Case history, Definition, Diagnosis, Management, Prognosis
Author: Dr. Farhat Naz
A 13 year old girl was admitted in hospital with complaints of fatigue and drooping of eyelids. According to mother she has difficulty in keeping her eyes open and starts drooping. Symptoms improve after some rest. The drooping appears better in morning and symptoms become worse with the passage of day and she becomes unable to maintain her eyes open at evening.
She had no birth complications and had normal developmental milestones. She used to become fatigued while playing. She was admitted to school at the age of 5. The mother used to lift her to school for three years as she was unable to walk herself. She had to quit school due to increased fatigue after 3 years.
Her parents first started noticing her drooping of lids at the age of nine. They visited ophthalmologist for same, but no work up was done for her disease. She feels difficulty in standing from sitting position, combing hair, eating and holding object like cell phone for long time. There is no history of shortness of breath, coughing or drooling. She was never hospitalized in past.
There is no family history of any muscle disease or disability in family.
On examination, she is a young pre pubertal girl with low body mass index. She has non symmetrical bilateral ptosis, affecting more in left eye. Upon attempting upward gaze, she has progressive worsening of ptosis over one minute.
Making the clinical diagnosis of juvenile Myasthenia her acetylcholine receptor (AChR) antibodies and anti MUSK antibodies were ordered and electromyography was planned. CT scan of chest was also ordered to rule out thymoma.
What will be the management approach for this patient?
Myasthenia Gravis in an autoimmune disease of neuro muscular junction characterized by muscle weakness due to defective neuromuscular signal transmission. It most commonly affects adults, predominantly females. This disorder is rare in children but can cause a management challenge for health practitioners. In this article we will discuss:
What is Juvenile Myasthenia?
How common is Juvenile Myasthenia?
What is Clinical presentation of Juvenile Myasthenia?
How to differentiate Juvenile from congenital Myasthenia?
What is diagnostic approach to Juvenile Myasthenia?
What is management approach to Juvenile Myasthenia?
What are the treatment options and available drugs for Juvenile Myasthenia?
Is there a benefit of thymectomy in juvenile Myasthenia?
What are preventive strategies and drugs to avoid in Myasthenia?
What is Myasthenic crisis and how it is managed?
What is prognosis of Juvenile Myasthenia?
What is Juvenile Myasthenia?
Juvenile Myasthenia is defined as development of symptoms of Myasthenia gravis before 18 years of age. It is a rare neurological disorder and differs from adult Myasthenia gravis in many clinical aspects. The disease predominantly involves ocular muscles with a greater chance of spontaneous remission in later life as compared to adult Myasthenia gravis.
Myasthenia gravis is a disease of neuromuscular junction mostly of autoimmune origin, where there is formation of antibodies against cmponents of muscle end plate causing defective transmission of impulse from nerve to muscles. Consequently, the nerve signals cannot be transmitted properly from the end of nerves to muscles, leading to weak muscle contraction and clinical manifestations of Myasthenia Gravis.
How common is Juvenile Myasthenia?
Juvenile Myasthenia is a rare disorder and incidence vary among different races, the disease is more common in females with incidence of about 1.5- 4/million population. Among juvenile Myasthenia only 20% present at <10 years of age. Incidence is more in black africans, Japanese and Chinese population as compared to Europeans as determined by various population based studies.
What is Clinical presentation of Juvenile Myasthenia?
The most common clinical presentation is ptosis(drooping eyelids) with variable ophthalmoplegia. Ptosis is typically asymmetric which differentiate it from congenital forms of Myasthenia.
In milder cases it is important to observe for fatigue with up gaze up to 1 minute.
Another important sign is improvement in ptosis after ice test, which is keeping an ice pack on eyes for 5 minutes and observing improvement in ptosis.
In more generalised forms the patient may experience proximal muscle weakness manifested as difficulty in standing from sitting position, climbing stairs, lifting arms above head, combing hair.
The more severe forms will cause involvement of bulbar muscles with dysarthria and difficulty in swallowing.
The involvement of respiratory muscles will lead to shortness of breath.
The symptoms are typically worse in the evening and will improve with rest.
Children with initially ocular Myasthenia may develop generalized form of the disease, and those who develop generalised Myasthenia, mostly do within 6 months of onset of symptoms. If ocular symptoms persist for more than 2 years there are less chances to develop generalized form and early onset of appropriate treatment may induce remission.
