Ataxia

ATAXIA

Ataxia is characterized by “unsteadiness” or “clumsiness,” which can result from lesions at multiple levels of the neuraxis. Ataxic disorders affect primarily movement, coordination, gait, and balance, and cognition as well.¹ Ataxia is a multifactorial syndrome with a wide etiology involving cortical, cerebellar, thalamic, spinal, and somatosensory pathways.

PATHOPHYSIOLOGY

Role of the cortex

Frontal lobe lesions can give rise to what is known as frontal ataxia. Frontal ataxia can result in truncal imbalance, gait hesitation, wide-based gait, falls, and disability.² Frontal lobe ataxia can also arise from disturbance of frontopontocerebellar tract (Arnold bundle).³

Role of the cerebellum

The cerebellum modulates functions that are generated in other areas of the brain. As a motor modulator, the cerebellum has two functions:

It balances contractile forces of muscles during motor activity.

It organizes complex motor actions.

Different regions of the cerebellum have different functions. Table 8.1 delineates the functions of the various cerebellar divisions.

Anatomical/functional correlations: A few brief key anatomical facts are useful in understanding the clinical findings of cerebellar dysfunction (Table 8.2).

Clinical manifestations of cerebellar dysfunction: Table 8.3 outlines how cerebellar dysfunction parallels cerebellar phylogenetic organization.

Table 8.1Functional Divisions of the Cerebellum

Phylogenetic Origin	Anatomical Location	Function Modulated
Archicerebellum	Midline Flocculonodular lobe	Vestibular function Eye movements
Paleocerebellum	Midline Vermis (anterior lobe) Pyramis Uvula Paraflocculus	Muscle tone Axial control Stance Gait
Neocerebellum	Midline/hemispheres Middle vermis Cerebellar hemispheres	Movement initiation, planning Fine motor programs Possibly cognition

Table 8.2Key Functional and Anatomical Facts of Cerebellar Dysfunction

Remember	Because	Implications
Location	The cerebellum is located in close proximity to vital brain structures.	• A swelling of the cerebellum or a cerebellar mass can cause hydrocephalus. • A swelling of the cerebellum or a cerebellar mass can displace other brain structures, causing herniation.
Anatomy	The hemispheres coordinate the arms and legs. The midline coordinates the trunk (balance).	• Lesions in the hemispheres result in limb ataxia. • Lesions in the midline result in gait and balance problems, truncal titubation, and a wide-based gait.
Decussation	The cerebellum features a double decussation.	• Lesions of the left cerebellum affect the left side. • Lesions of the right cerebellum affect the right side.
Function	The cerebellum is a motor modulator.	• Ataxia and gait problems can result not only from lesions of the cerebellum but also from lesions of the input and output pathways. Spinal sensory afferents (routed mainly through the medulla) Cortical motor afferents (routed through the pons) Thalamic output pathways (routed through the midbrain)

Table 8.3How Cerebellar Dysfunction Parallels Cerebellar Phylogenetic Organization

Region of Lesions	Type of Dysfunction
Midline cerebellar lesions	Impaired axial control, vestibular function, eye movements, balance, and postural stability
Hemispheric cerebellar lesions	Impaired motor planning, control of fine motor movements; impact on cognitive planning, organizing, and sequencing of executive planning functions parallels impact on motor planning and fine motor programs

Role of the thalamus

Ventrolateral thalamic lesions can result in contralateral ataxia, dysmetria, rebound, and overshoot phenomena. Most lesions are vascular in nature. These entities can be differentiated from ataxic hemiparesis syndrome, in which hemiparesis persists.⁴

Role of the spinal cord

Dorsal column lesions and large-fiber sensorimotor neuropathy can produce somatosensory ataxia. Vitamin B₁₂ deficiency and spinal degenerative diseases like Friedreich ataxia can give rise to ataxic gait.^5,6

Strokes affecting the anterior columns of the spinal cord can also give rise to ataxia, in addition to weakness, by affecting the vestibulospinal, reticulospinal, and ventral spinocerebellar tracts.

ETIOLOGY OF ATAXIA

The etiology of ataxia is multifactorial. The cause of primary ataxia can be a genetic disorder. The causes of secondary ataxia include an extensive list of diseases, such as neurodegenerative, infectious, vascular, traumatic, autoimmune, neoplastic, paraneoplastic, toxic, and demyelinating disorders.

