5: Chronic complications

Section 5 Chronic complications




Ocular complications 


Diabetic neuropathy 


Diabetic foot disease 


Diabetic nephropathy 


Diabetic cardiovascular disease 


Dermatological features of diabetes mellitus 


Musculoskeletal and connective tissue disease 


Infection and diabetes 



Ocular complications


Clinically significant ocular complications associated with diabetes include:



• transient visual disturbances secondary to osmotic changes (or briefer episodes secondary to hypoglycaemia)


• retinopathy – the predominant cause of blindness in type 1 diabetes


• cataracts – develop earlier in diabetic patients


• glaucoma – primary or secondary to diabetic retinopathy


• iritis – associated with autoimmune type 1 diabetes.



Diabetic retinopathy


Diabetic retinal disease is the commonest cause of visual impairment in patients with type 1 diabetes. Diabetic retinopathy is more than likely to occur in patients who have poorly controlled diabetes and its prevalence increases with the duration of diabetes. Fifty per cent of patients with type 1 diabetes will have some form of retinopathy after 10 years. Approximately 5–10% of patients with type 2 diabetes will present with retinopathy (with a small number having sight-threatening retinopathy).


The following risk factors have been shown to determine the development and progression of diabetic retinal disease:



• poor glycaemic control


• raised BP (BP)


• duration of diabetes


• microalbuminuria and proteinuria


• raised triglycerides


• anaemia


• pregnancy


• smoking


• serum cholesterol (for macular exudates and oedema).


Clinically significant macular oedema and hard exudate formation but not proliferative retinopathy or retinopathy progression appears to be associated with total, high density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol levels.


Patients with multiple risk factors should be considered at particularly high risk of developing diabetic retinal disease.



Pathology


Microvascular leakage and non-perfusion are the main aetiopathogenic processes. The tight junction of the endothelial cells constitutes the inner blood retinal barrier. Pericytes wrapped round the capillaries are thought to be responsible for the structural integrity of the blood vessel. In diabetic patients there is a reduction in pericytes and endothelial cells leading to a breakdown of this barrier.


Microaneurysms are the first clinically detectable lesions and represent a dilated part of the perivenular capillaries; they occur due to a reduction in the number of endothelial cells and pericytes. They appear as tiny round dots and can occur anywhere in the retina.


Intraretinal haemorrhages can also be dot or blot in shape if they lie in the deeper compact layers of the retina, or flame-shaped if they lie in the nerve fibre layer (obeying the arrangement of the nerve fibres).


Hard exudates appear yellow and waxy with relatively distinct margins and represent intraretinal deposition of serum lipids. They usually border normal and oedematous retina, are found in the posterior pole, and can often be seen in a circinate pattern around a cluster of microaneurysms.


Retinal oedema represents leaky capillaries and is often difficult to delineate with direct ophthalmoscopy. It should always be suspected in the presence of hard exudates. Visual acuity declines if the retinal oedema involves the fovea.



Pre-proliferative diabetic retinopathy


Pre-proliferative diabetic retinopathy develops in eyes that initially may show only simple background retinopathy, and is caused by retinal ischaemia.


Pre-proliferative diabetic retinopathy is characterized by:



• vascular changes consisting of venous changes in the form of ‘beading’, ‘looping’ and ‘sausage-like’ segmentation. The arterioles may also be narrowed and even obliterated, resembling a branch retinal artery occlusion.


• cotton-wool spots, caused by capillary occlusion in the retinal nerve fibre layer. Interruption of axoplasmic flow caused by the ischaemia, and subsequent build-up of transported material within the nerve axons, is responsible for the white appearance of these lesions.


• dark blot haemorrhages, which represent haemorrhagic retinal infarcts.


• intraretinal microvascular anomalies (IRMAs), representing either dilated pre-existing vessels or early intraretinal new vessels. They are found within an area of capillary non-perfusion.


Pre-proliferative changes suggest increasing retinal ischaemia and precede proliferative retinopathy. They indicate worsening retinopathy and a likely need for laser photocoagulation. The presence of ischaemic maculopathy should be assessed as it could lead to irreversible loss of vision.



