ABSTRACT
A. Anatomic Divisions 1. Anterior lobe: anterior to primary fissure, receives
majority of input from spinocerebellar tracts 2. Posterior lobe: between primary and dorsolateral fissures;
receives majority of input from neocortex 3. Flocculonodular lobe: receives input from vestibular
nuclei
B. Functional Subdivisions 1. Vestibulocerebellum
a. Function 1) Orienting eyes during movement 2) Coordinating position of head and limbs in response
to position and motion through connections with medial and lateral vestibulospinal tracts
3) Has a role in smooth pursuit b. Cerebellar component: flocculonodular lobe c. Afferents: information from vestibular nuclei (mossy
fibers) enters via inferior cerebellar peduncle to synapse in the flocculonodular lobe
d. Efferents: information from flocculonodular lobe returns to vestibular nuclei; this includes inhibitory Purkinje cell input to medial and lateral vestibular nuclei
e. Vestibular nuclei project to contralateral abducens nucleus and their axons also form the origins of vestibulospinal tracts
f. Note: Some output from the nodulus is transmitted to fastigial nucleus; from here, fastigial nucleus axons influence vestibular nuclei (bilaterally), the reticular formation, and contralateral ventrolateral thalamus
g. Dysfunction: vertigo, nystagmus, truncal ataxia, deficits in visual pursuit
2. Spinocerebellum-vermis (Fig. 9-1) a. Function
1) Monitors ongoing execution of movement (especially proximal limbs and axial musculature)
2) Role in maintenance of muscle tone b. Cerebellar component: vermis c. Afferents (mossy fiber): primary somatosensory input
via inferior cerebellar peduncle (from dorsal spinocerebellar and cuneocerebellar tracts, mostly muscle spindle input) and superior cerebellar peduncle (from ventral and rostral spinocerebellar tracts)
d. Efferents: information from vermis projects to fastigial nucleus
e. Efferents from fastigial nucleus
Functional Subdivisions of the Cerebellum
Vestibulocerebellum
Involves the flocculonodular lobe
Connections with the vestibular system
Spinocerebellum
Vermis-responsible for axial and proximal limb motor control (synaptic relay in fastigial nucleus)
Paravermis (intermediate zone)—responsible for distal limb motor control (synaptic relay in nucleus interpositus [globose and emboliform nuclei])
Cerebrocerebellum
Involves the lateral cerebellar hemispheres and dentate nucleus
Responsible for planning and initiation of movement, precision in control of rapid movements, and conscious assessment of errors in movement
1) Descending fibers to ipsilateral and contralateral reticular formation, origin of reticulospinal tracts
2) Descending fibers to ipsilateral and contralateral vestibular nuclei, origin of vestibulospinal tracts
3) Ascending fibers via superior cerebellar peduncle to primary motor cortex through synaptic relay in ventrolateral thalamic and red nuclei, influencing descending motor pathways
f. Dysfunction: syndromes may overlap with paravermal syndromes; truncal ataxia
3. Spinocerebellum-paravermis (intermediate lobe) (Fig. 9-2) a. Function
1) Monitors ongoing execution of limb movement 2) Postural tone 3) Modulates descending motor systems
b. Cerebellar component: paravermal region and anterior lobe
c. Afferents to paravermis: somatosensory information from dorsal spinocerebellar and cuneocerebellar tracts (via inferior cerebellar peduncle) ventral and rostral spinocerebellar tracts (via superior cerebellar peduncle)
d. Efferents: information from anterior lobe projects to nucleus interpositus (globose and emboliform nuclei)
e. Efferents from nucleus interpositus (ascends via decussating superior cerebellar peduncle) to 1) Contralateral red nucleus (its axons descend in
rubrospinal tract, which decussates immediately after it originates)
2) Contralateral ventrolateral thalamic nucleus, which projects to cerebral cortex
f. Dysfunction: limb dysmetria
4. Cerebrocerebellum (Fig. 9-3) a. Function: initiation, planning, and timing of movement;
precision in control of rapid movements and conscious assessment of errors in movement (fine dexterity)
b. Cerebellar component: lateral cerebellar hemispheres (posterior lobes)
c. Afferents (mossy fiber): corticopontocerebellar fibers via middle cerebellar peduncle
