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

MANAGEMENT OF PAINFUL DIABETIC NEUROPATHY IN THIS MILLENNIUM

Diabetic neuropathyDiabetic neuropathy InteroductionInteroduction PathogenesisPathogenesis Diagnosis & evaluationDiagnosis & evaluation

clinicalclinicalElectrophysiologyElectrophysiology

Lab investigationsLab investigationsBlood investigations- to r/o other causes.Blood investigations- to r/o other causes.Biopsy of nerves.Biopsy of nerves.

Monitoring and clinical scoring systemsMonitoring and clinical scoring systems Functional disability Functional disability RehablitationRehablitation

Vedanta admits realization

But defies verbal definition

Vedanta admits realization

But defies verbal definition

DIABETES MELLITUSDIABETES MELLITUS

1990 – 2000 – Decade of brain.1990 – 2000 – Decade of brain. 2001-2010 - Decade of pain control & research2001-2010 - Decade of pain control & research India – Diabetic capital of the world.India – Diabetic capital of the world. Every fifth Indian will be a diabetic.Every fifth Indian will be a diabetic. Every fifth diabetic in the world will be an Indian.Every fifth diabetic in the world will be an Indian. 32 million diabetics at present.32 million diabetics at present. 250% rise by 2035 – 100 million250% rise by 2035 – 100 million

Pure love ever gives

Never seeks

Pure love ever gives

Never seeks

Diabetic neuropathy-definitionDiabetic neuropathy-definition

A demonstrable disorder, either clinically A demonstrable disorder, either clinically evident or subclinical, that occurs in the evident or subclinical, that occurs in the setting of diabetes mellitus without other setting of diabetes mellitus without other causes for peripheral neuropathy.causes for peripheral neuropathy.

Manifestation may be somatic and/or Manifestation may be somatic and/or autonomicautonomic

Science is below the mind; Spirituality is beyond the mind

Nerve damage

Aldose reductase activity

PGI2,PG

Protein kinase C deficiency

GLA deficiency

HyperglycemiaOxidative stress

NO

Anti phospholpid antibodyAb to gangliosides.

Nerve growth factor deficiency

Microvasculopathy

1

5

3

4

2

Prevalence of PolyneuropathyPrevalence of Polyneuropathy(Variable depending on criteria)(Variable depending on criteria)

All patients All patients with with polyneuropathypolyneuropathy

Type 1Type 1 Type 2Type 2

Symtomatic Symtomatic polyneuropathypolyneuropathy

54%54% 45%45%

Neuropathy Neuropathy impairment impairment scale.+ 7 scale.+ 7 abnormal testsabnormal tests

15%15% 13%13%

(Rochester (Rochester study)study)

Classification of diabetic neuropathyClassification of diabetic neuropathy

DiffuseDiffuse Distal symmetric Distal symmetric

sensorimotor neuropathy sensorimotor neuropathy -large fiber -large fiber

-small fiber-small fiber AutonomicAutonomic Symmetric proximal lower Symmetric proximal lower

limb motor neuropathy limb motor neuropathy (Amyotrophy)(Amyotrophy)

FocalFocal MononeuropathiesMononeuropathies Entrapment neuropathiesEntrapment neuropathies Truncal neuropathyTruncal neuropathy Cranial neuropathyCranial neuropathy Focal amyotrophy.Focal amyotrophy.

What is mind no matter

What is matter never mind

What is mind no matter

What is matter never mind

Diagnosis of polyneuropathyDiagnosis of polyneuropathy3 challenges3 challenges Clinical signs & symptoms are due to Clinical signs & symptoms are due to

polyneuropahy.polyneuropahy. Categorisation of polyneuropathyCategorisation of polyneuropathy Etiology- history, investigationslab, Etiology- history, investigationslab,

immunological,histological,genetic.immunological,histological,genetic. 25 – 30% - cause not identified.25 – 30% - cause not identified.

Speak obligingly even if you cannot oblige

Evaluation of polyneuropathyEvaluation of polyneuropathy

History History Clinical examination.Clinical examination. Electrophysiological testing – extension Electrophysiological testing – extension

of clinical examinationof clinical examination Laboratory investigations.Laboratory investigations.

Every thing should be made as simple as possible;

but not simpler

Clinical characteristicsClinical characteristics Polyneuropathies of many different etiologies Polyneuropathies of many different etiologies

have similar signs & symptoms.have similar signs & symptoms. Though the features are common the patterns Though the features are common the patterns

are different.are different. The clinical features result fromThe clinical features result from

Lack of function – negative symptoms & signsLack of function – negative symptoms & signs

abnormal function – positive symptoms & signsabnormal function – positive symptoms & signs

Knowledge without action is useless;

Action without knowledge is foolish

Clinical characteristicsClinical characteristics Clinical course – acute, Clinical course – acute,

subacutesubacutechronic prgressive,chronic prgressive, remitting and relapsing formsremitting and relapsing forms

Distribution of involvement Distribution of involvement distal Vs proximal distal Vs proximal symmetrical Vs asymmetricalsymmetrical Vs asymmetricalUpper limb Vs lower limb Upper limb Vs lower limb

predominance.predominance.

