autonomic fibers. Axons are affected in a length dependent manner and there is a centripetal pattern of axonal degeneration.
33. Screening for DSP The early identification is justified as it offers a crucial oppurtunity to actively alter the course of suboptimal glycemic control and prevent morbidity. Optimal screening is desirable rapid and simple High inter-observer reproducibility Valid against objective criterion standard. Generalizable to wide range of clinical presentation.
34. Semmes-Weinstein Monofilament Examination (SWME) Semmes-Weinstein monofilament 5.07 (10 grams) 4 stimuli per foot on the dorsum of the first toe proximal to the nail bed. >1 insensate stimuli is associated with small chance of DSP as measured by NCS. >5 insensate stimuli is associated with high probability of DSP. An abnormal SWME is associated with a 3 year relative risk as high as 15 for ulceration or
35. Clinical scoring systems To summarize large volume of information from clinical examination and provide a quantitative value which can be followed longitudinally. Neuropathy Impairment Scale (NIS) in the lower limbs (LL) + 7 – (NIS[LL]+7) Michigan neuropathy screening instrument - has a 15 item questionnaire and a simple clinical examination of the feet. Toronto clinical scoring system .
36. Scoring systems (NIS[LL]+7) Neuropathy Impairment Scale (NIS) in the lower limbs (LL) + 7 – (NIS[LL]+7) – includes NCS, Vibration perception threshold (VPT), and autonomic function. (HR variability with deep breathing) all in percentile system converted into points. Time consuming, not used in primary care. The points are weigheted in favor of motor findings.
37. Scoring systems- Michigan neuropathy screening instrument An abnormal score in Michigan neuropathy screening instrument initiates referral for NCS – and the second evaluation is Michigan Diabetic Neuropathy Score. The scale is validated, employed in clinical research trials to monitor DSP. Time consuming , not used in routine practice. When they tell you to grow up, they mean stop growing P. Diccaso
38. Clinical scoring system – Toronto scoring system for DSPSymptom score Reflex score Sensory test scoreFoot pain Knee reflexes PinprickNumbness Ankle reflexes TemperatureTingling Light touchWeakness VibrationAtaxia Position senseUpper limbsymptomsPresent=1,absent=0 (numbness, tinglingas perceived in toes and in feet)Reflex scores absent=2, reduced=1, normal=0 for each side.Sensory test score abnormal=1, normal=0. Maximum score is 19.
39. Quantitative sensory testing(QST) QST provides quantitative information on sensory function. Non standardised. Contribute to clinical scales. Used in follow the progression. Limited objectivity and reliance on subjective responsiveness. Can be abnormal in CNS disorders. Visual perception Threshold (VPT) Thermal Threshold Testing (TPT) A good teacher is a perpetual learner
40. Diabetic Autonomic Neuropathy(DAN) DAN results from damage of myelinated and small myelinated fibers which cannot be assessed by conventional NCS.•BP changes during active standing•BP changes during passive tilt•BP changes during valsalva manuver•BP & HR changes during facial immersion in ice water.•BP changes during active standing•HR power spectral analysis. “ He who cannot forgive others destroy the bridge over s which he him m pass”- Annoy self ust
41. DAN- sympathetic- cholinergic Thermoregulatory sweat test. Quantitative pseudomotor axon-reflex test (QSART) Sympathetic skin response. Sweat imprint. It is not your position that makes you happy or unhappy It is your disposition
42. DAN-Parasympathetic Respiratory sinus arrythmia during deep breathing.(HR variability) HR changes during valsalva manuver (Valsalva ratio) HR changes during during active standing(ratio 30:15) HR power spectral analysis. Learn to adapt, adjust and accommodate Learn to give, not to take and learn to serve not to rule
43. Physiological changes & clinical consequences↑ threshold weakness & sensory lossDesynchronisation & areflexia and loss oftemporal dispersion vibration sense.Prolonged refractory period ↓ strength at maximal contractionExaggerated fatiguehyperpolarisationEctopic impulses → . spontaneous parasthesias
44. Differntial diagnosis Claudication Radiculopathy Charcoat’s neuroarthropathy Plantar fasciitis Tarsal tunnel syndrome OsteoarthritisA great many people think they are thinking when they are merely re arranging their prejudices W. James
46. Investigations Nerve biopsy Skin biopsy – 3mm - Immunostaining using pan neuronal stain – antibody to protein gene product 9.5,(PGP 9.5) a neuronal Ubiquitin carboxy terminal hydrolase. Other immunostains for VIP, CGRP, Substance P.A woman’s desire for revenge outlasts all her other emotions
47. Computer Assisted Sensory Evaluation (CASE) IV device - TEMPERATURE
48. Computer Assisted Sensory Evaluation (CASE) IV device - VIBRATION
49. Morphology- nerve biopsy Nerve biopsy – invasive procedure with definite morbidity. Sural nerve most commonly used. Routine biopsy is controversial. To rule out other causes like vasculitis etc.,. Light & electron microscopic studies are necessary. Can be done pre and post treatment to assess response – ongoing phase 3 trials with Aldose reductase inhibitors.
