Neuropathies & myopathies - an overview

08/04/2023 Jipmer physiologist 1

Neuropathies & Myopathies

Dr. Dinesh T,

Junior resident


Neuropathies


Definition

Damage to nerves which may be caused either by diseases or trauma to the nerve or as a component of systemic illness


• The neuropathy is a symptom of another disorder

• In most common forms of polyneuropathy, the nerve fibers most distant from the brain and the spinal cord malfunction first.

• Pain and other symptoms often appear symmetrically


• The peripheral nerves include:Cranial nerves

(with the exception of the second)

Spinal nerve roots Dorsal root ganglia Peripheral nerve trunks and their terminal

branches Peripheral autonomic nervous system


Symptoms in neuropathy

A wide array of symptoms can occur when nerves are damaged

o Paresthesia o Sensitivity to touch,

PositivePins and needlesTinglingBurning

NegativeNumbnessDeadnessAs if wearing shocks and walk


In chronic course symptoms worse, muscle wasting, paralysis, or gland dysfunction


Neuropathy - Signs

• Distal sensory loss• Distal weakness and

atrophy• Decreased or absent

reflexes– Ankle jerks lost first


Various classifications


Etiological Classification of neuropathies

Hereditary Neuropathies– Hereditary motor and sensory

neuropathy – type I– HMSN – Type II– Dejerine – Sottas Neuropathy HMSN- type III– HSMN – type IV– HSMN – type V

Inflammatory neuropathies• Immune mediated

o Guillain-Barré syndromeo Chronic inflammatory demyelinating

polyradiculoneuropathy• Infectious

– Leprosy – Diphtheria– Varicella – zoster

• Acquired metabolic and toxic neuropathies– Peripheral neuropathy in adult onset Diabetes– Metabolic and nutritional peripheral neuropathies – Neuropathies associated with malignancy– Toxic neuropathies

• Traumatic neuropathies


Medications Causing Neuropathies

o Axonal

Vincristine Paclitaxel Nitrous oxide Colchicine IsoniazidHydralazine Metronidazole Pyridoxine Didanosine Lithium Alfa interferon Dapsone

Phenytoin Cimetidine Disulfiram Chloroquine Ethambutol Amitriptyline

o Demyelinating Amiodarone Chloroquine Suramin Gold

o Neuronopathy Thalidomide Cisplatin Pyridoxine


Pathophysiological classification

• Motor , sensory, or autonomic• Mononeuropathy , polyneuropathy or

mononueritis multiplex• Focal, multifocal or symmetric • Proximal or distal • Axonal, demyelinating or both• Acute, sub acute or chronic


• Some neuropathies may affect all three types of nerves, others primarily affect one or two types.

• Predominately motor neuropathy• Predominately sensory neuropathy• Sensory-motor neuropathy• Autonomic neuropathy

• Impaired function and symptoms depend on the type of nerves that are damaged.


• Mononeuropathy involve damage to only one nerve

• When multiple nerves supplying one limb are affected-called polyneuropathy.

• Two or more isolated nerves in separate areas of the body are affected-called mononeuritis multiplex


o Focal neuropathies include common compressive neuropathies such as carpal tunnel syndrome, ulnar neuropathy ,peroneal neuropathy

oMultifocal neuropathy suggests a mononeuritis multiplex that may be caused, for example, by vasculitis or diabetes


Axonal degeneration

• Primary destruction of the axon with secondary degeneration of its myelin sheath

• Generalized abnormality in the neuron cell body- neuronopathy

• Abnormality in the axon - axonapathy


Segmental demyelination

Dysfucntion of Schwann cell or damage to the myelin sheath

Denuded axon provide signal for remyelination

Precursor cells within endoneurium replace injured cells

Cells proliferate and engulf axon.= remyelination in time


Neurophysiological classification

• Uniform demyelinating sensorimotor poly neuropathy• Segmental demyelinating, motor more than sensory

neuropathy• Axonal , motor more than sensory polyneuropathy• Axonal sensory polyneuropathy• Axonal mixed sensorimotor polyneuropathy• Mixed axonal and demyelinating sensorimotor

polyneuropathy


Uniform demyelinating sensorimotor poly neuropathy

• Hereditary motor sensory neuropathy- type I, III,IV

• Leucodystrophies• Tangier disease• Cockayne syndrome• Congenital cerebrotendinous xanthomatosis• Congenital hypomyelinating neuropathies


