Disorders of the Peripheral Nervous System

1. Disorders of the Peripheral Nervous System

2. Peripheral Nerve Disorders The spectrum of peripheral nerve disorders includes • Mononeuropathies (entrapment, trauma, etc) • Mononeuritis multiplex (DM, vasculitis) • Plexopathies (immune, neoplastic) • Radiculopathies (discs, immune) • Peripheral Neuropathies

3. Peripheral Neuropathies (PN) Peripheral neuropathies may be operationally defined as a “generalised disorder of peripheral motor, sensory or autonomic nerves, but excluding single nerve lesions caused by entrapment or trauma” (Warlow. 1991)

4. Peripheral Neuropathies (PN) Peripheral neuropathies are heterogeneous disorders with variation in peripheral nerve components involved, clinical course, pathology and presumed aetiology (Dyck et al. 1996; McLeod. 1995).

5. Peripheral Neuropathies (PN) >100 etiological factors have been identified in patients with PN (Asbury and Thomas. 1995; McLeod. 1995) Immune: GBS, CIDP, Paraneoplastic, VASCULITIS Vitamin deficiency: B1, B6, B12, Vit E Toxins and metals: OP, lead, ALCOHOL Endocrine: diabetes, thyroid, parathyroid Drugs: Vincristine, Isoniazid, phenytoin Genetic: HMSN, HLPP, HMN, ALD IDIOPATHIC

6. Workup of a patient with suspected Peripheral Neuropathy • History Time course (acute, subacute,chronic, episodic) Negative numbness Postive tingling, pain Weakness and loss of function Balance Postural dizziness PMH ?DM Medication Social, toxins, diet Family history

7. Workup of a patient with suspected Peripheral Neuropathy • Examination Gait (foot drop, stepage, unsteady Romberg positive) Cranial Nerves (retinopathy; facial, bulbar, or neck weakness, tonic pupils) Limbs Pseudoathetosis, Pes cavus, Clawing, Wasting, fasiculation Flaccidity, palpable nerves Distal weakness (radiculopathy) Reduced or absent DTRs Glove loss, allodynia (Small or large fibre) Systemic rash, BP

8. Workup of a patient with suspected Peripheral Neuropathy Neurophysiology Often indicates nerve pathology Demyelination (low velocities,  latencies) Axonal change (low amp SNAPs and CMAPs) Neuronopathy (very low or absent NAP) Special tests are needed to look at small fibre function

9. Workup of a patient with suspected Peripheral Neuropathy Bloods FBC, U&Es, Ca and LFTs, RBG, B12, Folate, VDRL, TFTs, Autoantibodies (VLCFAs etc) CSF (protein) NERVE BIOPSY (Aetiology not existence of neuropathy)

10. Guilllain Barre Syndrome (GBS) GBS is defined as “a syndrome of acute weakness of the limbs and reduced or absent reflexes, with or without sensory loss attributable to a disorder of the peripheral nerves not due to systemic disease” (Hughes. 1990). GBS is a clinical diagnosis though there are frequently abnormal laboratory features including an elevated CSF protein and evidence of peripheral nerve demyelination (Hughes. 1994; Hartung et al. 1998).

11. Guilllain Barre Syndrome (GBS) GBS is a leading cause of neuromuscular paralysis world-wide (UK annual incidence of 1.0-2.0 per 100,000, with age, and M>F) In 1859 Landry described 10pts with an ascending paralysis caused by peripheral nerve dysfunction 1916 Guillain, Barre and Strohl described an acute, monophasic, benign, flaccid paralysis in French soldiers in the First World War with trench fever and noted an increase in cerebrospinal fluid protein, though not cells albuminocytologic dissociation.

12. Guilllain Barre Syndrome (GBS) GBS is considered an immune-mediated disorder, strong supportive evidence includes • Frequent association with preceding infection or vaccination  • Coexistent auto-immune disease • Response to immunomodulatory therapy • Activated T cells and humoral responses against neural antigens

13. Guilllain Barre Syndrome (GBS) The typical clinical features of GBS reflect prominent involvement of motor nerves, and may progress for up to four weeks: Weakness of all four limbs with a proximal bias, Bilateral facial paralysis, and Weakness of bulbar muscles Weakness of respiratory muscles (VC) Reflexes are gradually reduced and then lost Sensory symptoms and signs (back pain) Autonomic failure is seen in a few (morbidity and mortality)

14. Guilllain Barre Syndrome (GBS) • The laboratory features of GBS also evolve with time- • Initial CSF protein is often normal, but becomes elevated within 3/52 in over 90% of patients. • Initial electrophysiological studies are often normal, but become abnormal within three weeks in the majority of patients (Abnormalities in motor conduction with proximal conduction block, prolonged distal motor latencies or generalised slowing of conduction are common; abnormalities of sensory nerve conduction are also common)