Hate screeches, fear squeals; conceits trumpets

but love since lullabies

Clinical characteristicsClinical characteristics Types of fiber involvementTypes of fiber involvement

Motor, large sensory, small sensory, Motor, large sensory, small sensory, autonomicautonomic

Inheritance – family history.Inheritance – family history. History of exposure to toxins and drugs, History of exposure to toxins and drugs,

concomittant illness. concomittant illness.

Learn to adapt, adjust and accommodate

Learn to give, not to take and learn to serve not to rule

Clinical manifestationsClinical manifestations

Motor - weakness,atrophy, fatigue.Motor - weakness,atrophy, fatigue. Sensory – sensory loss, paresthesias.Sensory – sensory loss, paresthesias. DTR – diminished or absentDTR – diminished or absent Autonomic dysfunctionAutonomic dysfunction Skeletal deformity.Skeletal deformity.

Teachers are reservoirs from which, through the process of education, the students draw the water of life

Neurological manifestationsNeurological manifestationsnegativenegative positivepositive

MotorMotor Weakness, Weakness, atrophy,fatigue atrophy,fatigue

reduced tonereduced tone

Fasciculations, Fasciculations, crampscramps

myokymiamyokymia

ReflexReflex Hypo or areflexiaHypo or areflexia __

Small fiberSmall fiber Decrease of pain & Decrease of pain & temperature sensation,temperature sensation,

Loss of visceral pain Loss of visceral pain sensationsensation

Foot ulcerationFoot ulceration

Spontaneous dull Spontaneous dull burning pain burning pain hyperesthesia hyperesthesia parasthesiaparasthesia

Love is selfishness and selfishness is lovelessness

Neurological manifestationsNeurological manifestationsnegativenegative positivepositive

Large fiberLarge fiber Decreased proprioceptionDecreased proprioception

Decreased vibration senseDecreased vibration sense

Reduction of touch pressure Reduction of touch pressure sensibilitysensibility

Sensory ataxiaSensory ataxia

Postural tremorPostural tremor

ParaesthesiasParaesthesias

Sharp tingling pain Sharp tingling pain (A delta type)(A delta type)

AutonomicAutonomic Orthostatic hypotensionOrthostatic hypotension

ArrythmiaArrythmia

GastroparesisGastroparesis

Constipation, ImpotenceConstipation, Impotence

Urinary retention, Decreased Urinary retention, Decreased sweatingsweating

HypertensionHypertension

Neuropathic Neuropathic diarrhoeadiarrhoea

OsteoarthropathyOsteoarthropathy

Axonal Vs Demyelination(Clinical)Axonal Vs Demyelination(Clinical)DemyelinatingDemyelinating AxonalAxonal

Muscle atrophyMuscle atrophy SlightSlight SevereSevere

WeaknessWeakness SevereSevere SevereSevere

ReflexesReflexes Global areflexiaGlobal areflexia Knee & UL Knee & UL preservedpreserved

Sensory signsSensory signs Motor > sensoryMotor > sensory SignificantSignificant

Risk factorsRisk factors

For Painful neuropathyFor Painful neuropathy HyperglycemiaHyperglycemia HypertensionHypertension Dysmetabolic syndromeDysmetabolic syndrome

HT+DM+IHD+DYSLIPIDEMIAHT+DM+IHD+DYSLIPIDEMIA

For painless neuropathyFor painless neuropathy Greater heightGreater height Male genderMale gender SmokingSmoking Total abstinence from Total abstinence from

alcoholalcohol High HbA1CHigh HbA1C

When they tell you to grow up, they mean stop growingWhen they tell you to grow up, they mean stop growing

Types of painful neuropathiesTypes of painful neuropathies

Acute (< 6 months)Acute (< 6 months) Truncal neuropathy.Truncal neuropathy. cachectic neuropathy-Acute, cachectic neuropathy-Acute,

painful,wt.loss,poor control of painful,wt.loss,poor control of DM DM

Insulin neuritis -Acute painful, Insulin neuritis -Acute painful, weight loss, good control of weight loss, good control of DMDM

Painful 3Painful 3rdrd cranial nerve palsy. cranial nerve palsy. Easy to treat.Easy to treat.

Chronic(> 6 months)Chronic(> 6 months) Distal symmetrical painful Distal symmetrical painful

sensorimotor sensorimotor polyneuropathypolyneuropathy

Entrapment neuropathies Entrapment neuropathies Difficult to treat.Difficult to treat.

Speak obligingly even if you cannot oblige

Clinical features – Clinical features – Distal symmetrical painful Distal symmetrical painful

sensorimotor polyneuropathysensorimotor polyneuropathy

Burning, superficial pain. Hypoalgesia in later Burning, superficial pain. Hypoalgesia in later stages.stages.

Defective thermal sensation.Defective thermal sensation. Impaired vasomotionImpaired vasomotion Defective autonomic functionDefective autonomic function Intact DTR and power till late stages.Intact DTR and power till late stages. Progressive with increasing duration of Progressive with increasing duration of

diabetes.diabetes. Related to glycemic control & complications.Related to glycemic control & complications.

