Neuromuscular Weakness in Children: Myasthenia

Myasthenia

1. Description of the problem

What every clinician needs to know

The term myasthenia applies to a group of disorders that have in common a defect in acetyl choline mediated neuromuscular transmission. The largest category is myasthenia gravis, an acquired autoimmune disease that results in antibody mediated injury to the post synaptic acetylcholine receptor complex with concomitant weakness due to failure of neuromuscular transmission.

Other less commonly encountered forms of the disease are neonatal myasthenia, in which genetically determined abnormalities in the neuromuscular junction that may affect the pre- or post-synaptic complex result in deranged synaptic function.

This segment will focus on myasthenia gravis, the acquired autoimmune form of the disease, by far the most common of the three.

Myasthenia gravis

Myasthenia gravis is an autoimmune disease mediated by antibodies directed against acetylcholine receptor complexes located on the post-synaptic end-plate of the neuromuscular junction. We traditionally conceptualize the effects of this process as compromising the efficiency of neuromuscular transmission resulting in fatigue and weakness.

Much of that rationale probably derived from the clinical presentation, in which fatigue plays a prominent role. Ptosis is a prominent symptom is most myasthenics and typically is minimal after waking in the morning and becomes progressively worse in the course of the day. In addition to the typical diurnal worsening of symptoms, variability over the course of time is also typical in this disease.

In terms of clinical semiology, the disease is categorized into three groups: ocular, bubar and generalized. These are, for the most part, artificial distinctions except for a cohort who present with purely ocular symptoms wherein, despite nearly complete immunopathogenic homology among the different groups, the clinical manifestations remain confined to extraocular muscles.

Ocular. These children come to medical attention because of acquired ptosis, the hallmark feature of myasthenia gravis, which may be unilateral or bilateral. On questioning they may admit to visual difficulties in the form of diplopia or visual obscuration on upgaze due to ptosis. Examination may disclose restricted extraocular motility, often in a pattern non-congruent with the distribution of cranial nerves. Symptoms and signs typically fluctuate over the course of a day or during the week.
Bulbar. Isolated bulbar weakness is rare and generally occurs in concert with ocular or generalized symptoms. Its manifestations include loss of facial expression, dysphagia, dysphonia, palatal insufficiency and intermittent airway obstruction, particularly during recumbency. Sleep disturbances may bring this symptom to light.
Generalized. The implications appear self-evident. The earliest manifestation is usually loss of endurance. This complaint is often diurnal in severity, with fatigue progressing as the day wears on. In addition to ocular and bulbar findings, there may be frank weakness of other muscle groups, sometimes to an unanticipated degree. Repetitive testing, such as serial deep knee bends, will often bring out subtle underlying weakness.

Myasthenic crisis

By the time patients exhibit extremity weakness, particularly in a resting state, the pathogenetic process of immunological neuromuscular blockade is well along and a true myasthenic crisis may be impending. It is preferable to intervene in this evolving process before the airway or respiratory effort are critically compromised. Obviously, an inpatient setting with a capacity for careful monitoring is required.

Myasthenic crisis usually develops in a patient with known myasthenia whose clinical symptoms have been escalating and resistant to treatment, but may be the initial manifestation of the disease. It may be precipitated by factors which upregulate immunological activity, such as intercurrent infection or vaccination. Life stressors also seem to be a common co-morbidity. Whether they represent the chicken or the egg in the equation varies case by case.

Whatever triggers may be involved, suspected impending myasthenic crisis is a medical emergency. The kinetics of the evolution of antibody mediated neuromuscular blockade are unpredictable and in the absence of overt respiratory failure, empirical clues suggesting the future clinical trajectory of the patient require serial observation and measurement. In most cases, an ICU environment is necessary initially to assess the progression of weakness and the potential need for, and ready availability to provide, airway protection and ventilatory support.

2. Emergency Management

Action plan

Admit and carefully observe the patient.The experience of the observer is probably as or even more important than the environment.

Use reproducible quantitative measures when possible, such as maximal negative inspiratory force (NIF), exhalation spirometry or other measures of respiratory muscle strength.

Listen to phonation. Vocal cord paralysis may develop independent of diaphragm or chest wall weakness.

Stop acetylcholinesterase inhibitors. The role for these drugs, in my view, lies in the ambulatory treatment setting where they are employed to treat functional disabilities that compromise quality of life. They will increase the efficiency of neuromuscular transmission; however, they shift the curve only slightly, are short acting and do not provide a sufficient margin for error to be relied upon to prevent airway or respiratory failure in a myasthenic. The have no place in the ICU and come into play only later in recovery from crisis.

