Peripheral nervous system pathology General informations about anatomy

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 hornspinal 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

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

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 fascicles Myelinated 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)

macrofag colagen fibră nemielinizată fibră mielinizată elastină limfocit mastocit capilar fibroblast neutrofil 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 diameter Smaller 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 axons Range in size from 0. 2 to 3 µm Enveloped 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

Pathology

General Reactions of the Motor Unit 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 axons Myopathy primary abnormality of the muscle fiber itself

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 remyelination Newly myelinated internodes are shorter than normal with thin myelin sheath

Onion bulbs: Thinly myelinated axon surrounded by concentrically arranged Schwann cells The 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 injury The distal part of the axon will initially degenerate Sprouting axonal branches from the proximal part (axonal regeneration 1 mm/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 unit Increased muscle fibers per motor unit

Peripheral nervous system

Disorders of the Peripheral Nervous System

Polineuropathies Diabetic neuropathy Evaluation of peripheral neuropathies Poliradiculoneuritis Lumbar and sacrate plexus

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

Polyneuropathy Pathologic involvement of peripheral nerves usually due to acquired toxic and metabolic states n Manifestations: n n Distribution – distal symmetrical (glovestocking distribution) First symptoms tend to be sensory loss or dysfunction (dysesthesias) Signs and symptoms of lower motor neuron disease (decreased DTRs, atrophy, weakness)

Polyneuropathy n Vary in: n Rate of disease evolution n Degree of severity n Small fiber vs. large fiber involvement n n 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 n Axonal vs. demyelinating

Common Causes of Polyneuropathy n Diabetes mellitus n Uremia n Vit. B deficiency n Critical illness n Hypothyroidism n Carcinomas n HIV

Common Causes of polyneuropathy n Drugs n n n n Amiodarone Antineoplastics (cisplatin, vincristine) Dapsone Hydralazine Isoniazid Pyridoxine Phenytoin Metronidazole n Toxins n n n Arsenic Diphtheria Toxin Inorganic lead Organophosphates Thallium

Clinical picture n n n Motor Sensory Trophic

Pathogenical Classification of polyneuropathy: n n n demielinating axonal mixt (diabetes, alcohol)

Classification of polyneuropathy: Axonal n Acute n – relatively uncommon Massive intoxications – arsenic n Subacute – metabolic/toxic n Chronic – 6 months- years n Hereditary neuropathies – slow course, absence of positive symptoms, mainly motor, absence of systemic disorder n n Most are autosomal dominant but some are also autosomal recessive Metabolic/toxic

Classification of polyneuropathy : Demyelinating Acute – Guillain-Barre Syndrome (GBS) n Subacute – all are acquired n n n Relapsing-remitting neuropathy (toxic) Chronic – n n Hereditary Inflammatory -CIDP Toxic Metabolic

Polyneuropathies �Genetic Neuropathies �Most common is Hereditary motor sensory neuropathy I and II – autosomal dominant peroneal muscular atrophy

Polyneuropathies n Acquired demyelinating n Acute : GBS – monophasic n Chronic : CIDP – slowly progressive or relapsing n May be treated with steroids, plasmapheresis and immunosuppressants

Polyneuropathies n Diabetic Polyneuropathy n n Due to long standing hyperglycemia May take almost any form

Polyneuropathies n Neuropathies of dysproteinemia n n Multiple myeloma –especially of the osteosclerotic type Benign monoclonal gammopathy Infectious: Lyme disease, lepper Neuropathies of HIV infection n n 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 n Autonomic neuropathies n Usually part of the more generalized polyneuropathy n Symptoms usually negative (postural hypotension, faintness, anhidrosis, hypothermia, bladder atony, obstipation, sexual impotence, dry eyes and mouth) n Positive symptoms include paroxysmal tachycardia, hypertension, diarrhea, hyperhidrosis

Polyneuropathies n Plexopathies n Causes: n n n n 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 n The PNS has an excellent ability to regenerate n 2 months to years n Depends on the nature of neuropathy (axonal vs demyelinating) n Depends on whether the cause of the neuropathy has been eliminated

Treatment n n Ethiological Symptomatic n n 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 n Simultaneous or sequential involvement of individual noncontiguous nerve trunks n Multifocal and random n 1/3 demyelinating n 2/3 axonal n Causes : Vasculitis - 50% (PAN, SLE, RA, mixed CTD) n Infectious –leprosy n Granulomatous disease n Idiopathic n