HMSN I (Charcot- Marie- Tooth I)

• HSMN I – AD is the most common hereditary neuropathy.

• CMT-I A chromosome 17p11 , CMT-IB chromosome 1q22 , CMT-IC 16p13, chromosome , CMT-IX chromosome Xq13.1

• Slowly progressive distal weakness • Foot deformity, areflexia , distal sensory loss• Upper limb ataxia, tremor, peripheral n

hypertrophy


Neurophysiological features

• Conduction velocity less than 25% of lower limit• Median motor forearm conduction< 38 m/s• Uniform NCV changes in adjacent nerves• Absence of conduction block and temporal

dispersion• F response• Needle EMG shows minimal fibrillations in distal

muscles.


Electrophysiological studies ( NCS ) showo Uniform slowing of NCVo Similar NCV slowing in adjacent nerveso Absence of conduction block and temporal

dispersiono Prolongation of F response commensurate with

NCV slowing

Uniform demyelinating sensorimotor poly neuropathy-


Segmental demyelinating motor more than sensory neuropathy

o Acute inflammatory demyelinating poly radiculo neuropathy AIDP

o Chronic inflammatory demyelinating poly radiculo neuropathy CIDP

o Multifocal motor neuropathy o Paraproteinemiao HIV neuropathyo Lyme diseaseo Diphtheria o Penicillamine


AIDP

o The prototypeo Distal paresthesia with symmetric weaknesso Distal areflexiao Variants are pure motor, pure sensory, autonomic,

relapsing, and Miller fisher typeso Cranial nerves esp facial n and bulbar may be involvedo Respiratory muscles are severely involved in about 25


Pathophysiology of GBS

• Pathological findings include inflammatory and demyelinating changes.

• Monocytes and macrophages appear to attack myelin sheaths.

• Myelinated fibers show segmental demyelination during the first few days. Segmental remyelination occurs subsequently.

• The lesions have a perivenular distribution


Chronic inflammatory demyelinatingpolyneuropathy

• Chronic progressive or relapsing neuropathy, motor > sensory.

• Electrophysiology: slow conduction velocity & conduction block

• Pathology: segmental demyelination and remyelination, onion bulbs, fibrosis and little or no lymphocytic

infiltration of tissue.


Segmental demyelinating motor more than sensory neuropathy

Nerve conduction studies o Slowing of motor and sensory conduction

velocityo Prolongation of terminal latencyo Conduction blocko Dispersion and prolonged or absent F waves


Axonal, motor more than sensory neuropathy

• Axonal type of GBS• Acute intermittent porphyria• HSMN type II , V• Toxic neuropathies such as lead, dapsone • Paraneoplastic syndrome • Metabolic – hypoglycemia• Critical care neuropathy


• Distal symmetric weakness and wasting with minimal sensory loss


Axonal,motor more than sensory neuropathy

• Nerve conduction studies• Reduced CMAP amplitude• NCV is normal• SNAP amplitudes are also decreased• Fibrillations appear in distal muscles


Sensory axonal polyneuropathy

• Diabetic neuropathy• Carcinomatous sensory neuropathy• HSMN type I- IV• Friedrich ataxia• Abetalipoproteinemia • Toxins - cisplatin• Pyridoxine overdosage• Vt –E neuropathy• Malabsorption• Acromegaly,


Diabetic neuropathy

• Onset of neuropathy depends upon the duration of illness

• 50% diabetics have peripheral neuropathy of which 80% have had the illness for >15 years

• Distal symmetric sensory or sensorimotor, autonomic, focal or multifocal asymmetric

• Symmetric neuropathy involves distal sensory , motor nerves .

