SMA and NMJ Disorders PDF

SPINAL MUSCULAR ATROPHY and NEUROMUSCULAR JUNCTION DISORDERS Prepared by: j.m.a.hester, PTRP DO NOT DISTRIBUTE WITHOUT PERMISSION  Spinal Muscular Atrophy Introduction It is the second most common fatal, autosomal recessive disease It is...

SPINAL MUSCULAR ATROPHY and NEUROMUSCULAR JUNCTION DISORDERS Prepared by: j.m.a.hester, PTRP DO NOT DISTRIBUTE WITHOUT PERMISSION  Spinal Muscular Atrophy Introduction It is the second most common fatal, autosomal recessive disease It is a varied group of inherited disorders It is characterized by symmetrical muscle weakness and muscle wasting Introduction Cause: degeneration of both anterior horn cells of the spinal cord and brainstem motor nuclei without pyramidal tract involvement Three categories of SMA occur in childhood: SMA type I (Werdnig–Hoffman disease) SMA type II SMA type III (Kugelberg–Welander disease) Epidemiology It has an incidence of 1/10000 The carrier frequency for SMA in the general population is estimated at about 1 in 40 to 50 individuals Etiology Genetic predisposition or it can be inherited An autosomal recessive (AR) disorder Genetic defect is located on chromosome 5q13 Survival motor neuron gene  Etiology 2 homologous genes SMN1 Produces most of the protein that the body uses SMN2 The total amount of SMN produced in patients with SMA, therefore depends on how many copies of SMN2 the patient has SMA I (severe): two or three gene copies of SMN2 SMA II: three copies of SMN2 SMA III: four to eight copies of SMN2  Pathophysiology alpha motor Decrease neuron and apoptosis motor neuron number of interneurons loss SMN affectation Motor neuron loss will result to: EMG → characterized by diminished compound motor unit action potentials (CMAP) that are often of short duration (+) Positive sharp waves and fibrillations Decreased number of motor unit motor unit number estimation (MUNE) Muscle biopsy → characterized by groups of small atrophic fibers interspersed with groups of large hypertrophic fibers Common clinical presentation Symmetrical muscle weakness Absent deep tendon reflexes Tongue fasciculation Intact sensation Normal cognitive function Types of spinal muscular atrophy SMA type I (Werdnig–Hoffman disease) SMA type II SMA type III (Kugelberg–Welander disease) Spinal muscular atrophy type I Types of spinal muscular atrophy A.k.a. Werdnig–Hoffman disease Within the first 3 months of life Reduced fetal movements during pregnancy or within the first weeks or months after birth with weakness and hypotonia at birth. Spinal muscular atrophy type I Types of spinal muscular atrophy Axial hypotonicity is often the first symptom noted Swallowing and sucking are impaired Muscle wasting is often severe Spontaneous movements are infrequent and of small amplitude Spinal muscular atrophy type I Types of spinal muscular atrophy Generalized hypotonia and symmetric weakness Proximal muscles are weaker than distal extremities Supine position of the patient is characterized by: Lower extremities → abducted and externally rotated in a “frog-leg” position. Upper extremities → adducted and externally rotated at the shoulders with a slightly flexed elbow Spinal muscular atrophy type I Types of spinal muscular atrophy (+) head lag on pull-to-sit Head will not be able to be maintained in midline Prone position is poorly tolerated Patient will not be able to prop and typically cannot turn their heads from side to side in prone Spinal muscular atrophy type I Types of spinal muscular atrophy Significant oral motor weakness Has a limited respiratory function and develop an abnormal paradoxical pattern of breathing (+) Appendicular muscle fasciculation and distal tremor (+) Tongue fasciculation Mild to moderate hip flexion, knee flexion, elbow flexion and wrist contractures (+) Ulnar drift of the fingers Absent deep tendon reflexes All motor milestones are delayed; 95% of all patients are dead by 18 months Spinal muscular atrophy type II Types of spinal muscular atrophy Disease onset is usually more insidious than that of SMA I Initial presentation is typically later in the first year of life when the child is noted to not be