Online Resource
Supplementary material to review article:
Second-generation antipsychotics and neuroleptic malignant syndrome: systematic review
and case report analysis
1. Supplementary methods: data extraction
The variables collected from each case report were:
1) author, date of publication;
2) age, gender, ethnicity, primary and secondary diagnosis;
3) type of SGA used before and at the moment closest to NMS insurgence, duration of treatment
with each SGA, daily dosage, and conversion to chlorpromazine equivalents according to recent
indications (Andreasen et al., 2010; Kroken et al., 2009);
4) type of other psychotropic drugs (SSRI, other antidepressants, lithium, other mood stabilizers,
benzodiazepines) used before and at the moment closest to NMS insurgence, duration of
treatment and daily dosage;
5) type of clinical interventions and pharmacological agents used to treat NMS. These were
classified in: transfer to ICU , intubation, fluids infusion, ECT, muscle relaxant (dantrolene,
benzodiazepines, baclofen), anticholinergic drugs (biperidene , benztropin), dopaminergic agents
(bromocriptine, L-dopa, carbidopa, pramipexole, amantadine, apomorphine), antipyretic drugs
(NSAIDS and others), antihypertensive drug, rechallenge with any AP;
6) patient clinical outcome: death, complete recovery, incomplete recovery.
1.1 Coding of symptoms
The aim was to code available information on the symptoms of NMS, namely their presence or
absence, duration and severity. Whenever a symptom was reported, it was coded as present and the
date of its onset was recorded, along with its score of severity and with the date when it subsided. In
order to improve the homogeneity of ratings the categorization of symptoms and the rating of their
severity was based on the items of the Francis-Yacoub NMS Rating Scale (FYNMS-RS) (Yacoub
and Francis, 2006), which we adapted for our scope (Table S1).
We agreed on a conservative approach to code the absence of symptoms: if authors explicitly stated
that a symptom of NMS was not observed, it was coded as absent. If symptoms were not mentioned
in the case report, they were considered as missing by default. Only in few cases, the absence of
symptoms were inferred from the description of the case (e.g. for a patient described as “awake and
collaborative”, catatonia was considered absent). Finally, a global severity score was calculated as
the sum of all items of symptom severity, excluding items for which cases had 30% or more
missing data.
Data extraction was performed by two clinically expert psychiatrists blind to each other (A.G. and
M.B.). First, 10 cases were used to set the benchmark, and discordances were solved by discussion.
When agreement could not be reached values were considered with the more conservative option
(symptom absent) or, for symptom severity, as the mean of the two ratings. Then, 10 cases were
independently rated to calculate inter-rater reliability, which was very good both for symptom
ratings of severity (ICC for average measures=0.99, p<0.001) and for total severity score (ICC for
average measures=0.99, p<0.001)
1.2 Temporal sequence and definition of events
In order to provide descriptive summaries on the course of NMS (duration, timing and symptoms’
onset and AP treatments) we extracted all available data relative to the temporal sequence of
relevant clinical events.
First of all we aimed at establishing when the date of NMS diagnosis could be set for each case.
This was defined as the day when NMS was diagnosed according to the clinician’s judgment or to
the use of standardized criteria. When it was not clearly stated in the paper, we used the day when
the description of the clinical picture would meet Levenson’s diagnostic criteria (Levenson, 1985).
To establish the date of remission from NMS and calculate NMS duration we used the definition
given in the clinical report.
The day of NMS diagnosis was established at an arbitrary reference date, equal for all cases.
Starting from this date, we inputted the dates of other clinically relevant events, based on the
authors’ report (e.g. if it was reported that patient had started the SGA four days earlier than NMS
diagnosis, we set this date at 27.12.12). When available, we recorded the dates of the initiation of
treatment with SGA, dosage modifications, symptoms’ onset and treatment for NMS.
Extraction of data related to temporal sequence of events was performed by two researchers (A.G.
and M.B.) with excellent reliability (ICC for average NMS duration=0.96, p<0.001).
Table S1. Coding of symptoms included in the analysis
Coded symptoms
Extrapyramidal symptoms (1-5)
Tremor
Rigidity
Dysphagia
Dysarthria
Other EPS
Hyperthermia (8)
Low
Moderate
Moderate-severe
Severe
Laboratory parameters (18,19, 22)
CK elevation
Not specified
Low
Moderate
Moderate-severe
Severe
WBC elevation
Not specified
Mild
Severe
Muscle damage
Altered mental status (6, 7)
Mental Status
Mild alteration
Moderate
Severe
Catatonia
Not specified
1 symptom
≥2 symptoms
Autonomic symptoms and vital
signs (9-11,14)
Diaphoresis
Tachycardia (BPM)
light
Moderate
Severe
Hypertension
light
Moderate
Severe
Hypertension
light
Moderate
Severe
Other autonomic
Definition and synonyms used in case reports
resting tremor
lead pipe, axial, neck/trunk/extremities, clasp knife, cog wheel
Dystonia, dyskinesia (tongue, or jaw, torticollis), bradykinesia
akathisia, oculogyric crisis
37 - 37.5 °C
37.5 - 39 °C
39 - 40 °C
≥40 °C
200 to 500 IU/l
501 to 1000 IU/l
1001 to 5000 IU/l
>5000 IU/l
11000 to 15000
>15000
Myoglobinemia or myoglobinuria
Generic alteration, mild fluctuation of conscience, sedation,
somnolence ,worsening of pre-existing mental state or symptoms of
illness
disorientation , incoherence, confusion, disorganization, severe
drowsiness, lethargy
Stupor, coma
Rating
(0-20)
0-4
0-4
0-4
0-4
0-4
(0-16)
4
8
12
16
(0-12)
0-4
1
1
2
3
4
0-4
1
4
8
0-4
(0-16)
3
4-6
8
4
4
8
(0-16)
90 - 100
101 - 120
>120
Systolic
140 - 160
161 - 180
>180
Diastolic
90 - 100
101 - 110
>110
nausea, vomit, urinary or fecal incontinence, acute urinary retention,
constipation, sialorrhea, dry mouth
0-4
0-4
1
2
4
0-4
1
2
4
0-4
1
2
4
-
2. Supplementary results.
Figure S1. Flow chart of included studies and case reports
Pubmed N = 918 abstracts
screened
6 primary studies included
Title /abstract screening: excluded citations (N=647)
N = 265
After screening of abstracts
18 potentially relevant, but no access to full text
resource
N = 247
Full text examination
Full text examination: excluded citations (N=105)
-
142 references, 186 cases of
NMS induced by SGA
monotherapy
30 for no NMS, not SGA, NMS induced by SGA
withdrawal, other reasons;
50 for polytherapy with FGA;
25 for polytherapy with other SGA.
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