Peripheral nervous system pathology

General informations about anatomy, physyology and pathology of the peripheral nervous system

Polineuropathies (general features, genetic neuropathies, diabethic neuropathy, diagnosis and avaluation of the peripheral nervous system

Guillain Barre syndrome (poliradiculoneuritis)

Lumbar, sacrate and coccigeal plexus

Neuron

Motor neuron: functional unit of the neuromuscular system

Consist of Lower motor neuron (anterior horn-spinal cord; cranial nerve motor nucleus-brain stem)Axon of that neuron

Multiple muscle fibers it innervates

Neuron-to-muscle-fiber ratio:

• Muscles with highly refined movements (extrinsic muscles of the eye) (1:10)

• Coarse and stereotyped movements (calf muscles) (1:1800)

Transmiterea informaţiei – depolarizare, potenţial de acţiune

Canale de sodiu

Canal de potasiu Canal de calciu

Sinapsele pot fi localizate oriunde – la nivelul dendritelor (1), corpului celular (2), axonului (3) sau terminatiilor axonale (4)

Synapse

Sinapsa

Normal peripheral nerve

Nerve fiber: principal structural component of peripheral nerve;

Composed of:• Axon • With its Schwann cells and

myelin sheath A nerve consists of numerous

fibers that are grouped into fasciclesMyelinated and unmyelinated

nerve fibers are intermingled within the fascicle

Three major connective tissue components of peripheral nerve

• Epineurium (encloses the entire nerve)• Perineurium (encloses each fascicle)• Endoneurium (surrounds individual nerve fibers)

colagen

fibră nemielinizată

fibră mielinizată

elastinămacrofag

capilarneutrofil

fibroblast

mastocit

limfocit

substanţă de bază

• Peripheral axons contain organelles and cytoskeletal structures (microfilaments, neurofilaments etc)

• Protein synthesis does not occur in the axon

• Axoplasmic flow (anterograde) delivers proteins and other substances synthesized in the perikaryon down the axon

• Retrograde transport system serves as a feedback system for the cell body.

Myelinated fiber in sural nerve (most commonly examined by biopsy)2 to 16 µm in diameterSmaller axons

• Average 4 µm• Twice as numerous as the larger axons

Axons are myelinated in segments (internodes) separated by nodes of Ranvier

A single Schwann cell supplies the myelin sheath for each internode

Unmyelinated axons

Far more numerous than myelinated axonsRange in size from 0.2 to 3 µmEnveloped by Schwann cell cytoplasm (5 to 20 axons in humans)The Schwann cells

• Pale oval nuclei• Elongated bipolar cell body

Myelin is composed of lipids and proteins

PathologyPathology

Two main responses of peripheral nerve to injury:

• Diseases that affect primarily the Schwann cell - segmental demyelination

• Involvement of the neuron and its axon leads to axonal degeneration May be followed by axonal regeneration and

reinnervation of muscle

Two principal pathologic processes seen in skeletal muscle

Denervation atrophy, which follows loss of axonsMyopathy primary abnormality of the muscle fiber itself

General Reactions of the Motor Unit

SEGMENTAL DEMYELINATION

Occurs • Dysfunction of the Schwann cell (as in

Guillain-Barré Syndrome) • Damage to the myelin sheath (e.g., in

hereditary motor and sensory neuropathy)Random and multifocal The denuded axon provides a stimulus for remyelinationNewly myelinated internodes are shorter than normal with thin myelin sheath

Onion bulbs:

Thinly myelinated axon surrounded by concentrically arranged Schwann cellsThe result of demyelination and remyelination (chronic demyelinating neuropathies)

AXONAL DEGENERATION AND MUSCLE FIBER ATROPHY

Axonal degeneration is the result of primary destruction of the axon, with secondary disintegration of its myelin sheath.

