Neurology

Muscle disease

Dermatomyositis

Introduction

  • Idiopathic inflammatory myopathy with a vasculopathy which affects Skin and muscles but 20 % association with malignancy of lung, breast, ovary or gut
  • T and B cell mediated inflammatory response around muscle capillaries with micro-infarction and damage
  • Antibodies to capillary endothelial cells.

Clinical

  • A symmetrical muscle weakness is proximal and progressive with tender muscles
  • Dysphagia and dysphonia
  • A scaly red palpable rash over the MCP or IP joints suggests Dermatomyositis
  • A periorbital oedema and purplish discolouration is significant and is called the "Heliotrope" rash
  • The rash may be over the medial malleolus and is called "Gottron's sign"
  • Over the shoulders and back - the shawl sign V type erythematous rash
  • "Mechanic's hands," a roughening and cracking of the skin of the tips and lateral aspects of the fingers
  • Cardiac involvement and Interstitial lung disease
  • Photosensitive rashes are common, Nailfold telangiectasia
  • CK is elevated (may be elevated 50-fold) as is aldolase, LDH and AST suggests myositis

Investigations

  • Muscle biopsy shows chronic inflammatory changes
  • EMG shows - fibrillation potentials, short duration low amplitude polyphasic potentials, bizarre high frequency discharges
  • Positive ANA
  • Anti-Jo-1 antibody, directed against histidyl-tRNA synthase
  • Anti -SRP (signal recognition particle) but are rare

Management

  • Immunosuppression e.g. Steroids 1mg/kg and then slowly tapered down
  • Methotrexate, Azathioprine, Mycophenolate
  • Skin disease - sunscreens for photosensitive rash
  • Chloroquine, Hydroxychloroquine

Polymyositis

Introduction

  • Acquired proximal inflammatory myopathy which has a poorer prognosis than Dermatomyositis and only the muscles affected
  • CD8+ T cell mediated muscle damage
  • NO RELATIONSHIP TO MALIGNANCY
  • Women > Men

Clinical

  • Proximal symmetrical Muscle weakness is progressive
  • Weight loss and neck weakness and Dysphagia
  • NO skin or eye or facial involvement

Investigations

  • Anti-Jo1 suggests increased risk of lung infiltrates and cardiomyopathy
  • CK is elevated (may be elevated 50-fold) as is aldolase, LDH and AST suggests myositis
  • Muscle biopsy shows chronic inflammatory changes
  • EMG shows - fibrillation potentials, short duration low amplitude polyphasic potentials, bizarre high frequency discharges
  • Anti-Jo-1 antibody in 30% directed against histidyl-tRNA synthase
  • Anti -SRP (signal recognition particle) 3

Management

  • Immunosuppression - Steroids 1mg/kg and then slowly tapered down
  • Methotrexate, Azathioprine, Mycophenolate

Inclusion body myositis

Introduction

  • Commonest cause of muscle disease in those over 50 and diagnosis requires muscle biopsy and inclusion bodies on electron microscopy
  • Poor response to immunosuppression.
  • It is an idiopathic T cell mediated inflammatory myopathy.

Clinical

  • Commoner in men and leads a slow protracted progress over the years.
  • Distal symmetrical or asymmetrical weakness and frequent falls
  • Selective weakness of the long flexors of the hands and wrists, weakened quadriceps.
  • Dysphagia may be seen in 60%.
  • Weakness may lead to falls and fractures
  • Muscle wasting

Investigations

  • ESR - usually normal and CK is only mildly raised (x3-5) compared with other idiopathic inflammatory myopathies
  • Muscle biopsy shows intracellular inclusions containing helical filaments similar to those found in brain in Alzheimer's disease
  • EMG - myopathic and neurogenic abnormalities
  • Muscle biopsy - abnormal fibres, filamentous inclusions in nucleus and cytoplasm seen on EM is needed to make the diagnosis

Management

  • IBM is less steroid responsive or responsive to Immunosuppression than the other inflammatory myopathies
  • Some are steroid responsive and may warrant immunosuppression
  • Gradual weakness with disability can be seen

Non inflammatory myopathy

Causes

  • Steroids
  • Thyrotoxicosis
  • Osteomalacia and Vitamin D deficiency
  • Addison's disease
  • Hyperthyroid - weak shoulder girdle
  • Steroids - proximal muscle wasting 325 Metabolic muscle diseases and other conditions
  • Pompe's disease

Glycogen storage disease

Aetiology

  • Autosomal recessive, Alpha glucosidase deficiency

Clinical

  • Variable presentations from neonate to child
  • Progressive proximal weakness, hypotonia, cardiac and respiratory problems
  • Hepatomegaly
  • Ranges from death in infancy to survival to adulthood

