Cross talk: Neurology and Diabetes

Surat Tanprawate, MD, MSc(Lond.), FRCP(T) The Northern Neuroscience Center in Collaboration with Division of Neurology Chiang Mai University

Early description of Diabetes

A disease with symptoms such as constant thirst (polydipsia), excessive urination (polyuria) and loss of weight.

He named the condition diabetes, meaning a flowing through.

Aretaeus, Greek physician (30-90CE)

Major complication of Diabetes

Cardiovascular complication
Non-cardiovascular complication
Nephropathy Neuropathy Diabetic foot Stroke

Kannel WB, McGee DL. JAMA 1979;241:20358

Neurological complication of diabetes

CNS: Cerebrovascular disease, Dementia
PNS: Neuropathies of diabetes-> diabetic foot

Stroke and Diabetes

- Risk factor of stroke - Outcome after stroke

Diabetes and Stroke

Relative risk 1.8-6 fold of stroke in DM
Coronary heart disease, cardiac arrhythmia

Diabetes

Micro- and macrovascular change

Atherosclerosis

Ischemic stroke

Arterial hypertension

Risk factor of stroke fatality

* * **
Steven RJ, et al. Diabetes Care 2004;27:201-07

4537 patients hospitalized for

a first-in-a-lifetime stroke To examine the relationship between diabetes and outcome at 3 months (disability, handicap, and death), controlling for risk factors, clinical presentation, and demographics.

Diabetic patients are more likely to have ...limb weakness (P< 0.02) ...dysarthria (P< 0.001) ...ischemic stroke (P< 0.001) ...lacunar cerebral infarction (P< 0.03) At 3 months, ...the case fatality rates were not higher in the diabetic groups (P0.33). ...Handicap (Rankin Scale) and disability (Barthel Index) were significantly higher in diabetic patients (P< 0.005 and P< 0.016, respectively).
Megnerbi SE et al. Stroke 2003;34;688-694

The Most successful treatment in stroke is to prevent stroke !

Stroke 2011;42;517-584

DIABETES CARE, VOLUME 36, SUPPLEMENT 1, JANUARY 2013 S11

The UK Prospective Diabetes Study (UKPDS)

Aggregate Clinical Endpoints

1977-1991: Type 2 DM 5102 patients; conventional (<270 mg/dl) vs intensive therapy(<108mg/dl)

ukpds

Primary prevention of stroke

UKPDS: conventional (<270 mg/dl) vs intensive therapy(<108mg/dl)
A reduction in MI, and all cause mortality was found, but stroke in incidence was not affected ACCORD: intensive(HbA1c<6%) vs standard HbA1c<7.9%) therapy no difference of fatal or non-fatal stroke ADVANCE: intensive vs non-intensive therapy no effect of more intensive therapy on risk of non-fatal stroke

Stroke 2011;42;517-584

Conclusion: stroke primary prevention in diabetes

There is no evidence that reduced glycemia decreases short-term risk of macrovascular events, including stroke, in patients with type 2 diabetes. A glycohemoglobin goal of 7.0% has been recommended by the ADA to prevent long-term microangiopathic complications in patients with type 2 diabetes. Whether control to this level also reduces the long-term risk of cardiovascular events and stroke requires further study.

Stroke 2011;42;517-584

Stroke 2011;42;227-276

Secondary prevention of stroke

ACCORD: pt. with type 2 DM and vascular disease (intensive vs conventional)
There was no significant difference in the rate of nonfatal stroke ADVANCE: pt. with type 2 DM and history of macrovascular disease(9% stroke)

There was no significant reduction in the occurrence of nonfatal stroke

Stroke 2011;42;517-584

Why does glycemic control fail to prevent Cerebrovascular disease?

Hypoglycemic event Glycemic variability

The UK Prospective Diabetes Study (UKPDS)

Hypoglycemic episode per annum

Intensive therapy Intensive therapy

Conventional therapy

Conventional therapy

Actual Therapy analysis

ukpds

Mechanisms by which hypoglycemia may affect cardiovascular events

Desouza C V et al. Dia Care 2010;33:1389-1394

Copyright 2011 American Diabetes Association, Inc.

