4. Discussion
4.1. Main
findings
We identified 123 cases of neurological sequelae associated with lithium
exposure published from 1965 to 2019, including 23 additional cases not
identified in prior reviews. Cerebellar sequelae were observed in an
overwhelming proportion of cases (79%). Nearly two out of three cases
(63%) had a maximal lithium plasma level <2.5 mEq/l
indicative of low/mild toxicity [19]. 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)
and by a history of fever and/or infection. Stratified analyses showed
that the association between fever/infection and occurrence of
cerebellar sequelae was restricted to cases with lithium plasma level
<2.5 mEq/l.
4.2. Interpretation of
findings
While the incidence of SILENT in the population of lithium users is
unknown, this complication may be considered as exceptional considering
that the 123 cases identified in the present review were published over
a 55-year period. The decreasing frequency of published cases after the
‘90s may be explained by a lower publishing rate of new cases, as is
often the case when a drug adverse effect is considered as already
well-documented in the literature. This decrease might also be related
to changes in prescribing practice over the last decades, with a wider
use of anticonvulsants and second-generation antipsychotics in bipolar
disorder, leading to low rates of lithium exposure in the general
population [17, 48, 49]. Due to the severity of this complication,
it is important to keep in mind that SILENT cases are still occurring
despite these changes in prescribing practices.
The clinical characteristics of the SILENT cases identified in the
present review are comparable to those reported in prior reviews [9,
11-15]. These severe complications of lithium treatment are most
frequently observed during routine lithium treatment, with fewer than
10% of cases occurring after accidental or intentional overdoses.
Consistently with this low rate of overdose, plasma lithium levels were
within the therapeutic range in a large proportion of cases. In cases
with toxic plasma lithium levels, several factors known to increase
plasma levels were noted such as anorexia [8], dehydration [50],
chronic kidney disease [51] or coprescription of diuretics [13,
38, 52, 53].
Typically, the inaugural clinical picture is an episode of acute lithium
poisoning with little symptomatic specificity. Neurological symptoms are
frequently observed during these episodes, such as tremor, rigidity,
hyperreflexia, myoclonia, disorientation, drowsiness or seizures, and
transient cerebellar symptoms (dysarthria, ataxia, nystagmus) may also
be present [6, 13]. Cases of SILENT without an acute lithium
poisoning phase are rare [54].
The questions raised since the observation of the first cases of SILENT
are why these neurological symptoms exceptionally persist after the
resolution of the acute episode, and why cerebellar sequelae are so
frequent in SILENT cases. The neurotoxicity of antipsychotic-lithium
polytherapy in general and of haloperidol-lithium was long considered as
a plausible hypothesis explaining the occurrence of these cases [12,
16] and is still mentioned as a key factor in the recent literature on
drug-induced cerebellar syndromes [37, 55]. However, the existence
of a causal link between exposure to haloperidol and the occurrence of
SILENT was soon questioned as the frequency of haloperidol-lithium
polytherapy was comparable in persons with and without neurological
sequelae [9, 56]. In the present review, half of the cases were
prescribed antipsychotics, a prescription pattern comparable to that
observed in persons with bipolar disorders treated in the last decades
of the 20th century [57]. No association was found
between exposure to antipsychotics and the occurrence of cerebellar
sequalae after adjusting for the other variables.
The striking elevated frequency of cases of SILENT with a history of
fever or infection, first noticed by Schou [9], is confirmed in the
present study. What the latter adds to prior narrative reviews is to
show that fever is associated with an increased risk of cerebellar
sequelae, independently from other characteristics, and that this
increased risk is restricted to cases with plasma lithium levels
<2.5 mEq/l (no/mild toxicity)[19]. In the group with
no/mild toxicity, more than two thirds (71%) of patients with
cerebellar sequelae had a history of fever/infection vs. 17% of
patients with other sequelae. Conversely, the presence of
fever/infection was not associated with the type of neurological
sequelae in the group of cases with lithium levels ≥ 2.5 mEq/l
(moderate/severe toxicity).