Investigations

  • Elevated CK
  • EMG Myopathic
  • Muscle Biopsy - vacuoles contain glycogen

Management

  • Supportive and Enzyme replacement therapies being looked at

McArdle's disease

Introduction

  • Glycogen storage disease - Myophosphorylase deficiency
  • McArdle's disease is an Autosomal recessive Glycogen storage disease type V due to a defect on Chromosome 11q13 such that Patient cannot use glycogen as a substrate for energy
  • Glycogen cannot be converted by myophosphorylase from glycogen to glucose 6 phosphate
  • Glycogen is the primary source of energy for high intensity muscle activity

Clinical

  • Usually comes on in an otherwise normal adult/adolescent/child.
  • Onset in childhood or adolescence with exercise induced muscle pain, weakness and stiffness requiring rest
  • Half of patients describe a "second wind" as patient switches to Free fatty acid metabolism
  • Muscles become contracted with exercise
  • Myoglobinuria occurs after strenuous exercise
  • Also exercise intolerance, fatigue, myalgia, cramps
  • Poor endurance, muscle swelling, and fixed weakness 3
  • Rhabdomyolysis and Myoglobinuria may lead to renal failure

Investigations

  • Muscle biopsy is required for the definitive diagnosis and show glycogen filled vacuoles
  • At rest, the serum CK is usually elevated in most patients and more so with exercise and reduced Lactate rises with exercise
  • DNA analysis from peripheral white cells defect on Chromosome 11q13

Management

  • Oral sucrose administration, moderate aerobic exercise, and supplementation with oral creatine and vitamin B6
  • Management is that Anaerobic exercise should be avoided or else Rhabdomyolysis can occur
  • Otherwise the prognosis is good with a normal life

Mitochondrial myopathies in general

Introduction

  • Maternally inherited mitochondrial DNA (mtDNA) encodes 22 tRNAs 2 rRNAs and most of the enzymes of the respiratory chain
  • The extent of mutated mtDNA and normal mtDNA within the cell determines the phenotype.
  • Some of the mitochondrial enzymes are from nuclear DNA so some mitochondrial diseases are inherited autosomally

Syndromes

  • Kearns-Sayre syndrome
  • MELAS syndrome
  • MERFF
  • Lebers hereditary optic neuropathy
  • NARP
  • Myopathy and diabetes
  • Affects eye muscles commonly with a progressive external with occurrence relative to the list of syndromes

Clinical

  • ophthalmoplegia (1), bilateral ptosis, Poor exercise tolerance
  • Myoclonus (2, 3), Generalised seizures (2,3 ,5)
  • ataxia (3, 4, 5), childhood and young adult stroke (2)
  • dementia (2, 3,5) encephalopathy (2) Polyneuropathy (4,5)
  • Deafness, optic atrophy (4) cataract, retinitis pigmentosa (1,5)
  • Migraine, Basal ganglion calcification, Dystonia
  • cardiomyopathy and conduction problems (1,4)
  • Sudden cardiac death (1), Diabetes, hypogonadal, diarrhoea and obstruction
  • skin lipomas, ichthyosis
  • red ragged fibres (1,3, 4) and lactic acidosis (2)

Investigations

  • Muscle Biopsy - red ragged fibres from an accumulation of mitochondria
  • CSF - elevated protein and elevated lactate
  • Serum - elevated pyruvate, lactate and alanine
  • MRI - non specific basal ganglia and cerebellar and cerebral changes

Management

  • No treatment only supportive
  • Genetic analysis and counselling

Malignant hyperpyrexia

Aetiology

  • Asymptomatic until anaesthesia using halothane or suxamethomium which causes a massive rise in intracellular Calcium ions causing sustained muscle contraction

Clinical

  • Severe sustained, Muscle spasm, shock, obtunded
  • Hyperpyrexia due to muscle contraction generating heat and Death from circulatory failure is possible

Investigations

  • Elevated CK

Management

  • Cooling, rehydration, supportive, Dantrolene

Familial Hypokalaemic periodic paralysis

Introduction

  • A rare cause of a treatable acute systemic weakness usually in caucasians

Aetiology

  • Altered membrane excitability due to changes in potassium levels
  • Can happen in any cause that disturbs potassium balance.
  • Mutations in skeletal muscle voltage gated calcium channel
  • CACL1A3 in most cases
  • Others have mutations in sodium channel alpha subunit (SCN4A)

Clinical

  • Muscle weakness legs >> arms
  • Can involve all muscles including skeletal, bulbar, respirator and cranial
  • Deep tendon Reflexes lost
  • Consciousness and sensation intact
  • Weakness can occur with Hypokalaemia but also normokalaemia and hyperkalaemia

