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Overview of cerebellar ataxia in adults

Overview of cerebellar ataxia in adults
Literature review current through: Jan 2024.
This topic last updated: Feb 22, 2023.

INTRODUCTION — Cerebellar ataxia is a common finding in patients seen in neurologic practice and has a wide variety of causes. Presentations vary widely, from acute cerebellar swelling due to infarction, edema, or hemorrhage that can have rapid and catastrophic effects, to chronic and slowly progressive cerebellar degeneration.

Here we set out to briefly describe the clinical/anatomic correlates of cerebellar disease, to provide a broad differential diagnosis for patients who present with cerebellar ataxia, and to provide a methodologic approach to the evaluation of patients with cerebellar signs. A special emphasis is placed on causes of cerebellar ataxia, both acquired and genetic, that are reversible when timely therapy is initiated.

Related topics review genetic ataxias in more detail:

(See "Overview of the hereditary ataxias".)

(See "Autosomal dominant spinocerebellar ataxias".)

(See "Friedreich ataxia".)

An approach to acute ataxia in children is also reviewed separately. (See "Approach to the child with acute ataxia".)

CLINICAL SYNDROMES — The anatomy of the cerebellum is complex. For the purposes of clinical localization, it is useful to distinguish between the midline cerebellum and the cerebellar hemispheres. Cerebellar syndromes can be divided into symptoms arising from one or the other, although there is significant clinical overlap [1].

Midline cerebellar structures include the vermis, the fastigial and interposed (globus and emboliform) nuclei, the vestibulocerebellum (flocculus and nodulus), and the paravermis/intermediate zone. The right and left cerebellar hemispheres include the dentate nuclei on each side.

Midline cerebellar dysfunction — Midline cerebellar structures are critical for motor execution, rapid and slow eye movements, balance/lower extremity coordination, and vestibular function. Damage to midline structures can result in:

Imbalance Patients tend to fall when standing with their feet together, whether their eyes are opened or closed. They may adopt a compensatory wide-based stance. They often have difficulties with gait, especially tandem walking. They may complain of a sensation of disequilibrium.

Truncal ataxia – Truncal ataxia manifests as swaying of the head and trunk when the patient is sitting. In severe cases, it results in the inability to sit unsupported by the arms. This is seen more often in severe midline injuries. Patients can also have bilateral upper limb ataxia, as seen in hemispheric dysfunction, especially if the paravermis/intermediate zone region of the cerebellum is damaged.

Titubation – Titubation is an involuntary, semirhythmic nodding of the head, neck, and/or trunk that is often seen with midline cerebellar dysfunction.

Lower-limb dysmetria – Dysmetria refers to an impaired ability to perform accurate movements during goal-directed tasks because of a faulty estimation of distance [2]. It can be seen with both midline and hemispheric cerebellar lesions. With midline cerebellar lesions, dysmetria may predominantly affect the lower extremities and can be elicited on heel-to-shin testing.

Saccadic intrusions – Saccadic intrusions are the most common ocular abnormality caused by midline lesions. Intrusions are irregular bursts of rapid eye movements that include opsoclonus, ocular flutter, square wave jerks, and macrosaccadic oscillations. They are often but not always a sign of midline cerebellar pathology.

Nystagmus – Horizontal gaze-evoked nystagmus is commonly seen with midline cerebellar injury. Often the nystagmus is more prominent when looking towards the side of the lesion, although nystagmus in all directions of gaze is usually present. (See "Overview of nystagmus".)

Down-beating nystagmus present in primary gaze or induced by up-gaze localizes to the cerebellar flocculus, as does rebound nystagmus, which is the induction of nystagmus upon return to primary gaze. Both of these can be seen in other processes [3]. Up-beating nystagmus can be seen with midline cerebellar vermis lesions as well as in brainstem lesions.

"Ocular dysmetria" is the term applied to hypermetric saccadic eye movements. After overshooting, the eyes rapidly correct their position to focus appropriately on the object in question. This finding is very suggestive of cerebellar dysfunction.

Vertigo – Vertigo with nausea and vomiting may result from damage to the vestibulocerebellum and is usually associated with saccadic intrusions and nystagmus.

