Diagnosis
Blood test
CSF
Brain MRI
Therapy
Mass lesions
Glioma, menigioma,abscess, focalmalformations,cerebellar lesions, tumor
Toxic agents,
alcohol,
drugs
Hb, Ht, liver tests, antiepileptic drugs, litium, statins, electrolytes, heavy metals
Cerebellar atrophy
Endocrine disorders
thyroid hormone (TSH), Anti-TPO antibodies
Malabsorption
Vitamin E, B1, B6, B12
Cerebellar, pontine,spinal cord posterior/lateral columns lesions
Auto-immune disorders
antibodies
to glutamic aciddecarboxylase (GAD)
Cerebellar atrophy
Celiac disease(gluten ataxia)
Antigliadin, tissue transglutaminase,endomysium antibodies
Cerebellar atrophy
Demyelinating disorders
Protein, electrophoresis IgG index,
Demyelinating lesions
Infections
Systemic evidence of infectious, viral screening infectious
Lymphocytes, glucose, viral infectious screening
Paraneoplastic syndromes
Onconeuronal antibodies
Onconeuronal antibodies
MRI non-specific; Cerebellar atrophy
FA, AVED
Cervical cord atrophy
SCA
Cerebellar or ponto-cerebellar atrophy
Diffuse cerebellar involvement is more often associated with toxic, metabolic, and paraneoplastic syndromes, and the presentation of symptoms may be subacute or chronic. In these latter forms, cerebellar atrophy is a non-specific feature and it may involve predominantly the vermis (as in chronic alcoholic degeneration), or the cerebellar hemispheres and the adjacent pontine and spinal cord structures.
In alcoholic cerebellar degeneration, the clinical syndrome is characterized by prominent ataxia of gait and legs, with difficulties in standing and frequent sway. In addition to the toxicity of alcohol, the clinical presentation may be aggravated by the onset of other concomitant symptoms due to vitamin B1 deficiency (Wernicke’s encephalopathy). Vitamin deficiencies may result from malabsorption and bowel diseases, causing a spinocerebellar degeneration associated with axonal sensory neuropathy as in the case of vitamin E deficiency, or combined spinal cord degeneration in B12 defect.
Severe and subacute truncal ataxia, limbs incoordination, and dysarthria may represent the clinical presentation in paraneoplastic cerebellar degeneration with neurological deficits most often preceding the detection of the underlying tumor [1, 5] (see Chap. 19).
34.4.3 Diagnostic Markers
MRI brain scan can exclude structural lesions or recognizable disease-specific abnormalities.
Vitamin deficiencies, endocrinological disorders, coeliac disease, immunological and paraneoplastic syndromes may be screened by appropriate hematochemical tests [6, 7] (Table 34.1). Chronic cerebellar damage may also be associated with drug compounds, such as lithium, phenytoin, amiodarone, toluene, and the anti-cancer drugs 5-fluorouracil and cytosinearabinoside. Heavy metals (lead compounds, mercury, and thallium) are cerebellar toxic agents.
34.4.4 Principles of Treatment
Of the most important therapeutic measures in ataxias caused by toxic agents is the immediate cessation of exposure. Strict abstinence and vitamin B1 supplementation improves alcoholic ataxia.
A multivitamin preparation, including vitamin E supplementation, is recommended in malabsorption syndromes.
In paraneoplastic cerebellar degeneration (PCD) (see Chap. 19), the obvious approach is the treatment of the underlying tumor; however, only exceptional cases respond to tumor removal or immunosuppressive therapy (plasma exchange, intravenous immunoglobulins, or steroids), with the exception of PCD associated with anti-Tr and anti-mGluR1 antibodies in Hodgkin’s disease.
There is no established treatment for anti-GAD ataxia, although improvement of ataxia after steroids and intravenous application of immunoglobulins has been reported [1, 3, 4]. The treatments of infectious and demyelinating diseases of the nervous system are described in more details in dedicated chapters (see Chaps. 5, 6 and 7).
34.4.5 Prognosis
Prognosis of the acquired infectious or toxic cerebellar ataxia may be good when the specific etiology agents can be promptly recognized and treated. These forms are potentially reversible with the treatment if this is given within the first months after manifestation of ataxia. Residual cerebellar deficits may become permanent when associated to cellular loss and damage to the cerebellar structures. The cerebellar degeneration associated with immune factors has a chronic progressive disease course, and may cause moderate to severe motor and cognitive disability.
34.5 Hereditary Degenerative Ataxias
34.5.1 Terminology and Definitions
The inherited cerebellar/spinocerebellar syndromes are subdivided by the mode of inheritance into autosomal dominant (AD), autosomal recessive (AR), X-linked and mitochondrial disorders [8, 9].
