Neurological manifestations of diabetes melitus..cover almost all variants

1. Neurological manifestations of DM
Dr. Ajay Kumar Yadav
PGY3,Internal medicine
IOM-TUTH, Kathmandu
2075/02/09

2. DIABETIC NEUROPATHY
• Probably the most common complication of DM
• Most common neuropathy in the Western world
• Based upon several large studies-approx 50 pc of pts with diabetes will
eventually develop neuropathy
• Substantial morbidity, including recurrent lower extremity infections,
ulcerations, and subsequent amputations.

3. Pathogenesis of diabetic neuropathy

4. Classification and staging of diabetic neuropathy

6. Classification of the diabetic neuropathies
 Hyperglycaemic neuropathy
 Generalised neuropathies
• Sensorimotor polyneuropathy
• Acute painful sensory neuropathy
• Autonomic neuropathy
 Focal and multifocal neuropathies
• Cranial neuropathies
• Thoracolumbar radiculoneuropathy
• Focal limb neuropathies {including compression and entrapment neuropathies}
• Proximal diabetic neuropathy
 Superimposed chronic inflammatory demyelinating polyneuropathy

7.  The most frequently encountered neuropathies include
• Distal symmetric polyneuropathy ( 50 pc )
• Autonomic neuropathy ( 7 pc )
• Thoracic and lumbar nerve root disease, causing polyradiculopathies ( 3 pc )
• Individual cranial and peripheral nerve involvement causing focal mononeuropathies,
especially affecting the oculomotor nerve (cranial nerve III) and the median nerve ( 25
pc )
• Asymmetric involvement of multiple peripheral nerves, resulting in a mononeuropathy
multiplex
@Rochester study

8.  Loss of vibratory sensation and altered proprioception reflect large-fiber
loss
 Impairment of pain, light touch, and temperature is secondary to loss of
small fibers

9. Types of nerve fibres

11.  HYPERGLYCAEMIC NEUROPATHY
• Uncomfortable dysaesthesiae or pain in the feet and lower legs, which rapidly
resolve on establishment of euglycaemia.
 DIABETIC SENSORY POLYNEUROPATHY
• Commonest form of diabetic neuropathy.
• Distal symmetric polyneuropathy : insidious onset
• Glove and stocking distribution
• Present with numbness, pain, and paraesthesiae,mainly distally in the lower limbs

12. AUTONOMIC NEUROPATHY

14.  Cranial neuropathy
• Isolated 3rd nerve palsy with pupillary sparing : MC
• IV ,VI ,VII cranial nerve can also be affected
 Entrapment neuropathies
• Carpal tunnel syndrome : Median nerve
• Ulnar neuropathy at wrist or elbow
• Peroneal neuropathy : compression at the fibula

15.  DIABETIC TRUNCAL RADICULONEUROPATHY
• Radicular pain, focal truncal sensory loss, and cutaneous hyperaesthesia and focal
weakness of the muscles of the anterior abdominal wall
• Spontaneous recovery usually occurs within 3 to 6 months.
 PROXIMAL DIABETIC NEUROPATHY
• Unilateral or commonly asymmetric bilateral lower limb motor neuropathy
(diabetic amyotrophy)
• The onset is most often subacute but it may be insidious.
• Spontaneous recovery is frequent, although not all patients recover fully

16.  Diabetic radiculoplexus neuropathy
• Aka Diabetic amyotrophy or Burns garland syndrome
• Severe pain in low back ,hip , and thigh in one leg
• Atrophy and weakness of proximal and distal muscles in the affected leg
apparent within few days or weeks : my progress for 18 months or more
• Often accompanied or heralded by severe wt loss
• Slow recovery : residual weakness , sensory loss and pain
• Lumbosacral ( MC ) > Thoracic > Cervical

17.  Diabetic neuropathic cachexia
• Diffuse diabetic polyradiculopathy superimposed upon severe peripheral
neuropathy.
• A/w unintended severe weight loss and depression
• Most frequently occurs in men with type 2 DM on OHA who are middle-aged
or older.
• Most patients improve spontaneously within 12 to 24 months, although some
have residual neurologic deficits.
• There is no specific therapy, and management is supportive.

