Sensory Polyneuropathies

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The terms "polyneuropathy," "peripheral neuropathy," and "neuropathy" are often often used interchangeably but in fact have distinct definitions.

• Peripheral neuropathy refers to any disorder of the peripheral nervous system which can include radiculopathies and mononeuropathies.
• Neuropathy is even more general, referring to any disorder of the central and peripheral nervous system
• Mononeuropathy means dysfunction of an individual peripheral nerve such as carpal tunnel syndrome
• Polyneuropathy is a generalised relatively homogenous disease process where many peripheral nerves are affected with the distal nerves being most prominently affected. Polyneuropathy has an extremely long differential diagnosis.
• Mononeuropathy multiplex means mononeuropathy multiple times, i.e. asymmetric symptoms such as a wrist drop and foot drop. This is much less common than polyneuropathy
• Radiculopathy is pathology of a nerve root, it is a type of mononeuropathy
• Polyradiculopathy and plexopathy means multiple nerve roots are affected

Anatomy

Characteristics of peripheral nerve fibres

Nerve Fibre	Myelin	Diameter (µm)	Conduction velocity (m/s)	General Function
Aα (I)	Yes	13-20	80-120	Proprioception: muscle spindle primary endings (Ia), golgi tendon organs (Ib), and alpha motor neurons
Aβ (II)	Yes	6-12	35-75	Discriminative sensitivity to mechanical stimuli (touch, vibration), proprioception, pain modulation (block nociceptive information, allodynia in sensitisation)
Aγ	Yes	4-8	15-40	Touch, pressure, and gamma motor neurons.
Aδ (III)	Thin	1-5	5-30	"rapid" pain, crude touch, pressure, temperature. AMH type I for rapid mechanical pain (high heat threshold >53C), AMH type II for rapid heat pain (lower heat threshold 43-47C).
B	No	1-3	3-14	preganglionic autonomic
C (IV)	No	0.2-1.5	0.5-2.0	"second" pain, mechanical, chemical, thermal, pruritis, and postganglionic autonomic. polymodal

Classification

General Classification

Peripheral neuropathy has many causes. It is not always possible to find the underlying cause. If diagnosis is possible then this enables more accurate prognostication, and potentially treatment for some causes. The differential diagnosis can be categorised in several ways.

1. Pattern of neurological signs and symptoms: sensory, motor, autonomic or mixed
2. Distribution of affected nerve: symmetrical versus asymmetrical, and distal versus proximal.
3. Fibre type involved: Large fibre versus small fibre. Large fibre neuropathies will typically show reduced reflexes, weakness, and reduced vibration and position sense. On the other hand, small fibre neuropathies have normal reflexes and strength, and more minimal findings of reduced sensation to pin prick and temperature.
4. Pathological process involved: Axonal versus demyelinating. Axonal loss for example in diabetic polyneuropathy, or demyelination for example in CIDP. Polyneuropathies can be associated with axonal loss (e.g., diabetic polyneuropathy) or demyelination (e.g., CIDP)
5. Time course: acute, subacute, or chronic. An acute onset suggests inflammatory, immunologic, toxic, or vascular aetiologies. Evolution over many years is suggestive of a hereditary or metabolic process.
6. Hereditary vs acquired: Hereditary polyneuropathies can manifest in adulthood or childhood and there is often a family history. Charcot-Marie-Tooth can be suspected with the presence of a distinctive pes cavus foot.
7. Primary vs secondary: Primary polyneuropathy e.g. chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and secondary polyneuropathy e.g. diabetes, toxin, and monoclonal gammopathy.

An example is Guillain Barre-syndrome. This condition manifests with multiple nerve root involvement acutely, and in most cases there is preferential involvement of the myelin sheath. It is therefore described as an acute demyelinating inflammatory polyradiculopathy. Using this schema narrows down the diagnostic possibilities.

