Cerebellar Diseases and Other Conditions Causing Ataxia

The different clinical types of ataxia can be classified in several ways:

By the affected neural structure(s):
- Cortical cerebellar ataxia.
- Olivopontocerebellar ataxia.
- Spinocerebellar ataxia.
By etiology (see also ▶ Table 6.37, ▶ Table 6.38):
- Hereditary (autosomal recessive, autosomal dominant, x-chromosomal) or sporadic.
- Acquired (= symptomatic).

Clinical features Ataxia is characterized by impaired coordination of movement and a dysfunctional interplay of agonist and antagonist muscles. Thus, it typically manifests itself as poorly controlled movements that tend to overshoot their target. The additional manifestations of the individual diseases causing ataxia depend on their etiology and the particular neural structure involved.

Note

Ataxia can be caused not only by cerebellar disease, but also by disease of the afferent and efferent pathways leading to and from the cerebellum, or of any afferent somatosensory or special sensory pathways. The underlying lesion may be in the cerebellum, but it may also be in the brainstem, spinal cord, peripheral nerves, sensory cortex, or thalamus.

An initial, clinically based classification of ataxia distinguishes symmetric from focal, asymmetric types ( ▶ Table 6.36). The table can serve as an overview and guide to the differential diagnosis of ataxia.

**Table 6.36** The differential diagnosis of symmetric and focal asymmetric ataxias
Symmetric ataxia	Focal asymmetric ataxia
Acute or chronic intoxication Electrolyte disturbance Acute viral cerebellitis Miller Fisher syndrome Postinfectious, ADEM Alcoholic-nutritional cerebellar damage Vitamin B₁ deficiency Vitamin B₁₂ deficiency Paraneoplastic cerebellar disease Antigliadin antibody syndrome Hypothyroidism Creutzfeldt–Jakob disease Hereditary cerebellar degeneration Familial episodic ataxia Multisystem atrophy Tabes dorsalis Psychogenic ataxia	Ischemic stroke Cerebellar hemorrhage Subdural hematoma Abscess Neoplasia (primary brain tumor, metastasis) Demyelinating plaque, multiple sclerosis Arteriovenous malformation, arteriovenous fistula Arnold–Chiari or Dandy–Walker malformation Psychogenic ataxia
Abbreviation: ADEM, acute disseminated encephalomyelitis.

Diagnostic evaluation When ataxia is suspected, the age at onset and the family history are diagnostically relevant:

If ataxia arises in childhood or adolescence in a patient with a positive family history, the diagnosis is probably an autosomal recessive ataxia. The most common of these is Friedreich ataxia.
If a parent is similarly affected, then the diagnosis is probably an autosomal dominant ataxia, for example, spinocerebellar ataxia.
Ataxia arising after age 40 years is less likely to be hereditary and may be an acquired ataxia, for example, of toxic origin (such as alcohol-induced cerebellar degeneration).

Individual types of ataxia can be diagnosed by molecular-genetic testing, imaging studies, or laboratory analysis.

Treatment The symptom complex called “ataxia” has no specific treatment, although coordination may be improved by physiotherapy. Certain types of ataxia of known cause can be correspondingly treated: examples include vitamin E administration in ataxia due to vitamin E deficiency and in Aβ-lipoproteinemia, a diet that is low in phytanic acid in Refsum disease, and a low-copper diet combined with chelators or zinc in Wilson disease.

6.11.2 Selected Types of Ataxia

Key Point

Disturbances of the cerebellum, like those of the cerebral hemispheres, are usually due either to vascular processes (ischemia, hemorrhage) or to tumors. Multiple sclerosis is a further common cause. In this section, we will also discuss other diseases that may present primarily with cerebellar dysfunction, including infectious, parainfectious, (heredo-)degenerative, toxic, and paraneoplastic conditions, as well as cerebellar involvement in general medical diseases.

