Laughter is not always funny

Maayan C, Katz E, Begin M, Yuvchev I, Kharasch VS. Laughter is not always
funny: breath-holding spells in familial dysautonomia. Clin Pediatr (Phila). 2015
Feb;54(2):174-8.

Abstract

Familial dysautonomia (FD) is a genetic disease characterized by primary autonomic dysfunction including parasympathetic hypersensitivity. Breath-holding spells (BHS) are believed to be caused by autonomic dysregulation mediated via the vagus nerve and increased in patients with a family history of BHS. Details and understanding of its pathophysiology are lacking. In this retrospective study of patients with FD, the incidence of BHS was higher at 53.3%, compared with previous studies in normal children. Laughter as a precipitating factor for BHS has not been previously reported in FD and occurred in 10% of patients in this study. Lower lung volumes, chronic lung disease, chronic CO2 retention, and inadequate autonomic compensation occur in those with FD leading to a higher incidence and severity of BHS when crying or laughing. Thus, FD may be a good model for understanding manifestations of the autonomic nervous system dysfunction and contribute to our knowledge of BHS mechanisms.

From the article:

A total of 10% (11/90) had an episode of BHS while laughing as well as while crying. Eighty percent of the BHS were pallid, 15% were undetermined (mostly mixed) and 5% were cyanotic.

Iron levels were variable, but supplemental iron treatments did not change frequency or severity of BHS.

The dynamics of airflow during laughter may predispose the patient with FD to BHS. Laughter is a series of repetitive expiratory efforts characterized by a decrease in inspiratory time and tidal volume. In normal subjects, fits of laughter consistently led to a substantial decrease in lung volumes in all respiratory compartments and remarkable dynamic compression of the airways. Intense laughter consists of repetitive forced expirations in a staccato pattern with a Valsalva-type effect leading to increased intrathoracic pressure, reduced venous return, decreased cardiac output, and transient reduction in cerebral perfusion. Normally, the body compensates by cerebral vascular autoregulation and autonomic reflexes, mechanisms that are dysfunctional in patients with FD.  Furthermore, in patients with FD, reduction in lung volumes due to kyphoscoliosis in conjunction with abnormal autonomic responses to hypocapnea and hypoxia, as well as parasympathetic hypersensitivity of lung stretch and J receptors, may be the mechanism for BHS during laughter.

There have been a few reported incidents of death from laughter throughout history. One example of fatal laughter was in 1956, when an Italian author Pietro Aretino suffocated from laughing too much. Laughter is known to cause atonia, syncope, cataplexy, and gelastic seizures. Furthermore, prolonged laughter can cause infarction of the pons and medulla oblongata.  Laughter syncope is a rare type of situational syncope associated with abnormalities in blood pressure and heart rate regulation. In Angelman syndrome, asystole during an outburst of laughing caused by severe vagal hypertonia has also been described. This is another genetic disease where a form of breath holding (laughter syncope) was observed in the milieu of abnormal hyperresponsiveness of the parasympathetic system. To our knowledge, there have been no reports of any deaths secondary to BHS in patients with FD.

Breath-holding spells are described as relatively benign except in “severe” cases resulting in hypoxic brain damage. Treatment options continue to be limited in efficacy. Iron supplements have been shown to reduce the incidence and severity of these events as iron deficiency may adversely affect the autonomic nervous system. Atropine and belladonna, both antiparasympathetic agents have been recommended. Piracetam and glutamate receptor antagonists may prevent hypoxic ischemic damage to the brain. Piracetam, chemical structure 2-oxo-1-pyrollidine acetamide, is similar to γ-aminobutyric acid, which is an inhibitory neurotransmitter. It is thought to decrease the frequency of BHS through a central mechanism by increasing cortical control on the subcortical field. Hypoxic ischemia following BHS increases extracellular glutamate, a principal excitatory neurotransmitter. Excess excitatory amino acids like glutamate are associated with convulsions and neuroexcitotoxicity. Thus drugs that affect sodium channels and decrease glutamate release have been shown to act effectively as anticonvulsants. Clonidine, an α2 adrenergic agonist can decrease intrapulmonary shunting. Selective serotonin reuptake inhibitor, tetrabenzene, and levetiracem have also been used.

                

Treatment of severe BHS in patients with FD must take into consideration parasympathetic hypersensi-tivity. Therefore antiparasympathetic drugs must be given only in low diluted doses with close monitoring and care. In addition, situations which may arouse anger, frustration, and crying should be avoided. The child should be placed a safe position that not only prevents injury from falls but also improves cerebral circulation (legs up).

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