Handbook of Clinical Neurology, Vol.
103 (3rd series)
Ataxic Disorders
S.H. Subramony and A. Dürr, Editors
# 2012 Elsevier B.V. All rights reserved
Chapter 12
Toxic agents causing cerebellar ataxias
MARIO MANTO*
Unit d’Etude du Mouvement (UEM); FNRS Neurologie, ULB Erasme, Brussels, Belgium
The cerebellum is particularly susceptible to intoxication
and poisoning. Amongst all the cerebellar cells, Purkinje
neurons are especially susceptible to this form of injury.
In humans, the most common cause of toxic lesion to the
cerebellar circuitry is alcohol-related (see Chapter 11).
Cerebellar circuits are also a main target of drug expo-
sure or environmental toxins, described in the present
chapter. Although figures for the prevalence and inci-
dence of cerebellar lesions related to intoxication and
poisoning are still missing in most cases, clinicians
should be aware of the list of agents that could cause
cerebellar deficits since toxin-induced cerebellar ataxias
are not uncommon in daily practice and because
the patient’s status may require urgent therapies when
the intoxication is life-threatening. The scientific com-
munity’s interest in environmental disorders is slowly
growing, as is the interest of the general population.
DRUGS
Anticonvulsants
PHENYTOIN
Phenytoin is frequently associated with cerebellar ataxia.
Patients may develop ataxic signs either during chronic
treatment or following acute intoxication (Masur et al.,
1989). Cerebellar signs may be subtle, such as asymptom-
atic nystagmus and mild ataxic gait, or severe (Selhorst
et al., 1972). Cerebellar signs may develop several years
after initiation of chronic treatment. Dose-related nystag-
mus is very common for serum concentrations above
20 mg/mL. Patients may recover completely from cerebel-
lar deficits. However, irreversible lesions may develop
(Chatak et al., 1976). Usually, patients who develop irre-
versible cerebellar deficits have been exposed to higher
doses for longer periods of time. Rarely, patients may
have a slight cognitive deficit or a peripheral neuropathy.
*Correspondence to: Mario Manto, MD, FNRS Neurologie ULB Erasme, 808 Route de Lennik, 1070 Bruxelles, Belgium. Tel/fax:
32-2-555.39.92. E-mail: mmanto@ulb.ac.be
Some patients may be susceptible to phenytoin toxicity –
for instance, those with prior asymptomatic cerebellar
insult or with myoclonic epilepsy. This rule is valid for
many cerebellotoxic agents. Intrauterine exposure to phe-
nytoin has been associated with pontocerebellar hypopla-
sia (Squier et al., 1990).
Patients taking drugs that increase the half-life of
phenytoin, such as ticlopidine (acting upon cytochrome
P450), require monitoring of blood levels of phenytoin,
especially when ticlopidine is initiated or when the
doses are increased.
Brain CT and brain MRI show cerebellar atrophy of
various degrees in patients developing irreversible cere-
bellar signs following chronic treatment with phenytoin.
Cerebellar atrophy has also been described following a
suicide attempt (Mascalchi et al., 1996) and after an acute
overdose (Kuruvilla and Bharucha, 1997). In some cases,
cerebellar atrophy is discovered in the absence of cerebel-
lar deficits. The correlation between cerebellar atrophy
and the duration of epilepsy remains a matter of
debate. Neuropathological studies show diffuse loss of
Purkinje cells and decreased number of granule cells
and Bergmann gliosis, with a relative sparing of basket
cell axons (Gilman et al., 1981; Anand et al., 1998).
Patients presenting with acute intoxication may need
to be monitored in an intensive care unit. Patients at
risk for developing cerebellar deficits should not
receive phenytoin (Eldridge et al., 1983).
CARBAMAZEPINE
Carbamazepine induces dose-dependent ataxic effects.
Typically, patients complain of dizziness and exhibit a
gaze-evoked nystagmus, action tremor, and ataxia of
stance/gait (Manto and Topka, 1996; Masland, 1982).
Impaired conscious state may mask the cerebellar defi-
cits. Half of the patients with overdose develop cerebellar
202 M. MANTO
signs (Bridge et al., 1994). These signs may be related to
involvement of afferents or efferents to the cerebellum.
Elderly patients appear more susceptible to carbamaze-
pine than young patients (Specht et al., 1997). Patients with
pre-existing cerebellar atrophy are at risk for developing
cerebellar signs at lower serum levels. Structural lesions
need to be looked for when cerebellar signs appear during
treatment with carbamazepine (Hori et al., 1987).