Graphic representations of glycemic control with high (a) or low (b) variability.

patients with similar glycosylated hemoglobin levels and mean glucose values can have markedly different daily glucose excursions

Egi, M., Bellomo, R., & Reade, M. C. (2009). Is reducing variability of blood glucose the real but hidden target of intensive insulin therapy?. Critical Care, 13(2), 302.
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Correlation between carotid IMT and glycemic variability in subjects without atherosclerotic lesion on MRA

Mo, Y., Zhou, J., Li, M., Wang, Y., Bao, Y., Ma, X., ... & Jia, W. (2013). Glycemic variability is associated with subclinical atherosclerosis in Chinese type 2 diabetic patients. Cardiovascular diabetology, 12(1), 1-9. 22

Decreased Intimae Media Thickness (IMT) by Sitagliptin (100mgqd) and Vildagliptin(50 mg bid)

* p< 0.05 vs baseline ; + p<0.05 vs sitagliptin group

23

Barbieri, M., Rizzo, M. R., Marfella, R., Boccardi, V., Esposito, A., Pansini, A., & Paolisso, G. (2013). Decreased carotid atherosclerotic process by control of daily acute glucose fluctuations in diabetic patients treated by DPP-IV inhibitors. Atherosclerosis.

PROactive: pt. with DM and macrovascular disease using pioglitazone

http://www.iristrial.org

The Insulin Resistance Intervention after Stroke (IRIS) trial is an ongoing study funded by the National Institute for Neurological Disorders and Stroke (NINDS) in which patients with TIA or stroke are randomly assigned to pioglitazone or placebo for a primary outcome of stroke and MI

Conclusion: diabetes and stroke

The incidence of stroke is high among diabetics
The severity of ischemic stroke and death are increased with DM We are waiting for the evidence of glycemic control to prevent stroke

Neuropathy of Diabetes

Definition

Diabetic neuropathy is defined as

The presence of symptoms and signs of peripheral nerve dysfunction in individuals with diabetes after the exclusion of other causes.

CIDP, vitamin B12 deficiency, alcoholic neuropathy, endocrine neuropathy

 The risk of developing symptomatic neuropathy in patients without neuropathic symptoms or signs at the time of initial diagnosis of diabetes is estimated to be

4% to 10% by 5 years 50% by 25 years

Clinical Pattern of Diabetic neuropathy

Cranial neuropathy

Truncal neuropathy

3/4 of all cases

Radiculoneuropathy - Distal sensory or sensorimotor polyneuropathy (DSDP)- Diabetic Autonomic Neuropathy (DAN) Small-fiber neuropathy - Diabetic amyotrophy

Mononeuropathy/multiple mononeuropathy

Major complication of Diabetic neuropathy

Foot ulcer

Charcots joint

Picture from Br J Sports Med 2003;37:3035

Risk of Foot Complications and Glycemia in Older-Onset Diabetes Patients (WESDR)

Ulcers and amputations
25 20 15 10 5 6.9-9.2 9.3-10.8 10.9-12.6 12.7-23.6

Odds ratio 1.6 for each absolute increment in A1C of 2%

Moss SE et al. Arch Intern Med. 1992;152:610-616.

Microfilament testing

Rith-Najarian SJ et al. Diabetes Care.1992;15:1386-1389

Management
Prevention Pathogenetic treatment Symptomatic treatment

DCCT: Result Summary

Improved control of blood glucose reduces the risk of clinically meaningful
Retinopathy Nephropathy Neuropathy 76% (P<0.002) 54% (P<0.04) 60% (P<0.002)

DCCT: risk of DPN and DAN are reduced with improved blood glucose control(DM type 1 and 2)
DCCT Research Group. N Eng J Med. 1993;329:977-986.

Clinical trials investigating effects of enhanced glucose control on neuropathy

Lancet Neurol 2012; 11: 52134

Proposed pathophysiology

Pathogenetic treatment

Symptomatic treatment
Pain control TACs, antiepileptic drugs, opioid like drug Treatment in dysautonomic symptom

gastrointestinal, sexual dysfunction, cardiac symptom

Conclusion: diabetes and neuropathy

The incidence of neuropathy and its complication are highly disable
Glycemic control can prevent diabetic neuropathy

reduced cognitive performance, in particular slowing of information processing speed

Thank you for your attention

Cause

Impair cerebral autoregulation Higher rate of stroke recurrence Higher rate of atherosclerotic risk

Mechanisms by which hyperglycaemia and diabetes may influence cellular ischaemia

Journal of Clinical Neuroscience 2002 (6), 618-626