PERIPHERAL NEUROPATHY

• Peripheral nerves serve different motor, sensory, and autonomic functions
• May affect
  • one nerve (mononeuropathy)
  • several nerves together (polyneuropathy)
  • several nerves not contiguous (Mononeuropathy multiplex)
• Further classified into those that primarily affect the
  • cell body (e.g., neuronopathy or ganglionopathy)
  • myelin (myelinopathy)
  • axon (axonopathy)
• Several changes are identified but are not disease specific:
  • Segmental Degeneration
  • Wallerian Degeneration
  • Axonal Degeneration
• Myelin sheath is the most susceptible to damage. It can break down as a primary process affecting Schwann Cells, myelin itself, or secondarily to the diseases affecting axon

Demyelination		Damage to Schwann cell causes myelin disruption and slowing of nerve conduction. Examples include GuillainBarr syndrome, diphtheria, hereditary sensorimotor neuropathies and Chronic Inflammatory Demyelinating polyneuropathy (CIDP).
Axonal degeneration		The axon dies back from the periphery. Examples include Diabetes, metabolic conditions and toxic neuropathies such as drugs and alcohol.
Wallerian degeneration		Changes occurring after division of a nerve, for example after traumatic section of the nerve.
Compression		Changes occurring after nerve entrapment, for example Carpal tunnel syndrome.
Infarction		Microinfarction of vessels supplying the nerve, for example in diabetes and polyarteritis nodosa.
Infiltration		Nerves infiltrated by inflammatory cells.

Causes  of peripheral neuropathy

1. Drugs (e.g. isoniazid, vincristine, phenytoin, nitrofurantoin, cisplatinum, heavy metals, amiodarone)
2. Alcohol abuse
   1. with or without vitamin B1 deficiency
3. Metabolic
   1. diabetes mellitus = Chronic; axonal may predominate
   2. chronic kidney disease
   3. chronic liver disease
4. Guillain–Barré syndrome
5. Malignancy
   1. carcinoma of the lung [paraneoplastic neuropathy]
   2. leukaemia
   3. lymphoma
   4. chemotherapy (e.g. vincristine, cisplatin, paclitaxel, etoposide)
6. Vitamin deficiency (e.g. B12) 
7. Vitamin excess (e.g. B6)
8. Connective tissue disease or vasculitis (e.g. PAN, SLE)
9. Hereditary (e.g. hereditary motor and sensory neuropathy)
10. Amyloidosis
11. HIV infection
12. Idiopathic

“DAM IT BITCH”

• D – Drugs and chemicals (Pb, phenytoin, metronidazole, amiodarone, hydralazine, vincristine, isoniazid, organic solvents, sulphonamides, nitrofurantoin, CO, OPs).
• A  – alcohol (with or without Thiamine deficiency)
• M – metabolic (diabetes, hypoglycemia, uraemia)
• I – infection (HIV, leprosy, lyme, diptheria, syphilis) or post infectious (GBS)
• T-  tumour (paraneoplastic phenomenon – lung, lymphoma, myeloma)
• B – B12 & other vitamin deficiency states, as well as pyridoxine excess
• I-  idiopathic and infiltrative (e.g. amyloidosis)
• T-  toxins (botulism, ciguatera, Tetrodotoxin, Saxitoxin, BRO, tick paralysis)
• C – connective tissue diseases (e.g. SLE, PAN, RhA) and congenital (e.g. CMT)
• H – Hypothyroidism

Causes of predominant Sensory neuropathy

1. Diabetes
2. Vitamin B12 deficiency
3. Small cell carcinoma of the lung
4. Renal failure

Causes of a predominant motor neuropathy

1. Guillain–Barré syndrome
2. chronic inflammatory polyradiculoneuropathy
3. Hereditary motor and sensory neuropathy
4. Diabetes mellitus
5. Other (acute intermittent porphyria, lead poisoning, diphtheria, multifocal motor neuropathy with conduction block)

Causes of a painful peripheral neuropathy “BADCAP”

1. Diabetes mellitus
2. Alcohol
3. Vitamin B1 or B12 deficiency
4. Carcinoma
5. Porphyria
6. Arsenic or thallium poisoning