Clinical features – Clinical features – Truncal neuropathyTruncal neuropathy

Truncal polyneuropathyTruncal polyneuropathy RareRare Occur in long standing DMOccur in long standing DM ““Bandlike” Painful Bandlike” Painful

symptoms in thoracic root symptoms in thoracic root distributiondistribution

Motor involvement- muscle Motor involvement- muscle herniation – asymmetric herniation – asymmetric bulge in abdominal wallbulge in abdominal wall

Truncal radiculopathyTruncal radiculopathy Acute onset of pain in a Acute onset of pain in a

radicular patternradicular pattern Asymmetrical painAsymmetrical pain Patchy sensory loss is a Patchy sensory loss is a

clue to the diagnosis.clue to the diagnosis.



Clinical features Insulin neuritis Clinical features Insulin neuritis

Acute painful, occurs 1 month after insulin Acute painful, occurs 1 month after insulin /OHA./OHA.

Due to rapid glycemic control.Due to rapid glycemic control. Nerves in these patients are under general Nerves in these patients are under general

hypoxia and use glucose under anaerobic hypoxia and use glucose under anaerobic conditions.conditions.

Once glucose is normalised in blood and nerves, Once glucose is normalised in blood and nerves, glucose is no longer available and the nerves glucose is no longer available and the nerves undergo degeneration.undergo degeneration.

Reputation is made in a moment; character is built in a life time

Insulin neuritis- contd..,Insulin neuritis- contd..,

Burning pain, paraesthesia, allodynia with Burning pain, paraesthesia, allodynia with nocturnal exacerbation.nocturnal exacerbation.

Depression is a feature.Depression is a feature. No weight loss.No weight loss. Sensory loss is mild. No motor signs.Sensory loss is mild. No motor signs. Complete resolution in 1 year.Complete resolution in 1 year.

A good teacher is a perpetual learner

Clinical features - Cachectic neuropathyClinical features - Cachectic neuropathy In patients with a poor control of DM.In patients with a poor control of DM. Wt.loss is prominent.Wt.loss is prominent. Severe burning pain- continuous or intermittent.Severe burning pain- continuous or intermittent. Subjective feeling of swollen limb. Subjective feeling of swollen limb. Allodynia is common- nocturnal exacerbation.Allodynia is common- nocturnal exacerbation. Sensory loss is mild.Sensory loss is mild. No motor signs.No motor signs.The Truth is fear and immorality are two of the greatest inhibitors of Performance to progress

Cranial nerve palsyCranial nerve palsy

Most common mononeuropathyMost common mononeuropathy Acute pain in the orbit, ptosis, opthalmoplegia, Acute pain in the orbit, ptosis, opthalmoplegia,

pupil spared.pupil spared. Usually unilateralUsually unilateral Complete recovery in 3 months.Complete recovery in 3 months. Vascular etiology suggested.Vascular etiology suggested. 66thth & 7 & 7thth cranial nerve involvement are cranial nerve involvement are

described.described.

Hate screeches, fear squeals; conceits trumpets

but love sings lullabies

Electrophysiology (EDX)Electrophysiology (EDX)

Confirm presence of PN.Confirm presence of PN. Demyelination or Axonal.Demyelination or Axonal. Motor, sensory or a combination.Motor, sensory or a combination. Assess severity and distribution.Assess severity and distribution. Follow the course of the disease.Follow the course of the disease.

Science is below the mind; Spirituality is beyond the mind

Axonal Vs Demyelination(EDX)Axonal Vs Demyelination(EDX)DemyelinatingDemyelinating AxonalAxonal

MCV/SCVMCV/SCV Slowing in 2 or Slowing in 2 or more nerves to more nerves to less than 60%less than 60%

Normal/ slightly Normal/ slightly reducedreduced

Conduction blockConduction block Present in one or Present in one or more motor more motor nerves.nerves.

NoNo

FibrillationFibrillation ScantyScanty Generally Generally prominentprominent

Axonal Vs Demyelination(EDX)Axonal Vs Demyelination(EDX)DemyelinatingDemyelinating AxonalAxonal

Motor/sensory Motor/sensory amplitudeamplitude

Slightly reducedSlightly reduced Significantly Significantly reducedreduced

Distal latencyDistal latency Prolonged in 2 or Prolonged in 2 or more nervesmore nerves

Normal/ slightly Normal/ slightly prolongedprolonged

Late responsesLate responses Prolonged or Prolonged or missing in 2 or missing in 2 or more nervesmore nerves

Normal/ slightly Normal/ slightly prolongedprolonged

EDXEDX Conduction block is the sign of focal Conduction block is the sign of focal

demyelinationdemyelination Conventional NCS measures distal segments.Conventional NCS measures distal segments. F latency and penetration measure proximal F latency and penetration measure proximal

segments.segments. Temporal dispersion and conduction block Temporal dispersion and conduction block

occur only in acquired neuropathiesoccur only in acquired neuropathies Asymmetrical and multifocal lesions Asymmetrical and multifocal lesions

distinguish acquired from inherited distinguish acquired from inherited polyneuropathies.polyneuropathies.

