VASCULAR COMPLICATIONS OF DIABETES - PART 5 ppsx

Risk factors for severity of diabetic polyneuropathy: intensive longitudinal assessment of the Rochester Diabetic Neuropathy Study cohort.. The data on remission of symptoms over time ar

CHAPTER 9 • PATHOPHYSIOLOGY OF DIABETIC NEUROPATHY 89

Insulin like growth factors (IGFs)

In cultured Schwann cells and the STZ-diabetic rat, IGF-1 demonstrates a tective effect via PI 3-kinase, in preventing glucose-mediated neuronal andSchwann cell apoptosis Both the STZ-diabetic and BB/W rat develop severehyperglycaemia and a deficiency in circulating IGF-I levels with neuroaxonaldystrophy (NAD) in the nerve terminals of the prevertebral sympathetic gan-glia and the distal portions of noradrenergic ileal mesenteric nerves In contrastthe Zucker Diabetic Fatty (ZDF) rat, an animal model of type 2 diabetes, alsodevelops severe hyperglycaemia but maintains normal levels of plasma IGF-Iand does not demonstrate NAD in sympathetic ganglia and ileal mesentericnerves However, IGF-I and IGF-I receptor mRNA levels have not been shown

pro-to differ in the sural nerve of diabetic patients compared with control subjects

C-Peptide

In experimental studies C-peptide has demonstrated effects on ATPase activity, endothelial nitric oxide synthase, expression of neurotrophicfactors and regulation of molecules controlling degeneration of the nodalapparatus in Type 1 diabetic nerves, as well as DNA binding of transcriptionfactors and modulation of apoptotic phenomena These findings have recent-

Na(+)/K(+)-ly been effectiveNa(+)/K(+)-ly translated into benefits in patients with Type 1 diabetes withthe demonstration of a significant improvement in sural sensory nerve con-duction velocity and vibration perception but without a benefit in either cold

or heat perception after 12 weeks of daily subcutaneous C-peptide treatment

Vascular endothelial growth factor (VEGF)

VEGF was originally discovered as an endothelial-specific growth factor with apredominant role in angiogenesis However, recent observations indicate thatVEGF also has direct effects on neurones and glial cells stimulating their growth,survival and axonal outgrowth Thus with its potential for a dual impact on boththe vasculature and neurones it could represent an important therapeutic inter-vention in diabetic neuropathy Although immunohistochemistry of sciaticnerves and dorsal root ganglia from STZ-diabetic rats demonstrates intenseVEGF staining in cell bodies and nerve fibers with no or very little VEGF expres-sion in controls Intramuscular gene transfer of plasmid DNA encoding VEGF-

1 or VEGF-2 in the STZ-diabetic rat and alloxan diabetic rabbit results in tion of nerve vascularity, blood flow and both large and small fibre dysfunction.Thus there is an intrinsic capacity to up-regulate VEGF but this appears insuffi-cient and may require exogenous delivery possibly via gene therapy A phase I/II,double-blind, placebo controlled study to evaluate the safety and impact ofphVEGF165 gene transfer in patients with diabetic neuropathy is currentlyunderway and will involve 192 patients over a period of four years

restora-SECTION II • DIABETIC NEUROPATHIES

90

IMMUNE MECHANISMS

Studies suggest that sera from type 2 diabetic patients with neuropathy tain an autoimmune immunoglobulin that induces complement-independ-ent, calcium-dependent apoptosis in neuronal cells The expression of thesecytotoxic factors has been related to the severity of neuropathy and the type

con-of neuronal cell killed Thus it has been suggested that such toxic factors maycontribute to diabetic neuropathy by acting in concert with hyperglycaemia

to damage sensory/autonomic neurones

FURTHER READING

Dyck PJ, Davies JL, Wilson DM, Service FJ, Melton LJ 3rd, O’Brien PC Risk factors for

severity of diabetic polyneuropathy: intensive longitudinal assessment of the Rochester

Diabetic Neuropathy Study cohort Diabetes Care 1999; 22: 1479–1486.

Eichberg J Protein kinase C changes in diabetes: is the concept relevant to neuropathy? Int Rev Neurobiol 2002; 50: 61–82.

Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O Multifactorial intervention

and cardiovascular disease in patients with type 2 diabetes N Engl J Med 2003; 348: 383–393.

