In this case, the patient’s presentation advanced over several days post treatment with three different second-generation antipsychotics for a first-time bipolar type I manic episode and within hours once the possibility of NMS or malignant catatonia was recognized. At that time, his symptoms insidiously progressed from apparent catatonia to what resembled NMS or malignant catatonia. The patient demonstrated stupor, mutism, diminished responses to voice and painful stimuli, stereotypic non-goal-directed behaviors, such as picking things up from the floor repetitively, responding to internal stimuli, and fixed gaze with occasional scanning of the room—all suggestive of catatonia (APA, DSM-5, 2013). Due to profound negativism and resistance to movement or inspection (lead pipe rigidity), muscle rigidity was appreciated. When muscle rigidity and low-grade fever were seen in the setting of autonomic instability, NMS became a concern.
At this time, the patient presented with agitation that evolved into profound mental status changes and finally into a state of stupor. He demonstrated superimposed bilateral hand tremor, low grade fever of 100.4 to 100.8F, and dysregulation of his vital signs with no dysrhythmias. Hours into this abrupt presentation, the patient developed elevation in creatine kinase, four times the upper limit of normal, with concern for rhabdomyolysis. However, he did not display sialorrhea, dysarthria, or dysphagia. A trial of Ativan to differentiate malignant catatonia from NMS did not interrupt the escalation of patient’s symptoms (Pileggi & Cook, 2016). Thus, at this point more of a concern for NMS than malignant catatonia was in question.
Eventually, the patient was transferred to the step-down unit (SDU) and stabilized. At the SDU, he was provided with dantrolene and antipsychotics were withdrawn. This resulted in good control of his heterogeneous symptoms. In spite of his receiving daily dosages of Ativan, his clinical picture progressed to a more neuroleptic malignant etiology when the antipsychotic was continued. This is suggestive of NMS, and ultimately, he responded to one dose of dantrolene combined with discontinuation of risperidone and higher dosages of Ativan. Prior to this point, the patient’s dosage of Ativan was not upregulated and only reached a minimum range recommended for catatonia before his symptoms resolved. The overlap between the timing of the first dose of dantrolene, not receiving a robust amount of Ativan, and removal of risperidone make the diagnosis unclear. Another point to consider is that cessation of anti-psychotics is indicated as a treatment for NMS but not for catatonia. Considering all the factors presented, dantrolene could have been curative―or have had no impact at all; we cannot be certain.
There is agreement that NMS and malignant catatonia can be indistinguishable from each other. Specifically, catatonia with pyrexia and autonomic instability are blurred by pathophysiology. It has been stated that NMS is a subcortical motor syndrome caused by dopaminergic dysregulation, whereas malignant catatonia is a GABAergic dysregulation from the cortical psychomotor region of the brain (Reilly, et al., 2017).
The pathophysiology of NMS is thought to be related to a dopamine antagonist effect. This effect causes inhibition of dopamine availability thus heightening a lead pipe muscle rigid appearance and ineffective ability to regulate autonomic organ functions. Usually, NMS is a rare life-threatening reaction to antipsychotics that commonly presents with pyrexia, autonomic instability, rigidity, and altered consciousness (Reilly, et al., 2017). Eventually, this can lead to complications such as metabolic acidosis, hypermetabolism, chest wall restriction, aspiration pneumonia or pulmonary emboli, and sudden respiratory arrest (APA, DSM-5, 2013).
The development course of NMS usually starts with altered mental status and varies from an onset of hours to days. Eventually, after the antipsychotic drugs are discontinued, resolution of symptoms resolves within one week. In our case, symptoms resolved within hours to one day of administration of multiple interventions, but most notably when the patient was given dantrolene, higher dosages of Ativan, withdrawal of antipsychotics and immediate intensive care was implemented. Notably, fatal rates have been reported to be between 10-20% when the diagnosis is unrecognized. Although most do not have a recurrence of NMS, some patients have a recurrence if antipsychotics are added back soon after the episode (APA, DSM-5, 2013). In our case antipsychotics were not attempted until one month later with no reoccurrence of NMS.
Suggested Course of Action
Our proposal is to have a high degree of suspicion when using antipsychotics per application of catatonia scales. Also, a trial of Ativan before administration of a more complex medication is warranted. Another topic considered in the literature is treatment of catatonia with therapeutic doses of Ativan (ranging from 8-24mg/day). Dual treatment with an antipsychotic and Ativan is another consideration (Spiegel et al., 2019). In our patient, it could be proposed that therapeutic dosage levels to prevent NMS and to treat catatonia were not reached given that a response was achieved after dantrolene was administered. It could also be suggested that either he was not given enough Ativan to prevent NMS, the dose of Ativan was not within therapeutic dosage ranges to treat catatonia, or he was given enough antipsychotic medication to induce NMS―or the diagnosis of NMS and malignant catatonia occurred concurrently.
The literature has suggested the need for more catatonia rating scales, specifically those that predict a surge in catatonia. Our patient’s scores were slowly increasing with an insidious onset of catatonia, which we believe slipped into an NMS reaction. BFCRS rating scales are elevated when the patient clinically improves. This was demonstrated in our case and the patient continued to have an elevated score, even after the clinical concern for catatonia was not appreciated.
In a study by Kirkhart et al. (2007), some subjects continued to have a score between 3 -12 even after physiological stabilization was achieved. They found that the verbiage describing symptoms of catatonia was ambiguous and had poor validity. More accurate rating scales would be helpful in predicting or ruling out NMS (Kirkhart et al., 2007). In fact, Carroll et al. found that there is not enough sensitivity to determine the appropriate treatment response when using BFCRS scoring (2008). Scales that differentiate between malignant catatonia and NMS would be ideal.
Clarity of diagnosis and validity of catatonia score scales to identify psychomotor syndromes are limited. Our case is anecdotal, and as a single case report, it is inherently limited. It is also understood that there is a blurring of the malignant catatonia and NMS diagnoses. One method suggested to distinguish between the two diagnoses is the use of neuroleptics implicating NMS versus a disease process such as malignant catatonia. For instance, catatonia is known to be a clinical consequence of various psychiatric DSM-5 diagnosis spectrums such as autism, schizophrenia, mood disorders and medical conditions. This has been supported by Asztalos (2014), who notes that there has been overlap in the neuropathological and pathophysiological aspects of the two diagnoses since the introduction of neuroleptics to treat catatonia began in the 19th century.
We may not have used the effective dosages of Ativan at the inception of his catatonic presentation and the level of similarity neuropathological and pathophysiological aspects of both diagnoses was not strongly considered. Catatonia dosage ranges were not achieved until the BFCRS scores were suspicious for prodromal NMS. At this point, the patient remained on a more therapeutic dose of Ativan for one day with worsening BFCRS scores. Not until dantrolene was utilized did the patient’s clinical picture start to resolve. It could have been that his psychomotor syndrome was already starting to respond to more therapeutic dosages of Ativan or that he truly was exhibiting the beginning stages of NMS and it resolved with the initiation of dantrolene and cessation of antipsychotics.
However, we were relying on the clinical presentation and BFCRS scores, which are known to be subjective. Thus, BFCRS scales have variable sensitivity and the definitions used to measure resolution of psychomotor syndrome lack clarity. Although in this case, scores correlated with our patient’s worsening clinical picture. Even after recovering clinically, his scores remained elevated, suggesting continuation of psychomotor syndrome. Additionally, his Ativan dosage was well below therapeutic levels during this time of elevated BFCRS score but he still continued to improve. Because all three were treated for at the same time, whether the patient had NMS, malignant catatonia, or catatonia syndrome remains unclear.