• Decreased sensation, loss of pain sensation – ulcer


Diabetic neuropathy

• Predominant pathology is axonal neuropathy.• In chronic cases segmental demyelination also seen

Pathophysiology –• Loss of small myelinated fibers and unmyelinated

fibers. But large fibers can also be affected.• Endoneurial arterioles show thickening, hyalination,

intense PAS positivity in the walls and extrensive reduplication basement membrane


Sensory axonal polyneuropathy

• Nerve conduction studies • Diminished or absent SNAP amplitude in

the setting of normal motor nerve conduction velocity


Axonal type of mixed sensorimotor neuropathy

• Nutritional deficiencies (vitamin deficincy, alcoholism)• Metabolic ( diabetic, uraemia, liver disease,

amyloidosis)• Connective tissue disorders (rheumatoid arthritis,

SLE, PAN)• Multiple myeloma• Carcinoma• Cryoglobunemia• Heavy metals – lead, arsenic, gold, mercury• Drugs- metronidazole, phenytoin etc


• Paresthesia and dyesthesia of feet and distal legs

• Wasting is marked• Loss of ankle reflex • Pathophysiology – evidence of

degeneration of distal portion of axons


Axonal type of mixed sensorimotor neuropathy

Nerve conduction studies• Reduced or absent SNAP • CMAP amplitude decreases and motor

conduction velocity also decrease in later stage

EMG• Fibrillations and positive sharp waves are

prominent in distal muscles.• Temporal dispersion on proximal stimulation is

not found as in demyelinating neuropathies


Mixed axonal loss and demyelinating neuropathy

• Diabetes • Uremia• Paraproteinemia


• Paresthesia, dyesthesia or numbness• Reduced vibration and two point

discrimination• Pathophysiology – segmental

demyelination and remyelination along with axonal degeneration


Mixed axonal loss and demyelinating neuropathy

• Nerve conduction studies • Reduced or unrecordable CMAP, SNAP or

both• Moderate to severe slowing of NCV with

temporal dispersion of CMAP


Clinical examination

• Thorough history and physical examination is needed.

• Cranial nerve examination • Motor , sensory, autonomic nervous system

examination• Fundus examination• Lymphadenopathy , hepatomegaly or

splenomegaly, and skin lesions


Lab tests:

• CBC, electrolytes, ESR• Fasting serum glucose, glycosylated hemoglobin, blood

urea nitrogen, creatinine,• Liver , kidney,, thyroid function studies• Inflammatory markers, • Total protein level • Vit D, B12, • Cytology• CSF • Urinalysis • Nerve biopsy


Electrophysiologic studies

• EMG and nerve conduction studies (NCS) are often the most useful initial laboratory studies in the evaluation of a patient with peripheral neuropathy

• Confirm the presence of a neuropathy • Provide information as to the type of fibers involved

(motor, sensory, or both), the pathophysiology (axonal loss versus demyelination) and a symmetric versus asymmetric or multifocal pattern of involvement.


• The limitations of EMG/NCS. – There is no reliable means of studying proximal

sensory nerves. – NCS results can be normal in patients with small-fiber

neuropathies– Lower extremity sensory responses can be absent in

normal elderly patients.

• EMG/NCS are not substitutes for a good clinical examination.

Electrophysiologic studies


Treatment

• The goal of treatment is to manage the underlying condition causing the neuropathy and repair damage, as well as provide symptom relief.


Treatment

• Medical management– Analgesics . – antiepileptic drugs, including gabapentin, phenytoin,

and carbamazepine– some classes of antidepressants, including tricyclics

such as amitriptyline. – Mexiletine– local anesthetics such as lidocaine or topical patches

containing lidocaine – Codeine/oxycodone


• Mechanical aids can help reduce pain and lessen the impact of physical disability.