d. Efferents from dentate nucleus (ascends via decussating superior cerebellar peduncle) to 1) Contralateral red nucleus (dentatorubral tract) 2) Contralateral ventrolateral thalamic nucleus (denta-
tothalamic tract), which projects to cerebral cortex e. Dysfunction: delay in initiation and termination of
movement and limb ataxia, limb dysmetria, dysarthria, intention tremor, kinetic tremor, nystagmus
C. Cytoarchitecture of Cerebellar Cortex (Fig. 9-4 and 9-5)
1. Granular layer: contains mainly granule cells, which receive most input from the mossy fibers, and Golgi cells, which modify granule cell output
2. Purkinje cell layer: contains Purkinje cells, the major source of output of cerebellar cortex
3. Molecular layer: contains mainly axons from granule cells (forming parallel fibers), Purkinje cell dendrites, basket cells, stellate cells
A. Purkinje Cells 1. Purkinje cells are large γ-aminobutyric acid
(GABA)ergic neurons 2. They send inhibitory projections to deep cerebellar nuclei 3. Purkinje cell axons form the primary (inhibitory) output
of the cerebellar cortex 4. Contain three synaptic domains
a. Distal dendritic spines: each Purkinje cell synapses with as many as 200,000 parallel fibers
b. Proximal dendritic processes: innervated by multiple synapses from a single climbing fiber
c. Cell body and axon hillock: inhibitory input from local interneurons (basket and stellate cells)
B. Climbing Fiber Input to Purkinje Cells (Fig. 9-5) 1. Climbing fibers arise primarily from neurons of
the inferior olivary nucleus; the axons form the
olivocerebellar pathway (essentially carries motor error signals to the cerebellum)
2. Each climbing fiber may contact up to 10 Purkinje cells, but each Purkinje cell has contact with only one climbing fiber
3. Climbing fibers modify responses of Purkinje cells to mossy fiber input
4. Complex spikes: powerful phasic excitation generated by Purkinje cell, which is activated by climbing fiber input a. Each action potential in the climbing fiber generates a
large depolarization in the Purkinje cell b. Bursts of small-amplitude action potentials following a
large-amplitude spike produced by voltage-dependent Ca2+ conductance
c. Synchronized, rhythmic firing produced by the electronic coupling of dendritic spines of neurons of the inferior olivary nucleus via gap junctions (may be responsible for the oscillatory properties of the inferior olivary nucleus
neurons and may partly explain palatal myoclonus) d. “Error detection and correction” function
1) Produced as a consequence of a transient change in ongoing limb movements
2) Complex spikes act to correct mismatches between the intended and actual movement
C. Mossy Fiber Input to Purkinje Cells (Fig. 9-5) 1. Mossy fibers arise from the vestibular nuclei, reticular
formation, spinal cord, pontine nuclei (i.e., vestibulocerebellar, spinocerebellar, cuneocerebellar, reticulocerebellar, and pontocerebellar pathways) a. Mossy fibers arising in the spinal cord relay sensory
information from the periphery via spinocerebellar tracts b. Mossy fibers arising in the pontine nuclei relay cortical
inputs via the corticopontocerebellar pathway 2. Mossy fibers form excitatory synapses on granule cells
(L-glutamate, via AMPA and metabotropic glutamate receptors)
Molecular layer
Stellate cell
Basket cell
Mossy fiber
Granule cell
Golgi cell
Parallel fiber
Climbing fiber
Purkinje cellPurkinje cell
Purkinje cell axon
Purkinje cell layer
Granular layer
White matter
Inhibitory
Excitatory
Inferior olivary nucleus
Deep cerebellar nuclei
a. Terminals (rosettes) contact the short dendrites of several granule cells, forming a complex called the glomerulus
b. Granule cells give rise to the parallel fibers in the molecular layer, which provide input to Purkinje cells
c. One mossy fiber contacts many granule cells d. Each granule cell receives input from many mossy fibers
3. Simple spikes: discharge by Purkinje cell activated by parallel fibers (temporal and spatial summation of input from several parallel fibers is needed to trigger a Purkinje cell)
4. High discharge rates (50-300 Hz) provide information continuously to Purkinje cells about movement and allow continuous modulation of movement
D. Basket Cells and Stellate Cells: spatial modulation of Purkinje cell output
1. Basket and stellate cells reside in the molecular cell layer