Classification of diabetic retinopathy


Conventionally involvement of retina in patients with diabetes has been classified as background, pre-proliferative retinopathy and proliferative retinopathy. Macula may be involved (maculopathy) with any of the above forms of retinopathy (Table 5.1).


Table 5.1 Grading system used for screening for diabetic retinopathy (UK National Guidelines)























RETINOPATHY (R)


Level R0: No visible retinopathy


Level R1: Background diabetic retinopathy (BDR) – mild


The presence of at least one of any of the following features anywhere:



• Dot haemorrhages


• Microaneurysms


• Hard exudates


• Cotton-wool spots


• Blot haemorrhages


• Superficial/flame-shaped haemorrhages



Level R2: Background diabetic retinopathy (BDR) – observable



• Four or more blot haemorrhages in one hemi-field only (inferior and superior hemi-fields delineated by a line passing through the centre of the fovea and optic disc)



Level R3: Background diabetic retinopathy (BDR) – referable


Any of the following features:



• Four or more blot haemorrhages in both inferior and superior hemi-fields


• Venous beading


• IRMA



Level R4: Proliferative diabetic retinopathy (PDR) – referable


Any of the following features:



• Active new vessels


• Vitreous haemorrhage



Level R5: Blind or phthisical eye


Level R6: Not adequately visualized



• Retina not sufficiently visible for assessment – technical failure

MACULOPATHY (M)


Level M0: No maculopathy

No features ≤ 2 disc diameters from the centre of the fovea sufficient to qualify for M1 or M2 as defined below.

Level M1: Lesions as specified below within a radius of > 1 but ≤ 2 disc diameters from the centre of the fovea


Level M2: Lesions as specified below within a radius of ≤ 1 disc diameter of the centre of the fovea



• Blot haemorrhages


• Hard exudates

PHOTOCOAGULATION (P)


Laser photocoagulation scars present

OTHER LESIONS (OL)
Other non-diabetic lesions present:


• Pigmented lesion (naevus)


• Age-related macular degeneration


• Drusen maculopathy


• Myelinated nerve fibres


• Asteroid hyalosis


• Retinal vein thrombosis


IRMA, intraretinal microvascular anomaly.


Another commonly used grading system is the Early Treatment Diabetic Retinopathy Study (ETDRS) system (Table 5.2).


Table 5.2 The Early Treatment Diabetic Retinopathy Study (ETDRS) system



















































Grade Features
NPDR
None Normal retina
Early Microaneurysms only
Mild Microaneurysms plus:


• retinal haemorrhages and/or

 

• hard exudates (> 1DD from fovea)

Moderate Mild; NPDR plus:


• haemorrhage and/or cotton-wool spots (< 5) and/or

 

• venous beading/looping or IRMA in one quadrant

Severe Moderate NPDR plus 4/2/1 rule:


• microaneurysm/haemorrhages in four quadrants, or



• venous beading/looping in two or more quadrants, or

 

• IRMA in one quadrant

Very severe Any two or more of the ‘severe categories’
PDR
PDR without HRC NVE or NVD < ½DD
PDR with HRC NVE or NVD > ½DD plus preretinal and/or vitreous haemorrhages

DD, disc diameter; HRC, high-risk changes; IRMA, intraretinal microvascular anomaly; NPDR, non-proliferative diabetic retinopathy; NVD, new vessels on the disc; NVE, new vessels elsewhere in the retina; PDR, proliferative diabetic retinopathy.



Screening


Diabetic retinopathy can progress significantly without the patient being aware of any problems. The primary aim of screening is the detection of potentially sight-threatening retinopathy in asymptomatic people so that treatment, where required, can be performed before visual impairment occurs.


Retinal screening is defined as the ongoing assessment of fundi with no diabetic retinopathy or non-sight-threatening diabetic retinopathy. Once sight-threatening eye disease develops, treatment is usually required. Diabetic retinopathy screening does not remove the need for a regular general eye examination to monitor changes in refraction and to detect other eye disease.


In patients with type 1 diabetes it takes 5–6 years for retinopathy to progress. In type 1 patients aged 11 years or older, it can take 1–2 years for retinopathy to progress. A population-based study demonstrated the prevalence of retinopathy to be 14.5% for any retinopathy and 2.3% for proliferative and pre-proliferative retinopathy in children and adolescents with insulin-dependent diabetes mellitus diagnosed before the age of 15 years and who were older than 9 years at the time of examination. Pre-proliferative retinopathy has been identified as early as 3.5 years after diagnosis in patients postpuberty, and within 2 months of onset of puberty.