May be Focal (such as trauma or ischemia) More generalized abnormality affecting

• The neuron cell body (neuronopathy) or • Axon (axonopathy)

Wallerian degeneration

Much more prominent after focal injuryThe distal part of the axon will initially degenerateSprouting axonal branches from the proximal part (axonal regeneration 1mm/day) Reestablishing contact with the muscle fibers

With axonal degeneration there is denervation atrophy of the muscle fibers within the affected motor unit

The atrophic fibers are smaller than normal and have a roughly triangular shape ("angulated").

Rounded zone of disorganized filaments in the center of the fiber (target fiber) –due to cytoskeletal reorganization

Reinnervation of atrophic muscle fiber:

From neighboring motor unitIncreased muscle fibers per motor unit

Peripheral nervous system

Disorders of the Peripheral Nervous System

PolineuropathiesDiabetic neuropathyEvaluation of peripheral neuropathiesPoliradiculoneuritisLumbar and sacrate plexus

Peripheral Neuropathy

Any disease of the peripheral nerves of any cause Polyneuropathy – distal symmetric distribution Mononeuropathy Multiplex – multifocal random Mononeuropathy – single nerve involvement

Polyneuropathy

Pathologic involvement of peripheral nerves usually due to acquired toxic and metabolic states

Manifestations: Distribution – distal symmetrical (glove-

stocking distribution) First symptoms tend to be sensory loss or

dysfunction (dysesthesias) Signs and symptoms of lower motor neuron

disease (decreased DTRs, atrophy, weakness)

Polyneuropathy

Vary in: Rate of disease evolution Degree of severity Small fiber vs. large fiber involvement

Small fiber symptoms : pain and temperature disturbances (numbness, painful paresthesias)

Large fiber symptoms and signs : weakness, areflexia, sensory ataxia or loss of position and vibration sense

Axonal vs. demyelinating

Common Causes of Polyneuropathy

Diabetes mellitus Uremia Vit. B deficiency Critical illness Hypothyroidism Carcinomas HIV

Common Causes of polyneuropathy

Drugs Amiodarone Antineoplastics

(cisplatin, vincristine) Dapsone Hydralazine Isoniazid Pyridoxine Phenytoin Metronidazole

Toxins Arsenic Diphtheria Toxin Inorganic lead Organophosphates Thallium

Clinical picture

Motor Sensory Trophic

Pathogenical Classification of polyneuropathy:

demielinating axonal mixt (diabetes, alcohol)

Classification of polyneuropathy: Axonal

Acute – relatively uncommon Massive intoxications – arsenic

Subacute – metabolic/toxic Chronic – 6 months- years

Hereditary neuropathies – slow course, absence of positive symptoms, mainly motor, absence of systemic disorder Most are autosomal dominant but some are also autosomal

recessive Metabolic/toxic

Classification of polyneuropathy : Demyelinating

Acute – Guillain-Barre Syndrome (GBS) Subacute – all are acquired

Relapsing-remitting neuropathy (toxic)

Chronic – Hereditary Inflammatory -CIDP Toxic Metabolic

Polyneuropathies

Genetic NeuropathiesMost common is Hereditary motor

sensory neuropathy I and II – autosomal dominant peroneal muscular atrophy

Polyneuropathies

Acquired demyelinating Acute : GBS – monophasic Chronic : CIDP – slowly progressive or

relapsing May be treated with steroids, plasmapheresis and

immunosuppressants

Polyneuropathies

Diabetic Polyneuropathy Due to long standing

hyperglycemia May take almost any form

Polyneuropathies

Neuropathies of dysproteinemia Multiple myeloma –especially of the osteosclerotic type Benign monoclonal gammopathy

Infectious: Lyme disease, lepper Neuropathies of HIV infection

Depends on the stage of the disease GBS or CIDP- following seroconversion (asymptomatic) Subacute to chronic mononeuritis multiplex (symptomatic) Late symptomatic –distal symmetric sensory polyneuropathy or

asymmetric painful polyradiculopathy involving the cauda equina caused by CMV

Polyneuropathies

Autonomic neuropathies Usually part of the more generalized polyneuropathy Symptoms usually negative (postural hypotension,

faintness, anhidrosis, hypothermia, bladder atony, obstipation, sexual impotence, dry eyes and mouth)