– Hand or foot braces can compensate for muscle weakness or alleviate nerve compression.

– Orthopedic shoes can improve gait disturbances and help prevent foot injuries in people with a loss of pain sensation.

• If breathing becomes severely impaired, mechanical ventilation can provide essential life support.

Treatment


• Surgical intervention often can provide immediate relief from mononeuropathies caused by compression or entrapment injuries.

– Repair of a slipped disk can reduce pressure on nerves where they emerge from the spinal cord; the removal of benign or malignant tumors can also alleviate damaging pressure on nerves.

– Nerve entrapment often can be corrected by the surgical release of ligaments or tendons.

Treatment


Myopathies


Definition

Neuromuscular disorders in which the primary symptom is muscle weakness due to dysfunction of muscle fiber

http://missinglink.ucsf.edu/lm/ids_104_musclenerve_path/student_musclenerve/subpages/infant.denervation.100x.html


Introduction

• Worldwide incidence of all inheritable myopathies is about 14%

• Overall incidence of muscular dystrophy is about 63 per 1 million.

• Worldwide incidence of inflammatory myopathies is about 5–10 per 100,000 people. More common in women

• Corticosteroid myopathy is the most common endocrine myopathy and endocrine disorders are more common in women

• Incidence of metabolic myopathies – increasing

Myopathy: symptoms

• Muscle pain and fatigue; exercise intolerance

• Proximal and symmetric weakness– Waddling gait; difficulty of rising from sitting,

climbing stairs; Gower’s sign– Hyperextension of the knee– Increased lordosis of the lumbar spine,

scoliosis– Contractures, tight Achilles tendons

• Myopathic face• Muscle atrophy; pseudohypertrophy• Myotonia• Tendon reflexes are normal or depressed

53Jipmer physiologist08/04/2023

Clinical examination

• Thorough clinical examination!• Observation – look for muscle

atrophy, deformities• Strength testing • Functional testing

– Stand up from a chair– Walk– Step up on a low stool

• REFLEXES and SENSATION

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Types of muscle diseases

• Hereditary muscle diseases– Denervation atrophy– Muscle dystrophies– Muscle channelopathies– Mitochondrial myopathies– Metabolic myopathies

• Acquired muscle diseases– Inflammatory myopathies– Endocrine and toxic myopathies– Infectious muscle diseases


Myopathic Disorders

• Inflammatory Myopathies– Polymyositis– Dermatomyositis– Inclusion body myositis– Viral

• Muscular dystrophies– Duchenne muscular – Limb-girdle– Congenital– Fasioscapulohumeral – Oculopharyngeal – Emery – Dreifuss – Distal (Welander)

• Myotonic Syndromes– Myotonic dystrophy – Inherited– Schwarz-Jampel– Drug-induced

• Congenital myopathies– Central core disease– Nemaline myopathy– Myotubular– Fiber-type disproportion

• Metabolic myopathies– Glycogenoses– Mitochondrial– Periodic paralysis

• Endocrine myopathies– Thyroid– Parathyroid– Adrenal/steroid– Pituitary

• Drug-induced/toxic


Diagnostic histological featuresof myopathies

• Absence of neurogenic abnormalities• Necrotic muscle fibers• Basophilic (regenerating) myofibers• Fibrosis of the endomysium• Special pathological features (inflammatory

cells, ragged red fibers etc.)

http://missinglink.ucsf.edu/lm/ids_104_musclenerve_path/student_musclenerve/subpages/infant.denervation.100x.html


Muscle dystrophies

• Hereditary myopathies, characterized by progressive weakness and muscle atrophy

• Genetic defect of proteins constituting the sarcolemma-associated cytoskeleton system


Duchenne muscular dystrophy

• First described in 1881- dystrophin gene discovered in the early 1980's


Duchenne muscular dystrophy• X-chromosome linked, recessive inheritance• 1 in 3500 live births,


Clinical features

• Onset of weakness before age 5• Progressive weakness, proximal>distal,

and muscle wasting• Gower’s sign • Hypertrophy of calves,• psuedohypertrophy of deltoid, gluteal• Skeletal deformities• Cardiomyopathy• wheel chair dependence by the age of 12,

respiratory infection at 16-18 years. Fatal in the third decade


Electrophysiology

• EMG changes – rate of muscle fiber destruction and extent of regeneration.