Direct ophthalmoscopy


The direct ophthalmoscope is the instrument of choice for fundus examination by medical students and physicians. It allows for a magnified, monocular image of the retina and optic disc.



Non-mydriatic camera


A non-mydriatic camera does not usually require the patient’s eyes to be dilated; however, a much greater success rate can be achieved if tropicamide or similar mydriatic eye drops are used. Non-mydriatic cameras operate by using an infrared-sensitive video camera image to position and focus the image of the retina. As no visible light is used, the patient’s pupil will not constrict, and a photograph can then be taken using the built-in flash. The flash duration is so short that the exposure is made before the pupil can react.


The Scottish Diabetic Retinal Screening programme uses the Topcon TRC-NW6, which incorporates one central and eight fixed peripheral internal fixation points. Using each of these fixation points will cover 85° of the retina. The central fixation point allows a repeatable photograph of the posterior pole.



Grading and quality assurance


Retinal photographs should be graded using digital images by an appropriately trained grader to facilitate quality assurance.


Automated grading can operate as the initial screener to exclude a majority of images with ‘no retinopathy’ before manual grading. The specificity of automated grading is lower than for manual grading, for equivalent sensitivity. Automated grading may be used for distinguishing no retinopathy from any retinopathy in a screening programme providing validated software is used. It has a similar sensitivity for detecting referable retinopathy, but may be less sensitive at detecting diabetic maculopathy (Table 5.3).


Table 5.3 Systematic screening for diabetic retinal disease







• Patients with type 1 diabetes should be screened from age 12 years


• Patients with type 2 diabetes should be screened from diagnosis


• Patients with diabetes with no diabetic retinopathy could be screened every 2 years – all others should be screened at least annually


• Visual acuity measurements often help in the interpretation of maculopathy


Either one-field 45–50° retinal photography or multiple-field photography can be used for screening purposes.



General principles of management of diabetic retinopathy



Glycaemic control


Tight glycaemic control reduces the risk of onset and progression of diabetic eye disease in type 1 and 2 diabetes. The Diabetes Control and Complications Study (DCCT) demonstrated that intensive glycaemic control reduces the risk of onset of diabetic retinopathy, progression of pre-existing retinopathy, and the need for laser for patients with type 1 diabetes. The UK Prospective Diabetes Study (UKPDS) demonstrated similar reduction in the risk of onset and progression in diabetic retinopathy in patients with type 2 diabetes.



Control of blood pressure


The UKPDS demonstrated that the risk of progression of diabetic retinopathy was decreased with tight control of BP (with either captopril or atenolol) and led to an almost 35% relative reduction in the need for retinal photocoagulation. Data from the UKPDS suggests that BP lowering rather than use of a specific agent may be responsible for the benefits. The EURODIAB Controlled Trial of Lisinopril in Insulin-dependent Diabetes (EUCLID) study (using lisinopril) and the Diabetic Retinopathy Candesartan Trials (DIRECT) demonstrated delay in the progression of retinopathy using drugs that act on the renin–angiotensin–aldosterone axis.



Management of dyslipidaemia


The Early Treatment Diabetic Retinal Screening (ETDRS) and DCCT revealed that raised serum cholesterol concentration was related to the development and progression of diabetic maculopathy. Recent studies suggest that aggressive lipid lowering is beneficial in prevention of progression of maculopathy.



Multifactorial risk reduction


The Steno-2 trial and other studies have shown the benefit of multiple interventions, which included behavioural therapy (dietary intervention, exercise and smoking cessation) and pharmacological intervention (reduction of BP, improvement in glycaemic control and lipid modification).