2. They are activated by the parallel fibers 3. They provide GABAergic inhibitory input to surround-
ing “off-beam” Purkinje cells, while each mossy fiber provides excitatory input to a cluster of granule cells that in turn stimulate via parallel fibers a central array of “on-beam” Purkinje cells
4. This arrangement of lateral inhibition around the central array of facilitatory Purkinje cells resembles centersurround antagonism and provides spatial modulation of cerebellar cortex output
E. Golgi Cells: temporal modulation of Purkinje cell output
1. Dendrites of Golgi cells are in both the granular layer (contacted by mossy fibers) and molecular layer (contacted by excitatory parallel fiber synapses)
2. Golgi cells provide feedback inhibition (GABAergic) to the glomeruli, control the “gain” of the granule cell, and shorten the duration of bursts in the parallel fibers
F. Cerebellar Nuclei 1. Dentate nucleus: receives input primarily from the
cerebellar hemispheres and projects primarily to the thalamus
2. Neurons in the cerebellar nuclei are tonically active and provide powerful excitatory postsynaptic potentials to their targets, including the motor relay nuclei of the thalamus, the red nucleus, vestibular nuclei, and reticular formation-via these projections, the cerebellum controls oculomotor, postural, and limb movements
3. Excitatory input to the deep cerebellar nuclei is via collaterals of mossy and climbing fibers, and inhibitory
input is from Purkinje cells; the function of deep cerebellar nuclei depends on summation of the excitatory and inhibitory inputs
4. Purkinje cell output is influenced by modulatory influence of climbing fiber and mossy fiber inputs to the same Purkinje cell
5. The response of cerebellar nuclear neurons consists of an initial excitation, Purkinje cell-mediated inhibition, and then rebound bursts of excitation; the inhibitory “pulse” is important for cortical and subcortical feedback for prompt initiation and termination of a particular movement
6. Olivary-cerebellar nucleus-olivary loop a. Direct excitatory input from the inferior olivary nucleus
to the cerebellar nuclei via climbing fiber collaterals b. Cerebellar nuclei, in turn, provide inhibitory GABAergic
projections to the inferior olivary nucleus 7. Olivomesodiencephalic loop
a. An excitatory loop involving projections from dentate nucleus to the mesodiencephalic junction and contralateral red nucleus and excitatory projections from these nuclei to the inferior olivary nucleus, and finally, the projection from the inferior olivary nucleus to dentate nucleus (Mollaret’s triangle)
b. This loop represents an excitatory, reverberating circuit that may be important in the pathophysiology of palatal myoclonus and essential tremor
A. Congenital Ataxias 1. Behr syndrome
a. Autosomal recessive inheritance b. Optic atrophy and cerebellar ataxia beginning in early
childhood; other features include nystagmus, scotoma, and bilateral retrobulbar neuritis
c. Spasticity, spastic ataxic gait, mental retardation, and posterior column sensory loss
d. Nerve biopsy findings consistent with chronic neuropathy with axonal degeneration and regeneration
2. Dandy-Walker syndrome (Fig. 9-6 A) a. Autosomal recessive or sporadic (Dandy-Walker variant
with hydrocephalus and facial dysmorphism has been associated with deletion involving chromosome 3q25)
b. Cystic dilatation of the fourth ventricle c. Dysplasia of the cerebellar vermis d. Heterogeneous clinical syndrome
Table 9-1. Differential Diagnosis for Cerebellar Disorders
Disease category Acute or recurrent ataxia Chronic progressive ataxia
1) Presenting symptoms usually within the first year of life: generally related to hydrocephalus and posterior fossa symptoms such as apneic spells, cranial nerve palsies, nystagmus, papilledema, bulging of anterior fontanelle
2) Infants may have poor head control and spasticity, poor feeding, and hyperirritability
3) Older children often have delayed motor and intellectual development, seizures in 20% to 30%
e. Associated with 1) Agenesis of the corpus callosum 2) Cortical heterotopias 3) Cerebral gyral abnormalities 4) Occipital encephalocele 5) Syringomyelia 6) Aqueductal stenosis 7) Hemimegalencephaly
