Kidd CJ, et al.

, J Anesth Clin Care 2023, 10: 084

DOI: 10.24966/ACC-8879/100084

HSOA Journal of
Anesthesia & Clinical Care
Research Article

cerebellar syndromes can be separated into three major categories:

Drug and Toxin-Induced prescribed medications, drugs of abuse, and environmental expo-
sures. Many medications can produce ataxic syndromes, including
Cerebellar Ataxias antiepileptics, antiarrhythmics, antineoplastics and antibiotics, which
form the highest risk agents. The risk of developing ataxia from these
Charles J Kidd1, Yamini Krishna Kathari2, Ken-neth Dalton3, agents is dependent on the dose and rate of increase. Furthermore,
Nawaz Hack4* age, renal function, and drug—drug interactions can predispose-
drug-induced ataxia. Those with prior cerebellar damage are also
1
University of Maryland , Department of Neurology, USA
more likely to have symptomatic worsening following new drug ad-
2
University of Maryland, Department of Medicine, USA ministration or uptitration. The neurologic examination is important
Department of Neurology, Uniformed Services University of the Health
3 in confirming a cerebellar origin of ataxia and can also be useful in
Sciences School of Medicine , Walter Reed National Military Medical Center, determining underlying etiology. Neurologic examination will often
Bethesda, MD 20814, USA reveal an ataxic gait with truncal titubation, saccadic abnormalities,
4
Department of Neurology, UTRGV Institute of Neuroscience, UTRGV School dysmetria, intention tremor and dysdiadochokinesia. Speech can also
of Medicine, Harlingen, TX78550, USA be involved with an ataxic dysarthria comprised of disturbances of
speech prosody and articulation [6,7]. Tone is frequently reduced,
often with pendular reflexes following cerebellar insult [8]. Sensory
Abstract ataxia will usually present with predominant gait disturbance wors-
Ataxia is the inability to coordinate voluntary movement and ened with the loss of vision and a positive Romberg’s sign. Particular
can present with a variety of symptoms involving dyscoordination drugs or toxins will often have a predisposition to preferentially affect
of gait and extremity movement, slurred speech, and abnormal eye only a portion of the cerebellum and thus produce unique clinical cer-
movements. Ataxia can be divided into either cerebellar or sensory. ebellar symptoms. Although the differential for acute cerebellar ataxia
Cerebellar ataxia originates from damage to the cerebellum or its is broad and includes etiologies such as ischemic and inflammatory
connecting tracts, while sensory ataxia is a result of damage to the insults, this review will focus on acute toxin-induced cerebellar atax-
afferent sensory pathways such as the dorsal column and large my- ia.
elinated proprioceptive fibers.
Antiepileptics
Keywords: Antiepileptics; Diplopia; Dysdiadochokinesia
Phenytoin

Introduction The antiepileptic medication with the highest risk of producing

ataxia and cerebellar dysfunction is phenytoin [9]. The risk is dose
The cerebellum is particularly susceptible to toxic insults due to dependent with a tendency for patients at a lower dose to develop
its complex and highly metabolic nature. Purkinje and granule cells nystagmus and truncal ataxia, whereas appendicular ataxia becomes
are the most frequently damaged cerebellar cells due to toxic agents more prominent at higher dosing [10]. Toxicity is dependent upon the
upon pathologic evaluation [1]. The purkinje cells are the sole output unbound plasma concentration of phenytoin and drug levels are sen-
fibers from the cerebellar cortex and provide inhibitory input to the sitive to physiologic changes such as hypoalbuminemia, malnutrition,
cerebellar nuclei [2]. The granule cells are the only excitatory cell and kidney injury [11]. Furthermore, serum phenytoin levelsneeds to
in the cerebellar cortex and help to form the complex network of be corrected if the serum albumin level is low because of its binding
connections intrinsic to the cerebellum. The cerebellum is a complex characteristics11. Up to 37% of patients on chronic phenytoin devel-
structure containing up to half of the neurons in the central nervous opataxia [9]. The presence of mild nystagmus is frequent and occa-
system [3-5].Although cerebellar findings are commonly encountered sionally can be used as an indicator of compliance with medication.
by the practicing neurologist, when acute and lesional causes of ataxia Most patients on phenytoin at a therapeutic level have nystagmus and
this tends to become increasingly prominent as the serum level exceeds
are ruled out, toxin-induced ataxia should be highly suspected. Toxic
20 mg/mL10. Other adverse events due to chronicexposure include
*Corresponding author: Nawaz Hack, Department of Neurology, UTRGV In- gingival hyperplasia and drug reaction with eosinophilia and systemic
stitute of Neuroscience, UTRGV School of Medicine, Harlingen, TX78550, USA symptoms (DRESS). Dangerous skin manifestations of acute intrave-
Email: [email protected] nous use include purple hand syndrome, Stevens-Johnson syndrome,
Citation: Kidd CJ, Kathari YK, Dalton K, Hack N (2023) Drug and Toxin-Induced toxic epidermal necrolysis and ischemia of the skin [12]. CYP2C9
Cerebellar Ataxias. J Anesth Clin Care 10: 084. and CYP2C19 are both involved in phenytoin metabolism and genetic
Received: October 22, 2023; Accepted: November 28, 2023; Published: De-
polymorphisms increase the risk of ataxia in this subset of the pop-
cember 04, 2023 ulation [13]. CYP2C9 mutations can lead to a reduction of the phe-
nytoin metabolic rate by 25-54%13. Due to their alterations in drug
Copyright: © 2023 Kidd CJ, This is an open-access article distributed under the
terms of the Creative Commons Attribution License, which permits unrestricted
metabolism, these patients show reduced volumes of cerebellar white
use, distribution, and reproduction in any medium, provided the original author matter and trends towards reduced cerebellar gray matter compared
and source are credited. to normal phenytoin metabolizers14. Although somewhat conflicting
Citation: Kidd CJ, Kathari YK, Dalton K, Hack N (2023) Drug and Toxin-Induced Cerebellar Ataxias. J Anesth Clin Care 10: 084.

