Abstract
Aim We aimed to review cases of Syndrome of Irreversible
Lithium-Effectuated Neurotoxicity (SILENT) characterized by neurological
sequelae following acute lithium toxicity and to explore whether
cerebellar sequelae are more frequent in cases presenting with fever
and/or infection.
Methods Case reports were identified from: (i) 6 reviews
published up to 2005; (ii) MEDLINE, Web of Sciences, Cochrane Library
and PsycINFO search.
Results We identified 123 SILENT cases published from 1965 to
2019, in which cerebellar sequelae were observed in an overwhelming
proportion (79%). Nearly two out of three cases (63%) had maximal
lithium plasma level <2.5 mEq/l (low/mild toxicity). Fever
and/or infection were reported in nearly half of the patients (48%).
The likelihood of presenting with cerebellar vs. other neurological
sequelae was independently increased by elevated plasma lithium level (≥
2.5 mEq/l) (OR=4.36, 95%CI 1.31-14.52, p = 0.02) and by a history of
fever and/or infection (OR=6.48, 95%CI 2.0-21.0, p = 0.002).
Conclusions During the SARS-CoV-2 pandemic, prescribers have to
be aware of the risks of cerebral sequelae associated with infection and
fever in lithium users, and should warn them of the need to consult in
case of fever to adjust their lithium dosage. As the occurrence of
SILENT is exceptional, there is no need to modify lithium treatment
preventively because of the pandemic as the benefit/risk balance of this
drug remains largely positive.
Key Words: lithium/ adverse drug reaction / neurotoxicity /
fever / infection
1. Introduction
Lithium has well-established
benefits regarding mood stabilization and prevention of suicide, which
most often outweigh the risks associated with its use [1-3].
Intoxication is the most dreaded complication of lithium exposure since
it is potentially life-threatening [4-7]. Exceptionally, lithium
poisoning may be complicated by the occurrence of irreversible
neurological sequelae. First described by Verbov in 1965 [8], this
complication was defined by Schou in 1984 as the persistence of
neurological sequelae more than two months after lithium discontinuation
[9]. In 1987, Adityanjee proposed to name this complication SILENT
(Syndrome of Irreversible Lithium-Effectuated NeuroToxicity) [10].
Although a wide range of persisting neurological syndromes have been
reported, a consistent finding across the literature is the high
proportion of cerebellar sequelae, especially ataxia and dysarthria
[9, 11-15]. The occurrence of neurological sequelae in lithium users
is a dramatic event as limited therapeutic resources are available
(physical rehabilitation, speech therapy and cognitive training) [11,
13].
The most well-documented characteristic of SILENT is that it may occur
in persons with plasma lithium levels within the therapeutic range, and
at any time during lithium treatment [9, 11-15]. The potential
neurotoxic impact of antipsychotic-lithium polytherapy has been widely
cited in the literature on the risk factors of SILENT since the
publication of four cases occurring in persons treated with haloperidol
and lithium [16]. The possible role of fever and infections in the
occurrence of cerebellar sequelae was first mentioned by Schou [9].
This hypothesis is supported by the high proportion of persons
presenting with infections and/or fever among SILENT cases [9,
11-15].
Due to its narrow therapeutic index of lithium, prescribers’ require
updated accurate knowledge about the medical and lifestyle conditions
increasing the risk of its adverse effects. At the onset of the
SARS-CoV-2 pandemic, at a time when every psychiatrist around the world
had to assess the benefit/risk ratio of psychotropic drugs in persons
with COVID-19, we were struck by the fact that very few psychiatrists
were aware that febrile infections might increase the risk of
irreversible neurological sequelae in lithium users. Since our last
review on this issue was undertaken nearly 30 years ago [15], we
suspected that our knowledge about this complication might be outdated,
motivating the current reappraisal of the literature. Of the five other
reviews on SILENT cases [9, 11-14], the last one performed by
Adityanjee included 90 cases published up to 2002 [11]. As
antipsychotic prescribing practices have changed dramatically in lithium
users since the introduction of second-generation antipsychotics
[17], it is of interest to explore whether SILENT cases are still
occurring. Furthermore, all prior reviews were exclusively narrative and
did not explore which putative risk factors were independently
associated with neurological outcome. Hence, the role of fever in the
occurrence of cerebellar sequelae needs to be clarified.
The aim of the present study was to review published SILENT cases and to
explore whether the occurrence of cerebellar neurological sequelae is
more frequent in SILENT cases presenting with fever and/or infection,
independently from other characteristics.