Table 1. Aetiological Classification

Painful Neuropathies
Symmetrical
Metabolic	Diabetes mellitus
	Hypoglycaemic (insulinoma)
	Hypothyroidism
Nutritional deficiency	Niacin (pellagra)
	Thiamine (beriberi)
	Multiple deficiencies
Toxic	Drugs	Alcohol
		Antiretroviral drugs
		Cytostatic drugs
		Isoniazid, hydralazine
	Metals	Thallium
		Arsenic
		Mercury
Immune mediated	Acute or chronic inflammatory demyelinating neuropathies
	Neuropathies associated with paraproteinemia and cryoglobulinemia
	Acquired amyloidosis
	Paraneoplastic neuropathies
Hereditary	Hereditary sensory and autonomic neuropathy (type I)
	Fabry's disease
Idiopathic
Asymmetrical
Mononeuritis/mononeuritis multiplex	Diabetic
Vasculitis neuropathies	Cranial neuropathy
	Trunk and limb mononeuropathy
	Diabetic amyotrophy
	Systemic vasculitis of the vasa nervorum associated with:	Polyarteritis nodosa
		Churg–Strauss syndrome
		Rheumatoid arthritis
		Lupus erythematosus
		Systemic sclerosis
		Wegener’s granulomatosis
	Isolated angiitis of peripheral nerves
	Infectious/parainfectious neuropathies	HIV related
		Borreliosis
		Herpes zoster
Physical injuries	Nerve entrapment – carpal tunnel and other nerve compression
	Root compression (intervertebral disc herniation)
	Neuroma: post-traumatic, postsurgical, postamputation
Plexus neuropathies	Idiopathic neuritis of brachial or lumbosacral plexus
	Post-traumatic
	Tumor infiltration
Radiation induced
Cranial neuralgias: trigeminal and glossopharyngeal neuralgia
Painless Neuropathies
Neuropathies with selective loss of pain sensation	Congenital insensitivity to pain with anhidrosis – HSAN type IV
	Congenital analgesia without anhidrosis – HSAN type V
Neuropathies (predominantly painless)	Leprosy

Painful Sensory Neuropathies

Primary types of painful sensory neuropathy. From uptodate

Type	Usual clinical setting
Idiopathic small fiber neuropathy	Prevalence increases with age Normal strength and deep tendon reflexes Normal position and vibration sensation Diminished pinprick sensation in lower extremities Normal electrodiagnostic testing Diminished sudomotor function Abnormal skin biopsy
Diabetic peripheral neuropathy	History or family history of diabetes Obesity, hypertension Diminished deep tendon reflexes Diminished distal sensation Usually abnormal electrodiagnostic testing Impaired glucose tolerance, impaired fasting glucose, elevated hemoglobin A1C
Hereditary neuropathies	Family history Pes cavus or hammer toe Usually diminished deep tendon reflexes Diminished distal sensation Abnormal electrodiagnostic testing
Neuropathy related to connective tissue disease	History of rheumatoid arthritis, systemic lupus erythematosus, mixed connective tissue disease, Sjögren syndrome Diminished deep tendon reflexes Diminished distal sensation Abnormal electrodiagnostic testing Positive for autoimmune antibodies
Vasculitic neuropathy	Known systemic vasculitis (but vasculitic neuropathy may occur in isolation) Multifocal examination findings Abnormal electrodiagnostic testing Positive for autoimmune antibodies, hepatitis B or C, cryoglobulins Abnormal nerve biopsy
Neuropathy associated with monoclonal gammopathy	Prevalence increases with age Variable examination findings depending upon mode of presentation (mononeuritis multiplex, distal polyneuropathy, radiculopathy, or plexopathy) Abnormal electrodiagnostic testing Monoclonal gammopathy (often IgM)
Paraneoplastic sensory neuropathy	Tobacco smoking, family history, asbestos exposure Solid tumor cancer (mainly lung) Diminished deep tendon reflexes Diminished distal sensation Abnormal electrodiagnostic testing Anti-Hu antibodies
Familial or acquired amyloid polyneuropathy	Family history or known plasma cell dyscrasia (acquired form) Diminished deep tendon reflexes Sensory loss Autonomic dysfunction (eg, postural hypotension, impotence, bladder dysfunction) Compressive mononeuropathy (mainly carpal tunnel syndrome) Abnormal electrodiagnostic testing Monoclonal gammopathy (acquired form)

Clinical Features

Polyneuropathies

In most polyneuropathies motor and sensory symptoms and signs are symmetrical but show a predominantly distal pattern. Usually the lower limbs are affected earlier and more severely than the upper limbs, and the trunk and head are the last to be affected and only in severe cases. Classically the sensory loss spreads proximally with worsening of the disease.