Whatever the Mind can conceive and Believe, the mind can Achieve

Napoleon Hill

EDX- RecommendationsEDX- Recommendations In clinical practice only a few cases fulfill the In clinical practice only a few cases fulfill the

classic criteria of one group or the other of classic criteria of one group or the other of neuropathiesneuropathies

rules- rules- Test several nerves.Test several nerves. Both upper & lower extremity should be sampled.Both upper & lower extremity should be sampled. Should include sensory & motor nerves.Should include sensory & motor nerves. Recording of F responses.Recording of F responses. Concentric needle examination is an important Concentric needle examination is an important

complementary examination.complementary examination.

Many Ideas grow better when transplanted into another mind than in the one where they sprang UP

O.W. Holmos

EDX- RecommendationsEDX- Recommendations Distal and proximal muscles of at least one lower Distal and proximal muscles of at least one lower

and upper extremity should be sampled.and upper extremity should be sampled. Paraspinal muscles should be sampled in Paraspinal muscles should be sampled in

suspected proximal involvement.suspected proximal involvement. In Ul – biceps and first dorsal interossei.In Ul – biceps and first dorsal interossei. In LL – anterior tibial and quadriceps.In LL – anterior tibial and quadriceps. Avoid intrinsic foot muscles – as repeated trauma Avoid intrinsic foot muscles – as repeated trauma

may show neurogenic abnormalities.may show neurogenic abnormalities. Ratio of sural to radial SNAPRatio of sural to radial SNAP Incorpotation of anthropometric factors.Incorpotation of anthropometric factors.

Diagnosis & monitoring Diagnosis & monitoring The neuropathies associated with DM represent The neuropathies associated with DM represent

insidious and progressive processes for which a insidious and progressive processes for which a disconnect exists between pathological severity disconnect exists between pathological severity and the development of symptoms.and the development of symptoms.

DSP leads to leg ulceration and amputation.DSP leads to leg ulceration and amputation. DSP is strongly related to glycemic control.DSP is strongly related to glycemic control. DSP affects motor, sensory, and autonomic DSP affects motor, sensory, and autonomic

fibers.fibers. Axons are affected in a length dependent manner Axons are affected in a length dependent manner

and there is a centripetal pattern of axonal and there is a centripetal pattern of axonal degeneration. degeneration.

Screening for DSPScreening for DSP The early identification is justified as it offers a The early identification is justified as it offers a

crucial oppurtunity to actively alter the course of crucial oppurtunity to actively alter the course of suboptimal glycemic control and prevent suboptimal glycemic control and prevent morbidity.morbidity.

Optimal screening is desirableOptimal screening is desirablerapid and simplerapid and simple

High inter-observer reproducibilityHigh inter-observer reproducibility

Valid against objective criterion standard.Valid against objective criterion standard.

Generalizable to wide range of clinical Generalizable to wide range of clinical

presentation. presentation.

Semmes-Weinstein Semmes-Weinstein Monofilament Examination Monofilament Examination

(SWME) (SWME) Semmes-Weinstein monofilament 5.07 (10 grams)Semmes-Weinstein monofilament 5.07 (10 grams) 4 stimuli per foot on the dorsum of the first toe 4 stimuli per foot on the dorsum of the first toe

proximal to the nail bed.proximal to the nail bed. >1>1 insensate stimuli is associated with small insensate stimuli is associated with small

chance of DSP as measured by NCS.chance of DSP as measured by NCS. >>5 insensate stimuli is associated with high 5 insensate stimuli is associated with high

probability of DSP.probability of DSP. An abnormal SWME is associated with a 3 year An abnormal SWME is associated with a 3 year

relative risk as high as 15 for ulceration or relative risk as high as 15 for ulceration or amputationamputation

Clinical scoring systemsClinical scoring systems

To summarize large volume of information To summarize large volume of information from clinical examination and provide a from clinical examination and provide a quantitative value which can be followed quantitative value which can be followed longitudinally.longitudinally.

Neuropathy Impairment Scale (NIS)Neuropathy Impairment Scale (NIS) in the in the lower limbs (LL) + 7 – (NISlower limbs (LL) + 7 – (NIS[[LLLL]]+7)+7)

Michigan neuropathy screening instrumentMichigan neuropathy screening instrument- - has a 15 item questionnaire and a simple has a 15 item questionnaire and a simple clinical examination of the feet.clinical examination of the feet.

Toronto clinical scoring systemToronto clinical scoring system..

Scoring systems Scoring systems (NIS(NIS[[LLLL]]+7) +7)

Neuropathy Impairment Scale (NIS) in the lower Neuropathy Impairment Scale (NIS) in the lower limbs (LL) + 7 – (NISlimbs (LL) + 7 – (NIS[[LLLL]]+7) – includes NCS, +7) – includes NCS, Vibration perception threshold (VPT), and Vibration perception threshold (VPT), and autonomic function. (HR variability with deep autonomic function. (HR variability with deep breathing) all in percentile system converted into breathing) all in percentile system converted into points.points.

Time consuming, not used in primary care. The Time consuming, not used in primary care. The points are weigheted in favor of motor findings.points are weigheted in favor of motor findings.