Ereditary neuropathies

Hereditary neuropathies n HMSN I – Charcot Marie-Tooth n n n Most frequently encountered. AD Demielinating type of Charcot-Marie Tooth disease Peripheral nerve hipertrophy – “onion bulbs” n n n 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 n HMSN II –axonal type of CMT n n n AD Debut 20 -40 years old; no nerve hypertrophies. HMSN III – Déjérine-Sottas n n n 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

Hereditary neuropathies n HMSN IV – Refsum disease n n n Neuropatia ereditară sensibilă la presiune (neuropatia tomaculară) n n n 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 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 n Afectarea preferenţială a fibrelor subţiri

Polineuropatia alcoolică n n n 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

Polineuropathies Diabetic neuropathy Evaluation of peripheral neuropathies Poliradiculoneuritis Lumbar and sacrate plexus

Diabetic Neuropathy · · n About 60 -70% of people with diabetes have mild to severe forms of nervous system damage, More than 60% of nontraumatic lowerlimb amputations in the United States occur among people with diabetes. Risk Factors n n n n 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 n Metabolic factors n n n n 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 n Somatic neuropathy n Symmetric polyneuropathy n Polyradiculopathy n Mononeuropathy n Autonomic neuropathy

Symmetric Polyneuropathy n n n Most common form of diabetic neuropathy Affects distal lower extremities and hands (“stocking-glove” sensory loss) Symptoms/Signs n n Pain Paresthesia/dysesthesia Loss of vibratory sensation Amyotrophy

Polyradiculopathy n Lumbar polyradiculopathy (diabetic amyotrophy) n n Thoracic polyradiculopathy n n Thigh pain followed by muscle weakness and atrophy Severe pain on one or both sides of the abdomen, possibly in a band-like pattern Diabetic neuropathic cachexia n n Polyradiculopathy + peripheral neuropathy Associated with weight loss and depression

Mononeuropathy n Peripheral mononeuropathy n n 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

Mononeuropathy n Cranial mononeuropathy n n Most frequently oculomotory nerves ( III, VI şi IV), facial nerve, optic nerve (optic anterior ischemic neuropathy) Diabetic oftalmoplegia n n Rare Rapid evolution (1 -2 days), with painful ophtalmoplegia

Autonomic neuropathy n Affects the autonomic nerves controlling internal organs n n n Peripheral Genitourinary Gastrointestinal Cardiovascular Is classified as clinical or subclinical based on the presence or absence of symptoms

Autonomic neuropathy n Cardiovasculary n n Gastrointestinal n n n Tachicardia, diminished tolerance for effort Cardiac denervarvation Ortostatic hypotension Esophageal dysfunction Gastroparesis diabetica Diarhea Constipation Incontinence Urogenital n n Erectile dysfunction Retrograd ejaculation Cistopathy Neurological bladder n Neurovasculary n n Metabolic and hypotalamic n n Intolerance to heat Gustative sudation Dry skin Unnoticed hypoglicemia Lack of response to hypoglicemia Autonomic dysfunction in connection to hypoglicemia Pupilary n Argyll-Robertson sign

Treatment n n Strict glycemic control Intervention on pathogenic pathways: n n n 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 n n n Tryciclic antidepressants, Gabapentin Pregabalin

Complications of Polyneuropathy n n Ulcers Charcot arthropathy Dislocation and stress fractures Amputation - Risk factors include: n n n 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 n n n 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 Sensory neuropathy Autonomic neuropathy - shape changess of foot - overcharging of pressure points - repeated microtrauma - lack of pain -Not using the defense mechanisms - altered skin reaction mechanisms -Altered skin mycrocirculation Ulcerations

Polineuropathies Diabetic neuropathy Evaluation of peripheral neuropathies Poliradiculoneuritis Lumbar and sacrate plexus

Diagnostic Tests n n Clinical examination Nerve conduction studies

Evaluation n Calibrated tuning fork Semmes–Weinstein Monofilaments Quantitative sensory testing (electrical, thermal, vibratory, sensory treshold)

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

Electrodiagnosis : EMG-NSS n n n n 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 n Indicated for : asymmetric and multifocal neuropathic disorders n In diseases characterized by nerve enlargements n In establishing the diagnosis in some genetically determined disorders n

