Cerebellar disorders have numerous causes, including congenital malformations, hereditary ataxias, and acquired conditions. Symptoms vary with the cause but typically include ataxia (impaired muscle coordination). Diagnosis is by history and physical examination, often supplemented by imaging and sometimes genetic testing. Treatment is usually supportive unless the cause is acquired and reversible.
(See also Overview of Movement and Cerebellar Disorders.)
The cerebellum has 3 parts:
Archicerebellum (vestibulocerebellum): It includes the flocculonodular lobe, which is located in the medial zone. The archicerebellum helps maintain equilibrium and coordinate eye, head, and neck movements; it is closely interconnected with the vestibular nuclei.
Midline vermis (paleocerebellum): It helps coordinate trunk and leg movements. Vermis lesions result in abnormalities of stance and gait.
Lateral hemispheres (neocerebellum): They control quick and finely coordinated limb movements, predominantly of the arms and hands.
There is growing consensus that in addition to coordination, the cerebellum controls some aspects of memory, learning, and cognition (1).
Ataxia is the archetypal sign of cerebellar dysfunction, but many other motor abnormalities may occur (see table ).
Signs of Cerebellar Disorders
Deficit | Manifestation |
|---|---|
Ataxia | Reeling, wide-based gait |
Decomposition of movement | Inability to correctly sequence fine, coordinated motor acts |
Dysarthria | Inability to articulate words correctly, with slurring |
Dysdiadochokinesia | Uncoordinated rapid alternating movements |
Dysmetria | Impaired ability to reach a target with goal-directed movement |
Hypotonia | Decreased muscle tone |
Nystagmus | Involuntary, rapid oscillation of the eyeballs in a horizontal, vertical, or rotary direction, with the fast component maximal toward the side of the cerebellar lesion |
Scanning speech | Slow enunciation with a tendency to hesitate at the beginning of a word or syllable |
Rhythmic, alternating, oscillatory movement of a limb as it approaches a target (intention tremor) or of proximal musculature when fixed posture or weight bearing is attempted (postural tremor); characterized by high amplitude and low frequency |
General reference
1. Koziol LF, Budding D, Andreasen N, et al. Consensus paper: the cerebellum's role in movement and cognition. Cerebellum. 2014;13(1):151-177. doi:10.1007/s12311-013-0511-x
Etiology of Cerebellar Disorders
The most common cause of cerebellar disorders is
Alcoholic cerebellar degeneration
Congenital malformations
Such malformations are almost always sporadic, often occurring as part of complex malformation syndromes (eg, Dandy-Walker malformation) that affect other parts of the central nervous system (CNS).
Malformations manifest early in life and are nonprogressive. Manifestations vary markedly depending on the structures involved; ataxia is usually present.
Hereditary ataxias
Hereditary ataxias may be autosomal recessive or autosomal dominant. Autosomal recessive ataxias include Friedreich ataxia (the most prevalent), ataxia-telangiectasia, abetalipoproteinemia, ataxia with isolated vitamin E deficiency, and cerebrotendinous xanthomatosis.
Friedreich ataxia results from a gene mutation causing abnormal repetition of the DNA sequence GAA in the FXN gene on the long arm of chromosome 9; the FXN gene codes for the mitochondrial protein frataxin. The GAA sequence is repeated 5 to 38 times within the FXNgene in people who do not have Friedreich ataxia; however, in people with Friedreich ataxia, the GAA sequence may be repeated 70 to > 1000 times (1, 2). Inheritance is autosomal recessive. Decreased frataxin levels lead to mitochondrial iron overload and impaired mitochondrial function.
In Friedreich ataxia, gait unsteadiness begins between ages 5 and 15 years; it is followed by upper-extremity ataxia, dysarthria, and paresis, particularly of the lower extremities. Tremor, if present, is slight. Upgoing plantar responses are often present. Reflexes and vibration and position senses are lost. However, in late-onset Friedreich ataxia (age > 25 years), reflexes may be preserved. Talipes equinovarus (clubfoot), scoliosis, and progressive cardiomyopathy are common. By their late 20s, patients may be confined to a wheelchair. Death, often due to arrhythmia or heart failure, usually occurs by middle age. Formal neuropsychological testing may detect a decline in cognitive function.
Omaveloxolone, an NF2 pathway activator, is available for the treatment of Friedreich ataxia. This medication can delay progression of ataxia by 1.5 to 2 years (Omaveloxolone, an NF2 pathway activator, is available for the treatment of Friedreich ataxia. This medication can delay progression of ataxia by 1.5 to 2 years (3).
Spinocerebellar ataxias (SCAs) are the main autosomal dominant ataxias. Classification of these ataxias has been revised with advances in genetic evaluation (4). Currently, at least 48 different gene loci are recognized; approximately 10 involve expanded DNA sequence repeats. Some involve a repetition of the DNA sequence CAG that codes for the amino acid glutamine, similar to that in Huntington disease.
