648940

research-article2016
TAN0010.1177/1756285616648940Therapeutic Advances in Neurological DisordersH Mitoma and M Manto

Therapeutic Advances in Neurological Disorders Review

The physiological basis of therapies for

Ther Adv Neurol Disord

2016, Vol. 9(5) 396­–413

cerebellar ataxias DOI: 10.1177/

1756285616648940

© The Author(s), 2016.

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Abstract:  Cerebellar ataxias represent a group of heterogeneous disorders impacting on

activities of daily living and quality of life. Various therapies have been proposed to improve
symptoms in cerebellar ataxias. This review examines the physiological background of
the various treatments currently administered worldwide. We analyze the mechanisms
of action of drugs with a focus on aminopyridines and other antiataxic medications, of
noninvasive cerebellar stimulation, and of motor rehabilitation. Considering the cerebellum
as a controller, we propose the novel concept of ‘restorable stage’. Because of its unique
anatomical architecture and its diffuse connectivity in particular with the cerebral cortex,
keeping in mind the anatomophysiology of the cerebellar circuitry is a necessary step to
understand the rationale of therapies of cerebellar ataxias and develop novel therapeutic
tools.

Keywords:  aminopyridines, cerebellar ataxias, motor rehabilitation, non-invasive cerebellar

stimulation, therapy

Introduction rehabilitation complements drug therapies in Correspondence to:

Hiroshi Mitoma, MD, PhD
Cerebellar ataxias (CAs) have originally been most cases. Recent studies report in particular on Department of Medical
described as being characterized by motor incoor- the efficacy of aminopyridines, acting as K+ chan- Education, Tokyo Medical
University, 6-7-1 Nishi-
dination [Manto, 2008; Bodranghien et al. 2016; nel blockers, and noninvasive cerebellar stimula- shinjyuku, Shinjyuku-ku,
Manto et al. 2012]. When persistent, CAs inter- tion in CAs [Ilg et  al. 2014]. Importantly, the Tokyo, 160-0023, Japan.
mitoma@tokyo-med.ac.jp
fere significantly with daily life activities. Although mechanisms of action of neuromodulation thera-
Mario Manto, MD, PhD
various therapies are available for CAs, treatment pies are based on physiological theories consider- Unité d’Etude du
of the underlying disease is available only for ing that the role of the cerebellum is to act as an Mouvement (UEM), FNRS,
Neurologie ULB-Erasme,
infarction/hemorrhage, metabolic/toxic disease, adaptive modulator. This modulator is assumed Brussels, Belgium
immune-mediated CAs (IMCAs) and some cer- to control timing of muscles discharges and syn- Université de Mons, Mons,
Belgium
ebellar malformations. In degenerative CAs, ther- ergy between muscles [Manto, 2008; Manto et al.
apies are missing or provide only minimal benefits. 2012]. However, a consensus on an integrated
One explanation for this important gap is that hypothesis is currently lacking [Manto, 2008;
therapies of CAs have not been developed on the Manto et al. 2012].
basis of the pathogenesis. A better understanding
of the mechanisms involved in the pathophysiology In this review, we examine the physiological back-
of degenerative CAs should clearly help the design ground of each therapy. First, we briefly summa-
of new treatments [Ilg et al. 2014]. rize the currently available treatments for each
CA. An algorithm for the diagnosis and therapy
There is no doubt that even novel therapies will of the most common CAs is proposed. We sug-
not completely abolish the clinical deficits associ- gest the concept of ‘restorable stage’ in which
ated with CAs, especially when a noticeable neu- an appropriate therapy can restore or augment
ronal loss has already occurred. Acting on residual cerebellar functions in the presence of residual
cerebellar function is thus an objective which cerebellar function. Finally, we discuss the patho-
deserves attention. In particular, neuromodula- physiological mechanisms underlying the action
tion therapies aim to reinforce residual cerebellar of neuromodulation therapies. The efficacy
function and could thus be potentially appropri- of aminopyridine, other drugs, noninvasive cere-
ate when cerebellar function is impaired. Motor bellar stimulation, and motor rehabilitation is

396 http://tan.sagepub.com
 H Mitoma and M Manto

Figure 1.  Algorithm for the diagnosis and treatment of patients with acute cerebellar ataxias. ACA/AC,
acute cerebellar ataxia/acute cerebellitis; CT, computed tomography; hemorrhage, cerebellar hemorrhage;
infarction, cerebellar infarction; injuries, cerebellar injuries; IMCA, immune-mediated cerebellar ataxia;
MRI, magnetic resonance imaging; MS, multiple sclerosis; rtPA, recombinant tissue plasmin activator;
Wernicke, Wernicke encephalopathy.

discussed from the viewpoint of cerebellar motor
control.
The aim of this study is mainly directed at a criti-
cal review of the impact of therapies on cerebellar
motor function, with an emphasis on the physiol-
ogy of the cerebellum. Possible treatment effects
on cerebellar cognition and affect are beyond the
scope of this review.
Presentation of the most common
cerebellar ataxias
Differential diagnosis on the basis of the clinical
presentation
Acute cerebellar ataxias. Figure 1 shows our
algorithm for the differential diagnosis of acute
CAs (ACAs). Cerebellar infarction, hemorrhage,
Wernicke encephalopathy, ACA/acute cerebellitis
(AC), immune-mediated CAs (IMCAs), or cere-
bellar injuries should be considered.
(1) Cerebellar stroke. Although cerebellar stroke
typically presents with a sudden onset,
some patients do not report an acute onset
and visit the hospital only a few days after
the onset of symptoms, complaining mainly
of dizziness, vertigo, or vomiting, or mild
instability. Thus, the differential diagnosis
of a gradual worsening of symptoms over a
period of a few days should also include
cerebellar stroke, in addition to Wernicke
encephalopathy, ACA/AC and IMCAs.
(2) ACA/AC. These terms are confusing.
Based on the criteria listed by Sawaishi
and Takada [Sawaishi and Takada, 2002],
ACA is defined as a self-limiting disease
caused by viral infection (especially chick-
enpox) or immunization-induced immune
mechanisms in childhood, whereas AC is
defined as a disease caused by direct inva-
sion of a pathogenic agent.
(3) IMCAs. In addition to Miller–Fisher
syndrome, some patients with IMCAs
(paraneoplastic cerebellar degeneration,
‘anti-glutamic acid decarboxylase (GAD)
antibodies associated CA) exhibit an ACA.
CAs with acute onset may also develop
in patients with multiple sclerosis (MS),
although cerebellar symptoms occurring in
isolation are not common in this disorder.
(4) Cerebellar injuries. Traumatic injury to the
posterior fossa is a heterogeneous condition

