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CLINICAL SPECTRUM OF MYASTHENIA GRAVIS IN NEONATOLOGY AND PEDIATRICS

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ABSTRACT: 

In this article, we try briefly to emphasize the features of myasthenia gravis in neonates and infants. Because, in this respect, exsist some different clinical forms towards with their particularities, we have pointed as much as possible, the relevant aspects concerning myasthenia at these periods.

 


 

In this article, we try briefly to emphasize the features of myasthenia gravis in neonates and infants. Because, in this respect, exsist some different clinical forms towards with their particularities, we have po-inted as much as possible, the relevant aspects concerning myasthenia at these periods.

Myasthenia Gravis is an autoimmune disease of the neuromuscular junction.The main symptom is the muscular wekness, but, with the distinction that in neonates and infants this weakness behave a distinctive character, sometimes difficult to detect due to the particular anatomical and physiological features at this age. Being caused by a problem with nerve impulses, at the contact point between nerve and muscle, myasthenia can often be confiised with another muscular disorder. For unknown reasons, the body’s immune system, in this context, will exert an attack directed against the acetylcholine receptor located in muscle.

As we previously said, the major symptom of myasthenia is muscle weakness, worsened by fatigue and generally improves with rest. Muscles that control eye movements/mobility, facial expression, chewing, swallowing are often involved. The neck, arms and legs muscles are also affected.

In more severe clinical situations, the breathing muscles can be incriminated too, having an fatal impact on the respiratory function, leading to the short-ness of breath.

 

TRANSITORYNEONATAL MYASTHENIA

Neonatal myasthenia gravis, is caused by transfer of specific M.G. antibodies between mother and newborn. When a myasthenic mother is pregnant the acetylcholine receptor antibodies can be trans-ferred to the fetus via placenta trough an active transfer mechanism. In these babies, serum acetylcholine receptor antibodies titers follow the same pattern as their mothers. The condition resolves spontaneously in the majority of infants (Papazian,1992). Neonates can manifest symptoms of neonatal transient myasthenia gravis even if their mothers was symptomati-cally free during pregnancy and delivery. If a mother with myasthenia gravis gives birth to an infant with neonatal myasthenia, then, her subsequent baby is also passible to have an increased risk of this kind of myasthenic transient.

The symptoms are: muscle weakness at birth, weak infant cry, facial weakness —» suckling and feeding difficulty, respiratory weakness.

Even in neonates we could speculate the hypothesis that a circulating factor is incriminate. This factor is believed to be the IgG immunoglobuline that binds to the acetylcholine receptor protein (AChRP) and thereby a decreased number in the available receptors at the level of neuromuscular junction, capable to in-teract with acetylcholine (Fenichel,1980). Weakness can occur late or can be delayed until the third day, but usually has its onset within hours of birth.

Having in view these attributes, in the speciality li-terature was reported that the difficulty in feeding is present in 81% of affected newborns and, generalized weakness and hypotonia in 70%. The symptoms in the newborn may reveal in a accurate mood maternal myasthenia, evocative neonatal neurologica! signs ma-kes felt their presence as well. Respiratory impairment is a serious complication requiring the transfer of the newborn to the pediatric intensive care unit where me-chanical respiratory assistance is mandatory.

Deep tendon reflexes are variable, weakness of cry and facial expression are notable, but less common are the extraocular movements and ptosis.Another con-sideration would be that the myasthenic face in the newborn is very hard to distunguish. Generally, in the first few days the course is characterized by a rapid worsening, followed by gradual improvement, even complete recovery.

The diagnosis of transient neonatal myasthenia gravis could be done by injecting 1,0 mg anticholin-esterase (intramuscular or subcutaneous) edropho-nium chloride (Tensilon), and a temporary reversal of symptoms can be seen in 10 minutes after injection.In most severely affected newborns, administration of 0,1 mg neostigmine metylsulphate, 20 minutes prior feeding will ensure a significant improvement in suckling and swallowing and also an adequate nutrition.

Now, the problem arises in order to confirm these by electrodiagnostic. In the newborns, the electro-miography is a very sensitive and delicate thing. It is true that is very difficult to perform and interpret . The neurologist specialized in adult electromiography is the less indicated person to made this, due to its un-familiarity with neonatological and pediatric features of the neuromuscular transmission.

Nevertheless repeated electrophysiological studies in transitory neonatal myasthenia gravis should performed on infants who demonstrate symptoms for more than 2 months. Is indicated repetitive nerve stimulation at rate of 2Hz.

