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?
Eight Patterns of Neuropathies 1.
Symmetric proximal and distal weakness with sensory loss (GBS)
Symmetric distal weakness with sensory loss (metabolic, drugs, toxins, amyloid, hereditary)
Asymmetric distal weakness with sensory loss (vasculitis, leprosy, Lyme sarcoid, HIV, compressive mononeuropathy)
Asymmetric distal weakness without sensory loss (ALS, MMN)
Asymmetric proximal and distal weakness with sensory loss (polyradiculopathy and plexopathy due to DM, meningeal carcinomatosis, idiopathic)
Symmetric sensory loss without weakness (cryptogenic sensory polyneuropathy, metabolic, drugs, toxins)
Asymmetric proprioceptive sensory loss without weakness (sensory neuronoapthy - ganglionopathy)
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
Neuropathies – Traditional classification Sensory Neuronopathy (ganglionopathy) Target: sensory nerve cell bodies in the dorsal root and trigeminal ganglia
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)
Node of Ranvier Myelin
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.
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,
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.
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.
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
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)
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
PMP22 duplication; 70%-80%
Myelin P0 protein 5%-10%
Lipopolysaccharide-induced tumor necrosis factor-alpha factor
Early growth response protein 2
PMP22 point mutations; less than 5%
Neurofilament light polypeptide
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%
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
Distal acquired demyelinating symmetric (MAG)
Lewis– Sumner syndrome
Weakness and sensory loss
Symmetric, distal and proximal (legs>arms)
Symmetric, mild distal (legs>arms)
Asymmetric, mostly distal, pain, Tinel’s (arms>legs)
Pure motor, asymmetric, mostly distal (arms>legs)
Symmetric, distal and proximal (legs>arms) Painful feet M>S
Lambda light chain
Uncommon (MGUS, MM, WM Connective tissue disease …)
Osteosclerotic myeloma Organomegaly Endocrinopathy Skin changes edema, ascites
Demyelination, more uniform slowing, greater axonal loss in LE, higher terminal latency index
Prednisone, IVIG, PLEX, immunosuppressants
IVIG Immunosuppressants Prednisone
Stem cell, dexamethasone Melphalan, Lenalidomide , Thalidomide, Bortezomib, anti-VEGF antibody (bevacizumab)
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
Prog. Weakness of >1 limb Areflexia