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PAEDIATRICS

Neuromuscular Disorders

Diploma of Paediatrics.

Dr Rakesh Patel

Neuromuscular Disorders

ApproachLocalisationInvestigationsExamples

NerveNMJMuscleOther

Neuromuscular Disorders

Approach

Presenting History

Presenting signs and symptomsClinical patterns

When considering a neuromuscular disease you should concentrate on the following .

Functional disability.Anatomical distribution.Temporal relationship in time.

Presenting History

Functional disabilityEspecially useful to help develop your differential diagnosis.

Look for selective involvement in these systems.

MotorSensoryAutonomic

Presenting History

Anatomical distributionArms vs. Legs

Most neuromuscular disorders are more prominent in the legs

or involve both arms & legs.

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Presenting History

Anatomical distributionProximal vs. Distal

Myopathies have a distribution of weakness that is usually proximal.

Neuropathies, sensory loss and weakness is usually more distal then proximal.

Presenting History

Anatomical distributionSymmetric vs. Asymmetric

Symmetric disorders are more common.MyopathiesNeuropathies

Asymmetric weakness: Commonly treatableOften related to inflammatory disorders.Local pathology.

Presenting History

Temporal relationshipCoarse

Acute: Days to Weeks Chronic: Months to Years Episodic

Diurnal variationOnset age

Paediatric: Neonatal; Childhood Adult: 20 to 60 years; Geriatric

HereditaryBy family history or examination of relatives.

Presenting History

Past historyBirth historyDevelopmental historyPast medical history

Family historyPatterns of inheritance

The Examination

Full neurological examinationMotorSensoryCognitive

Note the features

Long faciesBitemperal wastingOpen mouth

High arched palette

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Gower’s manoeuver

Described first by Sir William Richard GowersDifficulty rising from the floor because of proximal weakness.

PsuedohypertrophyNote the bulky musclesMuscles are firm to palpationHowever the muscle is weak on strength testing.

Champaign bottle legsDistal wasting of musclePoor dorsiflexionPoor eversionOften associated pescavus

Pes cavus

Slowly deforming Poor dorsiflexionPoor eversionOften ending in a fixed deformity

Percussion myotonia

Slow flexion of the thumb after percussion of the thenar prominenceOccurs in myotonicsyndromes

The Examination

CVSBP

Low pressureHR

Conduction defectsCardiomyopathy

Many myopathies and dystrophies

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The Examination

CVSCardiomegallyBlood pressure abnormalitiesConduction defects

ECGECHO

The Examination

RESChest shapeCough strengthRespiratory effort

Peak flowLung function tests

The Examination

ABDOOrganomegally

Storage diseases

CryptorchidismGubernaculum is made of striated muscle

The Examination

Skeletal

Putting it all together

Summarise the presenting featuresTaking into account the past historyTaking into account the family history

Summarise the clinical findingsMotor disabilitySensory disabilityWhere is the lesion

Go back to the basics – ‘The motor unit’

‘The motor unit’

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Where is the lesion?

Brain / Spinal CordAnterior horn cell

Nerve

NeuromuscularJunction

Muscle

Where is the lesion? - Brain

Floppy but strong.Initial hypotonia.Hypereflexia.Increasing tone.Cognitive delay.

Where is the lesion? - Brain

CongenitalDysplasiaGenetic

Down Syndrome

AcquiredCongenital infectionHypoxic ischemic injuryStroke

Where is the lesion? - Cord

WeakDistal>proximalMuscle wasting

very hypotonicreflexes reduced or absentsensation involvedcognition sparedOften mixed signs

Where is the lesion? - Cord

CongenitalSpina bifidaSacral agenesisSMA

AcquiredTraumaticInfective

Where is the lesion - Nerve

WeakVariable between distal>proximal

Reflexes reduced or absentFasciculationsFace usually sparedSensation involvedWastingAutonomic NS can be involved.

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Where is the lesion - Nerve

CongenitalCMT

AcquiredTraumaticInfectiveImmune

GBS

Where is the lesion - NMJ

WeaknessGeneralisedExtraocular muscles and face often involvedTemporal changes: Variable through day; Fatigue

Cognitive normalNormal reflexes.

Where is the lesion - NMJ

CongenitalCongenital myasthenic syndromes

InflammatoryMyasthenia gravis

ToxicTic paralysis

Where is the lesion - Muscle

WeakProximal; Symmetric; PersistentWeakness > Wasting

Poor reflexes+/- cognitive involvementOther features

MyotoniaCardiomyopathyFacial involvement

Where is the lesion - Muscle

CongenitalMyopathyDystrophy

InflammatoryDermatomyositis

InfectiveMyositis

Metabolic

Investigations

RoutineSpecific

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Investigations

Always start with the basicsFBCElectrolytesCa, MgGlucoseLFT’sBlood gas statusCK

Why do a CK?

Dystrophy Relatively high CKdegenerative loss and destruction of a previously normal architecture

Myopathy minimal increase in CKabnormality in architecture,

Investigations

Neurophysiological

EMGNCS

Often help to determine if the pathology lies in the nerve, neuromuscular junction or muscle.

EMG

Motor unit examination

Denervation produces reduced number of motor unit action potentials.

Denervation produces fibrillations.

Neuropathy with reinnervation produces increased amplitude motor unit potential.

EMG

Motor unit examinationMyopathy produces decreased size of motor unit potential.Myotonia produces a distinctive ‘dive bomber’ response.Myasthenia produces a decrementalresponse.

NCS

Demyelinationproduces slowed nerve conduction.

Axonal degenerationproduces decreased amplitude of nerve action potential.

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NCS

Proximal conduction block occurs in Guillain-Barre.

Abnormal F-wave (absent) and abnormal F-wave ratio (increased).

