Chapter 8: Disorders of Equilibrium

Equilibrium is the ability to maintain orientation of the body and its parts in relation to external space. It depends on continuous visual, labyrinthine, and proprioceptive somatosensory input and its integration in the brainstem and cerebellum. Disorders of equilibrium result from diseases that affect central or peripheral vestibular pathways, the cerebellum, or sensory pathways involved in proprioception. Such disorders usually present with one of two clinical problems: vertigo or ataxia.

VERTIGO

Vertigo is the illusion of movement of the body or the environment. It may be associated with other symptoms, such as impulsion (a sensation that the body is being hurled or pulled in space), oscillopsia (a visual illusion of moving back and forth), nausea, vomiting, or gait ataxia.

Vertigo must be distinguished from nonvertiginous dizziness, which includes sensations of light-headedness, faintness, or giddiness not associated with an illusion of movement. In contrast to vertigo, these sensations are produced by conditions that deprive the brain of blood, oxygen, or glucose (eg, excessive vagal stimulation, orthostatic hypotension, cardiac arrhythmia, myocardial ischemia, hypoxia, or hypoglycemia) and may culminate in loss of consciousness (syncope; see Chapter 12, Seizures & Syncope).

The first step in the differential diagnosis of vertigo is to localize the pathologic process to the peripheral or central vestibular pathways (Figure 8-1). Certain characteristics of vertigo, including the presence of any associated abnormalities, can help differentiate between peripheral and central causes (Table 8-1).

PERIPHERAL VERTIGO

Peripheral vestibular lesions affect the labyrinth of the inner ear or the vestibular division of the vestibulocochlear (VIII) nerve. Vertigo from peripheral lesions tends to be intermittent, lasts for briefer periods, and produces more distress than vertigo of central origin (see next section). Nystagmus (rhythmic oscillation of the eyes) is always present with peripheral vertigo; in this setting it is usually unidirectional and never vertical. Peripheral lesions commonly produce additional symptoms of inner ear or vestibulocochlear (VIII) nerve dysfunction, such as hearing loss and tinnitus (the illusion of hearing a nonexistent sound, such as ringing in the ears).

CENTRAL VERTIGO

Vertigo of central nervous system origin usually results from lesions that affect the brainstem vestibular nuclei or their connections; rarely, vertigo is produced by a cerebral cortical lesion, such as when it occurs as a symptom of complex partial seizures (see Chapter 12, Seizures & Syncope).

Central vertigo may occur with or without nystagmus; if nystagmus is present, it can be vertical, unidirectional, or multidirectional and may differ in character in the two eyes. (Vertical nystagmus is oscillation in a vertical plane; nystagmus produced by upgaze or downgaze is not necessarily in the vertical plane.) Vertigo from central lesions may be accompanied by intrinsic brainstem or cerebellar signs, such as motor or sensory deficits, hyperreflexia, extensor plantar responses, dysarthria, or limb ataxia.

ATAXIA

Ataxia is incoordination or clumsiness of movement that is not the result of muscle weakness. It can be caused by vestibular, cerebellar, or sensory (proprioceptive) disorders. Ataxia can affect eye movement, speech (producing dysarthria), individual limbs, the trunk, stance, or gait (Table 8-2).

VESTIBULAR ATAXIA

The same central and peripheral lesions that cause peripheral or central vertigo can also produce vestibular ataxia. Nystagmus is frequently present and is typically unilateral and most pronounced on gaze away from the side of vestibular involvement. Dysarthria is not a component of vestibular ataxia. Vestibular ataxia is gravity-dependent: Incoordination of the limbs becomes apparent only when the patient attempts to stand or walk.

CEREBELLAR ATAXIA

Cerebellar ataxia is produced by lesions of the cerebellum or its afferent or efferent connections in the cerebellar peduncles, red nucleus, pons, or spinal cord. Because of the crossed connection between the frontal cerebral cortex and the cerebellum, unilateral frontal disease can also occasionally mimic a disorder of the contralateral cerebellar hemisphere. The clinical manifestations of cerebellar ataxia consist of irregularities in the rate, rhythm, amplitude, and force of voluntary movements.

Hypotonia

Cerebellar ataxia is commonly associated with reduced muscle tone (hypotonia), which results in defective posture maintenance. Limbs are easily displaced by a relatively small force and, when shaken by the examiner, exhibit an increased range of excursion. The range of arm swing during walking may be similarly increased. Tendon reflexes take on a pendular quality, so that several oscillations of the limb may occur after the reflex is elicited. When muscles are contracted against resistance that is then removed, the antagonist muscle fails to check the movement and compensatory muscular relaxation does not occur promptly. This results in rebound movement of the limb.

Incoordination

In addition to hypotonia, cerebellar ataxia is associated with incoordination of voluntary movements. Simple movements are delayed in onset, and their rates of acceleration and deceleration are decreased. The rate, rhythm, amplitude, and force of movements fluctuate, so they appear jerky. Clinical manifestations include terminal dysmetria, or “overshoot” when the limb is directed at a target, and terminal intention tremor as the limb approaches the target. More complex movements may be decomposed into a succession of individual movements rather than a single smooth act (asynergia). Movements that involve rapid changes in direction or greater physiologic complexity, such as walking, are most affected.

Eye Movement Abnormalities

Because the cerebellum has a prominent role in controlling eye movements, ocular abnormalities are common in cerebellar disease. These include nystagmus and related ocular oscillations, gaze paresis, and defective saccadic and pursuit movements.

Anatomic Basis of Clinical Signs

Various anatomic regions of the cerebellum (Figure 8-2) have distinct functions, corresponding to the somatotopic organization of their motor, sensory, visual, and auditory connections (Figure 8-3).

1. Midline lesions—The middle zone of the cerebellum—the vermis and flocculonodular lobe and their associated subcortical (fastigial) nuclei—is involved in the control of axial functions, including eye movements, head and trunk posture, stance, and gait. Midline cerebellar disease results in a clinical syndrome characterized by nystagmus and other disorders of ocular motility, dysarthria, oscillation of the head and trunk (titubation), instability of stance, and gait ataxia (Table 8-3). Selective involvement of the superior cerebellar vermis, as in alcoholic cerebellar degeneration, produces exclusively or primarily gait ataxia, as predicted by the somatotopic map of the cerebellum (see Figure 8-3).

2. Hemispheric lesions—The lateral cerebellum (cerebellar hemispheres) helps coordinate movements and maintain tone in the ipsilateral limbs. The hemispheres also regulate ipsilateral gaze. Disorders affecting one cerebellar hemisphere cause ipsilateral hemiataxia and limb hypotonia as well as nystagmus and transient ipsilateral gaze paresis (inability to look voluntarily toward the affected side). Involvement of the medial (paravermian) portion of either cerebellar hemisphere can also produce dysarthria.

3. Diffuse disease—Many cerebellar disorders—typically toxic, metabolic, and degenerative conditions—affect the cerebellum diffusely. The clinical picture in such states combines the features of midline and bilateral hemisphere disease.

SENSORY ATAXIA

Sensory ataxia results from disorders that affect the proprioceptive pathways in peripheral sensory nerves, sensory roots, posterior columns of the spinal cord, or medial lemnisci. Thalamic and parietal lobe lesions are rare causes of contralateral sensory hemiataxia.

Sensations of joint position and movement (kinesthesis) originate in pacinian corpuscles and unencapsulated nerve endings in joint capsules, ligaments, muscle, and periosteum. These sensations are transmitted via heavily myelinated A fibers of primary afferent neurons, which enter the dorsal horn of the spinal cord and ascend uncrossed in the posterior columns (Figure 8-4). Proprioceptive information from the legs is conveyed in the medially located fasciculus gracilis, and information from the arms is conveyed in the more laterally situated fasciculus cuneatus. These tracts synapse on second-order sensory neurons in the nucleus gracilis and nucleus cuneatus in the lower medulla. The second-order neurons decussate as internal arcuate fibers and ascend in the contralateral medial lemniscus. They terminate in the ventral posterior nucleus of the thalamus, from which third-order sensory neurons project to the parietal cortex.

Sensory ataxia from polyneuropathy or posterior column lesions typically affects the gait and legs in symmetric fashion; the arms are involved to a lesser extent or are spared entirely. Examination reveals impaired sensation of joint position in the affected limbs, and vibration sense is also commonly disturbed. Vertigo, nystagmus, and dysarthria are characteristically absent.

HISTORY

SYMPTOMS & SIGNS

Vertigo

True vertigo must be distinguished from a light-headed or presyncopal sensation. Vertigo is typically described as spinning, rotating, or moving. When the description is vague, the patient should be asked specifically if the symptom is associated with a sense of movement, of either the patient or the environment.

The circumstances under which symptoms occur may also be diagnostically helpful. Vertigo is often brought on by changes in head position. In contrast, symptoms that occur upon arising after prolonged recumbency suggest orthostatic hypotension, and may be relieved immediately by sitting or lying down. Orthostatic hypotension and other cerebral hypoperfusion states can also lead to loss of consciousness, which is rarely associated with true vertigo.

Symptoms associated with vertigo may help to localize the site of the causal lesion. Hearing loss or tinnitus strongly suggests a disorder of the peripheral vestibular apparatus (labyrinth or vestibulocochlear [VIII] nerve). Dysarthria, dysphagia, diplopia, or focal weakness or sensory loss affecting the face or limbs points to a likely central (brainstem) lesion.

Ataxia

Ataxia associated with vertigo suggests a vestibular disorder, whereas ataxia with numbness or tingling in the legs is common in patients with sensory ataxia. Because proprioceptive deficits may be partly compensated for by other sensory cues, patients with sensory ataxia may report that their balance is improved by watching their feet when they walk or by using a cane or the arm of a companion for support. Thus, they may be less steady in the dark and have more difficulty descending than ascending stairs.