Conditions causing neuropathy with autonomic features

1. Alcoholism
2. Amyloidosis
3. Chemotherapy-related neuropathy
4. Diabetes
5. Heavy metal toxicity
6. Porphyria
7. Primary dysautonomia
8. Vitamin B12 deficiency

Autonomic signs include:

• Postural hypotension
• Urinary incontinence
• Diarrhoea (occasionally constipation)
• Abnormal sweating
• Impotence
• Diminished pupillary responses

Clinical presentation dependant on type of neuropathy

Mononeuropathies 

• typically caused by trauma, compressive forces or have a vascular aetiology.
• example
  • trauma to the lateral aspect of the knee
    • common peroneal nerve palsy
  • carpal tunnel syndrome

Polyneuropathies 

• Polyneuropathy is common 2.4% (8% over 55 yr)
• is diffuse symmetrical glove and stocking loss of peripheral nerve function, usually progressing proximally
• The speed of progression of the polyneuropathy coupled with its nature (axonal or demyelinating) can help identify its aetiology.
• example:
  • GuillainBarr syndrome:
    • cause acute demyelinating polyneuropathy
    • motor nerve fibres are predominantly affected with weakness
  • toxins
    • cause acute axonal polyneuropathies
    • pain is the predominant component, which tends to worsen to a peak over 2-3 weeks,
    • recovering over several months
  • diabetes or renal failure
    • causes chronic axonal polyneuropathies
    • symptoms usually begin in the toes before the fingers then spread proximally, as injury tends to be related to axonal length.
    • Sensory symptoms tend to precede motor symptoms.
  • chronic inflammatory demyelinating polyneuropathy (CIDP)
    • Sensory loss and weakness often present simultaneously in patients

Mononeuritis multiplex 

• simultaneous /sequential damage to multiple noncontiguous nerves
• due to
  • multiple infarcts of the vasa nervorum due to a systemic vasculitic process/vasculitis
  • Microangiopathy in diabetes mellitus

Disorders causing mononeuropathy multiplex

• Acute
  • Diabetes mellitus
  • Polyarteritis nodosum 
  • Connective tissue diseases, e.g. SLE, Rheumatoid arthritis
• Chronic
  • multiple compressive neuropathies 
  • sarcoidosis
  • acromegaly
  • leprosy
  • Lyme disease
  • Idiopathic

Axonal vs. demyelinating

Overview of axonal and demyelinating  neuropathies
Features	Axonal		Demyelinating
	Chronic	Acute	Chronic	Acute
Progression	Slow decline over years	Months to years of slow, yet incomplete recovery	Variable (periods of recovery, stabilization, exacerbations, or slow decline)	Variable
Characteristics	Affects longer axonsfirst (begins in lower extremities → sternum (intercostal nerves) → head)Early disease: sensory symptoms > motor symptoms	Similar, but symptoms more severeSignificant pain	Early disease: motor symptoms = sensory symptoms	Early disease: motor symptoms > sensory symptoms
	Distal muscle wasting : feet, lower legs, hands (severe cases) Distal sensory loss (pain, temperature, proprioception, vibration)  Reduced or absent distal reflexes (usually begins in the ankles)		Generalized muscle weakness: distal > proximal   Distal sensory loss (abnormal vibration and  Proprioception > pain or temperature) Diffusely reduced or absent reflexes
Associated conditions	Chronic idiopathic Axonal Polyneuropathy (CIAP) Diabetes Alcohol use disorder Hereditary motor sensory neuropathies Leprosy HIV Borreliosis Hypothyroidism Toxic polyneuropathy (e.g. due to cisplatin, doxorubicin)	Axonal Guillain-Barré syndrome	Chronic inflammatory demyelinating europathy (CIDP) Hereditary motor sensory neuropathies (Charcot-Marie-Tooth disease) Uremic polyneuropathy  Toxic polyneuropathy (e.g. due to diphtheria toxin  suramin, amiodarone)	Guillain-Barré syndrome