Muscular dystrophies and other disorders

Duchenne Muscular dystrophy

Introduction

  • Xp21 gene mutation causing a loss of dystrophin a protein needed for structural integrity of muscle action seen in 1/
  • The Gene for dystrophin is huge and
  • Dystophin is a subsarcolemmal structural protein connecting actin to the extracellular matrix
  • 30% are de novo mutations 33

Clinical

  • Proximal usual Limb girdle weakness
  • Delayed walking as infant and pseudohypertrophy of the calves
  • Gower's manoeuvre: Climbs up legs' on rising from the floor
  • Dilated cardiomyopathy
  • Wheelchair bound in teens
  • Respiratory muscle weakness and Death in 20/30s

Investigations

  • Grossly elevated CK x 50 and EMG - myopathic
  • ECG/Echo - cardiomyopathy
  • Muscle biopsy - fails to stain for dystrophin 3

Management

  • Spinal surgery for scoliosis
  • Corticosteroids to slow disease progression
  • Anabolic steroids may help muscle bulk
  • Assisted nocturnal ventilation can help improved survival
  • Avoid anaesthesia e.g. succinylcholine or halothane can cause a neuroleptic malignant syndrome

Becker Muscular dystrophy

Introduction

  • Like Duchenne also due to a mutation at Xp21 leading to reduced dystrophin levels but much less clinically severe in outcome

Clinical

  • As above but just with a much slower progression 3
  • Muscle pains and difficulty climbing steps
  • Other features similar to DMD

Investigations

  • Grossly elevated CK x 10 and EMG - myopathic
  • ECHO/ECG - cardiomyopathy
  • Muscle Biopsy - reduced dystrophin

Management

  • Conservative with a much better prognosis than Duchenne

Myotonic Dystrophy

Introduction

  • Autosomal dominant disorder with facial, cardiac and myotonic features
  • Affects gene for the myotonic dystrophy protein kinase
  • Seen in Male and female diagnosed age 15-40 CTG trinucleotide repeats and anticipation.
  • Type 1 - commoner CTG repeats chromosome 19 and Type 2 - CCTG repeat on Chromosome 3

Clinical

  • Frontal balding, Ptosis and cataracts and Smooth expressionless forehead
  • Wasted facial, Sternomastoid Shoulder and Quadriceps
  • Myotonia - difficulty relaxing following contraction - shake hands
  • Male and female infertility, Learning disability, Heart block, Diabetes
  • Presentation at birth with poor feeding in an affected mother where the condition may be undiagnosed and the child display a more severe phenotype

Investigations

  • ECG - heart block
  • Glucose tolerance test for diabetes if suspected
  • Genetic analysis to show trinucleotide repeats

Management

  • Genetic advice and counselling
  • Phenytoin or mexilietine may help myotonia
  • Early death may be due to cardiomyopathy

Facioscapulohumeral muscular dystrophy

Introduction

  • Autosomal dominant with a mutation on Chromosome
  • Heart unaffected

Clinical

  • Eye/ hearing problems
  • Facial weakness- can't whistle, Scapular "winging" on abduction
  • Humeral muscle weak but spared deltoids, Weakness at pelvic girdle
  • No cardiomyopathy
  • Exudative retinopathy
  • High frequency sensory hearing loss

Investigations

  • Genetic analysis
  • Mild elevated CK x 2-7 and EMG - myopathic

Management

  • Physiotherapy and Occupation therapy
  • Exudative retinopathy - treated with photocoagulation

Limb girdle dystrophy

Introduction

  • Not a specific disease
  • Autosomal dominant and recessive types
  • Various gene mutations e.g. Dystrophin, Sarcoglycan,Dysferlin

Clinical

  • Cardiomyopathy
  • Respiratory muscle involvement
  • Clinically similar to DMD and BMD with Pelvic and Shoulder girdle weakness

Investigations

  • Elevated CK
  • EMG confirms a primary myopathic process
  • Genetic analysis
  • ECHO/ECG - cardiomyopathy

Management

  • Supportive, Prognosis variable

Congenital myopathies

Introduction

  • These are present from birth and birth with very slow progression if at all
  • May be inherited AD or XLR
  • Various forms - Central core myopathy, Nemaline myopathy, Centronuclear myopathy

Clinical

  • Floppy baby, slow to walk
  • Proximal myopathy with Gower's sign.
  • Face and extraocular muscles
  • Pectus excavatum, pes cavus
  • Cardiomyopathy uncommon

Investigations

  • CK is normal or slightly elevated
  • EMG myopathic
  • Muscle biopsy shows distinct structural abnormalities

Management

  • Supportive