f. Differential diagnosis for posterior fossa collection of cerebrospinal fluid should include 1) Familial vermian agenesis (e.g., Joubert syndrome, see
below) 2) Trapped fourth ventricle 3) Enlarged cisterna magna (because of cerebellar
atrophy or agenesis or associated with benign infantile macrocephaly)
4) Arachnoid cyst (may present as posterior fossa mass in infancy or childhood or may cause hydrocephalus or may be asymptomatic) (Fig. 9-6 B and C)
3. Classic Joubert syndrome (Joubert syndrome type 1) a. Autosomal recessive inheritance, linked to chromosome 9 b. Hypotonia in infancy c. Developmental delay, ataxia, abnormal breathing pat-
tern, including episodic apnea and tachypnea, and later development of mental retardation
d. Oculomotor apraxia, nystagmus, ptosis e. Other features: renal disease, ocular colobomas, liver
fibrosis, polydactyly, pigmentary retinopathy f. Hypoplastic or dysplastic cerebellar vermis with enlarge-
ment of the fourth ventricle g. “Molar tooth sign” (brainstem abnormalities that resem-
ble a tooth): elongated superior cerebellar peduncle, deep interpeduncular fossa, dysplasia of the superior cerebellar vermis
4. Cerebello-oculorenal syndrome (Joubert syndrome type 2) a. Autosomal recessive inheritance, linked to chromosome 11 b. Phenotypic presentation similar to classic Joubert
syndrome c. Infantile onset of ataxia, hypotonia, psychomotor devel-
opmental delay, oculomotor disorders (oculomotor apraxia and nystagmus)
d. Ocular manifestations: retinal dystrophy (sometimes called “Leber’s congenital amaurosis”)
e. Renal abnormalities: cystic dysplastic kidneys or juvenile nephronophthisis
f. Polydactyly, high-arched palate, hypertelorism g. Molar tooth sign (as above), cerebellar vermian dysplasia,
kinked corpus callosum 5. COACH syndrome (cerebellar vermis hypoplasia,
oligophrenia, congenital ataxia ocular coloboma, and hepatic fibrosis) a. Early-onset ataxia, cerebellar vermis hypoplasia (molar
tooth sign) b. Moderate mental retardation c. Ocular coloboma d. Liver fibrosis e. Hypertelorism f. Progressive renal insufficiency has been reported
6. Gillespie syndrome a. Autosomal recessive inheritance b. Partial or complete aniridia: aplasia involving only the
pupillary zone of the iris, giving the appearance of fixed dilated pupils in a hypotonic infant; congenital cataracts; and corneal opacities
c. Nonprogressive cerebellar ataxia, associated with cerebellar hypoplasia
d. Mental deficiency 7. Gomez-Lopez-Hernandez syndrome (cerebellotrigeminal
dermal dysplasia) a. Craniosynostosis b. Gait and truncal ataxia, cerebellar anomaly c. Trigeminal anesthesia, absence of corneal reflexes,
corneal opacities, scalp alopecia d. Midface hypoplasia, apparently low-set ears, mental
retardation, and short stature 8. Marinesco-Sjögren syndrome
a. Rare autosomal recessive disorder b. Cerebellar ataxia, developmental delay, and mental
retardation c. Additional features: congenital cataracts, short stature,
skeletal deformities, hypogonadism d. Variable neuromuscular manifestations such as chronic
myopathy and demyelinating sensorimotor neuropathy e. Major clinical overlap with congenital cataracts facial
dysmorphism neuropathy (CCFDN) syndrome f. Features that distinguish Marinesco-Sjögren syndrome
from CCFDN include more severe mental retardation; marked cerebellar atrophy; chronic myopathy, with specific ultrastructural features seen on muscle biopsy; absence of facial dysmorphism; and microcornea
g. Muscle histopathology 1) Dystrophic-like changes: variation in fiber size, fibro-
sis, adipose tissue replacement, necrosis, proliferation of internal nuclei, rimmed vacuoles
2) Autophagocytosis: autophagic vacuoles 9. Congenital disorder of glycosylation, type Ia (carbohy-
drate-deficient glycoprotein syndrome type 1a) a. Psychomotor retardation b. Generalized hypotonia, hyporeflexia, truncal ataxia, cere-
bellar hypoplasia c. Demyelinating peripheral neuropathy d. Decreased serum glycoproteins (total serum glycopro-
teins deficient in sialic acid and in galactose and Nacetylglucosamine)
e. Reduced serum activity of N-acetylglucosaminyltransferase f. Type Ia: Phosphomannomutase affected, an enzyme
necessary for the synthesis of guanosine diphosphatemannose, mapped to chromosome 16p
10. Cerebellar ataxia 1 a. Other names include cerebelloparenchymal disorder III,