Carbamazepine is used not only to treat focal epilepsy,
but also for pain management and to treat manic-depres-
sive disorders. In the latter situation, the combined use
of lithium salts and carbamazepine requires close clinical
follow-up and biological monitoring (Rittmannsberger
and Lebhuler, 1992). Indeed, patients may develop a toxic
syndrome comprising confusion, drowsiness, nystagmus,
dysarthria, hyperreflexia, coarse tremor, and ataxia of
the limbs and trunk. The addition of carbamazepine to
chronic treatment with lithium salts may induce cerebellar
signs, even when blood levels of both drugs are within
the therapeutic range. Other drugs interacting with
carbamazepine are sodium valproate, erythromycin/
clarithromycin, verapamil, and viloxazine (Rothner et al.,
1987; Zitelli et al., 1987).
Patients presenting with acute carbamazepine intoxi-
cation may need to be monitored in an intensive care unit,
due to the possibility of drowsiness or coma. Electrolyte
imbalance should be corrected. Activated charcoal is still
used in many centers (Brahmi et al., 2006). It should be
kept in mind that total levels may be “therapeutic”, when
free levels are increased (Rothner et al., 1987).
OTHER ANTICONVULSANTS
Phenobarbital may induce transient ataxic signs. The most
common deficits are gaze-evoked nystagmus, kinetic
tremor, and ataxia of stance and gait. Most patients
will exhibit drowsiness. It is estimated that about 5% of
epileptic patients treated with barbiturates show cere-
bellar deficits. Nevertheless, evidence of cellular toxicity
and neuronal loss in adults is lacking. Experimental
studies underline the vulnerability of the cerebellum
during growth, but clinical implications are unclear.
Vigabatrin is an inhibitor of GABA transaminase
that can induce mild ataxic posture in about 5–10% of
adults with poorly controlled epilepsy. Gait ataxia is
dose related.
Gabapentin enhances GABAergic inhibition. About
7.7% of epileptic patients receiving gabapentin as
add-on therapy exhibit ataxia (Baulac et al., 1998).
The ataxia is reversible following discontinuation of the
drug. Despite this side effect, gabapentin can improve
ataxia in patients exhibiting isolated cerebellar atrophy
(Gazulla and Tintoré, 2007). This is a paradox. We have
seen several patients improving with administration of
gabapentin at high doses. The initiation of the treatment
may exacerbate ataxia temporarily, but this is followed
by an improvement of gait.
Lamotrigine added to chronic treatment with
carbamazepine may induce ataxic signs, as a result of a
pharmacodynamic interaction. Nevertheless, a genuine
cerebellar toxicity is unlikely.
Antineoplastics
5-FU
High doses of 5-FU may cause a disabling pancerebellar
syndrome (Moertel et al., 1964). Cerebellar signs may be
isolated or combined with signs of encephalopathy, rais-
ing the possibility of Wernicke–Korsakoff syndrome.
ARA-C
Doses above 3 g/m2 may induce a cerebellar syndrome.
Signs of intoxication develop usually with cumulative
doses above 24 g. Manifestations range from an
isolated nystagmus to irreversible cerebellar deficits
(Herzig et al., 1987). Patients initially develop somno-
lence and encephalopathy in most cases. An associated
neuronopathy is common. Age is a predisposing factor.
METHOTREXATE
Cerebellar structures are vulnerable to methotrexate,
especially when the drug is delivered by the intrathecal
route (Wizniter et al., 1987; Lesnik et al., 1998).
CISPLATIN, OXALIPLATIN, PACLITAXEL
Several drugs used to treat cancer may generate a poly-
neuropathy with predominant sensory ataxia sometimes
misdiagnosed as a cerebellar ataxia. Oxaliplatin may
cause cold-induced sensory symptoms (dysesthesia,
paresthesia) early after drug infusion, or a peripheral
neuropathy with sensory ataxia – which can mimic cer-
ebellar ataxia – during prolonged treatment (Gamelin
et al., 2002).
CAPECITABINE
Capecitabine in an antimetabolite agent (oral prodrug
of 5-FU) used for metastatic colorectal and breast
cancer and as an adjuvant therapy for colon cancer.
Capecitabine can induce a diffuse toxic encephalopathy
with seizure-like symptoms and disseminated white
matter alterations affecting supratentorial and infra-
tentorial structures (Niemann et al., 2004).
EPOTHILONE D
Epothilone D is second-line chemotherapy for prostate
cancer. The drug is considered as relatively toxic. Among
 TOXIC AGENTS CAUSING CEREBELLAR ATAXIAS
the side effects, ataxia occurs in about 8% of the patients
(Beer et al., 2007).
Other drugs
LITHIUM SALTS
Lithium salts are used mainly for acute mania and
prophylaxis of recurrent bipolar and unipolar affective
disorders. Toxicity may occur either during maintenance
therapy or following acute intoxication. The most com-
mon side effect of chronic treatment is an enhanced phys-
iological tremor affecting mainly the hands. Lithium salts
may cause hypothyroidism, which may aggravate the
ataxia (see also Amiodarone). Acute intoxication may
affect the cardiovascular, renal, and/or nervous system
(Simard et al., 1989). The spectrum of neurological defi-
cits is broad: coma, seizures, coarse tremor, hypokinesia,
rigidity, hyperreflexia. High fever is common during
intoxication. A neuroleptic malignant syndrome is often
suspected since neuroleptics and lithium salts are often
administered in combination in psychiatric patients.
