	Demyelinating	Axonal	Neuronal
Pattern	Proximal = distal	Distal > proximal; length-dependent	Non-length-dependent; UE, LE, face
Onset	Acute/subacute	Slow evolution	Rapid
Symptoms	Paresthesia and weakness	Dysesthesias and distal weakness	Paresthesias, gait ataxia
Sensory signs	Vibration and proprioception > pain and temperature	Pain and temperature affected > vibration and proprioception	Vibration and proprioception > pain and temperature
Motor	Distal and proximal weakness	Distal weakness	Proprioceptive weakness
DTRs	Areflexia	Distal areflexia	Areflexia
NCS	Velocity affected > amplitude	Amplitudes affected > velocity	Sensory amplitudes affected; radial > sural
Nerve biopsy	Demyelination and remyelination	Axonal degeneration and regeneration	Axonal degeneration but no regeneration
Prognosis	Rapid recovery	Slow recovery	Poor recovery
Causes	GBS, diphtheria, CIDP, DM, MMN	Toxic, metabolic, HIV, CMT2, DM	Sjögren's, cisplatin, pyridoxine

Fibre Type Classification

		Symptoms
Small Fibre	Diabetic Alcohol (mixed) Amyloidosis HIV (and Rx) Sjogren’s Syndrome Sarcoidosis Uraemia Leprosy Fabry disease HSAN	Pain – para/dysesthesia Reduced pin prick and temperature
Large Fibre	Sjogren’s Syndrome B12 Cisplatin Pyridoxine toxicity Friedreich’s ataxia	Numbness Tingleing Poor balance Reduced vibration, proprioception, reflexes
Small and large	Carcinomatous Diabetic (late) Hereditary
Motor predominant	GBS CIDP CMT Diabetic (amyotrophy) Porphyria Lead Multifocal motor neuropathy Brachial neuritis	Cramps Twitching Reduced strength and reflexes
Autonomic	Botulism GBS Amiodarone Vincristine Amyloid DM	Dry mouth, erectile dysf, gastroparesis, diarrhoea, syncope Orthostasis, unequal pupils
Mixed motor and sensory	CMT Alcohol

Symptom Classification

Talley and O’Connor

Causes of a painful neuropathy

1. DM

2. Alcohol

3. Vitamin B12 or B1

4. Carcinoma

5. Porphyria

6. Arsenic or thallium poisoning

7. Hereditary (most are not painful)

Causes of a predominantly sensory neuropathy

1. Carcinoma

2. Paraproteinaemia

3. Vitamin B6 intoxication

4. Sjogren’s syndrome

5. DM

6. Syphilis

7. Vitamin B12 deficiency (occasionally)

8. Idiopahtic

Proprioception/Vibration loss only

• Consider myelopathy - posterior spinal cord syndrome (Spinal Cord Disease)

• Neuroapthy – Especially DM and hypothyroidism

Pain/temperature loss only

• Consider central cord syndrome

• Syringomyelia

• Anterior spinal artery thrombosis

• Peripheral neuropathy (especially DM, amyloid, Fabry’s)

• Unilateral

o Brown sequard

o Lateral medullary syndrome

Clinical Approach


What?	Sensory Motor Autonomic Combination
Where?	Length-dependent vs non-length dependent? Symmetry vs Asymmetrical
When?	Acute Subacute Chronic
What setting?	Medical history (DM, cancer, medications) Alcohol Family history Occupational exposures

Burns and Mauermann (Neurology Clinical Practice 2011)

Clinico-pathological Differential Diagnosis

Axonal sensorimotor (Most are predominantly sensory, motor predominant in bold)

Demyelinating sensorimotor

Small Fibre

Pure Sensory, Large Fibre, Ataxic Neuropathy

Motor Neuropathies

Autonomic

Mononeuritis Multiplex

Plexopathies

Polyradiculopathies

Polyneuropathy and Optic Neuropathy

Myeloneuropathies (Combined Myelopathy and Polyneuropathy)

Neuromyopathies (Combined Myopathy and polyneuropathy)


