Transcript Acute Motor Neuropathy

Disorders of the Peripheral
Nervous System
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
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)
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).
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
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
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
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
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)
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 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.
Guilllain Barre Syndrome (GBS)
GBS is considered an immune-mediated disorder,
strong supportive evidence includes
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Frequent association with preceding infection or
vaccination
Coexistent auto-immune disease
Response to immunomodulatory therapy
Activated T cells and humoral responses against neural
antigens
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)
Guilllain Barre Syndrome (GBS)
The laboratory features of GBS also evolve with timeInitial 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 state
PNS myasthenia, polio, tetanus, botulism,
buckthorn poisoning, malignant meningitis
Guilllain Barre Syndrome (GBS)
Immunotherpy (Steroids, IVIG, Exchange)
Supportive care
Pain
Ventilation
Communication
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
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
Healthy Neuromuscular Junction
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
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 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
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
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
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
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
Myasthenia Gravis (MG)
• Diagnosis
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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
Repetitive Nerve Stimulation
(Supramaximal 2Hz)
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
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 features
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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)
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)
Repetitive Nerve Stimulation
(Supramaximal 2Hz)
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)
Muscle Disease
Does the patient
(i) have a muscle disorder and
(ii) is it acquired or inherited?
Inherited muscle disease : Congenital Myopathies
• Congenital myopathies
– Lack of structural proteins e.g. Merosin
deficient
– Ultrastructural appearance
• Central Core
• Nemaline Rod
Inherited muscle disease : Dystrophy
• Lack of structural proteins
– Dystrophinopathies (Becker, Duchenne)
– Sarcoglycanopathies (4 forms of LGMD)
• Alteration in muscle enzymes
– Calpain 3
– Myotonic dystrophy (DMPK)
Inherited muscle disease : Other
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Defects in muscle energy metabolism
– glyco(geno)lysis e.g. McArdles
– lipid oxidation
– CPT 1, CPT 2
– carnitine deficiency
– mitochondrial defects
Acquired muscle disease (i)
Drugs (statins, diuretics)
Endocrine (PTH,thyroid)
Inflammatory (PM, DM, IBM)
Infective (pyomyositis, viral myositis)
Toxic (venom)
Paraneoplastic (DM)
Acquired muscle disease (ii)
The spectrum of inflammatory myopathies
•Polymyositis
•Dermatomyositis
–Idiopathic
–Childhood
–Drug induced
–Adult
–Collagen vascular disease
–Malignancy associated
–Jo-1 and other antibodies
–Sarcoidosis
•Others
–Fascitis
Inclusion Body Myositis
–Focal myositis
–Orbital
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
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)
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
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
Symptoms of muscle weakness
Classically muscle disorders produce proximal weakness
with difficulties in
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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)
History of muscle weakness often
distinguishes acquired or
inherited myopathies
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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
Muscle Weakness (i)
• Manual muscle testing and MRC scores
• Giveway, pain, and fatigue
• Functional assessments, squat, timed
Gowers
• Hand held dynamometry
• Quantitative myometry
Muscle Weakness (ii)
Classically muscle disorders present with a
proximal or limb girdle pattern of weakness,
BUT
1. Proximal weakness may be due to
peripheral neuropathies
2. Myasthenia produces proximal weakness
but not wasting
3. Some myopathies produce distal weakness
Examination of the musculoskeletal
system may distinguish acquired or
inherited myopathies
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Atrophy
Hypertrophy (pseudo)
Contractures
Rigid spine
Myopathy: bulbar features
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Speech may be nasal
Swallowing problems
Aspiration symptoms
Beware “silent” aspiration
Neck weakness
Neurological causes of neck flexion weakness
Myopathic disorders
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FSH
Myotonic Dystrophy
Inflammatory myopathies
Neuropathic disorders
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GBS
CIDP
Anterior horn cell disorders
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MND
SMA
Neuromuscular disorders
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Myasthenia Gravis
Myoglobinuria
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Inflammatory myopathies
Glyco(geno)lysis
Lipid oxidation defect
Mitochondrial disorder
Brody’ syndrome
Drugs (heroin)
Respiratory Involvement in
Neuromuscular Disease (i)
• Respiratory problems occur because of
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Reduced central drive (myotonic dystophy)
Weak intercostal muscles
Weak diaphragmatic muscles (acid maltase)
Involvement of phrenic nerves (GBS)