• Fiber loss-Low amplitude short duration MUPs,• Fiber degeneration- polyphasic MUPs • Necrosis - fibrillations with low amplitude and

short duration• Nerve conduction studies – generally normal


• Elevated CPK levels to 20 to 100 folds• Variation in size and shape of muscle fibers and

small groups of necrotic and regenerating fibers- muscle biopsy.

• Absence of dystrophin gene in biopsied muscles or genetic defect analysis in WBCs


Management

• No specific treatment• Physiotherapy• Aerobic exercise• Low intensity anabolic steroids• Prednisone supplements • Orthoses (orthopaedic appliances used for

support) • Orthopaedic surgery • Critical care


Beckers muscular dystrophy

• Allelic defect in DMD gene.• 10 times less frequent than DMD• Better prognosis. Patient lives upto 40-50 years.• Mental retardation and heart failure can occur • Muscle biopsy – variable muscle fiber size with

aberrant large fibers. Endomysial fibrosis and fatty infiltration

• Patchy staining of DMD gene


ge

Gene Clinical feature Pathophysiology

Fascioscapulohumeral MD - AD FSHMD1B Progressive muscular weakness and atrophy involving the face, scapular, proximal arm and peroneal muscles myopathic face,

Dystrophic myopathy with inflammatory infiltrates

Oculopharyngeal MD - AD PABP2 Ptosis and extra ocular muscle weakness

Dystrophic myopathy incl rimmed vacuoles

Emery – Dreifuss MD – X - linked EMD, LMNA Triad of early contracture, humero- peroneal weakness and cardiac conduction defects

Mild myopathic changes. Absent emerin by immunohistochemistry

Congenital –MD AR Laminin alpha 2

Neonatal hypotonia , muscle weakness

Variable fiber size and extensive endomysial fibrosis

Congenital –MD – Fukuyama type AR Fukutin Neonatal hypotonia and MR

Variable fiber size and extensive endomysial fibrosis. CNS malformation

Congenital –MD Walker – warnburg type

Protein o mannosyl transferase

Neonatal hypotonia and MR, ocular malformation

Variable fiber size and extensive endomysial fibrosis. CNS, ocular malformation


ge

Gene Clinical feature Pathophysiology

Limb-girdle dystrophiesSarcoglycanopathies AR

Α, β, γ, δ sarcoglycans

α, β, γ, δ sarcoglycans

Starts between 2 and 20 yearsClinically indistinguishable from duchenne-dystrophyNo cardiac involvement

,

Normal dystrophin immunostaining, abnormal immunostaining with sarcoglycansGenetic defect analysis

Myotonic dystrophy AD CTG repeat expansion in a gene on chr. 19

• Myotonia: hyperexcitability of muscle membrane inability of quick muscle relaxation

• Progressive muscular weakness and wasting, most prominent in cranial and distal muscles

• Cataracts, frontal balding, testicular atrophy

• Cardiac abnormalities, mental retardation

Muscle biopsy showing mild myopathic changes and grouping of atrophic fast fibres

Myotonia congenita AD, AR Mucle cl geneAutosomal dominant form: Thomsen, autosomal recessive form: Becker

Myotonia (hyperexcitability of the muscle membrane): muscle stiffness and abnormal muscle relaxation, warm-up phenomenonHypertrophied muscles


Inflammatory myopathies

PATHOPHYSIOLOGY• Polymyositis and inclusion body myositis (IBM) have

autoaggressive CD8 lymphocytes that appear to attack myofibers and suggest an autoimmune role.