Axonal sensorimotor (Most are predominantly sensory, motor predominant in bold)
	Full list of causes	Common Causes	First line tests	Second line tests
Chronic	Metabolic · DM, uraemia, hypothyroidism, acromegaly, hepatic failure, hypoglycaemia/hyperinsulinaemia Nutritional · B12, Folate, Thiamine, vitamin E, copper, bariatric surgery Vascular · Vasculitis · Chronic hypoxia, polycythemia Neoplastic (infiltrative) · Leukaemia/lymphoma, Multiple myeloma, NF 1 and 2 Paraneoplastic · Various Infectious · HIV, HTLV-1, HCV, Whipple Toxic · Alcohol, Nitrous oxide Immune · Sjogren, SLE, RA, scleroderma, MCTD, Coeliac, primary biliary cirrhosis, hypereosinophic syndrome Paraprotein · MGUS, amyloidosis, Waldenstrom, cryoglobulinaemia Hereditary · CMT2, abetalipoproteinaemia, neuroacanthocytosis, adult onset Tay-Sachs	DM Alcohol B12 MGUS- associated Uraemia Hypothyroidism Thiamine	BSL, HbA1C B12 SPEP Electrolytes TSH Thiamine FBC	CXR ANA, ENA ANCA ACE Anti-neuronal antibodies Coeliac serology HIV HCV Lyme serology HTLV-1 Cryoglobulins Copper Vitamin E Vitamin B6 Salivary gland biopsy Fat pad biopsy Genetic: CMT2 testing

Demyelinating sensorimotor
	Full list of causes	Common Causes	First line tests	Second line tests
Acute	GBS Diptheria Hypophosphataemia Toxic (meds): amiodarone, tacolimus, bortezomib, Anti-TNF-alpha GVHD Arsenic Hexane (Glue sniffing)
Chronic	Inflammatory · CIDP · CIDP associated with SLE, IBD, DM, HIV, HCV, HBV, GVHD, Anti-TNFalpha agents · MMN Paraprotein/haematological disorders · MGUS – IgM/anti-MAG · MGUS – IgG/IgA · POEMS/Osteosclerotic myeloma · Castleman disease · Waldenstrom’s · Cryoglobulinaemia, melanoma, lymphoma Hereditary/genetic · CMT1, CMT4, DSD/CHN, CMTX · Lysosomal leukodystrophies · Lipoprotein disorders (Tangier disease) · Familial amyloid · Cerebrotendinous xanthomatosis · Cockayne syndrome · Mitochondiral disorders · HNPP Other · Severe DM	CIDP (and variants) MMN HNPP CMT1 (DM)	SPEP CSF GM1 Abs HbA1C	HIV HBV HCV Malignancy work-up Skeletal survey ANA PMP22 genetic testing Nerve biopsy