Involvement of neuromuscular junctions of
intercostal and diaphragmatic muscles
Respiratory Involvement in
Neuromuscular Disease (ii)
• Respiratory symptoms of Neuromuscular
Disease include
– Breathlessness on exertion and on lying flat
(diaphragmatic splinting)
– Nocturnal hypoventilation may result in
daytime hypersomnolence and early morning
headache
Respiratory Involvement in
Neuromuscular Disease (iii)
• Neuromuscular Disease reduce lung compliance and
cause restrictive and NOT obstructive defects in lung
function tests
– VCs and not Peak flow are the measure of choice
• Sniff pressures and diaphragmatic screening
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• Nocturnal oximetry and ear lobe blood gases
Serum Creatine kinase: value and limitations
The most sensitive enzyme for muscle disease
BUT
1. Normal: does not exclude muscle disease
(mitochondrial, lipid oxidation disorders, ?IM)
2. CK level only approximates the clinical course
3. Slightly abnormal are seen with intramuscular
injections, liver disease, neurogenic disorders
4. High CK does not equal Inflammatory myopathy
EMG : value and limitations
• EMG (unlike NCS) requires value judgments and is
investigator dependent
• EMG is crucial in excluding neuropathic disorders
• A myopathic EMG occurs in a variety of muscle
disorders
• The significance of EMG findings always depends on
the clinical context
Muscle biopsy : value and limitations
• Biopsy is straightforward but processing is technically
demanding
• Choice of muscle to biopsy (weak, avoid atrophied
muscles-endstage pathology)
• Like EMG muscle biopsy evaluation requires value
judgments and is investigator dependent
• Biopsy needs to be interpreted within the clinical context
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Avoid over interpretation: ragged red fibre, type II atrophy
If normal on review consider repeating
Inflammatory myopathy or myopathy with inflammation
Polymyositis v dermatomyositis
Polymyositis v Inclusion body myositis
Polymyositis (PM) -Clinical Features
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Adult onset inflammatory myopathy, very rare<16 years
Female>male
Subacute presentation (weeks to months) onset oft unclear
Initial myalgia  muscle tenderness
Proximal > distal weakness
Dysphagia, neck and occ respiratory muscle weakness
No rash
Dermatomyositis (DM) - Clinical Features
• Childhood and adult onset inflammatory myopathy
• Female>male
• Rash prior to or with muscle weakness (amyopathic), skin
features can include
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Heliotrope rash on eyelids  Facial erythema
Erythema of trunk and exposed areas
Erythema of knuckles with scaly eruption- Gottron rash
Dilated capillary loops at base of fingernails
Cracked, dirty lateral borders of hands “Mechanics” hands
Acute or subacute presentation (few weeks)
Initial myalgia  muscle tenderness
Proximal > distal weakness
Dysphagia, neck and occ respiratory muscle weakness
PM and DM-Associations
• Connective tissue disorders
– PM: SLE, Sjogren’s, RA
– DM: Scleroderma, MCTD (true overlap)
• Interstitial lung disease (ILD) DM>PM
– Autoimmune-anti-Jo-1
– Drug induced methotrexate
• Cardiac disease
– Myocarditis (rare)
– Steroids  hypertension  heart failure
– ILD  pulmonary hypertension  heart failure
• Vasculitis (very rare, DM>PM)
• Systemic features weight loss, fever, malaise DM>PM
Polymyositis and DermatomyositisLaboratory features
• Normal or elevated CK (X5-50)
• Raised ESR-but non-specific
• Myopathic EMG, “irritable”- myogenic
denervation
• Autoantibodies including Jo-1, ANA, in
some patients but non-specific
• Muscle biopsy necrosis, inflammation
PM and DM –Immunopathology (i)
Strong circumstantial evidence that PM and DM are
autoimmune
• More common in women
• A range of autoantibodies are commonly detected
• Myositis may arise or fluctuate in pregnancy
• Strong assoc with other both organ and non-organ specific
AI disorders PBC, Psoriasis, MG
• Can be induced by D-Penicillamine, like MG
PM and DM – Immunopathology (ii)
PM Muscle biopsies provide evidence of T cell mediated
cytotoxic process directed against unknown muscle
antigens
DM Muscle biopsies provide evidence of Humorally
Mediated microangiopathy directed against unknown
antigens expressed by muscle capillary endothelium
Treatment of Polymyositis and
Dermatomyositis (i)
• Prednisolone
– 1mg/kg day 60-100mg/day
– Response in 4-8 weeks, then taper dose and
change to alternate day regime
– Problems include
• Treatment failure
• Steroid side effects
• Steroid myopathy (EMG, muscle biopsy)
Treatment of Polymyositis and
Dermatomyositis (ii)
Immunosuppressants other than steroids are useful when
• Steroids relatively contraindicated (IDDM etc)
• “Steroid-sparing" effect required because of steroid
complications
• Repeated relapses on attempts to reduce steroid dosage;
• Steroids at an adequate dose ineffective after a 2- to 3month period
• Rapidly progressive disease with severe weakness and
respiratory failure
Treatment of Polymyositis and
Dermatomyositis (iii)
Choice of Immunosuppressants other than steroids is
largely empirical
• Azathioprine (1.5-2.0 and rarely 3 mg/kg day)
• Methotrexate (benefit?, lung fibrosis, RCT underway)
• Cyclophosphamide and cyclosporin are both effective
• Others (Tacrolimus, chlorambucil)
Immunomodulation with hIVIG or plasma exchange can
be useful in rapidly progressive disease (short lived)
Treatment of Polymyositis and
Dermatomyositis (iv)
Assessing the response to treatment
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Pain subjective, arthralgia as well as myalgia, CTD
Well being steroid effects
ESR non specific
CK chasing, the chemical cure
Weakness clinical exam and myometry
(repeat EMG and muscle biopsy)
Treatment of Polymyositis and
Dermatomyositis (v)
• Whilst prognostication is difficult poor
prognostic features can include
– Cardiac involvement
– Acute onset, very chronic course
– Prominent systemic features (fever, arthritis,
vasculitis)
– Lung fibrosis