2. Methods
2.1. Identification of cases and search
strategy
This review was conducted according to the guidelines of the Preferred
Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)
statement [18]. First, we considered the case reports identified in
the six reviews published between 1983 and 2005 on neurological sequelae
following lithium toxicity [9, 11-15]. Second, in order to identify
new case reports not included in these prior reviews, we performed a
MEDLINE, Web of Sciences, Cochrane Library and PsycINFO search from
inception through July 2020 using the term “lithium” in combination
with the following search terms (neurotox* OR neurologic* OR cerebel* OR
SILENT). We examined related references of selected papers. Titles and
abstracts of retrieved citations were screened, selected full-text
articles were assessed independently for eligibility and data were
extracted independently by two researchers. Disagreement was resolved by
discussion.
We considered articles meeting the following inclusion criteria: (i)
published in English, French, Spanish, Portuguese, Italian or German in
peer-reviewed journals; (ii) reporting cases of neurological sequelae
persisting more than two months after lithium discontinuation [9,
10]. We did not consider cases for which the observation period after
lithium discontinuation was not specified or lasted less than two
months, including cases with fatal outcome within the two-month period.
For each case, we extracted the following information: (i) reference:
first author’s name, journal, year of publication, (ii) demographic
characteristics: age, gender; (iii) characteristics of lithium
treatment: dose (mg/day), maximum plasma level (mEq/l); (iv)
co-prescribed drugs: antipsychotics, other drugs; (v) associated medical
conditions: fever, infection, dehydration, etc.; (vi) type of
neurological sequelae: cerebellar (irrespective of presence of other
sequelae) vs other (any other type of sequelae without associated
cerebellar sequelae). Lithium maximum plasma level (mEq/l) was
categorized according to the criteria proposed by the Extracorporeal
Treatments in Poisoning (EXTRIP) Workgroup [19]: i) no toxicity:
<1.5 mEq/l); (ii) mild toxicity: [1.5-2.5[ mEq/l; (iii)
moderate toxicity: [2.5–3.5[ mEq/l; (iv) severe toxicity:
> 3.5 mEq/l.
2.2. Statistical
analyses
Multivariate logistic regressions giving Odds Ratio and 95% confidence
intervals (OR, 95% CI) were used to identify the characteristics
independently associated with the type of neurological sequelae
(cerebellar vs. other). Age was categorized as < 50 vs. ≥ 50
ys. Lithium maximum plasma level (mEq/l) was dichotomized as “no/mild”
(<2.5 mEq/l) vs. “moderate/severe” (≥ 2.5 mEq/l) toxicity.
Antipsychotic exposure was categorized as present vs. absent
irrespective of the number and type of antipsychotics. Exposure to fever
and/or infection was defined by the presence of at least one of the two
conditions, irrespective of the cause of fever and the site of
infection. Strictly defined fever included only cases with reported
information on this symptom, irrespective of the cause. All the
variables (age, gender, lithium level, antipsychotic use, fever) were
simultaneously entered in the regression model. The models were not
adjusted for lithium dose as this information was missing in a large
proportion of cases.
3. Results
3.1. Results of literature
search
Figure 1 presents a flow chart of the eligibility process for this
review. One hundred cases published from 1965 to 2002 were identified in
the 6 prior reviews [9, 11-15]. The numbers of additional cases
fulfilling the inclusion criteria identified in each review are given in
the flow chart. The systematic search identified 23 additional cases
published from 1986 to 2019 [20-39].
Ultimately, we included 123 cases of neurological sequelae associated
with lithium exposure reported in 92 articles published from 1965 to
2019 (Table 1). The number of reported cases peaked in the ‘80s. More
than half of the 123 cases were published at the end of this decade,
while very few cases have been published since the beginning of the 21st
century (1960s: n=1; 1970s: n=21, 1980s: n= 48; 1990s: n=30; 2000s:
n=15; 2010s: n=8). Most articles (n=75, 81%) reported a single case,
and the maximal number of cases in an article was 7 [13].
3.2. Demographic
characteristics
There were 53% (n=65) females and 47% (n=58) males. The mean age of
cases was 46.8 (standard deviation 13.3, range 20-70), with 57 cases
(46.3%) aged ≤ 50 years.
3.3. Lithium
treatment
The median daily prescribed dose of lithium was 1200 mg (interquartile
range 900-1500). Twelve (9.8%) overdoses were reported (intentional
n=8, accidental n=3; not specified n=1).
Using the EXTRIP classification, the distribution of maximum lithium
level was: (i) no toxicity <1.5 mEq/l n= 42 (38.5%); (ii)
mild toxicity [1.5-2.5[ mEq/l n=27 (24.8%); (iii) moderate toxicity
[2.5–3.5[ mEq/l n=20 (18.4%); (iv) severe toxicity >
3.5 mEq/l n=20 (18.4%). A plasma level > 5 mEq/L
indicating the need for extracorporeal treatments (ECTRs) [19] was
reported in 7 (6.4%) of patients. Information on lithium level was
missing in 24 cases.