DR. SUBODH KUMAR MAHTO PGIMER,DR.RML HOSPITAL. NEW Delhi

1. 5

2. DISORDERS OF THE NEURO
MUSCULAR JUNCTION
DR. SUBODH KUMAR MAHTO
PGIMER,DR.RML HOSPITAL.
NEW Delhi

3. CONTENTS
• 1.Classification of Myaesthenic syndromes
• 2.Neuromuscular transmission
• 3.Defn and epidemiology of MG
• 5Defect in MG
• 6.Role of Thymus
• 7.Clinical features
• 8.Special situations
• 9.LEMS
• 10.Botulism
• 11.Miscellaneous

4. CLASSIFICATION
• ACQUIRED MYAESTHENIC SYNDROMES
• CONGENITAL MYAESTHENIC SYNDROMES

5. HEREDITARY MYAESTHENIC
SYNDROMES
• A.Pre-synaptic :
• 1.Episodic Ataxia
• 2.Paucity of synaptic vesicles
• B.Synaptic :
• 1.AChE deficiency
• 2.DOK 7 “synopathy”
• C.Post-synaptic :
• 1.Slow channel syndrome
• 2.Fast channel syndrome
• 3.Primary AChE deficiency
• 4.Rapsyn deficiency
• 5.Plectin deficiency

6. ACQUIRED MYAESTHENIC SYNDROMES
• A.Pre-synaptic :
• 1.Botulism
• 2.LEMS
• B.Synaptic :
• Insecticides
• C.Post-synaptic :
• 1.Myaesthenia Gravis
• 2.Snake venom toxins

7. NORMAL NEUROMUSCULAR
TRANSMISSION

11. ACETYL CHOLINE RECEPTORS

12. •MYAESTHENIA
GRAVIS
•(pseudoparalytica)

13. DEFINITION OF MYAESTHENIA GRAVIS
• MG is a neuromuscular disorder characterised
by weakness and fatiguability of skeletal
muscles.
• The underlying defect is a decrease in the
number of available acetylcholine receptors
(AChRs) at neuromuscular junctions due to
antibody mediated autoimmune attack.

14. EPIDEMIOLOGY
• Prevalence : 2-7 in 10,000, increasing
prevalence over past 50 years
• Affects individuals in all age groups----
• females have a bimodal distribution.
• males are predominantly affected in their
fifties.
• Overall female :male ::3:2

15. FUNDAMENTAL DEFECT
1.DECREASE IN
AChRs
RECEPTORS AT
POSTSYNAPTIC
TERMINAL
2.FLATTENING
OF POST
SYNAPTIC FOLDS

16. MECHANISMS OF DECREASED NM
TRANSNISSION
• 1.Accelerated turnover of AChRs by a
mecanism involving crosslinking and rapid
endocytosis.
• 2.Antibody and Complement mediated
damage to post synaptic membrane.
• 3.Blockade of active site of AChRs.

17. PRESYNAPTIC RUNDOWN
AMOUNT OF Ach
RELEASED PER
IMPULSE NORMALLY
DECLINES ON
REPEATED ACTIVITY

18. DECREMENTAL RESPONSE ON RNST
PRESYNAPTIC
RUNDOWN
+
DECREASED
EFFICIENCY OF
NEUROMUSCULAR
TRANSMISSION

19. ROLE OF THYMUS

20. THYMUS IN MG
•THYMUS IS ABNORMAL IN
75%
•HYPERPLASTIC IN 65%
•ACTIVE GERMINAL CENTRES
•THYMIC TUMOURS IN 10%
(THYMOMA)
•MUSCLE LIKE CELLS (MYOID
CELLS) WHICH BEARS AChRs
ON THEIR SURFACE ,MAY
SERVE AS ASOURCE OF
AUTOANTIGEN AND TRIGGER
AUTOIMMUNITY WITHIN
THYMUS

21. MYAESTHENIA GRAVIS SUBTYPES
• 1. OCULAR MG
• 2.GENERALISED MG
• 3.THYMOMATOUS MG
• 4.MuSK-Antibody MG
• 5.SERONEGATIVE MG

22. CLINICAL FEATURES
• 1.OCULAR MUSCLES
• 2.OROPHARYNGEAL MUSCLES
• 3.LIMB MUSCLES

23. • Ptosis or diplopia is the initial symptom in
approx 2/3 of patients.
• Difficulty in chewing,swallowing,or talking is
the initial symptom in 1/6.
• Limb weakness in 10%.
• Careful questioning reveals earlier
unrecognised myaesthenic symptoms.
• Course:Variable but usually progressive