• Page 2 of 11 •

in studies, duration and dose of phenytoin use are likely related to the Lamotrigine
degree of cerebellar atrophy [14].Management of phenytoin toxicity
involves withdrawal of the agent. It is important to recognize thatwith Lamotrigine is a medication that inhibits voltage-gated sodium
cessation of treatment, some patients recover completely with resolu- channels, thereby stabilizing neuronal membranes and reducing glu-
tion of the cerebellar dysfunction, whereas some may suffer from per- tamate release. Lamotrigine has been associated with severe dermato-
manent cerebellar impairment [15]. Neuropathologic examinations of logic reactions, often requiring slow titration of the medication.How-
these patients have demonstrated widespread loss of Purkinje cells, a ever, cerebellar symptoms are more common. In a review of prior
decline in the population of granule cells, and Bergmann gliosis with randomized controlled drug trials, the most frequent adverse events
relative sparing of basket cell axons [16]. related to lamotrigine use were ataxia, nausea, diplopia and dizziness.
The relative risk of diplopia was the highest amongthe adverse events
Carbamazepine, Oxcarbazepine, Eslicarbazepine at 3.79, while the relative risk of ataxia was 3.34 [19]. In this review,
ataxia developed in 15% of patients as compared to only 4.5% in
Carbamazepine, oxcarbazepine, and eslicarbazepine all pose sig-
placebo groups [19].
nificant risks of producing cerebellar ataxia9. Toxicity of these agents
produces nystagmus, ataxia, disequilibrium, headache and potential- Valproic Acid
ly alterations in mental status [12]. In a review of randomized pla-
cebo-controlled trials, oxcarbazepine had the highest absolute risk Valproic acid rarely causes ataxia as a direct adverse effect.How-
increase of producing ataxia, with patients being at 23 times higher ever, its effects on the metabolism of other medications and the risk
risk of developing ataxia compared to placebo9.In the same study, of encephalopathy from hyperammonemia have be known to produce
thenumber needed to harm was less than ten [9]. In a systematic re- ataxia [9,20]. Valproic acid can produce encephalopathy either byaf-
view of cohort studies, carbamazepine more frequently produced fecting hepatic function or precipitation of hyperammonemia. When
ataxia and dizziness than oxcarbazepine. Likely both agents are high- hyperammonemic encephalopathy due to valproic acid occurs with
er risk for this side effect than eslicarbazepine. All three agents appear normal hepatic function it is known as valproate-induced non-hepat-
to produce a largely dose-dependent level of nystagmus, action trem- ic hyperammonemic encephalopathy (VNHE) [21]. The features of
or and gait ataxia [10]. These side effects may be more common in the this form of encephalopathy include irritability, drowsiness and coma,
elderly or those with prior cerebellar insults [10,12]. Carbamazepine with movement symptoms of asterixis and cerebellar ataxia. Manage-
is a medication that may be combined with lithium, another cerebel- ment of valproate induced hyperammonemia includes dose reduction
lotoxic agent, for mood control. The combination of these drugs can or potential L-carnitine supplementation [22].
produce symptoms even when both medications are within therapeu- Benzodiazepines and Barbiturates
tic levels10. Clinicians should also be aware that certain medicines
that are CYP3A4 inhibitors suppress carbamazepine metabolism and Benzodiazepines function by increasing the frequency of opening
increase its serum concentration [13,14]. Some of the more common of chloride channels on GABA-A receptors, thereby reducing neu-
agents include clarithromycin, fluoxetine, verapamil, oxybutynin, ronal hyperexcitability. These medications, especially at high doses,
valproic acid, and loratadinec [15,16]. Severe carbamazepine toxicity produce ataxia to varying degrees depending upon the specific agent
can be deadly and lead to coma. If ataxia develops, free drug levels used9. This is more common in children, who present with a mild and
should be checked, and the medication reduced or discontinued. Per- reversible ataxia.Benzodiazepines do not appear to have a direct toxic
sistent ataxia after medication discontinuation is rare and there should effect on the cerebellum.
not be underlying damage to the cerebellum after cessation of the
medication. Barbiturates decrease cellular excitability by prolonging the open-
ing of chloride channels on GABA-A receptors. Toxicity isdose-de-
Lacosamide pendent and produces a neurologic syndrome mainly manifesting
In a randomized placebo-controlled trial of adjuvant lacosamide, with central nervous system depression.Other potential symptoms
with doses ranging from 200mg to 600mg per day, patients demon- includeintention tremor, gaze-evoked nystagmus and gait ataxia due
strated a largely dose dependent increase in dizziness, headache, nau- to cerebellar involvement [10,12,23].Up to 5% of epileptic patients
sea, ataxia, nystagmus and diplopia [17]. receiving phenobarbital will develop cerebellar signs. Thiopental is
another barbiturate with a high prevalence of ataxia, occurring in up
The prevalence of ataxia was 23% among patients taking lacos- to 12.7% in one review study [9].
amide 600mg per day, 13% in those taking 400 mg per day, 4% in
those taking 200 mg per day and only 3% in those receiving place- Other Antiepileptics
bo [17]. These effects led to higher patient discontinuation of lacos-
A variety of other antiepileptic agents have been known to pro-
amide, particularly at higher doses, as compared to placebo. In this
duce ataxia as a prominent side effect. Gabapentin functions on cal-
study lacosamide had minimal effects on other concurrent antiepilep-
cium channels to enhance GABAergic inhibition of neuronal firing.
tic concentrations compared to placebo.
It commonly produces a reversible ataxic syndrome with one study
In a phase III long term follow up trial of adjuvant lacosamide demonstrating ataxia in 7.7% of patients taking adjuvant gabapentin
therapy for partial onset seizures, 10.7% of patients withdrew due for epilepsy23,24. Other common side effects included somnolence
to adverse effects, with the most common being dizziness (in 1.6% (29.3%), vertigo (7.2%) and asthenia (14.6%) [24]. Ataxia was not
of patients) [18]. This study was conducted in a population who had strongly dose dependent, with the majority of patients experiencing
previously tolerated the medication at variable doses during a prior this symptom at doses less than 1200mg daily. Paradoxically, ga-
double blinded placebo-controlled trial. Lacosamide induced ataxia is bapentin is occasionally used totry to reduce ataxia due to cortical
most likely to occur with medication initiation or dose adjustment and cerebellar atrophy from a variety of inherited conditions [25]. It is
management often requires a dose reduction [17,18]. believed that there is a relative deficiency of GABAergic activity that
J Anesth Clin Care ISSN: 2378-8879, Open Access Journal Volume 10 • Issue 2 • 100084
DOI: 10.24966/ACC-8879/100084
Citation: Kidd CJ, Kathari YK, Dalton K, Hack N (2023) Drug and Toxin-Induced Cerebellar Ataxias. J Anesth Clin Care 10: 084.