A thorough description of each ataxia syndrome would be beyond the scope of this textbook, and we therefore discuss only the more important ones briefly. Friedreich ataxia is described in greater detail in a later chapter (section ▶ 7.6.2) among the other hereditary diseases of the spinal pathways.

Cerebellar Heredoataxias

Cerebellar heredoataxias are of genetic origin. The enzymatic defects and pathophysiologic mechanisms underlying each have not yet been determined, except in a few cases. The main types are listed in ▶ Table 6.37. Spinocerebellar ataxias involve both the cerebellum and the spinal cord and are associated with cognitive deficits as well (see sections ▶ 7.6.1 and ▶ 7.6.2).

**Table 6.37** Types of cerebellar ataxia
Disease	Clinical features	Remarks
*Autosomal recessive hereditary ataxias*
Friedreich ataxia	Lumbering, broad-based, unsteady gait, progressive from the first or second decade onward Later, clumsiness of the hands, explosive speech Typical Friedreich foot (see ▶ Fig. 7.15) Scoliosis, hypotonia	GAA triplet expansion on chromosome 9; impaired synthesis of the protein frataxin
Refsum disease (heredopathia atactica polyneuritiformis)	Ataxia of gait and limbs beginning in childhood or adulthood Polyneuropathy with areflexia and sensory loss Hearing impairment Retinitis pigmentosa Mental abnormalities	Lack of phytanic acid α-dehydrogenase
Aβ-lipoproteinemia (Bassen–Kornzweig syndrome)	Progressive ataxia, nystagmus, ophthalmoplegia, polyneuropathy Acanthocytosis, low cholesterol and triglyceride levels, vitamin E deficiency	Low serum lipoprotein, cholesterol, and triglyceride levels
Ataxia telangiectasia (Louis–Bar syndrome)	Onset in infancy with ataxia and choreoathetosis Frequent lung, ear, nose, and throat infections Slow eye movements Telangiectases in conjunctiva and joint creases	One of the chromosomal fragility syndromes
Spinocerebellar ataxia (different varieties, e.g., deficiencies of hexosaminidase, glutamate dehydrogenase, pyruvate dehydrogenase, ornithine transcarbamylase, or vitamin E)	Onset usually before age 10 y Ataxia with variable accompanying deficits, e.g., intellectual disability, visual or hearing impairment, polyneuritis, myoclonus Speech may be loud, deep, and harsh (“lion’s voice”) If hereditary, generally autosomal recessive
*Autosomal dominant hereditary cerebellar ataxias (ADCA)*
Cerebellar cortical atrophy (Holmes type = Harding type III)	Onset at age 20 y or later Cerebellar signs	Genetically heterogeneous, SCA 5 and SCA 6
Olivopontocerebellar atrophy (Menzel type = Harding type I)	Onset at age 20 y or later Cerebellar and noncerebellar signs including optic nerve atrophy, basal ganglionic dysfunction, pyramidal tract signs, muscle atrophy, sensory deficits, and sometimes dementia	Genetically heterogeneous, SCA 1–SCA 4; SCA 3 = Machado–Joseph disease
Cerebellar atrophy (Harding type II)	Onset after age 20 y with cerebellar signs and retinal degeneration	Corresponds to SCA 7
*Autosomal dominant hereditary episodic ataxias*
Familial periodic paroxysmal ataxia	Degenerative cerebellar ataxia with onset in childhood Manifests itself in attacks (paroxysms)	Gene defect on chromosome 19p Responds to acetazolamide
*Sporadic, nonhereditary ataxias*
“Atrophie cérébelleuse tardive à prédominance corticale”	Onset in late adulthood with slowly progressive gait and truncal ataxia, later arm ataxia Rarely, nystagmus, muscle hypotonia, and pyramidal tract signs	Symmetric degeneration of Purkinje cells, predominantly in the vermis; alcohol may be a precipitating factor in persons with an underlying genetic predisposition
Abbreviation: SCA, spinocerebellar ataxia.