Scoring systems- Michigan neuropathy Scoring systems- Michigan neuropathy screening instrument screening instrument

An abnormal score in Michigan neuropathy An abnormal score in Michigan neuropathy screening instrument initiates referral for NCS – screening instrument initiates referral for NCS – and the second evaluation is Michigan Diabetic and the second evaluation is Michigan Diabetic Neuropathy Score.Neuropathy Score.

The scale is validated, employed in clinical The scale is validated, employed in clinical research trials to monitor DSP.research trials to monitor DSP.

Time consuming , not used in routine practice.Time consuming , not used in routine practice.

When they tell you to grow up, they mean stop growing When they tell you to grow up, they mean stop growing P. DiccasoP. Diccaso

Clinical scoring system – Toronto Clinical scoring system – Toronto scoring system for DSPscoring system for DSP

Symptom scoreSymptom score Reflex scoreReflex score Sensory test scoreSensory test score

Foot painFoot pain

NumbnessNumbness

TinglingTingling

WeaknessWeakness

AtaxiaAtaxia

Upper limb Upper limb symptomssymptoms

Knee reflexesKnee reflexes

Ankle reflexesAnkle reflexes

PinprickPinprick

TemperatureTemperature

Light touchLight touch

VibrationVibration

Position sensePosition sense

Present=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.

Quantitative sensory testing(QST)Quantitative sensory testing(QST) QST provides quantitative information on QST provides quantitative information on

sensory function. Non standardised.sensory function. Non standardised. Contribute to clinical scales.Contribute to clinical scales. Used in follow the progression.Used in follow the progression. Limited objectivity and reliance on subjective Limited objectivity and reliance on subjective

responsiveness.responsiveness. Can be abnormal in CNS disorders.Can be abnormal in CNS disorders. Visual perception Threshold (VPT)Visual perception Threshold (VPT) Thermal Threshold Testing (TPT) Thermal Threshold Testing (TPT)

A good teacher is a perpetual learner

Diabetic Autonomic Diabetic Autonomic Neuropathy(DAN)Neuropathy(DAN)

DAN results from damage of myelinated DAN results from damage of myelinated and small myelinated fibers which cannot and small myelinated fibers which cannot be assessed by conventional NCS.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 destroys the bridge over which he himself must

pass” - Annoy

DAN- sympathetic- cholinergicDAN- sympathetic- cholinergic

Thermoregulatory sweat test.Thermoregulatory sweat test. Quantitative pseudomotor axon-reflex Quantitative pseudomotor axon-reflex

test (QSART)test (QSART) Sympathetic skin response.Sympathetic skin response. Sweat imprint.Sweat imprint.

It is not your position that makes you happy or unhappy

It is your disposition

DAN-ParasympatheticDAN-Parasympathetic

Respiratory sinus arrythmia during deep Respiratory sinus arrythmia during deep breathing.(HR variability)breathing.(HR variability)

HR changes during valsalva manuver HR changes during valsalva manuver (Valsalva ratio)(Valsalva ratio)

HR changes during during active HR changes during during active standing(ratio 30:15)standing(ratio 30:15)

HR power spectral analysis.HR power spectral analysis.



Physiological changes &Physiological changes &clinical consequencesclinical consequences

threshold threshold weakness & sensory lossweakness & sensory loss

Desynchronisation & Desynchronisation & temporal dispersiontemporal dispersion

areflexia and loss of areflexia and loss of vibration sense.vibration sense.

Prolonged refractory periodProlonged refractory period strength at maximal strength at maximal contractioncontraction

Exaggerated Exaggerated hyperpolarisationhyperpolarisation

fatiguefatigue

Ectopic impulses Ectopic impulses . . spontaneous parasthesiasspontaneous parasthesias

Differntial diagnosisDifferntial diagnosis

ClaudicationClaudication RadiculopathyRadiculopathy Charcoat’s neuroarthropathyCharcoat’s neuroarthropathy Plantar fasciitisPlantar fasciitis Tarsal tunnel syndromeTarsal tunnel syndrome OsteoarthritisOsteoarthritis

A great many people think they are thinking when they are merely re arranging their prejudices

W. James

InvestigationsInvestigations

Clinical examination – measuring thermal & Clinical examination – measuring thermal & vibration threshold. vibration threshold.

Routine hemogramRoutine hemogram Plasma Glucose estimation-Glycemic controlPlasma Glucose estimation-Glycemic control HbA1C levelsHbA1C levels Electrodiagnostic testing.- Nerve conduction Electrodiagnostic testing.- Nerve conduction

studies, Quantitative Sensory Testing (QST)studies, Quantitative Sensory Testing (QST)

InvestigationsInvestigations

Nerve biopsyNerve biopsy Skin biopsy – 3mm - Immunostaining using pan Skin biopsy – 3mm - Immunostaining using pan

neuronal stain – antibody to protein gene product neuronal stain – antibody to protein gene product 9.5,(PGP 9.5) a neuronal Ubiquitin carboxy 9.5,(PGP 9.5) a neuronal Ubiquitin carboxy terminal hydrolase.terminal hydrolase.

Other immunostains for VIP, CGRP, Substance P.Other immunostains for VIP, CGRP, Substance P.