Genetic Causes of Ataxia

No aspects of ataxia are more complex than its genetic etiologies.

Autosomal dominant cerebellar ataxias

Episodic ataxia is a rare genetic entity with autosomal dominant inheritance. Two distinct presentations have been identified, and genetic tests are available.

In episodic ataxia 1 (EA1), episodes of ataxia, with gait imbalance and slurring of speech, occur spontaneously or can be precipitated by sudden movement, excitement, or exercise. The attacks generally last from seconds to several minutes and may recur many times per day.

In episodic ataxia 2 (EA2), the ataxia lasts hours to days, with interictal abnormalities of eye movement. Exertion and stress commonly precipitate the episodes. EA2 notably is due to a genetic defect in a calcium channel (CACNA1A), and different genetic defects of this channel can cause genetically transmitted familial hemiplegic migraine.⁷

– A CAG repeat in this gene causes a progressive ataxia (spinocerebellar ataxia [SCA]6), and there are overlaps in symptomatology.^8,9

– Patients may have migrainous episodes as well as ataxia, and some patients with the SCA6 mutation may present with episodic ataxia.

– Acetazolamide may be helpful in the treatment of episodic ataxia.

Potential identifiable causes of ataxia in individuals who have a history suggestive of a dominant pedigree have proliferated.

There are currently 24 identified causes of autosomal dominant ataxia, including seven syndromes caused by CAG repeats encoding a polyglutamine protein domain (SCA1, SCA2, SCA3, SCA6, SCA7, SCA17, and dentatorubropallidoluysian atrophy [DRPLA]). Another five syndromes have other identified genetic causes.¹⁰ The search for the genetic locus and gene product in the remaining 12 are still ongoing. Currently, genetic testing is available for several of these disorders through a variety of sources.

– Worldwide, approximately 65% of identified families with an autosomal dominant ataxia have SCA1, SCA2, SCA3, SCA6, SCA7, or SCA8. The frequency of individual ataxic syndromes varies from one country to another.^11–17

– SCA3 is the most common form of autosomal dominant cerebellar ataxia, accounting for roughly 21% of identified families (see also Chapter 5). SCA3 is especially common in Brazil, Germany, and China.

– SCA1 is more prevalent in Italy and South Africa.

– DRPLA, a disease with protean manifestations that can present with ataxia, is an uncommon cause of ataxia worldwide. However, it is more prevalent in Japan and in some areas of the southeastern United States (see also Chapters 5 and 7).

– In approximately 30% of families with ataxia and autosomal dominant inheritance, the genetic cause is unknown.

In patients with an onset of ataxia and a family history, autosomal dominant ataxias should be considered. Table 8.4 lists the major known autosomal dominant disorders and their genetic causes. A full discussion of the causes of autosomal dominant ataxia is beyond the scope of this review; however, a few important points are relevant:

Some forms of autosomal dominant ataxia cause a “purely ataxic syndrome,” whereas in others, spasticity, neuropathy, cognitive changes, dystonia, and parkinsonism may be associated features. The identification of features not part of a purely motor ataxia may be helpful in diagnosing a specific disorder.

The genetic testing of unaffected relatives of individuals with a proven autosomal dominant SCA is a complex issue, and in many cases a genetic counselor should be involved before testing is undertaken.

Autosomal dominant ataxias that are due to trinucleotide repeats, such as CAG repeats, have the characteristic of anticipation, in which later generations may exhibit expansion of the repeat and an earlier onset of the disease. The offspring of male carriers are more likely to have a repeat expansion than are the offspring of female carriers.

A special comment is necessary with respect to SCA8. Although most cases of SCA8 appear to be associated with a CTG expansion, CTG expansions in the same region have been shown to occur in some healthy controls. The results of genetic testing in this disorder should therefore be interpreted with particular caution.

Autosomal recessive cerebellar ataxias

Identifiable autosomal recessive causes of ataxia are more common in children, including a host of metabolic abnormalities such as juvenile forms of GM2 gangliosidoses, sulfatide lipidoses, and other syndromes involving the deposition of abnormal metabolic intermediates.¹⁸