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Therapeutic Advances in Neurological Disorders 9(5)
Figure 2.  Algorithm for the diagnosis and treatment of patients with subacute, chronic or insidious cerebellar
ataxia (CA). Chiari, Chiari syndrome; IMCA, immune-mediated cerebellar ataxia; MRI, magnetic resonance
imaging; MS, multiple sclerosis.
which may cause cerebellar hematoma,
epidural hematoma or subdural hematoma.
Symptoms of ataxia are masked by an
impaired consciousness in many of patients.
Posterior fossa trauma may be associated
with a rapid neurological decline, which
results in a high rate of morbidity compared
with supratentorial trauma [Nixon et  al.
2014]. Thus, the importance of early iden-
tification is stressed [Nixon et al. 2014].
Imaging studies [computed tomography (CT)
and magnetic resonance imaging (MRI)] are used
for the differential diagnosis of the above entities.
In cerebellar stroke and cerebellitis, the swollen
cerebellum sometimes compresses the brainstem
or the fourth ventricle, resulting in obstruction of
cerebrospinal fluid (CSF). Thus, the presence or
absence of hydrocephalus should be carefully
determined.
Subacute, chronic, or insidious cerebellar ataxias.  Malformations
Figure 2 shows our algorithm for the differential
diagnosis of subacute, chronic, or insidious CAs.
After checking for an exposure to certain toxic
agents, such as ethanol, organic mercury, organic
solvent (toluene, thinner), certain medications
398 http://tan.sagepub.com
(e.g. phenytoin, metronidazole) and after exclud-
ing physical signs of hypothyroidism, imaging
studies (e.g. MRI) are conducted to look for a dis-
placement of the tonsil, a tumor, an inflammation
or a cerebellar atrophy. In general, the presence of
cerebellar atrophy is suggestive of degenerative
CAs. The severity of cerebellar atrophy correlates
with the degree of CAs. Further genetic analysis
should be conducted for the differential diagnosis
of autosomal dominant CAs (ADCAs) and auto-
somal recessive CAs. In the case of pure cerebel-
lar atrophy or multiple systemic atrophy, CA is
sporadic (although some cases of pure cerebellar
atrophy may have a genetic origin). The presence
of mild cerebellar atrophy relative to the clinical
presentation of CAs is often indicative of IMCAs.
Serological tests, including measurement of auto-
antibodies, should be performed for the diagnosis
of the subtype of IMCAs.
Decompressive surgery (posterior fossa decom-
pression, with or without spinal laminectomy) is
necessary in patients with Chiari syndrome who
present with compression of the brainstem by cer-
ebellar tonsil displacement [Greenberg, 2006].

Vascular diseases
Cerebellar infarction. The infarct core is usually
surrounded by the hypoxic area (i.e. ischemic
penumbra). The ischemic penumbra contains
electrically silent neurons that undergo cell death
without salvage, and provides the rationale for
immediate thrombolytic therapy [Astrup et  al.
1981]. The standard therapy is intravenous injec-
tion of recombinant tissue plasmin activator
within 4.5 h from the onset of infarction [Hacke
et al. 2008]. However, there are two problems in
the management of cerebellar infarcts. First, early
diagnosis within the 4.5 h window is sometimes
difficult, especially when the main complaints are
dizziness, vertigo, and vomiting [Wijdicks et  al.
2014]. Without careful attention to eye move-
ments, speech, and walking instability, the chance
for thrombolytic therapy might be missed. Sec-
ond, poststroke cerebellar swelling can compress
the brainstem sometimes with a delay, resulting in
reduced conscious level and appearance of brain-
stem signs, such as loss of corneal reflex and mio-
sis [Wijdicks et  al. 2014]. A large retrospective
study of 84 patients with extensive cerebellar
infarction showed that 40% of these patients
required craniotomies and 17% required ventric-
ular drainage [Jauss et  al. 1992]. After cranioto-
mies and drainage, 74% of these patients showed
good outcome [Jauss et  al. 1992]. Suboccipital
craniotomy with dural expansion is recommended
for cerebellar infarcts with wide areas of edema
[Wijdicks et al. 2014].
Cerebellar hemorrhage.  Some patients with cer-
ebellar hemorrhage are admitted in a state of
coma, while others show deterioration of con-
sciousness a few days after the onset [Jensen and
St Louis, 2005]. The main features that predict
clinical deterioration include systolic blood pres-
sure at admission of over 200 mmHg, pinpoint
pupils, abnormal corneal or occulocephalic
reflexes, extension of a hemorrhage into the ver-
mis, a hematoma greater than 3 cm, visible brain-
stem compression, presence of intraventricular
hemorrhage, upward herniation, and acute hydro-
cephalus [Jensen and St Louis, 2005]. In 1999,
the American Stroke Association Guidelines rec-
ommended surgical removal of the hemorrhage in
patients with a hematoma measuring over 3 cm in
size in case of neurological deterioration, and also
in patients with brainstem compression or hydro-
cephalus caused by ventricular obstruction. The
size requirement of the hematoma (i.e. >3 cm)
was abandoned in the 2010 revised guidelines
[Morgenstern et al. 2010].
http://tan.sagepub.com 399
H Mitoma and M Manto
Common problems underlying therapies for cere-
bellar stroke. The main purpose of cerebellar
stroke therapy is to avoid damage to neighboring
normal structures surrounding the site of infarc-
tion or hemorrhage, such as the ischemic penum-
bra or brainstem, so as to preserve the maximal
potential for reversibility. In particular, the
expanding edema or hematoma can potentially
compress brainstem tracts or the fourth ventricle,
the obstruction of which causes acute hydroceph-
alus. Both conditions can lead to coma and death.
Thus, repeated neurological examination and CT
or MRI are also recommended within the 72–96 h,
post stroke period [Wijdicks et al. 2014].
Metabolic and toxic diseases
Hypothyroidism, Wernicke encephalopathy, Nie-
mann-Pick disease type C, and cerebrotendinous
xanthomatosis. In the case of hypothyroidism-
induced CA, thyroid hormone (thyroxine) is
replenished [Rowland, 2005]. Wernicke encepha-
lopathy may or may not be related to alcohol
abuse [Scalzo et  al. 2015]. It is widely accepted
that clinical suspicion of vitamin B1 deficiency
requires an immediate treatment with vitamin B1
[Rowland, 2005; Scalzo et al. 2015]. Whole blood
sample should be taken before the commence-
ment of such therapy for definite diagnosis.
Niemann-Pick disease type C is a rare disorder
characterized by mutations in NPC1 or 2 gene,
leading to an intracellular lipid-trafficking deficit
with secondary accumulation of glycosphingolip-
ids [Patterson et  al. 2007]. A randomized con-
trolled study showed that miglustat, an inhibitor
of glucosylceramide synthesis, improves saccadic
eye movements, swallowing capacity, and ambu-
latory capacity [Patterson et al. 2007]. Recently,
2-hydroxypropyl-beta-cyclodextrins (HPBCD)
has gained attention as a promising candidate
[Camargo et  al. 2001; Nusca et  al. 2014; Vite
et  al. 2015]. HPBCD increases the solubility of
poorly water-soluble compounds such as choles-
terol [Vite et al. 2015]. Intrathecal administration
of HPBCD reduces ataxic symptoms and cell loss
in affected cats [Vite et al. 2015].
Cerebrotendinous xanthomatosis is another rare
disease caused by mutations in the CYP27A1
gene, a converting enzyme of cholesterol to cholic
and chenodeoxycholic acids [Keren and Falik-
Zaccai, 2009; Nie et al. 2014]. The reduced level
of cholic and chenodeoxycholic acids elicits, in
turn, a lack of cholesterol synthesis, resulting in a
Therapeutic Advances in Neurological Disorders 9(5)
Table 1.  Treatment of neoplasms within or surrounding the cerebellum.
Location WHO classification
Within the cerebellum
 Children Pilocytic astrocytoma Grade I
  Ependymoma Grade II, III
  Medulloblastoma Grade IV
 Adults Hemangioblastoma Grade I
  Metastatic tumor
Cerebellopontine angle
 Adults Vestibular schwannoma Grade I
  Meningioma Grade I
  Epidermoid cyst Grade I
WHO, World Health Organization.
high level of serum cholestanol and accumulation
of lipids in the central nervous system and con-
nective tissues [Keren and Falik-Zaccai, 2009]. It
is established that replacement therapy using che-
nodeoxycholic acid improves neurological symp-
toms and contributes to a better prognosis [Nie
et al. 2014]. Early diagnosis and long-term treat-
ment are recommended in these two autosomal
recessive inherited diseases [Nie et al. 2014].
Toxic diseases.  Exposure to toxic agents, such as
ethanol, organic mercury, organic solvent (tolu-
ene, thinner) and certain medications (e.g. phe-
nytoin, metronidazole) can induce CAs. The first
line of therapy is to remove the causative toxic
agent to prevent clinical worsening or cerebellar
atrophy [Rowland, 2005].
Neoplasms
Primary neoplasms causing CAs can be classified
into two groups: tumors that grow within the cer-
ebellum and tumors that grow outside the cerebel-
lum (mainly the cerebellopontine angle) with
compression of the cerebellum (Table 1)
[Greenburg, 2006]. Low-grade tumors [heman-
gioblastoma, pilocytic astrocytoma, vestibular
schwannoma, meningioma, and epidermoid cyst;
World Health Organization (WHO) grade I], with
no invasion of the cerebellar tissue, can be surgi-
cally excised. However, ependymoma (WHO
grade II or III) requires surgical excision followed
400 http://tan.sagepub.com
Therapy
 
