To the Editor: The special article on sympathoadrenal hyperactivity and the etiology of neuroleptic malignant syndrome by Ronald J. Gurrera, M.D.
(1), was enlightening. Although meticulously written and generously referenced, the article raises some interesting issues that we address here.
First, Dr. Gurrera drew attention to the fact that dopamine antagonism may not be essential for hyperthermia in neuroleptic malignant syndrome. This is based on a few anecdotal reports, which the author cites for support. However, how frequently does one encounter cases of neuroleptic malignant syndrome with hypothermia or neuroleptic malignant syndrome after a dose reduction or a discontinuation of antipsychotics? Furthermore, on the basis of this presumably unclear role of dopamine antagonism in hyperthermia, Dr. Gurrera mentions that in neuroleptic malignant syndrome, additional state-dependent factors are important mediators of dopamine antagonist effects, but he does not specify what these factors are.
Second, Dr. Gurrera mentions that the frontal lobes control sympathetic activity through the hypothalamus. However, through what mechanisms or neurotransmitters the frontal lobes effect this control requires clarification.
Third, the article delves into details on dopamine antagonism at the level of the spinal cord, which leads to sympathetic hyperactivity and the consequent emergence of the clinical features of neuroleptic malignant syndrome. However, dopamine antagonism at the level of the brain is meted out as just a passing reference. This engenders critical attention because the antipsychotic effect of neuroleptics is due to dopamine antagonism at the level of the brain and not at the level of the spinal cord. Is one to infer from this that patients prone to developing neuroleptic malignant syndrome have a variable sensitivity to dopamine blockade at different levels of the nervous system?
Fourth, does Dr. Gurrera purport to explain the altered sensorium so characteristic of neuroleptic malignant syndrome by disturbances in the neurotransmitters of the spinal cord? Emotional and psychological stresses associated with sympathetic hyperactivity appear a less convincing explanation for this altered sensorium.
Fifth, catatonia is stated to bear a strong resemblance to neuroleptic malignant syndrome, but no mention is made of γ-aminobutyric acid (GABA) in the pathophysiology of neuroleptic malignant syndrome. GABA has been implicated in catatonia; so have the frontal lobes
(2). Does GABA play a part in the frontal inhibition of sympathetic drive?
Finally, the article mentions that alternative hypotheses of neuroleptic malignant syndrome do not enable clinicians to make reliable treatment choices. But does this hypothesis make things any better? After learning of Dr. Gurrera’s strong bias for pinpointing peripheral sympathetic hyperactivity as being responsible for neuroleptic malignant syndrome, are we to believe that drugs blocking peripheral sympathetic receptors are a potential treatment modality for neuroleptic malignant syndrome?