An exception to the standard distal pattern is in acute inflammatory neuropathies. In these situations there can be early involvement of cranial nerves, upper limbs, and the respiratory tract. Cranial nerve involvement can occur with sarcoidosis, Lyme disease, Sjogren syndrome, metastatic meningeal disease, malignant nerve root infiltration, and rare metabolic neuropathies (Refsum, Tangier, and Riley-Day). Predominant upper limb symptoms can be seen in Sjogren syndrome, chronic immune neuropathies, prophyria, lead toxicity, amyloid, and some inherited neuropathies.

In most polyneuropathies there is impairment of both small and large fibre sensory function i.e. pain and temperature for small-fibre involvement; and joint position and vibration for large-fibre involvement. However some patients may have selective damage to either the small or large fibres.

In those with predominant small fibre neuropathy, they may have burning, painful dysaesthesiae, altered pinprick and temperature sensation, and autonomic dysfunction; but with normal motor function and tendon reflexes. In those with predominant large fibre neuropathy, there is loss of joint position and vibration sense, ataxia, areflexia, and variable loss of motor function.

Reflexes are generally diminished early on in the disease process, and may later become absent. Reflexes may be normal in small fibre neuropathies.

Positive Symptoms in Peripheral Neuropathies

Paraesthesiae are generally most prominent in the hands and feet in polyneuropathies. In other neuropathies there can be paraesthesiae in other parts of the body.

Numbness can be the only symptom in some neuropathies, but without objective sensory loss on exam.

Neuropathic pain can occur which can be spontaneous and/or paroxysmal. Allodynia and hyperalgesia may be some objective findings.

Investigations

The first step is grouping the neuropathy into a type (Table 1)

Nerve Function Testing

After grouping the neuropathy into a type, the next step is determining whether a polyneuropathy is axonal or demyelinating. This step requires nerve conduction studies and electromyography. The primary limitation of electrophysiology is that it can't assess small fibre function, only large fibre function. Small fibre function can only be assessed as part of quantitative sensory testing.

Blood Tests

This is to identify metabolic, nutritional, or toxic causes; measure immunoglobulins and immune mediated antineural antibodies; and genetic tests for inherited neuropathies. If B6 toxicity is suspected (e.g. vitamin intake) then can measure B6 levels.

CSF Tests

Looking for increased protein levels and cellular responses indicating radicular or meningeal involvement

Nerve and Muscle Biopsy

The role of biopsy is limited. It can be helpful in

• Mononeuritis multiplex: vasculitis, amyloidosis, leprosy, and sarcoidosis;
• Progressive subacute or chronic distal symmetric polyneuropathies
• Genetic conditions to confirm the diagnosis.

Painful neuropathies and their laboratory tests

Neuropathy	Blood	Urine	Biopsy
Diabetic	HbA1c	Glucose
Alcohol	LFTs
Vitamin Deficiency	B12
Vasculitis	Antinuclear antibodies		Biopsy
Sjogrens disease	Sjogren antibodies
AIDS	HIV antibodies, CD4
Primary amyloid	Protein electrophoresis	Protein electrophoresis	Biopsy
Fabry's disease	d-galactosidase Globotriasosylceramide	Globotriasosylceramide
Uraemic	UECs
Porphyric		d-aminolevulinic acid Porphobilinogen
Tangier's disease	Low cholesterol Low HDLs Low apoprotein
Churg-Strauss	Eosinophilia
Heavy metal	Arsenic, thallium
Familial amyloid			Biopsy
Hereditary			Biopsy
Charcot-Marie-Tooth			Biopsy
Cryoglubulinaemic			Biopsy

Resources

Peripheral Neuropathy - Watson and Dyck 2015 - 276 KB (f)

Concise review article

• Peripheral Neuropathy – The Clinical Problem Solvers (clinicalproblemsolving.com)