Neuromuscular Disorders Flashcards
Describe the pathology of Myasthenia Gravis
Autoimmune antibodies to Acetylcholine receptors (AChR antibodies) at the NMJ
Other antibodies: anti-muscle specific tyrosine kinase (anti MuSK)
What are the types of Myasthenia Gravis?
Neonatal myasthenia – transient, due to transplacental transfer of AChR antibodies. (Floppy but resolves by 3 months) from a myasthenic mother to foetus
Congenital myasthenic syndromes – genetic disorders of NMJ
Ocular myasthenia: affects eye muscles ptosis, ophthalmoplegia.
Limb muscle may be mildly involved.
Generalized myasthenia: affects eye muscles, bulbar and limb muscle
Which groups of people are affected by Myasthenia Gravis?
Girls>Boys
Symptoms of Ocular Myasthenia Gravis
Ptosis
Ophthalmoplegia
Diplopia
NB. May be bilateral or unilateral
When bilateral, usually one eye more affected
Mild facial weakness
Symptoms of Ocular Myasthenia Gravis
Ptosis
Ophthalmoplegia
Diplopia
NB. May be bilateral or unilateral
When bilateral, usually one eye more affected
Mild facial weakness
Symptoms of Generalized Myasthenia Gravis
Bulbar weakness - weakness of swallowing muscle
Limb weakness
Fatiguability - as patient uses muscle, it gets weak
Diurnal variation - patient is stronger in the morning, weaker as the day progresses.
Other associated autoimmune disorders (with MSG)
Thyroiditis
Collagen Vascular Disease
Type 1 diabetes
Thymoma (produces autoimmune antibodies)
Investigations for Myasthenia Gravis
Ice pack test: Put ice pack on affected eyelid for 3-5 minutes. The muscle rests and the appearance of bright eyes is a positive test.
Edrophonium chloride test (Tensilon test) - Acetylcholinesterase inhibitor - Within 1 minute patients eyes become bright
Neostigmine test - Acetylycholinesterase inhibitor - but works in 15 minutes.
Repetitive nerve stimulation - Strength of contraction decreases each time - Decremental response on Graph
Serum antibody assay
AChR antibodies – NB. Patients with OMG may be seronegative or have low antibody concentrations
Anti-MuSK antibodies
Trial of pyridostigmine - Given for 2 weeks because of slow action. Same response as other Acetylcholinesterase inhibitors
Management of Myasthenia Gravis
Anticholinesterase therapy (pyridostigmine is preferred, but also neostigmine in acute phase)
Immunotherapy: corticosteroids, Intravenous Immunoglobulin, plasmapheresis
?Thymectomy if you suspect Thymoma as source of antibodies
Immunosuppressants: methotrexate
How is DMD inherited? Who does it affect? What causes DMD?
X-linked muscular disorder
Mutation causes reduced dystrophin (DMD < 3%, BMD < 20% dystrophin production, so milder)
Dystrophin links muscle fibers - It’s absence leads to muscle weakness
Affects only males
Some female carriers may have cardiomyopathy
Clinical features of DMD
Boys
Delayed motor milestones
Gait disturbance - Waddling gait
Toe walking
Frequent falls
Proximal weakness
Difficulty rising from the floor/sitting position
Waddling gait
Gower’s sign
Other Clinical Features of DMD
Calf hypertrophy
Increased lordosis
Most children maintain the ability to walk or climb stairs until 8 years of age
Require wheelchair by 10-12 years
Contractures develop easily: TA - Archilles Tendon, knee, elbows
Scoliosis
Deterioration of vital capacity - nocturnal hypoventilation (present with morning headaches or daytime somnolence
Death usually from cardiomyopathy and respiratory insufficiency
Investigations for DMD
Diagnosis
Serum CK: very high in the 1000 (usual upper limit is 170.190)
Molecular genetic testing - to confirm DMD
Muscle biopsy - to confirm DMD
Other investigations
ECG - ‘Cause of arrythmias
Echocardiogram - For Cardiac Function
Pulmonary function test
Bone densitometry - because of poor mineralization. Done every year or every 2 years.
