Levodopa withdrawal and the neuroleptic malignant syndrome.

Levodopa withdrawal and the neuroleptic malignant syndrome Sir, In the paper: 'Levodopa withdrawal syndrome identical to neuroleptic-malignant syndrome' (Gibb & Griffith, 1986) the authors suggested that sudden withdrawal of dopaminergic drugs precipitated the development of neuroleptic-malignant syndrome (NMS) in their patient. However, it is difficult to reconcile the wide range of this patient's symp-tomatology with derangements of striatal and hypoth-alamic dopaminergic activity alone. We suggest that the factor operating in the patho-physiology of the NMS is based on hypothalamic endorphinergic dysregulation (Sandyk & Iacono, 1986). In that the hypothalamus: (1) controls autonomic functions, level of consciousness and motor activity (Clar, 1985; Ranson, 1939) and (2) is known to show early, selective degeneration in Parkinson's disease (Langston & Forno, 1978) and (3) cerebrospinal fluid beta-endorphin levels are reported to be reduced in both aging and Parkinson's disease (PD) (Nappi et al., 1985), and (4) L-dopa administration also reduced hypothalamic beta-endorphin content (Locatelli et al., 1983) and (5) the activity of the hypothalamus is partially under endorphinergic control (Gambert et al., 1980), then withdrawal of Sinemet in this patient would conceivably result in excessive opioid activity in an already compromised hypothalamus. In addition, increase in the activity of the intrinsic opioids would lead to inhibition of the locus coeruleus (LC) noradrenergic activity, possibly resulting in alterations of cerebral blood flow (CBF) and level of consciousness (Strahlendorf et al., 1980; Demenet, 1976). Furthermore, intracerebro-ventricular administration of beta-endorphins has been reported to produce rigidity and catalepsy in rats (Sandyk, 1985), and a similar mechanism could have operated in the patient reported by Gibb and Griffith. Thus, a sudden excess of endorphinergic activity within the hypoth-alamus, analogous to that which is seen in septic shock rather than primary derangements of the dopaminer-gic system, may have been the central factor in the precipitation of NMS described in the patient reported. Given that this patient succumbed and mortality in NMS approaches 25% (Friedman et al., 1985) then in the future a therapeutic trial of naloxone based on our explanation may be warranted. A neuroleptic malignant like syndrome due to levodopa therapy withdrawal. (1986). Levodopa withdrawal syndrome identical to neuroleptic malignant syndrome. HAGEN, T.C. (1980). Age-related changes in the central nervous system beta-endorphin and ACTH. A.E. (1983). Effect ofdopaminergic drugs on hypothalamic and pituitary immunoreactive beta-endorphin concentration in the rat.