Hemispheric cerebellar dysfunction — The cerebellar hemispheres are largely responsible for motor planning and coordination of complex tasks. Damage to one hemisphere leads to symptoms that are most notable in the ipsilateral limbs. Clinical signs of hemispheric cerebellar dysfunction include:

Dysdiadochokinesis – Dysdiadochokinesis, which is incoordination when performing rapid alternating movements, is a common finding in cerebellar disease. Specific testing includes having the patient alternately pronate and supinate the forearm and hand.

Dysmetria – Dysmetria of the hands and arms can be seen as past-pointing on finger-to-nose testing. Dysmetria is also commonly seen in the legs on heel-to-shin testing and leads to some degree of gait ataxia.

Limb ataxia – Limb ataxia is usually seen clinically as difficulty with coordinated tasks.

Intention tremor – Intention tremor is a type of kinetic tremor, which typically increases in severity (amplitude) as the hand moves closer to its target and is usually large in amplitude.

Ataxic dysarthria – Ataxic dysarthria is characterized by alternating loudness and fluctuating pitch levels, such that the emphasis is placed on syllables that should not be stressed. It can also manifest as scanning speech, which refers to slow enunciation with pauses in between syllables and words. Patients can also exhibit irregular articulatory breakdown, transient nasality, harshness, or breathiness.

Ocular findings – Ocular findings are generally less prominent, but broken smooth pursuits and ipsilateral gaze-evoked nystagmus are often seen.

Noncerebellar causes of ataxia — Weakness and/or sensory loss (both tactile and visual) are common causes of falls and can simulate features of cerebellar ataxia. Proprioceptive sensory loss in particular can cause both limb and gait ataxia. Moreover, the presence of proprioceptive deficits can significantly worsen cerebellar ataxia that would otherwise be subclinical.

A number of other processes, including hydrocephalus and vestibular disease (usually bilateral), also can produce clinical pictures similar to cerebellar ataxia and therefore need to be ruled out as part of the evaluation. While dizziness and vertigo are commonly seen in cerebellar disease, especially when the vestibulocerebellum is damaged, they rarely occur in isolation as the result of a cerebellar lesion. (See "Approach to the patient with dizziness" and "Evaluation of the patient with vertigo".)

ETIOLOGIC EVALUATION — There are many different etiologies for cerebellar disease (table 1 and table 2), and clinical presentations have significant overlap. The urgency and scope of the evaluation depends largely on the temporal onset of symptoms.

Acute ataxia (medical emergency) — The sudden onset of cerebellar ataxia over a period of minutes to hours is considered a medical emergency because it may represent an acute vascular event. In addition to neuroimaging, diagnostic screening for causative drugs and toxins is always an appropriate part of a comprehensive assessment (table 2).

Urgent neuroimaging — Patients who present with acute cerebellar ataxia require emergency neuroimaging with a noncontrast head computed tomography (CT) scan and/or brain magnetic resonance imaging (MRI) to evaluate for hemorrhage, ischemia/infarction, or significant cerebellar edema.

Importantly, CT has poor resolution in the posterior fossa due to bone artifact, and as such ischemic strokes can be missed, particularly in the acute setting. Patients with a negative head CT for whom suspicion of an acute cerebellar process is high should therefore go on to have an MRI. For patients who cannot undergo MRI due to implanted MRI-incompatible hardware or other contraindications, serial CT-based imaging may be indicated if clinical suspicion remains high.

Important causes — Important causes of acute ataxia are stroke, hemorrhage, toxins, medications, thiamine deficiency (Wernicke encephalopathy), and infections.

Vascular disorders – Cerebellar ischemia and hemorrhage are important causes of acute ataxia. Important risk factors include older age, hypertension, and diabetes.

Cerebellar ischemia – Cerebellar ischemia can result from multiple mechanisms affecting the vertebrobasilar arterial system (figure 1), including embolism, thrombosis, dissection, and vasculitis. (See "Posterior circulation cerebrovascular syndromes", section on 'Cerebellar infarction in PICA territory'.)

In most cases, occlusion of the vertebral arteries, basilar artery, or major branches feeding the cerebellar hemispheres results in ipsilateral limb ataxia and, in cases of damage to midline cerebellar structures, nystagmus, imbalance, vertigo, nausea, and vomiting. In addition, there can be associated brainstem findings that vary depending on the site of the lesion.

