Diabetic Neuropathy Evidence Based Medicine

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Diabetic Neuropathy Evidence Based
Medicine Cardiovascular Risk Link

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Case history

• 48yr old woman Type 2 DM 20 years
• Triple oral therapy HbA1c 11
• BMI 33, non smoker, TC7.6 (simva 20mg)
• BP 125/75, microalbuminuria (ramipril 5mg od)
• Main c/o burning pain in both feet at night
  (cant keep sheets on it)
• How would you manage this case?

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Diabetic peripheral neuropathy can be
defined as

• The presence of symptoms and/or signs of
  peripheral nerve dysfunction in people with
  diabetes after other causes have been excluded

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Features of DN

• Common complication affecting up to 50 patients
  with DM
• Diagnosed in the presence of 2 abnormal symptoms
  or signs
• Frequently asymptomatic mostly untreatable
• Requires careful examination/assessment to
  detect (NDS, NSS)
• Affects quality of life (pain, depression)
• Patients with DN are 15 times more likely to
  have LL amputation
• Foot problems are the commonest reason for
  in-patient admission
• Death most frequently due to cardiovascular
  disease

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Risk Factors

• Modifiable Glycaemic control
• Dyslipidaemia
• Hypertension
• BMI
• Smoking
• Excessive alcohol
• Prevention/delaying the onset of DM
• Non-modifiable Age of onset of diabetes
• Duration of DM
• Genetic factors
• Presence of other complications of DM

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Burden of DN

• Cost to the Patient pain
• loss of function
• depression
• loss of independence
• loss of earnings
• Cost to the Health Care Service GP,
  community/OP/IP services
• Cost to society Diabetes affects 246M
  (20- 30M)
• workforce
• welfare system
• Increasing prevalence across all age groups

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Aetiology

• Alterations in nerve blood flow
• Schwann cell (SC) dysfunction primary
  demyelination, secondary segmental demyelination
  due to impairment of axonal control of
  myelination, remyelination, SC proliferation,
  atrophy of denervated bands of SC, basal lamina
  hypertrophy.
• Neuronal degeneration progressive impairment of
  regeneration (esp. thin myelinated fibres)
• Neuronal damage caused by hyperglycaemia
  (activation of the polyol pway, synthesis of AGE
  products, excess activation of PKC-driven pways,
  ?microangiopathy of the vasa nervorum)
• Oxidative stress

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Types of Diabetic Neuropathy

• Sensorimotor Acute reversible (hyperglycaemic
  neuropathy)
• Persistent Symmetrical
• Focal Multifocal
• Autonomic Gustatory sweating
• Postural hypotension
• Gastroparesis
• Diabetic diarrhoea
• Neuropathic bladder
• ED
• Neuropathic oedema
• Charcot arthropathy

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Chronic Sensorimotor Neuropathy

• Affects 80 of those with DN
• AKA Length-Dependent Diabetic Polyneuropathy
  (LDDP)
• Insidious
• Burning/paraesthesia
• Weight loss
• Glove stocking sensory loss, absent ankle jerk
• Increased prevalence of other diabetic
  complications
• Sensorygtmotor abnormalities usual
• Persistent symptoms, risk of ulceration

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Acute Sensory Neuropathy

• Rapid onset
• Severe burning/aching
• Weight loss
• Mild sensory, motor unusual
• Unusual for concomitant complications
• Normal/minor abnormalities on EMG
• Complete recovery in 1 year

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Typical Symptoms

• Painful Burning Non-painfulAsleep
• (positive) Stabbing (negative) Dead
• Electric shock Numbness
• Squeezing Tingling
• Constricting Prickling
• Hurting
• Freezing
• Throbbing

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Identifying At-risk Patients

• What is the Evidence?
• Rochester cohort longitudinal assessment
• EURODIAB IDDM Complications Study
• Seattle Prospective Diabetic Foot Study
• DCCT

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Rochester Cohort Longitudinal Assessment (Dyck et
al.)