Glossary of pain terms
Term	Meaning
Allodynia	Pain perceived following non-noxious, innocuous stimulus (eg light touch causes burning pain)
Antalgia (antalgic)	Pain perception (noun), pain provoked action (adjective) (eg antalgic gait – altered gait due to the influence of pain)
Dysaesthesia	An altered perception of sensation with abnormal (often unpleasant) feeling associated with stimulation, such as touching over the affected area causes ‘strange feeling’
Hypaesthesia/hypoaesthesia	Reduced perception of stimulus (both words are interchangeable), Decreased sensation
Hyperalgesia	Increased perception of pain
Hyperaesthesia	Increased perception of stimulus (need not be pain)
Hyperpathia	Decreased sensation to one or more modalities while concurrently having increased perception of pain (hyperalgia) or pain with innocuous stimulation (allodynia)
Hypoalgia	Reduced perception of pain
Paraesthesia	Abnormal sensations, such as ‘pins and needles’, tingling, prickling, reduced or even loss of sensation. It implies abnormality anywhere along the sensory pathway from peripheral nerve to sensory cortex – the epitome of ‘neuropathic pain

Neuropathy vs Myopathy

Features suggestive of myopathy:

• The sensory supply should be preserved
• The reflexes should be preserved – can be absent in severe muscle disease
• Weakness predominantly proximal
• There should be no fasciculations
• There may be myocardial involvement (skeletal myopathies tend to be associated with cardiomyopathy)
• The muscles involved may be painful and tender(as in myositis)
• There may be muscle contractures, requiring splints

	Muscle bulk	Tone	Strength	Deep Tendon Reflex	Plantars	sensation	fasicualtion
UMN	N	🢁	N	🢁	🢁	N	–
Ant horn cell	Prox wasting	⇓	Proximal weakness	⇓⇓	⇓	N	+
P nerve	Distal wasting	⇓	Distal weakness	Distal ⇓	⇓	⇓	rarely
NMJ	N	N	fatigues	N-🢁	⇓	N	–
Muscle	selective	⇓	⇓	ß	⇓	N	–

causes of myopathies

• Denervation
• Dystrophies
• Ion Channel
• Congenital
• Genetic Metabolic
• Inflammatory
• Toxic
• Neuro-Muscular Junction
• Neoplasms

History

• #1. Where is the lesion?
• #2. The patterns of peripheral neuropathy… • Mononeuropathy? • Polyneuropathy?
• #3. What is the etiology?
• #4. What is the treatment?

• Quality of the pain
• When – small fibre more common at night
• Acute, subacute, chronic
• Diabetes
• Medications – ?chemo, anti-folate
• Social history – alcohol, nutritional defects
• Red flag for vasculitis neuropathy – asymmetric stepwise multiple mononeuropathies in non compressible nerves, painful
• CNS lesions
  • speech difficulty, double vision, ataxia, cranial nerve involvement, or, in cases of myelopathy, impairment of bowel and bladder functions. Deep tendon reflexes are usually brisk, and muscle tone is spastic

Physical exam

• Full Neuro
  • identifying sensory loss in the various modalities:
    • light touch
    • vibration
    • joint position sense
    • pain
    • temperature
  • Glove and stock distribution – peripheral neuropathy

The clinical response to sensory nerve injury:

	Loss of function “- symptoms”	Disordered function “+ symptoms”
Sensory “Large Fiber”	↓ Vibration – Impaired vibration – Vibration – 128 Hz ↓ Proprioception Hyporeflexia Sensory ataxia	Paresthesias
Sensory “Small Fiber” thermal, autonomic, pain	↓ Pain – Loss of protective sensation – Pinprick sensation -10g monofilament under great toes and metatarsal joints ↓ Temperature	Dysesthesias Allodynia

The clinical response to motor nerve injury:

	Loss of function “- symptoms”	Disturbed function “+ symptoms”
Motor nerves	Wasting	Fasciculation
Large fibre – myelinated	Hypotonia Weakness Hyporeflexia	Cramps

clinical response to autonomic nerve injury:

	Loss of function “- symptoms”	Disturbed function “+ symptom
Autonomic nerves	↓ Sweating Hypotension Urinary retention Impotence Vascular color changes	↑ Sweating Hypertension

• Consider if upper or lower motor neuron patterns
  • UMN signs
    • weakness without atrophy
    • absence of fasciculations
    • increased tone
    • exaggerated reflexes
  • LMN Signs
    • muscle atrophy
    • fasciculations
    • decreased reflexes
    • decreased tone
    • negative Babinsky sign
    • flaccid paralysis

Differentials – peripheral arterial disease, Raynauds, restless legs, hypothyroidism, multiple myeloma