• Page 3 of 11 •

occurs with Purkinje cell loss, producing ataxia that responds to ga- deficiency41. Symptoms of ataxia and other forms of neurotoxicity
bapentin or pregabalin administration25. Other medications altering have been seen 6-19 weeks after the medication is administered38.
GABAergic effects such as vigabatrin and tiagabine appear to cause Many cases note that the symptoms resolve with discontinuation of
similar degrees of ataxia9.Talampanel and zonisamide also have a the drug [41,42].
high risk of producing cerebellar ataxia, with the absolute risk in-
crease being 23.53 and 8.33 respectively [9]. Cytarabine
Antineoplastics Cytarabine is a chemotherapeutic agent that is used alone and in
combination to treat a variety of leukemias and lymphomas. It is a
5-Fluorouracil
structural analog of deoxycytidine and is converted to uracil arabino-
Over the last several decades, 5- fluorouracil (5-FU), a pyrimidine side by cytidine deaminase [43]. Uracil arabinoside is then converted
analog, has been used as a chemotherapeutic agent for the treatment to the active form of the drug (ara-C triphosphate) and can diffuse
of various solid tumors such as gastrointestinal and pancreatic can- into cells. Once intracellular, it competitively inhibits deoxycytid-
cers, head and neck cancer, and breast cancers [26,27]. 5-FU is an yl-triphosphate to inhibit DNA polymerase, DNA repair and RNA
antimetabolite that inhibits thymidylate synthase and blocks thymi- synthesis and DNA synthesis [43-45]. Neurotoxic manifestations
dine formation by interfering with DNA synthesis28. Typically, 5-FU with intrathecal cytarabine include headaches, meningismus, seizures
is used with other chemotherapy as part of a combination regimen
and myelopathy 43,46. With systemic therapy, toxicity can present as
[26,28].The most common side effects include bone marrow suppres-
seizures and cerebellar dysfunction. Acute cerebellar syndrome is the
sion, gastrointestinal side effects (diarrhea and stomatitis), alopecia,
and hand-foot syndrome26,28. Cardiotoxicity has been described and most common of the various neurotoxic profiles of cytarabine and is
is less common [29,30] while neurotoxicity is rare (occurring in less typically seen with use of high doses of the drug43. Signs and symp-
than 1% of patients treated with 5-FU) [31]. toms of cerebellar toxicity typically present three to eight days after
starting high dose cytarabine (HIDAC), and can occur either during
In a study conducted with 1240 patients who were treated with the first or subsequent cycles43. Patients present with truncal and/
5-FU either alone or in combination with other agents, only two pa- or limb ataxia, nystagmus, dysmetria, dysdiadochokinesia, and dys-
tients had side effects of neurotoxicity [26]. There are several case arthria, as well as headaches, changes in mental status, and seizures
reports of patients developing cerebellar ataxia, which is one of the
[43,47-50].
most common forms of neurotoxicity noted [26,31-33]. Another de-
scribed neurological adverse effect is cerebellar syndrome, which Cerebellar toxicity is dose related, and more dependent on the
can include cerebellar ataxia, dysphagia, and dysmetria, among other cumulative dose of cytarbine, as opposed to the duration of therapy
symptoms33. Peripheral neuropathy and even seizures can also be
[48-51]. Patients who are older than age 50, have prior neurologic
observed after treatment with 5-FU [32,33]. Acute neurotoxicity is
dysfunction, renal or hepatic impairment are at higher risk of devel-
dose related and can be self-limiting. However, there are some re-
ports of residual neurological symptoms even after several weeks of oping an acute cerebellar syndrome [43,49,52,53]. There is decreased
discontinuing 5-FU33. Using 5-FU in high doses (more than 2200 clearance of cytarabine and its metabolites in patients with renal and
mg/m2/week) or using it in combination with interferon alpha can in- hepatic dysfunction, leading to a longer duration of exposure [9,47].
crease the incidence of neurotoxicity [28,34]. Although it is not very The mainstay of treatment of cerebellar toxicity is discontinuation of
lipid-soluble, it can easily cross the blood-brain barrier28. A proposed cytarabine, and symptoms typically improve over the course of weeks
mechanism of neurotoxicity hypothesizes that fluoroacetate, which is to months [48,49]. However, in some patients, there may be residual
a byproduct of 5-FU catabolism, accumulates in nerve cells, causing symptoms even after discontinuation, with irreversible ataxia seen in
impairment of the urea cycle and increasing ammonia levels28,34. 16.7% of patients in one study [48,49,53]. Some patients were treated
Another possible mechanism proposes that 5-FU increases thiamine with dexamethasone for its anti-inflammatory effects, with improve-
metabolism, causing thiamine deficiency [34-37].
ment in symptoms [47]. In many cases, work up of cerebellar symp-
Capecitabine toms, including CT scans, EEG, lumbar puncture, and MRI can be
largely unrevealing [47]. In one case study, brain MRI did show dif-
Capecitabine is a prodrug of 5-FU that is converted preferentially fuse cerebellar high intensity lesions on T2 and hypointensity on T1,
in tumor tissue by thymidylate phophorylase, which is expressed in without gadolinium enhancement. Some brain MRI findings can be
higher levels in tumor tissue38. It has been shown to have the ad-
consistent with diffuse cerebellar atrophy [54]. In another case study,
verse effect of cerebellar syndrome, much like 5-FU, with ataxia,
a PET scan showed decrease in the 18-FDG uptake in the frontal,
nystagmus, slurred speech, and encephalopathy [38,39]. The mech-
anism is unclear, but there have been reports of severe neurotoxicity parietal and temporal lobes, as well as in the cerebellum [12].
in patients with reduced levels of dihydropyrimidine dehydrogenase
In post-mortem analysis of patients who experienced cerebellar
(DPD), which is the rate-limiting enzyme in 5-FU catabolism [38-40].
toxicity, there was noted to be degeneration of purkinje cells in the
Other possible mechanisms may be similar to the processes that cause
cerebellar hemispheres and the vermis [47,50]. Pathologic changes
cerebellar ataxia in patients receiving 5-FU [39]. This may impair
revealed reactive proliferation of glial cells, with patchy loss in the
the clearance of 5-FU, leading to higher concentrations of the drug
for prolonged periods of time in the plasma and CSF, contributing to molecular and granular layers of the cerebellum [47,50]. One study
the toxicity38. However, there are case reports that argue that DPD showed the loss of purkinje cells in the deeper areas of the cortical
deficiency may not always play a role, as some patients experience sulci, with comparative preservation to purkinje cells at the folial
marked cerebellar ataxiawithout any other toxicities to suggest DPD crests and in the posterior inferior cerebellum [53].

