Journal of the Neurological Sciences 277 (2009) 172–173

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Journal of the Neurological Sciences

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s

Short communication

The Syndrome of Irreversible Lithium-Effectuated Neurotoxicity (SILENT): One-year

follow-up of a single case
Fábio H.G. Porto a,⁎, Marco A.A. Leite a, Leonardo F. Fontenelle b, Rogério P. Marrocos c,
Natália F. Szczerback c, Marcos R.G. de Freitas a
a
Federal Fluminense University, Miguel de Frias 245, bl 3 apt 601, Niterói, Rio de Janeiro, 24220-005, Brazil
b
Federal University of Rio de Janeiro, Brazil
c
State University of Londrina, Brazil

a r t i c l e i n f o a b s t r a c t

Article history: In this article, we report the case history of a 44-year-old female patient with bipolar disorder who
Received 22 June 2008 developed the so-called Syndrome of Irreversible Lithium-Effectuated Neurotoxicity (SILENT). A detailed
Received in revised form 18 September 2008 description of our patient's neurologic status is provided at baseline (i.e. during lithium intoxication) and
Accepted 14 October 2008
after one year of follow-up, confirming the persistency of cerebellar signs and symptoms. Although rare, our
Available online 30 November 2008
report – which shows a severe and disabling form of SILENT – underscores the need to perform a strict
Keywords:
control of the putative risk factors argued to be associated with the development of this syndrome. In our
Side-effects of lithium case, the presence of fever and the administration of multiple doses of antipsychotics may have contributed
SILENT to the poor outcome exhibited by the patient.
Lithium toxicity © 2008 Elsevier B.V. All rights reserved.
Cerebellar syndrome

1. Introduction occasional manic and depressive episodes. More recently, however,

Lithium has been widely used in the treatment of psychiatric and
neurologic disorders, such as bipolar disorders and cluster headache
[1–3]. Since it has a low therapeutic index, toxic levels are frequently
seen in clinical practice [4,5]. In fact, lithium's adverse effects occur
not only during acute drug intoxication, but also in patients being
treated with therapeutic levels. Several neurologic disturbances are
related to lithium, most commonly tremor [6]. Fortunately, these
adverse effects are reversible upon drug discontinuation in most
cases. Rarely, however, lithium-induced persistent neurologic dis-
orders have been reported, particularly cerebellar dysfunction [7,8].
In this article, we report the case of a patient who developed
irreversible lithium induced neurotoxicity. A description of our patient's
psychiatric and neurologic status is provided at baseline (i.e. during
lithium intoxication) and after 1 year of follow-up, confirming the
persistency of the cerebellar symptoms. We also discuss the potential
risk factors associated with the development of the irreversible lithium
induced neurotoxicity exhibited by our patient.
2. Case report
Ms. A, a 44-year-old married, white woman, had a 22-year history of
bipolar disorder. Since age 22, when she exhibited a puerperal psychosis,
she has been regularly treated with lithium carbonate, 1200 mg/day.
Unfortunately, and despite adequate treatment, Ms. A still displayed
⁎ Tel.: +55 21 27194870x99791701; fax: +55 21 26299285.
during a particularly severe depressive episode, Ms. A attempted suicide
by ingesting 20 tables (i.e. 6 g) of lithium carbonate.
Ms. A was evaluated at an emergency room, with an acute
encephalopathy characterized by altered mental status, severe
disattention, disorientation for time and place and market fluctuation
of level of awareness. She also had tremor and dysarthria, and was
admitted for acute care. The clinical course was complicated by a lower
respiratory tract infection with fever. She became agitated and was
treated with injectable antipsychotic drugs (i.e. haloperidol 15 mg/
daily, chlorpromazine 75 mg/daily) in the aftermath of her admission.
She did not present muscular rigidity and the concentration of serum
creatine phosphokinase was normal. Unfortunately, however, we were
unable to determine the lithium level at the time of intoxication.
After 8 weeks, she finally recovered from the encephalopathy but
begun to display a coarse axial tremor and gait difficulties character-
ized by an unstable, ataxic gait. She was evaluated at our neuropsy-
chiatry unit eight weeks after the suicide attempt. On examination,
she had a gross axial tremor (predominantly in the head and trunk), an
ataxic broad-based gait, nystagmus, severe scanning dysarthria, and
limb incoordination. Despite being fully awake and oriented, Ms. A
was severely disabled by her neurological signs and symptoms. She
also exhibited depressive mood, anhedonia, and other neurovegeta-
tive signs consistent with a major depressive episode. Her scores on
the mini mental state examination (MMSE) were 30/30. Ms. A was free
from any medication at the time of our initial evaluation. The serum
lithium level at this time was undetectable. The brain magnetic
resonance image was normal. Blood tests showed no electrolytic