Other tests n n n Genetical Autonomic tests (heart rate variability) CSF

Polineuropathies Diabetic neuropathy Evaluation of peripheral neuropathies Poliradiculoneuritis Lumbar 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 n n An acquired disease of the peripheral nervous system Clinical: n n 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: n n 1. Paresthesiaes usually hearld the disease 2. Fairly symmetric weakness in the legs, later the arms and, often, respiratory and facial muscles n 3. Diminution and loss of the DTRs n 4. Albuminocytologic dissociation n 5. Recovery over weeks to months

Jean-Baptiste Octave Landry

Georges Guillain, Barre & Strohl 1916 Revue Neurologique Two soldiers in Amiens developing paralysis and loss of DTRs. A new diagnostic feature: albuminocytologic dissociation in the CSF No mention of Landry

Guillain-barre Syndrome Clinical features n n Progressive weakness and diminished deep tendon reflexes in a symmetric distribution. Ascending progression – most common n n 5 – 10% upper >> lower 5 -10% proximal >> distal

Guillain-barre Syndrome Clinical features n n Sensory disturbances: pain or paresthesias Cranial nerves Autonomic disturbances – infrequent but life threatening. 15 -20% progress to respiratory failure.

Clinical features n Stages: n n n Progression phase- days to weeks, max. 6 weeks. Period of major complications Plateau phase - days to weeks Recovery – weeks to months

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

Laboratory findings n Electrophysiological tests: n n n 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 n n Immune mediated disease Possible mechanism: auto. AB 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: n Inflammation and demyelination n More severe inflammation at the junction of dorsal and ventral roots at the site of the dural attachment. n Secondary axonal degeneration Motor and motor-sensory variants: n Axonal degeneration without an inflammatory response n The immune process is directed at the nodes of Ranvier n No demyelination

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

Infectious Systemic n Viral: Influenza, Coxsackie, EBV, Herpes, HIV, Hepatitis, CMV, WNV n n Bacterial: Campylobacter jejuni, Mycoplasma, E. coli n n Parasitic: Malaria, Toxoplasmosis n n n Hodgkins Hyperthyroidism Sarcoidosis Collagen Vascular d. Renal d. Other events: n n n Surgery Immunization Pregnancy Envenomization Bone marrow transplantation

Therapy n n Supportive Monitoring: BP, HR, RR, TEMP. n n n Frequent physical examinations to establish a trend. Serial lung function testing If dysphagia or shoulder weakness: respiratory assistance may be necessary.

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

Therapy n Corticosteroids: n n 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) n No indication as monotherapy, evidence of benefit if added to IVIG.

Therapy n Plasma exchange n n n 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 n IVIG n n 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 n n n 3% mortality Recovery- 1 -6 months 80% have complete recovery in 12 months

Polineuropathies Diabetic neuropathy Evaluation of peripheral neuropathies Poliradiculoneuritis Lumbar, sacrate and coccigeal plexus

Distribution of roots from the Lumbar and Sacral Plexuses n n n Hip Flexion n L 1, 2, 3 Knee Extension n L 2, 3, 4 Foot Dorsiflexion n L 4, 5 Foot Plantar Flexion n S 1, 2 Knee Flexion n L 5, S 1, S 2 Hip Extension n L 5, S 1, S 2

Dermatomes of the Leg

Clinical Principles n Detecting subtle weakness n Quadriceps/Gluteus maximus Stand on tip toes n n n Get up from squat n n Reflexes Gastrocnemius/Soleus Stand on heels n Tibialis Anterior n Knee Jerk - evaluates n Quadriceps muscle n Femoral Nerve n Primarily L 4 nerve root (also L 2, L 3) Ankle Jerk - evaluates n Gastrocnemius muscle n Tibial Nerve n Primarily the S 1 nerve root (also S 2)

Lumbar Plexus n n n Formed by the anterior rami of L 1 -L 4. 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 n n Formed by the anterior rami of L 4 -L 5 and S 1 -S 4. 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

n Branches n n Superior gluteal Pudendal Posterior femoral cutaneous Sciatic

Hip (coxal) joint / GLUTEAL MUSCLE GROUP FUNCTIONS Gluteus maximus Powerful hip extensor Functions: • Climbing • Walking uphill • Regaining upright posture from squatting • NOT in normal walking

Coccygeal Plexus n n Formed by the anterior rami of S 4 -S 5 and the coccygeal nerves. Supplies a small area of skin in the coccygeal region. Copyright 2009, John Wiley & Sons, Inc.

Obturator nerve n Enters thigh through obturator foramen; n Supplies medial group of muscles of thigh, obturator externus, and skin of medial side of thigh