• 264 Diabetic patients, follow-up after 7 years
• Independent risk factors for the development of
  polyneuropathy
• Glycated haemoglobin
• Duration of diabetes
• Type of diabetes
• Important covariates
• Severity of retinopathy
• Proteinuria

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EURODIAB IDDM Complications Study

• Study was undertaken to ID modifiable risk
  reduction strategies other
• than glycaemic control to help prevent DN
• 1272 Patients, follow-up over 7 years
• Laboratory Investigations Total, LDL, HDL, TG
• HbA1c
• Albuminuria
• Incidence of neuropathy 23.5
• Risk of neuropathy increased in those with
  deterioration in glycaemic
• Control (independent of baseline HbA1c)
• HTN, smoking, obesity, elevated TG and CVD at
  baseline are related to
• newly diagnosed neuropathy

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Seattle Prospective Diabetic Foot Study

• Factors associated with an increased risk of
  diabetic peripheral sensory
• neuropathy
• Age at entry into study
• Glycated Hb
• Hx of lower limb extremity ulceration
• Height

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DCCT

• Intensive therapy reduced the development of
  confirmed clinical neuropathy by 64 after 5
  years compared with conventional therapy
• Prevalence of abnormal nerve conduction was
  reduced by 44
• Prevalence of abnormal autonomic nervous system
  dysfunction was reduced by 53
• The electrophysiological abnormalities associated
  with diabetic neuropathy are delayed or prevented
  by intensive diabetes treatment
• The benefits of intensive therapy were apparent
  after 4 years of follow-up and extended at least
  8 years beyond the end of the DCCT

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Management of DPN 1

• Important to rule out PVD foot pain and other
  causes
• autoimmune autoAb screen, ESR, UE, LFT
• malignancy ESR, FBC, immunoglobulins, CXR/AXR
• metabolic Vitamin D associated leg pain,
  B12/folate
• toxic alcohol, lead, arsenic, mercury
• infective syphilis, HIV
• iatrogenic
• medication-related antibiotics metronidazole,
  nitrofurantoin, isoniazid, thalidomide,gold
  compounds
• chemotherapeutic agents vincristine,
  cysplatin
• CVS agents amiodarone, hydralazine,
  indapamide, anticonvulsants phenytoin
• cholesterol lowering agents fibrates,
  statins
• HIV drugs zidovudine (AZT), didanosine
  (DDI), stavudine (d4T), zalcitabine (DDC),
  ritonavir, amprenavir
• Education support leaflets can be obtained
  from http//www.diabeticfoot.org.uk

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Management of DPN 2

• Modification of risk factors
• Glycaemia HbA1c lt7
• Lipids TC lt 4, LDL lt 2.2, TG lt 1.4
• BP lt 140/80mmHg (lt125/75mmHg)
• BMI lt24 kg/m2
• Smoking STOP
• Prevention/delaying the onset of DM in at-risk
  groups
• Analgesia

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First Line

• Simple analgesia Paracetamol 1g qds,
• NSAIDS
• Tighter Glycaemic control will prevent
  progression of neuropathy but it is unlikely to
  improve symptoms in the majority of patients
• Second Line
• Tricyclic Antidepressants Amitriptyline 25-150mg
  daily
• Imipramine 25-150mg daily

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Third Line

• Opiate analgesia Codeine 15-60mg qds
• Dihydrocodeine 30mg qds
• Tramadol 50-100mg qds
• Oxycodone 10-60mg daily
• Fourth Line
• Consider Gabapentin, doses gt 1600mg/day usually
  needed
• Pregabalin
• Use with caution esp. in renally-impaired
  patients
• DO NOT STOP these medications abruptly as
  suicidal ideation is increased.

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Other Treatments

• SSRIs Duloxetine licensed in UK
• Topicals Capsaicin, ISDN spray
• Mexiletine Caution
• Bed cradle/Opsite dressing
• Complimentary and alternative therapies
  (acupuncture, TENS)
• Future therapies Antioxidants, eg. alpha lipoic
  acid
• Aldose reductase inhibitors, eg. Sorbinil,
  Ponalrestat, Tolrestat
• PKC inhibitors

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Case history

• 48yr old woman Type 2 DM 20 years
• Triple oral therapy HbA1c 11
• BMI 33, non smoker, TC7.6 (simva 20mg)
• BP 125/75, microalbuminuria (ramipril 5mg od)
• Main c/o burning pain in both feet at night
  (cant keep sheets on it)
• How would you manage this case?