J Anesth Clin Care ISSN: 2378-8879, Open Access Journal Volume 10 • Issue 2 • 100084
DOI: 10.24966/ACC-8879/100084
Citation: Kidd CJ, Kathari YK, Dalton K, Hack N (2023) Drug and Toxin-Induced Cerebellar Ataxias. J Anesth Clin Care 10: 084.

• Page 4 of 11 •

Immunosuppresants in lysosomal structures, creating lipid inclusion bodies in nerve cells.

The mechanism of peripheral neurotoxicity of amiodarone has been
Cyclosporine
thought to be due to axonal demyelination of peripheral nerves [69-
Cyclosporine and other calcineurin inhibitors are used to prevent 70] and due to lysosomal lipid deposits that can be caused by the
rejection of organ transplants and in immunological diseases. Most action of amiodarone on lysosomal metabolism [71,72].
commonly, a fine tremor can be noted as a side effect [23]. Cerebellar
toxicity can be seen, along with aphasia, seizures, and paresthesias Procainamide
[23,55,56]. Cyclosporine produces a cerebellar syndrome with pre-
Procainamide, which is used to treat cardiac arrhythmias, can
dominant nystagmus and postural instability [9]. It is hypothesized
that the cerebellar toxicity is not associated with plasma concentra- cause cerebellar toxicity with acute cerebellar ataxia when used in
tions of the medication. Cyclosporine may expose silent cerebellar le- high doses23,73. Onset of symptoms can be acute, appearing when
sions or infarcts, causing ataxia and other cerebellar signs and symp- serum concentration of the medication rises rapidly [73]. These symp-
toms [23]. These may occur months after cyclosporine is started, and toms typically resolve when procainamide is discontinued [23,73].
may be worsened by hypomagnesemia. In a study of 12 bone marrow Other well-known side effects of procainamide include drug-induced
transplant patients that developed neurotoxicity with cyclosporine, lupus, agranulocytosis, rash, Raynaud’s disease, induction of ar-
25% had cerebellar ataxia [56]. Patients can be at higher risk if they rhythmias, and QRS and QT prolongation [73,74]. In one case study,
are liver transplant recipients [23,57]. In many patients, brain MRI symptoms of ataxia began 10 days after initiation of procainamideand
will show evidence of subcortical white matter lesions, consistent resolved 3 days after discontinuation [73].
with a leukoencephalopathy [58-60]. Symptoms can begin a few days
to months after initiation of therapy [23,58]. Propafenone
Tacrolimus Propafenone is anantiarrhythmic associated with dose dependent
Tacrolimus is an immunosuppressant that is used widely after ataxia. Symptoms often resolve with lowering of the dose or cessation
transplantation to prevent rejection. Similar tocyclosporine, it has of the mediation [75].
been reported to cause neurotoxicity that can present as cerebellar Antimicrobials
ataxia [23,58,61]. Symptoms are typically mild and transient, resolv-
ing with discontinuation of the drug. Metronidazole
Antiarrhythmics Metronidazole can cause cerebellar toxicity when used for a
prolonged duration of treatment, typically over 6 weeks to several
Amiodarone
months [76,77]. Symptoms can include ataxia, paresthesias, slurred
Amiodarone is a commonly used antiarrhythmic in the treatment speech, hypotonia, seizures, and nystagmus [76,77]. Brain MRI can
of supraventricular and ventricular arrhythmias. Amiodarone has show evidence of toxicity with hyperintensities on T2 and FLAIR in
many well-known toxicities, including thyroid toxicity, pulmonary fi- the dentate nuclei, nodularity in the cerebellar parenchyma on T2, or
brosis, dermatological side effects, corneal deposits, and hepatotoxic- cerebellar edema with increased diffusion coefficients [76-80]. Other
ity [62,63]. Amiodarone can also be neurotoxic in 20-54% of patients brain MRI findings can include abnormalities in the Guillian-Mol-
and can cause a postural tremor, parkinsonism, peripheral neuropathy laret triangle, inferior olivary nuclei, central tegmental tracts, dorsal
and cerebellar deficits [23,62,64]. Cerebellar deficits can include trun- medulla and dorsal pons [81,82]. In one study, brain SPECT showed
cal or limb ataxia, wide-based gait, axial hypotonia, nystagmus, ver- lower perfusion of the left cerebellar hemisphere, in addition to T2
tigo, dysdiadochokinesia, dysmetria, dysarthria, and dysphagia [62- abnormalities in the dentate nuclei on brain MRI [83]. However, some
64]. Neurological workup including head CT, brain MRI, and EMG patients may not have any abnormalities on brain imaging [84].
may be unrevealing 63,64. Approximately 5-7% of patients treated
with amiodarone develop cerebellar toxicity [10,23,64]. In one study There is increased risk of toxicity with higher cumulative doses of
of 54 patients treated with amiodarone for ventricular arrhythmias, 25 to 1080 grams [78]. In a study of 793 cancer patients who received
54% had neurotoxicity [65]. Among those who develop cerebellar metronidazole, two developed cerebellar dysfunction [85]. In patients
toxicity, 52% will develop cerebellar symptoms within one month that received a cumulative dose of more than 30 grams, 8.6% de-
of therapy initiation, and in another 26% symptoms develop in 1-4 veloped metronidazole neurotoxicity [85]. In patients with alcoholic
months [64-65]. liver disease, serum concentrations of metronidazole may be high-
er and contribute to neurotoxicity86. Both the symptoms and MRI
Symptoms may improve with discontinuation of amiodarone over abnormalities are reversible after discontinuation of metronidazole.
months to years, while in some cases residual symptoms do not resolve Symptoms resolve in 24 hours to 2 weeks after stopping the drug
[62,64,65]. In one case report, symptoms improved with reduction [78,81,87]. Methylprednisolone has been used to promote neurologi-
amiodarone dosing by 50%, and resolved once the medication was cal improvement [88].
stopped. Another case report showed that intravenous amiodarone can
cause an acute cerebellar toxicity, which resolved quickly after the While the mechanism of cerebellar toxicity is unclear, one hypoth-
discontinuation of the drug [66]. In older patients, it may be safer to esis suggests that metronidazole causes an acute toxic insult leading
use lower doses of amiodarone to prevent toxicity62. Patients are at to localized vasogenic edema and axonal swelling [78,80]. In rat
increased risk with advancing age, diabetes, renal failure, and alco- models, high doses of metronidazole cause cerebellar lesions78,80.
holism [62-68]. The mechanism of cerebellar toxicity is unclear, but In dogs, metronidazole administration for prolonged periods was as-
may be due to amiodarone penetrating nerve tissue and accumulating sociated with Purkinje cell damage.
J Anesth Clin Care ISSN: 2378-8879, Open Access Journal Volume 10 • Issue 2 • 100084
DOI: 10.24966/ACC-8879/100084
Citation: Kidd CJ, Kathari YK, Dalton K, Hack N (2023) Drug and Toxin-Induced Cerebellar Ataxias. J Anesth Clin Care 10: 084.