Reducing glycated haemoglobin (HbA1c) by 1.5% (16.4 mmol/mol) and, if possible, to 7% (53 mmol/mol) in type 1 and 2 diabetes plus reducing BP to 144/82 mmHg significantly reduces the incidence and progression of sight-threatening diabetic eye disease. There is no evidence to suggest that lowering BP to a level below 130/75 mmHg has a deleterious impact on retinopathy progression. Therefore, reducing BP and HbA1c below these targets is likely to reduce the risk of eye disease further. Microvascular endpoints (including retinopathy) are decreased:



• by 37% with each 1% (11 mmol/mol) reduction in HbA1c


• by 13% for each 10-mmHg reduction in systolic BP.


Rapid improvement of glycaemic control can result in short-term worsening of diabetic retinal disease, although the long-term outcomes remain beneficial. This is often seen in the rapid improvement of glycaemic control in the first trimester of pregnancy. However, pregnancy is in itself is considered an independent risk factor for the progression of diabetic retinopathy.


Laser photocoagulation, if required, should be completed before any rapid improvements in glycaemic control are achieved.



Proliferative diabetic retinopathy


Proliferative diabetic retinopathy (PDR) affects about 5 –10% of the diabetic population and is more common in type 1 diabetes.


Neovascularization is the hallmark of PDR. New vessels are commonly seen along the retinal arcades, but can occur at the optic disc or elsewhere in the retina. As a general rule, the retina distal to the neovascularization should be considered as ischaemic, and it has been estimated that more than one-quarter of the retina has to be non-perfused before neovascularization occurs. Ischaemia upregulates the vascular endothelial growth factor (VEGF) that stimulates neovascularization. New vessels start as endothelial proliferations, and pass through the internal limiting membrane to lie in the potential plane between the retina and the posterior vitreous face. PDR can result in visual deterioration from ischaemia, haemorrhage and tractional retinal detachment involving the macula (Table 5.4).


Table 5.4 Guidelines for referral for specialist assessment of diabetic retinopathy

































Clinical problem Urgency (within)
Sudden loss of vision 1 day
Evidence of retinal detachment 1 day
New vessel formation (on the disc or elsewhere) 1 week
Vitreous or pre-retinal haemorrhage 1 week
Rubeosis iridis 1 week
Hard exudates within 1DD of the fovea or clinically significant macular oedema 4 weeks
Unexplained drop in visual acuity 4 weeks
Unexplained retinal findings 4 weeks
Severe or very severe non-proliferative retinopathy is present 4 weeks


Diabetic maculopathy


Involvement of the macula with exudative or ischaemic changes has a potential to involve the fovea, thus threatening vision. Exudative maculopathy may be amenable to treatment but ischaemic changes are not.


Diabetic maculopathy can present in the following patterns:



• Focal – focal leakage, characterized usually by the presence of a cluster of microaneurysms surrounded by retinal thickening and a complete or incomplete ring of hard exudates


• Diffuse – diffuse retinal thickening and exudation from capillaries often involving the fovea. Cystoid changes suggest chronicity of the condition


• Ischaemic – diagnosed ideally by fluorescein angiography, representing an enlarged or irregular foveal avascular zone. Clinically it may lack features; however, the hallmarks are reduced visual acuity, deep blot haemorrhages and IRMAs.



Laser photocoagulation


The efficacy of photocoagulation has been demonstrated in the Diabetic Retinopathy Study (DRS) and ETDRS studies. It is believed that the regression of neovascularization is due to the destruction of ischaemic and hypoxic retina with the reduction in angiogenic factors.


Panretinal photocoagulation is now the main modality of treatment for proliferative diabetic retinopathy and severe non-proliferative diabetic retinopathy (NPDR). Clinically significant macular oedema (CSMO) can be treated with focal or grid photocoagulation.


Panretinal laser involves the application of 500 μm of Argon laser photocoagulation spots, each separated by an interval of a similar spot size to the mid-peripheral retina. A row of laser burns are initially placed approximately three disc diameters temporal to the fovea to avoid getting closer to the fovea. About 1500 burns are usually required (in two to three sessions). Severe cases may require further photocoagulation. The aim is to cover the ischaemic areas and regression of new vessels occurs in almost 80% of cases. Fundus fluorescein angiography (FFA) should be undertaken initially to delineate the ischaemic areas, or should be done to ensure coverage of ischaemic areas with laser if good regression of neovascularization is not achieved even with initial retinal photocoagulation.