24. STAGES OF MYAESTHENIA GRAVIS
• ACTIVE
• INACTIVE
• BURNT –OUT
• Factors worsening symptoms:
• 1.Emotional upset
• 2.viral systemic illness
• 3.Hypo/hyperthyroidism
• 4.Pregnancy
• 5.Drugs

26. OCULAR MYAESTHENIA contd..
• Ptosis that shifts from one eye to another …
• Saccades are superfast…”quiver”
• After down gaze ,up gaze produces lid
overshoot……”lid twitch”
• “Enhanced Ptosis”….passively lifting a ptotic
eyelid my cause the opposite lid to fall.
• “Peek sign”…involuntary opening of eye.
• Cold applied to eyelid may improve weakness.
• Edrophonium*…improves some of the weak
ocular muscles.

27. MYAESTHENIC FATIGUE

28. OROPHARYNGEAL MUSCLES
• Nasal voice after prolonged speaking.
• Difficulty in chewing,swallowing and
maintenance of upper airway.
• Hoarseness due to laryngeal ms weakness
• Typical facial appearance..”sneer”
• Jaw weakness,patient may support aweak jaw
and neck with his fingers……giving a studious
appearance.

29. LIMB MUSCLES
• Weakness begins in limb/axial muscles in 20%
• Neck flexors are weaker tthan neck extensors.
• Rarely,MG presents initially with focal
weakness of single muscle groups..”dropped
head syndrome”.
• Long standing weakness may give rise to a picture of
myopathy,more commonly seen in MuSK positive
cases .

30. MuSK-Antibody MG
• Antibodies to MuSK have been reported in upto 50% of
patients with GMG who lack AChR antibodies.
• Predominantly in females*
• Begins from childhood through middle age
• Predominant weakness in cranial and bulbar muscles
• Electrodiagnostic abnormalities are not as widespread
as GMG
• Many patients do not improve with AChEI*
• More immunosuppressio is necessary
• Long term outcome is generally good
• Role of Thymectomy is unclear.

31. SERONEGATIVE MG
• “Double –seronegative MG”
• True frequency quite low
• Certain patients may have low-affinity anti-
AChR antibodies that can only be detected
using special specialised assays.

33. CLINICAL FEATURES
1.PTOSIS
2.MUSCLE
WEAKNESS(PROXIMAL)
3.FATIGUE-ACTIVITY
INDUCED
4.RESPIRATORY MUSCLE
FATIGUE
5.DIPLOPIA
6.NASAL REGURGITATION
7.FOOD REGURGITATION
8.DYSPHAGIA AND BULBAR
WEAKNESS

34. Contd..
• SPECIALISED SITUATIONS :
• Myaesthenic crisis (differentiation with cholinergic
crises)
• Childhood MG
• D-Penicillamine induced MG
• Pregnancy
• Transient Neonatal Myaesthenia Gravis
• CMS

35. MYAESTHENIC CRISIS
• Respiratory failure due to myaesthenic
weakness.
• Precipitating event:
• Infection,
• surgery,
• aspiration,
• or a medication change

36. CHILDHOOD MYAESTHENIA GRAVIS
• The onset of immune medited MG before 18
years of age is known as juvenile MG.
• Thymomas are rare in this age group.
• 20% of JMG and almost 50% of those with
onset before puberty are SERONEGATIVE.
• Efficacy of Thymectomy is doubtful in this age
group ,since the rates of spontaneous
remission are high.

37. PREGNANCY AND MG
• May improve ,worsen or remain the same.
• First trimester worsening is more common in first pregnancy.
• Third trimester worsening and post partum exacerbations are
more common in subsequent pregnancies.
• Complete remission may occur in late pregnancy.
• Women should delay pregnancy until the disease is stable.
• Oral AChEI are the first line drugs*
• Prednisolone is the immunosuppressive agent of choice
• Magnesium sulphate,MMF and i.v AChEI are contraindicated.
• Regional anaesthesia is preferred for delivery or CS.
• Breastfeeding is not a problem.

38. D-PENICILLAMINE Induced MG
• USED IN THE TREATMENT OF :
• RA
• Wilsons disease
• Cystinuria
• Resolves after stoping the drug.
• It is usually mild
• Often restricted to occular muscles
• Diagnosis: response to AChEi ,characterestic EMG and
elevated AChR antibodies.
• WHAT IF THE PATIENT’s SYMPTOMS PERSIST AFTER 1
YEAR OF STOPPING THE DRUG?