0022-510X/$ – see front matter © 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jns.2008.10.010
 F.H.G. Porto et al. / Journal of the Neurological Sciences 277 (2009) 172–173
abnormalities and no sign of acute infection. Cerebrospinal fluid
analysis was normal. Of note, Ms. A denied any sort of abnormal
involuntary movements before the attempted suicide.
A diagnosis of SILENT1 (Syndrome of Irreversible Lithium-Effectu-
ated Neurotoxicity) was made. Ms. A's bipolar disorder was then treated
with valproate (750 mg/daily) and sertraline (100 mg/daily), but she did
not comply with treatment plan and dropped out of treatment. One year
later, she was in a hypomanic state, but remained severely disable by her
cerebellar signs, i.e. gait difficulties, tremor and ataxia.
3. Discussion
In 1987, Adityanjee et al. [7] proposed the acronym SILENT, i.e.
Syndrome of Irreversible Lithium-Effectuated Neurotoxicity, to
describe patients in which the neurologic symptoms induced by
lithium toxicity persisted for at least two months after the
discontinuations of the drug in the absence of previous neurological
impairment. We describe an additional case of this rare syndrome and
its persistence over a period of one-year. Although rare, the dramatic
clinical picture exhibited by our patient underscores the need to
perform a strict control of potential risk factors argued to be
associated with the development of this syndrome.
Several neurologic symptoms secondary to lithium-induced
nervous system toxicity have been reported, either central or
peripheral, and acute or chronic. Fortunately, however, few cases of
irreversible dysfunction were described [7,8]. Typical lithium induced-
tremor can be postural, intentional and resting. Most commonly,
however, lithium causes a fine, 8–12 Hz postural tremor considered to
be an “enhanced” physiological tremor [6,10]. Cognitive side effects
and lack of coordination are also common among patients taking
lithium and may occur even in therapeutic window, but are almost
always tolerable and not disabling. At earlier stages of lithium
intoxication, ataxia, coarse tremor, dyskinesias, dysarthria, hyperre-
flexia and muscle weakness can be seen [16,17]. Lithium intoxication
can cause an encephalopathy with altered mental state, cerebellar
dysfunction (dysarthria, ataxia and nystagmus), seizures and rigidity,
frequently associated with high serum levels. Fever is a frequent
component of the intoxication syndrome [7]. Usually, this acute
toxicity is not persistent and gradually improves with reduction of the
lithium's plasmatic levels. Peripheral manifestations of lithium
toxicity include myasthenia-like syndrome, rhabdomyolysis and
proximal muscles weakness.
Persistent neurologic dysfunction associated to lithium can occur
after acute intoxication, but chronic use without intoxication has been
also implicated. Cerebellar symptoms are most frequently reported,
but extrapyramidal, cognitive, brainstem dysfunctions or a combina-
tion of these have also been reported. Several other “atypical”
presentations, like optic neuritis, downbeat nystagmus, and myopathy
were deemed secondary to lithium intoxication. Usually, neurologic
sequelae became apparent after the improvement of level of
consciousness or remission of the encephalopatic state [7,8].
A number of risk factors have been reported to predict the
development of persistent, lithium-induced neurological dysfunction,
including high serum levels during acute lithium-intoxication; presence
of fever; concomitant use of other drugs (e.g. antipsychotics, tricyclic
antidepressants, and anticonvulsivants); rapid correction of hypona-
tremia or lithemia; and coexistent illness, such as hypertension, chronic
renal failure, heart failure, acute gastroenteritis, and epilepsy [9,11].
Although plasmatic lithium levels were found to be elevated in
several cases of SILENT reported in the literature (i.e. mean level of
2.29 ± 1.67 Meq/L), [7] normal values have also been reported, [9,12,13]
thus suggesting that blood levels do not exhibit a straight relation with
intracellular level. This phenomenon may be best understood if one
takes into account the pharmacokinetics characteristic of lithium.
Compared to other body tissues, the blood brain barrier displays a
meager permeability for lithium, a feature that delays its penetration
173
into the central nervous system for approximately 24 h. Since
therapeutic and adverse effects of lithium depend on the concentra-
tion of the drug on target organs, there are significant differences in
the clinical presentation of acute and chronic forms of intoxication. In
acute intoxication, as in a suicide attempt, the initial rise in serum
level can be seen in the absence of neurological symptoms, at least
initially. In chronic use, high intracellular lithium concentration in
brain cells can occur, even with normal or low serum levels. Therefore,
patients in chronic therapy are more susceptible to neurologic adverse
effects after an acute raise in lithemia [14].
Another common feature associated with lithium induced persistent
neurologic damage is fever, which can be caused by the intoxication
itself, thus showing some resemblance to neuroleptic malignant
syndrome, or by secondary infection [7,8]. Infection can also be an
independent risk factor for persistent neurological damage. The
mechanism underlying this phenomenon is unknown, but it has been
hypothesized that fever may induce a rise in blood brain-barrier
permeability and an increase in the uptake of lithium by cerebellar cells.
Concomitant use of psychotropics was frequently reported in cases
of lithium-induced persistent neurologic damage, mainly antipsycho-
tics. Emilien and Maloteaux [15] suggested that antipsychotic drugs,
especially phenothiazines, might increase lithium influx in red blood
cells (RBC), thereby leading to neurotoxic effects. Other drugs, such as
amitryptiline, aspirin, verapamil, valproate, erythromycin, diuretics, b-
blockers, coproxamol, and nonsteroidal anti-inflammatory may also be
associated with increased risk of developing lithium neurotoxicity [7].
In our case, the presence of fever and the administration of multiple
doses of antipsychotics may have contributed to the poor outcome
exhibited by the patient. It remains to be clarified, however, whether the
afore-mentioned risk factors are independent from each other. Since the
information on lithium intoxication are generally provided by sparse case
reports, there is an urgent need to gather data on lithium intoxication in a
more systematic way, thus prompting the identification of independent
risk factors for SILENT and allowing their timely correction.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.jns.2008.10.010.
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