• A meta-analysis of 19 randomized controlled trials of ARIs was disappointing

as it demonstrated a small but statistically significant reduction in decline ofmotor NCV without benefit in sensory nerves

• Single-nucleotide polymorphisms of the genes for mitochondrial (SOD2)and extracellular (SOD3) superoxide dismutases may confer an increased riskfor the development of neuropathy

• 1, 2-diacylglycerol (DAG) induced activation pf protein kinase C (PKC), inparticular PKC-β has been proposed to play a major role in diabetic

Epidemiological studies of diabetic peripheral neuropathy (DPN) have

pro-duced widely varying figures on incidence and prevalence There are several

reasons for this and include differing criteria to define neuropathy and the use

of different populations i.e clinic versus hospital patients Furthermore, the

clinical complexity of DPN due to the relative involvement of sensory motor

and autonomic fibres has led to the use of multiple assessments to define DPN

These have commonly included varying combinations of positive and negative

symptoms, neurological deficits derived from a clinical examination,

quanti-tative sensory tests and electrophysiology To attempt to draw some valid

comparisons between different studies each of the end points utilized will be

evaluated separately The incidence or prevalence will be defined and the

nat-ural history and risk factors for the end point considered

POSITIVE SENSORY SYMPTOMS (PAINFUL NEUROPATHY)

Positive sensory symptoms arise spontaneously or as a response to stimuli

and they may be divided into painful and non-painful categories Table 10.1

presents the long list of positive sensory symptoms, which have been utilized

in different studies and provides an insight into the difficulties of how

differ-ent symptoms may be recorded and interpreted

Table 10.1 Descriptions of positive neuropathic sensory symptoms J Neurolog Sci 2001;

hyperalgaesia

* Allodynia: the perception of pain from a non-noxious stimulus.

Vascular Complications of Diabetes: Current Issues in Pathogenesis and Treatment, Second Edition

Edited by Richard Donnelly, Edward Horton Copyright © 2005 by Blackwell Publishing Ltd

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92

A prevalence of 27% was demonstrated in the only population-based study

to date and it employed questionnaires to define symptoms according topain, tingling, numbness, and the inability to feel hot or cold Other clinic orhospital based studies utilizing similar symptom profiles have reported aprevalence of painful symptoms which varies from 3–30%, although theirfocus was more heavily on pain Data on the natural history of painful neu-ropathy are conflicting, with one study showing a decrease in the intensity ofsymptoms with worsening of quantitative measures of nerve function, whilstanother study found an improvement of pain with improvement of sensoryfunction in individuals treated with continuous subcutaneous insulin infu-sions (CSII) Of course CSII has been shown to have a direct effect on painfulsymptoms via decreasing glucose flux

The data on remission of symptoms over time are inconsistent, with onestudy showing an overall reduction in the severity of pain scores but without anyfull remissions, whilst the majority of other studies have observed remissions.Despite the large number of studies in patients with painful neuropathythe risk factors remain ill defined Thus in a population based study thedegree of hyperglycaemia, hypertension and diabetes duration were deemedimportant, but in a clinic based study, symptoms were related to diabetesduration but not HbA1C

NEGATIVE SENSORY SYMPTOMS (HYPOAESTHETIC

NEUROPATHY)

Since it is well recognized that patients tend to underestimate their degree ofinsensitivity, there has been more reliance on quantitative sensory testingthan on symptomatology in studies of hypoesthesia The prevalence ofhypoesthesia may vary greatly according to the criteria used to define abnor-mality In a study that utilized three different quantitative sensory measure-ments in the same individuals, the prevalence of abnormalities varied from8–34%, highlighting the impact of different tests on the outcome data gener-ated The site chosen to measure the deficit is also an important factor as thepresence of hypoesthesia increases substantially as measurements becomemore distal Whilst vibration perception thresholds may be elevated in chil-dren with diabetes and also in adults at diagnosis of type 2 diabetes, agerequires careful consideration since normal values increase markedly withage, especially after the 6thdecade In patients with type 1 diabetes followedfrom diagnosis, abnormalities of thermal thresholds and electrophysiologypreceded any abnormality of vibration threshold in the first five years afterdiagnosis Early in the course of type 2 diabetes, small but statistically signif-icant increases of vibration and thermal thresholds have been observed overtwo years A study that utilized the 10 g monofilament apparently showed no

CHAPTER 10 • EPIDEMIOLOGY AND NATURAL HISTORY OF DPN 93

progression of neuropathy in the first few years of diabetes This simplyreflects that the 10 g monofilament is neither sensitive enough to detect earlyloss of sensation nor to detect a small change in progressive loss of sensation.This study highlights the inappropriate use of the 10g monofilament andshows that it is useful only to detect those at risk of foot ulceration i.e thosewith severe neuropathy Progression appears to be more rapid once decreasedsensation appears and has been consistently related to diabetes duration,degree of hyperglycaemia, and height