Complications of DMD
Loss of ambulation
Cardiomyopathy
Respiratory muscle weakness due to worsening respiratory function
Scoliosis
Decreased bone mineralization
Learning difficulty
Psychosocial problems
Management of DMD
Steroid treatment: Prednisone 0.75mg/kg daily
does not cure disease
Prolongs ambulation
Improves respiratory and cardiac function
Physiotherapy
Cardiac care
Respiratory care
Bone health - Give Calcium and Vitamin D
Scoliosis care
Sleep quality
Genetic counselling
Genetic modification therapy
Define the following terminologies for Neuromuscular Disorders
Hypertonia
Spasticity - Velocity dependent. It gives in as you continue to extend and flex joint vs. Rigidity - Increased tone continues throughout the full range of motion. (Doesn’t give in
Hypotonia
Flaccidity/floppiness
Hemiparesis/hemiplegia - weakness on one side of the body
Paraparesis/paraplegia - weakness in lower limbs
Tetraparesis/tetraplegia - weakness in all 4 limbs
Define the following terminologies for Musculoskeletal Disorders
Macrocephaly - Increased Head Circumference > +2 SD
Microcephaly - Decreased Head Circumference > -2SD
Scoliosis - Curvature of Spine
Arthrogryposis - Multiple contractures in multiple joints (Arthrogryposis multiplex congenita)
Posture - Relation of limbs to trunk whilst patient is at rest/lying down
Gait - Relation of limbs to trunk whilst patient is standing
Stature - Height
Neuromuscular disorders by localization
Brain
Spinal cord
Anterior horn cells
Peripheral nerve
Neuromuscular junction
Muscle
Generalized - eg. hypothyroidism
Common Presentations of Neuromuscular Disorders
Floppy infant: hypotonic and weak
Ventilator dependent neonate failing extubation
Arthrogryposis
Delayed motor development
Poor gait
Frequent falls
Difficulty with steps
Toe walking
Muscle pain or cramps
Stiffness
Other common presentations of neuromuscular disease
Foot deformity – high arched, flat foot, etc.
Episodic weakness
Exercise limitation
Recurrent apnoea
Chest wall deformities
Pain on or after exercise
Cardiomyopathies
Abnormal biochemistry: raised CK, raised ALT
Who is a floppy infant?
An infant with generalized hypotonia presenting at birth or in early life
Questions to ask in history of Floppy Infant
*pre-, peri- and postnatal history
*quality and quantity of fetal movements (For neuromuscular disorders with onset before birth. Compare with other child)
*breech presentation (Neuromuscular condition which prevented normal cephalic version)
*presence of either poly- (from impaired swallowing) or oligohydramnios.
*any clues to hypoxic-ischaemic encephalopathy
*Neonatal seizures or encephalopathic state
*The onset of the hypotonia – may distinguish between congenital and acquired etiologies.
*Enquire about consanguinity and identify other affected family members
What are the two approaches to the diagnostic problem on neuro examination?
Identifying the neuro-anatomical site of the lesion or insult.
Upper motor neuron (UMN) vs. lower motor neuron (LMN) lesion
Determine whether the hypotonia is accompanied by weakness or not .
Weakness is uncommon in UMN hypotonia except in the acute stages.
Hypotonia with profound weakness therefore suggests involvement of the LMN.
Useful indicators of weakness
Inability to cough and clear airway secretions
Swallowing ability as indicated by drooling and oropharyngeal pooling of secretions or cough during feeding.
The character of the cry — infants with consistent respiratory weakness have a weak cry.
Paradoxical breathing pattern — intercostal muscles paralysed with intact diaphragm.
Patterns of breathing in neuromuscular disorders
Brain: axial, truncal or generalized hypotonia
Cord: paraplegia or tetraplegia
Anterior horn cells: proximal > distal, LL > UL
Peripheral nerve: distal weakness
NMJ: generalized weakness
Muscle: proximal weakness
Specific Neuromuscular Conditions - BANP
Brain/spinal cord
Corticospinal tract disorder
Basal ganglia disorders
Cerebellar disorders
Anterior horn cell
Spinal muscular atrophy (SMA) - Congenital
Poliomyelitis - Acquired
Peripheral nerve
Charcot-Marie-Tooth disease (CMT) - Congenital
Guillian Barre syndrome (GBS) - Acquired
Neuromuscular junction
Myasthenia gravis - Congenital/Acquired
Botulinum toxicity - Acquired
Specific Neuromuscular Conditions - Muscle and Generalized
*Muscle
Congenital myopathy
Dystrophinopathies (Duchenne/Becker Muscular Dystrophy)
Myotonia dystrophies
Inflammatory (Dermatomyositis)
Metabolic (Pompe disease, mitochondrial myopathies)
*Generalized
Trisomy 21
Hypothyroidism
Prader Willi syndrome
What is Spinal Muscular Atrophy and how is it inherited?
Anterior horn cell disease
Autosomal recessive disorder
What causes SMA?
Deletion in the survival motor neuron 1 (SMN1)
Mutation in SMN1 -> degeneration of anterior horn cells -> progressive weakness and wasting of skeletal muscle
What makes SMA milder?
The number of copies of SMN2 gene, which produces defective protein.