50. Section of a sural nerve from a patient with diabetic neuropathy
51. Morphology- Skin punch biopsy Small nerve visualisation – assessment of cutaneous nerve fibers obtained from 3mm skin punch biopsy – promising in DSP. Immunohistochemistry- antibody to general neuronal marker protein gene product 9.5.(PGP 9.5) The relationship between epidermal nerve fibers and clinical scores is nonlinear. NATURE, TIME AND PATIENCE are the 3 great physicians
52. Morphology- Skin punch biopsy Reappearance is a marker fordiffuse peripheral nerve regeneration and recovery. Loss of dermal and epidermal nerve fibers in symptomatic dermatomes in truncal neuropathy and their reappearance on clinical recovery. At present not advocated for routine evaluation God is a comedian performing before an audience that is afraid to laugh
53. Skin Biopsy PGP 9.5 staining
54. Skin biopsy – various sites
55. Bench To Bed side Diabetic Peripheral Neuropathy Pain refractory to initial therapies Diabetic Peripheral Neuropathy Pain in the presence of comorbidity Non Diabetic Neuropathy in a patient with diabetes mellitus Rational Polypharmacy DPNPAs one is common to all numbers, it is often seen as the origin of all things
56. Key elements in Diagnosis of DPNP Establish diagnosis of DM or IGT Fasting plasma glucose ≥126mg/dL or serum glucose ≥ 200 mg/dL2 h after 75-g oral glucose load for diabetes . Serum glucose ≥140 mg/ dL but <200 mg/dL 2 h after 75-oral glucose load for impaired glucose tolerance Establish presence of neuropathy Use validated questionnaires (NPQ,BPI- DPN,MNSI) Use simple, handheld screening devices (10-g monofilament, 128-Hz tuning fork)
57. Bench To Bed side Diabetic Peripheral Neuropathy Pain refractory to initial therapies Diabetic Peripheral Neuropathy Pain in the presence of comorbidity Non Diabetic Neuropathy in a patient with diabetes mellitus Rational Polypharmacy DPNPAs one is common to all numbers, it is often seen as the origin of all things
58. AEDs Lamotrigine Carbamazepine 1. FDA approved for 1. Rash 10% Trigeminal Neuralgia 2. 2nd-line 2. Side effects 3. Insomnia Oxcarbazepine Topiramate 1. One study for NeP 1. Nagative results (3 - / 1 +) 2. Hyponatremia – 2. Weight loss (10-20%) monitoring of serum 3. Cognitive impairment sodium required 4. Nephrolithiasis (1.5%) 3. Rash – 4 % Valproate 4. Few Drug-drug 1. Nausea interaction 2. Sedation Levetiracetam 3. Fatal Hepatotoxicity - 1. No controlled studies Enzymes Tiagabine 4. Hair loss 1. No controlled studies 5. Hematologic effect (Platelet) 6. Drug-drug interactionsTwo symbolizes partnership implying that accomplishments are best through coordination.
59. Pharmacological Treatment of DPNP by Drug ClassClass Individual AgentsSNRI ( highly specific inhibition of serotonin and Duloxetine, Venlafaxine.Norepinephrine reuptake)Alpha 2 delta ligands ( modulate voltage – gated Pregabalin ( Lyrica), gabapentin.Calcium channelsTCAs( inhibit reuptake of serotonin and Teritiary( amitriptyline); secondaryNorepinephrine) ( desipramine)Opioids ( block mu opiod receptors) Tramadol, oxycodone CR, morphine; methadone levorphanol;hydromorphoneTopical agents Capsaicin; lidocaineAgents to AVOID ( never use) Meperidine, propoxyphene;NSAIDs; acetaminophen,amitriptyline ( for patients > 60 years); vitamin B6 ( >250 mg/d due to its potiential for neurotoxicity) pentazocine( due to CNS toxicity and reversal of its analgesic effect.