COMBINED ASSESSMENTS

Studies which have utilized various combinations of positive and negativesymptoms, quantitative sensory testing, abnormalities of the neurological examand electrophysiology have generally produced higher estimates of the preva-lence of neuropathy In one of the largest and earliest epidemiological studiesthe prevalence of neuropathy was greater than 40% after 25 years of known dia-betes duration The EURODIAB IDDM Complications Study provided anoverall prevalence for neuropathy of 28% However, among the 27 centresincluded in the study, the prevalence ranged from less than 20% in several cen-tres to over 50% in two centres This highlights the variability in interpretingexamination findings in different countries and also that the patients chosen forstudy in the different centres came from differing clinical populations In theDiabetes Control and Complications Trial (DCCT) ‘clinically detectable’ neu-ropathy was found in 39% of the participants who had type 1 diabetes In theEpidemiology of Diabetes Complications (EDC) Study, a prospective study ofpatients with type 1 diabetes, the overall prevalence of DPN at base-line was37% In the San Luis Valley Diabetes Study, a population based study of type 2diabetic patients, there was an overall prevalence of 28% The natural history ofDPN is difficult to ascertain from such studies Pirart’s study revealed strongunivariate associations between neuropathy and the duration of diabetes as well

as degree of hyperglycaemia The EURODIAB IDDM study has employed tivariate modeling to identify associations of neuropathy with age, duration ofdiabetes, HbA1Cand severe ketoacidosis Furthermore, the prevalence of neu-ropathy was related to elevated diastolic blood pressure and triglycerides anddecreased HDL-cholesterol In the DCCT impairment of nerve conduction wasfound to be associated with age, diabetes duration HbA1C, male gender and C-peptide deficiency In the EDC Study DPN at base-line was related to age, dia-betes duration, HbA1, HDL-cholesterol, hypertension and cigarette smoking.The SLVDS found that DPN was related to age, diabetes duration, HbA1Candinsulin use Several studies have also observed associations of DPN withretinopathy and nephropathy In a case-control study, DPN was associatedwith lifetime cigarette smoking in type 1 but not type 2 diabetes

mul-Table 10.2 Risk factors and their biological basis for DPN.

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CONCLUSION

Despite the seeming inconsistencies of findings in epidemiological studies ofdiabetic neuropathy, one thing is clear: DPN is very common At least one man-ifestation of DPN is present in well over 20% of individuals with diabetes.However, the prevalence of painful neuropathy appears to be appreciably lower Regarding natural history, some degree of abnormality occurs virtually fromthe diagnosis of Type 1 and particularly type 2 diabetes Once DPN is detectable,especially with an abnormality in vibration sense, there is a tendency towardrapid progression DPN is associated with the degree of hyperglycaemia, diabetesduration, height, conventional cardiovascular risk factors (including lipid andblood pressure indices), and other complications of diabetes Other risk factorssuch as alcohol consumption and cigarette smoking have been less consistent intheir associations with DPN The definitive risk factors that have been identifiedhave biological plausibility for their involvement in the pathogenesis of DPN

(Table 10.2) Duration and degree of hyperglycaemia indicate the extent of

over-all exposure to hyperglycaemia Height, as a proxy for nerve length entertains thehypothesis that the longer nerves are more susceptible to the metabolic and vas-cular consequence of diabetes Blood pressure and lipid indices would appear tostrengthen the assertion that vascular abnormalities contribute to the develop-ment and progression of DPN and the relation with other complications sug-gests they have common (vascular) pathogenetic pathways

Thus epidemiologic studies provide important clues for future mechanisticresearch and also provide support for mechanisms already defined in the patho-genesis of DPN Future epidemiological studies should pay particular attention

to the endpoints and methodology utilized

Risk factors and their biological basis for DPN Risk factor Biological basis

Age, duration of diabetes, HbA1C Measures of total exposure to primary inducer severe ketoacidosis of multiple pathogenetic pathways.