Surgical excision of the tumor
Surgical excision of the tumor, followed
by radiotherapy
Surgical excision of the tumor,
followed by radiotherapy. Additional
chemotherapy for high-risk patients
Surgical excision of the tumor
Radiotherapy. In case of a solitary tumor,
surgical excision can be considered
 
Surgical excision/Radiosurgery of the
tumor
Surgical excision/Radiosurgery of the
tumor
Surgical excision/Radiosurgery of the
tumor
sometimes by radiotherapy [Greenburg, 2006].
Primary high-grade tumors (medulloblastoma;
WHO grade IV) also require the combination of
surgery and radiotherapy, and even chemother-
apy, especially in high-risk cases [Greenburg,
2006].
In contrast, surgery is difficult in metastatic
tumors, except in cases of solitary tumors, espe-
cially since chemotherapy is usually ineffective.
Thus, the first-line treatment is radiotherapy
[Greenburg, 2006].
Acute cerebellar ataxia and acute cerebellitis
ACA usually follows a self-limited benign course
without complications. In contrast, AC is poten-
tially associated with cerebellar swelling, which
may result in compression of the brainstem or
obstructive hydrocephalus [Sawaishi and Takada,
2002]. Various bacteria and viruses are known to
cause AC, including Epstein–Barr virus (EBV),
Herpes simplex virus (HSV), Varicella zoster virus
(VZV), respiratory syncytial (RS) virus, Coxsackie
B3 virus, rubella virus, Listeria, Mycoplasma
pneumoniae, and Coxiella burnetti [Sawaishi and
Takada, 2002], although no microorganism is
identified in some cases [Sawaishi and Takada,
2002]. AC is caused by direct invasion of spe-
cific microorganisms and requires immediate
treatment with antiviral drugs (e.g. acyclovir for
HSV and VZV) or antibiotics (e.g. ampicillin for
 H Mitoma and M Manto

Table 2.  First-line immunotherapy for each subtype of immune-mediated cerebellar ataxia.

Multiple sclerosis
  Induction: oral PSL or mPSL
  Maintenance: interferon β
Gluten ataxia
 Diagnosis: autoantibodies: anti-gliadin Ab, anti-tranglutaminase 2, 6 Abs
  Induction and maintenance therapies: strict gluten-free diet
 Immunosuppressants or IVIg for patients who show no improvement or are negative for gluten-related
antibodies
Paraneoplastic cerebellar degeneration
 Diagnosis: autoantibodies: Anti-Yo, Hu, Tr, CV2, Ri, Ma2, VGCC, SOX1, ZIC4, PCA2 Abs
 Early removal of neoplasm must be the first objective of treatment. Induction therapy as soon as possible
(mPSL, IVIg, immunosuppressants, or plasma exchange). Discussion according to associated Abs. Long-
term oral PSL, IVIg, immunosuppressants for maintenance therapy
Anti-GAD Abs-associated cerebellar ataxia
 Diagnosis: autoantibodies: anti-GAD 65 Ab
  Induction therapy: mPSL, IVIg, immunosuppressants, plasma exchange, or rituximab
  Maintenance therapy: continuous oral PSL, IVIg, immunosuppressants, or rituximab
Abs, antibodies; mPSL, intravenous methylprednisolone; oral PSL: oral prednisolone; IVIg: intravenous immunoglobulins.

Listeria, minocycline for Coxiella burnetti)
[Sawaishi and Takada, 2002].
Deterioration of consciousness accompanied by
diffuse cerebellar swelling should be treated imme-
diately with mannitol or glycerol and corticoster-
oids [Sawaishi and Takada, 2002]. Development
of obstructive hydrocephalus requires immediate
surgical treatment (ventricular drainage and/or
suboccipital craniotomy with dural expansion)
[Sawaishi and Takada, 2002].
Immune-mediated cerebellar ataxias
MS is a representative disease of IMCAs. The
standard treatment for MS is an induction ther-
apy using corticosteroids, followed by mainte-
nance therapy using interferon β [Weier et  al.
2015]. Interestingly, new guidelines for the treat-
ment of other IMCAs have been proposed
recently [Mitoma et  al. 2015, 2016]. This cate-
gory includes gluten ataxia, paraneoplastic cere-
bellar degeneration, anti-GAD antibodies
associated CA, and steroid-response IMCA asso-
ciated with antithyroid antibodies. These diseases
can be differentiated by their clinical course and
specific associated autoantibodies. When CAs are
triggered by certain known antigenic stimulants,
priority should be given to treatment of the under-
lying condition [Mitoma et al. 2015]. For exam-
ple, gluten-free diet in gluten ataxia and surgical
removal of the neoplasm in paraneoplastic cere-
bellar degeneration. Progression of CAs after
treatment of the underlying condition requires
immediate immunotherapy. However, when CAs
are not triggered by any other condition (e.g.
anti-GAD antibodies associated CA, and steroid-
response IMCA associated with antithyroid anti-
bodies), induction immunotherapy is provided
first to minimize CAs, followed by maintenance
immunotherapy to prevent relapse [Mitoma et al.
2015]. Various combinations of immunothera-
pies have been used, ranging from intravenous
immunoglobulins, corticosteroids, immunosup-
pressants, plasmapheresis, and rituximab,
depending on the subtype of IMCA (Table 2)
[Mitoma et al. 2015].
Degenerative cerebellar ataxias
Friedreich’s ataxia, a representative sensory ataxia,
is caused by lack of frataxin. This mitochondrial
protein is involved in iron-sulfur cluster synthesis
[Stemmler et  al. 2010], which provides clues for
therapy [Ilg et al. 2014]. Ataxia with isolated vita-
min E deficiency is characterized by a deficit in
α-tocopherol transfer protein (a protein involved
in intracellular transport of α tocopherol). Patients
develop sensory ataxia with loss of propioception
and retinitis pigmentosa [Yokota et al. 1997]. Oral
supplementation of vitamin E was reported to halt
the progression of neurological symptoms and reti-
nitis pigmentosa [Yokota et al. 1997].
In contrast to sensory ataxias, therapies directed
against the cause of CAs have been disappointing