• Page 5 of 11 •

Mefloquine and extrapyramidal symptoms. Subcortical dementia, hyperreflexia,

choreoathetoid movements and extensor plantar responses may also
Mefloquine is used for malaria prophylaxis and treatment. In an be present. Rare cases of optic neuritis and osmotic demyelination
acute intoxication, patients may develop fevers, headaches, dizziness, have been described following lithium toxicity [105,106]. Acute in-
nausea, gait instability and other neuropsychiatric symptoms [89]. Fe- toxication will often present with leukocytosis without clear infection
male patients and those with lower BMI may be at higher risk [89-91]. and altered mental status. As cognitive status improves, cerebellar
Proposed mechanisms of toxicity include interfering with calcium ho- ataxia becomes apparent. An irregular coarse limb tremor can also be
meostasis in neurons, inhibiting acetylcholinesterase, and inhibiting useful in identifying the lithium toxidrome. The majority of cases of
potassium ATP channels [89,92,93]. Treatment is to discontinue the acute lithium toxicity will improve with dose reduction or cessation
drug and refrain from future use [23]. of the medication. Toxic metabolic insults can alter previously well
Isoniazid controlled lithium levels and should be evaluated when a new lithium
toxidrome develops without dose change.
Isoniazid is used as part of a treatment regimen for tuberculosis.
Common side effects are caused by its interaction with vitamin B6 Cases of SILENT can be very prolonged however most patients
and include peripheral neuropathy. Some reports describe the onset have at least partial improvement with time. Although the mechanism
of tremors, vertigo, slurred speech, nystagmus and limb and truncal of neurologic injury is unclear, pathologic reviews of SILENT have
ataxia weeks to months after initiation of treatment with isoniazid demonstrated cerebellar atrophy, Purkinje cell loss, cerebellar glio-
[94,95]. These symptoms improve with stopping the medication and sis, and demyelination at other central and peripheral nervous system
treating with pyridoxine [94,95]. At doses higher than 6 mg/kg, atax- sites [107-109]. Lithium toxicity is best avoided by strict monitoring
ia, seizures, dizziness, and slurred speech have been seen, but it is and regular dose adjustments. Toxicity treated with early hemodialy-
unclear if this is due to cerebellar toxicity [23]. In one case report, sis may reduce the risk of long-term neurologic sequelae.
brain MRI showed evidence of bilateral dentate nuclei lesions [96].
Chronic kidney disease may be a risk factor to developing neurotox-
Bismuth
icity [96]. Bismuth has been used in various formulations to treat skin and
Lindane gastrointestinal disorders, especially in the treatment of Helicobacter
pylori infections. Rare cases of chronic daily bismuth use have pre-
Overuse of lindane, which is used in the treatment of scabies and sented with ataxia, cognitive changes, tremors, myoclonus and sei-
lice, can cause hyperreflexia, hypertonia, limb and truncal ataxia and zures [23,110]. Prior high dose formulations in Australia and France
seizures [23,97]. Toxicity may be due to its interaction with GABA-B increased the frequency of this syndrome. Regular and excessive
receptors in the cerebellum [98]. use of over-the-counter bismuth formulations, such as peptobismol,
can rarely present with toxicity [111]. This syndrome can mimic
Other Medications Creutzfeld-Jacob disease due to the severity of spontaneous, reflex-
Lithium ive and movement-induced myoclonus. The mechanism of toxicity
is not clear. Bismuth-induced ataxia is often preceded by a subacute
The neurotoxic effects of lithium were known long before its progressive encephalopathy. Symptoms improve slowly with cessa-
use for mood disorders [99,100]. After its introduction for the man- tion of bismuth however permanent deficits in cognition may remain.
agement of psychiatric disorders in 1949, cases of both chronic and Those with chronic kidney disease are at higher risk for toxic effects
acute lithium induced neurotoxicity were described and some cases [112]. Cerebellar toxicity can be worsened in setting of hypoxia, caus-
of toxicity have led to permanent ataxia despite medication removal ing Purkinje cell loss [113].
[101-103]. Lithium toxicity often manifests with tremor and ataxia
and may occur acutely, subacutely or with chronic medication use.
Drugs of Abuse
Most commonly, ataxia will present subacutely and correlate with Alcohol
supratherapeutic concentrations of lithium9. Even at therapeutic
levels, toxicity can occur due to cerebellar neuronal tissue reten- Alcohol adversely effects GABAergic transmission, producing
tion of lithium [100]. Acute lithium toxicity may also be associated cerebellar ataxia due to its effects of granule cells in the cerebellum
with other neurologic manifestations including altered mental status, [10]. Alcohol may increase GABA release from the Golgi cells of
seizures, parkinsonism and enhanced reflexes10. Acute or chronic the cerebellum producing increased GABAergic inhibition of granule
toxicity can lead to the syndrome of irreversible lithium-effectuated cells. Increased granule cell tonic inhibition produces motor incoor-
neurotoxicity or SILENT [100]. Cases of SILENT often have pre- dination. The exact mechanism is complex and currently being inves-
dominant cerebellar symptoms however cognitive impairment and tigated [2,10]. Ethanol may further disrupt the mossy fiber-granule
extrapyramidal symptoms may be present. In a review of cases of cell-Golgi cell synaptic site leading to ataxia [2]. Alcohol intoxica-
SILENT, the average dose at which toxicity occurred was 1403mg/ tion produces a rostral vermis cerebellar syndrome characterized by
day, although toxicity could be seen in doses as low as 438mg/day. wide based ataxic gait with truncal titubation and relative sparing of
Patient age does not appear to correlate to the risk of permanent neu- extremity coordination. Dysarthric speech is often present, but hy-
rologic injury following lithium toxicity [104]. The mean serum con- potonia may be lacking [114]. Motor coordination issues develop at
centration at which SILENT occurred in one study was 2.29mM/L doses as low as 0.08g/L due to early cerebellar effects [115]. Older
[100,104]. Long lasting neurotoxicity may be more likely when used age correlates with earlier cerebellar coordination dysfunction at low-
in combination with other drugs such as haloperidol, thioridazine, er serum alcohol concentrations, allowing young adults to be able to
phenytoin, and chlorpromazine. Persistent neurologic symptoms are consume larger amounts of alcohol before ataxia becomes apparent
highly variable but commonly include ataxia, nystagmus, dysarthria [115].
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DOI: 10.24966/ACC-8879/100084
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Frontal lobes and the cerebellum are particularly susceptible to Marijuana