Laser treatment can be associated with pain, transient visual loss, loss of visual field (inevitable) and, sometimes, reduced visual acuity and choroidal damage.


In very aggressive cases of PDR, an intravitreal injection of an anti-VEGF can give a valuable window period until the laser photocoagulation takes effect which can take up to 2 weeks.



Macular laser


Laser photocoagulation is considered primarily for clinically significant macular oedema. This can be applied focally to leaking microaneurysms or in a grid pattern over the macula in case of diffuse macular oedema. The spot sizes used vary from 50-100 μm and power just sufficient to cause a minimal blanch. Use of higher power can result in reduction of visual acuity. Utmost care should be taken to avoid the foveal avascular zone. Ideally macular laser should be undertaken only after angiographic assessment.


Other modalities of locally managing macular oedema are with intravitreal injections of triamcinolone acetonide or anti-VEGF. The effects of these injections, however, are usually only short-lived.



Vitrectomy


Early vitrectomy is of proven value for improving long-term vision in patients with type 1 diabetes and persistent vitreous haemorrhage. Its value in type 2 diabetes is less certain. Patients with type 1 or type 2 diabetes who have severe fibrovascular proliferation threatening the macula with or without retinal detachment also have better visual acuity after vitrectomy.



• Patients with type 1 diabetes and persistent vitreous haemorrhage should be referred for early vitrectomy.


• Vitrectomy should be performed in patients with tractional retinal detachment threatening the macula and should be considered in patients with severe fibrovascular proliferation.


• Patients with type 2 diabetes and vitreous haemorrhage that is too severe to allow photocoagulation should be referred for consideration of a vitrectomy.



Cataract extractions in patients with diabetes


Visual outcome following cataract surgery in patients with diabetes is closely linked to age and severity of retinopathy present before surgery. Although postoperative progression of pre-existing proliferative diabetic retinopathy and CSMO has been documented, the balance of evidence does not show an increase in diabetic retinopathy or in the long-term incidence of CSMO following cataract extraction.



• Cataract extraction should not be delayed in patients with diabetes.


• Cataract extraction is advised when sight-threatening retinopathy cannot be excluded.


When cataract extraction is planned in the context of advanced eye disease that is not stabilized prior to surgery, the risk of disease progression and the need for close postoperative review should be discussed fully with the patient.



Pharmacological therapy


Fenofibrate reduces the risk of progression of retinopathy and the need for laser treatment in patients with type 2 diabetes. The outcomes were not explained by a change in the serum lipid profile and the effect was independent of its lipid-lowering properties.


Intravitreal triamcinolone may provide a short-term reduction in retinal thickness and a corresponding improvement in visual acuity. In the long term it does not appear to have any benefit over laser treatment. Triamcinolone may be useful in patients who do not respond to laser. There is a risk of raising intraocular pressure: in one study, 68% of patients were affected, with 44% requiring glaucoma medication and 54% of patients requiring cataract surgery.


A randomized clinical trial of patients with type 2 diabetes and raised serum lipid levels at baseline, found that atorvastatin reduced the severity of hard exudates following laser therapy (P  =  0.007), although the clinical significance of this is not certain. A similar study showed a non-statistically significant improvement in visual acuity and reduction in clinically significant macular oedema in patients on simvastatin.


There is insufficient evidence to warrant routine usage of anti-VEGF therapies for the treatment of proliferative diabetic retinopathy or diabetic macular oedema, either as stand-alone therapy or as an adjuvant to laser therapy.


There is no good evidence for any additional benefit of angiotensin converting enzyme (ACE) inhibitors in diabetic eye disease.


An angiotensin receptor blocker (ARB) appeared to reduce significantly the incidence of new-onset retinopathy in patients with type 1 diabetes, by 35% when measured as a change of three steps in the ETDRS scale, rather than the two steps in the original study design. Treatment with the ARB enhanced regression of retinopathy by 34% in patients with type 2 diabetes with early retinopathy.



Rehabilitation


Patients should be registered by their ophthalmologist as partially sighted (best corrected acuity 6/60) or blind (3/60 or worse). They should be assisted to register as blind/partially sighted as soon as they fulfil the criteria. Recognized disability will allow direct referral to a local low-vision network and/or visual impairment team for assessment and ongoing support. Low-vision aids and adapted everyday appliances are available. Pen injectors and other devices may be useful for patients requiring insulin treatment. With instruction, self-monitoring of capillary glucose is possible; modified glucose meters are available, including devices providing an audible result.


