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Disorders of the Peripheral Nervous System

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Title: 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)
  • gt100 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, UEs, 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 MgtF)
  • 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
Inherited muscle disease Congenital Myopathies
  • Congenital myopathies
  • Lack of structural proteins e.g. Merosin
    deficient
  • Ultrastructural appearance
  • Central Core
  • Nemaline Rod

36
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)

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

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

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 diseaseSLE, 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

51
Myoglobinuria
  • Inflammatory myopathies
  • Glyco(geno)lysis
  • Lipid oxidation defect
  • Mitochondrial disorder
  • Brody syndrome
  • Drugs (heroin)

52
Respiratory Involvement in Neuromuscular Disease
(i)
  • Respiratory problems occur because of
  • 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

53
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

54
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
  • Nocturnal oximetry and ear lobe blood gases

55
Serum Creatine kinase value and limitations
  • The most sensitive enzyme for muscle disease
  • BUT
  • Normal does not exclude muscle disease
  • (mitochondrial, lipid oxidation disorders, ?IM)
  • CK level only approximates the clinical course
  • Slightly abnormal are seen with intramuscular
    injections, liver disease, neurogenic disorders
  • High CK does not equal Inflammatory myopathy

56
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

57
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
  • 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

58
Polymyositis (PM) -Clinical Features
  • Adult onset inflammatory myopathy, very rarelt16
    years
  • Femalegtmale
  • Subacute presentation (weeks to months) onset oft
    unclear
  • Initial myalgia ? muscle tenderness
  • Proximal gt distal weakness
  • Dysphagia, neck and occ respiratory muscle
    weakness
  • No rash

59
Dermatomyositis (DM) - Clinical Features
  • Childhood and adult onset inflammatory myopathy
  • Femalegtmale
  • Rash prior to or with muscle weakness
    (amyopathic), skin features can include
  • 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 gt distal weakness
  • Dysphagia, neck and occ respiratory muscle
    weakness

60
PM and DM-Associations
  • Connective tissue disorders
  • PM SLE, Sjogrens, RA
  • DM Scleroderma, MCTD (true overlap)
  • Interstitial lung disease (ILD) DMgtPM
  • Autoimmune-anti-Jo-1
  • Drug induced methotrexate
  • Cardiac disease
  • Myocarditis (rare)
  • Steroids ? hypertension ? heart failure
  • ILD ? pulmonary hypertension ? heart failure
  • Vasculitis (very rare, DMgtPM)
  • Systemic features weight loss, fever, malaise
    DMgtPM

61
Polymyositis and Dermatomyositis-Laboratory
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

62
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

63
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

64
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)

65
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 3-month period
  • Rapidly progressive disease with severe weakness
    and respiratory failure

66
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)

67
Treatment of Polymyositis and Dermatomyositis (iv)
  • Assessing the response to treatment
  • 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)

68
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
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