Spontaneous remission is defined as resolution of symptoms without medication for 1 year or more. Remission is more common in pre pubertal age.
How to differentiate Juvenile from congenital Myasthenia?
There are three major types of neuromuscular disorders in childhood which include:
- 1. Transient neonatal Myasthenia
- 2. Congenital Myasthenia
- 3. Juvenile Myasthenia
Though all of these disorders are rare, but Juvenile Myasthenia is most common among all three. There are many congenital disorders which mimic Juvenile Myasthenia and include the following diseases:
- Congenital Myasthenic syndromes
- Congenital Myopathies
- Mytochondrial Myopathies
- Aquired demylenating neuropathies
careful evaluation is needed if symptoms are present at earlier age and auto antibodies are negative. An alternative diagnosis of juvenile Myasthenia should be considered if there is family history, symptoms are present from very early age or there is development of bony structure deformities like scoliosis.
Often there is delayed presentation of congenital Myasthenia and it is labelled as seronegative Juvenile Myasthenia, the patient is started on cholinergic drugs which causes worsening of symptoms. A careful family history should be taken and response of cholinergic drugs should be carefully evaluated.
Sometimes the symptoms of Myasthenia are present since birth in babies born to Myasthenic mothers due to transient muscle weakness due to maternal antibodies. The condition is self limiting and child may need ventilatory support till resoltion of symptoms.
What is diagnostic approach to Juvenile Myasthenia?
The diagnosis of Myasthenia is mostly clinical, and confirmed through Serological tests for antibodies, Electromyography and imaging for thymoma.
Serology
In people with Myasthenia gravis (MG), the immune system produces abnormal antibodies that interfere with the normal communication between nerve impulses and muscle contractions. The specific antibodies that may be present in people with MG include:
,Acetylcholine receptor(AChR) antibodies:
These antibodies attack the acetylcholine receptors on muscle cells, disrupting the normal transmission of nerve impulses to the muscles. In adults these antibodies are highly specific and sensitivity is more than 90% in generalised Myasthenia, while in case of children the sensitivity of AChR antibdies is 70-80% in generalised Myasthenia and much lower in ocular Myasthenia.
Anti muscle specific kinase(MuSK) antibodies:
These antibodies attack a protein called MuSK, which is involved in the development and function of the acetylcholine receptors. These antibodies are tested in patients who have negative test for AChR antibodies. The patients with MuSK antibodies have rapid progression and involvement of bulbar and respiratory muscles.
Antibodies to low density lipoprotein 4(LDLP4):
Antibodies to low density Lipo protein4(LDLP4) have been described in patients with Myasthenia but their exact specificity and pathogenesis is not fully determined.
Anti striated muscle antibodies:
These antibodies attack proteins in the muscle cells, causing inflammation and muscle weakness. These antibodies are mainly present in young adults with Myasthenia below 40 years of age.
Neurophysiology:
Electromyography (EMG): This test measures the electrical activity of muscles and can help determine if MG is affecting the muscles.
Single fiber electromyography (SFEMG): This is a specialized type of EMG that can help to confirm the diagnosis of MG with high sensitivity. Single muscle fiber is stimulated to confirm delayed neuromuscular transmission, the limitation of this test in children is that it needs patient’s cooperation which is sometimes difficult to achieve in children.
Repetitive nerve stimulation: This test involves stimulating a nerve and measuring the response of the muscle. This test serves as a supportive test to diagnose Myasthenia, low dose repeated nerve stimulation is given and decrease in response by 10% from first to fifth response is considered significant. It can help to determine if MG is affecting the nerve- muscle connection.
Edrophonium (Tensilon) test: This test involves injecting a medication called edrophonium, which is rapidly acting cholinesterase inhibitor. It temporarily improves muscle strength in people with MG. This test is mostly useful in suspected Myasthenia patients with predominantly ocular symptoms where it can be easily assessed.
The use of Tensilon test is limited nowadays due to its potential of over stimulation of cholinergic receptors causing severe bradycardia.
CT scan or MRI: These imaging tests may be used to diagnose abnormalities in the thymus gland (a gland in the chest that plays a role in the immune system) or other parts of the body.
It’s important to note that no single test can definitively diagnose MG. Instead, a combination of these investigations and the individual’s symptoms and medical history is typically used to make a diagnosis.
What is management approach to Juvenile Myasthenia?