ONSET & TIME COURSE

The mode of onset and time course may help to identify the cause of a disorder of equilibrium.

Sudden

Sudden onset of disequilibrium, without a prior history of such events, occurs with infarcts and hemorrhages in the brainstem or cerebellum (eg, lateral medullary syndrome, cerebellar hemorrhage or infarction).

Episodic

Episodic disequilibrium of acute onset suggests transient ischemic attacks in the basilar artery distribution, benign positional vertigo, Ménière disease, or vestibular migraine. Disequilibrium from transient ischemic attacks is usually accompanied by cranial nerve deficits, neurologic signs in the limbs, or both. Ménière disease is usually associated with progressive hearing loss and tinnitus as well as vertigo. Vestibular migraine produces headache or other migrainous symptoms (see Chapter 6, Headache & Facial Pain).

Chronic & Progressive

Chronic, progressive disequilibrium evolving over weeks to months is most suggestive of a toxic, nutritional, immune-mediated, or neoplastic disorder. Evolution over months to years is characteristic of an inherited spinocerebellar degeneration.

MEDICAL HISTORY

The medical history should be scrutinized for diseases that affect the sensory pathways (vitamin B₁₂ deficiency, syphilis), cerebellum (hypothyroidism), or both (multiple sclerosis, tumors, paraneoplastic syndromes) and for drugs that impair vestibular or cerebellar function (ethanol, sedative drugs, phenytoin, aminoglycoside antibiotics, quinine, salicylates).

FAMILY HISTORY

A hereditary degenerative disorder may be the cause of chronic, progressive cerebellar ataxia. Such disorders include spinocerebellar degenerations, Friedreich ataxia, ataxia-telangiectasia, and Wilson disease.

GENERAL PHYSICAL EXAMINATION

Several features of the general physical examination may provide clues to the underlying disorder.

1. Orthostatic hypotension is associated with tabes dorsalis, polyneuropathies, and spinocerebellar degenerations.

2. Skin may show oculocutaneous telangiectasia (ataxia-telangiectasia), or it may be dry with brittle hair (hypothyroidism) or have a lemon-yellow coloration (vitamin B₁₂ deficiency).

3. Pigmented corneal (Kayser–Fleischer) rings are seen in Wilson disease (see Chapter 11, Movement Disorders).

4. Skeletal abnormalities include kyphoscoliosis in Friedreich ataxia, hypertrophic or hyperextensible joints in tabes dorsalis, and pes cavus in certain hereditary neuropathies. Abnormalities at the craniocervical junction may be associated with Arnold–Chiari malformation or other congenital anomalies involving the posterior fossa.

NEUROLOGIC EXAMINATION

MENTAL STATUS EXAMINATION

Acute confusional state with ataxia suggests ethanol or sedative drug intoxication or Wernicke encephalopathy. Dementia with cerebellar ataxia is seen in Wilson disease, prion diseases (Creutzfeldt–Jakob disease and Gerstmann–Straüssler–Scheinker syndrome), hypothyroidism, paraneoplastic syndromes, and some spinocerebellar degenerations. Dementia with sensory ataxia suggests syphilitic taboparesis or vitamin B₁₂ deficiency. Amnesia and cerebellar ataxia are associated with chronic alcoholism (Korsakoff amnestic syndrome, see Chapter 5, Dementia & Amnestic Disorders).

STANCE & GAIT

Observation of stance and gait is helpful for distinguishing among vestibular, cerebellar, and sensory ataxia. Ataxia from any cause can produce a wide-based and unsteady stance and gait, often associated with reeling or lurching movements.

Stance

An ataxic patient asked to stand with the feet together may be reluctant or unable to do so. With urging, the patient may gradually move the feet closer together but will typically leave some space between them.

1. Patients with sensory ataxia and some with vestibular ataxia may be able to stand with the feet together and eyes open, using vision to compensate for the loss of proprioceptive or labyrinthine input. When the eyes are closed, eliminating visual cues, there is increased unsteadiness and sometimes falling (Romberg sign). With a vestibular lesion, the tendency is to fall toward the side of the lesion.

2. Patients with cerebellar ataxia cannot compensate for their deficit using visual input, and are unstable on their feet whether the eyes are open or closed.

Gait

1. The gait in cerebellar ataxia is wide-based, often with a staggering quality that can suggest drunkenness. Oscillation of the head or trunk (titubation) may be present. With a unilateral cerebellar hemisphere lesion, there is a tendency to deviate toward the side of the lesion when the patient tries to walk in a straight line or circle or marches in place with eyes closed. Tandem (heel-to-toe) gait, which requires walking with an especially narrow base, is always impaired in cerebellar ataxia.

2. In sensory ataxia, the gait is also wide-based, and tandem gait is poor. In addition, the feet are typically lifted high off the ground and slapped down heavily (steppage gait) to enhance proprioceptive input. Stability may be dramatically improved by letting the patient use a cane or lightly rest a hand on the examiner’s arm for support. If the patient attempts to walk in the dark or with eyes closed, gait is much more impaired.

3. Gait ataxia may also be a manifestation of conversion disorder or malingering. The most helpful observation in identifying factitious gait ataxia is that such patients may exhibit wildly reeling or lurching movements from which they are able to recover without falling, whereas recovery from such awkward positions actually requires excellent equilibrium.

CRANIAL NERVES

Abnormalities of extraocular (III, IV, and VI) and vestibulocochlear (VIII) nerve function are typically present with vestibular disease and often present with lesions of the cerebellum.

Eye Movements

1. The eyes are examined in the primary position of gaze (looking directly forward) to detect misalignment in the horizontal or vertical plane.

2. The patient is asked to turn the eyes in each of the cardinal directions of gaze (see Chapter 1, Neurologic History & Examination) to detect ocular nerve palsy or gaze paresis (inability to move the two eyes coordinately in any of the cardinal directions of gaze).

3. Nystagmus—an involuntary oscillation of the eyes—is characterized in terms of the positions of gaze in which it occurs (gaze-evoked nystagmus), its amplitude, and the direction of its fast phase. Pendular nystagmus, usually due to visual impairment beginning in infancy, has the same velocity in both directions, whereas jerk nystagmus has fast (vestibular-induced) and slow (cortical) phases. The direction of jerk nystagmus is defined by the direction of the fast component.

4. Fast voluntary eye movements (saccades) are elicited by having the patient rapidly shift gaze between targets in different regions of the visual field. Slow voluntary eye movements (pursuits) are assessed by having the patient track a slowly moving target such as the examiner’s finger.

5. Peripheral vestibular disorders produce unidirectional horizontal jerk nystagmus that is maximal on gaze away from the involved side.

6. Central vestibular disorders can cause unidirectional or bidirectional horizontal nystagmus, vertical nystagmus, or gaze paresis.

7. Cerebellar lesions are associated with a wide range of ocular abnormalities, including gaze paresis, defective saccades or pursuits, nystagmus in any or all directions, and ocular dysmetria (overshoot of visual targets during saccadic eye movement).

Hearing

Preliminary examination of the vestibulocochlear (VIII) nerve should include otoscopic inspection of the auditory canals and tympanic membranes, assessment of auditory acuity in each ear, and Weber and Rinne tests (Table 8-4) performed with a 256-Hz tuning fork.

1. In the Weber test, unilateral sensorineural hearing loss (from lesions of the cochlea or vestibulocochlear nerve) causes the patient to perceive the sound produced by a vibrating tuning fork placed at the vertex of the skull as coming from the normal ear. With a conductive (external or middle ear) disorder, sound is localized to the abnormal ear.

2. The Rinne test may also distinguish between sensorineural and conductive defects in the affected ear. Air conduction (tested by holding the vibrating tuning fork next to the external auditory canal) normally produces a louder sound than does bone conduction (tested by placing the base of the tuning fork over the mastoid bone). This also occurs with sensorineural hearing loss due to vestibulocochlear nerve lesions but is reversed in conductive hearing loss.

Positional Vertigo Testing

When vertigo occurs with a change in position, the Nylen–Bárány or Dix–Hallpike maneuver (Figure 8-5) is used to try to reproduce the precipitating circumstance. The head is rapidly lowered 30 degrees below horizontal and the eyes are observed for nystagmus, while the patient is asked to note the onset, severity, and cessation of vertigo. This is repeated with the head and eyes turned first to the right and then to the left.

Positional nystagmus and vertigo are usually associated with peripheral vestibular lesions and are most often a feature of benign positional vertigo. This is typically characterized by severe distress, a latency of several seconds between assumption of the position and the onset of vertigo and nystagmus, a tendency for the response to remit spontaneously (fatigue) as the position is maintained, and attenuation of the response (habituation) as the offending position is repeatedly assumed (Table 8-5). Positional vertigo can also occur with central vestibular disease.

Caloric Testing

Disorders of the vestibuloocular pathways can be detected by caloric testing. Caloric testing should be preceded by careful otoscopic examination and should not be undertaken if the tympanic membrane is perforated. The patient is placed supine with the head elevated 30 degrees to bring the superficially situated lateral semicircular canal into the upright position. Each ear canal is irrigated in turn with cold (~33°C) or warm (~44°C) water for 40 seconds, with at least 5 minutes between tests. Warm water tends to produce less discomfort than cold.

1. In the normal, awake patient, cold-water caloric stimulation produces nystagmus with the slow phase toward and the fast phase away from the irrigated ear. Warm water irrigation produces the opposite response and is generally better tolerated.

2. In patients with unilateral labyrinthine, vestibulocochlear (VIII) nerve, or vestibular nuclear dysfunction, irrigation of the affected side fails to cause nystagmus or elicits nystagmus that is later in onset or briefer in duration than on the normal side.

