Myasthenia gravis in children

a presentation of given during my internship in pediatric hospital benghazi.

1. Case

2. Benghazi pediatric medical centre Approach to myasthenia gravis in childhood Presented by DR: alsalheen elraied DR: maraie altopoly Under supervistion of DR amal DR : halima benamer Dr : wariada bashoon – consultant pediatric neurology

3. whats mysthenia gravis?

4. Myasthenia gravis (MG) is an autoimmune disease in which antibodies are directed at the postsynaptic membrane of the neuromuscular junction , leading to varying degrees of muscle weakness and fatigability .

5. History and examinations of myasthenia case The weakness in usualy in cranial in characteistic pattern. Weakness in characteristic distribustion ( exaocular muscle , muscle of face produce snarling expression when smiling . Speech has nasal timbre caused by weakness in palatine muscle. Difficlt in swallowing which give rise to nasal regurgitation and aspiration of liquid and solid ) The weakness in muscle of limb usualy in proximal asyemitrical fasion but with peserved deep tendon reflexes. Fluctuation and fatigue: worse in repeated activity improved by rest Effect of previous treatment . Examinations Ptosis , diplopaia On motor examination normal power but on repeated stimulation there is decrease in response . Normal or slightly dimminshed reflexs Special testing forward arm abduction (5min) Also counting number theres disphonia On raising eye lid up by concentration in up fingers

6. Investigation AntiACH immunoassay 85% + ve in generilized MG 50% in ocular MG . But if negative doesn’t exclude the diagnosis. About 40% of antiACHR negative pt having anti-MUSK positive in which the most prominent feature is bulbar symptom( dysarthria-dysphagia ). Repetive nerve stimulation : decremental response. Single fiber electromyography : blocking and jitter. Edrophonium chloride ( tensilon ) 2mg iv highly probable diagnosis. For ocular or cranial MG : must exclude intralcranial lesion by CT OR MRI.

7. Recommended investigation for associated MG diseases. Ct or MRI FOR mediastinum for disorder of thymus , hyperplasis Test for SLE ANA RF antithyroid antibodies Thyroid function test ( becuaese of association and they may exacerbate MG symptom. PPD testing because they may interfere with treatment. Fasting blood glucose HBA1C because with treatment.

8. CLINICAL TYPES Generalised MG : CRANIAL+PROXIMAL LIMB weakness Ocular mysthenia : ocular mainly symptom for 3consequetive years. MG crisis : when the weakness affecting respiratory muscle.

9. Childhood MG classifications according to age Congenital MG NEONATAL ( transient MG) Familial infantile MG Juevenile MG

10. 1-Congenital type : Maternal MG usually not present Onset at birth with ocular or generalized weakness The course of weakness usually fixed Family history often present Anti Ach R antibodies not present

11. Congenital myasthenia syndrome CMS comprise heterogenous groupe of disorder that are not autoammune but rather due genetic mutation incomponent of neuromuscular junction. Share many clinical feature of autoimmune MG but negative antibodies usually present in the first years of childhood with variable disability. There is often a positive family history, and diagnosis is aided primarily by electrophysiology and DNA analysis and occasionally by muscle biopsy .  With the exception of the autosomal dominantly inherited slow channel syndrome , the CMS are inherited by autosomal recessive mutations, which result in loss of function at the neuromuscular junction

12. 2-neonatal(transient) MG: -10-20% of infants born to mother with autoimmune MG -less common when myasthenia of the mother treated with immunosuppression -high anti-ACHR antibody titer -clinically : present with local or generalized weakness---respiratory depression----symptoms subsided over 1 to 4 weeks

13. 3-Familial infantile type: Maternal MG usually not present Onest from birth to 1year age Present with respiratory depression or generalized weakness The course of the disease either fatal or enter improvement over 2years of age Family history usually present Ant ChR antibodies not present

14. 4-Juvenile MG Has the same presentation and response to therapy as adult type It is Autoimmune Antibodies directed against AChR in skeletal muscle Cell and complement mediated process This leads to a reduced number and function of AChRs Almost never occurs before 1 year of age.

