Sensory Polyneuropathies
The terms "polyneuropathy," "peripheral neuropathy," and "neuropathy" are often often used interchangeably but in fact have distinct definitions.
Classification
The overall pathologic classification of neuropathic disorders is as follows
- Neuronopathies (pure sensory or pure motor or autonomic)
- Sensory neuronopathies (ganglionopathies)
- Motor neuronopathies (motor neuron disease)
- Autonomic neuropathies
- Peripheral neuropathies (usually sensorimotor)
- Myelinopathies
- Axonopathies
- Large- and small-fibre
- Small-fibre
Terminology
- Peripheral neuropathy refers to any disorder of the peripheral nervous system which can include radiculopathies and mononeuropathies. They are divided into myelinopathies and axonopathies. Axonopathies are divided into large and small fibre.
- 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
- Neuronopathy means the cell body is affected rather than the myelin or axon as in peripheral neuropathy. They classically present with sensory ataxia. Sensory ataxia can also be caused by large fibre neuropathy and pathology localised to the dorsal column.
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.
- Pattern of neurological signs and symptoms: sensory, motor, autonomic or mixed
- Distribution of affected nerve: symmetrical versus asymmetrical, and distal versus proximal.
- 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.
- 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)
- 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.
- 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.
- 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.
| 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 | |
Anatomy
Nerves are classified by size.
- 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 |
Painful Sensory Neuropathies
| Type | Usual clinical setting |
|---|---|
| Idiopathic small fiber neuropathy |
|
| Diabetic peripheral neuropathy |
|
| Hereditary neuropathies |
|
| Neuropathy related to connective tissue disease |
|
| Vasculitic neuropathy |
|
| Neuropathy associated with monoclonal gammopathy |
|
| Paraneoplastic sensory neuropathy |
|
| Familial or acquired amyloid polyneuropathy |
|
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.
| 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 |
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