Due to rarity of the disease, there are no universal guidelines for Juvenile Myasthenia but recently recommendations were published by European Neuromuscular Centre Workshop Study Group. Mostly the treatment of juvenile Myasthenia is derived from treatment guidelines for adult Myasthenia gravis, but there a few management aspects which should be specifically considered in children.
There should be multidisciplinary treatment approach to help children with Juvenile Myasthenia. The following disciplines should be involved in management:
- Paediatric Neurologist
- Ophthalmologist
- Neutritionist
- physical and rehabilitation therapist
- Psychotherapist
The management should include:
- Suppotive therapy
- Specific therapy
Supportive therapy:
There should be extensive support and monitoring to keep the child symptom free and avoid flare.
Early ophthalmologist referral should be done to avoid squint and amblyopia.
School authorities should be informed regarding the disease and educational programs should be modified to help these children to go through curriculum without getting over fatigued.
Special attention should be given to avoid the complications of immunosuppression specifically the corticosteroids. The advise should be given to take healthy food without getting overweight. Parents should be educated and provided a list of drugs to be avoided in Myasthenia.
Vaccination should be done for varicella and influenza.
Continuous psychosocial support should be given to recognize and avoid depressive symptoms.
A graded exercise program should be planned to improve muscle strength without getting fatigued.
Counselling of parents, guidance and support is important.
Specific Therapy:
Specific therapy is the treatment given to overcome the symptoms of Myasthenia. This includes:
- Drugs to improve symptoms
- Immunosuppression
- Surgical intervention (thymectomy)
- Treatment of exacerbations/ Myasthenia crisis.
Drugs for Myasthenia:
Cholinesterase Inhibitors (ChE-I): These are the drugs of first choice for symptomatic treatment of Myasthenia gravis. Pyridostigmine is a non selective cholinesterase inhibitor which prevents the breakdown of aetylcholine increasing its ability to bind post synaptic acetylcholine receptor thus improving the symptoms.
The starting dose is 1mg/kg, 3-4 times a day which can be increased to 1.5mg/kg 5 times a day. The maximum dose is up to 450mg/day.
Timing and dose can be adjusted according to activity of child and dose should be given 30-60 min before activity to minimize the symptoms.
Side effects include diarrhoea, salivation, sweating, nausea, hypotension, bradycardia.
Failure to control the symptoms with 1mg/kg 4 times a day is indication for initiation of immunosuppressive therapy.
Immunosuppressive therapy:
Predinisolone is recommended as first line therapy. Initial starting dose is 0.5mg/kg on alternate days which can be increased to 1.5mg/kg on alternate days(maximum100mg). Lower doses are needed in pure ocular Myasthenia.
The common side effects of prednisolone include increased appetite, weight gain, fluid retention, impaired glucose tolerance, dyspepsia, disturbed sleep. Long term side effects include myopathy and osteoporosis.
Second line immuno supressive agent should be introduced as steroid sparing agents when there is no response to steroids or the dose of prednisolone needs to be minimized to reduced the side effects of steroids.
Steroid sparing agents include azathyoprin, mycophenolate, tacrolimus, cyclosporin and rituximab.
Azathioprine is typically prescribed with prednisolone and gradually the dose of prednisolone is reduced to minimum effective dose. Azathioprine is a purine analog which causes supression of B and T cells. Starting dose of Azathioprine is 1mg/kg which can be increased to 2.5mg/kg at 2-4 weeks intervals. Azathioprine takes up to 12 months to become fully effective.
The side effects of Azathioprine include bone marrow suppression, gastrointestinal and liver dysfunction. Full blood count and liver functions should be monitored while on azathioprine.
Mycophenolate mofetil: This drug selectively inhibits B cell and T cell proliferation. It is used as second line drug in patients intolerant to Azathioprine.
Tacrolimus: It is calcineurin inhibitor and provide immunosuppressive effects through modulation of T and B cell activity. It is found beneficial in various clinical trials and found effective in ocular Myasthenia.
Side effects of tacrolimus include hypertension, headache, renal impairment, diarrhoea, infection and development of lymphomas and new onset diabetes.
Rituximab: It is monoclonal antibody which attaches CD20 on B cells causing cell death. This drug is reserved for refractory cases of Myasthenia. The drug is given intravenously at dose of 375mg/m2/week for 4 weeks or 750mg/m2 two weeks apart.