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Therapeutic Advances in Neurological Disorders 9(5)
in pure cerebellar degeneration [Ilg et al. 2014].
However, one therapeutic approach could be
effective in the Cuban type of spinocerebellar
ataxia type 2 (SCA2), which is associated with low
serum and CSF zinc concentrations [Velázquez-
Pérez et al. 2011]. In this regard, a double-blind,
placebo-controlled study shows that ZnSO4 sup-
plementation increased Zn level in the CSF and
resulted in a simultaneous improvement of the
subscore for gait, posture, and alternating hand
movements as well as a reduction of saccadic
latency as compared with placebo on the Scale
of Assessment and Rating of Ataxia (SARA)
[Velázquez-Pérez et  al. 2011]. Based on these
findings, checking plasma and CSF zinc concen-
trations is recommended in cases with pure cere-
bellar degeneration [Ilg et al. 2014].
Cerebellar injuries
Due to the progressive and worse prognosis, non-
surgical management should be considered only
when patients are fully consciousness and poste-
rior fossa lesions are small with little or no mass
effect [Nixon et  al. 2014]. Immediate surgical
removal of hematoma is recommended in the case
of an epidural hematoma greater than 30 cm3, a
subdural hematoma greater than 10 mm, or an
obstruction or compression of the fourth ventricle
[Nixon et al. 2014].
Prospective problems in treatment directed
against the underlying disease
In contrast to CAs associated with vascular, toxic
or metabolic diseases, and AC, certain subtypes
of IMCAs (paraneoplastic cerebellar degenera-
tions and chronic type of anti-GAD antibodies
associated CA) and degenerative CAs cannot be
prevented. However, new types of autoantibodies
that target intracellular signal transduction have
been discovered [Mitoma et al. 2015]. Details of
the mechanisms of cell death in degenerative CAs
have also been published in recent years [Ilg et al.
2014]. These findings could provide new clues to
keep cerebellar damage at a minimum level in
each disease.
Interestingly, a cross correlation of neurodegen-
eration with immune deficiency has been recently
reported. In addition, interposed nucleus neurons
may modulate the immune system via the hypo-
thalamus [Lu et al. 2015]. As a result, degenera-
tion of the nuclear neurons may have a direct
impact on the immune system.
402 http://tan.sagepub.com
Neuromodulation therapy using
aminopyridines
The K+ channel blockers aminopyridines [4-ami-
nopyridine (4-AP), 3, 4-diaminopyridine (3,
4-DAP)], have been used in patients with epi-
sodic ataxia 2 (EA2), in patients exhibiting a
downbeat nystagmus (DBN), and in patients
with other degenerative CAs.
Episodic ataxia 2
EA2 is characterized by attacks of ataxia [Jen et al.
2007]. Acetazolamide (a carbonic anhydrase inhib-
itor) decreases or attenuates such attacks in 50–70%
of the patients [Strupp et al. 2011]. However, this
effect was later found to wane with time in patients
on long-term treatment [Strupp et  al. 2011].
Furthermore, the adverse effects of acetazolamide
(renal tubular acidosis with nephrolithiasis, hyper-
hidrosis, paresthesia, and muscle stiffening) also
limit its clinical use [Strupp et al. 2011].
Clinical evidence.  Several case reports and retro-
spective studies have shown that 4-AP prevents
CA attacks [Strupp et  al. 2004, 2008; Claassen
et  al. 2013]. Strupp and colleagues conducted a
randomized, double-blind, and crossover clinical
trial of 10 patients treated with EA2 and provided
convincing evidence for the efficacy of 4-AP
[Strupp et al. 2011]. Before treatment, the patients
presented with episodic ocular ataxic symptoms,
sometimes accompanied by limb ataxia and ataxic
gaits. Treatment with 4-AP (5 mg three times
daily) significantly reduced the frequency of epi-
sodic CAs (placebo: 6.5 attacks/month; 4-AP:
1.65 attacks/month, p = 0.03). Furthermore,
4-AP tended to reduce the duration of the attack
(from 13.65 h after placebo to 4.45 h after 4-AP),
although the difference was not statistically sig-
nificant (p = 0.08). 4-AP also significantly reduces
the severity of attacks, as determined by the Ves-
tibular Disorders Activities of Daily Living Scale.
Mechanisms of action 
Aminopyridines do not improve cerebellar
synaptic transmission. A deficit in P/Q-type Ca2+
channels was previously assumed to impair cere-
bellar synaptic transmission, leading to the devel-
opment of CAs [Alvina and Khodakhah, 2010].
Specifically, it was thought that a decrease in
P/Q-type Ca2+ current reduces the inhibition of
deep cerebellar nuclei (DCN) in EA2 and that
aminopyridines could restore the depressive input
on DCN and thus improve CAs [Glasauer et al.
2005]. Although changes in cerebellar synaptic