Investigations

Biopsy

MuscleNerve

Often helps to determine what the pathological process is affecting the muscle or nerve.

Muscle biopsy

Gross section

HistologyEM

ImmunofluresenceWestern blot

Duchenne’s MD - Testing

Increased endomysial connective tissue with variable fibre size.Many contracted muscle fibres

Normal dystrophin staining

Absent dystrophin

Western blot of dystrophin from dystrophinopathies.1: Becker dystrophy; Dystrophin has reduced abundance but normal size.2: Becker dystrophy; Dystrophin has reduced size and abundance.3: Normal; Dystrophin has normal size and amount.4: Duchenne dystrophy; Almost no protein is present.5: Duchenne outlier; Dystrophin has severely reduced abundance.

Nerve biopsy

Histology

EM

Nerve biopsy

Demylination

Normally myelinated motor axon in muscle

Segmental demyelination of a motor axon

Large onion bulbs - abundant connective tissue around thinly myelinated axons

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Nerve biopsy

Axonal degeneration

Investigations

Genetic testingThere are several routine genetic tests that can be requested

HMSNMyopathies / Dystrophies

Duchenne / BeckerMyotonic dystrophy

SMA

Examples

Anterior horn cell (SMA)Nerve (CMT)Muscle (Duchenne)

Myotonic dystrophyCongenital myopathy

NMJ (MG)

Anterior horn cell disease

SMA

SMA - Genetics

Chromosome 5q

SMN1 (Telomeric SMN (SMNT)) geneMutated in 95% of SMA

SMN2 gene (Centromeric SMN (SMNC)) Number of copies inversely related to severity of SMA SMN1 - Deletion – Severe SMA

- Conversion to SMN2 – milder SMASMN2 - more copies correlate with milder SMA

- SMN2 mutations alone don’t cause SMA

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SMA – Type I

Werdnig-HoffmannOnset by 6/12 – never sitSymmetrical proximal weaknessAreflexicTongue fasciculationLife expectancy 12 months

Die of respiratory complications

SMA I - clinical

Weakness Diffuse; Proximal > Distal

Poor feeding Respiratory insufficiency: Paradoxical respirations Sparing of facial & oculomotor muscles.Fasciculations: Tongue

SMA – Type II

Kugelberg-WelanderOnset 6-12 monthsSit, but never walkRequire respiratory support

SMA – Type III

Kugelberg-WelanderOnset from 24 monthsWalk unaided, decreased reflexes+/- Tremor

Diseases of the nerve

CMTDemylinatingAxonal

Neuropathy

CMT (HMSN)Distal weaknessReflexes – reduced or absent(sometimes normal)Dominant, recessive and x-linked formsDemyelinating vs. axonopathy

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CMT

Prevalence Hereditary neuropathies: ~30 per 100,000

CMT Type 1: 15 per 100,000 CMT 1A: 10.5 per 100,000 CMT 2: ? 7 per 100,000

Common Genes

CMT 1A - 17p11 PMP-22CMT 1B - 1q22 PoCMT 1C - 16p13 LITAFCMT 1D - 10q21 EGR2CMT X - Xq13

Connexin32HMSN3 - 8q23, 17p11,

10q21

Muscle Disease

DystrophyMyopathyChannelopathies

Muscular dystrophy

Duchenne muscular dystrophySteady progressive X-linked muscular dystrophyPresents delay in walking, abnormal gait, frequent falling, difficulty climbing stairs.

Key featuresWaddling gait, abnormal runDifficulty rising form the floor (Gower’s sign)Proximal muscle weakness legs> arms Muscular pseudohypertrophy.

Associated featuresCardiomyopathy.

Cognitive effect – 30% have some MR, mean IQ 88 (46 to 134)

Deformities – equinovarus, scoliosis, fixed flexion deformities after loss of ambulation.

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DiagnosisCK grossly elevated

<5000 likely Becker>5000 likely Duchenne

EMG myopathicGenetic testingMuscle biopsy

Duchenne’s MD - Genetics

Xp21 mutations / deletions30% with new mutation

Gene product isolated in 1987 –DystrophinLargest gene cloned spanning 2 million base pairs consisting of 79 exons (0.6% gene).

Other muscular dystrophies

Limb-Girdle MDProximal muscle involvement, CK>5000

Facio-scapulohumeral MDAD, facial weakness, hearing loss

There are many others

Myotonic dystrophy

DM1 19q13.3 (dominant), dominant, 98%CTG repeats, anticipation

DM23q21, dominant, 8-60yrsCCTG repeat, 1st tetranucleotide repeat

DM315q21-24, dominant, adult onset

Myotonic dystrophy I

Normal CTG repeat length 3-3736-50 premutationDisease range of CTG repeat numbers:

Mildly affected or unaffected: 50 - 150 repeats Classic disease range: 100 - 1,000 repeats Severely affected range / congenital: 730 -4300 repeats

Congential myopathy

Central core myopathyAD, mild, hip dislocation, malignant hyperthermia

Nemaline myopathyvariable presentation, scoliosis, progressive, prominent respiratory involvement.

Myotubular myopathyptosis, ophthalmoplegia

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Channelopathies

Chloride channelopathiesMyotonia congenita

Sodium channelopathiesHyperkalemic periodic paralysisParamyotonia and myotonia

Calcium channelopathiesHypokalemic periodic paralysisMyasthenic syndrome

Diseases of the neuromuscular junction

Neuromuscular junction

Myasthenia GravisAutoimmune weakness and fatigability of ocular, bulbar and striated muscle.

Neuromuscular junction

Myasthenia GravisAntibodies to acetylcholine receptor in 50% children

A firm diagnosis is based upon A characteristic history and physical examinationTwo positive diagnostic tests, preferably serological and electrodiagnostic.