Positive symptoms include paroxysmal tachycardia, hypertension, diarrhea, hyperhidrosis

Polyneuropathies

Plexopathies Causes:

Trauma Cervical rib band Malignant tumor infiltration Radiation Idiopathic

Upper brachial plexopathy: weakness, atrophy and pain in the shoulder girdle and arm

Lower brachial plexopathy: weakness, atrophy and sensory loss or pain in the distal arm and hand

Recovery

The PNS has an excellent ability to regenerate

2 months to years Depends on the nature of neuropathy

(axonal vs demyelinating) Depends on whether the cause of the

neuropathy has been eliminated

Treatment

Ethiological Symptomatic

pain – carbamazepine, phenitoin, gabapentin, pregabalin, triciclic antidepressants

Muscle cramps – baclofen (Lioresal), benzodiazepines in small doses

Cauzalgia –alfa lipoic acid, eventually haloperidol, levomepromazin

Nerve trophic substances (benfothiamine, alpha lipoic acid, B vitamins)

Mononeuritis multiplex

Simultaneous or sequential involvement of individual noncontiguous nerve trunks

Multifocal and random 1/3 demyelinating 2/3 axonal Causes :

Vasculitis - 50% (PAN, SLE, RA, mixed CTD) Infectious –leprosy Granulomatous disease Idiopathic

Ereditary neuropathies

Hereditary neuropathies

HMSN I – Charcot Marie-Tooth Most frequently encountered. AD Demielinating type of Charcot-Marie Tooth disease Peripheral nerve hipertrophy – “onion bulbs”

Starts between 5 and 20 years Motor deficit is more important in lower limbs:

steppage; pes escavatum. Sensory deficits are discrete. Autonomic damage (cold feet and legs, livedo reticularis, other trophic changes, pupilary abnormalities, heart rhytm abnormalities).

Essential tremor, OT reflexes are abolished, enlargement of peripheral nerves

Associated with optic atrophy – HMSN type VI Associated with retinitis pigmentosa – HMSN type

VII

HMSN I

Hereditary neuropathies

HMSN II –axonal type of CMT AD Debut 20-40 years old; no nerve hypertrophies.

HMSN III – Déjérine-Sottas AD or AR Hypo- de- and remielination; “onion bulb” aspect Starts at 1-10 years Developpment slowing; motor distal deficits and

atrophies; rapid sensory damage (parestesiae); peripheral nerve enlargement; kyphoscoliosis, nonreactive pupils and nistagmus, intelectual impairment

Quickly evolving

HMSN IV – Refsum disease AR; first symprtoms before 20 years; Segmental demielination, “onion bulb”

aspect, Retinită pigmentară, polineuropatie, ataxie

cerebeloasă, hipoacuzie, ihtioză, anosmie, cardiomiopatie, tulburări ale scheletului

Dozarea acidului fitanic Neuropatia ereditară sensibilă la

presiune (neuropatia tomaculară) AD; demielinizare segmentară; îngroşare

internodală în formă de cârnat Decadele 2-3 de viaţă, paralizii recurente de

nervi periferici după compresiuni Neuropatii ereditare senzitive şi

autonome Afectarea preferenţială a fibrelor subţiri

Hereditary neuropathies

Polineuropatia alcoolică

Degenerescenţă axonală (influenţa directă a alcoolului) cu demielinizare secundară (malnutriţie)

Debut insidios (săptămâni/luni); ocazional acut – zile Tulburări simpatico-motorii, senzaţie de arsură, durere la

compresiunea maselor musculare, crampe musculare, ataxia mersului, mononeuropatii

PolineuropathiesDiabetic neuropathyEvaluation of peripheral neuropathiesPoliradiculoneuritisLumbar and sacrate plexus

Diabetic Neuropathy· About 60-70% of people with diabetes

have mild to severe forms of nervous system damage,

· More than 60% of nontraumatic lower-limb amputations in the United States occur among people with diabetes.

