An approach to a patient with peripheral neuropathy

1. APPROACH TO A PATIENT
WITH PERIPHERAL
NEUROPATHY
BY:
Dr. Tikal Kansara
R2 Medicine D Unit

2. GLOBAL BURDEN
• Overall prevalence – 2 to 4 %
– But increases to 8 % in patients over 55 years of
age (Does not include traumatic neuropathies)
• In developed world, Diabetes Mellitus is the
most common cause (Dutch study of 362,693
patients – mononeuropathy (4.3/1000/year), carpel
tunnel syndrome (2.3/1000/year), diabetic neuropathy
(0.72/1000/year), post herpetic neuralgia
(0.42/1000/year)
• In developing countries, leprosy is the most
common cause
• In India, with rise in incidence of diabetes,
diabetic neuropathy is also likely to increase

3. • Over 100 causes of neuropathy
• Among several sudies, around 20 to 50 %
patients remain undiagnosed

4. BASIC ANATOMY

5. Components of a Peripheral Nerve
• Peripheral Nerves including the cranial nerves
(except the Ist and IInd)
• Spinal Nerve Roots
• Dorsal Root Ganglia
• Peripheral Nerve trunk with its terminal
branches
• Peripheral Autonomic Nervous System

6. Components of a Peripheral Nerve

8. Components of a Peripheral Nerve
Inflammation of interstitium
Necrotising panarteritis
Endoneural
amyloid
deposition
Vasculitis,
ischemic
infarctions

10. Pathogenic Mechanism of Peripheral
Nerve Damage
• Several changes are identified but are not
disease specific:
– Segmental Degeneration
– Wallerian Degeneration
– Axonal Degeneration
• Myelin sheath is the most suseptible to
damage. It can break down as a parimary
process afecting Schwann Cells, myelin itself,
or secondarily to the diseases affecting axon.

11. • Focal degeneration of myelin
sheath with sparing of the
axon is called segmental
Degeneration.
• The characteristic change is
the disappearance of sheath
over segments of variable
length, bounded on each end
by a preserved segment of
myelin.
Segmental Degeneration
(Demyelinating)

12. Wallerian Degeneration
• It is the reaction of both
axons and myelin distal
to the site of disruption
of an axon.
• Described as “dying-
forward” phenomenon

13. Axonal Degeneration
• A “dying-back” phenomenon which
typically occurs in a generalised
metabolically determined
polyneuropathy
• Axon affected progressively from distal-
most site to the proximal, with
dissolution of myelin parallel with axon.
Certain toxic and metabolic processes
affect axons uniformly along their
length or impair anterograde axonal
trasnport to the periphery; functional
impairment is proportioanl to the size
and length of axon blocked.

14. • Destruction of proximal spinal root – gradual
destruction of distal motor nerve and its myelin sheath.
(Wallerian degeneration)
• Neuronal motor cell body undergoes characteristic
morphological change but does not die.
• Destruction of dorsal spinal root produces secondary
Wallerian Degneration of posterior columns of spinal
cord, but not of the peripheral sensory nerve.

15. Types of Nerves and their function

16. Topography
• Mononeuropathy
–Single peripheral nerve involvemment
• Trauma, compression or entrapement
– Carpel Tunnel Syndrome, Ulnar nerve entrapement,
peroneal nerve entrapement
• Related to pregnancy, thyroid disease or
occupation
• Or due to hereditary disorder liable to pressure
palsy

17. • Mononeuropathy multiplex
– Multiple, separate, noncontiguous peripheral
nerves either simultaneously or sequentially
• Leprosy, Vasculitis (PAN, Churg-Strauss Syndrome, RA,
Sjogren’s Syndrome) and requires urgent diagnosis
• Superficial peroneal or sural nerve palsy often helpful
(Vasculitis)
• Polyneuropathy
– A general degeneration of nerves that spread
typically towards the center of body

18. • Ganglionopathy / Neuronopathy
– Sensory neuronopathies (SN) are specific group
diseases characherised by primary degeneration of
dorsal root ganglia and their projections
– Multifocal sensory symptoms are often associated
with ataxia
• Localised
– Herpes Zoster
• Immune
– Sjogren’s syndrome
– Autoimmune Heptitis
– Celiac Disease
• Idiopathic
– Pan-sensory
– CANVAS (Cerebellar Ataxia, Neuronopathy, Vestibular Areflexia
Syndrome)
• Hereditary

20. Vital Questions to ask for
• What systems are involved?
• What is the duration of weakness?
• What is the nature of sensory involvement?
• Is there evidence of Upper Motor Involvement?
• What is the temporal evolution?
• Is there evidence of hereditary neuropathy?
• Does the patient have any other medical
conditions?

21. Symptomatology of peripheral
neuropathy
• Symptoms comprises the following types:
– Motor Symptoms
– Sensory Symptoms
– Autonomic Symptoms
– Trophic Symptoms

22. Sensory Symptoms
Loss of function
“- symptoms”
Disordered function
“+ symptoms”
Sensory
“Large Fiber”
↓ Vibration
↓ Proprioception
Hyporeflexia
Sensory ataxia
Paresthesias
Sensory
“Small Fiber”
↓ Pain
↓ Temperature
Dysesthesias
Allodynia

23. Motor Symptoms
Loss of function
“- symptoms”
Disturbed function
“+ symptoms”
Motor nerves
Large fibre
Wasting
Hypotonia
Weakness
Hyporeflexia
Orthopedic deformity
Fasciculation
Cramps
•Initially distal motor weakness is common – difficulty in turning
keys of lock, unfasten buttons and opening lids of bottles and jars
•Proximal Motor Weakness – Difficulty in keeping and bringing
down bags in upper parts of closets, hanging shirts, climbing stairs

24. Autonomic Symptoms
Loss of function
“- symptoms”
Disturbed function
“+ symptoms”
Autonomic
nerves
↓ Sweating
Hypotension
Urinary retention
Impotence
Vascular color changes
GI Complaints
↑ Sweating
Hypertension