Other Cranial Nerves

Papilledema associated with disequilibrium suggests an intracranial mass lesion, usually in the posterior fossa, causing increased intracranial pressure. Optic atrophy may be present in multiple sclerosis, neurosyphilis, or vitamin B₁₂ deficiency. A depressed corneal reflex or facial palsy ipsilateral to the lesion (and the ataxia) can accompany cerebellopontine angle tumor. Weakness of the tongue or palate, hoarseness, or dysphagia results from lower brainstem disease.

MOTOR SYSTEM

Examination of motor function in a patient with a disorder of equilibrium should disclose the pattern and severity of ataxia and any associated pyramidal, extrapyramidal, or lower motor neuron involvement that might suggest a cause. The clinical features that help distinguish cerebellar disease from disease involving these other motor systems are summarized in Table 8-6.

Muscle Tone

1. Hypotonia is characteristic of cerebellar disorders; with unilateral cerebellar hemispheric lesions, the ipsilateral limbs are hypotonic.

2. Extrapyramidal hypertonia (rigidity) may occur in disorders that affect both the cerebellum and basal ganglia (eg, Wilson disease, acquired hepatocerebral degeneration, and some spinocerebellar ataxias).

3. Ataxia with spasticity may be seen in conditions that affect both the cerebellum and upper motor neuron pathways (eg, multiple sclerosis, posterior fossa tumors or congenital anomalies, vertebrobasilar infarction, some spinocerebellar ataxias, Friedreich ataxia, and vitamin B₁₂ deficiency).

Coordination

1. Truncal stability is assessed by examining gait (discussed earlier) and by observing the seated, unsupported patient. In addition to gait ataxia, patients may show oscillation of the head or trunk (titubation) and truncal ataxia while seated, causing a tendency to fall (toward the affected side with a lateralized cerebellar lesion).

2. Movement of the arm is observed as the patient’s finger tracks back and forth between his or her own nose or chin and the examiner’s finger. With cerebellar ataxia, an intention tremor characteristically appears near the beginning and end of each such movement, and the patient may overshoot the target.

3. When the patient is asked to raise the arms rapidly to a given height—or when the extended and outstretched arms are displaced by a sudden force—there may be overshoot (rebound). Impaired ability to check the force of muscle contractions can also be demonstrated by having the patient flex the arm at the elbow against resistance, and then suddenly removing the resistance. If the limb is ataxic, continued contraction without resistance may cause the hand to strike the patient (whose head should be turned to the side to avoid being hit in the face).

4. Ataxia of the legs is demonstrated by the supine patient’s inability to run the heel of the foot smoothly up and down the opposite shin.

5. Ataxia of any limb is reflected by irregularity in the rate, rhythm, amplitude, and force of rapid successive tapping movements.

Weakness

1. Pure vestibular, cerebellar, or sensory disorders do not cause weakness, but weakness may occur in disorders that also affect motor pathways.

2. Distal weakness can be seen in disorders that produce sensory ataxia, such as polyneuropathies and Friedreich ataxia.

3. Paraparesis may be superimposed on ataxia in vitamin B₁₂ deficiency, multiple sclerosis, foramen magnum lesions, or spinal cord tumors.

4. Ataxic quadriparesis, hemiataxia with contralateral hemiparesis, or ataxic hemiparesis suggests a brainstem lesion.

Abnormal Involuntary Movements

1. Chorea or parkinsonism (see Chapter 11, Movement Disorders) may accompany cerebellar signs in multiple system atrophy, Wilson disease, acquired hepatocerebral degeneration, certain autosomal dominant spinocerebellar ataxias (eg, SCA3 or Machado–Joseph disease), dentatorubral-pallidoluysian atrophy, and ataxia-telangiectasia.

2. Myoclonus is a prominent manifestation of Creutzfeldt–Jakob disease and dentatorubral-pallidoluysian atrophy, both of which may also produce ataxia.

SENSORY SYSTEM

Joint Position Sense

In sensory ataxia, joint position sense is always impaired in the legs and may be defective in the arms. Joint position sense is tested by asking the patient to detect passive movement of the joints, beginning distally and moving proximally, to establish the upper level of any deficit in each limb. With normal joint position sense, it should be possible to detect even the smallest displacement of a joint by the examiner. Abnormal position sense also can be demonstrated by positioning a limb and having the patient, with eyes closed, place the opposite limb in the same position.

Vibration Sense

Vibration sense is also frequently impaired in sensory ataxia. The patient is asked to detect vibration of a 128-Hz tuning fork placed on a bony prominence. Successively more proximal sites are tested to determine the upper level of the deficit in each limb. The patient’s threshold for detecting vibration is compared with the examiner’s ability to detect it in the hand that holds the tuning fork.

REFLEXES

1. Tendon reflexes are typically hypoactive, with a pendular quality, in cerebellar disorders; unilateral cerebellar lesions produce ipsilateral hyporeflexia.

2. Hyporeflexia of the legs is a prominent manifestation of Friedreich ataxia, tabes dorsalis, and polyneuropathies that cause sensory ataxia.

3. Hyperactive reflexes and extensor plantar responses may accompany ataxia caused by multiple sclerosis, vitamin B₁₂ deficiency, focal brainstem lesions, and certain autosomal dominant spinocerebellar ataxias.

INVESTIGATIVE STUDIES

BLOOD TESTS

Blood studies may disclose low vitamin B₁₂ levels and hematologic abnormalities (macrocytic anemia, leukopenia with hypersegmented neutrophils, thrombocytopenia with giant platelets) in vitamin B₁₂ deficiency, decreased levels of thyroid hormones in hypothyroidism, elevated hepatic enzymes and low ceruloplasmin and copper concentrations in Wilson disease, immunoglobulin deficiency and elevated α-fetoprotein in ataxia-telangiectasia, or autoantibodies in autoimmune (including paraneoplastic) cerebellar degenerations.

DNA TESTING

Blood, saliva, and other sources can be tested for gene defects associated with a variety of disorders that cause disorders of equilibrium. These include certain autosomal dominant spinocerebellar ataxias, dentatorubral-pallidoluysian atrophy, ataxia-telangiectasia, fragile X-associated tremor/ataxia syndrome, and Friedreich ataxia.

CEREBROSPINAL FLUID

The cerebrospinal fluid (CSF) shows elevated protein with cerebellopontine angle, brainstem, or spinal cord tumors; hypothyroidism; and some polyneuropathies. Increased protein concentration with pleocytosis is found in infectious or parainfectious encephalitis, paraneoplastic cerebellar degeneration, and neurosyphilis. Elevated pressure and bloody CSF characterize cerebellar hemorrhage, but lumbar puncture is contraindicated if cerebellar hemorrhage is suspected. CSF VDRL is reactive in tabes dorsalis, and oligoclonal immunoglobulin G (IgG) bands may be present in multiple sclerosis or other inflammatory disorders.

CT & MR IMAGING

Computed tomography (CT) can demonstrate posterior fossa tumors or malformations, cerebellar infarction or hemorrhage, and cerebellar or brainstem atrophy associated with degenerative disorders (eg, spinocerebellar ataxias). Magnetic resonance imaging (MRI) provides better visualization of posterior fossa lesions, including cerebellopontine angle tumors, and is superior to CT for detecting lesions of multiple sclerosis. MRI can also detect endolymphatic hydrops in the inner ear in Ménière disease.

EVOKED POTENTIALS

Visual evoked potentials may be helpful in evaluating patients with suspected multiple sclerosis. Brainstem auditory evoked potentials can localize disease to peripheral vestibular pathways and help identify cerebellopontine angle tumors.

CHEST X-RAY & ECHOCARDIOGRAPHY

The chest X-ray may reveal a lung tumor in paraneoplastic cerebellar degeneration, and the chest X-ray or echocardiogram may provide evidence of cardiomyopathy associated with Friedreich ataxia.

AUDIOMETRY

This is useful in vestibular disorders associated with auditory impairment and can distinguish conductive, labyrinthine, vestibulocochlear (VIII) nerve, and brainstem disease. Tests of pure tone hearing are abnormal when sounds are transmitted through air with conductive hearing loss and when transmitted through either air or bone with labyrinthine or vestibulocochlear (VIII) nerve disorders. Speech discrimination is markedly impaired with vestibulocochlear (VIII) nerve lesions, less impaired in labyrinthine disorders, and normal with conductive hearing loss or brainstem disease.

ELECTRONYSTAGMOGRAPHY

This can detect and characterize nystagmus, including that elicited by caloric stimulation.

Table 8-7 provides a list of peripheral vestibular disorders and features helpful in their differential diagnosis.

BENIGN POSITIONAL VERTIGO

Positional vertigo is vertigo that occurs upon changing head position. It is usually associated with peripheral vestibular lesions, but also may be due to central (brainstem or cerebellar) disease.

PATHOGENESIS

Benign positional vertigo is the most common cause of vertigo of peripheral origin. It results from canalolithiasis, in which debris (otoconia) floating in the endolymph stimulates a semicircular canal, most often the posterior canal. Benign positional vertigo may follow head trauma, but in most instances, no precipitating factor can be determined. When head trauma is the cause, the labyrinth is the usual site of injury. However, fractures of the petrosal bone may lacerate the vestibulocochlear (VIII) nerve, producing vertigo and hearing loss; hemotympanum or CSF otorrhea suggests such a fracture.

CLINICAL FINDINGS

The syndrome is characterized by brief (seconds to minutes) episodes of severe vertigo and nystagmus, which may be accompanied by nausea and vomiting. Symptoms may occur with any change in head position but are usually most severe in the lateral decubitus position with the affected ear down. Episodic vertigo typically continues for several weeks and then resolves spontaneously; in some cases, it is recurrent. Hearing loss is not a feature.