damage from chronic alcohol use. Decreased myelination may be ap-
parent on pathologic studies of these areas, particularly in the white The predominant psychoactive constituent of marijuana is tetrahy-
matter [12]. Chronic alcohol toxicity will lead to loss of granule cells drocannabinol (THC).Cannabinol and cannabidiol present in marijua-
and atrophy of the cerebellum with the greatest effect in the superior na plants can also produce less potent psychoactive responses [123].
anterior vermis. Intrauterine exposure to alcohol is alsodamaging to There are two specific cannabinoid receptors: CB1 receptors present
the development of the cerebellum and will produce long term neu- in the basal ganglia, substantia nigra, cerebellum, hippocampus and
robehavioral abnormalities. Interestingly, recent animal studies of frontal cortex, and CB2 receptors which are not present in the central
choline supplementation prior to alcohol exposure in pregnant mice nervous system [124]. Neurologic signs of marijuana use are highly
ameliorated the level of cerebellar dysfunction of the pups [116].
dose dependent. In dogs high doses of marijuana exposure were asso-
Choline may be beneficial in the prevention of the toxic effects on
the cerebellum if given prior to exposure [116,117]. Alcohol is often ciated with ataxia, depression, disorientation, and tremors. Non-neu-
associated with thiamine deficiency or Wernicke’s encephalopathy rologic signs included hypersalivation, hypothermia, and mydriasis
which can produce both a sensory and cerebellar gait ataxia. [125].
Phencyclidine Recreational use of low or moderate doses leads to euphoria, lack
Phencyclidine (PCP) is a noncompetitive N-methyl-D-aspartate of inhibition, mydriasis, hypersalivation, conjunctival injection, in-
(NMDA) receptor antagonist that can present with cerebellar ataxia, creased appetite, and elevated heart rate [126]. High doses produce
tremor and nystagmus.PCP can be inhaled, ingested or injected either vomiting, hypertension, tremor, ataxia, hallucinations and stupor
intravenously or subcutaneously. It has a rapid onset of action over [126,127].
2-5 minutes when inhaled or smoked [118]. PCP is lipid, water, and
alcohol soluble and therefore can have a very large volume of dis- Children are more susceptible to the depressive effects of canna-
tribution with varying effects depending on body habitus and blood bis and toxicity can produce rapid onset ataxia, sedation, tachycardia,
alcohol concentration. It has greatest affinity for the NMDA receptor respiratory depression and coma [128]. Management of toxicity is
complexes in the hippocampus, neocortex, basal ganglia, and limbic generally supportive however in severe cases in children can be treat-
system [119]. At moderate doses PCP also inhibits the reuptake of ed with benzodiazepines with close monitoring of respiratory status
dopamine, serotonin, and norepinephrine while simultaneously stim- [128].
ulating production of dopamine and norepinephrine through tyrosine
hydroxylase activity [118,119] .Given the wide pharmacologic effects Cocaine
of this drug, the clinical manifestations are extremely variable with
the most common findings of nystagmus and hypertension being Cocaine is a psychostimulant that may present with acute ataxia
found in 57% of patients [120]. due to its risk of producing ischemic and hemorrhagic strokes, includ-
ing in the cerebellum [10,129]. In rat models, cocaine has been shown
Intoxicated patients will often present with violent behavior, anal-
to alter the immunoreactivity to serotonin in the cerebellum, affecting
gesia, hypertension, nystagmus and tachycardia. Rapidly waxing and
waning agitation and sedation with slurred speech, nystagmus and the development of Purkinje cells [130].
ataxia will be present. Decreased pain perception, pinpoint pupils, Heroin
sympathomimetic effects, and bizarre horizontal, vertical, rotary nys-
tagmus can help differentiate an ataxic PCP intoxication from other Heroin use can lead to changes in cognition, personality, ataxia,
toxidromes. PCP may also lead to increased tone with hyperreflexia, dementia, coma and death. Chronic use has been shown to lead to
myoclonus, choreoathetoidor dystonic movements such as opistho- loss of the cerebellar purkinje cell layer and proliferation of Bergman
tonos and torticollis [120]. High doses of PCP can lead to coma, hy- glia [131]. In chronic heroin users, the loss of Purkinje cells has been
perthermia and death. Although cerebellar effects are present in the observed [23].
majority of patients with PCP, overt ataxia is less common with about
10% having this manifestation to a significant degree [118,120,121]. Methadone
PCP intoxication is diagnosed with urine toxicologic screen, which
Ingesting methadone can cause an acute toxic encephalopathy with
will remain positive for 2-4 days following drug use. However, di-
changes in the level of consciousness due to cerebellar edema causing
phenhydramine, dextromethorphan and venlafaxine can produce false
obstructive hydrocephalus [132,133]. Cerebellar edema may also lead
positives with some screening urine drug tests [120,121]. Manage-
to watershed infarcts and can appear to be similar to an infectious
ment of intoxication is largely supportive. Use of benzodiazepines
cerebellitis on brain MRI133. Treatment includes methylprednisolone
may be warranted in patients without psychosis, given the risk of ex-
and drainage of CSF, with possible need for a decompressive craniot-
acerbating hyperthermia and dystonic movements with antipsychotic
omy [23,132].
use [118]. In patients without hyperthermia, atypical antipsychotics
are beneficial in controlling psychosis, and require close cardiac mon- Nicotine
itoring.Diphenhydramine can be useful to treat dystonic movements
brought on by this drug. Although intoxication syndromes usually re- Nicotine is toxic to the cerebellum and can cause depletion of
solve over 4-8 hours, large ingestions may take weeks to fully recover purkinje cells [23,134]. Chronic toxicity in rat models demonstrated
[120]. PCP has been shown to be toxic to Purkinje cells in rat studies, decreased purkinje cells in the cerebellar vermis and loss of cerebel-
leading to permanent cerebellar damage [122]. The mechanism of this lar white matter [135,136]. Nicotine can exacerbate ataxia in patients
injury was felt to be due to excessive excitatory activity from climb- with pre-existing ataxia, such as in patients with multiple system at-
ing fibers originating in the inferior olive [122]. rophy or spinocerebellar ataxia [137,138].
J Anesth Clin Care ISSN: 2378-8879, Open Access Journal Volume 10 • Issue 2 • 100084
DOI: 10.24966/ACC-8879/100084
Citation: Kidd CJ, Kathari YK, Dalton K, Hack N (2023) Drug and Toxin-Induced Cerebellar Ataxias. J Anesth Clin Care 10: 084.