15. Guilllain Barre Syndrome (GBS) As GBS is a clinical syndrome it is important to exclude both other causes of neuropathy and other neurological disorders: CNS spinal cord compression, brainstem disorders including locked in state PNS myasthenia, polio, tetanus, botulism, buckthorn poisoning, malignant meningitis

16. Guilllain Barre Syndrome (GBS) Immunotherpy (Steroids, IVIG, Exchange) Supportive care Pain Ventilation Communication Prognosis Monophasic, 10-25% significant disability at 1yr

17. The Anatomy of the Neuromuscular Junction • Motor neurone terminates as a bouton or pre-synaptic nerve terminal separated from the muscle by a thin synaptic cleft (Motor endplate) • The blood nerve barrier is relatively deficient at the NMJ • Nerve and muscle are kept in close proximity by bridging protein (laminin), with release zones and the crests of post synaptic folds aligned • The skeletal neuromuscular junction is the most studied and best understood synapse

18. Healthy Neuromuscular Junction

19. The Physiology of Neuromuscular transmission • Neuronal Action potential invades the pre-synaptic nerve terminal • Depolarisation triggers opening of VGCCs • Calcium influx triggers quantal release of ACh • ACh binds to post synaptic nAChRs • Ca and Na ions influx through nAChR triggering muscle membrane depolarisation via VGSCs- CMAP and muscle contraction

20. Spontaneous and Nerve Evoked Endplate Responses

21. Myasthenia Gravis (MG) MG is the most common disorder of neuromuscular transmission Incidence 2-6 per 106 , prevalence 40 per 106 population MG is an acquired autoimmune disease characterised by the formation of anti- nAChR antibodies MG is common in young women, and older men MG is characterized by fluctuating and fatigable weakness Weakness may be limited to a few muscles, such as the extraocular muscles, bulbar, limb or be generalised in fashion As the weakness is often worse with activity and improved by rest, it is often worse in the evening

22. Myasthenia Gravis (MG) Ocular features: ptosis, diplopia, ophthalmoplegia Facial weakness esp ob oculi and oris (snarl) Bulbar weakness: nasal speech, reduced gag, swallowing problems, aspiration (silent), weak neck (dropped) Limb weakness: proximal, fatiguable Reflexes: normal Respiratory weakness: diaphragm and intercostal

23. Myasthenia Gravis (MG) Sources of Diagnostic Confusion Ocular thyroid, orbital myositis, cavernous sinus, III, IV,VI, brainstem lesions, botulism, MFS variant of GBS Facial GBS, myopathies Bulbar LMN MND, skull base, polymyositis Neck MG, MND, FSH, IM, GBS Limbs Myopathies, LEMS, Motor Neuropathies

24. Myasthenia Gravis (MG) MG is a defect of neuromuscular transmission with reduced efficacy of Acetyl Choline at the post synaptic motor endplate due to pathogenic antibodies which • Block the nAChR, • Down regulate the nAChR • & cause complement dependent destruction of the motor endplate

25. Myasthenia Gravis (MG) The immunopathogenesis of MG is unclear but involves • Genetic factors (HLA B8) • Thymus • Vast majority of young onset cases are autoimmune and associated with thymic hyperplasia • Around 10% of patients with MG, often older patients) have an associated thymic tumour (oft striated muscle Abs) • Seronegative (10% gen, 50% OMG) • Neonatal MG

26. Myasthenia Gravis (MG) • Diagnosis • Typical clinical picture • Detection of anti-AChR antibodies in serum (90%) • Positive Tensilon test (atropine) • Repeptitive nerve stimulation at low frequency leads to a decrement in compound muscle action potential amplitude

27. Repetitive Nerve Stimulation (Supramaximal 2Hz)

28. Myasthenia Gravis (MG) Treatment • Symptomatic (pyridostigmine oft with probatheline) • Thymectomy • Hyperplasia (trans-sternal approach), • Thymoma (locally invasive) • Immunotherapy • steroids, and other agents including Azathioprine • plasma exchange, • IVIG

29. Lambert Eaton Myasthenic syndrome (LEMS) • A defect of neuromuscular transmission with reduced quantal release of Acetyl Choline from the presynaptic nerve terminal • Pathogenic antibodies directed against voltage gated calcium channels (VGCCS) expressed at the NMJ and autonomic ganglia • 2/3 patients with LEMS have cancer, most commonly Small cell lung Ca (express VGCCs)

30. Lambert Eaton Myasthenic syndrome (LEMS) • Clinical features • Dry mouth • Fatigable weakness of proximal muscles (like MG) • Wasting of proximal muscles (X MG) • Depressed reflexes (X MG) • Ocular and bulbar weakness rare (X MG)