Peripheral and central causes of positional vertigo usually can be distinguished by the Nylen–Bárány or Dix–Hallpike maneuver (see Figure 8-5). Vertigo evoked by this maneuver is always accompanied by positional nystagmus when the underlying cause is peripheral, and is typically unidirectional, rotatory, and delayed in onset by several seconds after assumption of the precipitating head position. If the position is maintained, nystagmus and vertigo resolve within seconds to minutes. If the maneuver is repeated, the response is attenuated. In contrast, positional vertigo of central origin tends to be less severe, and positional nystagmus may be absent. In contrast, there is no latency, fatigue, or habituation in central positional vertigo.

When benign positional vertigo is documented in this manner, no additional diagnostic investigation (eg, auditory or vestibular testing or imaging) is required.

TREATMENT

The mainstay of treatment is repositioning (Epley) maneuvers, which use gravity to move endolymphatic debris out of the semicircular canal and into the vestibule, where it can be reabsorbed. In one such maneuver (Figure 8-6), the head is turned 45 degrees in the direction of the affected ear (determined clinically, as described earlier), and the patient reclines to a supine position, with the head (still turned 45 degrees) hanging down over the end of the examining table. The head, still hanging down, is then turned 90 degrees in the opposite direction, to 45 degrees toward the opposite ear. Next, the patient rolls to a lateral decubitus position with the affected ear up, and the head still turned 45 degrees toward the unaffected ear and hanging down. Finally, the patient turns to a prone position and sits up.

Vestibulo-suppressant drugs (Table 8-8) may also be useful in the acute period. Vestibular rehabilitation, which promotes compensation for vestibular dysfunction through the recruitment of other sensory modalities, may also be helpful.

MÉNIÈRE DISEASE

Ménière disease is characterized by repeated episodes of vertigo lasting from ~20 minutes to ~12 hours, accompanied by tinnitus and progressive, low- to medium-frequency sensorineural hearing loss. It is thought to be the second most common peripheral cause of vertigo, after benign positional vertigo.

PATHOGENESIS

Most cases are sporadic, but up to ~10% cluster in families. Onset is usually between ages 20 and 50 years, and men are affected more often than women. Symptoms are thought to result from an increase in the volume of labyrinthine endolymph (endolymphatic hydrops), which results in distension of the endolymphatic space and its encroachment on the perilymphatic space. The cochlear duct and saccule are affected most often. The cause of endolymphatic hydrops is unknown, but immune mechanisms may be involved.

CLINICAL FINDINGS

At the time of the first acute attack, patients already may have noted the insidious onset of tinnitus, hearing loss, and a sensation of fullness in the ear. Acute attacks are characterized by vertigo, nausea, and vomiting and recur at intervals ranging from weeks to years. Hearing deteriorates in a stepwise fashion, with bilateral involvement in ~15% to ~50% of patients. As hearing loss increases, vertigo tends to become less severe.

Physical examination during an acute episode shows spontaneous horizontal or rotatory nystagmus (or both) that may change direction. Although spontaneous nystagmus is characteristically absent between attacks, caloric testing usually reveals impaired vestibular function. The hearing deficit is not always sufficiently advanced to be detectable at the bedside. Audiometry shows low-frequency pure-tone hearing loss that fluctuates in severity, impaired speech discrimination, and increased sensitivity to loud sounds. Endolymphatic hydrops can be demonstrated by MRI.

TREATMENT

Symptomatic management of acute attacks is with antihistamines, benzodiazepines, or other drugs listed in Table 8-8. Between episodes, patients may be treated with a low-salt diet and diuretics, such as hydrochlorothiazide (50 mg orally daily) plus triamterene (25 mg orally daily), or with the histamine H₃ receptor antagonist betahistine (16-48 mg orally three times daily). In persistent, disabling cases, vestibular ablation by intratympanic gentamicin, vestibular (VIII) nerve section, or labyrinthectomy may be beneficial.

ACUTE PERIPHERAL VESTIBULOPATHY

This term is used to describe a spontaneous attack of vertigo of inapparent cause that resolves spontaneously and is not accompanied by hearing loss or central nervous system dysfunction. It includes disorders diagnosed as acute labyrinthitis or vestibular neuronitis and may follow a febrile illness. Acute peripheral vestibulopathy may result from viral infection (eg, reactivation of latent herpes simplex virus in vestibular ganglia), but this association has never been proven. Acute peripheral vestibulopathy is considered the third most common cause of peripheral vertigo, after benign positional vertigo and Ménière disease.

The disorder is characterized by the acute onset of vertigo, nausea, and vomiting, typically lasting up to 2 weeks. Symptoms may recur, and some degree of vestibular dysfunction may be permanent. During an attack, the patient appears acutely ill, typically lies on one side with the affected ear upward, and is reluctant to move the head. Nystagmus with the fast phase away from the affected ear is always present. The vestibular response to caloric testing is defective in one or both ears but auditory acuity is normal.

Acute peripheral vestibulopathy must be distinguished from central causes of acute vertigo; the latter are suggested by vertical nystagmus, altered consciousness, motor or sensory deficit, or dysarthria.

Treatment of acute peripheral vestibulopathy is with a 10- to 14-day course of prednisone (20 mg orally twice daily), the drugs listed in Table 8-8, or both.

OTOSCLEROSIS

Otosclerosis is caused by immobility of the stapes. Its most distinctive feature is bilateral conductive hearing loss, but sensorineural hearing loss and recurrent episodic vertigo may also occur, whereas tinnitus is infrequent. Auditory symptoms usually begin before 30 years of age, and familial occurrence is common. Imaging studies may be diagnostically useful. Sodium fluoride, vitamin D, intratympanic dexamethasone, and surgical stapedectomy are recognized treatments.

CEREBELLOPONTINE ANGLE TUMOR

PATHOGENESIS

The most common tumor in the cerebellopontine angle—a triangular region in the posterior fossa bordered by the cerebellum, lateral pons, and petrous ridge—is the histologically benign acoustic neuroma. Also termed neurilemoma, neurinoma, or schwannoma, it typically arises from the neurilemmal sheath of the vestibular portion of the vestibulocochlear (VIII) nerve in the internal auditory canal. Less common tumors at this site include meningiomas, epidermoid tumors, and lipomas.

Acoustic neuromas usually occur as isolated lesions in patients 30 to 60 years old, but may also be a manifestation of neurofibromatosis. Neurofibromatosis 1 (von Recklinghausen disease) is a common autosomal dominant disorder arising from mutations in the gene for neurofibromin 1 (NF1). Characterized by unilateral acoustic neuromas, neurofibromatosis 1 is associated with café-au-lait spots on the skin, cutaneous neurofibromas, axillary or inguinal freckles, optic gliomas, iris hamartomas, and dysplastic bony lesions. Neurofibromatosis 2 is a rare autosomal dominant disorder caused by mutations in the gene for merlin (NF2). Its hallmark is bilateral acoustic neuromas, which may be accompanied by other central or peripheral nervous system tumors, including neurofibromas, meningiomas, gliomas, and schwannomas.

PATHOPHYSIOLOGY

Cerebellopontine angle tumors produce symptoms by compressing or displacing the cranial nerves, brainstem, and cerebellum and by obstructing CSF flow. Because of their anatomic relationship to the vestibulocochlear (VIII) nerve, the trigeminal (V) and facial (VII) nerves are often affected.

CLINICAL FINDINGS

Symptoms & Signs

Insidious hearing loss is usually the initial symptom. Less often, patients present with headache, vertigo, gait ataxia, facial pain, tinnitus, a sensation of fullness in the ear, or facial weakness. Vertigo ultimately develops in 20% to 30% of patients, but nonspecific unsteadiness is more common. Symptoms may be stable or progress over months or years.

Unilateral sensorineural hearing loss is the most common finding on examination. Other frequent findings are ipsilateral facial palsy, depressed or absent corneal reflex, and sensory loss over the face. Ataxia, spontaneous nystagmus, other lower cranial nerve palsies, and signs of increased intracranial pressure are less common. Unilateral vestibular dysfunction can usually be demonstrated with caloric testing.

Laboratory Findings

Audiometry shows a sensorineural deficit with high-frequency pure-tone hearing loss, poor speech discrimination, and marked tone decay. CSF protein is elevated in approximately 70% of patients, usually in the range of 50 to 200 mg/dL. The most useful imaging study is MRI of the cerebellopontine angle. Acoustic neuromas may cause abnormal brainstem auditory evoked potentials.

DIFFERENTIAL DIAGNOSIS

Meningioma should be considered in patients who present with more than isolated vestibulocochlear (VIII) nerve disease. Cholesteatoma is suggested by conductive hearing loss, early facial weakness, or facial twitching, with normal CSF protein. Metastatic carcinoma may also present as a lesion in the cerebellopontine angle.

TREATMENT

Treatment is complete surgical excision. Patients with acoustic neuroma and neurofibromatosis 2 may benefit from bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGFA). In untreated cases, severe complications can result from brainstem compression or hydrocephalus.

TOXIC VESTIBULOPATHIES

ALCOHOL

Alcohol can cause acute positional vertigo beginning as early as ~30 minutes after ingesting amounts sufficient to produce blood levels ≥40 mg/dL. Alcohol diffuses into the cupula, then into the endolymph, leaves the cupula, and finally leaves the endolymph. Because alcohol is less dense than endolymph, this renders the peripheral vestibular system gravity-sensitive, resulting in two phases of vertigo that together last up to ~12 hours. During the first phase, the cupula is lighter than endolymph, and vertigo is accompanied by nystagmus that beats toward the lower ear with the patient in the lateral recumbent position. About 3.5-5 hours after this phase resolves, as endolymph becomes heavier than the cupula, vertigo returns, with nystagmus that beats toward the upper ear in lateral recumbency.

