A review of the diagnosis and management of peripheral neuropathy in type 2 diabetes.

The prevalence of diabetes worldwide has risen tremendously over the last few decades and parallels the rise in obesity and sedentary lifestyle that is now widespread in our modern society.

*CD Mathers and D Loncar (2006) as cited by the WHO (2017), state that ‘the number of people with diabetes worldwide has risen from 108 million in 1980 to 422 million in 2014’. Unfortunately diabetes prevalence has been rising more rapidly in middle- and low-income countries, countries that have least capacity to deal with the many problems associated with diabetes.

In Papua New Guinea (PNG) for instance, according to the International Diabetes Federation (IDF) out of the estimated 3,952,000 adults 12.9% of them are living with diabetes.  This equates to about 507,900 adults with diabetes, *IDF (2017).

This is a staggering increase from the mere 0.2% prevalence reported in very early studies in PNG. In the early 1960s, Hingston and Prince found ‘no cases of diabetes in 407 adults in the Hula district of Central Province and only 2 of the 1057 adult subjects tested in four suburban communities in Port Moresby (PNG’s Capital City) had diabetes’ *Hingston and Prince (1962) as cited by G D Ogle (2001).  .

Long term, uncontrolled diabetes leads to a number of complications that cause morbidity and early loss of lives. These complications can be divided into macrovascular and microvascular complications.

Macrovascular complications include coronary artery disease, peripheral vascular disease and cerebrovascular disease while the microvascular complications include retinopathy, diabetic kidney disease (formally termed diabetic nephropathy) and diabetic neuropathy.

There are number of factors at play in the pathogenesis of microvascular complications of diabetes.  The underlying common factor seems to be chronic hyperglycemia which leads to hyperglycemia inside various tissue cells which absorbs glucose through insulin independent mechanisms. Intracellular hyperglycemia in these tissues triggers various other pathological processes that ultimately leads to dysfunctional vascular epithelial function which further leads to the development of other pathological process, *K Vithian and S Hurel (2010).

Diabetic neuropathy are a group of microvascular complications of diabetes that affect the nerves and the following classification of diabetic neuropathy is based on a modification of the classification proposed by PK Thomas by J G Llewelyn (2003).

Classification of Diabetic Neuropathy

  • Generalised neuropathy
    • – hyperglycaemic neuropathy
    • – symmetric distal polyneuropathy with/without autonomic neuropathy
    • – acute painful sensory neuropathy variants
  • Focal and multifocal neuropathy
    • –cranial neuropathies
    • –focal limb neuropathies
    • –thoracolumbar radiculoneuropathy
    • –lumbosacral radiculoplexus neuropathy (Bruns-Garland syndrome)

This report is focused diabetic peripheral neuropathy (DPN) which is the most common type of diabetic neuropathy. The pain that can arise from DPN ‘can be one of the most distressing and debilitating of all the complications of diabetes’ AJM Boulton (2005).  Therefore for a general practitioner who cares for people with diabetes it is an important condition to be familiar with and confident in diagnosing and managing.

 

From an international consensus meeting attended by various professional from ‘diabetologists, neurologists, primary care physicians, podiatrists and diabetes specialist nurses’ AJM Boulton et al (1998) as cited by AJM Boulton (2005) define diabetic peripheral neuropathy as “the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes”

This definition highlights that in people with diabetes the patient’s clinician, before making the diagnosis DPN must exclude other causes (which we shall discuss briefly later) of signs and/or symptoms of peripheral nerve dysfunction.

DPN can be divided into acute sensory neuropathy and chronic symmetrical sensorimotor neuropathy which is the most common form of DPN, AJM Boulton (2005).

In daily clinical practice a confident diagnosis of chronic symmetrical sensorimotor neuropathy can be made by the use of one of several approaches using well-validated questionnaires and clinical examination tools.

One such approach includes the use of Michigan Neuropathic Screen Instrument (MNSI) (Fig1) coupled with quantitative neurological examinations and if required a nerve conduction study (NCS) can be done however in most cases a NCS is not essential, AJM Boulton (2005).