transmission were evident in some animal models
of EA2, they are relatively minor, presumably due
to compensation by other Ca2+ channels [Mat-
sushita et  al. 2002; Ovsepian and Friel, 2008].
Alvina and Khodakhah also demonstrated that at
therapeutic concentrations, 4-AP did not increase
the spontaneous activities of Purkinje cells (PCs)
or the release probability at parallel fiber–PC
and PC–DCN neuron synapses [Alvina and
Khodakhah, 2010].
Aminopyridines restore distorted precision of
PC pacemaking. The P/Q-type Ca2+ current is
coupled with activation of KCa channels [Wom-
ack et al. 2004]. However, KCa channels limit the
maximum PC firing rate by contributing to slow
afterhyperpolarization, which plays a crucial role
in the regulation of spontaneous firing [Womack
and Khodakhaha, 2003]. Thus, in P/Q-type volt-
age-gated Ca2+ channel mutations associated with
EA2, impaired precision of intrinsic PC pacemak-
ing is expected. This assumption was clearly dem-
onstrated in experiments involving ataxic mutation
mice [Walter et  al. 2006]. Distorted pacemaking
was associated with lesser activation of KCa with
each action potential, leading to a lower ampli-
tude afterhyperpolarization and reduced potas-
sium conductance during interspike intervals.
In addition, the authors reported that 1-ethyl-
2-benzimidazolinone (EBIO), an activator of KCa
channels, restored the regularity of PC firing,
resulting in improvement of ataxic movements in
mutant mice.
Alvina and Khodakhah demonstrated that thera-
peutic concentrations of 4-AP blocked the Kv1
family of K+ channels, leading to a prolongation
of the duration of action potentials and an increase
in afterhyperpolarization, which resulted in resto-
ration of pacemaking precision in PCs of mice
with P/Q-type Ca2+ channel mutations [Alvina
and Khodakhah, 2010]. The mechanisms of
action of 4-AP are currently explained as follows:
4-AP-induced blockade of the Kv1 family of K+
channels widens action potentials; the broader
action potential induces larger Ca2+ influx, which
compensates the reduced P/Q-type Ca2+ current
density associated with EA2 mutation; and
restored Ca2+ currents result in additional activa-
tion of Ca2+-dependent K+ conductance [Alvina
and Khodakhah, 2010]. Importantly, 4-AP-
induced restoration of pacemaking precision cor-
related with improvement of ataxic movements in
P/Q-type Ca2+ channel mutant mice [Alvina and
Khodakhah, 2010].
http://tan.sagepub.com 403
H Mitoma and M Manto
Figure 3.  A scheme of cerebellar neural circuits.
CF, climbing fiber; GABAergic IN, GABAergic interneuron;
GC, granule cell; MF, mossy fiber; PC, Purkinje cell; PF,
parallel fiber. +, excitation (excitatory neurons: open
circles); –, inhibition (inhibitory neurons: filled circles).
Restoration of PC pacemaking could improve
CAs. Timing is essential for the production of
rapid movements and coordination of dynamic
interaction in multijoint movements [Manto et al.
2012; Ivry, 1997]. Certain ataxic signs are due to
a deficit in the control of timing [Manto, 2008;
Manto et  al. 2012]. The physiological assump-
tion that the cerebellum acts as a time control
machine originates from Braintenberg who com-
pared the cerebellar cortex to a clock with a sys-
tem of delay lines (corresponding anatomically to
parallel fibers) [Braitenberg and Atwood, 1958].
Llinās proposed that rhythmic activities of the
inferior olive nucleus synchronize a group of PC
(via the climbing fibers) so as to fine tune timing
(see Figure 3) [Llinas, 2009]. Recently, a tempo-
ral processing within the cerebellum has also been
proposed [Manto et al. 2012; Ivry, 1997].
A series of studies on EA2 and aminopyridines
showed that the accuracy of pacemaking in PCs
correlated with the capacity of coordination in
P/Q-type voltage-gated Ca2+ channel mutation
mice [Alvina and Khodakhah, 2010; Walter et al.
2006]. The correlation between the accuracy of
PC pacemaking and coordination could be
explained by the notion of temporal processing.
Thus, it is argued that a distorted PC pacemak-
ing, which potentially serves as an inappropriate
clock [Walter et al. 2006], might impair cerebellar
timing control so as to result in CAs, although the
exact mechanism in the cerebellar circuitry
remains unclear. Clinically, these studies have
proved that the function of PC pacemaking can
be a therapeutic target in EA2.
Therapeutic Advances in Neurological Disorders 9(5)
Downbeat nystagmus
DBN is the most frequent form of acquired per-
sistent fixation nystagmus [Baloh and Spooner,
1981; Pierrot-Deseilligny and Milea, 2005]. It
consists of two phases: a spontaneous upward
drift and a fast downward phase during gaze
straight ahead [Baloh and Spooner, 1981; Pierrot-
Deseilligny and Milea, 2005]. DBN occurs not
only in patients with degenerative CAs, but also
in those with infarction, Chiari syndrome, MS,
and IMCAs [Baloh and Spooner, 1981; Pierrot-
Deseilligny and Milea, 2005; Kalla et al. 2007].
Clinical evidence.  Aminopyridines have been
reported to improve DBN in patients with various
pathologies [Kalla et  al. 2007; Strupp et  al. 2003;
Kalla et al. 2004]. Strupp and colleagues conducted
a placebo-controlled, double-blind study to exam-
ine the effects of 3, 4-DAP (20 mg/day) on DBN in
17 patients, including five patients with degenera-
tive CAs, three patients with infarction, one patient
with Arnold–Chiari syndrome, and eight patients
with idiopathic DBN [Strupp et  al. 2003]. They
reported that 3, 4-DAP reduced the mean slow
phase velocity from 7.2 ± 4.2° to 3.5 ± 2.5° in
DBN. Kalla and colleagues examined the effects of
4-AP (at a dose of up to 50 mg/day) in 15 patients
with DBN (four patients with degenerative CAs,
five patients with idiopathic DBN, and six patients
with other etiologies) and healthy controls [Kalla
et al. 2007]. Their results also confirmed that 4-AP
decreased DBN during gaze straight ahead in 12 of
the 15 patients, and especially reduced spontane-
ous upward drift in four patients with degenerative
CAs. They concluded that 4-AP improved fixation
by restoring gaze-holding ability.
Mechanisms of action.
Restoration of flocculus/paraflocculus function.
Vestibulocerebellar lesions are thought to be the
main etiology of DBN [Pierrot-Deseilligny and
Milea, 2005; Kalla et al. 2007]. Previous studies
in monkeys showed that bilateral ablation of the
flocculus and paraflocculus elicited DBN [Zee
et al. 1981]. Furthermore, in a patient with DBN
and CAs, Bensea and colleagues demonstrated
reduced cerebral glucose metabolism bilaterally
in the region of the cerebellar tonsil and flocculus/
paraflocculus and that treatment with 15 mg/day
of 4-AP lessened hypometabolism and simultane-
ously improved DBN [Bensea et al. 2006]. Taken
together, floccular and parafloccular dysfunction
seems to be responsible for the development of
DBN; 4-AP successfully restores ocular coordina-
tion in these areas.
404 http://tan.sagepub.com
No clear mechanism for DBN improvement at
neural circuitry level. It has been assumed that
reinforcement of PC excitability in the floccu-
lus/paraflocculus may improve DBN [Kalla et al.
2007]. However, taking into consideration the
finding that 4-AP at therapeutic concentrations
fails to increase output [Alvina and Khodakhah,
2010], it is likely that the mechanism of action
of 4-AP is more complex. While the neural
mechanism underlying DBN remains obscure,
several explanations have been proposed for the
spontaneous upward drift: tonic imbalance of the
central vestibular pathway in vertical eye move-
ments [Baloh and Spooner, 1981]; imbalance of
the vertical smooth pursuit tone [Zee et al. 1981];
defective function of the neural velocity-to-
position integrator for gaze holding [Glasauer et al.
2003]; and on-directions asymmetry (only ~10%
of PCs have on directions for upward gaze veloc-
ity) [Marti et al. 2005]. Still, further physiological
in vitro and in vivo studies are necessary to identify
the exact cerebellar dysfunctions that elicit DBN,
and the mechanisms of action of aminopyridines
associated with restoration of these changes.
Degenerative cerebellar ataxias
Efficacy of aminopyridines in this group of CAs
remains controversial. Randomized, double-
blind studies are lacking. The efficacy of 4-AP at
10 mg twice daily was examined in 16 patients
with SCA1, 3, and 6 [Giordano et  al. 2013].
Significant improvement was observed in the 8 m
walking test and speech rate test, but not in the
SARA score and nine-hole peg test. The authors
concluded that 4-AP can induce short-term
(14 days) improvement in CAs. In contrast, oth-
ers reported that, while treatment with 3, 4-DAP
at 20 mg twice daily improved DBN, it had no
beneficial effects on other CAs in 10 patients
with SCA6 and 5 patients with 16q22.1-linked
ADCA [Tsunemi et  al. 2010]. The same treat-
ment also had no effect on international coopera-
tive ataxia rating scale (ICARS) and postural
sway. The contradictory results might be due to
differences in the effects of 4-AP on each clinical
cerebellar sign. In this regard, Schniepp and col-
leagues reported that 4-AP at 5 mg three times
daily improved gait variability in stepping in 31
patients with various pathologies, without
improvements in gait speed or cadence, both of
which reflect stability [Schniepp et al. 2012]. In
agreement with the observed variability in the
efficacy of 4-AP on different clinical cerebellar
signs, it is noteworthy that stepping and stability