A familial disorder affecting successive generations is suggestive of autosomal dominant cerebellar ataxias (ADCA). Genetic classification of autosomal dominant cerebellar ataxias (ADCAs) includes more than 35 subtypes of SpinoCerebellar Ataxias (SCA), which are numbered in the order of locus or gene description (SCA1-SCA36) with approximately 20 genes identified. In addition, the ADCA group also includes the episodic ataxias (EA), with 7 loci (EA1-7) and 4 genes identified, and the dentato-rubro-pallidal-luysian atrophy (DRPLA) [10–13].
An X-linked mode of inheritance is associated with the Fragile X tremor/ataxia syndrome (FXTAS).
The autosomal recessive cerebellar ataxias (ARCA) are rare, genetic heterogeneous diseases with more than 20 different clinical and genetic subtypes [8, 9, 14]. ARCA usually begin before the age of 20 years. Friedreich’s ataxia (FRDA) and ataxia-telangiectasia (AT) are the most frequent forms. The presence of multiple affected sibs in a single generation or consanguinity in the parents supports the idea of an autosomal recessive mode of inheritance. In ARCAs, as in other autosomal recessive diseases, carriers of only one disease causing mutation in a gene (heterozygote) are not at risk of developing the disease.
34.5.2 Clinical Features
SCAs are diseases of the entire nervous system, and present a wide and overlapping range of neurological symptoms including ataxia of gait and limbs, dysarthria, spasticity, extrapyramidal movement disorders, retinopathy, optic atrophy, peripheral neuropathy, sphincter disturbances, and cognitive impairment [10–13]. All patients also present oculomotor disturbances, of cerebellar and supranuclear origin. Later in the disease, pontine involvement may cause slow saccades and ophthalmoparesis [10–13].
Men with a fragile X premutation present in the sixth decade with progressive intention tremor, ataxia, and parkinsonism, cognitive decline, and peripheral neuropathy.
In EAs, the disease presents with recurrent, discrete episodes of ataxia, giddiness, and vertigo with or without interictal abnormalities.
There are over 35 SCAs genetic subtypes, and their prevalence varies between different populations. The most frequent subtypes are those caused by expanded CAG repeats (SCA1, SCA2, SCA3, SCA6, SCA7, SCA17, and DRPLA), and among these, SCA3 is the commonest subtype worldwide. The clearest genotype-phenotype correlation is found between the CAG repeat length and the age at onset, disease severity, and progression.
Age at onset is usually in adulthood for the ADCA, and more frequently before age 20 in ARCA and in EA. The course of all these diseases is chronic progressive.
Friedreich’s ataxia is the most common of the autosomal recessive ataxias and the most common hereditary ataxia overall with a prevalence of approximately one person in 50,000 in Caucasian populations [14, 15]. Age at onset is typically 5–25 years. Clinically, Friedreich’s ataxia is characterized by early-onset progressive gait and limb ataxia, dysarthria, loss of vibration and proprioceptive sense, areflexia, abnormal eye movements, and pyramidal weakness. Cardiomyopathy, diabetes, scoliosis, and pes cavus are other common systemic complications [14, 15].
34.5.3 Diagnosis of Inherited Cerebellar Ataxias
34.5.3.1 Genetic Tests
In case of a family history compatible with autosomal dominant inheritance, the initial genetic testing should include SCA1, 2, 3, 6, 7, and 17, as they comprise the most common forms of SCAs. This screening may allow a genetic diagnosis in 50–60 % of ADCA cases. Diagnosis of the other SCAs genetic subtypes requires wide genetic screening and the search of specific mutations [8, 16, 17] (Table 34.2).
Table 34.2
Autosomal dominant ataxias: genetic subtypes and main clinical features
Disease | Gene | Main associated symptoms | Age at onset |
|---|---|---|---|
SCA1 | ATXN1 | Dementia, nystagmus, slow saccades pyramidal signs, neuropathy | 4–74 |
SCA2 | ATXN2 | Dementia, slow saccades, hyporreflexia, amyotrophy, neuropathy, myoclonus, rare Parkinsonism | 6–67 |
SCA3 | ATXN3 | Nystagmus, diplopia, ophthalmoplegia, eye-lid retraction, Parkinsonism, spasticity neuropathy | 5–65 |
SCA4 | Puratrophin-1 (PLEKHG4) | Pure cerebellar syndrome or associated with axonal sensitive neuropathy | 19–72 |
SCA5 | β-III Spectrin (SPTBN2) | Pure cerebellar syndrome, down-beat nystagmus, bulbar symptoms in juvenile cases. Slow progression | 15–50 |
SCA6 | CACNA1A | Pure cerebellar syndrome, sometimes episodic ataxia at onset, double vision, pyramidal signs, deep sensory loss, migraine. (Disease is allelic to episodic EA2 and Familial Hemiplegic Migraine) | 19–77 |
SCA7 | ATXN7 | Retinal degeneration, ophthalmoplegia, pyramidal signs | 0.1–76 |
SCA8 | ATXN8 (Kelch-like) | Sensory neuropathy, slow progression
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