15.   Differential diagnosis of JMG. muscular dystrophies Neurotoxins For example, botulism, Guillain-Barré syndrome Acute disseminated encephalomyelitis Multiple sclerosis Brainstem tumour Hypothyroidism

16. Classification according to antibodies the various subgroups of autoimmune MG respond differently to treatment. USUALY defined according to subgroups. [1)early-onset MG ( 3) thymoma -associated MG ; ( 4)MG with anti- MuSK antibodies ; ( 5)ocular MG: symptoms only from periocular muscles ; ( 6)MG with no detectable AChR and MuSK antibodies;

17. Juvenile mysthenia gravis In the majority of cases MG is caused by antibodies to the nicotinic acetylcholine receptor ( AChR ). Antibodies to the AChR are found in over 80% adults with generalised disease but only in 55% of adults with weakness confined to the oculomotor muscles. Patients with AChR antibodies are often referred to as seropositive . AChR antibodies are probably less frequent in prepubertal patients than in adolescent and adult patients . Antibodies to muscle-specific kinase ( MuSK ) and to Leucine rich protein 4 (LRP4) have been reported in some seronegative patients

18. Cont.. The most frequent clinical presentation of JMG is with ptosis , which is often associated with other ocular symptoms namely unilateral or asymmetric ophthalmoplegia , strabismus, and lid twitch, which may only be elicited after sustained upgaze   Most children also develop generalised muscle weakness , which presents as painless fatigability of the bulbar and limb musculature, with resultant dysphonia , dysphagia , and proximal limb weakness. Weakness is often fluctuating and usually becomes more pronounced through the day and improves with rest. Children are at risk of choking or aspiration and are at increased risk of chest infection. Occasionally, impairment of the respiratory muscles necessitates ventilatory support. This is known as “ myasthenic crisis”.

19. Prepubertal children presenting with JMG have some interesting and distinct clinical features compared with those who present around or after puberty . Prepubertal JMG is more likely to manifest as ocular myasthenia .  There is an equal male: female ratio ,   in contrast to the female predominance that is seen in peri -/ postpubertal children , and a better prognosis, with a higher rate of spontaneous remission in prepubertal presenters . Peri - or postpubertal patients presenting with JMG share more similarities with adult-onset MG .

20. Diagnosis JMG is primarily a clinical diagnosis with classical patterns of fluctuating weakness and fatigability as described above . A number of diagnostic tools are available to aid with diagnosis . In very young children it is particularly important to distinguish between autoimmune myasthenia and congenital myasthenic syndromes (CMS) as the treatment options, prognosis, and genetic implications are very different .

21. Cont.. As conclusion the diagnosis must always be confirmed by investigation : Because 1- other treatable condition may resemble MG 2- treatment of myasthenia may involve surgery and prolonged use of drugs of potentially advers side effects Investigation include : Antibodies Electrodiagnostic study Anticholinesterase test.

22. Treatment principle

23. Treatment Principles The clinical response and evaluation is most important, but there tends to be a correlation between MG severity/activity and AChR antibody concentration in the individual patientpolicy regarding full drug withdrawal is recommended . A low-dose prednisolone , azathioprine , or other immunoactive drugs can in such patients be sufficient to maintain the stable condition, but also necessary to avoid new exacerbations . Younger patients in particular, not least after thymectomy , can obtain a full clinical remission without any need for continued drug treatment The prognosis has improved srikely as result of advances of treatment which conisst of Anticholinesterase inhibitor Thymectomy Immunosupression Ttt of maysthenic crisis

24.   Acetylcholinesterase Inhibitors Acetylcholinesterase inhibitors are first-line treatment in JMG and provide symptomatic relief. In mild cases and in some cases of ocular MG , acetylcholinesterase therapy may be sufficient. Pyridostigmine is a long-acting cholinesterase inhibitor that is commonly used. Dosing is usually 4–6 times per day and is tailored to effects. Overdosage with anticholinesterase medication may cause increase weakness and other side effects With muscarinic side effect (diarrhea-abdominal cramp-salivations-nausea) so atropine ( diphenoxylate ) – lepromide for GI symptoms. Cautious use in MuSK -positive children is advised due to risk of acetylcholine hypersensitivity .