• However,a major question exists about the etiology of IBM.

• Dermatomyositis is thought to be caused by auto antibodies, possibly targeting an antigen of the endothelium. Fiber injury may be caused by ischemia.


Dermatomyositis Polymyositis Incusion body myositis

Sub acute progressive weakness

Sub acute progressive weakness

Slowly progressive weakness,

proximal>distal proximal>distal proximal and distal.

Children and adults, women

adults, women adults, mostly men

Characteristic rash and periorbital heliotrope.

Electromyogrammyopathic potentials, spontaneous

myopathic potentials, spontaneous

myopathic potentials, spontaneousactivity

Elevated serum creatine kinase activity.

Elevated serum creatine kinase activity

Mildly elevated serum creatine kinase or normal.

inflammatory myopathy affectingchiefly the perimysium with perifascicular atrophy.

inflammatory myopathy chiefly the endomysium

: inflammatory myopathy affectingchiefly the endomysium, but chronic and hasrimmed vacuoles and amyloid inclusions

Usually respond to glucocorticoids or IVGG.

respond to glucocorticoids does not respond to glucocorticoids.


Polymyositis Inclusion body myositis Dermatomyositis


Congenital myopathies

• Group of muscle disorders • Early onset• Slowly progressive• Hereditary • Generalised or proximal weakness and wasting• Hypotonia• Contractures• Normally or mildly elevated CPK • Normal or myopathic EMG


Congenital myopathies

Central core disease Nemaline myopathy

Myotubular myopathy

Inheritence AD AD , AR XL, AD, AR

Gene RYR- 1 gene AD –NEM1 -TMP3AR- NEM2 - NEBAR- NEM3 - ACTAAR- NEM4 – TMP2AR- NEM5 - TNNT1AR- NEM7 - CFL2

XL – MTM1 AD – DNM2AR – BIN1

Clinical features Early onset hypotonia and weakness . Floppy infant . Associated skeletal deformities

Chilhood weakness .variable presentation. Floppy infant

Severe congenital hypotonia. Floppy infant .poor prognosis

Pathophysiology Cytoplasmic cores are distinct from surroundingSarcoplasm.

Aggregates of subsarcolemmal spindle shaped rods

Abundance of centrally located nuclei involving the majority of muscles


Distal myopathies

• Welander distal myopathy• Miyoshi distal myopathy


Metabolic myopathies

• Disorders of muscle energy metabolism• Disorders of lipid metabolism• Mitochontrial myopathies


Mitochontrial myopathies

• Kearn – sayre syndrome• Myoclonic – epilepsy with ragged red fibers• Mitochontrial myopathy, lactic acidosis, stroke• Mitochontrial myopathies with recurrent

myoglobunuria• Mitochontrial DNA depletion syndrome• Progressive external opthalmoplegia and ragged

red fibers


Endocrine myopathies

• Thyrotoxic myopathies• Cushing syndrome and steroid myopathy• Myopathy associated with oarathyroid disorders.


Toxic myopathies

• Myotonic disorders• Necrotizing myopathies• Acute muscle necrosis• Mitochontrial myopathy• Hypokalemic myopathy• Inflammatory myopathy• Autophagic myopathy• Focal myopathy• Envenomation myopathy


Muscle channelopathies

Nachannelopathies

Clchannelopathies

Cachannelopathies

Hyperkalemicperiodic paralysis

Myotoniacongenita(Thomsen andBecker type)

Malignanthyperthermia

Paramyotoniacongenita

Hypokalemicperiodic paralysis

Potassiumaggravatedmyotonia


Treatment

o There is no single treatment for myopathy. o Treatment of the symptoms to specific cause-

targeting treatments. o Drug therapy o Physical therapy o Bracing for support, o Surgery o Massage


Care !….the best rehabilitation method

Neuropathies & myopathies - an overview

Health & Medicine

Transcript of Neuropathies & myopathies - an overview