Intermittent cerebellar ataxia can be seen with transient vertebrobasilar ischemia. In such cases, symptoms may worsen with positional changes.

Cerebellar hemorrhage – Cerebellar hemorrhage may result from a number of etiologies, including hemorrhagic conversion of ischemic infarction, hypertensive hemorrhage, aneurysmal rupture, and bleeding from arteriovenous malformation. Cerebellar hemorrhage usually originates in the dentate nucleus and may extend into the fourth ventricle and cerebellar hemispheres (image 1). Midline cerebellar symptoms are common. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Neurologic signs and ICH location'.)

Cerebellar ischemic and hemorrhagic stroke are commonly associated with headache and can be complicated by edema of the cerebellum. This edema can lead to compression of the adjacent brainstem and the fourth ventricle, resulting in hydrocephalus from compression of cerebrospinal fluid outflow through the fourth ventricular foramina and eventually downward herniation and death if left untreated. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Intracranial pressure management'.)

This makes any vascular injury to the cerebellum a neurologic emergency requiring rapid imaging, aggressive monitoring, and potentially surgical intervention to achieve the best outcomes. When the cerebellum is the only structure damaged, patients may achieve a near full recovery of function if the acute swelling and compression issues can be overcome. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Cerebellar hemorrhage'.)

Medications and toxins – Medications and toxins can lead to transient or permanent cerebellar ataxia and should be explored in most patients with acute (and chronic) presentations where an etiology is not readily apparent (table 2).

Antiseizure medications – Antiseizure medications, especially those that affect sodium channel conductance such as phenytoin, are associated with ataxia. In the same category are carbamazepine, oxcarbazepine, lacosamide, lamotrigine, rufinamide, and zonisamide. Ataxia is also seen with benzodiazepines, felbamate, phenobarbital, and valproic acid in the setting of hyperammonemia. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects".)

Some degree of nystagmus is common even with therapeutic doses of phenytoin, but severe ataxia is usually only seen at higher blood levels. Effects are usually reversible when the medicine is stopped, but chronic administration of phenytoin in particular can lead to permanent cerebellar degeneration.

Chemotherapy – Chemotherapy can be associated with both reversible and permanent cerebellar ataxia. Cytarabine, often used in treatment of leukemias and lymphomas, and fluorouracil, which is used in various cancer treatments including colon cancer therapy, are the most common chemotherapeutics associated with acute cerebellar ataxia.

-Cytarabine – High doses of cytarabine cause an acute cerebellar syndrome in 10 to 25 percent of patients. (See "Overview of neurologic complications of conventional non-platinum cancer chemotherapy", section on 'Cytarabine'.)

-Fluorouracil – An acute cerebellar syndrome occurs rarely in patients receiving fluorouracil; the ataxia associated with fluorouracil may not develop until weeks to months after the chemotherapy has been administered. (See "Overview of neurologic complications of conventional non-platinum cancer chemotherapy", section on 'Fluorouracil'.)

-Others – Additional chemotherapeutic agents that may be associated with acute cerebellar ataxia include capecitabine, hexamethylmelamine, procarbazine, vincristine, and other vinca alkaloids. As a separate issue, certain chemotherapeutic agents, including cisplatin and oxaliplatin, are associated with the development of sensory ataxia caused by neurotoxicity affecting dorsal root ganglia and peripheral nerves. (See "Overview of neurologic complications of platinum-based chemotherapy".)

Toxins and poisons – Toxins and poisons associated with cerebellar ataxia include alcohol, carbon tetrachloride, heavy metals, phencyclidine, and toluene (table 2). Perhaps the most common cause of acute-onset cerebellar ataxia is excessive alcohol ingestion, which usually produces a midline cerebellar syndrome, characterized by ataxia of legs and gait with relative sparing of the arms. (See "Ethanol intoxication in adults".)

Wernicke encephalopathy – Patients with thiamine deficiency can present acutely or subacutely with the trial of ataxia, delirium, and ophthalmoplegia. (See 'Excessive alcohol and vitamin deficiencies' below.)

Infectious etiologies – A number of infectious etiologies are linked to the development of acute cerebellar ataxia (table 1).