Other potential support includes:



• Braille instruction


• large-print and audio books


• guide dog provision.


Depression is understandably common. Peer support organized through patient organizations can often be helpful.



Cataract


A cataract is an opacity of the crystalline lens of the eye. It is usually asymptomatic in the early stages of development, but may progress to cause significant visual impairment or even blindness. The commonest variety of cataract is the so-called senile cataract. Cataracts are features of certain syndromes or therapies that may also be associated with diabetes, for example:



• myotonic dystrophy


• chronic corticosteroid therapy.


Epidemiological studies indicate that diabetes mellitus is a significant risk factor for cataract formation in patients aged up to 70 years. The incidence of cataract is increased several-fold compared with incidence in the non-diabetic population; the opacity also progresses more rapidly in diabetic patients. Good glycaemic control reduces the risk of cataract extraction.



Tip box


Cataracts are more common in diabetic patients and appear earlier than in non-diabetic people.


Rarely, diabetes is associated with the development of an acute form of rapidly developing lens opacity known as a ‘snowflake cataract’. This usually occurs in young insulin-dependent patients and typically, though not invariably, follows a period of particularly poor glycaemic control. The cataract may appear and mature within weeks.



Diabetic neuropathy


The wide variability in symmetrical diabetic polyneuropathy prevalence data is due to lack of consistent criteria for diagnosis, variable methods of selecting patients for study, and differing assessment techniques. In addition, because many patients with diabetic polyneuropathy are initially asymptomatic, detection is extremely dependent on careful neurological examination by the primary care clinician.


In the UK, the prevalence of diabetic neuropathy among the hospital clinic population is thought to be around 30%. Using additional methods of detection, such as autonomic or quantitative sensory testing, the prevalence may be higher.




Race


No racial predilection has been demonstrated for diabetic neuropathy.



Sex


Male patients with type 2 diabetes appear to develop diabetic polyneuropathy earlier than female patients.



Age


Diabetic neuropathy can occur at any age, but is more common with increasing age and duration of diabetes.


Diabetic neuropathy can manifest with a wide variety of sensory, motor and autonomic symptoms:



• Sensory symptoms may be negative or positive, diffuse or focal.


• Motor problems may include distal, proximal, or more focal weakness.


• The autonomic nervous system is composed of nerves serving the heart, skin, eyes, gastrointestinal system and genitourinary system. Autonomic neuropathy can affect any of these organ systems.



Classification of neuropathy


A generally accepted classification of peripheral diabetic neuropathies divides them broadly into symmetrical and asymmetrical neuropathies. Development of symptoms depends on total hyperglycaemic exposure plus other risk factors such as raised lipid levels, BP, smoking, and high exposure to other potentially neurotoxic agents such as ethanol. Establishing the diagnosis requires careful evaluation, as patients with diabetes may present with a neuropathy from another cause.



Symmetrical polyneuropathies


Symmetrical polyneuropathies involve multiple nerves diffusely and symmetrically:



• Distal symmetrical polyneuropathy:


• Most common manifestation of diabetic neuropathy.

• Sensory, motor and autonomic functions affected in varying degrees, with sensory abnormalities predominating.

• Chronic symmetrical symptoms affecting peripheral nerves in a length-dependent pattern (the longest nerves affected first).

• Commonly presents as numbness and painful paraesthesias, which begin in the toes and ascend proximally in a stocking-like distribution over months and years.

• When sensory symptoms reach the knees, the hands often develop similar symptoms, progressing proximally in a glove-like distribution.

• Mild weakness of foot muscles and decreased ankle and knee reflexes occur commonly.

• Loss of sensation predisposes to development of foot ulcers and gangrene.

• With impaired proprioception and vibratory perception, gait may be affected, causing a sensory ataxia.

• Small-fibre neuropathy:


• Distal symmetrical neuropathy involving predominantly small-diameter sensory fibres (Aδ and C fibres).

• Manifests as painful paraesthesias that patients perceive as burning, stabbing, crushing, aching or cramp-like, with increased severity at night (particularly exacerbated by bedclothes).