Classification of SMA
Classified based on severity
Type 1: Werdnig-Hoffman disease (severe type)
Type 2: intermediate type SMA
Type 3: Kugelberg-Welander disease (mild type)
Type 0: Very severe, in utero, results in still birth, or neonatal death
Type 4: Adult onset
Describe the age at onset, development and Prognosis of the SMA types
Type >Age at onset >Development > Prognosis
1 < 6 months> Never sit unsupported >Most die within the first year of life. Usually due to RTI
2> 6-18 months> Sit but never walk unsupported >May grow into late childhood
3> > 18 months> Walk unsupported at some stage> Often grows into adulthood
Clinical features of SMA
Alert, normal facial expression (Normal/Superior cognition, no facial weakness)
*Symmetrical flaccid paralysis
*Pattern of weakness: proximal > distal, legs > arms
*Absent deep tendon reflexes
*Tongue fasciculations
*Intercostal muscle weakness with sparing of the diaphragm - paradoxical/Seesaw breathing
*Weakness of the bulbar muscle > weak cry, poor suck and pooling of secretions
*Contractures
*Survival depends on respiratory and bulbar functions (aspiration risk)
Diagnosis of SMA - History and Physical Exam
History: decreased fetal movement, floppiness at birth, delayed motor milestones, recurrent aspiration and RTI,
Physicals Exam: floppy infant, cognitively bright child, normal facial expression, proximal > distal weakness, tongue fasciculation, bell shaped chest - ‘cause of persistent use of diaphragm, paradoxical breathing, contractures
Investigations for SMA
Serum Creatine Kinase: normal or mildly raised (To rule out muscle disease)
ECG: may show baseline fibrillations
DNA analysis: to test for deletion on SMN1
Muscle biopsy - muscle atrophy
Electromyogram
Supportive management and Definitive treatment for SMA
*Supportive Management:
Respiratory care
Prompt treatment of respiratory infections
Chest physiotherapy
Physiotherapy
Nocturnal BiPAP (Prevents poor oxygenation of brain so no morning headaches)
*Definitive treatment
Genetic modification drugs(experimental)
Is Guillian Barre Congenital or Acquired?
Acquired
What are the common and less common causes (variants)?
Commonly due to acute inflammatory demyelinating polyneuropathy (AIDP) - Affects myelin
Less common variants include:
Acute axonal neuropathy - Affects axon
Chronic inflammatory demyelinating polyradiculoneuropathy CIDP)
Miller-fisher syndrome - AIDP + Cranial nerve involvement
Presentation of AIDP. Phases of AIDP. Associations
Acute (reaches maximum within 48-72 hours, monophasic
Demyelinating
Peripheral nerves are the target of an abnormal immune response
Antecedent viral infection (about half of patients)
RTI > GI infections
Progressive phase plateau phase recovery phase
Clinical Features of GBS
*Progressive motor weakness with areflexia
*Ascending or descending (recovery in reverse)
*Relatively symmetrical
*Weakness progresses rapidly - same as recovery, reaching a nadir by 2-4 weeks
*Autonomic dysfunction (arrhythmia, labile BP, GI dysfunction)
*Facial weakness (MFS)
*Respiratory paralysis
*Bulbar dysfunction
*Recovery of function within 2-4 weeks
Investigations for GBS
NB. Diagnosis of GBS is clinical: progressive weakness + areflexia
Investigations to support diagnosis and rule out differentials include:
CSF: Albuminocytologic dissociation after 1st week (↑protein, no/low cells) supports GBS
Stool: for polio and non-polio enteroviruses
Nerve conduction studies
To help differentiate demyelinating type from the axonal type
Demyelinating: slow nerve conduction velocity
Axonal: decreased amplitude
Others
Blood: for campylobacter, Coxsackie
Serology for mycoplasma, EBV, CMV, VZV, Borrelia
MRI of brain and spine - not recommended: the nerve roots lights up on contrast studies in GBS
Differential Diagnosis of GBS
Poliomyelitis
Non-polio enterovirus infections
Transverse myelitis
Botulinum toxin
Tick paralysis
Porphyria
Diphtheria
Spinal cord compression
Viral myositis
Case Definition of Acute Flaccid Paralysis
Any child less than 15 years who has AFP or a person at any age with paralytic illness in whom the clinician suspects Polio
Acute: the paralysis is of sudden onset (progresses and reaches maximum level within 72 hours of onset)
Flaccid: floppy, not rigid, not stiff
Paralysis: loss of muscle strength (weakness, limitation of movement)
(For a true AFP, all 3 conditions should be met)
Management of Acute Flaccid Paralysis
Notify as a case of AFP: disease control officer/public health unit
Two (2) stool samples collected 24-48 apart, within 14 days of onset of paralysis in two different specimen containers
Place specimen in cold box below 8*C between frozen ice packs
Send to WHO-accredited lab within 3 days (If last 2 conditions aren’t satisfied sample will be rejected)
Management of Guilian Barre Syndrome
Respiratory support: admit to ICU if
rapidly progressive
Vital capacity < 50%
IVIG - Mop up antibodies
Plasma exchange - Mop up antibodies
NB. Corticosteroids not helpful: may produce some initial improvement but tends to prolong the course
Physiotherapy
Recovery is usually in reverse order to the progression