pulling to stand Proximal weakness and wasting of the extremities and trunk musculature Spinal muscular atrophy type II Types of spinal muscular atrophy (+) Tongue fasciculation (+) Fine resting tremor (Tecklin) DTRs are depressed and usually absent in the lower extremities Appendicular or thoracic muscle wall fasciculation may be observed Motor skills that employ a long lever arm are most difficult for these patients Spinal muscular atrophy type II Types of spinal muscular atrophy Contractures LE → knee flexors and ankle plantarflexors UE → elbow flexors and wrist flexors Patient do not ambulate independently Some of these children may learn to walk with bracing or an assistive device Ambulation is often not functional Spinal muscular atrophy type II Types of spinal muscular atrophy Predisposed to kyphoscoliosis Feeding and swallowing difficulties are seldom a problem These children often survive into adulthood Spinal muscular atrophy type III Types of spinal muscular atrophy A.k.a. Kugelberg–Welander Disease It is characterized by symptoms of progressive weakness, wasting, absent reflexes and fasciculation Age of onset: can vary from the toddler years into adulthood Motor milestones may be delayed in infancy Spinal muscular atrophy type III Types of spinal muscular atrophy Proximal muscles are usually involved first Deep tendon reflexes are decreased Contractures and progressive spinal deformities are uncommon as long as the child remains ambulatory Spinal muscular atrophy type III Types of spinal muscular atrophy (+) Exaggerated lumbar lordosis and anterior pelvic tilt (+) Waddling gait pattern with pelvic drop and lateral trunk lean over the stance-phase side Facial weakness is sometimes noted Fasciculation are noted in about half of the patients Calf pseudohypertrophy has been occasionally noted, but wasting of affected musculature is more prominent. Deep tendon reflexes are diminished → absent  SMA I SMA II SMA III (WERNIG HOFFMAN) (KUGELBERG WELANDER) Onset 18 months IIIa 3 years Genetics SMN1: AR homozygous SMN1: AR homozygous SMN1: AR homozygous SMN2: men In late-onset MG After age 50 years Women < men Myasthenia gravis Clinical presentation muscle weakness and fatigability → most commonly in the muscles controlling eye movement, chewing, swallowing, and facial expressions Hallmark: Fatigable and rapidly fluctuating asymmetric ptosis Ocular muscle dysfunction is usually one of the first symptoms Myasthenia gravis Clinical presentation Exacerbated with exercise, heat or time of a day Cranial nerve affectation (+) ptosis, diplopia, weak eye opening and eye closing Weakness of jaw muscle Weakness of facial muscle → myasthenic snarl Bulbar involvement Dysarthritic, dysphonic speech, dysphagia and nasal quality of speech Myasthenia gravis Clinical presentation Tongue occasionally shows the characteristic triple grooved appearance with two lateral and one central furrow Proximal muscles are affected more than distal Weakness of neck muscles Fatigue may be demonstrated by movement against a constant resistance Limb reflexes are often hyperactive and fatigue on repeated testing Muscle wasting (15% of cases) Stress, infection and pregnancy and drugs that alter neuromuscular transmission all exacerbate the weakness Myasthenia gravis Ancillary procedures and tests Anticholinesterase drugs are used to confirm diagnosis Endrophonium test Serology: Anti-Muscle specific Kinase (anti-MUSK) antibodies are found in a proportion of anti-AchR negative patients Elevated acetylcholine receptor antibodies Muscle biopsy: loss of junctional folds and receptors Myasthenia gravis Single-fiber EMG is the most sensitive test for myasthenia gravis Electrodiagnostic: Decrementing responses in a distal hand muscle on repetitive nerve stimulation at 2 or 3 Hz Chest x-ray: large mediastinal mass CT of chest Myasthenia gravis Myasthenia gravis Pharmacological treatment Anticholinesterase drugs This is the longest established form of treatment It enhanced the receptor stimulation Myasthenia gravis Pharmacological treatment Steroids For generalised and occasionally severe ocular disease Prednisone 60 mg/day