60. Recommendation for First- and Second- Tier Agents for DPNP Agent type Reasons for recommendation Agent name First tier > 2 RCTs in DPN Duloxetine,oxycodone CR, pregabalin, TCAs Second tier 1 RCT in DPN; > 1 in other Carbamazepine, gabapentin painful neuropathies lamotrigine, tramadol, venlafaxine ER Topical Mechanism of action Capsaicin, lidocaine Others > RCTs in other painful Bupropion, citalopram neuropathies or other methodone, paroxetine, evidence phenytoin, toriramate. As one is common to all numbers, it is often seen as the origin of all things
61. Bench To Bed side Diabetic Peripheral Neuropathy Pain refractory to initial therapies Diabetic Peripheral Neuropathy Pain in the presence of comorbidity Non Diabetic Neuropathy in a patient with diabetes mellitus Rational Polypharmacy for DPNPAs one is common to all numbers, it is often seen as the origin of all things
62. Factors to consider in choosing First –Tier AgentsFactor Recommended AvoidMedical co morbiditiesGlaucoma Any other first tier agent TCA sOrthostatic phenomena Any other first tier agent TCA sCardiac or TCA selectrocardiographic Any other first tier agentabnormality TCA sHypertension Any other first tier agentRenal insufficiency Any other first tier agentHepatic insufficiency Any other first tier agent Duloxetine Any other first tier agent Pregabalin,TCAsFalls and balance issues
63. Factors to consider in choosing first tier agentsFactor Recommended AvoidPsychiatriccomorbidities Duloxetine,TCAs oxycodoneCRDepression Any other first tier agent pregabalinAnxiety Duloxetine,Pregabalin oxycodoneCRSuicidal ideation TCAs , oxycodone CRSomatic issues Any other first tier agentsleep Second tier agentErectile dysfunction Venlafaxine All first tier agentsOther factors TCA s oxycodoneCR Duloxetine,PregabalinCost Oxycodone, PregabalinDrug interactions Duloxetine,TCAs Duloxetine,Weight gain oxycodoneCR TCAs,PregabalinEdema Any other first tier agent Pregabalin
64. Bench To Bed side Diabetic Peripheral Neuropathy Pain refractory to initial therapies Diabetic Peripheral Neuropathy Pain in the presence of comorbidity Non Diabetic Neuropathy in a patient with diabetes mellitus Rational of Poly pharmacyAs one is common to all numbers, it is often seen as the origin of all things
65. Bench To Bed side Diabetic Peripheral Neuropathy Pain refractory to initial therapies Diabetic Peripheral Neuropathy Pain in the presence of comorbidity Non Diabetic Neuropathy in a patient with diabetes mellitus Rational Polypharmacy in DPNPAs one is common to all numbers, it is often seen as the origin of all things
66. Rational Polypharmacy for Diabetic Peripheral Neuropathic PainFirst- tier Add-on therapy AvoidAgentsSNRIs alpha 2 delta ligends,opoids, topical agents other SNRIs, TCAs tramadolalpha 2 SNRIs, TCAs, opioids, tramadol, topicals other alpha 2 deltaDeltaTCAs alpha 2 delta, opioids, topicals SNRIs, tramadolOpioids SNRIs, alpha 2 delta, TCAs, topicals Other opioidsTramadol alpha 2 delda, opioids, topicals SNRIs, TCAsTopical SNRIs, alpha 2 delda, TCAs, Opioids, tramadol None Topicals As one is common to all numbers, it is often seen as the origin of all things
67. Diabetes mellitus is a difficult disease with apotentially very painful prognosis. Hence thestrategies and treatment options are needed to address their issues.As one is common to all numbers, it is often seen as the origin of all things
68. Functional impairment in peripheral neuropathy“He can’t walk and chew gum at the same time” Human bipedal ambulation requires the ability to control and propel an elevated center of mass over two limbs which provide a narrow and variable base of support. The CNS requires timely and accurate somatosensory, visual and vestibular inputs –to prevent falls. Applied Vedanta is called yoga
69. Functional impairment in peripheral neuropathyGreatest fall risk inconsistently associated with falls Increased BMI- F >M Age, Severe peripheral Gender, neuropathy - M>F Nerve conduction Short unipedal stance times (normal 10 secs) abnormalities Rombergism Medications used Comorbidities Develop the heart; art comes automatically
70. Rehabilitation Prevention and treatment of peripheral neuropathy. Maximising vision Upper & lower extremity strengthening Weight loss Environmental modification Balance training External aids.Reputation is made in a moment; character is built in a life time
71. DM neuro suspected Assess NIS, NSS S&S S&S S&S of DAN of SF neu Of LF neu QAFT QST EMG,NCV,QST LF neuro DAN SF neuro Motor S & S Sen S & S Prox &dis distalB12, Lyme,toxins,imm. electrophoresis Fam H/o & imm. Testing r /o DM Anti GM Ab DSN Diffuse motor neu
72. The future…In all nations, history is disfigured byfable,till at last evidence (philosophy)comes to enlighten man; and when itarrives in the midst of this darkness, itfinds the human mind so blinded bycenturies of error, that it can hardlyundeceive it. Essai sur Les Moeurs – Voltaire.
73. Dedicated to my family formaking everything worthwhile
74. READ not to contradict or confute Nor to Believe and Take for Granted but TO WEIGH AND CONSIDER THANK YOU“ My opinions are founded on knowledge but modified by experience”