An Approach to Diagnosing and Managing Neuroleptic Malignant Syndrome, Atypical Neuroleptic Malignant Syndrome and Serotonin Syndrome using a Flowchart Algorithm

    

    

    Figure 3:  Malignant Cerebrotoxic Syndrome.
    
    

Although aNMS traverses the spectrum between NMS and SS, many cases would still not receive a diagnosis of NMS if the rather stringent diagnostic criteria in the DSM-V are adhered to, i.e. severe muscle rigidity and hyperthermia associated with the use of neuroleptic medication being the necessary cardinal features for the diagnosis of NMS. On the other hand, many investigators prefer using the term ‘serotonin toxicity’ as fulminant SS tends to imply serotonin ‘storm’ or ‘crisis’, usually implicated by monoamineoxidase inhibitor (MAOI) drugs in drug regimens and methylenedeoxymethamphetamine (MDMA) abuse which induce higher elevation of serotonin levels [1].

The problem

In the treatment of psychiatric disorders, pharmacological monotherapy has been advocated by experts and is likewise echoed in various clinical practice guidelines. However, this may not be the case in the real world setting as there are frequently multiple co-morbidities to address, as well as the tendency to prescribe a combination of drugs either due to lack of efficacy with a singular agent or for augmentation purposes [14]. Selective serotonin reuptake inhibitor (SSRI) drugs and neuroleptic agents are also being increasingly used, either alone or in combination, in off-label endeavors for conditions where agitation, insomnia and pain are prominent presentations [15]. This multi-drug use practice has garnered a rising trend [16] and may well sustain itself into the future unless collaborative uniform guidelines are implemented.

Until then, patients will be subjected to an increased risk of adverse effects due to multiple pharmacokinetic and pharmacodynamic interactions when SSRIs and atypical antipsychotics are prescribed together. It would be useful at this point to mention that common pathways metabolize some antidepressants (e.g. tricyclic group of drugs) and neuroleptics (e.g. atypical antipsychotics) – both drugs competitively inhibit each other’s degradation, which may increase serum levels of the other. Hence, there is a likelihood of producing NMS, or even SS, when they are concurrently used [17]. The result of co-administration of these drugs makes an accurate diagnosis of NMS and SS increasingly difficult, particularly the milder forms. Also, antipsychotic-lithium combinations have been thought to predispose patients to NMS. Lastly, it should be noted that long-term treatment with antidepressants might result in a cholinergic receptor super supersensitivity, thereby evoking dopaminergic state [18].

Recommendation

Proposed algorithm

Considering the widespread practice of polypharmacy, as well as lack of monitoring where adherence to established treatment regimes is concerned, a diagnostic and management algorithm would then be the most practical way to approach these conditions. The first step would be to recognize any signs and/or symptoms indicative of toxic reactions to prescribed psychotropics that potentially develop into NMS, aNMS or SS, keeping in mind that more often than not, information on the offending drug(s) is unavailable. Broadly, these can be grouped into hyperthermia, movement phenomena (tremors/ myoclonus or EPS), autonomic disturbances and mental changes (agitation or confusion). Organic conditions presenting in a similar manner should be ruled out early on and other causes of elevated CPK levels arising from muscle insult and catatonia duly considered (normal range 38-174 units/L for males, 96-140 units/L in females). Elevated CPK levels (>1,000 units/L), leukocytosis (>10,000/mm3), elevations in liver transaminases and platelets, and increased urea/ creatinine levels all aid in confirming diagnosis; having said that, these parameters may also be non-specific, hence equal attention should be paid to emerging clinical features, especially where aNMS is concerned as relying purely on marked CPK elevation can result in an incorrect diagnosis [5]. To that effect, Boot & de Haan had suggested periodical evaluation of clinical symptoms and CPK activity over a longer period in patients with grossly elevated CPK levels [19].

Higher levels of CPK denote more muscular damage and increased severity of illness – extreme skeletal muscle rigidity resulting in muscle necrosis would explain the elevations in CPK level, lactate dehydrogenase (LDH), alanine aminotransferase (ALT) and aspartate aminotransferase (AST). In severe muscle damage, myoglobinuria and rhabdomyolysis could lead to renal failure and have been, over the past couple of decades, duly identified as predictors of mortality in NMS. Last but not least, as iron is involved in catecholamine synthesis, its deficiency should result in decreased synthesis of dopamine. This phenomenon would be exacerbated by dopamine antagonist drugs, featuring catatonic rigidity as a common presentation. A laboratory profile that entails elevated CPK levels, leukocytosis, increased LDH/ALT/AST and elevated low serum iron has been said to occur in 75% or more of NMS cases [20]. As these laboratory data are not usually associated with SS, particular attention should therefore be paid to those abnormal indices during the differential diagnosis of MNS from SS.

Thus, careful deliberation of the above mentioned symptom clusters, as well as the duration of persisting signs, may point to which end of the spectrum the condition likely lies. Severe rigidity is suggestive of NMS, whereas any form of myoclonus would point towards SS, and that should thereafter guide the decision on treatment with dantrolene and bromocryptine (or amantadine) - the dopamine agonists for NMS and aNMS - or diazepam and cyproheptadine (and/ or propanolol) - the serotonin antagonists for SS. The most serious adverse effect of dantrolene is severe hepatotoxicity; although rare, it may occur after prolonged exposure to high dosing [20]. If by this stage the diagnosis is still uncertain, bromocryptine should be avoided as it has been known to worsen SS.

Fortunately basic supportive care with hydration and removal, or even mere dose reduction, of the offending drug may be sufficient in the majority of cases of mild to full-blown SS, with the former commonly resolving in 24 hours and the latter taking possibly up to a week. But on the other hand, although NMS becomes a selflimiting condition after the discontinuation of the implicated agent, it would still take 1-2 weeks for its signs and symptoms to completely resolve with supportive care; this is provided there is no depot antipsychotic involved [20]. To systematize this decision-making process, a simple proposed algorithm already used in clinical practice by the Neurobehavioral Unit at Penang Adventist Hospital is hereby delineated in a flowchart form (Figure 4).

    

    

    Figure 4:  Proposed management flowchart for Neuroleptic Malignant Syndrome, Atypical Neuroleptic Malignant Syndrome and Serotonin Syndrome.