AMINOGLYCOSIDES

Aminoglycoside antibiotics are widely recognized ototoxins that can produce both vestibular and auditory symptoms. Streptomycin, gentamicin, and tobramycin are the agents most likely to cause vestibular toxicity, and amikacin, kanamycin, and tobramycin are associated with hearing loss. Aminoglycosides concentrate in the perilymph and endolymph and exert their ototoxic effects by destroying sensory hair cells. The risk of toxicity is related to drug dosage, plasma concentration, duration of therapy, conditions—such as renal failure—that impair drug clearance, preexisting vestibular or cochlear dysfunction, and concomitant administration of other ototoxic agents.

Symptoms of vertigo, nausea, vomiting, and gait ataxia may begin acutely; physical findings include spontaneous nystagmus and the Romberg sign. The acute phase typically lasts 1 to 2 weeks and is followed by gradual improvement. Prolonged or repeated aminoglycoside therapy may be associated with chronic, progressive vestibular dysfunction.

SALICYLATES

Salicylates, when used chronically and in high doses, can cause vertigo, tinnitus, and sensorineural hearing loss—all usually reversible when the drug is discontinued. Symptoms result from cochlear and vestibular end-organ damage. Salicylism is characterized by headache, tinnitus, hearing loss, vertigo, nausea, vomiting, thirst, hyperventilation, and sometimes a confusional state. Severe intoxication may be associated with fever, skin rash, hemorrhage, dehydration, seizures, psychosis, or coma. Laboratory findings include a high plasma salicylate level (≥0.35 mg/mL) and combined metabolic acidosis and respiratory alkalosis. Treatments include gastric lavage, activated charcoal, forced diuresis, peritoneal dialysis or hemodialysis, and hemoperfusion.

QUININE & QUINIDINE

Quinine and quinidine can produce cinchonism, which resembles salicylate intoxication in many respects. Manifestations include tinnitus, impaired hearing, vertigo, visual deficits (including disordered color vision), nausea, vomiting, abdominal pain, hot flushed skin, and sweating. Fever, encephalopathy, coma, and death can occur. Symptoms usually result from overdosage, but can also be due to idiosyncratic reactions to therapeutic doses.

CISPLATIN

Cisplatin is an antineoplastic drug used to treat solid tumors of the ovary, testis, uterine cervix, lung, head and neck, bladder, and other tissues. It causes ototoxicity, which is commonly bilateral and irreversible, in a high percentage of patients. Tinnitus, hearing loss, and vestibular dysfunction may all occur.

VESTIBULOCOCHLEAR NEUROPATHY

Involvement of the vestibulocochlear (VIII) nerve by systemic disease is an uncommon cause of vertigo. Basilar meningitis from bacterial, syphilitic, or tuberculous infection or sarcoidosis can compress the vestibulocochlear and other cranial nerves, but hearing loss is a more common consequence than vertigo. Metabolic disorders associated with vestibulocochlear neuropathy include hypothyroidism, diabetes, and Paget disease.

Many disorders can produce acute or chronic cerebellar dysfunction (Table 8-9). Some of these may also involve central vestibular pathways (eg, Wernicke encephalopathy, vertebrobasilar ischemia or infarction, multiple sclerosis, and posterior fossa tumors). For this reason, cerebellar and central vestibular disorders are considered together here.

ACUTE DISORDERS

DRUG INTOXICATION

Pancerebellar dysfunction—manifested by nystagmus, dysarthria, and limb and gait ataxia—is a prominent feature of intoxication with ethanol, sedative-hypnotics, anticonvulsants, and some hallucinogens. The severity of symptoms is dose-related; therapeutic doses of sedatives or anticonvulsants commonly produce nystagmus, but other cerebellar signs imply toxicity. Because drug-induced cerebellar ataxia is often associated with altered consciousness, drug intoxication is discussed in detail in Chapter 4, Confusional States.

WERNICKE ENCEPHALOPATHY

Pathogenesis

Wernicke encephalopathy (discussed in more detail in Chapter 4, Confusional States) is an acute disorder comprising the clinical triad of ataxia, ophthalmoplegia, and confusion. It is caused by thiamine (vitamin B₁) deficiency and is most common in chronic alcoholics, but may occur as a consequence of malnutrition from any cause.

Clinical Findings

Cerebellar and vestibular involvement both contribute to ataxia, which affects gait primarily or exclusively; the legs are ataxic in only about 20% of patients, and the arms in 10%. Dysarthria is rare. Other findings include an amnestic syndrome or global confusional state, horizontal or combined horizontal and vertical nystagmus, bilateral lateral rectus palsy, and absent ankle reflexes. Caloric testing shows bilateral or unilateral vestibular dysfunction. Conjugate gaze palsy, pupillary abnormalities, and hypothermia can occur.

Diagnosis & Treatment

The diagnosis should be suspected in alcoholic and other malnourished patients and is confirmed by the clinical response to thiamine. Ocular palsies improve within hours and ataxia, nystagmus, and confusion within a few days. Horizontal nystagmus may persist. Ataxia is fully reversible in only approximately 40% of patients, in whom recovery takes weeks to months.

VERTEBROBASILAR ISCHEMIA & INFARCTION

Transient ischemic attacks and strokes in the vertebrobasilar system (see also Chapter 13, Stroke) are often associated with ataxia or vertigo.

Internal Auditory Artery Occlusion

The internal auditory (labyrinthine) artery originates from the anterior inferior cerebellar (or, less commonly, basilar) artery (Figure 8-7) and supplies the vestibulocochlear (VIII) nerve. Isolated occlusion of this vessel causes vertigo and nystagmus, with the fast phase directed away from the involved side, and unilateral sensorineural hearing loss.

Lateral Medullary Infarction

Lateral medullary infarction, which is caused by occlusion of the proximal vertebral artery and, less often, the posterior inferior cerebellar artery, produces Wallenberg syndrome (Figure 8-8). Clinical manifestations vary, but the most common are listed here, together with their likely anatomic correlates.

1. Vertigo, nausea, vomiting, and nystagmus (vestibular nucleus)

2. Loss of pain and temperature sense over the contralateral limbs and trunk (lateral spinothalamic tract)

3. Loss of pain and temperature sense over the ipsilateral face (spinal trigeminal nucleus and tract)

4. Truncal and gait ataxia (vestibular nucleus and inferior cerebellar peduncle)

5. Ipsilateral limb ataxia (inferior cerebellar peduncle)

6. Ipsilateral Horner syndrome (descending sympathetic tract)

7. Dysphagia, dysarthria, hoarseness, and ipsilateral palatal paralysis (nucleus ambiguus)

Cerebellar Infarction

The cerebellum is supplied by the superior cerebellar, anterior inferior cerebellar, and posterior inferior cerebellar arteries. The territory supplied by each of these vessels is highly variable, but the superior, middle, and inferior cerebellar peduncles are typically supplied by the superior, anterior inferior, and posterior inferior cerebellar arteries, respectively.

Signs of cerebellar infarction include ipsilateral limb ataxia, lateropulsion (falling toward or, less commonly, away from the side of the lesion), and hypotonia. Headache, nausea, vomiting, vertigo, nystagmus, dysarthria, ocular or gaze palsies, facial weakness or sensory loss, and contralateral hemiparesis or hemisensory deficit may also occur. Occlusions of the superior cerebellar, anterior inferior cerebellar, and posterior inferior cerebellar arteries may be clinically indistinguishable, but associated brainstem findings can help in this regard. Thus, midbrain, pontine, and medullary signs may suggest infarction in the superior cerebellar, anterior inferior cerebellar, and posterior inferior cerebellar territories, respectively. Brainstem infarction or compression by cerebellar edema can result in coma and death.

Diagnosis is by CT or MRI, which differentiates between infarction and hemorrhage and should be obtained promptly. Brainstem compression is an indication for surgical decompression and resection of infarcted tissue, which can be lifesaving.

Paramedian Midbrain Infarction

Paramedian midbrain infarction, caused by occlusion of the paramedian penetrating branches of the basilar artery, affects the oculomotor (III) nerve root fibers and red nucleus (Figure 8-9). The result (Benedikt syndrome) is ipsilateral oculomotor (III) nerve involvement (producing medial rectus palsy with a fixed dilated pupil) and contralateral limb ataxia (typically affecting only the arm). Cerebellar signs result from involvement of the red nucleus, which receives a crossed projection from the cerebellum in the ascending limb of the superior cerebellar peduncle.

CEREBELLAR HEMORRHAGE

Pathogenesis

Cerebellar hemorrhage (see also Chapter 13, Stroke) is usually due to hypertensive vascular disease; less common causes include anticoagulation, arteriovenous malformation, blood dyscrasia, tumor, and trauma. Hypertensive cerebellar hemorrhages are usually located in the deep white matter of the cerebellum and commonly extend into the fourth ventricle.

Clinical Findings

Hypertensive cerebellar hemorrhage causes the sudden onset of headache, which may be accompanied by nausea, vomiting, and vertigo, followed by gait ataxia and impaired consciousness, usually evolving over hours.

At presentation, patients can be fully alert, confused, or comatose. The blood pressure is typically elevated, and nuchal rigidity may be present. The pupils are often small and sluggishly reactive. Ipsilateral gaze palsy (with gaze preference away from the side of hemorrhage) and ipsilateral peripheral facial palsy are common. The gaze palsy cannot be overcome by cold-water caloric stimulation. Nystagmus may be present, and the ipsilateral corneal reflex may be depressed. The patient, if alert, exhibits ataxia of stance and gait; limb ataxia is less common. In the late stage of brainstem compression, there is spasticity in the legs and extensor plantar responses.

