Classification of Peripheral Nerve Disease Mononeuropathy Plexopathy Brachial plexopathy Lumbar plexopathy Sacral plexopathy

Radiculopathy Cervical radiculopathy Thoracic radiculopathy Lumbosacral radiculopathy

Multiple mononeuropathy (mononeuritis multiplex) Polyneuropathy Symmetrical polyneuropathy Asymmetrical polyneuropathy?

Polyradiculoneuropathy

Eight Patterns of Neuropathies 1.

Symmetric proximal and distal weakness with sensory loss (GBS)

2.

Symmetric distal weakness with sensory loss (metabolic, drugs, toxins, amyloid, hereditary)

3.

Asymmetric distal weakness with sensory loss (vasculitis, leprosy, Lyme sarcoid, HIV, compressive mononeuropathy)

4.

Asymmetric distal weakness without sensory loss (ALS, MMN)

5.

Asymmetric proximal and distal weakness with sensory loss (polyradiculopathy and plexopathy due to DM, meningeal carcinomatosis, idiopathic)

6.

Symmetric sensory loss without weakness (cryptogenic sensory polyneuropathy, metabolic, drugs, toxins)

7.

Asymmetric proprioceptive sensory loss without weakness (sensory neuronoapthy - ganglionopathy)

8.

Autonomic symptoms and signs

Etiology of Acquired Polyneuropathies •

Dysmetabolic –Diabetes mellitus –Renal disease, liver disease –Vitamin deficiencies (B1, B2, B6, FA, B12) –B6 toxicity –Primary amyloidosis

•

Immune-mediated –GBS –CIDP –Vasculitis –Connective tissue disease –Monoclonal gammopathies , MGUS, MAG, GM1 … –Plexitis (brachial, lumbosacral)

•

Infectious –Herpes zoster –Leprosy, Lyme, HIV, sarcoidosis

•

Cancer related –lymphoma, myeloma, carcinoma related,

• •

Drugs or toxins Unknown etiology –cryptogenic sensory and sensorimotor

Neuronopathy

Myelinopathy

Axonopathy dying-back

Neuropathies – Traditional classification Sensory Neuronopathy (ganglionopathy) Target: sensory nerve cell bodies in the dorsal root and trigeminal ganglia

Neuronopathy

Segmental demyelination (myelinopathy)

Axonal degeneration (axonopathy)

Target: myelin sheaths or Schwann cells Remyelination of demyelinated segments thinner-than-normal myelin sheaths and internodes of shortened length. Repeated episodes of demyelination and remyelination produce proliferation of multiple layers of Schwann cells around the axon, termed an onion bulb.

Target: distal axonal breakdown and progresses toward the nerve cell body, (dying-back or length-dependent polyneuropathy)

Myelinopathy

Axonopathy dying-back

Axonal

Advanced axonal

Demyelinating

Mononeuritis multiplex

Node of Ranvier Myelin

Axon Paranode

Node

Paranode

Juxtaparanode

Internode

The nodal axolemma and the paranode can be the focus of the nerve injury, these immune mediated neuropathies could be more properly classified as nodo-paranodopathies.

nodo-paranodopathies

The nodes can be exclusively damaged by autoimmune processes, resulting in development of neuropathies. Dysfunction and disruption of the nodal region are common mechanisms in acute (and possibly chronic) neuropathies associated with antibodies to GM1, GD1a and GD1b. The common mechanism explains the spectrum of severity ranging from reversible conduction failure ( RCF) with prompt recovery to axonal degeneration with poorer outcome in the different neuropathies and some features of the continuum between AMAN and AMSAN.

Nodo-paranodopathies (neuropathies associated with antibodies to gangliosides)

GM1 GD1a AMAN IgG IgG AMSAN IgG IgG ASAN PCB FS MMN IgM Autoantibodies

AMAN, AMSAN, ASAN, PCB, FS, MMN,

GT1a

GQ1b GD1b

IgG IgG IgG

acute motor axonal neuropathy; acute motor-sensory axonal neuropathy; acute sensory ataxic neuropathy; pharyngeal-cervical-brachial weakness; Fisher syndrome; multifocal motor neuropathy.

IgG

EDX in polyneuropathy Collective results of nerve conduction studies and electromyography are useful in defining the polyneuropathy. EDX of a polyneuropathy requires both motor and sensory conduction studies of multiple nerves in upper and lower extremities bilaterally combined with needle EMG. EDX to demonstrate the characteristic symmetry of abnormality.

