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  Neurological involvement in diabetes mellitus 07/02/2020 9:22am (UTC)

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Diabetes mellitus is a unique endocrinological disorder, the poor control of which leads to complications involving almost all systems of human body. Among them, the neurological manifestations deserve special attention. In 1798, Rollo, first noted involvement of the nervous system in diabetes; Presently we know that virtually every aspect of nervous system and its supporting tissues from, the cerebral cortex to the effector organs, may be involved in diabetes.

Peripheral nervous system involvement is seen more frequently than central nervous system involvement. This is referred to as diabetic neuropathy.

Pathophysiology of diabetic peripheral neuropathies
   This is an extensively studied field over years. As of today, the precise mechanism responsible is still unclear. The widely accepted theories include;
         1. Metabolic hypothesis
         2. Vascular Anomalies.
   Among these, the metabolic hypothesis is most popular. This content that the unused glucose in DM is shunted into the polyol pathway wherein glucose is converted into sorbitol by aldose reductase and subsequently to fructose by sorbitol dehydrogenase. Accumulation of sorbitol and fructose leads to reduced membrane Na+-K+ ATPase activity, intra-axonal Na+ accumulation, reduced neural conduction velocity and structural breakdown of nerve. There is also reduction in nerve myoinositol secondary to decreased Na-K ATPase activity. Myo-inositol is a hexose similar to glucose and is found 90-100 times more concentrated in peripheral nerves than in plasma. Hyperglycemia competitively inhibits Na+ dependent transport of myo-inositol into nerve cells. Decreased nerve myoinositol leads to decreased Na+-K+ ATPase which again retards myoinositol uptake.

Other suggested metabolic anomalies are
   1. Reduction in rate of synthesis of intra-axonal proteins.
   2. Reduction in nerve Na-K ATPase.
   3. Alterations in protein kinase.

   4. Reduced aminoacid incorporation into dorsal root ganglia.
   5. Reduced incorporation into myelin of glycolipids and amino acids.
   6. Reduced nerve L-carnitine levels.
   7. Excessive glycogen accumulation.
   8. Increased non-enzymic peripheral nerve protein glycosylation.
   9. Increased oxygen free radical activity.
   10. Nerve hypoxia.

Vascular hypothesis stresses the early development of reduced endoneurial blood flow, increased endoneurial vascular resistance and decreased oxygen tension. The important causes include formation of advanced glycation products (AGE), increased oxygen free radical activity and reduced endothelial N2O activity. Irreversible structural changes occur in vessel walls and peripheral nerves as a result of AGE which are formed by binding of early glycosylation products to proteins with long half lives, such as collagen and DNA; from which they don't dissociate. ACE accumulation leads to early atherogenesis,

                                          Table No. 1 Classification of diabetic neuropathy

  A. Generalised Polyneuropathy
                 1. Distal symmetric polyneuropathy
                                                  - Predominantly sensory
                                                  - Predominantly motor
                                                  - Mixed sensorimotor
                  2. Acute painful diabetic neuropathy.
                  3. Autonomic neuropathy
                  4. Subclinical polyneuropathy.

  B. Multiple mononeuropathies.
               1. Proximal lower extremity motor neuropathy (Diabetic amyotrophy/femoral

                   neuropathy/ polyradiculopathy/ Brans-Garland Syndrome)
               2. Truncal neuropathy.

 C. Mononeuropathy
              1.  Cranial mononeuropathy (3rd nerve, 6th nerve,
                   5th nerve, Optic nerve, 7th nerve, 8th nerve)
              2.  Compression mononeuropathy, (Carpal tunnel syndrome)

                                            Table No. 2 Autonomic Neuropathies

 A. Cardiovascular:
            Postural hypotension
            Resting tachycardia
            Painless myocardial infarction
           Sudden death (with or without association with general anaesthesia)
           Prolonged QT interval.

 B. Gastro Intestinal
          Oesophageal motor iricoordination
          Gastric dysrrhythmia, hyporno tility (Gastroparesis diabeticorum)
          Uncoordinated intestinal motility
          (Diabetic diarrhoea, spasms)
          Intestinal hypomotility (Constipation)
         Gall bladder hypocontraction (Cholecystopathy)
         Anorectal dysfunction (Faecal incontinence)

 C. Genito urinary
        Diabetic cystopathy (Impaired bladder sensation. Post micturition dribbling) Male

        Impotence Ejaculatory disorders Reduced vaginal lubrication

 D. Respiratory
       Impaired breathing control
       Sleep apnoea
       Decreased bronchial response to cold air

 E. Thermo regulation
       Pseudomotor (Diminished, excessive or gestatory sweating) Vasomotor   

       (vasoconstriction, vasodilation, neurogenic oedema)

 F. Pupillary Miosis

     Disturbances of dilation Argyl-Robertson-like pupils.