Diagnosis & Treatment

The diagnosis of cerebellar hemorrhage can be missed or delayed, and death result, if gait is not tested promptly in every patient with hypertension and either acute headache or depressed consciousness. This is because gait ataxia is often the earliest neurologic sign in this condition.

The CSF is frequently bloody, but lumbar puncture should be avoided if cerebellar hemorrhage is suspected, because it may lead to brain herniation. Diagnosis is by CT. Treatment consists of surgical evacuation of the hematoma, which can be lifesaving.

INFLAMMATORY DISORDERS

Viral Infection

Cerebellar ataxia can result from cerebellitis due to a variety of viral infections. Among these, varicella-zoster is most common in children, and reactivation of varicella-zoster or Ebstein–Barr virus is most common in adults. Less frequent causes include coxsackie virus, echo virus, influenza virus, and parvovirus B19. Truncal ataxia is usually the most prominent sign of cerebellar involvement and may be accompanied by headache, nausea, vomiting, and altered consciousness. Viral cerebellitis is usually self-limited and recovery is good, especially in children.

JC polyoma virus, which causes progressive multifocal leukoencephalopathy, can infect the cerebellum of immunocompromised patients. Progressive multifocal leukoencephalopathy is discussed in more detail in Chapter 5, Dementia & Amnestic Disorders.

Bacterial Infection

Bacterial infection is an uncommon cause of cerebellar ataxia, but 10% to 20% of brain abscesses are located in the cerebellum, and ataxia may be a feature of encephalitis due to Listeria monocytogenes. Listeria typically affects healthy adults who consume tainted foods, such as cheese, meat, or fruit. A prodromal flulike illness is followed by a neurologic disorder that involves the brainstem and cerebellum. Signs include ataxia, cranial nerve (especially V, VI, VII, IX, and X) palsies, hemiparesis, altered consciousness, and meningismus. MRI shows diffuse and focal, abscess-like lesions and CSF shows pleocytosis. Treatment is with ampicillin (2 g IV every 4 hours), often together with gentamicin (1.5 mg/kg IV loading followed by 1-2 mg/kg IV every 8 hours).

Fungal Infection

Fungal infection of the cerebellum is rare but may occur in immunocompromised patients or following neurosurgical procedures or epidural injections. Organisms involved include Aspergillus.

Prion Infection

Prion diseases (Creutzfeldt–Jakob and Gerstmann–Straüssler–Scheinker syndrome) can produce cerebellar ataxia associated with dementia. These are discussed in more detail in Chapter 5, Dementia & Amnestic Disorders.

Acute Postinfectious Cerebellar Ataxia of Childhood

Acute postinfectious cerebellar ataxia of childhood is the most common cause of acute ataxia in children. It usually affects children aged 1-6 years and follows a viral illness or vaccination. Gait ataxia is the most prominent clinical feature. MRI is typically normal; CSF may show mild pleocytosis. Most patients recover completely within one month.

Acute Disseminated Encephalomyelitis

Acute disseminated encephalomyelitis, a monophasic illness caused by immune-mediated demyelination of CNS white matter, may affect the cerebellum, producing ataxia. Other common features include impaired consciousness, seizures, focal neurologic signs, and myelopathy (see Chapter 9, Motor Disorders).

Fisher Variant of Guillain–Barré Syndrome

Ataxia, ophthalmoplegia, and areflexia characterize this variant of Guillain–Barré syndrome (see Chapter 9, Motor Disorders). Incomplete forms of the Fisher variant and forms that overlap with classic Guillain–Barré syndrome also occur. Symptoms develop over days and are thought to be caused by autoantibodies against GQ1b ganglioside located on ocular motor and dorsal root ganglion nerves. Ataxia primarily affects the gait and trunk, with lesser involvement of the individual limbs; dysarthria is uncommon. Ophthalmoplegia can involve the pupils as well as extraocular muscles. CSF protein may be elevated and anti-GQ1b antibodies may be detected in the blood. Respiratory insufficiency is rare, and the usual course is a gradual and often complete recovery over weeks to months.

EPISODIC DISORDERS

MOTION SICKNESS

Motion sickness affects up to 30% of the general population, with susceptibility influenced by genetics, age (peak ~9 years), and concurrent disorders (eg, migraine). Symptoms are triggered by real or perceived movement of the affected individual or of his or her environment, as occurs during vehicular travel, watching 3D movies, or using virtual reality devices. Features include nausea, vomiting, vertigo, headache, pallor, sweating, salivation, anorexia, osmophobia, and a sensation of warmth. Motion sickness may be prevented by lying supine or viewing the horizon while traveling, and habituation therapy may be effective in the long term. Muscarinic anticholinergic drugs (eg, scopolamine, 1.5 mg transdermally) and H1 antihistamines (eg, dimenhydrinate, 50 mg orally) are useful for acute attacks, but dopamine D₂ and serotonin 5-HT₃ receptor antagonist anti-emetics are not.

VESTIBULAR MIGRAINE

Vestibular migraine is characterized by episodic vertigo accompanied by other features of migraine attacks, such as headache, photophobia, phonophobia, or visual aura. Treatment includes vestibular rehabilitation training and drugs used for other forms of migraine, as discussed in detail in Chapter 6, Headache & Facial Pain.

AUTOSOMAL DOMINANT EPISODIC ATAXIAS

Episodic ataxias are autosomal dominant disorders characterized by transient attacks of cerebellar ataxia that may be precipitated by physical or emotional stress. Episodic ataxia 1 (EA1) results from mutations in KCNA1, which codes for the Kv1.1 voltage-gated potassium channel. Attacks last from seconds to minutes and may occur many times per day; myokymia—a quivering, involuntary movement of muscle—commonly occurs between episodes.

EA2 is caused by mutations in CACNA1A, which codes for the α_1A subunit of the P/Q-type voltage-gated calcium channel; this gene is also affected in spinocerebellar ataxia 6 (SCA6; discussed later in this chapter) and familial hemiplegic migraine (see Chapter 6, Headache & Facial Pain). Attacks are more prolonged than in EA1, typically lasting for hours, and nystagmus and slowly progressive ataxia persist between acute episodes. Acetazolamide (500 mg orally four times daily) can often prevent or relieve acute symptoms in EA2.

EA5 likewise affects voltage-gated calcium channels, but in this case the mutation is in CACNB4, which encodes the β subunit. EA6 is due to mutations in SLC1A3, which encodes the EAAT1 glial glutamate transporter. Glutamate uptake is reduced, leading to enhanced excitatory input onto cerebellar Purkinje cells. EA1 and EA6 are thought to impair channel function through dominant negative effects, whereas EA2 involves haploinsufficiency; the mechanism in EA5 is uncertain.

CHRONIC DISORDERS

MULTIPLE SCLEROSIS

Pathogenesis

Multiple sclerosis (see also Chapter 9, Motor Disorders) is characterized clinically by remitting and relapsing neurologic dysfunction at multiple sites in the central nervous system. Because these include vestibular, cerebellar, and sensory pathways, multiple sclerosis can produce disorders of equilibrium. Symptoms and signs are associated with demyelination and axonal loss, which primarily affect white matter.

Clinical Findings

Cerebellar signs are present in approximately one-third of patients on initial examination and ultimately develop in twice that number. Nystagmus, dysarthria, and limb ataxia are common, but vertigo is less so. Gait ataxia is a presenting complaint in 10-15% of patients and is usually due to cerebellar involvement.

Diagnosis

The diagnosis relies on a history of multiple episodes of neurologic dysfunction separated in both time and space. Subclinical lesions may be evident from physical findings such as optic neuritis, internuclear ophthalmoplegia, or pyramidal signs, or from laboratory investigations. CSF analysis may reveal oligoclonal bands, elevated IgG, increased protein, or a mild lymphocytic pleocytosis. Visual, auditory, or somatosensory evoked response recording (see Chapter 2, Investigative Studies) can also document subclinical sites of involvement. CT or MRI shows demyelination.

Treatment

Treatment is discussed in Chapter 9, Motor Disorders.

ALCOHOLIC CEREBELLAR DEGENERATION

Pathogenesis

A characteristic cerebellar syndrome may develop in chronic alcoholics, probably as a result of nutritional deficiency. Degenerative changes in the cerebellum are largely restricted to the superior vermis (Figure 8-10), which is also the site of involvement in Wernicke encephalopathy.

Clinical Features

Alcoholic cerebellar degeneration is most common in men between ages 40 and 60 years. Patients typically have a history of daily or binge drinking lasting 10 or more years with associated dietary inadequacy. Most have experienced other medical complications of alcoholism, such as liver disease, delirium tremens, Wernicke encephalopathy, or polyneuropathy. Cerebellar degeneration usually has an insidious onset and progresses gradually over weeks to months, eventually reaching a plateau of dysfunction. In occasional cases, ataxia appears abruptly.

Gait ataxia is universal and almost always the problem that brings the patient to medical attention. The legs are ataxic on heel-knee-shin testing in approximately 80% of patients. Common associated findings include distal sensory deficits in the feet and absent ankle reflexes, which result from polyneuropathy. Ataxia of the arms, nystagmus, dysarthria, hypotonia, and truncal instability are less frequent. CT or MRI may show cerebellar atrophy (Figure 8-11).

Treatment

Patients should receive thiamine because of the likely role of thiamine deficiency in pathogenesis. Abstinence from alcohol and adequate nutrition may help prevent progression.

TOXIN-INDUCED CEREBELLAR DEGENERATION

Purkinje cells and granule cells of the cerebellum are selectively vulnerable to a variety of toxins. These may cause cerebellar degeneration associated with nystagmus, dysarthria, and ataxia affecting the limbs, trunk, and gait. In addition to alcohol, this syndrome can be produced by phenytoin, lithium, amiodarone, fluorouracil, cytarabine, toluene, lead, mercury, and thallium. Treatment is discontinuation of the offending agents and, for fluorouracil, administration of thiamine (vitamin B₁), but toxin-induced cerebellar syndromes may be irreversible.