Although neurological signs are usually reversible after
acute intoxication, patients may exhibit a severe cerebellar
syndrome with scanning speech, tremor, and ataxic gait
(Manto et al., 1996). Intensive care monitoring is recom-
mended to prevent irreversible sequelae.
AMIODARONE
Amiodarone is a commonly used antiarrhythmic medica-
tion, with a thyroxin-like structure. The main neurologi-
cal side effects are postural tremor, peripheral
neuropathy, and cerebellar deficits. Risk factors are
advanced age, renal failure, diabetes mellitus, and alco-
holism (Arnaud et al., 1992). About 5–7% of patients
on amiodarone develop a cerebellar toxicity (Garretto
et al., 1994). Extracerebellar signs may occur also, includ-
ing encephalopathy, rest tremor, dyskinesia, myoclonus,
and proximal myopathy. Cerebellar ataxia may disappear
very slowly following drug discontinuation or may
persist for several years, due to the very long half-life
of elimination of the drug. Patients should be screened
for a thyroid dysfunction, which is a common side effect
of amiodarone and which can trigger cerebellar signs.
PROCAINAMIDE
High-dose procainamide, used in cardiac arrhythmia,
may cause an acute cerebellar ataxia which resolves
after discontinuation of the drug (Schwartz et al., 1984).
CICLOSPORIN AND CALCINEURIN INHIBITORS
Calcineurin inhibitors are used in organ transplantation
and in immunological diseases. The most common neu-
rological side effect of ciclosporin is a fine tremor.
203
Other neurological signs may develop: behavioral disor-
ders, aphasia, seizures, cerebellar ataxia, vestibular def-
icits, motor spinal cord syndrome, and paresthesia
(Palmer and Toto, 1991). Cerebellar toxicity of ciclosporin
is probably not related to the plasma levels of the drug.
Silent cerebellar lesions, such as a silent infarction, may
be unraveled by the medication. Cerebellar deficits may
appear several months following initiation of treatment.
Hypomagnesemia may trigger subacute episodes of ataxia
associated with ciclosporin (Thompson et al., 1984). A leu-
koencephalopathy may occur following transplantation
(Belli et al., 1993). The so-called “reversible posterior leu-
koencephalopathy syndrome” is characterized by exten-
sive white matter lesions predominating in the posterior
regions of the cerebral hemispheres. Recipients of orthoto-
pic liver transplants might be particularly at risk for severe
presentations (Bechstein, 2000). Patients previously
exposed to cytotoxic agents (such as cisplatin) might
be more susceptible (Rangi et al., 2005). The main
differential diagnosis is progressive multifocal leukoence-
phalopathy. Cerebellar lesions may be reminiscent of
watershed zones (Bartynski et al., 1997). Acute cerebellar
edema occurs exceptionally and requires immediate brain-
stem decompression (Nussbaum et al., 1995). Although
clinical deficits may be potentially reversible after drug
withdrawal, cerebellar atrophy may develop over time
after cessation of tacrolimus (Kaleyias et al., 2006).
Differential diagnosis of cerebellar deficits in cases of
renal failure include stroke and action myoclonus–renal
failure syndrome when there is a history of familial
disease (Badhwar et al., 2004). When the intoxication with
calcineurin inhibitors has a subacute course, cerebellar
paraneoplastic syndrome should be considered also.
BISMUTH
Bismuth compounds have long been used in skin
creams and for treating gastrointestinal disorders.
Recently, they have been administered in combination
with antibiotics for the treatment of Helicobacter
pylori-associated peptic ulcers. Bismuth can induce
encephalopathic symptoms, including seizures, delir-
ium, myoclonic jerks, and cerebellar deficits (Gordon
et al., 1995). The latter include a coarse tremor in the
limbs and gait ataxia. Patients with chronic renal failure
are at risk (Playford et al., 1990). Stereological studies
have shown that hypoxia can amplify the cerebellar
toxic effects of bismuth, causing a significant loss of
Purkinje cells (Larsen et al., 2005). Differential diagno-
sis of bismuth intoxication includes Creutzfeldt–Jakob
disease, myoclonic epilepsy, and Hashimoto’s encepha-
lopathy. The chelator 2,3-dimercapto-1 propanesulfonic
acid (DMPS) has been used to enhance the renal clear-
ance of bismuth (Playford et al., 1990).
204 M. MANTO
BROMIDES/BROMVALERYLUREA
Bromide salts used to be administered for sleep disorders.
Intoxication occurred mainly in Japan. The clinical picture
included a variable combination of cerebellar deficits
(mainly slurred speech and gait ataxia), pyramidal
signs, and extrapyramidal features, especially dystonia
(Kawakami et al., 1998). Cases presenting with impaired
consciousness or peripheral neuropathy have been reported.