31. Lambert Eaton Myasthenic syndrome (LEMS) Diagnosis Typical clinical picture Detection of anti-VGCC antibodies in serum Positive Tensilon test (like MG) Repeptitive nerve stimulation at low frequency leads to a decrement in compound muscle action potential amplitude (like MG) Repeptitive nerve stimulation at high frequency leads to a increment in compound muscle action potential amplitude (X MG)

32. Repetitive Nerve Stimulation (Supramaximal 2Hz)

33. Lambert Eaton Myasthenic syndrome (LEMS) Treatment • Treating the underlying lung tumour improves LEMS • Treatment for LEMS per se • Symptomatic (mestinon, 3-4 DAP) • Immunotherapy (steroids, plasma exchange, IVIG)

34. Muscle Disease Does the patient have a muscle disorder and is it acquired or inherited?

35. Congenital myopathies Lack of structural proteins e.g. Merosin deficient Ultrastructural appearance Central Core Nemaline Rod Inherited muscle disease : Congenital Myopathies

36. Lack of structural proteins Dystrophinopathies (Becker, Duchenne) Sarcoglycanopathies (4 forms of LGMD) Alteration in muscle enzymes Calpain 3 Myotonic dystrophy (DMPK) Inherited muscle disease : Dystrophy

37. Defects in muscle energy metabolism glyco(geno)lysis e.g. McArdles lipid oxidation CPT 1, CPT 2 carnitine deficiency mitochondrial defects Inherited muscle disease : Other

38. Drugs (statins, diuretics) Endocrine (PTH,thyroid) Inflammatory (PM, DM, IBM) Infective (pyomyositis, viral myositis) Toxic (venom) Paraneoplastic (DM) Acquired muscle disease (i)

39. Acquired muscle disease (ii) The spectrum of inflammatory myopathies • Dermatomyositis • Childhood • Adult • Malignancy associated • Polymyositis • Idiopathic • Drug induced • Collagen vascular disease • Jo-1 and other antibodies • Sarcoidosis • Others • Fascitis • Focal myositis • Orbital Inclusion Body Myositis

40. Clinical features of myopathies • Muscle pain • Muscle weakness (limb, bulbar, respiratory) • Breathlessness (respiratory or cardiovascular) • Palpitations (cardiomyopathy or arrthymia) • Skin rash and other systemic features • Myoglobinuria

41. Muscle Pain • Muscle disorders associated with contractures (glycolytic myopathies) • Conditions associated with cramps (idiopathic, neurogenic etc) • Muscle disorders associated with muscle stiffness (myotonias, PMR, FM) • Muscle disorders causing localised or diffuse myalgia (IM, PMR, FM, Mitochondrial) (Kissel and Miller 1999)

42. Causes of muscle pain (i) • Drug or toxin induced • alcohol • Via hypokalaemia: diuretics • Other mechanisms: statins, heroine • Secondary to systemic disease • defects of calcium metabolism: hyper or hypo PTH • defects of thyroid function: hyper or hypo thyroidism • connective tissue disease:SLE, MTCD, SS, etc

43. Causes of muscle pain (ii) Primary muscle diseases Inflammatory myopathies: • polymyositis • dermatomyositis • IBM Defects in muscle energy metabolism: • glycogenolysis • lipid oxidation • mitochondrial defects Dystrophies: • dystrophinopathy • facioscapulohumeral dystrophy Others • PROMM

44. Symptoms of muscle weakness Classically muscle disorders produce proximal weakness with difficulties in • Reaching for high objects • Combing hair • Getting up from low chairs • Getting up stairs • Getting up on to a bus Bulbar symptoms- dysphagia, dysarthria Breathlessness (RS)

45. History of muscle weakness often distinguishes acquired or inherited myopathies • Pre-natal (foetal movements) • Peri-natal (delivery, flat, floppy infant) • Motor milestones (sit, crawl, walk, run) • School (level of sporting achievement) • Occupational hository Armed forces

46. Muscle Weakness (i) • Manual muscle testing and MRC scores • Giveway, pain, and fatigue • Functional assessments, squat, timed Gowers • Hand held dynamometry • Quantitative myometry

47. Muscle Weakness (ii) • Classically muscle disorders present with a proximal or limb girdle pattern of weakness, • BUT • Proximal weakness may be due to peripheral neuropathies • Myasthenia produces proximal weakness but not wasting • Some myopathies produce distal weakness

48. Examination of the musculoskeletal system may distinguish acquired or inherited myopathies • Atrophy • Hypertrophy (pseudo) • Contractures • Rigid spine

49. Myopathy: bulbar features • Speech may be nasal • Swallowing problems • Aspiration symptoms • Beware “silent” aspiration • Neck weakness

50. Neurological causes of neck flexion weakness Myopathic disorders • FSH • Myotonic Dystrophy • Inflammatory myopathies Neuropathic disorders • GBS • CIDP Anterior horn cell disorders • MND • SMA Neuromuscular disorders • Myasthenia Gravis