cerebellar hypoplasia, nonprogressive Norman type b. Autosomal recessive inheritance, chromosome 9q c. Nonprogressive autosomal recessive congenital cerebellar
ataxia and mental insufficiency
d. Short stature e. Severe loss of granule cells; heterotopic Purkinje cells
11. Cerebellar ataxia 3 a. Infantile-onset nonprogressive cerebellar ataxia b. Normal intellectual function c. Brisk deep tendon reflexes and, occasionally, spasticity d. Short stature, pes planus e. Magnetic resonance imaging (MRI): cerebellar vermian
atrophy 12. Dysplastic gangliocytoma of the cerebellum
(Lhermitte-Duclos disease) a. Typical presentation in young adults with symptoms of
increased intracranial pressure due to obstructive hydrocephalus
b. Cowden disease (multiple hamartomas syndrome): predisposing and associated condition
c. MRI: laminated increased T2 signal d. Pathology: cellular disorganization, hypertrophied gran-
ule cells, and axonal hypermyelination in the molecular layer of the cerebellum, with global hypertrophy of the cerebellum and coarse gyri macroscopically
B. Familial Ataxias-Autosomal Recessive 1. Friedreich’s ataxia
a. Genetics and pathogenesis 1) In more than 90% of persons affected, a mutation
involves expansion of GAA triplet repeats within the first intron of the FRDA gene (chromosome 9q13q21.1), impairing exon splicing and decreased production of frataxin protein
2) Point mutation (about 6%) 3) Frataxin protein is likely located in mitochondria and
is possibly a mitochondrial iron transporter 4) Deficiency of frataxin may cause excess intramito-
chondrial iron and subsequent oxidative stress 5) Reduced frataxin levels in skeletal muscle, heart, pan-
creas, liver, kidney, central nervous system (spinal cord > cerebellum > cerebral cortex)
6) The length of the repeat correlates directly with the severity of disease and the presence of cardiomyopathy and inversely with age at onset
b. Typically develops around the time of puberty, with gait disorder and clumsiness
c. Mixed sensory and cerebellar ataxia d. Cerebellar dysfunction
1) Progressive limb and gait ataxia, cerebellar dysarthria 2) Early ataxia of the lower limbs and axial control; sub-
sequent appendicular ataxia of the upper limbs and cranial musculature
3) Results from the loss of Purkinje cells, degeneration of
the dentate nucleus, axonal loss and demyelination of the superior cerebellar peduncles, and degeneration of the spinocerebellar tracts
e. Sensory symptoms 1) Mainly large-fiber sensory loss (vibratory and proprio-
ceptive), areflexia 2) Axonal sensory neuropathy 3) Likely secondary to involvement of large myelinated
fibers (scanty paranodal and segmental demyelination), with wallerian degeneration of the posterior columns, nuclei gracilis and cuneatus, and medial lemniscus (Fig. 9-7)
4) Degeneration of the dorsal root ganglia (Fig. 9-8) f. Pyramidal involvement
1) Initially, may be mild; mainly extensor plantar responses
2) Eventually, may cause weakness in lower extremities, spasticity, and flexor spasms
3) Distal wasting and amyotrophy, mainly in the lower extremities
4) Degeneration of the corticospinal tracts is most severe in lumbar segments and least apparent in cervical segments (Fig. 9-7)
g. Progressive bulbar deficits (dysarthria, dysphagia) h. Skeletal abnormalities
1) Kyphoscoliosis (Fig. 9-9 A and B) 2) Pes cavus, pes planus, and equivarus
i. Other manifestations that may be involved 1) Cardiac involvement: widespread T-wave inversions,
hypertrophied cardiomyopathy (50% of cases), asymmetrical septal hypertrophy, symmetrical concentric ventricular hypertrophy, or subaortic stenosis
2) Diabetes mellitus 3) Optic atrophy 4) Sensorineural hearing loss 5) Sphincter disturbance, usually mild
j. Nerve conduction studies: normal compound muscle action potentials and reduced or absent sensory nerve action potentials
k. Prognosis 1) Slow, variable progression 2) Age at death varies, usually late 30s (range, 21-69 years) 3) Wheelchair-dependent usually in second decade
l. Treatment 1) Possible benefit of idebenone on heart wall thickness 2) Combination of coenzyme Q and vitamin E may
improve cardiac and skeletal muscle bioenergetics 3) Possible role of iron chelation therapy 4) Close monitoring for cardiac abnormalities, diabetes,
scoliosis, hearing loss, etc.