Because of interference with chloride measurement, a
pseudo-hyperchloremia may be observed (Bonnotte et al.,
1997). Brain MRI demonstrates cerebellar atrophy, some-
times with concomitant atrophy of the pontine
tegmentum. Hemoperfusion is recommended to remove
bromvalerylurea from blood (Ishiguro et al., 1982).
MEFLOQUINE
Mefloquine is an antimalarial drug administered for
prophylaxis. An acute intoxication may occur, with
fever, nausea, headache, dizziness, clumsiness, and gait
instability. Drug discontinuation and future avoidance
are recommended.
ISONIAZID
Isoniazid is widely used for treating tuberculosis, includ-
ing tuberculous meningitis. Toxic effects are mostly
related to the interaction with vitamin B6. The most com-
mon side effects reported affect the nervous system and
liver (Spencer and Schaumburg, 1980). Peripheral neurop-
athy may occur with daily doses of 6 mg/kg. At higher
doses, seizures, dizziness, ataxia, and slurred speech have
been reported. However, there is no clear demonstration
that this is due to a genuine cerebellar toxicity.
LINDANE
Lindane is one of the treatments of choice for scabies
and lice. Overuse may cause nervous system toxicity.
Patients exhibit hyperreflexia, hypertonia, limb and trun-
cal ataxia, choreoathetosis, and seizures (Spencer and
Schaumburg, 1980). Lindane interacts with GABA-B
receptors in the cerebellum (Anand et al., 1998).
PERHEXILINE MALEATE
Perhexiline may cause a sensorimotor peripheral neu-
ropathy. A cerebellar syndrome may be associated
(Turpin et al., 1983). Cerebellar toxicity might result
from disturbances of lipid turnover (Nick et al., 1978).
CIMETIDINE
Although ataxia has been reported in cases of intoxication
with cimetidine, the causal relationship is not established
due to concomitant factors.
METRONIDAZOLE
Metronidazole exerts a peculiar toxicity on cerebellar
nuclei. MRI shows edema with increased diffusion
coefficients in cerebellar nuclei (Heaney et al., 2003).
Patients may recover clinically and radiologically after
cessation of therapy.
GLYCOPROTEIN IIB/IIIA INHIBITORS
Glycoprotein IIb/IIIa inhibitors, such as eptifibatide,
are commonly used in the treatment of acute coronary
syndromes. The following side effects have been
reported in animal studies: dyspnea, ptosis, cerebellar
dysfunction, hypotonia, and petechial hemorrhages
(Parakh et al., 2009). Eptifibatide overdose is very
rare in humans and can be managed conservatively
with cessation of infusion and monitoring. Clear
delineation of cerebellar toxicity is missing. Platelet
transfusion may be necessary in case of acute throm-
bocytopenia (Epelman et al., 2006). Patients with
renal dysfunction have a higher risk of bleeding, and
hemodialysis can restore hemostasis (Sperling et al.,
2003). lest
ZALEPLON
Zaleplon is a recently described hypnotic agent, with a
selective activity on the benzodiazepine omega 1 recep-
tor subtype. Ataxia has been reported following a
suicide attempt, along with drowsiness, slurred speech,
dizziness, and confusion (Forrester, 2006; Sein Anand
et al., 2007). The cerebellar origin of ataxia remains to
be demonstrated.
NICOTINE
There is clinical and experimental evidence that nicotine
is cerebellotoxic (Manto and Jacquy, 2002). Cigarette
smoking may exacerbate ataxia in multiple system atro-
phy (Johnsen and Miller, 1986). Moreover, nicotine may
worsen dysarthria and ataxia of the trunk and limbs in
spinocerebellar ataxia (Houi et al., 1993). Nicotine
exerts a deleterious effect on cerebellar development
in animals (Chen et al., 1998).
Drug abuse and addiction
COCAINE
Intoxication with cocaine can cause seizures, an
impaired conscious state ranging from mild drowsiness
to severe lethargy, delirium, and cerebellar ataxia.
Patients may present with a clinical picture suggesting
neuroleptic malignant syndrome (Daras et al., 1995).
Patients are at risk of developing mild or severe cerebel-
lar infarctions (Aggarwal and Byrne, 1991). Other toxic
 TOXIC AGENTS CAUSING CEREBELLAR ATAXIAS
agents, such as phenytoin, may be added to ‘crack’
cocaine and contribute to neurological deficits (Katz
et al., 1993). Neonates exposed to cocaine during
pregnancy have been found to present brain lesions
unsuspected clinically (Dixon and Bejar, 1989).
HEROIN
Heroin ingestion may induce a toxic spongiform leu-
koencephalopathy (Weber et al., 1998). Cerebellar signs
usually start several days after the last consumption.