are controlled separately and independently in
the cerebellum [Ienaga et al. 2006]. Further ran-
domized, double-blind studies are necessary to
determine the effects of aminopyridines on spe-
cific aspects of CAs.
Neuromodulation therapy using other drugs
Clinical evidence
Several studies have reported the efficacies of
other drugs on degenerative CAs (Table 3). For
example, a few randomized double-blind and
placebo-controlled studies have shown signifi-
cant improvements in clinical ataxic scales after
treatment with riluzole, an agonist of small con-
ductance potassium channel and an inhibitor of
glutamate release, and varenicline, an agonist
of α4β2 nicotinic acetylcholine receptors
[Ristori et  al. 2010; Romano et  al. 2015;
Zesiewicz et al. 2012]. Furthermore, two open-
label studies showed that acetyl-DL-leucine
and acetazolamide improved SARA score and
Ataxic Rating Scale, respectively [Strupp et al.
2013; Yabe et al. 2001]. However, the extent of
score change was not large enough to improve
the daily lives of patients. Thus, the efficacies of
these drugs in CAs, especially in terms of
improvements in activities of daily life, need to
be confirmed in large randomized double-blind
and placebo-controlled studies.
Mechanisms of action
Mechanisms of actions are not fully understood.
The efficacies of these drugs seem to be mediated
through multiple mechanisms [Ilg et  al. 2014;
Romano et al. 2015]. Of these diverse and het-
erogeneous actions, the following two assump-
tions form the basis of a plausible working
hypothesis: adjustment of neuronal activities in
DCN; and augmentation of cerebellar functions
through modulatory afferent systems (cholinergic
afferents).
It is assumed that riluzole restores an exaggerated
firing rate of CN neurons [Ilg et al. 2014]. Since
CN neurons receive profound inhibitory outputs
from the cerebellar cortex via PCs, degeneration of
PCs could elicit hyperactivities in CN neurons (see
Figure 3). However, recent physiological studies
have described a critical role for the neuronal activ-
ity in the dentate nucleus (DN, one of DCN) in
coordinating the control of movements of the
upper limbs [Ishikawa et al. 2014]. For example,
http://tan.sagepub.com 405
H Mitoma and M Manto
the release of DNs generated by reduced inhibition
from PCs, that is disinhibition, facilitates the exe-
cution of wrist movements, while suppression of
the DNs by increased PC activity contributes to
the stabilization of proximal muscles and improves
task performance (see Figure 3). Thus, exagger-
ated activities of CN neurons might interfere with
the production of appropriate cerebellar outputs
using disinhibition or inhibition circuit mecha-
nism, leading to limb CA [Ishikawa et  al. 2014].
Under these conditions, adjustment of DCN neu-
ronal activity could be a therapeutic target (see
Figure 3). Similarly, acetyl-DL-leucine modulates
the activities of ventral vestibular neurons [Vibert
and Vidal, 2001], which might contribute to
adjustment of neural activity in the vestibular cer-
ebellar cortex.
Varenicline might also facilitate cerebellar func-
tions. Although the cerebellum receives relatively
few cholinergic projections, fibers originating from
the vestibular nuclei terminate in the nodulus and
ventral uvula and use acetylcholine as neurotrans-
mitter or coneurotransmitter [Jaarsma et al. 1997].
Application of carbachol, a nicotinic and mus-
carinic receptors agonist, in the rabbit flocculo-
nodular lobe increased the amplitude of the
vestibulo-ocular reflex [Tan and Collewjin, 1991].
These physiological findings coincide with the
clinical finding of varenicline-induced improve-
ment in gait scores [Zesiewicz et al. 2012].
Summary for anti-cerebellar ataxia
medications
The results of experimental and clinical studies
on EA2 suggest that distortion of PC pacemaking
is a potential therapeutic target in CAs.
Aminopyridines restore the pacemaking and
result in clinical improvement of CAs in patients
with EA2. However, the efficacy of aminopyri-
dines in CAs remains controversial, with the
exception of the clinical signs of DBN and step-
ping irregularities in gaits. Several placebo-
controlled clinical trials are currently underway to
determine the therapeutic effects of a sustained
form of 4-AP in patients with EA2 and patients
with ataxic gaits [Ilg et al. 2014].
In EA2, mutations in the P/Q-type voltage-gated
Ca2+ channel elicit KCa channel dysfunction,
leading to distortion of PC pacemaking. Thus,
aminopyridines restore specific etiology itself
(P/Q-type-voltage-gated Ca2+–KCa channels–PC
pacemaking system) in EA2. In contrast, in
Therapeutic Advances in Neurological Disorders 9(5)

Table 3.  Drug trials in patients with degenerative cerebellar ataxias.

Drug Study, study design
Riluzole Ristori et al. [2010]
Randomized, double-
blind, placebo-
controlled study
Riluzole Romano et al. [2015]
Randomized, double-
blind, placebo-
controlled study
Varenicline Zesiewicz et al. [2012]
Randomized, double-
blind, placebo-
controlled study
Acetyl-DL- Strupp et al. [2013]
leucine Open-label study
Acetazolamide Yabe et al. [2001]
Open-label study
ICARS, International Cooperative Ataxia Rating Scale; SARA, Scale of Assessment and Rating of Ataxia.
Patients, etiologies Daily dose, Outcome, significant improvement
duration
40 patients 50 mg twice daily Significantly higher number of
Different etiologies for 8 weeks patients with five-point ICARS score
drop in riluzole group
Improvement was noted in
subscore of static function, kinetic
function, and dysarthria
55 patients 50 mg twice daily Decrease in SARA score (by 1.02 ±
38 degenerative for 12 months 2.15) was noted in 14 of 28 (50%)
CAs (different patients of the riluzole group
etiologies), 19 compared with 3 of 27 (11%) of the
Friedreich ataxia placebo group
20 patients 1 mg titration for Improvements were noted in
SCA3 4 weeks SARA subscores of gait, stance,
1 mg twice daily rapid alternating movements, and
for 8 weeks also in timed 25 ft walk and Beck
Depression Inventory scores
13 patients 5 g/day for 1 SARA score decreased from 16.1 ±
Different etiologies week 7.1 to 12.8 ± 6.8. Improvements were
noted in subscores of gait, finger-to-
nose-test, heel-to-shin-test, finger
chase, rapid alternating movements,
and speech. Improvements were
also noted in 8 m walking time,
9-Hole-Peg test, the number of
‘’PATA’’ repetition over 10s (PATA
rate), and quality of life scale
9 patients 250–500 mg/day Improvements were noted in
SCA6 for 22 months subscores of gait and posture.
Kinetic movements decreased in
Ataxia Rating scale. The amplitude
of body sway also decreased

degenerative CAs, aminopyridines are expected Noninvasive cerebellar stimulation

to reinforce a number of lost cerebellar functions
mainly by potentiation of one cerebellar element,
PC pacemaking, alone. Interestingly, nystagmus
and gait stepping, which improve following treat-
ment with aminopyridines, share common
rhythm-related properties. Taken together, the
difference in therapeutic roles might explain the
difference in efficacies of aminopyridines in EA2
and degenerative CAs.
So far, excepted for aminopyridines, there is no
convincing evidence for any therapeutic effects at
activities of daily life level for other drugs.
However, few clinical data suggest potential effi-
cacies in adjustment of CN neuronal activities (an
element underlying cerebellar outputs) and acti-
vation of cholinergic facilitative afferents. Further
studies should be conducted.
Clinical evidence
The anatomical location of the cerebellum below
the skull is particularly well suited for noninvasive
electrical stimulation and, therefore, it is not sur-
prising that several trials are ongoing in various
forms of CAs.
Benussi and colleagues have studied the effects
of a single session of anodal transcranial direct
current stimulation (anodal tDCS) in 19 patients
with ataxia in a double-blind, randomized, sham-
controlled study [Benussi et  al. 2015]. The
authors studied clinical scores (SARA, ICARS)
as well as the nine-hole peg test, and the 8 m
walking time. The authors found a positive effect
in terms of performances compared with the
sham trial.