25. Thymectomy Recent studies says : thymectomy increases the probability of remission or improvement of symptoms in AChR seropositive , nonthymomatous , autoimmune MG . More recent reviews of children including prepubertal patients, also suggested increased remission rates after thymectomy . Current evidence suggests that thymectomy should not be recommended in MuSK -positive disease as it is unclear whether it confers any benefit . Thymectomy in pure OMG remains controversial . Whereas OMG is not life threatening, patients may be dependent on long-term immunosuppressant medications, including corticosteroids, with the resultant side effects which can be substantial in children.. Thymectomy is not proven to reduce risk of progression of OMG to generalised JMG and is not routinely indicated in pure OMG in children but has been performed in refractory cases . A variety of surgical methods for thymectomy have been described: full or partial sternotomy , thorascopic , or transcervical approaches After thymectomy there is increased risk of antimuscarinic side effects of cholinesterase inhibitors, and they should therefore be used under close

26. Immunosuppressive therapy It include Glucocorticoid therapy Other agent ( cyclophosamide – calcineurin inhibitors) Steroid sparing agent( azathioprine and mycophenolate mofetil ) Plasmapherisis and IV immunoglobulin The indivual choice of drugs should be guided by relative risk and benefite according to the case : For sever cases use IV immunoglobulin and plasmapherisis . For intermediate controle ( steroid – cyclosporin - tacrolimus ). For long term controle usualy use of stroid sparing agent

27.  Immunosuppressive Therapies Corticosteroids are often effective and are the mainstay of therapy but can worsen symptoms in the first few weeks of use, particularly if started at high doses , Because of the numerous adverse effects associated with long-term high-dose steroids, steroids are often used in combination with a steroid-sparing immunosuppressant, for example , azathioprine .  Children are at particular risk of steroid side effects, including growth failure, susceptibility to severe infection, and delay in receiving live vaccinations .

28. Azathioprine is a purine analogue that suppresses B and T cell proliferation. It has been found to be effective when used alone, but is most commonly used in combination with prednisolone as a steroid-sparing agent. Beneficial effects may take months to be seen but eventually result in weaning of steroid doses Some studies have suggested that azathioprine or corticosteroids may reduce the likelihood of progression of OMG to the generalised form of disease . Studies suggests that cyclosporin either as monotherapy or with corticosteroids, or cyclophosphamide in conjunction with corticosteroids, improves symptoms of MG within 1 year Mycophenolate mofetil (MMF) blocks purine synthesis by selectively inhibiting proliferation of activated T and B lymphocytes .  A recent retrospective study of AChR seropositive patients, which included children (age range 11–87 y), concluded some benefit of MMF when used either as monotherapy or in conjunction with prednisolone

29. Tacrolimus inhibits interleukin 2.  Efficacy studies have been carried out in adults and postpubertal children and have shown early and sustained improvement of symptoms with tacrolimus , allowing dose reduction of prednisolone and in many cases its complete withdrawal.  A case has also been reported of tacrolimus being successfully used as adjunctive therapy in refractory pure ocular myasthenia in a 3-year-old girl . Rituximab is a chimeric IgG monoclonal antibody that depletes B cells and has been used in refractory JMG

30. Plasma Exchange/Intravenous Immunoglobulin (IVIG) Improvement in symptoms after plasma exchange or administration of IVIG is usually temporary, 4–10 weeks. Their use is therefore largely reserved to optimise condition for surgery before thymectomy and in management of myasthenic crisis. single randomised controlled trial showed no evidence for superior benefit of plasma exchange over IVIG in treatment of myasthenic crisis .

31. management of myasthenic crisis Myasthenic crisis is defined as excerbation of weakness sufficient to endanger life : It is uauslay consist of respiratory failure . Crisis rarely accure in good managed case The most common cause of crisis is intercrrent infections. The myasthenic patient with fever should be treated as immunoconpromised case in ICU With AB and respiratory assestance And plasmapherisis and IV immunoglobulin which is hasten recovery.

32. Patient assesment Interval assement form Which use clinical assesment by history and examination to asses the pts response to treatment. Useful tool for treatment reevaulation . Using AchR antibody titre Provide valuable informations about treatment effectiveness.

33. In summary myasthenia gravis Is Rapidly fatigable weakness (characteristic ), double vision, upper airway weakness diagnosis and assesment of ttt : Largely on a clinical basis, by eliciting a history of fluctuating weakness and by physical findings of rapidly fatigable Weakness other diagnostic tool in repetitive stimulation test : Rapid loss of activity after repetitive stimulation of the same muscles Also tensilon test : A very short-acting acetylcholinesterase inhibitor administered intravenously In myasthenia, Tensilon usually produces a rapid, dramatic increase in strength. A positive test is consistent with (but does not diagnose) myasthenia gravis. ttt include ; Acetylcholinesterase inhibitors (e.g., pyridostigmine ); immunosuppressive drugs and thymectomy

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