HYPOTHYROIDISM

Hypothyroidism can cause a subacute or chronically progressive cerebellar syndrome, which is most common in middle-aged and elderly women. Symptoms evolve over months to years. Systemic symptoms (eg, myxedema) usually precede the cerebellar disorder.

Gait ataxia is universal and is the most prominent finding. Limb ataxia is also common and may be asymmetric. Dysarthria and nystagmus occur less frequently. Other neurologic disorders related to hypothyroidism may coexist with cerebellar involvement, including sensorineural hearing loss, carpal tunnel syndrome, neuropathy, or myopathy.

Diagnosis and treatment are discussed in Chapter 4, Confusional States.

AUTOIMMUNE CEREBELLAR DEGENERATION

Paraneoplastic Cerebellar Degeneration

Autoimmune cerebellar degeneration can occur as a remote (paraneoplastic) effect of systemic cancer. Lung cancer (especially small-cell), ovarian cancer, Hodgkin disease, and breast cancer are the most commonly associated neoplasms.

Paraneoplastic degeneration affects the cerebellar vermis and hemispheres diffusely. The cause appears to be autoimmunity involving antineural antibodies, which are directed against either neuronal nuclear antigens or antigens expressed more specifically in the cell membranes or cytoplasm of cerebellar Purkinje cells (Table 8-10).

Cerebellar symptoms can appear either before or after the diagnosis of cancer and typically evolve over months. Gait and limb ataxia are prominent, and may be asymmetric. Dysarthria is common but nystagmus is rare. Involvement of additional regions besides the cerebellum may produce dysphagia, dementia, memory disturbance, pyramidal signs, or neuropathy.

Onconeural antibodies can sometimes be detected in the blood, and the CSF may show a mild lymphocytic pleocytosis or elevated protein.

Diagnosis may be difficult when neurologic symptoms precede the discovery of cancer. Dysarthria, dysphagia, and ataxia of the arms help distinguish paraneoplastic cerebellar degeneration from syndromes produced by chronic alcoholism or hypothyroidism. However, Wernicke encephalopathy should always be considered because patients with cancer may suffer from malnutrition.

Treatment is of the underlying tumor, supplemented in some cases by immunotherapy with immunoglobulin G, corticosteroids, cyclophosphamide, tacrolimus, rituximab, mycophenolate, or plasma exchange. The disorder usually progresses steadily, but may stabilize or remit with treatment.

Other Autoimmune Cerebellar Degenerations

Autoimmune cerebellar degeneration also occurs in patients without cancer who produce autoantibodies against transglutaminase, glutamic acid decarboxylase, or thyroid antigens.

Gluten ataxia is manifested by gait ataxia, lower limb ataxia, and nystagmus. It appears to result from autoantibodies against gluten proteins (gliadins) that cross react with transglutaminases in the small intestine (TG2) and brain (TG6). Symptoms of gluten enteropathy (celiac disease) are typically absent, but intestinal biopsy may show immune deposits. MRI may show cerebellar atrophy, and anti-transglutaminase antibodies are commonly present in the blood. The mainstay of treatment is a gluten-free diet.

Anti-glutamic acid decarboxylase (GAD) cerebellar ataxia is associated with autoantibodies against the enzyme (GAD) that synthesizes γ–aminobutyric acid (GABA), the brain’s principal inhibitory neurotransmitter. Gait ataxia is the most consistent clinical feature, but limb ataxia, dysarthria, and nystagmus can also occur. Intravenous immunoglobulin and corticosteroids may be beneficial. Anti-GAD antibodies are also implicated in stiff-person syndrome (see Chapter 9, Motor Disorders).

Hashimoto encephalopathy is a steroid-responsive encephalopathy associated with autoimmune thyroiditis. In addition to ataxia, confusional states, seizures, and myoclonus may occur. Patients are typically euthyroid when ataxia is first diagnosed, and MRI shows little or no cerebellar atrophy. Antibodies against thyroid antigens and α-enolase may be detected in the blood. Treatment is with corticosteroids.

AUTOSOMAL DOMINANT SPINOCEREBELLAR ATAXIA

Autosomal dominant spinocerebellar ataxia (SCA) encompasses a group of over 40 genetically and clinically heterogeneous disorders (Table 8-11).

Genetics

Several types of mutations can produce autosomal dominant SCA, including expansion of CAG trinucleotide repeats coding for polyglutamine (polyQ) tracts, expansion of tri- or pentanucleotide repeats in noncoding regions, and point mutations. Of these, the polyQ disorders are the most common and best characterized. They affect a wide range of proteins, including ion channels, receptors, enzymes, and cytoskeletal proteins.

A striking feature of polyQ disorders is that the underlying trinucleotide expansion is unstable and tends to enlarge with time. This leads to anticipation, in which the age at onset decreases, the disease severity increases, or both, in successive generations.

In addition to SCAs, polyQ disorders include spinal bulbar muscular atrophy (Kennedy disease, see Chapter 9, Motor Disorders) and Huntington disease (see Chapter 11, Movement Disorders).

Pathogenesis

PolyQ expansions confer a toxic gain of function on the target protein. The abnormally long polyQ tract predisposes the protein to conformational changes, misfolding, and proteolytic cleavage (Figure 8-12). As a consequence, protein fragments are generated that are prone to aggregate and, in some cases, translocate from the cytoplasm to the nucleus. Neuronal dysfunction and death are thought to result from some combination of direct toxicity of abnormal proteins or their cytoplasmic or nuclear aggregates; impaired proteasomal function, axonal transport, or nuclear function; and protein-protein interactions.

Clinical Findings

The autosomal dominant SCAs show considerable clinical variability, even within a given family. In general, they are associated with an adult-onset, slowly progressive cerebellar syndrome in which gait ataxia is an early and prominent feature. Other manifestations are dysarthria, diplopia, and limb ataxia. Extracerebellar findings are common, including cognitive, pyramidal, extrapyramidal, motor neuron, peripheral nerve, or macular involvement.

The most common SCAs are 1, 2, 3, 6, and 7. SCA1 produces gait ataxia, limb ataxia, and dysarthria, with brainstem involvement but little cognitive abnormality. SCA2 is notable for the association of ataxia and dysarthria with slow saccadic eye movements and polyneuropathy. SCA3 (Machado–Joseph disease) is especially common in patients of Portuguese ancestry; ataxia is accompanied by eyelid retraction, reduced blinking, external ophthalmoplegia, dysarthria, dysphagia, and sometimes parkinsonism or peripheral neuropathy. SCA6 is comparatively less severe, progresses more slowly, and is more limited to cerebellar involvement than other SCAs. SCA7 is distinguished by retinal degeneration leading to blindness, in addition to ataxia.

Atrophy of the cerebellum and sometimes also of the brainstem may be apparent on CT or MRI (Figure 8-13). However, definitive diagnosis is by genetic testing. There is no specific treatment, but occupational and physical therapy and devices to assist ambulation may be helpful, and genetic counseling may be indicated.

DENTATORUBRAL-PALLIDOLUYSIAN ATROPHY

Dentatorubral-pallidoluysian atrophy (DRPLA) is a dominantly inherited disorder that results from a polyglutamine expansion in the ATN1 gene coding for the protein atrophin 1. DRPLA causes ataxia, chorea, dementia, seizures, and myoclonus. Because of the prominent extrapyramidal features, this disorder is discussed in Chapter 11, Movement Disorders.

ATAXIA-TELANGIECTASIA

Pathogenesis

Ataxia-telangiectasia (also known as Louis–Bar syndrome) is an inherited autosomal recessive disorder with onset in infancy. It results from loss-of-function mutations in the ataxia-telangiectasia mutated (ATM) gene, which codes for a serine/threonine protein kinase related to phosphatidylinositol 3-kinase. Deletions, insertions, and substitutions all have been described. A defect in the repair of DNA double strand breaks is thought to be involved in pathogenesis.

Clinical Findings

Ataxia-telangiectasia is characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, sinopulmonary infections, and lymphoid tumors. Patients typically suffer from progressive pancerebellar degeneration characterized by nystagmus, dysarthria, and gait, limb, and trunk ataxia. Choreoathetosis, loss of vibration and position sense in the legs, areflexia, and disorders of voluntary eye movement are almost universal findings. Mental deficiency is commonly observed in the second decade.

Oculocutaneous telangiectasia usually appears in the teen years. The bulbar conjunctivae are typically affected first, followed by sun-exposed areas of the skin, including the ears, nose, face, and antecubital and popliteal fossae. The vascular lesions, which rarely bleed, spare the central nervous system.

Immunologic impairment usually becomes evident later in childhood, with recurrent sinopulmonary infections in more than 80% of patients. Malignancies occur in approximately one-third of patients and include non-Hodgkin lymphoma, leukemia, and Hodgkin disease.

Other common clinical findings are progeric changes of the skin and hair, hypogonadism, and insulin-resistant diabetes mellitus. The characteristic laboratory abnormalities include decreased circulating levels of IgG2, IgA, and IgE and elevation of α-fetoprotein and carcinoembryonic antigen levels.

Atypical phenotypes may be associated with later (including adult) onset, slower progression, absence of telangiectasia, and movement disorders rather than ataxia as the primary neurologic manifestation.

Because the vascular and immunologic manifestations of ataxia-telangiectasia occur later than the neurologic symptoms, the condition may be confused with Friedreich ataxia, which also manifests in childhood (see later). Ataxia-telangiectasia can be distinguished by its earlier onset (before age 4 years), associated choreoathetosis, and the absence of kyphoscoliosis.