Note

The most common hereditary ataxia is Friedreich ataxia, an autosomal disorder with onset usually in the first or second decade of life that generally leads to death between the ages of 30 and 40 years. Its typical manifestations are the following:

Unsteady gait, particularly with eyes closed; areflexia, pyramidal tract signs.
Dysphagia, cerebellar dysarthria, oculomotor disturbances (gaze-evoked nystagmus, square-wave jerks, abnormal suppression of the vestibulo-ocular reflex, ▶ Fig. 12.6).
Optic nerve atrophy.
Early loss of proprioception and vibration sense.
Distal muscle atrophy, typical foot deformity (pes cavus), kyphoscoliosis.
Cardiac manifestations (conduction abnormalities, cardiomyopathy), diabetes mellitus.
Cognitive disturbances.
Dementia.

Symptomatic Types of Ataxia and Cerebellar Degeneration

Aside from hereditary and idiopathic types of ataxia and cerebellar degeneration, there are also types that reflect particular underlying illnesses, including a wide variety of cerebellar and systemic diseases ( ▶ Table 6.38). The clinical manifestations vary depending on the cause. Other systems and organs are often involved.

**Table 6.38** Causes of symptomatic ataxia and cerebellar degeneration
Cause or precipitating factor	Examples and remarks
Local disease: mass lesion or ischemia	Malformation, cerebellar tumor, infarct, hemorrhage, inflammation, trauma or other physical causes
Infection	Often in the aftermath of an infectious disease, e.g., mononucleosis Acute cerebellar ataxia in childhood arises a few days or weeks after a chickenpox infection, less commonly after another viral illness. The patient is usually a preschool-aged child. Unsteady gait, ataxia, tremor, and nystagmus are the characteristic signs; they usually resolve spontaneously in a few weeks. Acute cerebellitis is similar to the foregoing and affects both children and adults. In older patients, the manifestations can persist
Systemic diseases	For example, multiple sclerosis, macroglobulinemias
Toxic conditions	Tardive cerebellar atrophy in chronic alcoholism, other toxic causes (diphenylhydantoin, lithium, organic mercury, piperazine, methotrexate, 5-fluorouracil, DDT)
Metabolic and hormone-associated conditions	Familial AVED (an autosomal recessive condition that clinically resembles Friedreich ataxia), vitamin B deficiency Hypothyroidism and myxedema Malresorption syndrome, gluten intolerance (gluten-induced ataxia with or without gastrointestinal manifestations)
Paraneoplastic conditions	Subacute cerebellar cortical atrophy
Further causes	Heatstroke Miller Fisher syndrome (see section ▶ 11.2.3) Cranial polyradiculitis (see section ▶ 11.2.3) Creutzfeldt–Jakob disease (see section ▶ 6.7.9): ataxia is sometimes the first sign of this disease
Abbreviations: AVED, ataxia with vitamin E deficiency; DDT, dichlorodiphenyltrichloroethane.

Additional Information

Intermittent cerebellar manifestations are found mainly in the following diseases:

Pyruvate dehydrogenase deficiency.
Hartnup disease.
Familial periodic paroxysmal ataxia.
Multiple sclerosis.

The differential diagnosis of cerebellar ataxia must also include disease processes that cause ataxia but do not involve the cerebellum:

(Contralateral) frontal lobe lesions.
Paresis of any cause.
Lesions of the afferent sensory pathways (e.g., polyneuropathy or posterior column lesion).
Lesions of the parietal sensory cortex.

A prolonged beridden state (“bed ataxia”) and psychogenic mechanisms are further possible causes.

6.12 Dementia

Key Point

Unlike the terms “intellectual disability” and “oligophrenia,” which refer to congenital disturbances, the term “dementia” refers to an acquired degeneration of intellectual and cognitive abilities that persists for at least several months or takes a chronically worsening course, leading to major impairment in the patient’s everyday life. The clinical picture is dominated by personality changes as well as neuropsychological and accompanying neurologic (particularly motor) deficits. Reactive changes, including insomnia, agitation, and depression, are common.

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