25. What is the distribution of weakness?
• Distal, proximal or both
• Focal and asymmetric or symmetric
• Symmetric distal and proximal weakness –
Immune demyelinating polyneuropathy (Acute &
Chronic)
• Asymmetric acute or subacute sensory and motor
symptoms and signs – radiculopathies,
compressive mononeuropathies, mononeuritis
multiplex must be coinsidered

26. Is there evidence of upper motor
neuron involvement?
• If symmetric distal sensory symptoms and
signs (distal sensory neuropathy), but
additional symmetric upper motor neuron
involvement – Combined Degeneration
– Vitamin B12 Deficinecy
– Copper Deficiency
– HIV Infection
– Severe Hepatic Disease

27. What is the Temporal Evolution?
• Acute (days to 4 weeks)
– Vasculitis – hyperacute mononeuropathies 24 – 72 hours
– AIDP
• Subacute (4 to 8 weeks)
– CIDP
• Chronic (>8 weeks)
– Diabetes
– Hereditary
• Monophasic, progressive or relapsing
– Monophasic – GBS
– Progressive – Diabetes, CIDP
– Relapsing – Recurrent GBS

28. Is there evidence of Hereditary
Neuropathy?
• Very slowly progressive weakness over many
years – with minimal sensory symptoms but
significant sensory signs – Hereditary
Neuropathy
• Eg. CMT Disease – arch and toe abnormalities
(High or flat arched, hammer toes, etc.)
• Evidence from remote history like funny feet,
unevenly worn shoes, childhood onset
clumsiness especially in sports and tasks that
require fine coordination

29. Does the patient have any other
medical condition?
• Associated medical conditions
– Diabetes
– Systemic Lupus Erythemstosus
– Anaemia
• Preceding or concurrent infections
– Diarrhoea in GBS
• Surgeries
– Gastric bypass and nutritional neuropathies
• Medications
– Toxic Neuropathy
• Alcohol
• Dietary Habits
• Dental Fixatures (zinc leading to copper deficinecy)

30. Past History
• Concurrent illness, particularly organ failure,
endocrine disorders, and connective tissue
disease
• Diabetes, and latent diabetes, should always
be sought.

31. Family History
• Detailed family history is often crucial, and if
negative
– Examination of relatives; atleast tapping the ankle
jerk
– Recording a lower limb motor conduction velocity
• Worthwhile to ask for family history of
porphyria, if present

32. Drugs causing neuropathies
• Axonal
– Vincrisitne, Paclitaxel, Nitrous oxide, Colchicine,
Isoniazid, Hydralazine, Metronidazole, Pyridoxine,
Chloroquine
• Demyelinating
– Amiodarone, chloroquine, gold
• Neuronopathy
– Thalidominde, cisplatin, pyridoxine

33. • Sensory Neuropathy
– Cisplatin, Paclitaxel, etoposide, colchicine,
thalidomide, disulfiram, pyrodixine, INH, lithium,
gold
• Motor Neuropathy
– Dapsone, lead
• Sensory – Motor Neuropathy
– Vincristine, vinblastine, cytarabine, metronidazole,
amiodarone, thallium

34. General Examination
• Purpura, Livodereticularis – Vasculitis, Cryoglobulinemia
• Fabry’s disease – Angiokeratomas
• Skin pigmentation – Leprosy, POEMS, adrenoleukodystrophy
• Icthyosis – Refsum’s Disease
• Mees’ line – Arsenic / Thallium Intoxication
• Alopecia – Thallium Poisoning, Hypothyroidism, SLE
• Maculoanaesthetic patches with thickened nerves - Leprosy
• Orange Tonsils – Tangier’s disease
• Pes cavus, high-arched feet and mutilation – Hereditary
neuropathy
• Macroglossia – Amyloidosis
• Chelosis/Glossitis – Multivitamin deficiency

35. Livedo reticularis

36. Purpura

37. Angiokeratomas

38. Skin Pigmentation

39. Icthyosis

40. Mee’s lines

41. High Arched Foot

42. Thickenend Nerves in Neuropathy
• Leprosy
• Neurofibromatosis
• Roussy Levy Syndrome
• Refsum’s disease
• Amyloidosis

43. SYSTEMIC EXAMINATION
• CENTRAL NERVOUS SYSTEM EXAMINATION
– Higher Functions
Altered in
– Porphyria, HIV, Lead and other toxins, alcohol
– Nutritional: Megaloblastic Madness
– Cranial Nerve affection
• CN III, IV, VI: Diabetes, MFS, Diphtheria
• CN V: Sjogren’s Syndrome, Arsenic, Lyme, Amyloidosis,
Leprosy
• CN VIII, IX, X - Diptheria

44. • Motor System
– Axonal Neuropathy & Hereditary Neuropathies
• Prominent and early wasting and atrophy
– Demyelinating Neuropathy
• Less and disuse wasting as compared to axonal type
– Deformitity
• Claw Hand: Leprosy, Diabetes, Amyloidosis
• Foot deformities: CMT, HMSN, HSAN
– Trophic Changes:
• Diabetes, Leprosy, Hereditary Neuropathies

45. • Sensory Examination:
– Reflexes
• Usually diminished or absent; especially ankle jerk
• Exaggerated Knee with ankle absent
– Vit B12 deficiecny, HIV myeloneuropathy, Friedrich’s ataxia
• Gait Disturbances:
– Ataxias, high stepping gaits, etc

46. • RESPIRATORY SYSTEM EXAMINATION
– Asthma – Churg-Strauss Syndrome
– Sarcoidosis
– Tuberculosis – HIV
– Carcinoma Lung
– Connective Tissue Disorder
• CARDIOVASCULAR SYSTEM
– Cardiomyopathy: Diptheria, Alcohol, Amyloidosis
– Pericarditis: Connective Tissue disorder

47. • PER ABDOMEN EXAMINATION
– Hepatosplenomegaly
• HIV, lymphoma, connective tissue disorder,
paraneoplastic, amyloidosis
• Tenderness: Porphyrias, toxins: lead, thallium
• OPHTHALMIC EXAMINATION
– Cataracts: Diabetes
– Microaneurysms: Diabetes
– Optic disc edema: AIDP, CIDP, POEMS
– Xerophthalmia: Sjogren’s Syndrome, Sarcoidosis

