Peripheral nervous system pathology General informations about anatomy, physyology and pathology of...
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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