Lesions are hypodense on brain CT and hyperintense
on brain MRI (T2 sequence) and are typically symmet-
rical, usually predominating in white matter. Intoxica-
tion may be fatal (Ryan et al., 2005). Loss of Purkinje
neurons has been found in chronic abusers (Oehmichen
et al., 1996).
PHENCYCLIDINE
Phencyclidine is a non-competitive NMDA receptor
antagonist which can act as a neurostimulator
(Deutsch et al., 1998). Complications of phencyclidine
consumption include: disorders of behavior, hallucina-
tions, lethargy, catatonia, seizures, constricted pupils,
athetosis, and dystonia. Children are at risk for devel-
oping cerebellar signs, mainly ataxia of stance/gait
and nystagmus (Schwartz and Einhorn, 1986). Inten-
sive care therapy may be required, especially in
patients with increased blood pressure, fever, and
bronchospasm.
HERBS
Ceremonial herbs used for social events may induce cer-
ebellar ataxia. Kava, used mainly in the South Pacific,
is a plant extract that can cause postural ataxia and
limbs tremor, probably via a disruption of GABAergic
pathways (Singh and Singh, 2002).
METHADONE
Methadone is currently used for the management of
opioid addiction. Accidental ingestion can induce an
acute toxic encephalopathy presenting with impaired
consciousness due to obstructive hydrocephalus caused
by severe cerebellar edema (Anselmo et al., 2006).
Swelling of the cerebellum may be associated with
watershed injuries, which share some similarities
with lesions induced by heroin intoxication (see above)
and may mimic a para-infectious cerebellitis on brain
MRI (Mills et al., 2008). Successful treatment with
methylprednisolone and external drainage of cerebro-
spinal fluid has been reported. Urgent decompressive
occipital craniotomy may be required.
205
ENVIRONMENT
Metals
MERCURY
Humans are still exposed to methylmercury and mercury
vapor, especially in the Amazon area where gold mining
remains an industrial activity (Clarkson, 1997; Lodenius
and Malm, 1998). The intoxication in Minamata Bay
resulted in an epidemic due to seafood contamination.
Patients exhibit an association of constricted visual
fields, sensory deficits in the extremities due to periph-
eral neuropathy, and cerebellar deficits (Ninomiya
et al,. 1995; Korogi et al., 1998). The inferior and middle
parts of the vermis and the cerebellar hemispheres are
particularly susceptible (Korogi et al., 1994). Chelators
(BAL and/or penicillamine) are used to treat mercury
poisoning.
The cerebellum might be particularly vulnerable to
combined exposure to methylmercury and polychlori-
nated biphenyls (PCBs; organochlorines used as coolants,
in transformers and capacitors, in flexible PVC coatings,
or as pesticide extenders). PCBs are highly lipophilic
molecules. Both toxic categories interfere with cerebellar
development, and in combination could act upon ryano-
dine-sensitive calcium signaling, leading to impaired
motor learning (Roegge and Schantz, 2006).
LEAD
The main causes of lead intoxication are ingestion of
paints, sniffing of leaded gasoline, flour contamina-
tion, exposure to lead stearate, and contamination from
automobile batteries. Toxicity seems greater in children
(Finkelstein et al., 1998). Abdominal pain is common.
Blood studies show various degrees of anemia. Lead
is neurotoxic for the central (in particular, the frontal
cortex, hippocampus, and cerebellum) and the periph-
eral nervous system (peripheral motor neuropathy).
Cerebellar ataxia may be prominent in adults (Mani
et al., 1998). Cerebellar intoxication may present as a
pseudotumor with obstructive hydrocephalus, due to
edema (Pappas et al., 1986, Johnson et al., 1993). Cere-
bral calcifications and hyperintense lesions on brain
MRI are common. Chelation therapy is required when
the intoxication is confirmed.
MANGANESE
Exposure to manganese, a divalent cation, can result in
psychiatric symptoms, attention deficits, learning
impairment, and lack of coordination (Donaldson, 1987;
Klos et al., 2006). Subchronic manganese sulfate inhala-
tion in monkeys is associated with significant elevations
of the metal concentration in the frontal cortex, olfactory
206 M. MANTO
cortex, cerebellum, and white matter (Dorman et al.,
2006). Manganese inhibits NMDA receptor function in
an activity-dependent manner (Guilarte and Chen, 2007).
Experimentally, manganese blocks the binding of MK-
801, a well-known NMDA receptor channel antagonist,
to the NMDA receptor channel. Manganese is now con-
sidered as a competitive antagonist of MK-801 binding
to the NMDA receptor channel. In addition, manganese
is able to permeate the channel, a possible mechanism
by which manganese could disseminate in neuronal net-
works (Guilarte and Chen, 2007). Inhibition of NMDA
receptors is particularly potent in the cerebellum, proba-
bly because cerebellar NMDA receptors have a different
subunit composition than forebrain NMDA receptors.