A woman’s desire for revenge outlasts all her other emotions

Computer Assisted Sensory Evaluation (CASE) IV device - TEMPERATURE

Computer Assisted Sensory Evaluation Computer Assisted Sensory Evaluation (CASE) IV device - VIBRATION(CASE) IV device - VIBRATION

Morphology- nerve biopsyMorphology- nerve biopsy Nerve biopsy – invasive procedure with definite Nerve biopsy – invasive procedure with definite

morbidity.morbidity. Sural nerve most commonly used.Sural nerve most commonly used. Routine biopsy is controversial.Routine biopsy is controversial. To rule out other causes like vasculitis etc.,.To rule out other causes like vasculitis etc.,. Light & electron microscopic studies are Light & electron microscopic studies are

necessary.necessary. Can be done pre and post treatment to assess Can be done pre and post treatment to assess

response – ongoing phase 3 trials with Aldose response – ongoing phase 3 trials with Aldose reductase inhibitors.reductase inhibitors.

Section of a sural nerve from a patient with Section of a sural nerve from a patient with diabetic neuropathydiabetic neuropathy

Morphology- Skin punch biopsyMorphology- Skin punch biopsy Small nerve visualisation – assessment of Small nerve visualisation – assessment of

cutaneous nerve fibers obtained from 3mm skin cutaneous nerve fibers obtained from 3mm skin punch biopsy – promising in DSP.punch biopsy – promising in DSP.

Immunohistochemistry- antibody to general Immunohistochemistry- antibody to general neuronal marker protein gene product 9.5.(PGP neuronal marker protein gene product 9.5.(PGP 9.5)9.5)

The relationship between epidermal nerve fibers The relationship between epidermal nerve fibers and clinical scores is nonlinear.and clinical scores is nonlinear.

NATURE, TIME AND PATIENCE are the 3 great physicians

Morphology- Skin punch biopsyMorphology- Skin punch biopsy

Reappearance is a marker fordiffuse peripheral Reappearance is a marker fordiffuse peripheral nerve regeneration and recovery.nerve regeneration and recovery.

Loss of dermal and epidermal nerve fibers in Loss of dermal and epidermal nerve fibers in symptomatic dermatomes in truncal neuropathy symptomatic dermatomes in truncal neuropathy and their reappearance on clinical recovery.and their reappearance on clinical recovery.

At present not advocated for routine evaluationAt present not advocated for routine evaluation

God is a comedian performing before an audience

that is afraid to laugh

Skin Biopsy PGP 9.5 staining

Skin biopsy – various sitesSkin biopsy – various sites

Bench To Bed sideBench To Bed side

Diabetic Peripheral Neuropathy Pain Diabetic Peripheral Neuropathy Pain refractory to initial therapiesrefractory to initial therapies

Diabetic Peripheral Neuropathy Pain in the Diabetic Peripheral Neuropathy Pain in the presence of comorbiditypresence of comorbidity

Non Diabetic Neuropathy in a patient with Non Diabetic Neuropathy in a patient with diabetes mellitusdiabetes mellitus

Rational Polypharmacy DPNPRational Polypharmacy DPNP

As one is common to all numbers, it is often seen as the origin of all things

Key elements in Diagnosis of Key elements in Diagnosis of DPNPDPNP

Establish diagnosis of DM or IGTEstablish diagnosis of DM or IGTFasting plasma glucose ≥126mg/dL or serum glucose ≥ 200 Fasting plasma glucose ≥126mg/dL or serum glucose ≥ 200 mg/dL2 h after 75-g oral glucose load for diabetes .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 Serum glucose ≥140 mg/ dL but <200 mg/dL 2 h after 75-oral glucose load for impaired glucose tolerance glucose load for impaired glucose tolerance

Establish presence of neuropathyEstablish presence of neuropathy Use validated questionnaires (NPQ,BPI- DPN,MNSI)Use validated questionnaires (NPQ,BPI- DPN,MNSI) Use simple, handheld screening devices (10-g Use simple, handheld screening devices (10-g monofilament, 128-Hz tuning fork)monofilament, 128-Hz tuning fork)


Diabetic Peripheral Neuropathy Pain Diabetic Peripheral Neuropathy Pain refractory to initial therapiesrefractory to initial therapies



Rational Polypharmacy DPNPRational Polypharmacy DPNP


AEDsAEDsCarbamazepineCarbamazepine 1.1. FDA approved for FDA approved for

Trigeminal NeuralgiaTrigeminal Neuralgia2.2. Side effectsSide effectsOxcarbazepineOxcarbazepine1.1. One study for NePOne study for NeP2.2. Hyponatremia – monitoring Hyponatremia – monitoring

of serum sodium requiredof serum sodium required3.3. Rash – 4 % Rash – 4 % 4.4. Few Drug-drug interactionFew Drug-drug interactionLevetiracetamLevetiracetam1.1. No controlled studiesNo controlled studiesTiagabineTiagabine 1.1. No controlled studiesNo controlled studies

LamotrigineLamotrigine1.1. Rash 10%Rash 10%2.2. 2nd-line2nd-line3.3. InsomniaInsomniaTopiramateTopiramate1.1. Nagative results (3 - / 1 +)Nagative results (3 - / 1 +)2.2. Weight loss (10-20%)Weight loss (10-20%)3.3. Cognitive impairmentCognitive impairment4.4. Nephrolithiasis (1.5%)Nephrolithiasis (1.5%)ValproateValproate1.1. NauseaNausea2.2. SedationSedation3.3. Fatal Hepatotoxicity - Fatal Hepatotoxicity -

Enzymes Enzymes 4.4. Hair lossHair loss5.5. Hematologic effect (Platelet)Hematologic effect (Platelet)6.6. Drug-drug interactionsDrug-drug interactions

Two symbolizes partnership implying that accomplishments are best through coordination.