• Loss of pain and temperature sensation with relative sparing of distal reflexes and proprioception.

• Diabetic autonomic neuropathy:


• Pure autonomic neuropathy is rare.

• Diabetic autonomic neuropathy is relatively common if ‘looked for’.

• Some degree of autonomic involvement is present in most patients with diabetic polyneuropathy.

• Signs and symptoms may include sudomotor symptoms (dry skin due to lack of sweating or excessive in certain areas), orthostatic hypotension, resting tachycardia, loss of sinus arrhythmia, bowel or bladder dysfunction, and small pupils sluggishly reactive to light.

• Diabetic neuropathic cachexia:


• Occurs more often in older men.

• Precipitous and profound weight loss followed by severe and unremitting cutaneous pain, small-fibre neuropathy and autonomic dysfunction.

• Symptoms usually improve with prolonged improved glycaemic control.

• Symptoms are often refractory to other pharmacological treatment. Limited anecdotal improvement is reported with non-pharmacological treatments such as sympathectomy, spinal cord blockade and electrical spinal cord stimulation.

• Recovery may be incomplete and prolonged over many months.


Asymmetrical neuropathies


Asymmetrical neuropathies include single or multiple cranial or somatic mononeuropathies. Syndromes include median neuropathy of the wrist (carpal tunnel syndrome), single or multiple somatic mononeuropathies, thoracic radiculoneuropathy, lumbosacral radiculoplexus neuropathy and cervical radiculoplexus neuropathy. These syndromes usually have a monophasic course, may appear acutely or subacutely, and have a weaker association with glycaemic control than symmetrical polyneuropathies.




• Cranial mononeuropathy:


• Cranial nerves (CN) III, IV, VI, VII and II are most often involved.

• CN III, IV and VI disease often manifests as acute or subacute periorbital pain or headache followed by diplopia. Muscle weakness is typically in the distribution of a single nerve, and pupillary light reflexes are usually spared. Complete spontaneous recovery usually occurs within 3 months.

• Facial neuropathy manifests as acute or subacute facial weakness (taste is not normally involved) and can be recurrent or bilateral. Most recover spontaneously in 3–6 months.

• Anterior ischaemic optic neuropathy manifests as acute visual loss or visual field defects (usually inferior altitudinal). The optic disc appears pale and swollen; flame-shaped haemorrhages may be present.

• Somatic mononeuropathies:


• Focal neuropathies in the extremities caused by entrapment or compression at common pressure points or by ischaemia and subsequent infarction.

• Entrapment and compression tend to occur in the same nerves and at the same sites as in individuals without diabetes.

• Median nerve entrapment at the wrist (carpal tunnel syndrome) is more common in patients with diabetes and can be treated in the same manner as in patients without diabetes; the symptoms are often bilateral.

• Neuropathy secondary to nerve infarction presents acutely with focal pain associated with weakness and variable sensory loss in the distribution of the affected nerve. Multiple nerves may be affected (mononeuritis multiplex).

• Diabetic thoracic radiculoneuropathy:


• Patients older than 50 years are affected most often; it is more common in diabetes mellitus type 2 and is often associated with significant weight loss.

• Coexisting diabetic distal symmetrical polyneuropathy is often present.

• Burning, stabbing, boring, belt-like or deep aching pain usually begins unilaterally, then may become bilateral. Skin hypersensitivity and allodynia (pain with normally innocuous touch) may occur. Numbness in a dermatomal distribution, most prominent in distal distribution of intercostal nerves.

• Single or multiple spinal roots are involved. Contiguous territorial extension of symptoms may occur in a cephalad, caudal or contralateral direction.

• In the trunk, thoracoabdominal neuropathy or radiculopathy may cause chest and/or abdominal pain in the distribution of thoracic and/or upper lumbar roots.

• Weakness presents in the distribution of the affected nerve root, for example bulging of the abdominal wall from abdominal muscle paresis (thoracic root).

• Diabetic radiculoplexus neuropathy:


• Occurs in patients older than 50 years with poorly controlled diabetes and is more common in men than in women.

• Significant weight loss occurs in 50% of patients.