In the adult cerebellum, the NR1/NR2C subtype predomi-
nates, whereas in forebrain structures NR1, NR2A, and
NR2B subunits are most common (Monyer et al., 1994).
Overall, chronic exposure to manganese produces a
dysfunction of the glutamatergic system.
ALUMINIUM
Celphos (aluminium phosphide) has caused intoxication
in the Varanasi region, India (Tripathi and Pandey,
2007). Neuropathological studies showed degenerated
neurons in the cerebellar cortex with infiltration of
round cells into the molecular layer and loss of den-
drites in Purkinje cells. Several abnormalities were
observed in the cerebral cortex, such as a disorganiza-
tion of the different layers and round-shaped neurons
with a convex border. Areas of necrosis were observed
throughout the brain.
THALLIUM
Thallium salts are colorless, odorless, and tasteless.
These properties have greatly contributed to intoxica-
tion and poisoning. Most cases are related to oral inges-
tion and inhalation of contaminated dust, snorting,
dermal absorption, or homicide attempts (Wainwright
et al., 1988; Meggs et al., 1997). The clinical syndrome
includes loss of consciousness, seizures, blurred vision,
tremor, ataxia, and symptoms related to peripheral
neuropathy (Sabbioni and Manzo, 1980; Gilman et al.,
1981). Hypertension, cardiac arrhythmias, and respira-
tory failure may develop. Alopecia is suggestive,
appearing several days after the exposure. Polarized
light reveals dark zones at the level of hair roots.
Electrophysiological investigations show evidence of
distal axonopathy. Ataxia has a mixed origin, peripheral
and cerebellar. Experimentally, Purkinje cells are
particularly vulnerable to thallium (Meggs et al.,
1997). Multilamellar cytoplasmic bodies and abnormal
mitochondria have been observed in the cerebellar
cortex (Hasan et al., 1978).
Recommendations for the management of thallium
intoxication include intensive care monitoring, antidotes
(D-penicillamine with Prussian blue), hemodialysis,
forced diuresis, and supplementation with potassium
chloride (Vergauwe et al., 1990; Malbrain et al., 1997).
GERMANIUM
Germanium poisoning causes peripheral neuropathy
presenting with sensory ataxia and myopathy (Fujimoto
et al., 1992; Asaka et al., 1995). Cerebellar ataxia is
extremely rare.
URANIUM
Uranium can induce an extrapyramidal syndrome, asso-
ciated with cerebellar ataxia and peripheral neuropathy
(Goasguen et al,. 1982).
VANADIUM
Vanadium toxicity has been confirmed experimentally
(Garcia et al., 2005). The cerebellum and hippocampus
are the main targets in rats exposed to sodium metava-
nadate given by the intraperitoneal route. Lesions might
be related to production of free radicals.
Toluene/benzene derivatives
Toluene is an industrial organic solvent. It can be invol-
untarily or voluntarily inhaled. Toluene intoxication is
common in glue-sniffing and following chronic expo-
sure in working areas that are poorly ventilated. In chil-
dren, the main presentation is an acute encephalopathy
with coma, seizures, behavioral abnormalities, and
cerebellar ataxia (King, 1982). In adults, headache,
hyperactivity, memory impairment, and cerebellar
ataxia may occur (Boor and Hurtig, 1977; Saito and
Wada, 1993). Cerebellar symptoms may be prominent,
with patients exhibiting dysarthria, kinetic tremor, gait
ataxia, and occasionally a downbeat nystagmus
(Damasceno and de Capitani, 1994). Although patients
may recover in a few months, a permanent cerebellar
syndrome may occur (Ikeda and Tsukagoshi, 1990).
Another source of intoxication is chronic thinner intox-
ication, which particularly affects teenagers and young
adults (Uchino et al., 2002). Cerebellar ataxia and
decreased visual acuity are suggestive of the intoxica-
tion. Patients often exhibit a postural tremor.
Brain MRI shows areas of white matter hyperinten-
sities in the cerebrum, brainstem, and cerebellum on
T2-weighted images or with the FLAIR sequence
(Yamanouchi et al., 1995). A dysfunction of the vestibu-
locerebellar and spinocerebellar afferent pathways has
been suggested based on the analysis of postural sway
in factory workers exposed to hexane, xylene, and
 TOXIC AGENTS CAUSING CEREBELLAR ATAXIAS 207
toluene (Yokoyama et al., 1997). Experimentally, tolu- Carbon monoxide
ene inhibits nicotinic acetylcholine receptors, which play
Carbon monoxide is a gas responsible for hypoxia,
an important role in brain development (Chan et al.,
leading to cardiopulmonary arrest in cases of severe
2008). Long-term changes in nicotine sensitivity may
intoxication, due to its high affinity for hemoglobin
result. A sodium-dependent disturbance of GABA
oxygen-binding sites. Carbon monoxide still account
metabolism has been proposed to explain cerebellar
for a large number of deaths and notable morbidity
toxicity (Stengard et al., 1993).