48. Differencial Diagnosis of Peripheral
Neuropathy / Pitfalls in diagnosis @ nerve
level
• In patients with neuropathic symptoms, spinal
cord is the most common differential
• Spinal Canal Stenosis – intermittent
claudiacation symptoms, but in advanced
stages, may present with persistent symptoms
simulating peripheral neuropathy
• In elderly, co existance of cervical spondylitic
meylopathy with late onset predominantly
sensory axonal neuropathy

49. • In the same way, spondylotic radiculopathies
may co-occur with upper limb entrapement
neuropathies
• As stated before, coexistance with CNS disease
is common, Vitamin B12 deficiency,
neuroacanthocytosis, spinocerebellar
syndromes
• Lacunar stroke may rarely present with
sensory loss in the region of median or ulnar
nerve distribution

50. Various classifications of
neuropathies

51. Neuropathies by pattern of
involvement
• Focal
– Entrapement
• Myxoedema
• Rheumatiod arthritis
• Amyloidosis
• Acromegalyt
– Compressive neuropathies
– Trauma
– Ischemic lesions
• Diabetes mellitus
• Vaculitis
– Leprosy
– Sarcoidosis
– Neoplastic infiltration or compression

52. • Multifocal
– Diabetes mellitus
– Vaculitis
• Polyarteritis nodosa
• Systemic lupus erythematosus
• Sjogren’s syndrome
– Sarcoidosis
– Leprosy
– HIV/AIDS
– Multifocal variant of CIDP
– Hereditary predisposition to pressure palsies

53. Neuropathies with less common
patterns of involvement
Neuropathies with cranial nerve involvement
– Diabetes mellitus
– Guillian-Barre Syndrome
– HIV/AIDS
– Lyme disease
– Sarcoidosis
– Neoplastic invasion of skull base or meninges
– Diptheria
– Friedrich’s ataxia

54. Neuropathies predominant in upper limbs
– Porphyria
– Lead neuropathy

55. Neuropathies with rapid/abrupt onset
• Ischemic neuropathies
• Polyarteritis nodosa
• Rheumatoid arthritis
• Diabetes mellitus
– Cranial neuropathies
– Diabetes amyotrophy
• Nerve compression
– Hemorrhage
– Swelling within a restricted anatomic compartment
– Direct external compression
• Penetrating wounds

56. Neuropathies by clinical course
• Acute
– Guillian-Barre Syndrome
– Acute intermittent porphyria
– Critical illness polyneuropathy
– Diptheric neuropathy
– Thallium toxicity
• Subacute
– Maintained exposure to toxic agents/medications
– Persisting nutritional deficiency
– Abnormal metabolic state
– Paraneoplastic syndrome
– CIDP

57. • Chronic
– Hereditary motor sensory neuropathies
– Dominantly inherited sensory neuropathies
– CIDP
• Relapsing/remitting course
– Guillian-Barre Syndrome
– CIDP
– HIV/AIDS
– Toxic
– Porphyria

58. Laboratory Tests
• First line screening tests
– Blood counts, ESR
– Blood sugar
– Liver and renal function tests
– Serum Vitamin B12 levels
– Paraprotein levels
– Thyroid funtion tests
– Vasculitis Profile

59. NERVE CONDUCTION STUDIES (NCS)
• NCS is a medical diagnostic test commonly
used to evaluate the function, especially the
ability of electrical conduction, of the motor
and sensory nerves
• Three important conclusions are
– Confirm that the disease process is due to
neuropathy
– Find out subclinical neuropathies
– Prognosticate the condition

61. Evoked Potentials
•Electrical signals passes
recording and reference
electrodes and is shown on
oscilloscope
•Time to onset and amplitude
of the electrical signal is
measured

62. Amplitude
Reduced in axonal
blockade

63. Latency
Prolonged in
demyeliating lesions

64. Nerve Conduction Velocity

65. AXONAL
DEGENERATION
SEGMENTAL
SEGMENTATION
Motor Nerve Conduction Studies
CMAP amplitude Decreased Normal
Distal Latency Normal Prolonged
Conduction Velocity Normal Slow
F wave Normal or absent Prolonged or absent
H reflex Normal or absent Prolonged or absent
Sensory Nerve Conduction Studies
SNAP amplitude Decreased Normal or decreased
Distal latency Normal Prolonged
Conduction velocity Normal Slow

66. • If Hx, examination, EDx and the above
mentioned Ix does not reveal a diagnosis,then
– Revise family history or examine the relatives
• Nerve Biopsy – Vasculitis restricted to nerves
or neuropathy of recent origin, amyloid, CIDP
• Anti-Hu antibodies
• CSF
– AIDP, CIDP and other chronic immune-medicated
axonal neuropathies
– Significant pleocytosis shoud raise the suspicion of
Borrelia, Sarcoidosis, HIV

67. • Genetic Testing
– E.g. PMP22 duplication test and others in CMT
– Due to high mutation rate, genetic disorder can
also be considered without a family history
• Anti-ganglioside antibodies elevated in
patients with multifocal motor neuropathy
with conduction block (MMN-CB) in 50%
patients
• Anti-GQ1b IgG – Miller-Fisher Syndrome
• Motor Axonal Variant of GBS – Anti-GM1 and
anti-GDI antibodies

68. • Nerve Biopsy
– Places where electron microscope, teased fibre
technique and immunohistochemistry are
available
– Indications: Suspicion of vasculitis , amyloid
deposition, leprosy, sarcoidosis or immune
neuropathies (eg CIDP)
– Location: superficial sensory nerves are generally
used. Superficial peroneal nerve in legs &
superficial radial nerve or branch of ulnar nerve
• Combined nerve and muscle biopsy may
sometimes be required