Though rituximab is found effective in refractory patients and in Anti MuSk Myasthenia, there is more chance of infection, progressive multifocal leuko encephalopathy (PML) and long term B cell suppression.
Methotrexate, cyclosporin and cyclophosphamide are other immunosuppressive drugs Reserved for refractory cases of Myasthenia.
Is there a benefit of thymectomy in juvenile Myasthenia?
In adults 10-15% Myasthenia patients are diagnosed with thymoma but it is extremely rare in children.Thymectomy is recommended treatment in adult Myasthenia and also advised in post-pubertal children with more generalized symptoms.
Thymectomy is not routinely recommended in juvenile Myasthenia in pre puberty, it is usually recommended in children with thymic hyperplasia or thymoma with generalised symptoms, not responding to cholinesterase inhibitors and immunosuppressive thetapy.
What are preventive strategies and drugs to avoid in Myasthenia?
There are certain factors that aggravate Myasthenia gravis and can precipitate crisis.
The aggravating factors may be related to routine daily life activities, therefore a careful watch over the symptoms should be kept and the parents should be educated regarding the condition causing aggravation of Myasthenia symptoms. The following conditions can aggravate Myasthenia.
Infection, illness, fatigue and inadequate sleep, over exertion, pain, stress, depression, extreme weather, bright lights, some foods, medication and household cleaners and pesticides.
Knowledge of possible aggravating factors can help in adopting preventive strategies, thus minimizing the development of Myasthenia crisis.
There is a list of medicines which can aggravate Myasthenia, therefore the parents and health practitioners should be well aware of drugs causing disease aggravation and precipitating Myasthenia crisis. The following groups of drugs should be avoided in Myasthenia to minimize the aggravation of symptoms.
- Aminoglycosides (gentamycin,, amikacin, streptomycin)
- Quinolones (ciprofloxacin, levofloxacin)
- Tetracyclines ( doxycyclin, minocyclin, tetracycline)
- Antimalarials: (Chloroquine, hydroxychloroquine)
- Antihypertensives
- Beta blockers, (propanolol, bisoprolol, metoprolol)
- Calcium channel blockers (verapamil, amlodipine)
- Antiarrythmics (procainamide, quinidine)
- Muscle relaxants: (Succinylcholine)
- Rheumatic drugs (penicillamine)
- Immunotherapy (checkpoint inhibitors)
- Antipsychotics (risperidone, chlopromazine)
- Miscellaneous (magnesium salts, botulinum toxin)
What is Myasthenic crisis and how it is managed?
Myasthenic crisis is sudden deterioration in Myasthenia symptoms which need urgent hospitalization and ventilatory support. The exact incidence of Myasthenia crisis is unknown but studies suggested up to 10 % incidence.
The symptoms will start with increasing weakness with difficulty to swallow and child becomes short of breath listless and drowsy.
There could be multiple triggers to cause Myasthenia crisis, the most common is infection. Change in regime or dose of drug can cause flare of Myasthenia symptoms. Many antibiotics for infections can exacerbate the symptoms of Myasthenia therefore careful history should be taken to know the underlying trigger for deterioration.
The patient should be admitted and provided with ventilatory support, initially non invasive ventilation is given and if no improvement then intubation and invasive ventilation should be given.
The specific therapy during Myasthenia crisis is
- Plasma exchange (PLEX)or
- IV Immuno globulins (IVIG)
Plasma exchange is treatment of choice in Myasthenia crisis as it causes rapid improvement and reversal of symptoms and removes auto antibodies from circulation. Sometimes, IV access is not possible in small children for plasma exchange, then other options should be considered.
IV Immunoglobulins are recommended for adults and Juvenile Myasthenia crisis, they are also recommended to improve symptoms before undergoing surgery. The dose is 2g/kg in divided doses over 2-5 days.
Cholinesterase inhibitors are not given while patient is on ventilator and corticosteroids are given at higher dose to improve respiratory distress.
What is prognosis of Juvenile Myasthenia?
The prognosis of Juvenile Myasthenia is better as compared to adults, especially if symptoms start at pre puberty and predominantly involve ocular muscles.
If th symptoms of ocular Myasthenia stay localized over six months, there are more chances of spontaneous remission. If symptoms stay mild for up to 2 years or more, there are less chances of deterioration in later life. The chances of remission are more in AChR antibodies negative Myasthenia.
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