worldwide. About 2–26% of patients die from acute
Cases of paradichlorobenzene (PDB) intoxication
intoxication (Pahwa, 1997). Symptoms may be initially
have also been described (Cheong et al., 2006). PDB is
subtle, occasionally restricted to a mild headache.
a common household deodorant found in toilet bowl
Carbon monoxide induces immediate or delayed
fresheners. Both the acute intoxication and addiction
neurological alterations, including memory loss, cogni-
can be associated with dysarthria, tremor, and gait ataxia.
tive impairment, neuropsychiatric manifestations, and
A withdrawal encephalopathy with cognitive, pyramidal,
deficits linked to basal ganglia or cerebellar dysfunction
extrapyramidal, and cerebellar features may develop.
(Savoldi et al., 1973; Kulakowska et al., 2000). An inter-
val of several weeks between the intoxication and the
Hyperthermia appearance of neurological deficits is not exceptional.
Imaging studies show lesions principally in the basal
Episodes of hyperthermia (usually above 40.5
C) can
ganglia (globus pallidus), thalamus, and white matter.
induce a cerebellar syndrome, either transient or perma-
They correspond to areas of severe edema (O’Donnell
nent. Heat stroke and neuroleptic malignant syndrome
et al., 2000; Takahashi et al., 2001). MRI may demon-
are the commonest causes worldwide.
strate extensive cerebellar white matter lesions or cere-
Neurological examination shows deficits ranging
bellar atrophy (Manto and Jacquy, 2002). Single-photon
from an isolated cerebellar dysarthria or an isolated gait
emission computed tomography (SPECT) studies may
ataxia to a pancerebellar syndrome (Manto and Topka,
reveal a reduction of cerebellar blood flow. Necropsy,
1996). Symptoms may resolve within 3–10 days. Cerebel-
histological examination, and DNA ladder assay provide
lar deficits may also be part of a diffuse encephalopathy
evidence for the presence of apoptosis as well as necrosis
presenting clinically with seizures and confusion
in human cases of carbon monoxide intoxication.
(Lawden et al., 1994). Follow-up studies with brain CT
Experimental studies have shown that carbon mon-
or MRI have demonstrated that cerebellar atrophy may
oxide induces an impairment of the differentiation of
appear in the months following an episode of hyperpy-
cerebellar GABA synthesizing neurons (Benagiano
rexia (Mohapatro et al., 1990) and be evident while
et al., 2005). Chronic exposure induces a delayed
patients are showing satisfactory clinical improvement.
impairment of soluble guanylate cyclase activation by
Purkinje cells are particularly vulnerable to heat-
nitric oxide (Hernández-Viadel et al., 2004). The sup-
induced injury. Neuropathological studies have shown
pression of cerebellar long-term depression (LTD) may
a severe diffuse loss of Purkinje cells associated with
be due to this effect. Patients suffering from carbon
heat shock protein 70 expression by Bergmann glia
monoxide intoxication should be transferred immedi-
(Bazille et al., 2005). Degeneration of Purkinje cell
ately to hyperbaric units.
axons results in myelin pallor of the white matter
of the folia and of the hilum of the dentate nuclei.
Chemical weapons
DNA internucleosomal breakages are identified by in-
situ end labeling in the dentate nuclei and centromedian Prominent brainstem–cerebellar symptoms have been
nuclei of the thalamus and are associated with deg- reported in Japan in patients exposed to diphenylarsinic
eneration of the cerebellar efferent pathways (superior acid poisoning, derived from agents used as chemical
cerebellar peduncles, decussation of the superior cere- weapons (Ishii et al., 2004). These highly toxic agents were
bellar peduncles and dentatothalamic tract). Ammon’s initially developed with the goal of eliminating the will
horn and other areas susceptible to hypoxia appear of soldiers to fight (Pearson and Magee, 2002). A recent
uninjured (Bazille et al., 2005). contamination of ground water in Kamisu City (Japan)
High fever may become an emergency. Cooling of has been reported (Ishizaki et al., 2003). Typical symp-
the body and monitoring of vital functions are recom- toms include prominent ataxia, diplopia, myoclonus, as
mended. Prevention of heat stroke should not be under- well as symptoms related to oligohemia (Ishii et al.,
estimated in populations at risk, especially in the elderly. 2004). In rodents, derivatives of diphenylarsinic acid
Preventive strategies include limiting sun exposure, cause pyknosis of Purkinje neurons beginning very early
regular use of sunscreens, fluid and ion replacement, after a single administration. Oxidative and nitrosative
and acclimatization (Yaqhb and Al Deeb, 1998). stress contribute to cerebellar toxicity (Kato et al., 2007).