• Page 7 of 11 •

Toxins And Heavy Metals [23]. MRI brain findings include cerebral calcifications and hyper-
intense lesions23. Lead intoxication is treated with chelating agents.
Bromide
Toluene
Methyl bromide is a colorless gas and has versatile uses. It can be
used as an insecticide, solvent, refrigerant, methylating agent and in Toluene is an industrial solvent found is gasoline, paints, glues
fire extinguishers [139]. It has been shown to be toxic to both the cen- and rubber manufacturing. Toluene preferentially affects areas of the
tral and peripheral nervous systems in multiple studies [23,139,140]. CNS with high lipid content such as myelin [12]. Although the exact
Case reports of bromide intoxication (through occupational exposure mechanismof CNS damage is unknown,toluene intoxicationcan pro-
from insecticides or bromide-containing compounds that are part of duce lightheadedness, altered cognition, and ataxia. Tremor may be
over-the-counter sleep aids) had a constellation of symptoms includ- present in the head and extremities and severe toxicity can cause an-
ing cerebellar deficits with slurred speech and gait ataxia, as well as osmia, hearing loss, personality changes, spasticity and hyperreflexia.
pyramidal and extrapyramidal signs [139,140]. Cerebellar atrophy White matter damage can produce a clinical picture similar to leuko-
and sometimes pontine tegmental atrophy can be seen on brain MRI encephalopathy with dementia. Non-neurologic affects include eye
[23]. Other findings on brain MRI include lesions in the cerebellar and respiratory irritation and hepatorenal damageb [146]. Cerebellar
dentate nuclei, periaqueductal region, dorsal midbrain and pons139. toxicity can occur with either acute or chronic exposure. Diagnosis
Lesions can also be seen in the posterior putamen, subthalamic nuclei, can be made with either serum toluene levels or urine hippuric acid
dorsal medulla oblongata, inferior cerebellar peduncles and areas of levels. MRI can be useful and may show both cerebral and cerebellar
the midbrain [141]. Avoidance of bromides after acute insult is imper- atrophy with T2 white matter hyperintensities within the deep struc-
ative. In one case, an acute intoxication was treated with hemoperfu- tures of the brain including the periventricular area, internal capsu-
sion, which is a procedure similar to hemodialysis [142]. lar, and brainstem pyramidal regions [12]. Management is supportive
with avoidance of further toxic exposures.
Mercury
Carbon Monoxide
There are several major formulations of mercury that pose a risk
of exposure tohumans [143]. Purkinje cells require high levels of oxygen and are susceptible to
hypoxia [10]. Carbon monoxide (CO) produces hypoxia by binding
Although modern use of mercury in industrial products is rare, hemoglobin and limiting oxygen saturation of red blood cells. Severe
in the past it was commonly found in thermometers, batteries, light acute CO toxicity can damage Purkinje cells and lead to irreversible
bulbs, and electrodes. Some prior dental amalgams contained mercu- cerebellar symptoms in addition to behavioral changes, cognitive im-
ry and produced a risk for mercury vapor inhalation, which cancause pairment and parkinsonism.
multiorgan dysfunction with renal, pulmonary and gastrointestinal
effects. The absolute amount of mercury vapor produced by a dental Discussion
filling is low and toxicity requires chronic exposure to multiple dental
amalgam fillings. While modern fillings no longer contain mercury, Initial evaluation of either acute or subacute ataxia requires neu-
exposure to liquid mercury from antiques can produce vapor toxicity roimaging to rule out lesional causes such as stroke, tumor, hemor-
[143]. Neurologically,vapor exposurecauses a peripheral neuropathy rhage, or inflammatory insult. When no clear cause is discovered with
and erethism (severe behavioral, mood, and cognitive change). Meth- neuroimaging, a close review of a patient’s medication list for drugs
yl mercury or organic mercury is present in some fish and predomi- commonly associated with ataxia is warranted in addition to a urine
nantly affects the central nervous system, producing perioral and dis- drug screen. Although medicationinduced ataxia often develops after
tal extremity parasthesias, ataxia, and optic atrophy with early visual the initiation of a new drug or a change in dose, it is important to
field constriction and hearing loss. On pathologic evaluation, meth- remember that some medications such as phenytoin, valproate, and
yl mercury preferentially damages neurons of the visual cortex and lithium can lead to ataxia without a clear dose change. Initiation of a
granule cells in the cerebellum143.A regional decrease in blood flow drug that does not normally cause ataxia but may alter the metabolism
may be present in the cerebellum on single photon computed tomog- of one that does should be considered. Furthermore, an acute meta-
raphy following mercury exposure [144].Methyl mercury toxicity can bolic or infectious insult can cause ataxia and cerebellar symptoms to
cause cerebellar atrophy in 27% of intoxicated patients144.Ethyl mer- develop in a patientwho previously tolerated high risk medications
cury was previously found in some parenteral vaccines in the form without issues. The elderly, those with abnormal renal function, and
of thimerosal, a component used as a preservative to prevent fungal patient’s with significant polypharmacy are at high risk of drug in-
growth. Although only present in low levels and non-toxic in adults, duced ataxia and close monitoring after the initiation of a medication
there is concern for toxic levels in infants receiving frequent vaccina- with the risk of ataxia as an adverse effect is required. Illicit drug
tions, prompting discontinuation of this preservative [145]. Currently induced ataxia should also be considered when no clear medica-
thimerosal is no longer a component of vaccines in the United States. tion appears to be leading to a new acute ataxia. Additionally, when
Organic mercury toxicity from sources such as fish responds poorly to thorough evaluation for an acute or subacute toxicity is unrevealing
chelation.On the other hand, inorganic mercury toxicity can be man- consideration of environmental exposures to toxic substances such
aged with early chelator therapy such as dimercaprol, in addition to as solvents, heavy metals, and toluene should be considered. Man-
supportive measures [143,144]. agement of possible medication induced ataxia should entail remov-
al of a single agent at a time and monitoring for improvement. The
Lead majority of drug induced ataxias completely resolve with cessation
of the offending agent. However, many may take days to months to
Lead intoxication can occur due to ingesting paintsand can be
see improvement. Some medications can lead to permanent cerebel-
worse in children[23]. Symptoms and signs include abdominal pain,
lar damage despite cessation,including phenytoin, lithium and cytara
anemia, central and peripheral neurotoxicity and cerebellar ataxia
J Anesth Clin Care ISSN: 2378-8879, Open Access Journal Volume 10 • Issue 2 • 100084
DOI: 10.24966/ACC-8879/100084
Citation: Kidd CJ, Kathari YK, Dalton K, Hack N (2023) Drug and Toxin-Induced Cerebellar Ataxias. J Anesth Clin Care 10: 084.