Risk Factors Glucose control Duration of diabetes Damage to blood vessels Mechanical injury to nerves Autoimmune factors Genetic susceptibility Lifestyle factors – smoking, diet

Pathogenesis of Diabetic Neuropathy

Metabolic factors High blood glucose Advanced glycation end products Sorbitol Abnormal blood fat levels Oxydative stress

Ischemia Nerve fiber repair mechanisms Both axonal and demielinative pathologic

processes

Classification of Diabetic Neuropathy

Somatic neuropathy Symmetric polyneuropathy Polyradiculopathy Mononeuropathy

Autonomic neuropathy

Symmetric Polyneuropathy

Most common form of diabetic neuropathy

Affects distal lower extremities and hands (“stocking-glove” sensory loss)

Symptoms/Signs Pain Paresthesia/dysesthesia Loss of vibratory sensation Amyotrophy

Polyradiculopathy

Lumbar polyradiculopathy (diabetic amyotrophy)

Thigh pain followed by muscle weakness and atrophy

Thoracic polyradiculopathy Severe pain on one or both sides

of the abdomen, possibly in a band-like pattern

Diabetic neuropathic cachexia Polyradiculopathy + peripheral

neuropathy Associated with weight loss and

depression

Mononeuropathy Peripheral mononeuropathy

Single nerve damage due to compression or ischemia

Monophasic evolution Occurs in wrist (carpal tunnel syndrome),

elbow, or foot (unilateral foot drop) Mononevritis multiplex – random

involvement of several unrelated nerves

Cranial mononeuropathy Most frequently oculomotory

nerves ( III, VI şi IV), facial nerve, optic nerve (optic anterior ischemic neuropathy)

Diabetic oftalmoplegia Rare Rapid evolution (1-2 days),

with painful ophtalmoplegia

MononeuropathyMononeuropathy

Autonomic neuropathy

Affects the autonomic nerves controlling internal organs Peripheral Genitourinary Gastrointestinal Cardiovascular

Is classified as clinical or subclinical based on the presence or absence of symptoms

Autonomic neuropathy Cardiovasculary

Tachicardia, diminished tolerance for effort

Cardiac denervarvation Ortostatic hypotension

Gastrointestinal Esophageal dysfunction Gastroparesis diabetica Diarhea Constipation Incontinence

Urogenital Erectile dysfunction Retrograd ejaculation Cistopathy Neurological bladder

Neurovasculary Intolerance to heat Gustative sudation Dry skin

Metabolic and hypotalamic Unnoticed hypoglicemia Lack of response to

hypoglicemia Autonomic dysfunction in

connection to hypoglicemia Pupilary

Argyll-Robertson sign

Treatment

Strict glycemic control Intervention on pathogenic pathways:

Aldoz-reductase inhibitors –block the calea polyol pathway Alpha lipoic acid (600-800 mg/zi) Gamma linolenic acid NGF (possibly)

Preventing/improvement of symptoms: analgetics, antidepressants Tryciclic antidepressants, Gabapentin Pregabalin

Complications of Polyneuropathy

Ulcers Charcot arthropathy Dislocation and stress fractures Amputation - Risk factors include:

Peripheral neuropathy with loss of protective sensation

Altered biomechanics (with neuropathy) Evidence of increased pressure (callus) Peripheral vascular disease History of ulcers or amputation Severe nail pathology

Diabetic foot Joint and tegumentary lesions in patients with

neuropathy and/or peripheral vascular disease 40-60% of non traumatic amputations 30-50% of amputees will repeat the procedure for the

opposite limb during the next 1-3 years.

Motor neuropathy

- shape changess of foot- overcharging of pressure points- repeated microtrauma

Sensory neuropathy

- lack of pain- Not using the defense

mechanisms

Autonomic neuropathy

- altered skin reaction mechanisms

- Altered skin mycrocirculation

Ulcerations

PolineuropathiesDiabetic neuropathy

Evaluation of peripheral neuropathiesPoliradiculoneuritisLumbar and sacrate plexus

Diagnostic Tests

Clinical examination Nerve conduction studies

Evaluation

Calibrated tuning fork Semmes–Weinstein Monofilaments Quantitative sensory testing (electrical,

thermal, vibratory, sensory treshold)