69. Specific Neuropathies

70. Hereditary Neuropathies
• Charcot-Marie-Tooth disease
• Hereditary Neuropathy with liability to pressure
palsies (HNPP)
• Hereditary Neuralgic Amotrophy (HMA)
• Hereditary Sensory and Autonomic Neuropathy
(HSAN)
• Fabry’s disease
• Refsum’s disease
• Tangier’s disease
• Porphyria
• Familial Amyloid polyneuropathy

71. RARE HEREDITARY NEUROPATHIES
HEREDITARY DISORDERS OF LIPID METABOLISM
Metachromatic leukodystrophy
Krabbe’s disease (globoid cell leukodystrophy)
Fabry’s disease
Adrenoleukodystrophy / adrenomyeloneuropathy
Refsum’s disease
Tangier disease
HEREDITARY ATAXIAS WITH NEUROPATHY
Friedreich’s ataxia
Vitamin E deficiency
Spinocerebellar ataxia
Abetalipoproteinemia (Bassen-Kornzweig disease)

72. RARE HEREDITARY NEUROPATHIES
DISORDERS OF DEFECTIVE DNA REPAIR
Ataxia-Telangictesia
Cockayne’s Syndrome
GIANT AXONAL NEUROPATHY
PORPHYRIA
Acute Intermittent Porphyria (AIP)
Hereditary coprophyria (HCP)
Varigate porphyria (VP)
FAMILIAL AMYLOID POLYNEUROPATHY (FAP)
Transthyretin-related
Gelsolin-related
Apolipoprotein A1-related

73. Aquired Neuropathies
• Primary or AL Amyloidosis
• Diabetic Neuropathy
• Hypothryiodism
• Sjogren Syndrome
• Rheumatiod Arthritis
• Systemic Lupus Erythematosus
• Systemic Sclerosis (Scleroderma)
• Mixed Connective Tissue Disorder (MCTD)
• Sarcoidosis
• Hypereosinophilic Syndrome
• Celiac Disease (Gluten – induced Enteropathy)
• Uremic Nephropathy
• Chronic Liver Disease
• Critical Illness Polyneuropathy
• Leprosy
• Lyme Disease
• Diphtherritic Neuropathy
• HIV

74. Diabetic Neuropathy
• Distal symmetric sensory and sensorimotor
polynneuropathy
• Autonomic neuropathy
• Diabetic neuropathic cachexia
• Polyradiculoneuropathies
• Cranial neuropathies
• Other mononeuropathies

75. Diabetic Distal Symmetric Sensory and
Sensorimotor Polyneuropathy (DSPN)
• Begins in toes, gradually progress over time
upto legs and into arms and legs
• When severe, sensory loss also occurs on
trunk, initially over midline anteriorly and
then laterally
• Tingling, burning, deep aching pains occur

76. Diabetic Autonomic Neuropathy
• Abnormal sweating, dysfunctional
thermoregulation, dry eyes and mouth, pupillary
abnormailties, cardiac arrythmias, postural
hypotension, GI abnormalities (gastroparesis,
post prandial bloating, chronic diarrhoea or
constipation) and genitourinary disturbances
(impotence, retrograde ejaculation, incontience)
• Tests for autonomic dysfunction are abnormal –
sympathetic skin responses and quantitative
sudomotor axon reflex testing

77. Diabetic Radiculoplexus Neuropathy
(Diabetic Amyotrophy or Bruns-
Garland Syndrome)
• Severe pain in lower back, hip and thigh in one leg
• Atrophy and weakness of proximal and distal
muscles in the affected leg becomes appatent
within a few days to weeks
• Severe weight loss
• Recovery is slow and partial with residual
weakness, sensory loss, and pain
• ESR, CSF protein are elevated
• Presentation maybe like the typical lumbosacral
radiculoplexus neuropathy, thoracic radiculopathy
or even an uncommon cervical
polyradiculoneuropathy

78. Diabetic Mononeuropathies
• Median neuropathy at wrist
• Ulnar neuropathy at elbow
• Peroneal neuropathy at fibular head
• Cranial Neuropathies
– Seventh cranial nerve
– Third cranial nerve palsy (typically pupil sparing)

79. HIV
• HIV- related distal symmetric polyneuropathy
• HIV – related inflammatory demyelinating
polyneuropathy
• HIV – related progressive radiculopathy
• HIV – related multiple mononeuropathies
• HIV – related neuronpathy / ganglionopathy

80. HIV – Related Distal Symmetric
Polyneuropathy (DSP)
• DSP most common neuropathy in HIV-AIDS
• Characterised by numbness and painful
paresthesias in distal extremities
• Immune mediated – cytokines from
surrounding inflammation
• Antiretroviral drugs – Dideoxycytidine,
stavudine causes painful sensory neuropathy

81. HIV – Related Inflammatory
Demyelinating Polyneuropathy
• AIDP and CIDP occurs in HIV
• AIDP during the time of sero-conversion, while
CIDP can occur at any stage in the disease
• Elevated protein levels, lymphocytic
pleocytosis is evident on CSF; which helps to
distinguish it from idiopathic AIDP/CIDP

82. HIV – related progressive
polyradiculopathy
• Acute progressive lumbosacral
polyradiculopathy occurs secondary to CMV
infection
• Severe radicular pain, numbness and
weakness in legs – usually asymmetric

83. HIV – related multiple
mononeuropathies
• Weakness, numbness, paresthesias, and pain
occur in distribution of affected nerves
• Axonal degeneration with necrotizing
vasculitis or perivascular inflammation occurs

84. HIV – related sensory neuronopathy /
ganglionopathy
• Dorsal root ganglianitis occurs and
neuronopathy is the presenting feature
• Sensory ataxia

85. Nutritional Neuropathies
• Cobalamin (Vitamin B12) deficiency
– Numb hands typically appear before lower
extremity parasthesias
– Large fibre sensory loss affecting proprioception &
vibration with sparing of small fibre modalities,
sensory ataxia
– Diffuse hyporeflexia and absent Achilles reflex
– Sometimes – optic atrophy with behavioral
changes may be visible