Small Fibre
	Causes	Common	First line tests	Second line tests
	Idiopathic Endocrine/Metabolic · B12, Hypothyroidism, DM Infection · HCV · HIV Immune · Sjrogens, SLE · Paraneoplastic · Sarcoidosis · Vasculitis Genetic/hereditary · Fabry disease · Tangier Disease · HSAN Paraprotein · MM, cryoglobulinaemia Toxic · Arsenic, thallium, nucleoside analogues, chemotherapy	Idiopathic DM Amyloidosis Alcoholic HIV Sjrogens SLE	BSL, HbA1C SPEP HIV serology ANA, ENA Electrolytes TSH FBC B12	Lipid profile Coeliac serology ACE Paraneoplastic (Anti-Hu) Cryoglobulins HCV Alpha-galactosidase Skin biopsy Fad-pad biopsy Salivary gland biopsy
Pure Sensory, Large Fibre, Ataxic Neuropathy
	Causes	Common	First line tests	Second line tests
Sensory neuronopathy	· Sjrogens · Paraneoplastic · Idiopathic · Toxic: Pyridoxine excess, cisplatin, thalidomide, linezolid, metronidazole, taxanes · HIV · EBV		ANA, ENA Anti-neuronal Ab’s Vit B6 HIV
Demyelinating	· Acute: o Ataxic GBS o Fisher Syndrome o Diptheria · Chronic: o Sensory CIDP o Anti-MAG/IgM MGUS o CANOMAD o CISP		Anti-MAG SPEP Anti-Gq1b
Misc.	· Tabes dorsalis · Coeliac · HTLV-1 or 2 · Vitamin B12, B1, E · Anti-sulfatide antibodies		Syphilis Coeliac serology B12 Thiamine	HTLV Vitamin E
Motor Neuropathies
	Causes	Common	First line tests	Second line tests
Axonal	Acute/subacute: · GBS - AMAN · Porphyria · Toxic: lead, dapsone, amiodarone, vincristine Chronic: · Distal hereditary motor neuropathies · CMT2		CSF Porphyrins Heavy metals Genetic testing
Demyelinating	· GBS-AIDP · MMN · CIDP · CMT1 and CMT 4 · Toxic: amiodarone		CSF Anti-GM1 Genetic testing
Autonomic
	Causes	Common	First line tests	Second line tests
	Acute/subacute: · GBS · Paraneoplastic · Autoimmune autonomic ganglionopathy (ganglionic AchR antibodies) · Sonnective tissue diseases · Post-viral Chronic · DM · Amyloidosis · Hereditary o HSANs Porphyria, Fabry · Infectious o HIV, leprosy, diphtheria, Chagas · Toxic o Vincristine, heavy metals, alcohol	DM	BSL, HbA1C	CSF Anti-neuronal antibodies ANA, ENA SPEP HIV Heavy metals
Mononeuritis Multiplex
Sensory and motor Axonal	Vasculitis Sarcoidosis Infections (HIV, HCV, HBV, CMV) Neoplastic Coeliac Diabetes
Sensory and motor Demyelinating	HNPP CIDP (MADSAM GBS/AIDP Tangier disease
Motor Demyelinating	MMN
Motor axonal	Multifocal acquired motor axonopathy (MAMA)
Sensory axonal	Wartenberg migrant sensory neuropathy Sensory perineuritis
Plexopathies
Brachial	Immune brachial plexus neuropathy (neuralgic amyotrophy) Hereditary neuralgia amyotrophy HNPP Thoracic Outlet syndrome Diabetic Trauma
Lumbosacral	Diabetic Retroperitneal haematoma Psoas abscess Perioperative (hip or obstetric surgery)
Either	Neoplasm Radiation Infection (Lyme, herpes, ehrlichiosis) Immune (Sarcoid, CTDs) Vasculitiss Toxic (heroin) Amyloidosis
Polyradiculopathies
Inflammatory/Infectious	Lyme Herpes zoster EBV HIV Sarcoidosis Diabetic radiculoplexus neuropathy CISP CTDs
Structural/ischaemic	Spinal stenosis Large herniated disc Arachnoiditis Epidural lipomatosis Radiation Dural AVM Meningeaal carcinomatosis Neoplasms NF
Polyneuropathy and Optic Neuropathy
	· B12 · Copper def · Thiamine def · Tobacco-alcohol amblyopia · Cyanide · Hereditary o CMT2, HMNS-VI, LHON · Toxic: Amiodarone, chloramphenicol, chloroquine, disulfiram, ethambutol, isoniazid, linezolid, penicillamine, vincristine
Myeloneuropathies (Combined Myelopathy and Polyneuropathy)
	Vitamins · B12, copper, vitamin E, folate Toxic · Nitrous oxide, organophosphates Inflammatory · CTD Infections · HTLV1, HIV, Lyme Hereditary · Adrenomyeloneuropathy, HSP subtypes · CMT2A/HMSN-V, CMT2H, CMT2D, SCA subtypes
Neuromyopathies (Combined Myopathy and polyneuropathy)
	· Uraemia · Sarcoid · Amyloidosis · Paraneoplastic · CTD · Acromegaly · HIV, HTLV1, Lyme · Critical illness myopathy, neuropathy · Mitochondrial disorders · Inclusion body myositis · Adult polyglucosan body disease · Toxic: colchicine, chloroquine, amiodarone, L-tryptophan, vincristine

Mononeuroapthy

• Numerous individual nerve syndromes (see Mononeuropathies)

Mononeuropathy (Mononeuritis) Multiplex

• Multifocal involvement of multiple individual peripheral nerves

• If the cause is inflammatory the term mononeuritis is used

• Vasculitis is a common cause

• Acute

o DM

o Vasculitis

• Chronic

o Multiple compressive neuroapthies

o Sarcoidosis

o Acromegaly

o Leprosy

o Lyme disease

o Carcinoma

o Idiopathic

Polyneuropathies

Widespread, symmetric dysfunction of the peripheral nerves

Causes

• Diabetic

• Toxic

• Nutritional

• Infections

• Inherited

• Neoplastic

• Critical illness neuropathy

OR AD VINDICATES:

• Alcohol

• Diabetes

• Vitamins (B12, B6, B1)

• Infections (HIV, leprosy)

• Neoplastic (MM, carcinoma)

• Drugs - inc. chemotherapy (Cisplatin, thalidomide)

• Inherited (CMT)

• CIDP/ Critical Illness/ CLD

• Amyloidosis (and Autoimmune)

• Toxic (Uraemia, heavy metals (lead))

• Endocrine (Hypothyroidism, acromegaly)

• Sarcoidosis

DRUGS (see below)

C4 T(o) B(low) up CAP

· Chemotherapy

1. Platinums

2. Vincristine

3. Taxanes

4. Thalidomide

· TB meds

o Ethambutol

o Isoniazid

· Colchicine

· Amiodarone

· Phyenytoin

Diabetic neuropathies (see complications of DM)

Toxic neuropathies

• Axonopathy

o Toxins

- Lead

- Mercury

o Drugs

- Colchicine

- Dapsone (motor)