 G. Neuroendocrinal:
     Reduced Pancreatic polypeptide release Reduced somatostatin release Reduced

     motilin+ GIF release Enhanced gastrin release-Reduced nonepinephrine release

     (orthostatic/exercise induced)
 Elevated Immunoreactive atrial natriuretic hormone Impaired glucose counter regulation 

 (Hypoglycemia un awareness)

                                                               Table No. 3
                                            Central nervous system involvement
               A. High incidence of stroke
               B. Chronic diabetic encephalopathy
               C. Greater Association of DM with:
                         Huntington's chorea Tardive dyskinesia Tremor Parkinson's disease.

                                                               Table No. 4
                                        Staging of diabetic peripheral neuropathy
              Stage 0-   No neuropathy - No symptoms and fewer than two abnormalities on

                              testing (nerve conduction, neurological examination, muscle strength,     

                              threshold for vibration, cooling or warming or autonomic function).
              Stage I -   Asymptomatic neuropathy - No symptoms and 2 or more abnormalities on

             Stage II -   Symptoms of a lesser degree than stage III along with 2 or more

                              functional abnormalities on testing.
            Stage III -   Disabling neuropathy - Disabling symptoms and 2 or more functional


                                                   Vascular hypoxic changes are manifested as
             1. Basement membrane thickening & reduplication

             2. Endothelial cell swelling and pericyte degeneration
             3. Occlusive platelet thrombi
             4. Closed capillaries
             5. Epineuiial vessel atherosclerosis
             6. Multifocal ischemic proximal nerve lesions

     Reduction in nerve growth factor (NGF) and insulin are other proposed mechanisms for neuropathy in diabetics.

Fathogenesis of CNS complications
       Adverse effects of hyper or hypoglycemia
                 - Repeated hypoglycemia leading to laminar necrosis of cortex, cell loss of

                   dentate gyrus of hippocampus and caudate atrophy. Hypoglycemia disrupts 

                   neuronal dendritic tree while hypoxia damages axons.
                 - Chronic hyperglycemia decreases glucose transport to brain, so acute lowering

                    of blood sugar to normal in chronic DM lead to symptoms of hypoglycemia.
                 -  Hyperglycemia per se is an independent risk factor for stroke. Hypertension and

                    accelerated atherosclerosis occurs in these patients.
                 - Higher frequency of cerebral infraction
                 - due to impaired cerebral blood flow and autoregulation, reduced RBC

                   deformability, impaired PG synthesis.
                   Hyperglycemia interferes with metabolism of monoamine neurotransmitters like

                   Dopamine, 5
                  HT, norepinephrine, neuropeptides like sub.P somatostatin, neuropeptide Y,

                  VIP, enkephalins, endorphins and vasopressin; leading to effects on mood/

                  appetite and pain perception.

Clinical classification of peripheral neuropathy
Distal symmetric poly neuropathy: Most common diabetic neuropathy; Sensory form is commonest. Distal parts of longest nerves affected. Involves territory of overlapping terminals of many nerves. Feet affected before hands. 'Glove and stocking' loss of sensation occurs. Vibration sense is the earliest to be lost because of the early involvement of large fibres. Electrophysiological study to detect nerve conduction velocity confirms diagnosis.

    Motor involvement is usually less prominent. But there can be loss of bulk of hand muscle as well as muscles of feet leading to claw hand and pes cavus. This, together with sensory changes may mimic "Charcot-Marie-Tooth" disease. There can be fasciculations in muscles, confusing the picture with motor neuron disease.

   Acute painful neuropathy: First described by Ellenberg as diabetic neuropathic cachexia. Occurs more commonly in males. Manifests as lancinating pain in distribution of dermatomes. Commonly involves lower extremities. There is no sensory loss, but contact hypersensitivity and decreased reflexes are seen. Thermal discrimination threshold is lowered in these patients. Pain subsides spontaneously after weeks.

   Diabetic Pseudotabes: When multiple nerve roots are involved in the painful neuropathy along with posterior column degeneration and loss of position sense, there will be lancinating pain and ataxia. When this is complicated by pupillary involvement and trophic ulcers, the picture is described as pseudotabes.

   Autonomic neuropathy: Bedside assessment is done with study of autonomic dysfunction of cardiovascular system. Postural hypotension - ie, drop in systolic blood pressure of more than 30 mm of Hg upon assuming standing position from sitting.

   Valsalva Ratio: The ratio of longest R-R interval in ECG to the shortest R-R interval during valsalva manoeuvre is normally more than 1.2. In autonomic neuropathy it is less than 1.1. The ratio of 38th beat after standing relative to 15th beat should be more than 1, if less than 1, indicates autonomic neuropathy.