Height Proxy for longer nerves being more susceptible

to metabolic/vascular mechanisms Dyslipidaemia Inducer of vascular dysfunction

Hypertension Inducer of vascular dysfunction

Nephropathy and Retinopathy Common vascular basis for all complications

*Alcohol consumption May aggravate neuropathy

*Cigarette smoking May aggravate vascular dysfunction

* Less consistent associations with DPN

CHAPTER 10 • EPIDEMIOLOGY AND NATURAL HISTORY OF DPN 95

CURRENT ISSUES

• Epidemiological studies of diabetic peripheral neuropathy (DPN) have

produced widely varying figures on incidence and prevalence

• The prevalence of painful symptoms varies from 3–30%

• The 10 g monofilament is neither sensitive enough to detect early loss of

sensation nor to detect a small change in progressive loss of sensation –

and should only be used to detect those at risk of foot ulceration

• The EURODIAB IDDM study has identified associations between

neuropathy and age, duration of diabetes, HbA1C, diastolic blood

pressure, triglycerides and decreased HDL-cholesterol

FURTHER READING

EURODIAB IDDM Study Group Prevalence of diabetic peripheral neuropathy and its

relation to glycaemic control and potential risk factors: the EURODIAB IDDM

com-pliction study Diabetologia 1996; 39: 1377–1386

The EURODIAB Prospective Complications Study (PCS) Group Cardiovascular risk

factors predict diabetic peripheral neuropathy in type 1 subjects in Europe.

CHAPTER 11

DETECTION/SCREENING/ASSESSMENT

Rayaz A Malik MB.ChB, PhD, MRCP 97

SYMPTOMS

Patients often have difficulty in describing the symptoms of neuropathy

Therefore when physicians record symptoms in clinical practice they must

avoid ‘interpreting’ or ‘translating’ what patients report, rather they should

record the patient’s description verbatim For simple screening, a number of

questionnaires are available and include the Neuropathy Symptom Score

(NSS), Michigan Neuropathy Screening Instrument (MNSI), and more

recently the NSS +4 Where a response to treatment is being assessed, visual

analogue or verbal descriptive scales are used, but few have been validated for

diabetic neuropathy

Signs

Composite scores which quantify the degree of neurological deficit in the

lower limbs were pioneered by Dyck and co-workers who first described the

Neuropathy Disability Score (NDS) and later the Neuropathy Impairment

Score (NIS) A modified NDS has been used in several large studies (Table

11.1) and has been shown to predict foot ulceration in a large prospective

community study A clinical scoring system which documents and monitors

neuropathy in the clinic has been validated by the Toronto group

CLINICAL SCREENING

Whilst the simple hand held screening devices are less sensitive than the

more sophisticated QST devices, they are cheap, portable and easy to use

Currently the most widely and sometimes perhaps inappropriately used

device is the Semmes-Weinstein monofilament The lack of perception of

pressure to gentle pressure applied to the handle sufficient to buckle the

nylon filament defines an abnormal response Although filaments of many

different sizes are available, the 10 g or 5.07 (10 x log of the force generated to

deform the filament) monofilament should be used In identifying feet at

risk of ulceration it has a sensitivity of 86–100% The commonest algorithm

recommends four sites per foot (hallux and metatarsal heads 1, 3, and 5)

Although a recent study suggests that there is little advantage gained from

multiple site assessment Additionally a recent study has shown that

fila-ments manufactured by a number of companies actually buckle at 8 g rather

than the validated 10 g monofilament The graduated Rydel-seiffer tuning

fork is widely used in Europe, particularly in Germany It allows the assessor

to define a threshold on a 0–8 scale and has been shown to correlate well

Vascular Complications of Diabetes: Current Issues in Pathogenesis and Treatment, Second Edition

Edited by Richard Donnelly, Edward Horton Copyright © 2005 by Blackwell Publishing Ltd

Table 11.1 Neuropathy Disability Score.

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with other QST measures The recently reported Neuropen combines theassessment of pain using a neurotip with pressure using a 10 g monofilament

QUANTITATIVE SENSORY TESTING (QST)

QST may be defined as any procedure requiring a power source where the sity and characteristics of the stimuli are well controlled and where the detectionthreshold is determined in parametric units that can be compared to establishednormal values QST measures the three major modalities of vibration, thermaland pain thresholds and has been shown to detect sub-clinical neuropathy, trackits progression and predict those patients at risk of foot ulceration Despite the

inten-strengths and weaknesses of QST (Table 11.2) it has been used as a primary

effi-cacy measure in a number of completed and on-going clinical trials of DPN

Vibration perception threshold (VPT)

VPT reflects the activation of mechanoreceptors (i.e Pacinian and Meissnercorpuscles), conduction in peripheral large diameter myelinated axons, andtransmission through the dorsal column spinal pathways Vibratory thresholds