Polyneuropathy EDX protocol

NCV 1. To test most involved site when mild or moderate, least involved if severe. 2. Peroneal motor (EDB); stimulate at ankle, fibular head and knee. If abnormal or no responses: Peroneal motor (TA); stimulate at fibular head and knee. 3. Tibial motor (AH); stimulate at ankle and knee. 4. Ulnar motor (hypothenar); stimulate at wrist, elbow, above elbow, axilla and Erb’s point. 5. Median motor (thenar); stimulate at wrist, elbow, above elbow, axilla and Erb’s point. 6. F responses. 7. SNAP (sural , superficial peroneal, median, ulnar, radial nerve amplitude and conduction velocity). 8. Evaluation of opposite extremity. 9. Evaluation of specific suspected abnormality. 10. If prominent cranial involvement: Facial CMAP, Blink reflex studies

Needle EMG Examination TA, GA, EHL, FDI, paraspinal muscles. Intrinsic foot muscles can be considered. Abnormalities should be confirmed by examination of at least one contralateral muscle.

Demyelinating polyneuropathies

A. Uniform demyelination B. Segmental demyelination

Uniform demyelinating, mixed sensorimotor polyneuropathy CMT 1A CMT 1B DSD Metachromatic leukodystrophy Krabbe’s globoid leukodystrophy Adrenomyeloneuropathy Congenital hypomyelinating neuropathy Tangier disease’ Cockayne’s syndrome Cerebrotendinous xanthomatosis

Segmental demyelinating, motor > sensory polyneuropathy AIDP CIDP MMN POEMS MGUS NHPP CMTX1 Adrenomyeloneuropathy Refsum Diphtheria Acute arsenic polyneuropathy Pharmaceuticals Amiodarone Perhexiline High dose Ara-C Lymphoma Carcinoma Lyme disease Acromegaly Systemic lupus erythematosus Glue sniffing neuropathy Cryoglobulinemia

Axonal loss, motor > sensory polyneuropathy Porphyria Axonal Guillain- Barré syndrome CMT2 CMT4 (some) Lead neuropathy Dapsone neuropathy Vincristine neuropathy

Axonal loss sensory neuronopathy or neuropathy

HSAN types I- V Friedreich's ataxia Spinocerebellar degeneration. Abetalipoproteinemia Primary biliary cirrhosis Acute sensory neuronopathy Cisplatinum toxicity Paraneoplastic sensory neuronopathy Chronic idiopathic ataxic neuropathy Sjogren's syndrome Fisher variant GBS Paraproteinemias Pyridoxine toxicity Idiopathic sensory neuronopathy Styrene-induced peripheral neuropathy Crohn's disease Thalidomide Nonsystemic vasculitic neuropathy Chronic gluten enteropathy Vitamin E deficiency.

Axon loss, mixed sensorimotor polyneuropathy Amyloidosis Chronic liver disease Nutritional diseases Vitamin B12 deficiency Folate deficiency Whipple’s disease Post-gastrectomy syndrome Gastric restriction surgery for obesity Thiamine deficiency Alcoholism Sarcoidosis Connective tissue diseases Toxic neuropathy

Mixed axon loss and demyelinating sensorimotor polyneuropathy

Diabetes mellitus

Uremia

Classification of Diabetic Neuropathies Generalized Symmetrical Polyneuropathies Distal sensory or sensorimotor polyneuropathy Small-fiber neuropathy Autonomic neuropathy Large-fiber sensory neuropathy Focal and Asymmetrical Neuropathies Cranial neuropathy (single or multiple) Truncal neuropathy (thoracic radiculopathy) Limb mononeuropathy (single or multiple) Proximal motor neuropathy (radiculoplexopathy, amyotrophy) Combinations Polyradiculoneuropathy Diabetic neuropathic cachexia

Acquired (segmental) vs Hereditary (uniform)

47 m/s

30 m/s

43 m/s 5 mV

CIDP produces variable conduction velocities between fibers with observed dispersion and conduction block.

