Sensory Polyneuropathies

There are more than 100 different causes of peripheral neuropathy. Musculoskeletal Physicians mostly see those associated with neuropathic pain, which helps narrow the differential diagnosis. Neurologists typically divide sensory symptoms into negative and positive symptoms. Negative symptoms are things like numbness; while positive symptoms are things like hyperalgesia, allodynia, and paraesthesia.
==Terminology==
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. 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.
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
This article deals with peripheral neuropathies.
==General Classification==
Peripheral neuropathy has many causes, many which can manifest with neuropathic pain as a component. It is not always possible to find the underlying cause, and especially in the elderly can be multifactorial. 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.
=== Aetiological Classification ===
Table 1. Aetiological ClassificationRavikiran Shenoy et al. Peripheral neuropathies. Wilson's Chronic Pain. 2008
Painful Neuropathies 	Painful Neuropathies 	Painful Neuropathies
Symmetrical 	Symmetrical 	Symmetrical
Metabolic 	Diabetes mellitus 	
Metabolic 	Hypoglycaemic (insulinoma) 	
Metabolic 	Hypothyroidism 	
Nutritional deficiency 	Niacin (pellagra) 	
Nutritional deficiency 	Thiamine (beriberi) 	
Nutritional deficiency 	Multiple deficiencies 	
Toxic 	Drugs 	Alcohol
Toxic 	Drugs 	Antiretroviral drugs
Toxic 	Drugs 	Cytostatic drugs
Toxic 	Drugs 	Isoniazid, hydralazine
Toxic 	Metals 	Thallium
Toxic 	Metals 	Arsenic
Toxic 	Metals 	Mercury
Immune mediated 	Acute or chronic inflammatory demyelinating neuropathies 	
Immune mediated 	Neuropathies associated with paraproteinemia and cryoglobulinemia	
Immune mediated 	Acquired amyloidosis 	
Immune mediated 	Paraneoplastic neuropathies 	
Hereditary 	Hereditary sensory and autonomic neuropathy (type I) 	
Hereditary 	Fabry's disease 	
Hereditary 	Primary erythromelalgia 	
Idiopathic 	including Small fibre neuropathy 	
Asymmetrical 	Asymmetrical 	Asymmetrical
Mononeuritis/mononeuritis multiplex 	Diabetic 	
Vasculitis neuropathies 	Cranial neuropathy 	
Vasculitis neuropathies 	Trunk and limb mononeuropathy 	
Vasculitis neuropathies 	Diabetic amyotrophy 	
Vasculitis neuropathies 	Systemic vasculitis of the vasa nervorum associated with: 	Polyarteritis nodosa
Vasculitis neuropathies 	 	Churg–Strauss syndrome
Vasculitis neuropathies 	 	Rheumatoid arthritis
Vasculitis neuropathies 	 	Lupus erythematosus
Vasculitis neuropathies 	 	Systemic sclerosis
Vasculitis neuropathies 	 	Wegener’s granulomatosis
Vasculitis neuropathies 	Isolated angiitis of peripheral nerves 	
Vasculitis neuropathies 	Infectious/parainfectious neuropathies 	HIV related
Vasculitis neuropathies 	 	Borreliosis
Vasculitis neuropathies 	 	Herpes zoster
Physical injuries 	Nerve entrapment – carpal tunnel and other nerve compression 	
Physical injuries 	Root compression (intervertebral disc herniation) 	
Physical injuries 	Neuroma: post-traumatic, postsurgical, postamputation 	
Plexus neuropathies 	Idiopathic neuritis of brachial or lumbosacral plexus 	
Plexus neuropathies 	Post-traumatic 	
Plexus neuropathies 	Tumor infiltration 	
Radiation induced 	 	
Cranial neuralgias: trigeminal and glossopharyngeal neuralgia	 	
Painless Neuropathies 	Painless Neuropathies 	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 	
=== Diagnostic Classification of Painful Neuropathies ===
Primary types of painful sensory neuropathy. From uptodateS Rutkove. Overview of polyneuropathy. Uptodate. Accessed 20/01/23
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)
==Anatomy==
Nerves are classified by size.
==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. 
Examination should look for both negative and positive sensory components (see Pain Oriented Sensory Testing), as well as for potentially motor deficits (for a sensorimotor neuropathy). 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. 
Negative sensory symptoms are usually confined to the anatomical territory of a peripheral nerve, plexus, or nerve root. On the other hand, positive sensory symptoms are frequently found outside of this territory due to central sensitisation. 
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 	 	
Thyroid disease 	TFTs 	 	
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 	FBC for Eosinophilia 	 	
Heavy metal 	Arsenic, thallium 	 	
Familial amyloid 	 	 	Biopsy
Hereditary 	 	 	Biopsy
Charcot-Marie-Tooth	 	 	Biopsy
Cryoglubulinaemic 	 	 	Biopsy
==Treatment==
Unfortunately peripheral nerve fibres have limited capacity for repair, hence treatment is about symptom management rather than cure.
==Resources==
*Peripheral Neuropathy – The Clinical Problem Solvers (clinicalproblemsolving.com)
==References==
Category:Polyneuropathies