ClassClass Individual AgentsIndividual Agents

SNRI ( highly specific inhibition of serotonin and Duloxetine, Venlafaxine.SNRI ( highly specific inhibition of serotonin and Duloxetine, Venlafaxine.Norepinephrine reuptake)Norepinephrine reuptake)

Alpha 2 delta ligands ( modulate voltage – gatedAlpha 2 delta ligands ( modulate voltage – gated Pregabalin ( Lyrica), gabapentin.Pregabalin ( Lyrica), gabapentin.Calcium channelsCalcium channels

TCAs( inhibit reuptake of serotonin andTCAs( inhibit reuptake of serotonin and Teritiary( amitriptyline); secondary Teritiary( amitriptyline); secondary Norepinephrine)Norepinephrine) ( desipramine) ( desipramine)

Opioids ( block mu opiod receptors) Opioids ( block mu opiod receptors) Tramadol, oxycodone CR, morphine; Tramadol, oxycodone CR, morphine; methadone levorphanol;hydromorphonemethadone levorphanol;hydromorphone

Topical agents Capsaicin; lidocaineTopical agents Capsaicin; lidocaine

Agents to AVOID ( never use)Agents to AVOID ( never use) Meperidine, propoxyphene;NSAIDs;Meperidine, propoxyphene;NSAIDs; acetaminophen,amitriptylineacetaminophen,amitriptyline ( for patients > 60 years); vitamin B6 ( for patients > 60 years); vitamin B6

( >250 mg/d due to its potiential for ( >250 mg/d due to its potiential for neurotoxicity) pentazocine( due to CNS neurotoxicity) pentazocine( due to CNS toxicity and toxicity and reversal of its analgesic effect.reversal of its analgesic effect.

Pharmacological Treatment of DPNP by Drug Class

Agent type Reasons for recommendation Agent nameAgent type Reasons for recommendation Agent name

First tierFirst tier > > 2 RCTs in DPN2 RCTs in DPN Duloxetine,oxycodone CR, Duloxetine,oxycodone CR, pregabalin, TCAspregabalin, TCAs

Second tierSecond tier1 RCT in DPN; 1 RCT in DPN; > > 1 in other Carbamazepine, gabapentin1 in other Carbamazepine, gabapentinpainful neuropathiespainful neuropathies lamotrigine, tramadol, lamotrigine, tramadol,

venlafaxine ER venlafaxine ER

TopicalTopical Mechanism of actionMechanism of action Capsaicin, lidocaineCapsaicin, lidocaine

OthersOthers > > RCTs in other painfulRCTs in other painful Bupropion, citalopramBupropion, citalopramneuropathies or otherneuropathies or other methodone, paroxetine,methodone, paroxetine,evidenceevidence phenytoin, toriramate.phenytoin, toriramate.


Recommendation for First- and Second- Tier Agents for DPNP


Diabetic Peripheral Neuropathy Pain refractory Diabetic Peripheral Neuropathy Pain refractory to initial therapiesto initial therapies



Rational Polypharmacy for DPNPRational Polypharmacy for DPNP


Factors to consider in choosing First –Tier AgentsFactors to consider in choosing First –Tier Agents

Factor Factor RecommendedRecommended AvoidAvoid

Medical co morbiditiesMedical co morbidities

Glaucoma Glaucoma

Orthostatic phenomenaOrthostatic phenomena

Cardiac or Cardiac or electrocardiographic electrocardiographic abnormalityabnormality

HypertensionHypertension

Renal insufficiencyRenal insufficiency

Hepatic insufficiencyHepatic insufficiency

Falls and balance issues Falls and balance issues

Any other first tier agentAny other first tier agent







TCA sTCA s

TCA sTCA s

TCA sTCA s

TCA sTCA s

DuloxetineDuloxetine

Pregabalin,TCAsPregabalin,TCAs

Factors to consider in choosing first tier agentsFactors to consider in choosing first tier agents

Factor Factor Recommended Recommended Avoid Avoid Psychiatric Psychiatric comorbiditiescomorbidities