406 http://tan.sagepub.com

In two patients presenting with SCA2, the combi-
nation of tDCS of the cerebellum and the motor
cortex (tCCDCS: transcranial cerebello-cerebral
DC stimulation) was associated with a reduction
of postural or action tremor as well as hyperme-
tria [Grimaldi et al. 2014b]. An effect on the tim-
ing of antagonist muscle commands was observed.
Despite these positive effects on ataxia, we are still
lacking rigorous large-scale clinical trials. Given
the heterogeneity of CAs, this is mandatory.
Mechanisms of action
There is a consensus that both transcranial mag-
netic stimulation (TMS) and tDCS can effec-
tively influence cerebellar functions in the motor
and cognitive domains [Grimaldi et al. 2014a]. In
the motor domain, effects on motor adaptation
and learning, visually guided tracking tasks, and
motor surround inhibition have been observed.
For the cognitive operations, effects on verbal
working memory, semantic associations and pre-
dictive language processing have been observed.
Both TMS and tDCS tune the excitability of the
cerebellar cortex, which impacts on the degree of
inhibition of cerebellar nuclei. Applying TMS
over the cerebellum induces changes in the
amplitudes of motor evoked potentials elicited
from the primary motor cortex (M1) as demon-
strated by Ugawa in the so-called paradigm of
cerebellum-brain inhibition (CBI) [Ugawa et al.
1995]. tDCS induces a polarity-dependent site-
specific modulation of cerebellar activity not only
from the electrical standpoint but also by impact-
ing on the metabolism [Grimaldi et  al. 2016].
Cathodal tDCS over the cerebellum decreases
the ability of TMS to elicit CBI of M1, whereas
anodal tDCS exerts the opposite effect [Galea
et al. 2009].
The modulation of CBI by tDCS is not accompa-
nied by changes in spinal or brainstem excitabil-
ity. The possibility to tune noninvasively the
activity of the cerebellar cortex, in particular the
Purkinje neurons which control the nucleo-tha-
lamic drive, and the observation of physiological
effects on locomotor adaptation [Jayaram et  al.
2012] open strong perspectives for the manage-
ment of gait ataxia, which is one of the most disa-
bling symptoms in cerebellar patients.
Repeated TMS can also affect CBI. For instance,
continuous theta burst stimulation can suppress
CBI [Carrillo et  al. 2013]. However, clinically
http://tan.sagepub.com 407
H Mitoma and M Manto
relevant studies in terms of efficacy against ataxic
deficits are lacking.
Overall, it is concluded that tDCS has a potential
therapeutic role in the symptomatic management
of motor or cognitive deficits in patients with
CAs, but several key questions remain unan-
swered. What is the optimal current and where
exactly should it be applied over the cerebellum?
How many stimulation sessions should be deliv-
ered? Which subsets of patients are responsive?
Motor rehabilitation
Clinical evidence
Several lines of evidence indicate the efficacy of
motor rehabilitation in CAs elicited by limited
lesions in the cerebellum (e.g. vascular diseases,
tumors, MS). However, whether motor rehabili-
tation can improve symptoms of degenerative
CAs remains a matter of debate. This is especially
true when the insult is rapidly progressive in
nature and affects the entire cerebellum.
Two recent cohort studies have provided evidence
for the effectiveness of motor rehabilitation in
degenerative CAs [Ilg et al. 2009, 2010; Miyai et al.
2012]. These studies were conducted in 16 patients
with ataxia (age: 61.4 ± 11.2 years; 10 patients
with degenerative CAs and 6 patients with sensory
ataxia; disease duration: 12.9 ± 7.8 years; baseline
SARA score: 15.8 ± 4.3) [Ilg et al. 2010] and 42
patients with ataxia (age: 62.5 ± 8.0 years; all had
degenerative CAs; disease duration: 11.3±3.8
years; baseline SARA score: 11.3 ± 3.8) [Miyai
et al. 2012]. The results showed that motor reha-
bilitation produces the following results:
(1) Four-week intensive rehabilitation (1 h ×
3 per week; 2 h × 5 + 1 h × 2 per week)
[[Ilg et  al. 2010; Miyai et  al. 2012]
improved balance, gait and interlimb
coordination in SARA score, and in score
for activities of daily living by a Functional
Independence Measure. Improvement in
trunk ataxia in the SARA score was more
impressive than in limb ataxia.
(2) Four-week intensive rehabilitation is
more effective in patients with mild atro-
phy than in patients with severe atrophy.
(3) Persistent improvement was noted up to
12 weeks, but not 24 weeks, after inten-
sive rehabilitation, following cessation of
rehabilitation.
Therapeutic Advances in Neurological Disorders 9(5)
(4)  
Long-term program of 1 h homework
training per day was associated with
1-year benefits, despite gradual decline in
motor performance associated with natu-
ral progression of the disease.
(5)  Low-intensity homework training up to
30 min per week failed to maintain
improvement.
(6) Even 26 weeks after the first intensive
rehabilitation, reboost of rehabilitation
induced similar improvement compared
with the first intensive rehabilitation.
Thus, these results show the efficacy of intensive
rehabilitation therapy, especially when combined
with reboost rehabilitation in degenerative CAs.
Mechanisms of action
Motor rehabilitation reinforces cerebellar motor
learning and development of a new internal
model. Recent physiological studies have pro-
vided convincing evidence that the cerebellum
coordinates movements in a predictable fashion
[Manto et  al. 2012]. According to the internal
model theory [Kawato et al. 1987], neural mecha-
nisms that mimic the input or output characteris-
tics of a motor apparatus are assumed to be
embedded in the cerebellum. The forward internal
model can predict sensory consequences in
response to issued motor commands, whereas the
inverse internal model can calculate the predicted
motor commands from desired movements. The
internal model is acquired through motor learn-
ing, which leads to acquisition of skillful move-
ments [Deuschl et  al. 1996]. Various types of
cerebellar synaptic circuitries contribute to motor
learning. For example, the Marr–Albus–Ito
hypothesis proposed that error signals from climb-
ing fibers decrease parallel fiber inputs onto PCs
[Ito, 2006] and thus eliminate inadequate outputs
(see Figure 3). However, this hypothesis remains
to be approved [Manto, 2008]. Although these
theories of internal model and motor learning
have not yet been confirmed with certainty in real
cerebellar neural circuits [Manto et al. 2012], the
efficacy of motor rehabilitation can be explained
by these hypotheses. Motor rehabilitation seems
to promote motor learning and establishing a new
internal model in the residual and intact portion
of the cerebellum, leading to compensation of the
impaired coordinated movements.
Motor rehabilitation facilitates change in strategies
for motor control. An alternative mechanism for
408 http://tan.sagepub.com
the efficacy of rehabilitation is a change in strat-
egy for motor control. Motor rehabilitation
includes a combination of restorative and com-
pensatory techniques [Ilg et al. 2014]. For acqui-
sition of compensatory techniques, patients are
trained to replace rapid multi joint movements
with sequential single joint movements, and to
walk under careful visual-guided movements,
instead of predictive walking [Ilg et al. 2014]. In
these compensatory movements, motor com-
mands are calculated without cerebellar involve-
ments. Patients will try to perform movements
under a new strategy that does not involve the
cerebellum.
In this regard, intention tremor or action myo-
clonus, a cerebellar sign induced by cerebellar
efferent systems, occurs in visually guided move-
ments, in which the cerebellum operates accord-
ing to predictive controls for exact trace. However,
memory-guided movements are diminished due
to lesser involvement of the cerebellum in such
movements [Mitoma et al. 1993].
Taken together, using compensatory techniques
(change in motor strategy), the physical activities
of daily living could improve without improve-
ment in cerebellar functions.
Conclusion
Early therapy during ‘restorable stage’ of
preserved cerebellar functions
Various treatments directed towards the cause of
CA have been designed for patients with malfor-
mations, vascular diseases, neoplasms, metabolic
diseases, and IMCAs. The aim of such therapies
is to stop disease progression (minimize cell loss
and preserve cerebellar function). The preserva-
tion of cerebellar function is physiologically iden-
tified in the early stage of IMCAs [Mitoma et al.
2016]. Using a technique based on the ratio of
feedforward or feedback control, we quantified
and compared the control modes in patients with
early IMCAs and those with degenerative CAs
[Mitoma et al. 2016]. Patients with early IMCAs
showed no or slight atrophy, suggesting minimal
cell death. The operation of feedforward control
could be an index of survival of cerebellar func-
tion. Interestingly, motor control in patients with
early IMCAs was opposite to that in patients with
degenerative CAs, although both groups of
patients showed similar clumsiness in tracking
tasks. The cerebellar feedforward control is still
 H Mitoma and M Manto