There is no specific treatment for ataxia-telangiectasia, but antibiotics are useful in the management of infections. X-rays should be avoided because of the hypersensitivity to ionizing radiation present in this disorder.

FRAGILE X-ASSOCIATED TREMOR/ATAXIA SYNDROME

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an X-linked disorder caused by gain-of-function mutations (CGG expansions) in the 5′ untranslated region of the fragile X mental retardation 1 (FMR1) gene. White matter tracts, including the middle cerebellar peduncles, are prominently involved. FXTAS affects males primarily and presents at an average age of 60 years, with features that include intention tremor and cerebellar ataxia. Diagnosis is by DNA testing.

MULTIPLE SYSTEM ATROPHY

Multiple system atrophy is a neurodegenerative proteinopathy associated with deposition of α-synuclein in affected neurons. It produces autonomic dysfunction and either parkinsonism or ataxia. Multiple system atrophy is discussed in more detail Chapter 11, Movement Disorders.

HEPATOCEREBRAL DEGENERATION

Hepatocerebral degeneration refers to diseases that impair the function of both the liver and brain, including acquired (non-Wilsonian) hepatocerebral degeneration (eg, that due to liver cirrhosis with portosystemic shunting) and hereditary disorders. Ataxia may be a feature in both cases. Wilson disease, a disorder of copper metabolism characterized by copper deposition in a variety of tissues, is an important cause of hereditary hepatocerebral degeneration. It is an autosomal recessive disorder that results from mutations in the ATP7B gene, which codes for the β polypeptide of a copper-transporting ATPase. Because extrapyramidal features are usually the most prominent neurologic manifestations, Wilson disease is discussed in more detail in Chapter 11, Movement Disorders.

PRION DISEASES

Creutzfeldt–Jakob disease (described in Chapter 5, Dementia & Amnesia) and Gerstmann–Straüssler–Scheinker syndrome (a rare, autosomal dominant disorder) are prion diseases that can produce ataxia. Cerebellar signs are present in approximately 60% of patients with Creutzfeldt–Jakob disease, and patients present with ataxia in approximately 10% of cases. Cerebellar involvement is diffuse, but the vermis is often most severely affected. In contrast to most other cerebellar disorders, depletion of granule cells is frequently more striking than Purkinje cell loss.

Patients with cerebellar manifestations of Creutzfeldt–Jakob disease typically complain first of gait ataxia. Dementia is usually evident at this time, and cognitive dysfunction always develops eventually. Nystagmus, dysarthria, truncal ataxia, and limb ataxia are all present initially in approximately one-half of patients with the ataxic form of Creutzfeldt–Jakob disease. The course is characterized by progressive dementia, myoclonus, and extrapyramidal and pyramidal dysfunction. Death typically occurs within 1 year after onset.

POSTERIOR FOSSA TUMORS

Tumors of the posterior fossa cause cerebellar symptoms when they arise in the cerebellum or compress it from without. Common posterior fossa tumors in children include medulloblastoma, cystic astrocytoma, ependymoma, and brainstem glioma, whereas hemangioblastoma, choroid plexus papilloma, meningioma, and metastases from outside the nervous system (especially the lung and breast) predominate in adults.

Clinical Findings

Patients with cerebellar tumors usually present with headache from increased intracranial pressure or with ataxia. Nausea, vomiting, vertigo, cranial nerve palsies, and hydrocephalus are common. The nature of the clinical findings varies with the location of the tumor. Most metastases are located in the cerebellar hemispheres, causing asymmetric cerebellar signs. Medulloblastomas and ependymomas, on the other hand, tend to arise in the midline, with early involvement of the vermis and hydrocephalus.

Hemangioblastoma may occur as one feature of von Hippel–Lindau disease, which results from a dominant mutation in the VHL tumor suppressor gene, and may also cause retinal hemangioblastoma, renal or pancreatic cysts, and polycythemia. Ependymomas commonly arise in the fourth ventricle, which predisposes to seeding through the ventricular system and hydrocephalus.

Diagnosis & Treatment

CT scan or MRI is useful for diagnosis, but biopsy may be required for histologic characterization. Methods of treatment include surgical resection, irradiation, and chemotherapy. Corticosteroids are useful in controlling tumor-associated edema. Total resection may be curative for cystic astrocytoma of the cerebellum and meningioma. Medulloblastoma shows wide variation in prognosis based on molecular subgrouping.

POSTERIOR FOSSA MALFORMATIONS

Congenital anomalies affecting the cerebellum and brainstem include malformations of the hindbrain (cerebellar agenesis, Dandy–Walker malformation, arachnoid cyst) or cranial vault (Arnold–Chiari malformation). Vestibular or cerebellar symptoms presenting in adulthood are most common in type I Arnold–Chiari malformation, which consists of downward displacement of the cerebellar tonsils through the foramen magnum. Clinical manifestations are related to cerebellar involvement, obstructive hydrocephalus, brainstem compression, and syringomyelia (a cyst or syrinx in the spinal cord). Type II Arnold–Chiari malformation is associated with meningomyelocele (protrusion of the spinal cord, nerve roots, and meninges through a fusion defect in the vertebral column) and has its onset in childhood. Type III Arnold–Chiari malformation is accompanied by encephalocele (herniation of posterior fossa contents through an occipital or cervical bony defect).

Cerebellar ataxia in the type I malformation usually affects the gait and is bilateral; in some cases, it is asymmetric. Hydrocephalus leads to headache and vomiting. Compression of the brainstem by herniated cerebellar tissue may be associated with vertigo, nystagmus, and lower cranial nerve palsies. Syringomyelia typically produces a cape-like distribution of defective pain and temperature sensation.

Arnold–Chiari malformation can be diagnosed by CT or MRI studies that demonstrate cerebellar tonsillar herniation. Patients with headache, neck pain, hydrocephalus, or other symptoms related to compression of the cerebellum or brainstem may benefit from surgical decompression of the foramen magnum. Neuropathic pain may respond to antidepressants or anticonvulsants (see Chapter 12, Seizures & Syncope).

Sensory ataxia is usually the result of impaired proprioceptive sensation due to lesions of the peripheral sensory nerves (sensory neuropathy), dorsal root ganglia (sensory neuronopathy), or posterior columns of the spinal cord (myelopathy) (Table 8-12). Clinical findings include defective joint position and vibration sense in the legs and sometimes the arms, unstable stance with Romberg sign, and a gait of slapping or steppage quality.

SENSORY NEUROPATHY OR NEURONOPATHY

Polyneuropathies that affect large myelinated sensory fibers and sensory neuronopathies (which target dorsal root ganglia) may present with ataxia. Prominent examples include the Hu antibody-positive sensory neuronopathy associated with small-cell lung cancer, sensory neuronopathy from consumption of high doses of pyridoxine, and the Fisher variant of the Guillain–Barré syndrome. These are discussed in more detail in Chapter 10, Sensory Disorders.

MYELOPATHY

Myelopathies that affect the posterior columns can also cause ataxia. A common cause of this syndrome is multiple sclerosis, discussed earlier as a cause of cerebellar ataxia and in Chapter 9, Motor Disorders, as a cause of myelopathy.

COMBINED LESIONS

Several diseases can affect both peripheral and central sensory pathways (Figure 8-14). Examples include neurosyphilis (tabes dorsalis) and combined systems disease from vitamin B₁₂ deficiency, which are discussed elsewhere as causes of dementia (see Chapter 5, Dementia & Amnesia) or sensory disturbance (see Chapter 10, Sensory Disorders). Another example is Friedreich ataxia, discussed next.

FRIEDREICH ATAXIA

Friedreich ataxia, an autosomal recessive disorder with onset usually in childhood, is the most common cause of hereditary ataxia. It results from an expanded GAA trinucleotide repeat in a noncoding region of the FXN gene, which causes loss-of-function of a mitochondrial protein, frataxin. The key pathologic findings are degeneration of the dorsal root ganglia, large myelinated axons of peripheral sensory nerves, corticospinal tracts, and dentate nuclei of the cerebellum, with secondary involvement of the spinocerebellar tracts, posterior columns, and dorsal nucleus of Clarke.

Clinical Findings

The average age at onset is approximately 13 years, with longer GAA repeats correlating with earlier onset. The initial symptom is usually progressive gait ataxia, followed by limb ataxia, dysarthria, and sensory gait ataxia. Neurologic examination shows knee and ankle areflexia, impaired joint position and vibration sense in the legs, leg (and sometimes arm) weakness, and extensor plantar responses. Pes cavus (high-arched feet with clawing of the toes caused by weakness and wasting of the intrinsic foot muscles) is often present, but can also occur in other neurologic disorders (eg, Charcot–Marie–Tooth disease).

Severe progressive kyphoscoliosis may lead to chronic restrictive lung disease. Cardiomyopathy may result in congestive heart failure, arrhythmia, and death. Other abnormalities include visual impairment from optic atrophy and diabetes mellitus.

Atypical phenotypes may be seen with smaller GAA expansions and include late (>25 years) or very late (>40 years) onset and preserved reflexes. These syndromes are characterized by slow progression and a paucity of non-neurologic features.

Friedreich ataxia can usually be differentiated from other cerebellar and spinocerebellar degenerations by its early onset and the presence of prominent sensory impairment, areflexia, skeletal abnormalities, and cardiomyopathy. Definitive diagnosis is by genetic testing.

Treatment & Prognosis

There is no current treatment for the neurologic manifestations of Friedreich ataxia. Orthopedic procedures or devices may improve kyphoscoliosis and gait disorder. The average duration of symptomatic illness is approximately 25 years, with death occurring at a mean age of approximately 40 years. Cardiomyopathy and infection are the usual causes of death.