18.  ACUTE PAINFUL DIABETIC NEUROPATHY
• Acute or subacute onset
• Characterised by burning or aching pain felt mainly in the lower limbs, and very
rarely in the hands or over the upper limbs and trunk.
• Accompanied by widespread cutaneous contact hyperaesthesia
• Treatment is by strict glycaemic control
• Recovery usually occurs over a period of 6–9 months

19.  Acute painful diabetic neuropathies
• Treatment-induced diabetic neuropathy (TIDN)
• Diabetic neuropathy that occurs in the setting of unintended severe
weight loss: Diabetic neuropathic cachexia
• Diabetic neuropathy that is seen with intentional weight loss (diabetic
anorexia)

20.  Treatment-induced neuropathy of diabetes (TIND)
• Aka insulin neuritis
• Small fiber neuropathy that occurs in patients with chronic hyperglycemia who
experience rapid improvement in glycemic control
• The main clinical manifestations are severe, treatment-resistant pain and
autonomic dysfunction, along with worsening of retinopathy and nephropathy
• The investigators defined the condition by the acute onset of neuropathic pain or
autonomic dysfunction within eight weeks of a large improvement in glycemic
control (ie, a decrease in HbA1C of ≥2 percentage points over three months).

21. Treatment of diabetic neuropathy
• Strict glycemic control : NCV usually improves but symptom of diabetic
neuropathy will not necessarily improve
• Aggressive control : TIND
• Treat HTN and dyslipidemia
• Avoid neurotoxins : alcohol and smoking
• Suplement vitamin def.
• Foot care

22. • Chronic painful neuropathy : Duloxetine , Amitryptyline , Gabapentin,
Pregabalin , Valproate or opoid
• USFDA approved : Duloxetine and pregabalin
• No direct comparisons available
• Switch to other agents if no response or S/E develops

23. Treatment of diabetic autonomic neuropathy
 Postural hypotension
• High salt intake
• Drugs : Fludrocortisone , midodrine , clonidine , octreotide , yohimbine :
limited success
 Gastroparesis
• Dopamine antgonists ( metoclopropamide , Domperidone )
• Erythromycin : motilin receptor antagonist : IV > oral
 Impotence
• Intracavernosal injection of PGE1
• Sildenafil

24. Diabetic foot

30. Neurological manifestations of hypoglycemia
• Unlike most other body tissues, the brain requires a continuous supply of
glucose.
• Very limited endogenous glycogen stores, and does not produce glucose
intrinsically.
• Although it accounts for 2% of body weight, the brain utilizes 25% of the
body’s glucose due to its high metabolic rate
• The brain areas most vulnerable to hypoglycemia are (in order) the
subiculum, small and medium sized caudate neurons, area CA1 of the
hippocampus, the dentate gyrus and superficial cortical layers,
specifically layers 2 and 3

31. Fig. 3. Key Aspects of Hypoglycemia induced Neuronal Cell Death. From Suh : Glia55:1280–
1286 (2007)

33.  Recurrent exposure to hypoglycemia, particularly in insulin treated type 1
diabetes, but to a lesser extent in type 2 diabetes can chronically impair
the counter-regulatory response to hypoglycemia.
 Two recognized syndromes
• Hypoglycemia associated autonomic failure(HAAF)
• Impaired awareness of hypoglycemia (IAH).

35. Headache

36.  Cognitive disturbances and dementia
• Longitudinal cohort of 16,667 patients showed a greater risk of dementia
among those with hypoglycemic episodes, with an attributable risk of
dementia of 2.39% per year

37.  Hypoglycemic hemiplegia
• Incidence : 2%
• On average the weakness resolved over a period of 1 hr to 3 days once
normoglycaemia was maintained.
• Hypoglycemia must be excluded in a patient presenting with symptoms
consistent with TIA or stroke.
• Current guidelines for the treatment of stroke patients with IV tPA exclude
those with a glucose level below 50 mg/dL if their symptoms are likely
attributable to the hypoglycemia

38. • Unlike ischemic stroke, hypoglycemic changes on MRI are often
bilateral, affect the cortex, hippocampus and basal ganglia, and do
not necessarily correspond to a vascular territory
• Hypoglycemic brain death preferentially affects neurons, whereas
ischemia tends to affect glial and endothelial cells as well.
• Hypoglycemia generally spares axons while damage from ischemia
affects all parts of the neuron.