Figure 4.  A scheme of the decline of cerebellar functions and the concept of ‘restorable stage’. Proper
therapies could restore cerebellar functions in patients whose cerebellum is at ‘restorable stage’, meaning
that there is still a sufficient preservation of cerebellar functions. After a given threshold of neuronal loss or
dysfunction in the cerebellar circuitry, cerebellar functions cannot be restored anymore because the loss of
computational capacities of the remaining cerebellar modules is too severe. Motor Cx, motor cortex.

present in the former group, though with ill-
defined property, whereas it is abolished in the
latter (Figure 4).
Consistent with these physiological data, the con-
trol of autoimmunity by immunotherapy is fol-
lowed by two types of clinical courses in IMCAs
[Mitoma et al. 2015]: patients with early stage CA
(without cerebellar atrophy) showed full or partial
recovery, whereas patients with advanced stage
CA (with moderate cerebellar atrophy) showed
persistent CAs, though without progression.
Similar responses are also observed in neuromod-
ulation therapies. Motor rehabilitation is more
effective in patients with mild atrophy than in
patients with severe atrophy [Ilg et al. 2010; Miyai
et al. 2012]. Taken together, the difference in the
clinical course is probably due to differences in
compensatory abilities in the residual
cerebellum.
In CAs associated with other diseases, proper
therapies could also restore cerebellar functions
in patients at ‘restorable stage’ with sufficient pre-
served cerebellar functions. Thus, early diagnosis
and therapy are important to prevent worsening
beyond the ‘restorable stage’. In this physiological
scheme, there is a minimal threshold for the pre-
dictive controller (a dotted line in Figure 4).
From the clinical standpoint, the rationale for a
threshold is for instance that patients with slowly
progressive tumors may be remarkably asympto-
matic for a long time before manifesting CA
[Dow and Moruzzi, 1958; Manto, 2002]. The
minimal threshold would reflect ‘cerebellar
reserve’. Thus, techniques such as transplanta-
tion of stem cells aim to increase the minimal
threshold (in Figure 4, a downward shift of a dot-
ted line) by reconstruction of entire cerebellar cir-
cuits and reinforcement of ‘cerebellar reserve’.
Understanding the efficacy of neuromodulation
therapy based on cerebellar function
Many assumptions have been proposed to clarify
the role of the cerebellum in the coordination of
movements [Manto et al. 2012]. Two main mod-
els have been proposed to explain the principle of
the cerebellar neural machinery [Galliano and De
Zeeuw, 2014]. The hypothesis of Braintenberg
considers the cerebellum as a timing control
machine [Braitenberg and Atwood, 1958]. This
model assumes that the climbing fiber mediated
inputs synchronize the activity of PCs for fine
tuning of timing (Figure 3) [Llinas, 2009]. In
contrast, the Marr–Albus–Ito hypothesis consid-
ers the cerebellum as a learning machine [Ito,
2006]. This model proposes that the climbing
fiber mediated inputs, which convey error signals,
depress inappropriate parallel fiber mediated
inputs through long-term depression, so as to for-
mulate an internal model (Figure 3) [Ito, 2006].

http://tan.sagepub.com 409
Therapeutic Advances in Neurological Disorders 9(5)
There is no integral theory that covers these two
divergent hypotheses. However, the efficacy of
aminopyridines could be explained by the timing
control machine model, whereas the efficacy of
motor rehabilitation could be explained by the
learning machine model.
However, irrespective of the operation principle,
the on/off signals are formulated in CN neurons
(these cells are the output neurons of the cerebel-
lum) through the mechanism of disinhibition or
inhibition on CN neurons from the cerebellar
cortex neurons (Figure 3) [Ishikawa et al. 2014].
Importantly, two separate groups of neurons, the
cerebellar cortex neurons (granule cells, PCs, and
inhibitory interneurons) and CN neurons, formu-
late cooperatively on/off cerebellar output signals.
This geometrical structure, crystal-like architec-
ture [Galliano and De Zeeuw, 2014] allows clini-
cians to potentiate impaired on/off cerebellar
outputs by facilitating the cerebellar cortex with
noninvasive stimulation. Some drugs, riluzole
and acethyl-DL-leucine, which adjust the activi-
ties of CN neurons, might also restore the capac-
ity of the generation of the on/off signal in the
cerebellum.
In conclusion, the understanding of the physio-
logical basis of the various therapies is a critical
step for clinicians dealing with CAs. We suggest
that some degree of reversibility can be achieved
if the therapies of CAs are administered as early
as possible and take into account the pathogene-
sis behind the disorder. Novel therapies should
take into account the mechanisms of the cerebel-
lar circuitry in order to be effective. The trial and
error strategy that has prevailed in CAs should be
abandoned.
Funding
MM is supported by the FNRS-Belgium.
Conflict of interest statement
The authors declare that they have no conflict of
interest.
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