is initially used Immunosuppressants Azathioprine and cyclosporine Plasmapheresis Plasma filtration removes antibodies and other circulating factors and has short term benefit (4–6 weeks) Myasthenia gravis Surgical management Thymectomy There are two indications for this: When thymoma is present When myasthenia is generalised and benefits of surgery outweigh risks Myasthenia gravis PT management Patient education about energy conservation Breathing exercises Adaptive equipments Assistive device Exercise protocol Myasthenia gravis Emergency treatment – myasthenic/cholinergic crises Identify and treat precipitating cause Sit patient at 45°, clear airway, give nasal O2 if overt respiratory failure – intubate and ventilate Cholinergic crisis s/sx worsening weakness increased sweating, saliva and bronchial secretions small pupils (miosis) eventual respiratory failure Myasthenia gravis Emergency treatment – myasthenic/cholinergic crises Myasthenic crisis Cholinergic crisis IV neostigmine 8–12 mg/24 hrs with Withdraw all anticholinesterases Atropine 0.5 mg TID Prednisolone 100 mg daily Monitor respiratory function (vital capacity) Consider plasmapheresis or IVIG Wean from ventilation when appropriate Change IV to oral anticholinesterases when Re-introduce oral anti-cholinesterases in low able to swallow dose and gradually increase Myasthenia gravis Neonatal form of myasthenia gravis Suggested by poor crying/sucking and floppy limbs Presents within 48 hours of birth and may persist until the end of 3rd month. Cause: passive transplacental passage of IgG (acetylcholine receptor antibodies). Treatment: anticholinesterases is required until spontaneous recovery occurs. Myasthenia gravis Congenital myasthenias These non-immunologic disorders are due to pre, post and mixed synaptic defects They generally present in infancy though onset can be delayed into adult life. Characteristically fatiguing weakness affects limb (with associated skeletal abnormalities when early age of onset), ocular, bulbar and respiratory muscle groups AChR antibodies are absent Treatments: anticholinesterases or 3,4-diaminopyridine Lambert Eaton Myasthenic Syndrome (LEMS) An autoimmune disorder of the neuromuscular junction Autoimmune response against active site on presynaptic membrane (voltage-gated calcium channel) IgG voltage-gated calcium channel antibodies (VGCCAs) block the cholinergic synapse resulting in reduced acetylcholine release Strong association with malignancy → oat cell carcinoma of the lung (most common) Lambert Eaton Myasthenic Syndrome (LEMS) Clinical features Male > Female Weakness of lower then upper limbs with a tendency to fatigue Second wind phenomenon Rarely affected → Ocular and bulbar muscle Proximal pattern of wasting Diminished tendon reflexes Autonomic (cholinergic) dysfunction → impotence, dry mouth and visual disturbance Lambert Eaton Myasthenic Syndrome (LEMS) Diagnosis Rapid repetitive nerve stimulation 20 Hz or a brief voluntary maximal contraction Incrementing response to repetitive nerve stimulation A postactivation increase in CMAP of more than 200% is seen Lambert Eaton Myasthenic Syndrome (LEMS) Treatment 3,4-diaminopyridine and pyridostigmine can improve symptoms Immunosuppression with steroids, plasmapheresis or IVIG can suppress the underlying immunological abnormality This syndrome may respond to the removal of the underlying neoplasm if present Botulism Rare disorder Caused by bacterium Clostridium botulinum Mode of infection: oral ingestion or wound infection Begins 2-7 days after ingestion Severe involvement → NMJ is completely blocked and no facilitation with rapid stimulation Botulism Clinical features Rapid-onset paralysis of the eye muscles, followed by rapid spread to other parts of the body Bulbar symptoms first → ptosis, dysphagia, dysarthria Gastrointestinal symptoms → diarrhea, nausea, vomiting Respiratory and cardiac dysfunction Needle EMG reveals normal or polyphasic MUAPs with low amplitudes and short durations (+) toxins in the blood and stool Botulism Treatment Trivalent ABE antitoxin Wound debridement and antibiotic Recovery → collateral sprouting Thank you!