86. Thiamine Deficiency
• Consequence of chronic alcohol abuse,
recurrent vomitting, total parentral nutrition
and bariatric surgery
• Mild sensory loss to burning dysesthesias in
toes and feet and aching and cramping in
lower legs followed by distal sensory loss

87. Copper Deficiency
• Myeloneuropathy
• Lower limb paresthesias, weakness, spasticity
and gait difficulties
• Most commonly large fibres sensory function
is affected, but sometimes; small fibres are
affected too

88. Leprosy (Hansen’s Disease)
• Most common cause of peripheral neuropathy
in Southeast Asia, Africa and South America
• Superficial cutaneous nerves of the ears and
distal limbs are commonly affected
• Mononeuropathies, multiple
mononeuropathy occurs
• Slowly progressive distal symmetric
sensorimotor polyneuropathy

89. • Sensory NCVs usually absent in lower limbs
and reduced in amplitude in arms
• Motor NCS reduced amplitude in affected
nerves and also shows delayed latent
conduction velocities

90. Acute Inflammatory Demyelinating
Polyneuropathies
• Clinical Features
– Areflexic motor paralysis with or without sensory
disturbances
– Ascending paralysis with dysesthesias in the extremities
– Facial diparesis in 50 % of patients
– Lower cranial nerves also be involved
– Pain in neck, shoulder, back or over spine in 50 % patients
– Autonomic dysfunction (fluctuation in BP, arrythmias)
• Bladder dysfunction not a prominent feature, but if
present suggests some alternative diagnosis (spinal
cord)

91. Subtypes of GBS
SUBTYPE FEATURES ELECTRODIAGNOSIS
Acute inflammatory
demyelinating
polyneuropathy (AIDP)
Adults more than
children; anti-GM1
antibodies
Demyelinating
Acute motor axonal
neuropathy (AMAN)
Children and yourng
adults, maybe seasonal;
anti-GD1a antibodies
Axonal
Acute motor sensory
sxonal neuropathy
(AMSAN)
Mostly adults, recovery
slow and often
incomplete
Axonal
Miller Fisher Syndrome
(MFS)
Adults and children;
ophthalmoplegia, ataxia
and areflexia; anti-GQ1B
antibodies
Axonal or demyelinating

92. Antecedent Events
• 70% GBS occurs 1 – 3 weeks after acute infectious
process, usually respiratory or gastrointestinal
• 20 – 30 % cases in western world after C. jejuni
infection
• Others include – HHV, CMV, EBV, M. peumoniae
• Older type of rabies vaccine, prepared in nervous
system, is implicated as a trigger for GBS in
developing countries.
• GBS also occurs in lymphona. HIV-seopositive
patients, SLE

93. Immunopathogenesis
of GBS

94. Laboratory Features
• CSF – elevated protein levels without accompanying
pleocytosis
• CSF normal if symptoms <= 48 hours
• In AIDP, the earliest features are prolonged F-wave
latencies, prolonged distal latencies, and reduced
amplitude of compound muscle action potentials (CMAP)
• Late findings, slowing of conduction velocity, conduction
blocks, temporal dispersion may be appreciated
• In primary axonal pathology, Edx shows reduced
amplitude of CMAPs without conduction slowing or
prolongation of distal latencies

97. Diagnosis
Brighton Criteria for GBS
• Level 1 of diagnostic certainity
– Motor (B/l and flaccid)
– Reflexes
– Antecedent illness
– Edx
– CSF
– Absence of any alternative diagnosis
• Level 2 of diagnostic certainty
– Above except as in
– CSF / Edx
• Level 3 of diagnostic certainty
– Motor
– Reflexes
– Antecedent illness
– Alternative diagnosis

98. Treatment
• Plasmapheresis
• IVIg

99. Chronic Inflammatory Demyelinating
Polyneuropathy
• Onset gradual over a few months or longer
• Acute onset form of CIDP when GBS deteriorates > 9
weeks after onset or relapse three times
• Weakness of limbs is symmetric but can be asymmetric
in multifocal aquired demyelinating sensory and motor
(MADSAM) neuropathy variant
• Some have chronic progressive course, while others
have replasing and remitting course
• Some have only motor findings, while some have pure
sensory ataxia
• Tremors in 10 % patients

100. Pathogenesis
• Biopsy reveals – inflammation and onion-bulb
appearance (from recurernt remyelination and
demyelinatin)
• CIDP responds to glucocorticoids
• Some patients have antibodies against P0, myelin
P2, PMP22 or neurofuscin
• 25% patients have monoclonal gammopathy and
antibodies against myelin-associated glycoprotein
(MAG)

101. Diagnosis
• Clinical, CSF and Edx
• CSF
– Albuminocytological dissociation
• Edx
– Variable degrees of conduction slowing, prolonged distal latencies,
distal and temporal dispersion of CMAPs, and conduction block
– Presence of conduction block is hallmark of aquired demyelinating
process
– Axonal loss, secondary to demyelination, is present in 50% patients
• Serum protein electrophoresis and immunofixation –
Monoclonal gammopathy
• CIDP – exclude vasculitis, collagen vascular disease (especially
SLE), chronic hepatitis, HIV, amyloidosis, and diabetes

102. Treatment
• Treatment initialted when progression is rapid or
walking is compromised
• High dose IVIg, PE and glucocorticoids all more
effective than placebo
• Patients who fail this therapy, should be given a
trial of
– Azathioprine, methotrexate, cyclosporine, and
cyclophosphamide
– Anti-CD20 (Rituximab) is also promsing
• Fails to respond to treatment, think of POEMS
(monoclonal gammopathy)

103. Charcot-Marie-Tooth Disease
• Most common type of hereditary neuropathy
• Classified on the basis of nerve conduction
velocities, predominant pathology and
inheritance pattern
– Type I – Demyelinating
• Nerve Conduction Velocity < 38 m/s
– Type II – Axonal
• Nerve Conduction Velocity > 38 m/s
• CMT 1, 2 & 3 – Autosomal Dominant; CMT 4 –
Autosomal Recessive