These findings suggest that two distinct pathophysiological pathways may
lead to neurological sequelae induced by lithium. This hypothesis is
speculative and has to be regarded as an oversimplification of the
complex relationships between cerebellar sensitivity to both lithium
neurotoxicity and fever. Schematically, the first pathway is
characterized by an episode of lithium poisoning with elevated lithium
levels leading to a wide range of neurological sequelae, including
cerebellar ones, perhaps because the lithium neurotoxic threshold is
reached everywhere in the nervous system. The second pathway is marked
by the occurrence of cerebellar sequelae after a febrile intercurrent
episode in patients with lithium levels within the therapeutic range or
moderately elevated, perhaps because the lithium neurotoxic threshold is
lower in this brain area in the event of fever. The biological
plausibility of a causal link between fever and risk of cerebellar
sequelae in lithium users is supported by the long-known sensitivity of
the cerebellar cortex to heat and hyperthermia [13, 37]. The most
consistent neuroanatomical findings found by brain imaging and
post-mortem studies are cerebellar atrophy and loss of Purkinje cells
[43, 46, 54, 58-62].
4.3. Implications for clinical
practice
Decades after the event, prescribers who have encountered such cases
keep a vivid memory of patients confined to a wheelchair [9, 46]. As
therapeutic resources are limited, prevention of SILENT is crucial and
requires prescribers’ awareness about the following points, which
synthesize the key findings with implications for clinical practice
drawn from current and prior reviews [9, 11-15]:
- SILENT may occur at any time during lithium treatment, from a few days
after treatment to decades after.
- SILENT may occur even when lithium plasma levels are within the
therapeutic range. Hence, the clinical symptoms of neurotoxicity are
more important than the lithium level for deciding modifications of
lithium treatment.
- Fever dramatically increases the risk of cerebral sequelae. The
literature demonstrates that all causes of fever (infection,
neuroleptic malignant syndrome, heat stroke, etc.) appear to be
associated with this increased risk, and it is possible that no
minimal hyperthermia can be considered as safe [27].
- Based upon the literature and the present findings, we recommend the
interruption of lithium or at least a dose reduction in the event of
fever. As no guidelines are currently available regarding this point,
it might be recommended to halve the dosage of lithium. Even if there
is a risk of mood recurrence due to lithium withdrawal [63, 64],
this risk may be considered as low when the treatment is interrupted
only over a few days, and it is negligible compared to the risk of
neurological sequelae. Hence, the strategy recommended for lithium in
the event of fever or infection should be very close to that
recommended for clozapine, the other psychotropic drug with a narrow
therapeutic index [65-68].
- When lithium users benefit from therapeutic education about the
symptoms of neurotoxicity and conditions promoting the occurrence of
these symptoms (dehydration, coprescription of diuretics or NSAID,
etc), they should receive special warning about the fact that fever,
irrespective of its cause, may induce lithium toxicity and that they
must consult in the event of fever in order to adapt their dosage.
It is beyond the scope of the present paper to review the management of
lithium poisoning: the cornerstones are the early identification of
neurotoxic symptoms and the use of aggressive lithium removal methods
[5, 6, 19, 69]. Owing to the low incidence of SILENT, no study has
examined which strategy may help to prevent neurological sequelae.
However, neurological symptoms are known to persist more frequently at
intensive care unit discharge in patients with lithium poisoning not
treated by extracorporeal toxin removal [6].
4.5.
Limitations
The present review is limited by the fact that data were extracted from
published case reports who may not be representative of all cases of
neurological sequelae occurring in persons exposed to lithium. For
instance, we cannot exclude that a publication bias may exist for cases
presenting with cerebellar symptoms, leading to an overrepresentation of
such cases in the literature. However, such a bias, if any, should not
have impacted the direction and strength of the association between
fever and occurrence of cerebellar sequelae, as a systematic publication
bias of cases with fever and cerebellar symptoms is unlikely.
Furthermore, we may have missed some published cases, but we have little
reason to suspect that we selectively missed cases presenting with
features different than those identified in the present review. Lastly,
a third unknown factor and therefore not adjusted for in the present
analysis, and independently associated with increased risk of fever and
increased risk of cerebellar sequelae, may confound this association.
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 the event
of fever to adjust their lithium dosage. As the occurrence of SILENT is
exceptional, there is no need to preventively modify lithium treatment
because of the pandemic as its benefit/risk balance remains largely
positive, including with respect to neuroprotection [70, 71].