Risk factors and their biological basis for DPN

Right Left Vibration perception threshold

128 Hz tuning fork; apex of big toe:

normal = can distinguish vibrating/

not vibrating

Temperature perception on

dorsum of the foot

Use tuning fork with beaker of Normal = 0 Abnormal = 1

ice/warm water

Pin-prick

apply pin proximal to big toe nail

just enough to deform the skin;

trial pair = sharp, blunt ;

normal = can distinguish sharp /

not sharp

Achilles reflex Present = 0

Present with reinforcement = 1 Absent = 2 NDS Total out of 10

CHAPTER 11 • DETECTION/SCREENING/ASSESSMENT

have been shown to detect not only sub-clinical neuropathy in children andadolescents with type 1 diabetes but also provide a strong indication of risk forfuture ulceration In a 4-year prospective study patients with base-line VPT >25volts with the biothesiometer were seven times more likely to develop footulcers Recently in 187 type 2 diabetic patients multivariate logistic regressionhas shown that an elevated VPT score was the strongest predictor of foot ulcer-ation (relative risk of 25.4) In a large prospective study of 1,035 type 1 and type

2 diabetic patients, each one unit increase in vibration threshold (voltage scale)

at base-line increased the hazard of foot ulceration by 5.6% over one year

Electrophysiology

Multiple consensus panels have recommended electrophysiology in the uation of diabetic peripheral neuropathy (DPN), and in its use as a primarymeasure of therapeutic efficacy in multicentre clinical intervention trials The

eval-99

Table 11.2 Strengths and limitations of QST.

Strengths and limitations of QST Strengths

• Accurate control of stimulus characteristics

• Ability to assess multiple modalities

• Use of well established psychophysical procedures to enhance sensitivity

• Measures function over a wide range of intensity and hence neuropathic severity

• Measures sensation at multiple anatomical sites

• Data from large, age-matched normal groups available for comparison

Limitations

• Semi-objective measure affected by the subject’s motivation and cooperation

• Affected by age, gender, body mass, history of smoking and alcohol consumption

• Expectancy and subject bias

• Affected by any change along the entire neuroaxis from nerve to cortex.

• Chronic liver/renal disease

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speed of both sensory and motor conduction, amplitude of the propagatingneural signal, density and synchrony of muscle fibres activated by maximalnerve stimulation, and the integrity of neuromuscular transmission areassessed When used together they are objective, non-invasive and highly reli-able However, the standard procedure of maximal nerve conduction veloci-

ty (NCV) has major limitations as it reflects the integrity of only a small set of large diameter and heavily myelinated axons It also misses subtle butimportant early alterations such as a reduction in Na+/K+adenosine triphos-phatase activity, which would primarily diminish the ability of neurones torapidly re-establish transmembrane ion gradients and can only be assessed bydefining refractory cycles and axonal recovery A number of principal factors

sub-influence the speed of NCV (Table 11.3) In early diabetic neuropathy the

slowing of NCV is thought to be related to an alteration in nodal ion bution, a diminished length constant of large diameter axons due to analtered cross-sectional volume and demyelination which is further augment-

distri-ed at later stages by Wallerian degeneration

NCV provides a sensitive, but nonspecific index on the onset of DPN andcan be valuable in detecting sub-clinical deficits It diminishes by approximate-

ly 0.5 metres/sec/year In a study of 133 patients with newly diagnosed type 2 betes, NCV deteriorated by 3.9 and 3.0 metres/sec in the sural and peronealnerves respectively over 10 years In the Diabetic Control and ComplicationsTrial (DCCT) the sural and peroneal nerve velocities in the conventionallytreated group diminished by 2.8 and 2.7 metres/sec, respectively over the 5-yearstudy period The changes in NCV relate to glycaemic control as in the DCCTthe incidence of abnormal NCV was 40.2% in the conventionally treated groupand only 16.5% in the group receiving intensive insulin therapy In a study of 45type 1 diabetic patients a regression analysis has shown that a 1% change inHbA1 is associated with a 1.3 metres/sec change in maximal nerve conduction The peak amplitude of either the sensory response (SNAP) or the com-pound muscle action potential (CMAP) reflects the number of responding

dia-Table 11.3 Principle factors governing electrophysiological alterations in diabetic

neuropathy.

Principle factors governing electrophysiological alterations in

diabetic neuropathy

• Integrity and degree of myelination of the largest diameter fibres

• Mean cross-sectional diameter of the responding axons

• Representative internodal distance in the segment under study

• Micro-environment at the nodes

• Distribution of ion channels