- Ethambutol

- Isoniazid

- Pyridoxine

- Taxol

- Thalidomide

- Vincristine

- Bortezomib

• Myelinopathy

o Amiodarone

o Perhexiline

• Sensory Neuronopathy

o Platinum compounds

o Taxol

Nutritional Neuropathies

• Thiamine

• Pyridoxine

• Vitamin B12

• Vitamin E

Infections

• HIV

• HIV treatment

• Lymre disease

• Herpes

• Leprous neuritis

Inherited

Charcot-Marie-Tooth Disease

• Also called

• Hereditary Motor and Sensory Neuropathy

• (Peroneal muscular atrophy )

• Chronic distal sensory and motor neuropathy

• Most common heritable neuromuscular disorder (10 to 40/100,000 or 1/2500)

• Caused by mutations in >24 specific genes each with a specific phenotype

• Most genes are involved in Schwann cell function or myelination

• Generally early age of onset up to 20 years (however subtypes present later)

• Mostly AD transmission

CMT Type 1

• Demyelinating

• 5 types (CMT1A – CMT1E) based on genetics

• Type 1A most common (70-80%)– due to duplication of PMP22 gene

Clinical

• Onset often first or second decade

• Slowly progressive weakness, wasting and sensory impairment, predominantly involving the distal legs

• Weakness of – intrinsic foot, peroneal and anterior tibial

• Foot deformities (due to imbalance between intrinsic and long extensors):

o Hammer toes

o High arched feet (pes cavus)

• Loss of ankle reflexes in all patients (knee and upper limb reflexes variably involved)

• In 2/3 patients the upper limbs become involved in later life

• Palpably enlarged nerves in 25%

• Mild Kyphosis in 10%

• Can be significant worsening during pregnancy (?Effect of progesterone)

• Some patients have an upper limb tremor (Roussy-Levy Syndrome)

· Type 2 - (30%) – largely axonal

Investigations

• NCS

• Slow CV in all nerves (<75% of LLN)

• Slowing in upper extremities in most cases – CV <38m/s

• CMT1A CV usually 20-25ms

• CMT1B CV usually 15ms/ or less

• Generally low or absent SNAPs

• Biopsy

• Hypertrophic neuropathy - onion bulb formation, increased frequency of fibers with demyelinated and remyelinated segments, an increase in endoneurial area, and loss of large myelinated fibers

DDX:

CIDP – is a major differential diagnosis – factors that help differentiate include asymmetric pattern and raised protein in CSF

Prognosis/Natural history

• Most slowing evolves during first 3-5 years and then minimal change

• The degree of slowing has poor correlation with disability

CMT Type 2

Axonal injury

Clinical features

• Later onset than type 1 – usually teenage years – but can be later into middle life.

• Similar to type 1 however in general less severe.

• 20% of patients with mutations are asymptomatic

Investigations

Biopsy

• preferential loss of large myelinated fibers, without

significant demyelination

Other types of CMT

X-Linked CMT (CMTX)

7-16% of CMT

Similar to CMT1

Males severely affected

Female carriers often have very mild disease

Need to caution about travelling to high altitude as has been associated with worsening

CMT Type 3

Rare

Most cases are sporadic, some AR

Severe neuropathy often associated with severe weakness and disability.

Severe slowing and demyelination

High CSF protein

CMT Type 4

Multiple forms, all autosomal recessive

Onset in early childhood

Often associated with other congenital abnormalities

Severe slowing consistent with demyelination

Clinical features

· Wasting and weakness of the distal muscles of the legs (inverted champagne bottle legs)

· Deformities

o Hammer toes

o High arched feet (pes cavus)

· Distal sensory loss

o Both pain and vibration sense

o Often mild with minimal symptoms

· Loss of reflexes

o Universally at ankles and to a lesser extent elsewhere

· Tremor may occur in 10%

Investigations

Nerve conduction studies

· Type I

o Decreased velocities in both motor and sensory

· Type II

o Velocities are near normal

Nerve biopsy- sural nerve

· Can help confirm diagnosis

CSF

· May be helpful to help exclude CIDP which is major differential

Management

Ascorbic acid and anti-progesterones have been trialled but were not effective.

Avoid worsening of neuropathy

Avoid medications that can cause neuropathy

Moderate alcohol

Prompt treatment of diabetes

Physiotherapy

Strengthening, posture and balance excercises

Orthoses to support foot

Pain management

Neuropathic pain management

Treat resultant joint and muscle pain

Surgical treatment

Osteotomy, arthrodesis, plantar fascia release

Genetic counselling

Hereditary Neuropathy with Liability to Pressure Palsy

· A form of CMT disease

· Recurrent episodes of focal entrapment neuropathy

· Peroneal, ulnar, radial and median

· Associated with specific genetic abnormality