Electrodiagnostics

Objective proof of lesions Quantitative evaluation Spreading and type of nerve damage

Electrodiagnosis : EMG-NSS

Neurophysiologic study Neuropathy vs. myopathy Localization of lesion in the AHC, root, plexus, or distal

nerve trunk, NMJ, muscle Generalized polyneuropathy or multifocal neuropathy Upper vs. lower motor neuron disease Axonal vs. demyelinating neuropathy Activity (acute, chronic, regenerating) If in the peripheral nerve trunk, the site of the lesion

Electromyogram – Nerve Stimulation Studies (nerve conduction velocity)

Nerve Biopsy

Done in the sural nerve Indicated for : asymmetric and

multifocal neuropathic disorders

In diseases characterized by nerve enlargements

In establishing the diagnosis in some genetically determined disorders

Other tests

Genetical Autonomic tests (heart rate variability) CSF

PolineuropathiesDiabetic neuropathyEvaluation of peripheral neuropathies

PoliradiculoneuritisLumbar and sacrate plexus

Guillain Barre syndrome

Guilllain Barre Syndrome (GBS)

GBS is defined as “a syndrome of acute weakness of the limbs and reduced or

absent reflexes, with or without sensory loss attributable to a disorder of the peripheral nerves not due to systemic disease” (Hughes. 1990).

GBS is a clinical diagnosis though there are frequently abnormal laboratory features including an elevated CSF protein and evidence of peripheral nerve demyelination (Hughes. 1994; Hartung et al. 1998).

Guillain-Barre Syndrome

An acquired disease of the peripheral nervous system

Clinical: Major features: weakness and areflexia The most common cause of acute flaccid

paralysis in all ages. No specific test to confirm the diagnosis A syndrome rather than a disease

The typical illness evolves over weeks usually following an infectious disease:

1. Paresthesiaes usually hearld the disease

2. Fairly symmetric weakness in the legs, later the arms and, often, respiratory and facial muscles

3. Diminution and loss of the DTRs

4. Albuminocytologic dissociation

5. Recovery over weeks to months

Jean-Baptiste Octave Landry

Georges Guillain

Guillain, Barre & Strohl 1916Revue Neurologique

Two soldiers in Amiens developing paralysis and loss of DTRs.A new diagnostic feature: albuminocytologic dissociation in the CSFNo mention of Landry

Guillain-barre Syndrome Clinical features

Progressive weakness and diminished deep tendon reflexes in a symmetric distribution.

Ascending progression – most common 5 – 10% upper >> lower 5-10% proximal >> distal

Guillain-barre SyndromeClinical features

Sensory disturbances: pain or paresthesias Cranial nerves Autonomic disturbances – infrequent but life

threatening. 15-20% progress to respiratory failure.

Clinical features

Stages: Progression phase- days to weeks, max. 6

weeks. Period of major complications Plateau phase - days to weeks Recovery – weeks to months

Laboratory findings:

CSF normal cell count – up to 10 lymphocytes elevated protein – 80-200 mg/dl , after 1 week

Laboratory findings

Electrophysiological tests: 80% abnormal studies Multiple nerves must be studied Evidence of multifocal demyelination in motor and

sensory nerves. prolonged distal latency Reduction of the F WAVE response and H-REFLEX.

H REFLEX – single most sensitive test for early GBS, absent in 97% of pts in the first week (Gordon at al. neurol 2001)

Pathophysiology

Immune mediated disease Possible mechanism: autoAB bind to

glycoproteins on peripheral myelin , causing a cascade of events which eventually destroy the myelin.