Another useful approach that can be easily and quickly performed in a clinical practice setting employs the use of a modified Neuropathy Disability Score (MNDS), (Fig 2.). According to E L Feldman (1994) this approach consists of firstly a clinical neurological examination followed by routine nerve conduction measurements including vibratory threshold perception, pain, and light touch which were assessed with a 128 Hz tuning fork, a pin, and a 10-g filament, respectively.

 

The maximum score using the MNDS is 10 while a score of 6 or above has been shown to increase the risk of insensate foot ulcerations.

According to EL Feldman et al (1996) as cited by Porte D, S S Robert, Ellenberg M and Rifkin H (1997) in the 5th Edition of Ellenberg and Rifkin’s Diabetes Mellitus (1996), some common and easily excludable causes of peripheral neuropathy other than diabetes include but not limited to:

  • VitB12 and of Folic acid deficiency
  • Hypothyroidism
  • Chronic alcoholism
  • Systemic Lupus Erythematosus (SLE)
  • Paraneoplastic syndrome (especially due to small cell carcinoma of the lung)
  • Dysproteinemias and paraproteinemias
  • Amyoloidosis
  • Gullen Barre’s Syndrome
  • Sarcoidosis
  • Heavy metals (lead, mercury, arsenic)

It is prudent to exclude these other causes of peripheral neuropathy and in general a:

Good history taking (alcohol, family history of neuropathy, drug history, etc) and a few basic blood tests such as: Vitamin B12 and folate values serum protein electrophoresis, antinuclear antibodies (ANA), extractable nuclear antigen (ENA) double stranded DNA (dsDNA) , rheumatoid factor (RF), Thyroid function test (TFT), full blood count (FBC), erythrocyte sedimentation rate (ESR) and C-Reactive protein (CRP), Urea, and electrolytes creatinine (UECs) and liver function tests (LFTs) should be enough to secure diabetes peripheral neuropathy and exclude other serious and most treatable causes, J G Llewelyn (2003).

Once the diagnosis of diabetic peripheral neuropathy is confidently made and other more sinister causes of PN ruled out the appropriate management can then be provided and treatment response be monitored using the same tools described above.

Firstly the patient needs to be educated on his or her the diagnosis and they should be advise about the various treatment options available.  They should also be advised about the need for monitoring their response to treatment and reassured that with proper treatment they will experience improvement in their symptoms.

A number of pharmacological agents have been shown to be effective in the treatment of painful DPN and the most common ones used include:

  • tricyclic agents like amitriptyline at dosages of 25 to 150 mg daily and Imipramide at dosages of 25 to 150 mg daily.
  • Selective serotonin reuptake inhibitors (SSRI) like Paroxitene at a dose of 40 mg daily and citalopram at a dose of 40mg daily.
  • Anticonvulsants like Gabapentine at dosages of 900 to 1800 mg daily, Pregabalin at dosages of 160 to 600mg daily, Lamotrigine at dosages of 200 to 400mg daily and carbamezapine up to 800mgs daily.

The anticonvulsants have the best side effect profile out of these pharmalogical agents, AJM Boulton (2005)

The two landmark studies in type 1 diabetes mellitus and type 2 diabetes mellitus, the Diabetes Control and Complications Trial (DCCT) DM, Nathan et al (1993) and the United Kingdom Prospective Diabetes Study (UKPDS) Group (1998) respectively, both demonstrated that the intensive management of blood glucose led to a huge reduction in the incidence of microvascular complications

Newer pharmacological agents that have been shown to be effective yet requiring more research especially on their side effect profile include local anaesthetic arrhythmic agents in particular mexiletine, STM Krishnan et al 2004 as cited by AJM Boulton (2005), NMDA receptor antagonist, C N Sang (2002) and the opioids analgesics tramadol ‘has been confirmed to be efficacious in a randomized, controlled trial, and a follow-up study suggests that it can be used safely for up to 6 months of sustained pain relief’ Y Harati (2002) as cited by AJM Boulton (2005).

Together with the use of the above agents the usual advise about well fitting footware and care when walking to avoid injury to the feet must be given as well as general advise about exercise and healthy living.

The involvement of other health professional as part of a multidisciplinary team is also available.  In a patient with DPN who is identified to be at an increased risk of foot ulceration should be referred to a podiatrist for specialized foot care.