Molecular Genetics of Charcot-Marie-Tooth Type 1

Gene Symbol

Chromosomal Locus

Protein Name

CMT1A

PMP22

17p11.2

PMP22 duplication; 70%-80%

CMT1B

MPZ

1q22

Myelin P0 protein 5%-10%

CMT1C

LITAF

16p13.3-p12

Lipopolysaccharide-induced tumor necrosis factor-alpha factor

CMT1D

EGR2

10q21.1-q22.1

Early growth response protein 2

CMT1E

PMP22

17p11.2

PMP22 point mutations; less than 5%

CMT1F

NEFL

8p21

Neurofilament light polypeptide

Locus Name

Electrodiagnostic findings suggestive of demyelination

1. Conduction block 2. Conduction velocity slowing greater than can be explained by axonal loss A. Prolonged distal motor latencies B. Slow conduction velocity Motor conduction slowing 80% 80% 80% 120% >150%

Median

48

38.4

33.6

4.5

5.6

6.7

31.0

37.2

46.5

Ulnar

48

38.4

33.6

3.6

4.5

5.4

32.0

38.4

48.0

Peroneal

42.0

33.6

29.4

6.6

8.2

9.9

56.0

67.2

84.0

Tibial

42.0

33.6

29.4

6.6

8.2

9.9

58.0

69.6

87.0

CIDP with concurrent disorders • • • • • • • • • • • • • • • • •

MGUS (5% polyneuropathy) Multiple myeloma (3:100,000/ year) Plasmacytoma Waldenström’s macroglobulinemia (5% polyneuropathy, IgM  chain in 80%) POEMS HIV Chronic Active hepatitis Inflammatory bowel disease Connective tissue disease Bone marrow and organ transplants Lymphoma Hereditary neuropathy Diabetes mellitus Thyrotoxicosis Nephrotic syndrome CNS demyelination Seminoma

Chronic Inflammatory Demyelinating Neuropathies: Clinical features

CIDP

Distal acquired demyelinating symmetric (MAG)

Lewis– Sumner syndrome

MMN

POEMS

Weakness and sensory loss

Symmetric, distal and proximal (legs>arms)

Symmetric, mild distal (legs>arms)

Asymmetric, mostly distal, pain, Tinel’s (arms>legs)

M>S

S>M

Pure motor, asymmetric, mostly distal (arms>legs)

Symmetric, distal and proximal (legs>arms) Painful feet M>S

CSF protein

Elevated

Elevated

Elevated

No

Elevated

M protein

Uncommon

IgM

Uncommon

Uncommon

Lambda light chain

Antineural antibodies

Uncommon

Anti MAG

Uncommon

Anti GM1

Systemic

Uncommon (MGUS, MM, WM Connective tissue disease …)

No

No

No

Osteosclerotic myeloma Organomegaly Endocrinopathy Skin changes edema, ascites

Motor NCV

Demyelination

Demyelination

Demyelination

Demyelination

Demyelination, more uniform slowing, greater axonal loss in LE, higher terminal latency index

Sensory NCV

Abnormal

Abnormal

Abnormal

Normal

Abnormal

Treatment

Prednisone, IVIG, PLEX, immunosuppressants

?Rituxan ?IVIG

IVIG Immunosuppressants Prednisone

IVIG ?cyclophosphamide

Stem cell, dexamethasone Melphalan, Lenalidomide , Thalidomide, Bortezomib, anti-VEGF antibody (bevacizumab)

VEGF

Classification of Guillain-Barré syndrome and typical antiganglioside antibodies

Clinical variants - Acute inflammatory demyelinating polyradiculoneuropathy (AIDP) - Acute motor and sensory axonal neuropathy (AMSAN) - Acute motor axonal neuropathy (AMAN) - Acute motor conduction block neuropathy (AMCBN) - Acute sensory neuronopathy - Acute pandysautonomia - Regional variants Fisher’s syndrome Oropharyngeal –cervical-brachial - Overlap Fisher’s syndrome/ GBS overlap syndrome

Antibodies Unknown GM1, GM1b, GD1a GM1, GM1b, GD1a, GalNac-GD1a GD1b

GQ1b, GT1a GT1a GQ1b, GM1, GM1b, GD1a,

GBS - GBS is a rare but important disease that can lead to life threatening respiratory failure

- Structural similarities between a triggering infectious organism and peripheral nerve tissue are important in its pathogenesis - Treatment consists of rapid administration of intravenous immunoglobulin or plasma exchange, which shortens the time to recovery

- Around 10% of patients die from respiratory failure, pulmonary emboli, or infection - Around 20% of patients have residual disability, with weakness or persistent sensory disturbance - GBS should be considered in any patient developing rapidly progressive limb weakness - Absent reflexes are a “red flag” for GBS in patients with rapidly progressive weakness - Patients with suspected GBS should be referred to hospital as an emergency - A history of weakness preceded by respiratory or GI infection suggests GBS

Diagnostic criteria for GBS Required

Supportive

Doubtful

Prog. Weakness of >1 limb Areflexia

Progression