DepressionDepression

AnxietyAnxiety

Suicidal ideationSuicidal ideation

Somatic issuesSomatic issues

sleepsleep

Erectile dysfunctionErectile dysfunction

Other factorsOther factors

CostCost

Drug interactionsDrug interactions

Weight gainWeight gain

Edema Edema

Duloxetine,TCAsDuloxetine,TCAs


Duloxetine,PregabalinDuloxetine,Pregabalin


Second tier agent Second tier agent

VenlafaxineVenlafaxine

TCA s oxycodoneCRTCA s oxycodoneCR

Oxycodone, PregabalinOxycodone, Pregabalin

Duloxetine, Duloxetine, oxycodoneCRoxycodoneCR


oxycodoneCR oxycodoneCR pregabalinpregabalin

oxycodoneCRoxycodoneCR

TCAs , oxycodone CRTCAs , oxycodone CR

All first tier agentsAll first tier agents

Duloxetine,PregabalinDuloxetine,Pregabalin

Duloxetine,TCAs Duloxetine,TCAs

TCAs,PregabalinTCAs,Pregabalin

PregabalinPregabalin





Rational of Poly pharmacyRational of Poly pharmacy






Rational Polypharmacy in DPNPRational Polypharmacy in DPNP


Rational Polypharmacy for Rational Polypharmacy for Diabetic Peripheral Neuropathic PainDiabetic Peripheral Neuropathic Pain

First- tier First- tier Add-on therapyAdd-on therapy Avoid AvoidAgentsAgents

SNRIsSNRIs alpha 2 delta ligends,opoids, topical agents other SNRIs, TCAs alpha 2 delta ligends,opoids, topical agents other SNRIs, TCAs tramadoltramadol

alpha 2 SNRIs, TCAs, opioids, tramadol, topicals other alpha 2 deltaalpha 2 SNRIs, TCAs, opioids, tramadol, topicals other alpha 2 deltaDeltaDelta

TCAsTCAs alpha 2 delta, opioids, topicals alpha 2 delta, opioids, topicals SNRIs, tramadol SNRIs, tramadol

OpioidsOpioids SNRIs, alpha 2 delta, TCAs, topicals SNRIs, alpha 2 delta, TCAs, topicals Other opioids Other opioids

Tramadol alpha 2 delda, opioids, topicals SNRIs, TCAsTramadol alpha 2 delda, opioids, topicals SNRIs, TCAs

Topical SNRIs, alpha 2 delda, TCAs, Opioids, tramadol NoneTopical SNRIs, alpha 2 delda, TCAs, Opioids, tramadol None TopicalsTopicals


Diabetes mellitus is a difficult disease Diabetes mellitus is a difficult disease with a potentially very painful prognosis. with a potentially very painful prognosis.

Hence the strategies and treatment Hence the strategies and treatment options are needed to address their options are needed to address their

issues.issues.


Functional impairment in Functional impairment in peripheral neuropathyperipheral neuropathy

““He can’t walk and chew gum at the same time”He can’t walk and chew gum at the same time” Human bipedal ambulation requires the ability Human bipedal ambulation requires the ability

to control and propel an elevated center of mass to control and propel an elevated center of mass over two limbs which provide a narrow and over two limbs which provide a narrow and variable base of support.variable base of support.

The CNS requires The CNS requires timely and accuratetimely and accurate somatosensory, visual and vestibularsomatosensory, visual and vestibular inputs –to inputs –to prevent falls.prevent falls.

Applied Vedanta is called yogaApplied Vedanta is called yoga

Functional impairment in Functional impairment in peripheral neuropathyperipheral neuropathy

Greatest fall riskGreatest fall risk Increased BMI- F >MIncreased BMI- F >M Severe peripheral Severe peripheral

neuropathy - M>Fneuropathy - M>F Short unipedal stance Short unipedal stance

times (normal 10 secs)times (normal 10 secs) Medications usedMedications used

inconsistently inconsistently associated with fallsassociated with falls

Age,Age, Gender,Gender, Nerve conduction Nerve conduction

abnormalitiesabnormalities Rombergism Rombergism Comorbidities Comorbidities

Develop the heart; art comes automatically

RehabilitationRehabilitation Prevention and treatment of peripheral Prevention and treatment of peripheral

neuropathy.neuropathy. Maximising visionMaximising vision Upper & lower extremity strengtheningUpper & lower extremity strengthening Weight lossWeight loss Environmental modificationEnvironmental modification Balance trainingBalance training External aids.External aids.

Reputation is made in a moment; character is built in a life time

DM neuro suspected

Assess NIS, NSSAssess NIS, NSS

S&S of DAN

QAFT EMG,NCV,QSTQST

DAN

LF neuroSF neuro

S&S Of LF neu

S&S of SF neu

Motor S & SSen S & S

Prox &dis distal

Fam H/o & imm.Testing r /o DM Anti GM Ab

B12, Lyme,toxins,imm.electrophoresis

DSNDiffuse motor neu

The future…The future…

In all nations, history is disfigured by In all nations, history is disfigured by fable,till at last evidence (philosophy) fable,till at last evidence (philosophy) comes to enlighten man; and when it comes to enlighten man; and when it arrives in the midst of this darkness, it arrives in the midst of this darkness, it finds the human mind so blinded by finds the human mind so blinded by centuries of error, that it can hardly centuries of error, that it can hardly undeceive it.undeceive it.

Essai sur Les Moeurs – Voltaire.Essai sur Les Moeurs – Voltaire.

Dedicated to my family for Dedicated to my family for making everything worthwhile making everything worthwhile

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”

management of painful diabetic neuropathy in this millennium

Health & Medicine

diabetic polyneuropathy

diabetic neuropathydefinition

clinical features

peripheral neuropathy

investigations lab

mind spirituality

unremitting character

verbal definition