Acute Motor Neuropathy

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Acute Motor Neuropathy

Disorders of the Peripheral Nervous System

Peripheral Nerve DisordersThe spectrum of peripheral nerve disorders includesMononeuropathies (entrapment, trauma, etc)

Mononeuritis multiplex (DM, vasculitis)

Plexopathies (immune, neoplastic)

Radiculopathies (discs, immune)

Peripheral Neuropathies

Peripheral Neuropathies (PN) Peripheral neuropathies may beoperationally defined as a generalised disorder of peripheralmotor, sensory or autonomic nerves, but excluding single nerve lesionscaused by entrapment or trauma (Warlow. 1991)

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

Peripheral Neuropathies (PN) >100 etiological factors have been identified in patients with PN (Asbury and Thomas. 1995; McLeod. 1995)

Immune: GBS, CIDP, Paraneoplastic, VASCULITISVitamin deficiency: B1, B6, B12, Vit EToxins and metals: OP, lead, ALCOHOLEndocrine: diabetes, thyroid, parathyroidDrugs: Vincristine, Isoniazid, phenytoinGenetic: HMSN, HLPP, HMN, ALDIDIOPATHIC

Workup of a patient with suspected Peripheral Neuropathy

History Time course (acute, subacute,chronic, episodic)Negative numbnessPostive tingling, painWeakness and loss of functionBalancePostural dizzinessPMH ?DMMedicationSocial, toxins, dietFamily history

Workup of a patient with suspected Peripheral NeuropathyExaminationGait (foot drop, stepage, unsteady Romberg positive)Cranial Nerves (retinopathy; facial, bulbar, or neckweakness, tonic pupils)LimbsPseudoathetosis, Pes cavus, Clawing, Wasting, fasiculationFlaccidity, palpable nervesDistal weakness (radiculopathy)Reduced or absent DTRsGlove loss, allodynia (Small or large fibre)Systemic rash, BP

Workup of a patient with suspected Peripheral NeuropathyNeurophysiologyOften indicates nerve pathologyDemyelination (low velocities, latencies)Axonal change (low amp SNAPs and CMAPs)Neuronopathy (very low or absent NAP)

Special tests are needed to look at small fibrefunction

Workup of a patient with suspected Peripheral NeuropathyBloodsFBC, U&Es, Ca and LFTs, RBG, B12, Folate, VDRL, TFTs, Autoantibodies (VLCFAs etc)

CSF (protein)

NERVE BIOPSY (Aetiology not existence of neuropathy)

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).

Guilllain Barre Syndrome (GBS)GBS is a leading cause of neuromuscular paralysisworld-wide (UK annual incidence of 1.0-2.0 per100,000, 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 soldiersin the First World War with trench fever and noted anincrease in cerebrospinal fluid protein, though not cellsalbuminocytologic dissociation.

Guilllain Barre Syndrome (GBS) GBS is considered an immune-mediated disorder, strong supportive evidence includes Frequent association with preceding infection orvaccinationCoexistent auto-immune diseaseResponse to immunomodulatory therapyActivated T cells and humoral responses against neuralantigens

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 musclesWeakness of respiratory muscles (VC)Reflexes are gradually reduced and then lostSensory symptoms and signs (back pain) Autonomic failure is seen in a few (morbidity and mortality)

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)

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 statePNS myasthenia, polio, tetanus, botulism, buckthorn poisoning, malignant meningitis

Guilllain Barre Syndrome (GBS) Immunotherpy (Steroids, IVIG, Exchange)

Supportive carePainVentilationCommunication

Prognosis Monophasic, 10-25% significant disability at 1yr

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 NMJNerve 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

Healthy Neuromuscular Junction

The Physiology of Neuromuscular transmissionNeuronal Action potential invades the pre-synaptic nerve terminalDepolarisation triggers opening of VGCCsCalcium influx triggers quantal release of AChACh binds to post synaptic nAChRsCa and Na ions influx through nAChR triggering muscle membrane depolarisation via VGSCs- CMAP and muscle contraction

Spontaneous and Nerve Evoked Endplate Responses

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 theformation of anti- nAChR antibodies

MG is common in young women, and older men

MG is characterized by fluctuating and fatigable weaknessWeakness may be limited to a few muscles, such as the extraocularmuscles, 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

Myasthenia Gravis (MG)Ocular features: ptosis, diplopia, ophthalmoplegia

Facial weakness esp ob oculi and oris (snarl)

Bulbar weakness: nasal speech, reduced gag, swallowingproblems, aspiration (silent), weak neck (dropped)

Limb weakness: proximal, fatiguable

Reflexes: normal

Respiratory weakness: diaphragm and intercostal

Myasthenia Gravis (MG) Sources of Diagnostic ConfusionOcular 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

Myasthenia Gravis (MG)

MG is a defect of neuromuscular transmission withreduced efficacy of Acetyl Choline at the post synapticmotor endplate due to pathogenic antibodies which Block the nAChR, Down regulate the nAChR& cause complement dependent destruction of the motor endplate

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

Myasthenia Gravis (MG)Diagnosis Typical clinical pictureDetection 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

Repetitive Nerve Stimulation (Supramaximal 2Hz)

Myasthenia Gravis (MG)TreatmentSymptomatic (pyridostigmine oft with probatheline)

Thymectomy Hyperplasia (trans-sternal approach), Thymoma (locally invasive)

Immunotherapy steroids, and other agents including Azathioprineplasma exchange, IVIG

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)

Lambert Eaton Myasthenic syndrome (LEMS)

Clinical featuresDry mouthFatigable weakness of proximal muscles (like MG)Wasting of proximal muscles (X MG)Depressed reflexes (X MG)Ocular and bulbar weakness rare (X MG)

Lambert Eaton Myasthenic syndrome (LEMS)

Diagnosis Typical clinical pictureDetection of anti-VGCC antibodies in serumPositive 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)

Repetitive Nerve Stimulation (Supramaximal 2Hz)

Lambert Eaton Myasthenic syndrome (LEMS)

Treatment

Treating the underlying lung tumour improves LEMS

Treatment for LEMS per seSymptomatic (mestinon, 3

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