CONGENITAL MYASTHENIA
Congenital myasthenia, generally differs from myasthenia gravis, due to the fact that the disrup-ted communication between nerve and muscle isn’t autoimmune mediated so it’s not caused by antibodies, but by genetic defects. This genetic cause of the disease separates the congenital form of myasthenia from myasthenia gravis and Lambert-Eaton myasthenic syndrome.

Types of congenital myasthenia gravis
There are classified in different types of congenital myasthenia gravis as: presynaptic, synaptk and post-synaptic defects and synaptophaty. These can be briefly described in what follows.

Postsynaptic congenital myasthenic syndromes
This feature of congenital myasthenia is most common and is characterized by three types of dysfunction: with too few acetylcholine receptor, and two types of poorly funcţional acetylcholine receptors in the muscle such as “slow-channelsyndrome”and “fast-channel syndrome .

Another subtype is end-plate acetylcholine receptor (AChR) deficiency- the most prevalent subtype of congenital myashenic syndrome (40%) due to the in-adequate number of acetylcholine receptors clustered on the muscle side of the synapse.The severity ranges widely from mild or severe. Cholinesterase inhibitors like Mestinon is used in this sense, among with 3,4- dyaminopyridine. Its inheritance is autosomal recessive (Engel, AG.,2007).

Kinetic deffects
1. Slow-channelsyndrome – can behave a wide range of severity, causing important disabilities begining with age 10 —» little disability around age 60 or be-yond. The cervical, wirst and extensor finger muscles are affected. This kind of congenital myasthenic syndrome cannot be treatd with cholinesterase inhibi-tors, but, instead, can be treated with quinidine and fluoxetine. From genetic point of view, this type is generally, but not always autosomal dominant.
2. Fast-channel syndrome – describe a severity range from mild to severe and is autosomal rcessive. The fast channel syndrome is the „mirror image” of slow-channel syndrome. The tratment aims to use a combination of cholinesterase inhibitors and 3,4-dy-aminopyridine.

Other postsynaptic forms of congenital myasthenia mutations at the level of gene that encodes rapsyn and plectin proteins.
Dysfunction in rapsyn is recessive and can be treated with cholinesterase inhibitors and ephedrine. The plectin cases occur rarely and particularly affect the ocular, facial and limb muscles.

Synaptic congenital myasthenic syndromes
End-plate acetylcholinesterase (AChE) deficiency – 14% of cases less improved in course and after treatment. The medication used for other form of congenital myasthenic syndromes could exacerbate the symptoms. Several patients improves with ephedrine-sulphate and artracurium. If symptoms arises at birth as they do usually, they could be severe or lethal, but, instead are less severe when they arise during infancy. This type is caused by a deficiency of acetylcholinesterase.

Presynaptic congenital myasthenic syndromes
The presynaptic types of congenital myasthenic syndromes are rare. In all cases of congenital myasthenic syndromes they acoount for 8%.

1. Choline acetyltransferase (ChAT) deficiency this form is responsible in newborn for the episodic or sleep apneea, being very particular and different from the rest because the symptoms are generally restricted to spontaneous episodes of severe shortness of breath and bulbar (cry, chewing, suclking, swallowing) weakness. Symptoms can sometimes last in some forms for weeks after an episode. Episodes may also be an-nounced by an febrile burst.
2. Congenital myasthenia gravis with paucity of vesicles and reduced quantal release. This form particularly respond when Mestinon is administrated.

Other presynaptic forms of congenital myasthenia
Myasthenia via Dok-7 synaptophaty. Is caused by a mutation in the Dok-7 gene, being an important protein with role in maturation and maintenance of the synapse. Symptoms are similar to the so-called familial limb girdle myastheia which lacks or features much less severe ocular and bulbar involvement, with an impact to limb-girdle and axial muscles.

Symptoms of congenital myasthenia gravis, usually appears in the first years of childhood, but maybe not detected until much later and occasionaly could remain onknown until adulthood. In infancy the symptoms usually appaer as „floppiness” and a failure to meet developmental milestones, such as rolling or sitting up. Some infants could have also episodes of chocking or pauses in breathing.The symptoms could be installed in preschool period and they appear as weakness during physical activities or an inability to perform age-specific actions such as running or climbing or to manipulate several toys. In addition, if eye muscle is involved, children may have droopy eyelids „lazy eye” or double vision. When mouth or throat muscles are involved children will speak with difficulty and a weak sound emission or swallowing.