   Subclinical polyneuropathy: Detected only by nerve conduction study.

Proximal lower extremity motor neuropathy:
   Common in middle aged and old patients with type II diabetes. 2 types i.e. subacute type and ischernic mononeuropathy multiplex of acute onset. Burning or aching pain over anterior thigh or lumbar and perineal regions followed by weakness and atrophy of the quadriceps. Patient is unable to get up from kneeling or sitting position. Usually no or little sensory abnormalities are detected. Many patients improve spontaneously in 1-3 years reflecting slow rate of axonal regeneration. This condition is also known as Diabetic Amyotrophy.

   Truncal neuropathy : Develops usually in 6th decade. Pain and dysesthesia in the lower anterior chest and upper abdomen with nocturnal intensification. Can resemble preeruptive phase of herpes zoster or suggest a para vertebral spinal tumour compressing nerve.

Usually resolves spontaneously is 2-6 months of onset.
   Cranial neuropathy: Third nerve affection is the most common. No relation to diabetic control or medication taken for diabetes. Begins abruptly, preceded by retroorbital intense pain for about 1-7 days. Pain is absent in 50% cases. Pupils are spared. Next in frequency is the 6th nerve involvement leading to a lateral rectus palsy. Both usually recover spontaneously in 6-12 weeks, recurrent and bilateral lesions can occur.

   5th nerve involvement is usually manifested as severe pain over the face. Motor weakness of muscles of mastication is less common.

   Optic nerve involvement manifested as optic atrophy is seen in 0.6% of cases only. Subclinical damage to optic nerve has been recently investigated in many western countries. Visual Evoked Response recording in diabetics without overt visual deficits or other retinal diseases have shown significant abnormalities in the P100 and P75 latencies. This is a sensitive way of assessing early optic pathway damage in diabetics. It has also been shown that strict control of blood sugar in diabetics can partially improve the VHP abnormalities in diabetics, pointing to partial reversibility of optic nerve damage in early stages.

   7th nerve damage in diabetics is rather difficult to attribute to diabetes only. Its distinction from idiopathic Bell's palsy is uncertain. Eighth nerve damage was believed unlikely to be due to diabetes. But recently studies of auditory evoked potentials have shown changes in latencies showing a definite involvement of 8th nerve also in diabetes.

   Compression neuropathy: Common nerves affected are-median nerve {Carpal Tunnel Syndrome), ulnar nerve (Gyon's canal Syndrome), lateral popliteal nerve, lateral cutaneous nerve of thigh (Meralgia paresthetica) and posterior tarsal nerve (Tarsal Tunnel Syndrome). Usually seen in ojd patients with diabetes.

   Higher CNS abnormalities: Behavioural and cognitive functions impairment is seen more in children with diabetes. Repeated episodes of hypoglycemia contribute to this. An entity called chronic diabetic encephalopathy has been described in these cases.

   Among various types of strokes seen in diabetes, ischemic infarctions rank first.

   Most common locations are internal capsule, pons, caudate nucleus, putamen and thalamus. Lacunar infarction leads to pure motor hemiparesis, pure sensory stroke, ataxic hemiparesis and dysarthria clumsy hand syndrome. Other lesions in diabetes include asymptomatic carotid stenosis, TIA's etc.

Treatment modalities for diabetic neuropathy
       A. Symptomatic: for painful neuropathy : Amitriptyline -10-20 mg every night increase up to 150mg/day for 3-6 weeks, contraindicated with heart block, recent MI, CHF, urinary tract obstruction, orthostatic hypotension and narrow angle glaucoma.
                            - Desipramine-200mg/day X5 weeks.
                            - Phenytoin
                            - Disadvantage
                            - Inhibits insulin secretion
                            - Other drugs tried include carbamazepine (400-1200mg/day), Clonazepam

                              (shooting pains), Baclofen (5mg BID), Clonidine (75-100 meg to start with

                              gradually increase); Lidocaine I/V (5mg/kg over 30mts). Oral mexiletine

                              (lOmg/kg/day), Topical capsaicin ointment (Depletes substance P from

                              nociceptive afferent and type C fibres), Tramodol HCI (50mg TID, not to 

                              be used with other MAO inhibitors), Calcitonin nasal spray- for resistant

                              painful neuropathy.

Carpal tunnel syndrome and other compressive neuropathies require decompression of nerve concerned.

Autonomic neuropathy (Orthostatic hypotension) treated with high salt diet, elastic stockings and oral fludrocortisone.

Diabetic diarrhoea treated with atropine loperamide and diphenoxylate.
Gastroparesis and bloating are treated by prokinetic GI drugs like cisapride, domperidone etc.