Plasmapheresis is the most rapid and efficient way to remove pathogenic antibodies in this disease. Different institutions often embrace idiosyncratic pheresis protocols. A triple volume plasma exchange performed in three sessions can extract in the range of 90% of the total body burden of pathogenic IgG.

These can be performed on alternate days over a 5-day interval, which allows for repletion of clotting factors and re-equilibration of the circulating IgG pool with the extravascular compartment on off days to obtain a maximal exchange gradient during pheresis. More aggressive protocols may require replacement of platelets and clotting factors with fresh frozen plasma.

Corticosteroids are an efficient way of inhibiting B-cell activity triggered by the sudden depletion of circulating IgG due to plasmapheresis and will, in most cases, be an integral part of the pharmacotherapeutic regimen during recovery. There is no objective data on which to base dosage recommendations; however, I have used methylprednisolone at a dose of 5 mg/kg/day divided BID for the first week of treatment followed by a slow taper of an oral preparation.

In the past, some centers would customarily admit patients to the hospital to initiate high dose corticosteroid treatment because of the fear that it could precipitate a myasthenic crisis. This practice was not evidence based or mechanistically understood. It was experientially driven, and probably fueled by coincidence. The adrenalin rush of a narrowly averted disaster, however, can be a very persuasive conditioner of behavior and this habit continues in the hands of some practitioners.

Nevertheless, corticosteroids have preferred effects on B-cell function and markedly inhibit antibody production and clonal expansion. They act synergistically with plasmapheresis after removal of pathogenic antibodies to limit antibody production rebound. Underlying infection. Many chronic myasthenics are immunocompromised by their treatment regimens and prone to opportunistic pathogens. A careful inventory for infection that may have triggered the crisis and can continue to blunt efforts to modulate immunological dysregulation is essential, followed by aggressive anti-infective intervention.Patience. As this maelstrom of immunological forces comes into some sort of dynamic equilibrium, the threshold for effective neuromuscular transmission can be quite tenuous. Sudden changes in the functional requirements to sustain respiratory activity can exceed the compensatory reserves of compromised neuromuscular junctions. The process of weaning respiratory support should be slow and gradual.

3. Diagnosis

Pathophysiology

Myasthenia gravis is an autoimmune disease mediated by antibodies directed against elements of the most-synaptic end-plate of the neuromuscular junction. In the majority of patients, the pathological antibodies are targeting epitopes located on or adjacent to the acetylcholine receptor, ultimately resulting in degradation of the receptors and compromised efficiency of neuromuscular transmission.

A smaller segment of this population have antibodies toward MUSK (MUscle Specific Kinase), which is an integral component of the post-synaptic membrane playing a role in the distribution of ACh receptors in post synaptic clefts.

Finally, a group of patients who otherwise exhibit all of the typical clinical and electrophysiological features of myasthenia gravis have no detectible confirmatory circulating receptor antibodies. It is likely, however, that the failure to detect antibodies in this cohort is related more to the limits of our immunological diagnostic ability than to an alternate disease mechanism.

Epidemiology

Prognosis

Myasthenia gravis is a chronic autoimmune disorder that seems to have a built-in self-regulatory mechanism that allows the disease over time to ultimately go into remission. The data are less than optimal but in aggregate suggest that there is a baseline remission rate of roughly 8-10% per year, such that within 5 years of diagnosis, roughly 40 % of children will have achieved spontaneous remission.

There is data to support the notion that the percentage of patients achieving remission can be augmented with thymectomy. This surgery increases the likelihood of achieving remission at the 5-year mark to 70%. It appears that those who fail to go into a remission within 5 years have an equal likelihood of doing so later at the baseline rate of 8-10% per year.

The original study that looked at this issue in children also concluded that thymectomy was most likely to be efficacious when performed within the first year from the onset of symptoms. Ocular symptoms appear to be less responsive to thymectomy.

There is, understandably, debate regarding when thymectomy should be considered, as opposed to waiting for the disease activity to abate on its own. My own approach has been that once the disease has demonstrated its potential lethality (by virtue of an ICU admission) a recurrent crisis should be prevented if and however possible. For me, this means the initial ICU admission becomes the first episode in a staging process with thymectomy occurring prior to discharge from that hospitalization.

Special considerations for nursing and allied health professionals.

What's the evidence?

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