• Page 8 of 11 •

bine. Antiepileptics represent an important and common cause of new 12. Dolbec K, Dobbs MR, Ibraheem M (2020) Toxin-Induced Cerebellar
ataxia and warrant close monitoring of patients on these medications Disorders. Neurol Clin 38: 843-852.
for signs of cerebellar dysfunction. Although nearly all antiepileptics 13. Adithan C, Gerard N, Vasu S, Balakrishnan R, Shashindran CH, et al.
can produce ataxia to some degree, medications that have their prima- (2003) Allele and genotype frequency of CYP2C9 in Tamilnadu popula-
ry mechanism of action on sodium ion channels represent the highest tion. Eur J Clin Pharmacol. 59: 707-709.
risk. Purkinje cells are susceptible to medications that alter ion chan- 14. Twardowschy CA, Werneck LC, Scola RH, Borgio JG, De Paola L, et al.
nel conductance as they contain a high proportion of small conduc- (2013) The role of CYP2C9 polymorphisms in phenytoin-related cerebel-
tance calcium activated potassium channels important for regulation lar atrophy. Seizure 22: 194-197.
of purkinje cell firing patterns [147]. 15. Ghatak NR, Santoso RA, McKinney WM (1976) Cerebellar degeneration
following long-term phenytoin therapy. Neurology. 26: 818-820.
It is important to have a broad differential with new ataxia and to
determine if new medications, toxins, or drugs may be contributing to 16. Crooks R, Mitchell T, Thom M (2000) Patterns of cerebellar atro-
a patient’s presentation. phy in patients with chronic epilepsy: a quantitative neuropathological
study. Epilepsy Res 41: 63-73.
Author Contributions 17. Ben-Menachem E, Biton V, Jatuzis D, Abou-Khalil B, Doty P, (2007)
Conceptualization, K.R.D., C.J.K., YKK and NH;original draft Efficacy and Safety of Oral Lacosamide as Adjunctive Therapy in Adults
with Partial-Onset Seizures. Epilepsia. 48: 1308-1317.
preparation, C.J.K, YK, K.R.D and N.H.; review and editing, Y.K.K,
N.H. and C.J.K. All authors have read and agreed to the published 18. Husain A, Chung S, Faught E, Isojarvi J, McShea C, et al. (2012) Long-
version of the manuscript. term safety and efficacy in patients with uncontrolled partial-onset
seizures treated with adjunctive lacosamide: Results from a phase III
Funding open-label extension trial. Epilepsia 53: 521-528.

This research received no external funding. 19. Panebianco M, Bresnahan R, Ramaratnam S, Marson A (2020) Lamotrig-
ine add-on therapy for drug-resistant focal epilepsy. Cochrane Database
Conflicts of Interest of Systematic Reviews.

20. Verma R, Kori P (2012) Valproate-induced encephalopathy with predom-

The authors declare no conflict of interest. inant pancerebellar syndrome. Indian J Pharmacol. 44: 129.
Disclosures 21. Segura-Bruna N, Rodriguez-Campello A, Puente V, Roquer J (2006) Val-
proate-induced hyperammonemic encephalopathy. Acta Neurol Scand
The views expressed in this article are those of the authors and do 114: 1-7.
not necessarily reflect the official policy of the Department of Defense
or the U.S. Government. 22. Beversdorf D, Allen C, Nordgren R (1996) Valproate induced encepha-
lopathy treated with carnitine in an adult. Journal of Neurology, Neuro-
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DOI: 10.24966/ACC-8879/100084
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