40.  Seizure
• The majority of the seizures were GTCS, most recurred
 Hypoglycemic coma
• Most feared, and devastating effects
• MR images of those in persistent vegetative state from hypoglycemia
revealed lesions in the bilateral basal ganglia, cerebral cortex, substantia
nigra, and hippocampus
• Two markers of neuronal injury, NSE and S-100 may predict death or
otherwise poor outcome in profound hypoglycemic coma

41. Neurological complications of DKA
 Ischemic stroke
 Venous sinus thrombosis
 CNS infections
 Cerebral edema
• Rare but fatal complication
• Occurs in children who seem to be metabolically returning to normal generally
3-12 hrs after initiation of therapy
• Incidence : 0.7-1% in chidren
 31% of deaths due to DKA
 20% of all diabetic deaths

42. Hyperglycemic hyperosmotic state
• The prototypical patient with HHS is an elderly individual with type 2 DM,
with a several-week history of polyuria, weight loss, and diminished oral
intake that culminates in mental confusion,lethargy, or coma.
• Relative insulin deficiency and inadequate fluid intake are the underlying
causes of HHS

44. CEREBROVASCULAR DISAESE
• In a study in Sweden, the highest rise was 6-fold in diabetic males but 13-fold in
diabetic females.
• Greatest rise in the 5th and 6th decades
• Most ischaemic strokes are the result of lacunar infarcts.
• The main source of thromboembolic strokes in diabetic patients is the internal
carotid artery.

45. • The frequency of TIA is also increased
• Hypertension is the main risk factor for strokes in diabetic patients.
• The prevalence of cerebral haemorrhage and subarachnoid haemorrhage has been
reported to be the same or less in diabetic than in nondiabetic patients

46. Some genetic disorders associated with DM
• MITOCHONDRIAL DISORDERS
 MODY
 Maternally inherited diabetes combined with sensorineural deafness (MIDD)
• Usually present between 30 and 40 years of age
• Impaired insulin secretion rather than insulin resistance
 MELAS
 Kearns-Sayre syndrome
 Ragged red fibres

47. • FRIEDREICH’S ATAXIA
 Autosomal recessive spinocerebellar degeneration
 GAA repeat expansion on chromosome 9q
 Gene product frataxin : mitochondrial protein : deficiency leads to abnormal
energy metabolism.
 Between 10% and 20% of patients with Friedreich’s ataxia develop diabetes.
 This always begins after the onset of the neurological symptoms and is insulin
dependent.
 Ketoacidosis may occur

48. • WOLFRAM SYNDROME
 AR inheritance
 Form of insulin dependent diabetes (type 1) associated with diabetes insipidus,
optic atrophy causing blindness and deafness (hence DIDMOAD syndrome)
• Neurological manifestations include late onset cerebellar ataxia, psychiatric
disturbances, anosmia, apnoeic episodes, and startle myoclonus.

49. Congenital malformations of the nervous system
• 3-8% of all births to diabetic women, representing 2–4-fold increase over
non-diabetic mothers.
• The malformations included anencephaly, microcephaly, hydrocephalus,
encephalocele, cerebral diplegia, Dandy-Walker syndrome, Arnold-Chiari
malformation, spina bifida, and sacral agenesis.
• Anencephaly and spina bifida were the commonest, occurring in 0.57% (a
3-fold increase) and 0.56% (a 2-fold increase) respectively.
• The caudal regression syndrome (sacral agenesis, phocomelic diabetic
embryopathy), although rare, is particularly associated with maternal
diabetes, occurring in 0.2%-0.5% of pregnancies, representing a 200-fold
increase over the rate in the general population