208 M. MANTO
Insecticides/herbicides exhibit impaired consciousness, vomiting, slurred speech,
gait ataxia, and respiratory symptoms (Tibballs, 1995;
Table 12.1 lists the conditions associated with insecticide
Tarben et al., 1998). Cerebellar deficits are reversible.
or herbicide intoxication. The cerebellum may be a
privileged target following exposure. SAXITOXIN (SHELLFISH POISONING)
Paraquat is used in agriculture as a herbicide. It is
Saxitoxin is a potent neurotoxin contaminating a mol-
structurally very close to the dopaminergic neurotoxicant
lusc (Mytilus). It binds to voltage-sensitive sodium
MPTP (1-methyl-1,2,3,6-tetrahydropyridine) (Li et al.,
channels, found at high densities in the cerebellar cor-
2005). Paraquat crosses the blood–brain barrier and is
tex (Purkinje cells, parallel fibers, basket cells) (Mourre
taken up by neural cells (Shimizu et al., 2001). It gener-
et al., 1990). Patients present with gastrointestinal and
ates oxidative stress, activates glutamatergic pathways,
neurological signs. Cerebellar deficits may be predomi-
and causes neuronal death (Shimizu et al., 2003). A toxic
nant, hence the term ataxic shellfish poisoning (Rhodes
effect on cerebellar granule neurons has been recently
et al., 1975). Patients often complain of paresthesias.
shown (Gonzalez-Polo et al., 2004). Experimentally,
Cerebellar deficits usually have a benign course.
paraquat potentiates glutamate toxicity in immature
cultures of granule cells (Stelmashook et al., 2007). CYANIDE
Deliberate self-harm by ingestion of organophosphate
Cyanide intoxication results from accidental acute
insecticides, such as dimethoate, is a common health
exposure, suicide attempt (ingestion), or from asphyxi-
problem in Sri Lanka (Fonseka et al., 2003). The poisoning
ation due to hydrocyanic fumes (Pahwa, 1997). Clinical
results in an initial life-threatening cholinergic crisis, fol-
presentation includes headache, coma, and seizures.
lowed by various neurological and psychiatric manifesta-
The mortality rate is high. Survivors may develop
tions. Cerebellar signs may appear about a week after
irreversible neurological sequelae, mainly parkinsonian
ingestion and may have a self-limiting course.
signs, postural tremor, dystonia, and dementia (Carella
Other cerebellar toxins et al., 1988). A combination of extrapyramidal and
cerebellar signs has been reported (Rosenow et al.,
EUCALYPTUS OIL
1995). Cerebellar hemorrhage and cerebellar atrophy
Intoxication follows ingestion or application of home have been observed. Cyanide interferes with oxida-
remedy for skin allergy. Children are at risk. Patients tive enzymes, GABAergic metabolism, and cGMP

Table 12.1
Cerebellotoxic insecticides and herbicides

Substance Exposure Clinical symptoms Pathological studies

Chlordecone Workers exposed to insecticides Pleural pain

Arthralgias
Tremor
Gait instability
Opsoclonus
Pseudotumor cerebri
Peripheral neuropathy
Paraquat Non-selective herbicide Neuronal degeneration in basal ganglia
Apoptosis of brain cortical cells
Apoptosis in cerebellar granule cells
Phosphine Toxic fumigant Headache
Nausea and vomiting
Cough
Paresthesias
Diplopia
Kinetic tremor
Gait difficulties
Carbon disulfide Production of cellophane Encephalopathy Diffuse neuronal degeneration in
Industrial solvent Cognitive deficits cerebral cortex and basal ganglia
Production of tetrachloride Movement disorders Loss of Purkinje cells
Pesticides Peripheral neuropathy
 TOXIC AGENTS CAUSING CEREBELLAR ATAXIAS
homeostasis. Treatment includes rest, oxygen delivery,
amyl nitrite, sodium thiosulfate, and hydroxocobalamin
(Beasley and Glass, 1998).
ENVENOMATION-RELATED
CEREBELLAR TOXICITY
SCORPIONS
Victims of scorpion envenomation exhibit local and
systemic symptoms. Local manifestations are paresthe-
sia, pain, and edema (Pardal et al., 2003). Neurological
deficits may be prominent. The majority of patients
present the classical symptom of “electric shock”,
affecting nearly 90% of the victims (Pardal et al.,
2003). Myoclonus and cerebellar ataxia are the main
deficits in some series. Ataxia may involve predomi-
nantly the upper limbs, with typical dysmetria.
Complications following scorpion sting can be severe
and even fatal (Gadwalkar et al., 2006). Cerebellar
stroke is a potential complication which should be
recognized quickly. Indeed, cerebellar infarctions may
be bilateral and extensive (Gadwalkar et al., 2006).
Stroke results from various mechanisms such as acute
hypertension, myocarditis, disseminated intravascular
coagulation, and toxin-induced vasculitis. Supportive
care and administration of antivenom serum should
be considered.
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