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.
Table 8-9.Causes of Acute or Chronic Cerebellar Ataxia. ||Download (.pdf) Table 8-9. Causes of Acute or Chronic Cerebellar Ataxia.
Drug intoxications: ethanol, sedative-hypnotics, anticonvulsants, hallucinogens
Vertebrobasilar ischemia or infarction
Alcoholic cerebellar degeneration
Toxin-induced cerebellar degeneration
Autoimmune cerebellar degeneration
Autosomal dominant spinocerebellar ataxias
Fragile X-associated tremor/ataxia syndrome
Multiple system atrophy
Posterior fossa tumors
Posterior fossa malformations
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 (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.
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.
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.
Principal arteries of the posterior fossa. (Used with permission from Waxman SG. Clinical Neuroanatomy. 26th ed. New York, NY: McGraw-Hill; 2010.)
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.
Lateral medullary infarction (Wallenberg syndrome) showing the area of infarction (blue) and anatomic structures affected.
Vertigo, nausea, vomiting, and nystagmus (vestibular nucleus)
Loss of pain and temperature sense over the contralateral limbs and trunk (lateral spinothalamic tract)
Loss of pain and temperature sense over the ipsilateral face (spinal trigeminal nucleus and tract)
Truncal and gait ataxia (vestibular nucleus and inferior cerebellar peduncle)
Ipsilateral limb ataxia (inferior cerebellar peduncle)
Ipsilateral Horner syndrome (descending sympathetic tract)
Dysphagia, dysarthria, hoarseness, and ipsilateral palatal paralysis (nucleus ambiguus)
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.
Paramedian midbrain infarction (Benedikt syndrome). The area of infarction is indicated in blue.
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.
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.
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.
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 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 of the cerebellum is rare but may occur in immunocompromised patients or following neurosurgical procedures or epidural injections. Organisms involved include Aspergillus.
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.
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 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 α1A 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.
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.
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.
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 is discussed in Chapter 9, Motor Disorders.
ALCOHOLIC CEREBELLAR DEGENERATION
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.
Distribution of atrophy in alcoholic cerebellar degeneration. Midsagittal view of the cerebellum showing loss of Purkinje cells, confined largely to the superior vermis.
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).
CT scan in alcoholic cerebellar degeneration, showing marked atrophy of the midline cerebellar vermis with relative sparing of the cerebellar hemispheres. (Used with permission from A. Gean.)
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 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).
Table 8-10.Autoimmune Cerebellar Degenerations. ||Download (.pdf) Table 8-10. Autoimmune Cerebellar Degenerations.
|Syndrome ||Antibody ||Associated Neoplasm |
|Paraneoplastic cerebellar degeneration || |
Anti-voltage-gated calcium channel (P/Q type)
Breast, uterus, ovary
Small cell lung carcinoma
Small cell lung carcinoma, thymoma
Small cell lung carcinoma
|Gluten ataxia ||Anti-transglutaminase 2, 6 ||— |
|Anti-GAD cerebellar ataxia ||Anti-glutamic acid decarboxylase ||— |
|Hashimoto encephalopathy ||Anti-thyroglobulin, anti-thyroperoxidase, anti-α-enolase ||— |
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).
Table 8-11.Clinical and Genetic Features of Autosomal Dominant Spinocerebellar Ataxias (SCAs). ||Download (.pdf) Table 8-11. Clinical and Genetic Features of Autosomal Dominant Spinocerebellar Ataxias (SCAs).
|Syndrome1 ||Clinical Features ||Examples2 ||Gene ||Protein ||Mutation3 |
|ADCA I ||Cerebellar ataxia + ophthalmoplegia, dementia, extrapyramidal signs, optic atrophy or amyotrophy. ||SCA1 ||ATXN1 ||Ataxin-1 ||CAG repeat |
| || ||SCA2 ||ATXN 2 ||Ataxin-2 ||CAG repeat |
| || ||SCA3/MJD (Machado–Joseph disease) ||ATXN3 ||Ataxin-3 ||CAG repeat |
| || ||SCA8 ||ATXN8 ||Ataxin-8 ||(CTG•CAG) repeat |
| || ||SCA28 ||AFG3L2 ||ATPase family gene 3-like protein 2 ||Various missense |
|ADCA II ||Cerebellar ataxia + retinal degeneration ||SCA7 ||ATXN7 ||Ataxin-7 ||CAG repeat |
|ADCA III ||Pure cerebellar ataxia ||SCA6 ||CACNA1A ||Calcium channel, P/Q-type voltage-gated, α1A subunit ||CAG repeat |
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).
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.
Proposed mechanisms of polyQ protein processing and toxicity. In polyQ diseases including several autosomal dominant spinocerebellar ataxias, a gene containing a CAG trinucleotide repeat (CAGn) undergoes mutation by expansion of the repeat. The resulting abnormal protein (QnQQQQ) contains an abnormally long polyQ tract, which induces conformational changes that promote misfolding. The misfolded protein is subject to proteolytic cleavage, which generates abnormal and possibly toxic fragments, which may also have an increased tendency to be translocated from the cytoplasm to the nucleus, to aggregate, or both. As a result of these events, neuronal function is impaired, and neurons may eventually die. How neurotoxicity and neuronal death ultimately occur is unknown, but there may be multiple mechanisms, and these may differ across polyQ diseases. Possible contributing factors include direct toxicity of misfolded and cleaved protein monomers or oligomers, or of cytoplasmic or nuclear aggregates (red in figure); impaired proteasomal degradation, axonal transport, or nuclear function; and interactions between polyQ proteins and other cellular proteins.
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.
CT scan in spinocerebellar atrophy, showing an atrophic cerebellum and brainstem. (Used with permission from A. Gean.)
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 (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.
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 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 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.
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.
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.
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.
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).