Manifestations of SCAs vary. Some of the most common SCAs affect multiple areas in the central and peripheral nervous systems; neuropathy, pyramidal signs, and restless leg syndrome, as well as ataxia, are common. Some SCAs cause only cerebellar ataxia.
SCA type 3, formerly known as Machado-Joseph disease, may be the most common dominantly inherited SCA worldwide. Symptoms include ataxia, parkinsonism, and possibly dystonia, facial twitching, ophthalmoplegia, and bulging eyes.
Acquired conditions
Acquired ataxias may result from nonhereditary neurodegenerative disorders (eg, multiple system atrophy), systemic disorders, multiple sclerosis, cerebellar strokes, repeated traumatic brain injury, or toxin exposure, or they may be idiopathic. Systemic disorders include alcohol use disorder (alcoholic cerebellar degeneration), thiamin deficiency, celiac disease, heatstroke, hypothyroidism, and vitamin E deficiency.
Toxins that can cause cerebellar dysfunction include carbon monoxide, heavy metals, lithium, phenytoin, and certain solvents. Toxic levels of certain medications (eg, antiseizure medications, sedatives in high doses) can cause cerebellar dysfunction and ataxia., heavy metals, lithium, phenytoin, and certain solvents. Toxic levels of certain medications (eg, antiseizure medications, sedatives in high doses) can cause cerebellar dysfunction and ataxia.
Rarely, subacute cerebellar degeneration occurs as a paraneoplastic syndrome in patients with breast cancer, ovarian cancer, small cell carcinoma of the lung, or other solid tumors. Cerebellar degeneration may precede the discovery of the cancer by weeks to years. Anti-Yo, now called PCA-1 (Purkinje cell cytoplasmic antibody type 1) is a circulating autoantibody that occurs in the serum or cerebrospinal fluid (CSF) of some patients, especially women with breast or ovarian cancer.
In children, primary brain tumors (medulloblastoma, cystic astrocytoma) may be the cause; the midline cerebellum is the most common site of such tumors. Rarely, in children, reversible diffuse cerebellar dysfunction follows viral infections.
Etiology references
1. Pandolfo M. Friedreich ataxia. Arch Neurol. 2008;65(10):1296-1303. doi: 10.1001/archneur.65.10.1296
2. Cook A, Giunti P. Friedreich's ataxia: clinical features, pathogenesis and management. Br Med Bull. 2017;124(1):19-30. doi: 10.1093/bmb/ldx034
3. Lynch DR, Chin MP, Boesch S, et al. Efficacy of omaveloxolone in Friedreich's ataxia: Delayed-start analysis of the MOXIe extension. Mov Disord. 2023;38(2):313-320. doi: 10.1002/mds.29286
4. Lange LM, Gonzalez-Latapi P, Rajalingam R, et al. Nomenclature of genetic movement disorders: Recommendations of the International Parkinson and Movement Disorder Society Task Force - An update. Mov Disord. 2022;37(5):905-935. doi: 10.1002/mds.28982
Diagnosis of Cerebellar Disorders
History and physical examination
MRI
Sometimes genetic testing
Diagnosis of cerebellar disorders includes a thorough family history and search for acquired systemic disorders.
Neuroimaging, typically MRI, is done. Genetic testing is done if family history is suggestive.
Treatment of Cerebellar Disorders
Treatment of the cause if possible
Usually only supportive
Riluzole, an antiglutamatergic agent, is probably helpful for short-term treatment of ataxia of various causes (eg, hereditary, multiple system atrophy, spinocerebellar, Friedreich). Some studies suggest that amantadine could improve motor coordination, but overall evidence for its effectiveness in the treatment of ataxia is insufficient (Riluzole, an antiglutamatergic agent, is probably helpful for short-term treatment of ataxia of various causes (eg, hereditary, multiple system atrophy, spinocerebellar, Friedreich). Some studies suggest that amantadine could improve motor coordination, but overall evidence for its effectiveness in the treatment of ataxia is insufficient (1, 2).
Some systemic disorders (eg, hypothyroidism, celiac disease) and toxin exposures can be treated; occasionally, surgery for structural lesions (tumor, hydrocephalus) is beneficial. However, treatment is usually only supportive (eg, exercises to improve balance, posture, and coordination; devices to help with walking, eating, and other daily activities).
Treatment references
1. Zesiewicz TA, Wilmot G, Kuo SH, et al. Comprehensive systematic review summary: Treatment of cerebellar motor dysfunction and ataxia [RETIRED]: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018;90(10):464-471. doi: 10.1212/WNL.0000000000005055
2. Ristori G, Romano S, Visconti A, et al. Riluzole in cerebellar ataxia: a randomized, double-blind, placebo-controlled pilot trial. . Riluzole in cerebellar ataxia: a randomized, double-blind, placebo-controlled pilot trial.Neurology. 2010;74(10):839-845. doi:10.1212/WNL.0b013e3181d31e23
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