B. Prevention of neuropathy
According to Diabetes Control and Complications 'trial, adequate metabolic control is the best treatment to prevent diabetic complications. Other modalities available are-

             Aldose reductase inhibitors
             Alrestatin, statil (ponalrestat), sorbinil ONO- 2235 (epalrestat), Zopolrestat.


        - Dietary Myo-inositol supplementation
        - Gangliosides: Cronassial (withdrawn due to association to LGB syndrome)
        - Gamma Linolenic acid: Presursor of prostaglandins (dose: 480mg/day)
        - Acetyl L carnitine (ALCAR): undergoing trial.
        - Growth factors: NGF (recombinant preparation) IGF-I Trials in progress
        - Alpha Lipoic acid: Lipophilic free radical scavenger-increases glucose entry
        - Vitamin C by competitive mechanism, blocks glycosylation of proteins
        - Aminoguanidine: Inhibits formation of AGE, Studies in human pending.

1. Yodallah Harati: Diabetes and nervous system. Endo and Meta. clinics of North         

            America, Vol. 25, 325-47, 1996.
        2. J.D. Ward: Diabetic neuropathy- In British Medical Bulletin, Vol.45 115-126, 1989.
        3. Harold E.Bays, MA. Pfeifer: Peripheral diabetic neuropathy, In Med Clin. North

            America, Vol.72,1439-59.1988.
        4. Simeon Locke: Nervous system and diabetes - In Joslin's Diabetes, llth edn.562-76,

        5. Jose Biller, Betsy B Love; Diabetes and Stroke; In Med. Clin.North America, Vol. 77,

            95-108, 1993.
        6. Mark A Ross: Neuropathies associated with diabetes. In Med. Clin. North America,

            Vol. 77, 111-121, 1993.
        7. Y. Harati: Frequently asked questions about diabetic peripheral neuropathies. In

            Neural Clin. of N. America, Vol.10, 783-801, 1992.
        8. Foster DW: diabetes mellitus, in William's Text book of Endocrinology, 8th edn,

            1255-1333, 1992.

  What is Diabetes?

1. Diabetes mellitus : a historical review

2. Insulin-some physiological considerations,

3. Epidemiology of diabetes mellitus

4. Pathogenesis of diabetes mellitus in young

5. Impaired glucose tolerance

6. Secondary diabetes mellitus.

7. Laboratory diagnosis and work up for assessment of complications & of diabetes mellitus

8. Oral glucose tolerance test.

9. Neurological involvement in diabetes mellitus

10. Glycation products in diabetes mellitus

11. Diabetes mellitus in adolescence

12. Diabetic keto acidosis

13. Case of brittle diabetes

14. Lipoprotein disorders in diabetes mellitus

15. Diabetes and cardiovascular system

16. Myocardial infarction in diabetes

17. The Syndrome of insulin resistance.

18. Gastro intestinal manifestation of diabetes mellitus

19. Pregnancy and diabetes

20. Skin manifestations of diabetes mellitus

21. Diabetic nephropathy

22. The diabetic foot

23. Sexual dysfunction m diabetes mellitus

24. Joint and Bone manifestation of diabetes mellitus

25. Alcohol and diabetes mellitus

26. Live: and. diabetes mellitus

27. Management of infections m diabetes

28. Diabetes mellitus and surgery

29. Canter arid diabetes

30. Diabetes in elderly

31. Non drug therapy of diabetes mellitus

32. Nutrional approaches in the management of diabetes mellitus

33. Insulin therapy in diabetes mellitus

34. Insulin sensitivity

35. Insulin resistance

36. Oral drugs in non insulin dependent diabetes

37. Lactic acidosis

38. Use of indigenous plant products in diabetes

39. Prevention of diabetes mellitus

40. Pancreatic transplantation in Type I DM (IDDM)

41. Hypoglycemia

42. Diabetes and eye

43. Diabetes mellitus and pulmonary tuberculosis

44. Pitfalls in diagnosis and management of diabetes mellitus

45. Mortality patterns in diabetes mellitus

46. Diabetic education

47. Diabetes mellitus and associated syndromes

48. Diabetes mellitus: socio economic considerations

49. Obesity and diabetes mellitus

50. Proinsulin

51. C-Peptide

52. Glucagon

53. Drug induced diabetes mellitus

54. Insulin anologues

55. Insulin delivery system

56. Micro nutrients in diabetes mellitus

57. Defects in glucose metabolism in neonates

58. Sulphonylurea failure

59. Diabetes control and complications

60. Diabetes mellitus & oral health

61. Common procedures for recording data in diabetes

62. Profile of a lean Type-2 diabetes mellitus

63. Management of post prandial

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