105. • CMT Type 1
– (anterior compartment) – inverted champagne
bottle legs
– First to third decade of life with distal weakness
(e.g. footdrop); but many remain asymmtomatic
– Reduced sensations to all modalities on
examination
Three copies of
peripheral myelin
protein – 22 (PMP-
22)

106. • CMT Type 2
– Usually becomes symptomatic in second decade
of life;
– Clinically indistinguishable from CMT1; but NCVs
show a slightly higher velocity
• CMTDI – dominant Intermediate, NCVs faster
than in CMT1, but slower than CMT2
• CMT3
– Hereditary demyelinating sensorimotor
polyneuropathy in infancy or childhood
• NCVs usually in 5 – 10 m/s

107. • CMT4
– Severe, childhood-onset sensorimotor
polyneuropathy inherited as autosomal recessive
pattern
– EDx & histology shows demyelinating and axonal
features

108. • CMT1X
– X-linked dominant disorder; with clinical features
similar to CMT1 and CMT2, but more severe in
men than in women
– 10 – 15 % of CMT overall
– First two decades of life with atrophy and
weakness of distal arms and legs, pes cavus, and
hammertoes
– NCVs in between 15 – 35 m/s; (among which
majority in 25 – 35 m/s – intermediate slowing)
– Mutation in connexin 32

109. Hereditary Neuralgic Amotrophy
(HMA)
• Autosomal dominant; mutation in Septin 9 (SEPT 9)
• Recurrent attacks of pain, weakness and sensory loss in
the distribution of brachial plexus, which begins in
childhood; with recovery in weeks or months
(sensorimotor)
• Confused with brachial plexitis
• Occurs in postpartum state, stress or following surgery
• Clincal:
– Slighly dysmorphic features including hypotelorism,
epicantal folds, cleft palate, syndactyly, micrognathia, and
facial asymmetry occurs
• NCV – Axonal neuropathy

110. • Clinical patterns
– Classic (severe pain followed by paresis and
symptom-free interval in between)
– Chronic (interictal persistance of pain and paresis)

111. • Treatment:
– NSAIDS in combination with opoids and/or TCAs
like amitryptylline or BZDs
– Supportive physical therapy including
transcutaneous electrical neurostimulation (TENS)

112. Hereditary Neuropathy with Liability to
Pressure Palsies (HNPP)
• Second or third decade of life; due to a single
copy of PMP-22; autosomal dominant
• Painless numbness and weakness in the
distribution of a single peripheral nerve,
although multiple mononeuropathies can
occur; which takes weeks or months to resolve
• Precipitated by trivial compression of nerves –
wearing a backpack, leaning on elbows,
crossed legs

113. Hereditary Sensory and Autonomic
Neuropathy (HSAN)
• Sensory and Autonomic dysfunction predominated
over muscle weakness
• HSAN 1 in adults – second to forth decade of life,
autosomal dominant
• Degeneration of small myelinated and unmyelinated
nerve fibres
– Severe loss of pain and temperature sensations, gross foot
and hand deformities, bone loss, recurrent osteomyelitis,
amputed digits – self mutilating behaviour
– Sometimes, bladder dysfunction, reduced sweating in feet
can occur

115. Fabry’s disease
• Angiokeratoderma corporis
diffusum; X-linked dominant
disorder.
• Angiokeratomas – umbilicus,
scrotum, inguinal region
andperineum
• Burning pain in hands and feet
occur, but disease presents with
other system complications like
HTN, Renal disease, cardiac disease
and stroke, dialted cardiomyopathy
• Mutation in a-galactosidase gene,
acumulation of ceramide trihexoside
in nerves and blood vessels

116. Refsum’s Disease
• Infancy to early childhood with tetrad of:
– Peripheral Neuropathy
– Retinitis Pigmentosa
– Cerebellar ataxia
– Elevated CSF protein levels
• Progressive distal sensory loss and weakness,
leading to foot drop in their 20s

118. Tangier Disease
• Autosomal recessive disorder with reduced
amount of HDL cholestrol
– Asymmetric multiple mononeuropathies
– Slowly progressive symmetric polyneuropathy
predominantly in legs
– Pseudo-syringomyelia pattern with dissociated
sensory loss

119. Primary or AL Amyloidosis
• Multiple myeloma, Waldenstrom macroglobulinemia,
lymphoma or plasmacytomas
• 30 % patients with neuropathy – painful dysesthesias
and burning sensation of feet. Sometimes
mononeuritis multiplex can occur
• Slowly progressive eventually with large fibre sensory
loss
• Autonomic dysfunction with postural hypotension,
syncope, bowel and bladder disturbances,
constipation, impotence and impaired sweating

120. • Monoclonal protein may be composed of IgG,
IgA, IgM, or only free light chain. Lambda is more
common than kappa light chain
• CSF protein is often increased (with normal cell
count) mimicking neuropathy
• Nerve Biopsy – axonal degeneration and amyloid
deposition
• Chemotherapy reduces the concentration of
monoclonal proteins, and autologous stem cell
transplantation may prolong survival, but
improvement of neuropathy is controversial

121. Hypothyroidism
• Commonly associated with proximal
myopathy, but some patients typically develop
Carpel Tunnel Syndrome
• Generalised neuropathy characterised by
painful paresthesias and numbness in legs and
hands can occur
• Rx – Correction of hypothyroidism

122. Sjorgen’s Syndrome
• Complex of sicca complex of xerophthalmia,
xerostomia, dryness of mucus membranes,
can be complicated by neuropathy
• Length-dependent axonal sensorimotor
neuropathy of small fibre or cranial
neuronopathy, particularly of trigeminal nerve
• Progressive tingling and numbness of trunk
and limbs, or face (with sometimes face >
limbs)

123. • Patients with sensory ganglionopathies
develop progressive numbness and tingling of
the limbs, trunk, and face in a non-length-
dependent manner; so that face or arms are
affected more than legs
• ANAs, SS-A/Ro and SS-B/La antibodies in the
serum
• NCVs & nerve biopsy – axonal degeneration
• Vasculitis is suspected, immunosuppressive
agents can be beneficial