In Papua New Guinea most of the pharmacological agents listed above are available but unfortunately relatively expensive and in general are not accessible to the vast majority of the estimated 507,900 adults with diabetes whom are not covered by any form of medical insurance.  Furthermore the quality of diabetes care is greatly hindered by the lack of qualified professionals with an interest in diabetes and a limited resources.  As an example as of the date of writing this report, HbA1c an indispensable test in diabetes care is still not available at Port Moresby General Hospital and at private health facilities the cost of this test is on average around K150 ($45 USD), a price that is simply out of the question for the average Papua New Guinean.  With this sort of situation one can imagine the huge burden that is suffered by people living with diabetes in PNG and calls for urgent action by the relevant authorities.

NSI

Fig 1: MNSl questionnaire. Ref: E L Feldman (1994)

NSI

Fig 2 Modified Neuropathy Disability Score (MNDS),  E L Feldman (1994)

Reference:

AJM Boulton (2005), ‘Management of Diabetic Peripheral Neuropathy’, CLINICAL DIABETES • Volume 23, Number 1, 2005, available at: http://clinical.diabetesjournals.org/content/diaclin/23/1/9.full.pdf, accessed: 10/12/2017

CD Mathers and D Loncar, ‘Projections of global mortality and burden of disease from 2002 to 2030’, PLoS Med, 2006, 3(11):e442. Available at: https://pdfs.semanticscholar.org/0480/2b396ff6ead07f733e3d7cda9bf93def57cf.pdf , accessed: 09/12/2017

K Vithian and Steven Hurel (2010), ‘Microvascular complications: pathophysiology and management’, Clinical Medicine, 2010, Vol 10, No 5: 505–9

International Diabetes Federation (IDF) (2017), ‘IDF Western Pacific members’, available at:

https://www.idf.org/our-network/regions-members/western-pacific/members/112-papua-new-guinea.html , accessed: 9/12/2017

G D Ogle (2001), ‘Type 2 diabetes mellitus in Papua New Guinea – an historical perspective’, PNG Med J 2001 Sep-Dec; 44(3-4):81-87, available at: http://pngimr.org.pg/png_med_journal/Type%202%20-%20Sep-Dec%202001.pdf, accessed: 9/12/2017

UK Prospective Diabetes Study (UKPDS) Group (1998), ‘Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)’, The Lancet, Volume 352, No. 9131, p837–853, 12 September 1998, available at: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(98)07019-6/fulltext accessed: 9/12/2017

DM Nathan et al, (1993), ‘The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus’, N Engl J Med. 1993 Sep 30;329 (14):977-86, available at: http://www.nejm.org/doi/pdf/10.1056/NEJM199309303291401, accessed: 9/12/2017

J G Llewelyn (2003), ‘THE DIABETIC NEUROPATHIES: TYPES, DIAGNOSIS AND MANAGEMENT’ J Neurol Neurosurg Psychiatry2003;74 (Suppl II):ii15–ii19, available at: http://jnnp.bmj.com/content/jnnp/74/suppl_2/ii15.full.pdf, accessed: 9/12/2017

Porte D, S S Robert, Ellenberg M and Rifkin H (1997), Ellenberg & Rifkin’s Diabetes Mellitus, 5th Edn, , USA: McGraw-Hill Professional Publishing, 1997

E L Feldman (1994), ‘A Practical Two-Step Quantitative Clinical and Electrophysiological Assessment for the Diagnosis and Staging of Dianetic Neuropathy’ DIABETES CARE, VOLUME 17, NUMBER 11, NOVEMBER 1994

C N Sang (2002), ‘Dextromethorphan and memantine in painful diabetic neuropathy and postherpetic neuralgia: efficacy and dose-response trials’. Anesthesiology 96:1053–1061, 2002

American Diabetes Association (ADA) and American Academy of Neurology (AAN) (1988),

‘CONSENSUS STATEMENT, Report and Recommendations of the San Antonio Conference on Diabetic Neuropathy’ DIABETES CARE, VOL. 11, NO. 7, JULY/AUGUST 1988

 

 

About Dr. Poyap J Rooney

Dr. Rooney is a medical doctor who has gained both his undergraduate medical degree and more recently his post graduate masters degree in clinical biochemistry at the University of Papua New Guinea.
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