Pathology

Depend upon the form of GBS. AIDP and MILLER-FISHER: Inflammation and demyelination More severe inflammation at the junction of dorsal and

ventral roots at the site of the dural attachment. Secondary axonal degenerationMotor and motor-sensory variants: Axonal degeneration without an inflammatory response The immune process is directed at the nodes of Ranvier No demyelination

Pathophysiology

50 – 70% have an antecedent illness within the previous 4 weeks. URTI, gastroenteritis C. Jejuni – more severe symptoms CMV, EBVImmunizations: “swine flu” vaccine (1976) Rabies vaccine

Infectious Systemic Viral: Influenza, Coxsackie,

EBV, Herpes, HIV, Hepatitis, CMV, WNV

Bacterial: Campylobacter jejuni, Mycoplasma, E. coli

Parasitic: Malaria, Toxoplasmosis

Hodgkins Hyperthyroidism Sarcoidosis Collagen Vascular d. Renal d.

Other events: Surgery Immunization Pregnancy Envenomization Bone marrow transplantation

Therapy

Supportive Monitoring: BP, HR, RR, TEMP.

Frequent physical examinations to establish a trend.

Serial lung function testing If dysphagia or shoulder weakness:

respiratory assistance may be necessary.

Therapy

Indications for transfer to ICU: Respiratory failure Autonomic dysfunction Bulbar dysfunction Bilateral facial weakness aspiration

Therapy

Corticosteroids: First immunotherapy for GBS “Corticosteroid medications do not seem to

help improve symptoms or lessen nerve damage from Guillain-Barre syndrome” - The Cochrane Database of Systematic Reviews 2000 (6 RCT’s, 195 pts treated with steroids vs 187 pts with supportive care)

No indication as monotherapy, evidence of benefit if added to IVIG.

Therapy

Plasma exchange reduce length of stay in the ICU and in hospital Reduce need for and period of ventilation Reduce length to unaided walking and neurological

sequele. 4 double-volume exchanges on alternate days over 1

week. exchange with albumin 5% more beneficial when started within seven days of the

disease onset.

Therapy

IVIG Probably same effects as plasma exchange

or even superior More available, less side effects 2 g/ Kg over 2-4 days Caution: early transient relapse after IVIG

administration

Prognosis

3% mortality Recovery- 1-6 months 80% have complete recovery in 12 months

PolineuropathiesDiabetic neuropathyEvaluation of peripheral neuropathiesPoliradiculoneuritis

Lumbar, sacrate and coccigeal plexus

Distribution of roots from the Lumbar and Sacral Plexuses

Hip Flexion L 1, 2, 3

Knee Extension L 2, 3, 4

Foot Dorsiflexion L 4,5

Foot Plantar Flexion S1, 2

Knee Flexion L5, S1, S2

Hip Extension L5, S1, S2

Dermatomes of the Leg

Clinical Principles Reflexes

Detecting subtle weakness

Get up from squat Quadriceps/Gluteus maximus

Stand on tip toes Gastrocnemius/Soleus

Stand on heels Tibialis Anterior

Knee Jerk - evaluates Quadriceps muscle Femoral Nerve Primarily L4 nerve root (also L2, L3)

Ankle Jerk - evaluates Gastrocnemius muscle Tibial Nerve Primarily the S1 nerve root (also S2)

Lumbar Plexus

Formed by the anterior rami of L1-L4.

Supplies the anterolateral abdominal wall, external genitals, and part of the lower limbs.

Femoral nerves, obturator nerves.

Copyright 2009, John Wiley & Sons, Inc.

Sacral Plexus

Formed by the anterior rami of L4-L5 and S1-S4.

Supplies the buttocks, perineum, and lower limbs.

Gives rise to the largest nerve in the body- the sciatic nerve.

Lies in pelvic cavity, anterior to sacrum and piriformis

Branches Superior gluteal Pudendal Posterior femoral

cutaneous Sciatic

Gluteus maximusPowerful hip extensor

Functions:

• Climbing

• Walking uphill

• Regaining upright posture from squatting

• NOT in normal walking

Hip (coxal) joint / GLUTEAL MUSCLE GROUP FUNCTIONS

Coccygeal Plexus

Formed by the anterior rami of S4-S5 and the coccygeal nerves.

Supplies a small area of skin in the coccygeal region.

Copyright 2009, John Wiley & Sons, Inc.

Obturator nerve

Enters thigh through obturator foramen;

Supplies medial group of muscles of thigh, obturator externus, and skin of medial side of thigh