124. Rheumatoid Arthritis
• Seen in 50% of patients
• Vasculitis
• Mononeuropathy multiplex, generalised
pattern or combination of both
• Also be due to drugs used to treat RA (tumor
necrosis blockers, leflunomide)
• Responsive to immunomodulating therapies

125. Systemic Lupus Erythmatosus (SLE)
• 2 to 27% patients develop neuropathy
• Slowly progressive sensory loss beginning in
feet
• Burning pain and paresthesias with normal
reflex (small fibers)
• NCS – pure small-fiber neuropathy
• Immunosuppressive therapy is beneficial in
SLE with vasculitis

126. Systemic Sclerosis (Scleroderma)
• Distal symmetric, mainly sensory, polyneuropathy
complicated 5 – 67% of scleroderma cases
• Cranial mononeuropathies, commonly trigeminal,
produces numbness and dysesthesias in the face
• Muliple mononuropathies also occur
• EDx & Biopsy – axonal sensory >> motor
polyneuropathy

127. Uremic Neuropathy
• 60 % of patients with renal failure develops
polyneuropathy – length dependent
numbness, tingling, allodynia and mild distal
weakness
• Rapidly progressive weakness and sensory
loss, very similar to GBS, can occur which
improves by increasing the intensity of dialysis
or with transplantation
• Mononeuropathies (eg CTS can occur)

128. Sarcoidosis
• Cranial nerve – VII – affected bilaterally
• Radiculopathy or polyradiculopathy
• If generalised root involvement is present, then it
mimics GBS
• Multiple mononeuropathies or a generalised,
slowly progressive, sensory greater than motor
polyneuropathy can occur
• EDx – Axonal Neuropathy

129. Celiac Disease (Gluten-induced
enteropathy or nontropical sprue)
• Ataxia and peripheral neuropathy occurs in 10%
of patients with celiac disease
• Generalised sensorimotor polyneuropathy, pure
motor neuropathy, multiple mononeuropathies,
autonomic neuropathy, small-fiber neuropathy,
and neuromyotonia
• Nerve biopsy – loss of large myelinated fiber
– (Secondary to malabsorption of Vitamin B12 and E)

130. Inflammatory Bowel Disease
• UC & Crohn may be complicated by GBS, CIDP,
generalised axonal sensory or sensorimotor
polyneuropathy, small fibre neuropathy or
mononeuropathy

131. Lyme Disease
• Neurological complications occurs in second
and third stages of infection
• Facial neuropathy is most common and is
bilateral
• Other nerves are symmetrically affected
• It is a primary axonopathy
• Rx - Antibiotics

132. Diphtheritic Neuropathy
• 20 – 70 % patients develop peripheral
neuropathy by a toxin released by bacteria
• In third to forth week of illness, decreased
sensation in throat, dysphagia, dysarthria,
hoarseness and blurred vision due to impaired
accomodation occurs
• More generalised neuropathy occurs 2 to 3
months later, characterised by numbness,
paresthesias, weakness of arms and legs and
respiratory failure

133. • CSF protein can be elevated with or without
pleocytosis
• EDx – diffuse axonal sensorimotor
polyneuropathy
• Antitoxin and antibiotics should be given
within 48 hours of symptom onset; however, it
does not alter the natural history of associated
peripheral neuropathy

134. Herpes Varicella-Zoster Virus
• 2/3rd adults there is dermal zoster with pain
and paresthesias in dermatomal region
followed within a week or two by vesicular
rash in same distribution
• Weakness in muscles innervated by roots
corresponding to dermatological distribution
of skin lesions occurs in 5 – 30% patients
• About 25 % patients have continued pain
(post herpetic neuralgia – PHN)

135. Cytomegalovirus
• Acute lumbosacral polyradiculopathy and
multiple mononeuropathies in patients with
HIV and other immune deficiency disorders

136. Epstein-Barr Virus
• Associated with GBS, cranial neuropathies,
mononeuropathy multiplex, brachial
plexopathy, lumbosacral radiculoplexopathy,
and sensory neuronopathies

137. Chronic Liver Disease
• Generalised senorimotor neuropathy –
numbness, tingling, and minor weakness in
the distal aspects of lower limbs
• EDx – sensory >> motor axonal neuropathy

138. Critical Illness Polneuropathy
• Acute generalised weakness leading to admission in ICU
are GBS and myasthenia gravis
• However, weakness developing in critically ill patients
while in ICU is caused by critical illness poluneuropathy
(CIP) or critical illness myopathy (CIM)
• Complication of sepsis or multiple organ failure
– Leads to inability to wean patient off the ventilator
• Exact mechanism is not known; but circulating toxins and
metabolic abnormalities are associated with sepsis and
multiorgan failure impair axonal transport or
mitochondrial function, leading to axonal degeneration

139. Neuropathies Associated With
Malignancy
• Mechanism of neuropathy
– Direct effect of cancer by invasion or compression
of the nerves
– Remote or paraneoplastic effect
– Toxic effect of treatment
– Consequence of immune compromise by
immunosuppressive medications
• Most common is lung cancer.

140. Paraneoplastic Sensory
Neuronopathy/ Ganglionopathy
• Paraneoplastic encephalomyelitis/sensory
neuronopathy (PEM/SN) – Small – Cell
Carcinoma
• Polyclonal antineuronal antibodies (IgG) –
anti-Hu antigen
• Numbness or parasthesias in distal
extremities, sensory ataxia, motor
neuronopathy (pseudoathetosis, inability to
walk, stand or even sit without support)

141. • Neurological symptoms precede on an
average of 6 months before identification of
SCLC
• Even though, most of subacute sensory
neuropathies are idiopathic, more than half
the cases have underlying lung cancer
– So in selected cases, it is necessaryto screen for
paraneoplastic antibody, or even PET Scan for
early diagnosis of the tumor

142. Other malignancies
• Lymphoma
• Multiple myeloma
• As a complication of bone marrow
transplantation
• Associated with monoclonal gammopathy of
uncertain significance
• Even as a complication of chemotherapy

143. Toxic Neuropathies
• Chloroquine and Hydroxychloroquine
– Neuromyopathy
• Pyridoxime (Vitamin B6) Toxicity
– Severe sensory neuropathy with dysesthesias
• Lead
– Most common presentation is encephalopathy
– But primary motor neuropathy can also occur
• Weakness – usually beginning in arms, involving wrist
and finger extensors.