Investigations

Complete blood count	—
Comprehensive metabolic panel	—
Erythrocyte sedimentation rate	—
Fasting blood glucose level	—
Thyroid-stimulating hormone level	—
level	—
Vitamin B12
If indicated by clinical suspicion
Glucose tolerance test, A1C level	Diabetes mellitus
HIV antibodies	HIV
Hepatic panel	Liver disorders
Lyme antibodies	Lyme disease
Rapid plasma reagin, VDRL	Syphilis
Urinalysis (including 24-hour urine collection)	Heavy metal toxicity, porphyrias, multiple myeloma
Urine and serum protein electrophoresis with immunofixation	Demyelinating neuropathy
Angiotensin-converting enzyme levels	Sarcoidosis
Antinuclear antibodies, P-ANCA, C-ANCA	Vasculitis
Tests for uncommon conditions
Paraneoplastic panel	Underlying malignancy
Antimyelin-associated glycoprotein and antiganglioside antibodies	Sensorimotor neuropathy
Antisulfatide antibodies	Autoimmune polyneuropathy
Cryoglobulins	Cryoglobulinemia
Salivary flow rate, Schirmer test, rose bengal test, labial gland biopsy	Sjögren syndrome
Cerebrospinal fluid analysis	Acute or chronic inflammatory demyelinating neuropathy
Genetic testing	Hereditary neuropathy

• Other tests

1. Electrodiagnostic studies can help determine whether the neuropathy is the result of
   • damage to the axons (axonal neuropathy)
   • the myelin (demyelinating neuropathy)
   • both (mixed)

1. nerve conduction studies
   1. assess the shape, amplitude, latency, and conduction velocity of an electrical signal conducted over the tested nerve.
   2. Demyelinating disease: ↓ impulse conduction velocity, normal amplitude of response 
   3. Axonal disease: normal impulse conduction velocity, ↓ amplitude of response
2. electromyography (EMG).
   1. can detect active axonal damage, as evidenced by the presence of spontaneous muscle fiber activity at rest resulting from the absence of neuro-regulation (denervation).
   2. The motor unit action potential on voluntary muscle contraction also is assessed.
   3. Can differentiate between neuropathy and myopathy
   4. Polyneuropathy findings may include spontaneous electrical activity (fibrillation potentials) and reduced interference pattern.

• Normal nerve conduction studies and needle EMG significantly decrease the likelihood of peripheral neuropathy, whereas abnormal nerve conduction findings confirm the diagnosis.
• limitation of electrodiagnostic studies
  • are able to test only the large, myelinated nerve fibers.
  • limits their sensitivity in detecting neuropathies of the small nerve fibers (i.e., those with pain, temperature, and autonomic functions).
  • specialized test directed at autonomic functions, and other non-electrodiagnostic tests (e.g., epidermal skin biopsy) may yield the diagnosis.

2. NERVE BIOPSY
   • Sural and superficial peroneal nerve biopsy
     • when confirmation of the diagnosis is needed before initiating aggressive treatment 
   • Epidermal skin biopsy
     • can be performed in patients with burning, numbness, and pain, and in whom small, unmyelinated nerve fibers are suspected to be the cause.
   • Small nerve fiber damage may constitute the earliest stages of some peripheral neuropathies and cannot be detected by electrodiagnostic studies.

• Principles of Treatment
• eliminating offending agents, such as toxins or medications
• correcting a nutritional deficiency;
• treating the underlying disease (e.g., corticosteroid therapy for immune-mediated neuropathy)
• Acute inflammatory neuropathies
  • require more urgent and aggressive management with intravenous immunoglobulin or plasmaphereis.
  • respiratory function testing
  • hemodynamic monitoring
• treat neuropathic pain
  • antiseizure medications (e.g., gabapentin [Neurontin], topiramate [Topamax], carbamazepine [Tegretol], pregabalin [Lyrica])
  • antidepressants (e.g., amitriptyline)
  • Topical patches & sprays containing lidocaine (Lidoderm) or capsaicin (Zostrix) 
• Refer patients to:
  • Podiatry : for foot care (e.g., appropriate shoes, foot hygiene)
  • Physical therapy : for exercises (including balance and gait retraining)
  • Occupational therapy: for home hazard assessment and modification