Management of painful diabetic neuropathy in this millennium
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
2
Protein 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 2
with
polyneuropathy
Symtomatic 54% 45%
polyneuropathy
Neuropathy 15% 13%
impairment
scale.+ 7 (Rochester
abnormal 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 polyneuropathy
3 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 positive
Motor Weakness, Fasciculations,
atrophy,fatigue cramps
reduced tone myokymia
Reflex 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 Axonal
Muscle atrophy Slight Severe
Weakness Severe Severe
Reflexes Global areflexia Knee & UL
preserved
Sensory 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 Axonal
MCV/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 Axonal
Motor/sensory Slightly reduced Significantly
amplitude reduced
Distal latency Prolonged in 2 or Normal/ slightly
more nerves prolonged
Late 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 DSP
Symptom score Reflex score Sensory test score
Foot pain Knee reflexes Pinprick
Numbness Ankle reflexes Temperature
Tingling Light touch
Weakness Vibration
Ataxia Position sense
Upper limb
symptoms
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.
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 loss
Desynchronisation & areflexia and loss of
temporal dispersion vibration sense.
Prolonged refractory period ↓ strength at maximal
contraction
Exaggerated fatigue
hyperpolarisation
Ectopic impulses → . spontaneous parasthesias
44. Differntial diagnosis
Claudication
Radiculopathy
Charcoat’s neuroarthropathy
Plantar fasciitis
Tarsal tunnel syndrome
Osteoarthritis
A 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
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
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 DPNP
As 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 DPNP
As 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 interactions
Two symbolizes partnership implying that accomplishments are best through coordination.
59. Pharmacological Treatment of DPNP by Drug Class
Class Individual Agents
SNRI ( highly specific inhibition of serotonin and Duloxetine, Venlafaxine.
Norepinephrine reuptake)
Alpha 2 delta ligands ( modulate voltage – gated Pregabalin ( Lyrica), gabapentin.
Calcium channels
TCAs( inhibit reuptake of serotonin and Teritiary( amitriptyline); secondary
Norepinephrine) ( desipramine)
Opioids ( block mu opiod receptors) Tramadol, oxycodone CR, morphine;
methadone levorphanol;hydromorphone
Topical agents Capsaicin; lidocaine
Agents 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 DPNP
As one is common to all numbers, it is often seen as the origin of all things
62. Factors to consider in choosing First –Tier Agents
Factor Recommended Avoid
Medical co morbidities
Glaucoma Any other first tier agent TCA s
Orthostatic phenomena Any other first tier agent TCA s
Cardiac or TCA s
electrocardiographic Any other first tier agent
abnormality
TCA s
Hypertension Any other first tier agent
Renal insufficiency Any other first tier agent
Hepatic insufficiency Any other first tier agent Duloxetine
Any other first tier agent Pregabalin,TCAs
Falls and balance issues
63. Factors to consider in choosing first tier agents
Factor Recommended Avoid
Psychiatric
comorbidities Duloxetine,TCAs oxycodoneCR
Depression Any other first tier agent pregabalin
Anxiety Duloxetine,Pregabalin oxycodoneCR
Suicidal ideation TCAs , oxycodone CR
Somatic issues Any other first tier agent
sleep Second tier agent
Erectile dysfunction Venlafaxine All first tier agents
Other factors TCA s oxycodoneCR Duloxetine,Pregabalin
Cost
Oxycodone, Pregabalin
Drug interactions Duloxetine,TCAs
Duloxetine,
Weight gain oxycodoneCR TCAs,Pregabalin
Edema 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 pharmacy
As 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 DPNP
As one is common to all numbers, it is often seen as the origin of all things
66. Rational Polypharmacy for
Diabetic Peripheral Neuropathic Pain
First- tier Add-on therapy Avoid
Agents
SNRIs alpha 2 delta ligends,opoids, topical agents other SNRIs, TCAs
tramadol
alpha 2 SNRIs, TCAs, opioids, tramadol, topicals other alpha 2 delta
Delta
TCAs alpha 2 delta, opioids, topicals SNRIs, tramadol
Opioids SNRIs, alpha 2 delta, TCAs, topicals Other opioids
Tramadol alpha 2 delda, opioids, topicals SNRIs, TCAs
Topical 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 a
potentially very painful prognosis. Hence the
strategies 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 neuropathy
Greatest 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 distal
B12, 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 by
fable,till at last evidence (philosophy)
comes to enlighten man; and when it
arrives in the midst of this darkness, it
finds the human mind so blinded by
centuries of error, that it can hardly
undeceive it.
Essai sur Les Moeurs – Voltaire.
76. 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”