Congenital myasthenia rarely appears and could be presented as a neonatal hypotonia.The ophtalmo-plegia maybe parţial or complete but is almost always symetrical.

Arthrogryposis multiplex congenita
Decreased fetal movements may cause arthrogryposis multiplex congenita, denoting fixed joints defor-mities. Clubfoot is the main frequent manifestation, but symmetrical flexion deformities may be present in all limb joints (Fenichel,1980). Intrauterine immobili-zation may be a possible mechanism explaining us why congenital joint deformities develop. The differential diagnosis is the same with the floppy infant syndrome/ neonatal hypotonia. The primary neuropathologi-cal events may be in the brain, spinal cord, peripheral nerves or muscle of the fetus. Extra fetal factors such as oligohydramnios must be taken in consideration. The features deals only with neuromuscular causes of arthrogryposis, being divided into myophatic or/and neu-rogenic. In this case acetylcholine receptors antibodies in the serum could be absent, as electrodiagnostic the single-fiber electromyography with axonal stimulation could reveal prolonged mean jitter. The muscle biopsy is less indicated or maybe to exclude a myogenic cause from a neurogenic incriminator, the staining for cho-linesterase could be generally negative.

There we could speak as well about arthrogryposis due to the trans-placental transfer of acetylcholine receptor antibodies. There are cases in which the baby are delivered by elective caesarean and died in the immediate post-partum period. The implication of myasthenia gravis for both, mother and baby will be always under attention. Arthrogryposis could be seen also in infants born from diabetic mothers.

Figure 1. 55th day of life.
Dry and scaly skin, clenched fi ngers,abduction deformities of shoulders, flexion deformities at elbows,excessive jaundnice and weight loss.
Arthrogryposis multiplexcongenita (Adapted after Neslihan et al., 2005).

 

 

FAMILIAL INFANTILE MYASTHENIA GRAVIS
Clinical onset of the familial form during the neonatal or early infantile period in siblings of non-myasthenic parents is even less common (Conomy et al,1975).Children with familial infantile myasthenia will have severe respiratory and feeding difficulties at birth, being also flaccid. Under medication effect, (as for example Tensilon reverses the weakness and respiratory distress within 10 minutes of injection plus the continued administration of neostigmine) within weeks, symptoms disappear spontaneously. Of course, medication can be gradually reduced in dose, and why not withdrawn.Pay attention to the minor respiratory infection because as coincidence myasthenic crisis can occur with severe apneea and sudden death.The symptoms can be also presented as :salivary inconti-nence, loss of head control, muscular hypotonia,weak cry, ineffectual movements in sucking and swallowing, ineffectual movements of trunk and limbs, muscular hypotonia,dysphagia.

 

 

Figure 2. A little girl with familial myasthenia.
Age: 6 months. Asymmetric ptosis, peaked lips and apparent habitually openedmouth.
No atrophy of the face or other visible musculature.(Adapted after Conomy, 1975).

 

 

 

Familial mysthenia differs from congenital myasthenia because of the absence of the ophtalmoplegia and the presence of severe apneea and „blue asphyxia” immediately after birth.

 

CONCLUSIONS

Having in view that myasthenia gravis include a heterogenous spectrum of both, newborn and childhood distinctive particularities, it demands a special attention in diagnosis, especially with regards on congenital forms. The electrodiagnostic and muscle biopsy should be indicated with great prudence in newborn babies especially Adjustment of therapy according with the form or subtype of myasthenia, must be thought by an neonatal neurologist or pediatric neurologist in order to avoid the unpleasant events.

 

BIBLIOGRAPHY

  1. Papazian, O. „Transient neonatal myasthenia gravis”, J.Child.Neurology 1992,Jul:7 (3) :325.
  2. Fenichel, G. M. „Neonatal Neurology” Ed. Churchill Liv-ingstone,1980.
  3. Engel, A. G. „The therapy of congenital myasthenic syndromes” Neurotherapeutics 2007 Apr; 4 (2):252-7.
  4. John P. Conomy et al., „Familial Infantile myasthenia gravis: A cause of sudden death in young children”. The Journal of Pediatrics, September 1975.
  5. Neslihan Tekin et al., „Clinical and pathological aspects of ARC syndrome in two siblings”. The Turkish Journal of Pediatrics 2005;47:67-70.

 

Correspondence to:
Centre of Neurobiology and Molecular Physiology,Bucharest – Clinical Institute Fundeni, Neurology Clinic, Bucharest