Final Diagnosis -- Multiple System Atrophy

DIAGNOSIS

Multiple system atrophy.

DISCUSSION

Multiple system atrophy (MSA) is a progressive neurodegenerative disease characterized by glial cytoplasmic inclusions (GCIs) in oligodendroglia of the brain and spinal cord. GCIs consist of fibrillar aggregates of ?-synuclein protein that are also immunoreactive for ubiquitin [8]. Occasional cytoplasmic inclusions may be found in astrocytes; neuronal cytoplasmic and nuclear inclusions are also occasionally seen [9].

Current consensus criteria recognize two forms of MSA: MSA with predominant parkinsonian symptoms (MSA-P) and MSA with predominant cerebellar ataxia (MSA-C) [4]. Autonomic failure is most typical of MSA-P but can occur with either form. The clinical picture depends on the specific areas of brain and spinal cord affected in a given individual, and clinical and pathologic overlap between these forms is common. Bladder dysfunction is a common initial complaint. Most patients develop parkinsonism at some stage, with symptoms of bradykinesia with rigidity, tremor, and/or postural instability. Evidence of autonomic failure includes orthostatic hypotension and syncope. Cerebellar disease may manifest as gait ataxia, ataxia of speech, or oculomotor dysfunction. Lower motor neurons signs may be seen [9].

MSA is also causes extrathoracic respiratory compromise. Respiratory features include stridor, inspiratory sigh, and new or increased snoring. Symptoms manifesting during sleep, such as obstructive sleep apnea and rapid eye movement (REM) sleep behavior disorder, are common [1, 2, 3, 5]. The pathophysiological abnormalities underlying sleep apnea and laryngeal stridor in patients with MSA can lead to sudden death [7]. Central sleep apnea in MSA has been attributed to loss of ventral medullary neurons and degeneration of the pontomedullary network . The ventilatory response to hypoxia may also be affected and contribute to the apnea [1]. Laryngeal stridor in MSA may originate from paradoxical tonic contraction of adductor laryngeal muscles with or without abnormal relaxation or paralysis of abductor muscles [1].

In summary, this patient presented with exertional dyspnea and developed dysphagia, dysphonia, variable extrathoracic respiratory obstruction, and severe obstructive sleep apnea. While her clinical examination did not document cerebellar or extrapyramidal abnormalities, her signs and symptoms have all been suggested as "red flags" for MSA [6], and the neuropathologic examination showed the characteristic GCIs of this disorder, particularly in the medulla and spinal cord. The medullary involvement explained her neurologic and respiratory signs. Her obstructive sleep apnea could also be explained on the basis of MSA and was the most likely cause of her sudden death. The relatively mild denervation of the diaphragm played no more than a minor role in her death, though her motor neuron loss was responsible for at least part of her weakness. Her case reflects an unusual presentation of a classic disease and illustrates the importance of a complete autopsy, including a complete neuropathologic examination, in cases of sudden unexpected death.

REFERENCES

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Contributed by Efstathia Andrilopoulou, MD, Carla L. Ellis, MD, MS, Barbara J. Crain, MD, PhD