• The course is generally monophasic with improvement over many months; however, some residual deficits often remain.

• The syndrome may occur in the cervical or lumbosacral distributions and is referred to in the literature by various designations including diabetic amyotrophy, Bruns–Garland syndrome and diabetic plexopathy, among others.

• The most frequent initial symptom is sudden, severe, unilateral pain in the hip/lower back or shoulder/neck. Weakness then develops days to weeks later. Atrophy of the limb musculature may occur. Allodynia, paraesthesias and sensory loss are common.

• Symptoms usually begin unilaterally and may later spread to the opposite side.

• Reflexes in the affected limb may be depressed or absent.


Physical signs


The clinical signs and symptoms are usually in keeping with where the neuropathy fits into the classification described above.


Distal symmetrical sensorimotor polyneuropathy due to diabetes must occur in the presence of diabetes as outlined by the American Diabetes Association or World Health Organization. The severity of polyneuropathy should be commensurate with the duration and severity of the diabetes, and other causes of sensorimotor polyneuropathy should be excluded. Longer nerve fibres are affected to a greater degree than shorter ones, because nerve conduction velocity is slowed in proportion to a nerve’s length.


The first clinical signs that usually develop is decrease or loss of vibratory and pinprick sensation over the toes. As disease progresses, the level of decreased sensation may move upward into the legs and then into the hands and arms, a pattern often referred to as ‘stocking and glove’ sensory loss. A glove–stocking distribution of numbness, sensory loss, dysaesthesia and night-time pain may develop. The pain can feel like burning, pricking sensation, achy or dull. Pins and needles sensation is common. Loss of proprioception, the sense of where a limb is in space, is affected early. These patients cannot feel when they are stepping on a foreign body, such as a splinter, or when they are developing a callous from an ill-fitting shoe. Consequently, they are at risk for developing ulcers and infections on the feet and legs.


Very severely affected patients may lose sensation in a shield distribution on the chest. Deep tendon reflexes are commonly hypoactive or absent, and weakness of small foot muscles may develop. More focal findings may be seen with injury to specific nerves as described above. Loss of motor function results in dorsiflexion, contractures of the toes and loss of the interosseous muscle function, and leads to contraction of the digits, so-called ‘hammer toes’. These contractures occur not only in the foot but also in the hand, where the loss of the musculature makes the hand appear gaunt and skeletal.



Treatment


Despite advances in the understanding of the metabolic causes of neuropathy, treatments aimed at interrupting these pathological processes have been limited. Thus, with the exception of tight glucose control, treatments are for reducing pain and other symptoms.


Options for pain control include tricyclic antidepressants (TCAs), serotonin reuptake inhibitors (SSRIs) and antiepileptic drugs (AEDs). It is suggested that TCAs and traditional anticonvulsants are better for short-term pain relief than newer-generation anticonvulsants. A combination of medication may be superior to a single agent.


The only two drugs approved by the US Food and Drug Administration (FDA) for diabetic peripheral neuropathy are the antidepressant duloxetine and the anticonvulsant pregabalin (Fig. 5.1). Before trying a systemic medication, people with localized diabetic periperal neuropathy occasionally get relief from their symptoms with lidocaine patches.


image

Figure 5.1 Treatment algorithm for management of painful diabetic peripheral neuropathy. TCA, tricyclic antidepressant.


(Source: Wong et al (2007). Reproduced with permission.)


In addition to pharmacological treatment there are several other modalities that help some patients. These have been shown to reduce pain and improve quality of life, particularly for patients with chronic neuropathic pain: interferential stimulation, acupuncture, meditation, cognitive therapy, and prescribed exercise.



Tricyclic antidepressants


TCAs include imipramine, amitriptyline, desipramine and nortriptyline. These drugs are effective at decreasing painful symptoms but suffer from multiple side-effects that are dose-dependent. One notable side-effect is cardiac toxicity, which can lead to fatal arrhythmias. At low dosages used for neuropathy, toxicity is rare, but if symptoms warrant higher doses complications are more common. Among the TCAs, amitriptyline is most widely used for this condition, but desipramine and nortriptyline have fewer side-effects.

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Mar 10, 2017 | Posted by in ENDOCRINOLOGY | Comments Off on 5: Chronic complications

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