144. • Thallium
– Burning parasthesias of the feet, abdominal pain and
vomitting
– First week – Pigmentation of hairs, acne-like rash in
malar area of face, hyperreflexia
– Second & third week – autonomic instability with
labile heart rate and BO
– Third to forth week – hyporeflexia and alopeciA
• Arsenic
– Mimics GBS
– Abrupt onset abdominal pain, nanusea, vomitting,
pain and diarrhoea follwed several days later by
burning sensation in feets and hands

145. Cryptogenic (Idiopathic) Sensory and
Sensorimotor Polyneuropathy
• SCPN – diagnosis of exclusion
• 6ht or 7th decade of life
• Distal numbness, tingling, often burning pain
that begins in feet and eventually involves the
fingers and hands
• Both small and large fibre loss on neurological
exam and EDx

146. Common Mononeuropathies
• Median neuropathy
• Ulnar neuropathy at elbow – “Cubital Tunnel
Syndrome”
• Radial neuropathy
• Lateral femoral cutaneous neuropathy (Meralgia
paresthetica)
• Femoral neuropathy
• Sciatic neuropathy
• Peroneal neuropathy

147. Plexopathies
• Brachial Plexus
– Immune-medicated brachial neuropathy
– Brachial plexopathies associated with neoplasms
– Perioperative Plexopathies
• Lumbosacral Plexopathies
• Recurrent Neoplastic disease or radiation
induced plexopathy

148. Multifocal Motor Neuropathy
• Uncommon neuropathy presents as slowly
progressive motor weakness and atrophy
developing over years in distribution of selected
nerve trunks
• Sensory fibres are spared; >75 % males
• < 50% patients presents with high titres of
polyclonal IgM antibody to ganglioside GM1
• Demyelinating and mild inflammatory changes at
the sites of conduction block
• Treatment – IVIg; sometimes rituximab or
cyclophosphamide

149. Neuropathies with Monoclonal
Gammopathy
• Multiple Myeloma
• Monoclonal gammopathy of undetermined
signifance

150. Multiple Myeloma
• Polyneuropathy occurs in 5% of the patients of
MM who exhibit either lytic or diffuse
osteroporotic bone lesions
• Sensorimotor, mild and slowly progressive and
do not reverse with supression of myeloma

151. Specific Characteristics of
osterosclerotic MM
• Demyelinating in nature and resembles CIDP
• Respond to radiation therapy or removal of
primary lesion
• Assocciated with lambda light chain. Lytic lesions
are associated with kappa light chain
• Refractory to typical treatment of CIDP
• Associated with other systemic findings:
– Organomegaly
– Endocrinopathy
– Skin Changes
• These features with polyneuropathy and Monoclonal
Gammopathy forms POEMS Syndrome

152. Monoclonal Gammopathy of
Undetermined Significance
• Immunoglobulin types IgG, IgA and IgM
• Sensorimotor neuropathy
• Generally males, >50 years
• Do not respond to immunotherapies desgined
to reduce monoclonal proteins
• Indistinguishable from CIDP
• Demyelination and remyelination occurs

153. Vasculitic Neuropathy
• Common in PAN (Polyarteritis Nodosa);
ooccuring in half the cases clinically and in
100% cases on post mortem examination
• Multifocal (asymmetric) motor-sensory
neuropathy (mononeuropathy multiplex) due
to ischemic lesions of nerve trunks and roots

154. • Suspected when mononeuropathy multiplex
occurs in conjugation with constitutional
symptoms (fever, anorexia, weight loss, malaise)
• Diagnosis by combined nerve and muscle biopsy
• Connective Tissue Disorders
– Rheumatoid Arthritis
– Cryoglobulinemia
– Wegener’s
– SLE
– Systemic Sclerosis

155. Metachromatic Leukodystrophy (MLD)
• MLD is a rare autosomal recessive lysosomal
storage disease that causes progressive
demyelination of CNS and PNS
• Disease diagnosed in childhood
• Result of consangious marriage
• Arylsulfatase A deficiency
• Children in 1 to 2 years of age presents with
progresive weakness, hypotonia and diminished
reflexes

157. Krabbe disease
• Globoid celll leukodystrophy which is a fatal
degenerative disorder that affects the myelin
sheath of nervous system

158. Adrenoleukodystrophy
• Disorder of peroxisomal fatty acid beta oxidation
which results in accumulation of very long chain
fatty acids in tissues throughout the body
• Affects myelin in CNS, adrenal cortex and Leydig
cells of testis
• A variant of ALD; adrenimyeloneuropathy has age
of onset 21 – 37 and presents with progressive
neuropathy, paraparsis and cerebral involvement

159. Friedreich’s Ataxia
• Autosomal recessive ataxia resulting from mutation in
gene locus 9 (leading to GAA triplet repeats; reduced
frataxin)
• Causes progressive damage to the nervous system.
• Clinical Features:
– Muscle weakness in arms and legs
– Loss of coordination
– Vision and hearing defects
– Slurred speech
– Diabetes & heart disorders
– High-arched palate

160. • Pathology
– Sclerosis and degeneratino of dorsal root
ganglion, spinocerebellar tracks, lateral
corticospinal tracks and posterior column
– Loss of myelin in large myelinated fibres

161. Treatment of Neuropathy in general
• Treat the underlying cause
– Eg. Plasmapheresis, IVIg in AIDP
– Steroids in CIDP
• Symptomatic
– For Sensory Neuropathy
• TCAs, Gabapentin, pregabalin
• Carbamazepine, Phenytion, Vanlafaxine
• Mexiletine
– For Motor Neuropathy
• Rehabilitation and Physiotherapy