39. TRANSIENT NEONATAL MG
• 10 TO 20 % of new borns whose mothers have
immune mediated MG.
• Maternal antibody level correlate with the
frequency and severity of TNMG
• Arthrogryposis multiplex congenita
• Risk in successive pregnancy :
• ROLE OF PROPHYLACTIC PLEX/IVIG
• Features in affected newborns :
• DURATION OF SYMPTOMS IN NEWBORN : 2-12
weeks

40. CONGENITAL MYAESTHENIC
SYNDROMES

41. CMS
• Group of NMJ disorders caused by genetic
defects of muscle end plate molecules involved in
NMT.
• Usually AR, except SLOW CHANNEL SYNDROME.
• 2:1 male preponderance.
• Ophthalmoplegia,universally present.
• Limb weakness rarer than GMG.
• Thymectomy and Immunosuppression are not
effective.
• Rapsyn deficiency is the commonest

43. LAMBERT EATON MYAESTHENIC
SYNDROME
Lambert Eaton and Rooke in 1956
OAT CELL CA LUNG

44. LEMS
• Target : P/Q type VGCC on presynaptic
cholinergic nerve terminals at the NMJ and in
autonomic ganglia.
• M:F = 5:1
• Onset –subacute,
– myaesthenia may precede discovery of tumour by
months or years.
• First difficulty usually in :
– getting up from chair
– Climbing stairs
– walking

45. LEMS..contd..
• Shoulder muscles affected later.
• Ptosis,dysarthria,dysphagia ---not the usual
mode of presentation.
• Study by O’Neill : (n=50)
– Proximal leg weakness=50
– Arm=39
– Diplopia=25
– Ptosis=21
– Dysarthria=12

46. Contd..
• Autonomic symptoms—dryness of mouth
,difficulty in micturition,and impotence
• OTHER NEUROLOGIC FINDINGS OF NEOPLASIA:
• 1.Polyneuropathy
• 2. Polymyositis
• 3.Dermatomyositis
• 4.Multifocal Leucoencephalopathy
• 5.Cerebellar degeneration.

47. • ASSOCIATED MALIGNANCIES:
• 1.Oat cell CA Lung—60%
• 2.Breast
• 3.Prostate
• 4.Stomach
• 5.Rectum
• 6.Lymphoma
• 1/3 patients have no cancer

48. • EXAMINATION:
• Less weakness than the symptoms suggest
• DTR: almost always absent or diminished.
• Strength may increase initially with activity
but later declines
• Response to Edrophonium is less marked than
in MG

49. LEMS vs MG

50. PARAMETERS LEMS (INVERSE MG) MYAESTHENIA GRAVIS
1.Sexual predilection M:F=5:1 Females predominate *
2.Pathophysiology Antibodies agaist p/q
VGCC
Against AChR
3.Involvement Starts off with proximal
muscles*
Predominant ocular
involvement
4.Other findings of
neoplasia
Present* absent
5.Autonomic smptoms present absent
6.Effect of Exercise Weakness improves* Weakness aggravates
7.DTR Absent or diminished Normal or decreased
8.Association M.C Oat cell ca Lung Thymoma /thymic hyperplasia
9.Role of thymus Nil* Present
10.RNST Incremental response Decremental response
11.Treatment Aminopyridines AChEI

51. BOTULISM

52. • BOTULINUM TOXINS : 8 types (A,B,Cα,Cβ,D,E,F,G
)—Zinc Endopeptidase.
• Types A,B –m.c cause of botulism in U.S
• Blocks the release of Ach from presynaptic nerve
terminals and the parasympathetic and
sympathetic ganglia.
• B,D,F,G----act on Synaptobrevin
• C----Syntaxin
• A,B----SNAP 25

54. OTHER CAUSES OF ABNORMAL NMT
•Envenomation by
animal toxins is the
commonest cause of
NMJ toxicity worldwide

56. • Funnel web,black widow spiders
• Tick paralysis :postsynaptic effect*
• Snake envenomation: Elapidae,Hydrophiidae*
– Acts both pre and post synaptically
• Marine Envenomations.
(fish,mollusc,dinoflagellate)

57. HEAVY METAL
TOXICITY
ORGANOPHOSPHOROUS
INSECTICIDES

59. Henrique
Mecking 1970
Christopher
Robin
Milne
Died in
1996
Aristotle
Onassis
Prominent
Greek
shipping
magnate

60. Dr.DEBOPRIYO MONDAL