Meningoencephalitis – Meningoencephalitis can produce symptoms of cerebellar ataxia with or without encephalopathy. Affected patients often have headache, neck stiffness, and fever, depending on the inciting agent. However, a pure cerebellar ataxia as the only sign can be seen, especially in certain viral infections.

Possible viral pathogens include varicella-zoster virus and Epstein-Barr virus (among many others), and bacterial etiologies include typical (Streptococcus pneumoniae, Neisseria meningitidis) and atypical (Lyme, listeria, mycoplasma, tuberculosis, malaria) bacteria. The diagnosis is established by lumbar puncture (LP). (See "Clinical features and diagnosis of acute bacterial meningitis in adults" and "Aseptic meningitis in adults".)

Postinfectious cerebellitis – Postinfectious cerebellitis is a condition classically seen between one and six weeks after varicella or measles infections in children but can also occur after Epstein-Barr or other viral infections and vaccinations in teenagers and young adults [4]. Brain MRI studies may be normal or can demonstrate diffusion and T2-weighted cerebellar hemispheric abnormalities [5]. The exact mechanism of the autoimmune response is unclear, but some cases are associated with autoantibody production (molecular mimicry).

Postinfectious cerebellitis is usually a monophasic illness that has complete resolution regardless of treatment, but it can be complicated by cerebellar edema requiring interventions such as glucocorticoid treatment, surgical decompression, or ventriculoperitoneal shunting for hydrocephalus [6].

Approach to subacute and chronic presentations — The diagnosis of an underlying cause in patients presenting with subacute or chronic ataxia is challenging, as there are numerous potential etiologies. Clinical experience at medical centers that see large numbers of patients with ataxia demonstrates that between 10 and 15 percent of patients who present with apparently sporadic, slowly progressive ataxia are found eventually to have a genetic cause of their symptoms.

Moreover, many of the etiologies listed as having acute or subacute onset can sometimes present over a longer time course and therefore still need to be considered in the differential diagnosis of patients presenting with a chronic progressive ataxia. Perhaps most sobering is that a cause was not found in up to half of all cases of ataxia in one large case series [7], and our own experience mirrors these studies.

History — The time course of symptom onset is a key feature of the history. This allows the clinician to separate patients with acute, potentially life-threatening problems who require urgent evaluation from those whose evaluation can proceed in a stepwise fashion in the outpatient setting.

Review of systems – A review of systems aims to identify associated symptoms pointing to an underlying etiology, particularly in the case of subacute ataxia. Clinicians should inquire about headache, neck pain or stiffness, fever/chills, weight loss, recent viral syndrome or other illness, and change in eating habits or diet.

Medications – The medication list should be reviewed (table 2). Patients should be asked about the use of over-the-counter medications, herbal remedies, alcohol, and other substances.

Past medical history – The presence or absence of other systemic problems can often help to delineate different etiologies of ataxia. Some systemic symptoms that can inform the differential diagnosis of ataxia include the following (table 3):

Ocular – Ataxia is associated with a retinopathy in spinocerebellar ataxia (SCA) type 7 and some mitochondrial disorders.

Pulmonary Pulmonary symptoms or findings on a screening chest radiograph are seen in systemic infections, neurosarcoidosis, and lung cancer with paraneoplastic cerebellar degeneration (PCD), among other disorders.

Cardiac – Cardiomyopathy is seen in Friedreich ataxia and other mitochondrial disorders, as well as some vasculitic and autoimmune causes of ataxia.

Autonomic – Orthostatic hypotension, urinary difficulties, and constipation due to autonomic dysfunction are seen with multiple system atrophy (MSA) and other parkinsonian disorders. (See 'Sporadic neurodegenerative disorders' below.)

Gastrointestinal – Gastrointestinal complaints are seen in Whipple disease, vitamin deficiencies, gluten enteropathy, hepatocerebral degeneration, and mitochondrial and metabolic disorders.

Rheumatologic – A rheumatologic diagnosis or a history consistent with autoimmune disease is suggestive of glutamic acid decarboxylase (GAD) 65-associated ataxia, Sjögren's disease, lupus, multiple sclerosis (MS), vasculitis, and other autoimmune disorders.

Dermatologic Skin findings are prominent in lupus, Lyme disease, and ataxia-telangiectasia (AT), among others.

Oncologic – A history of cancer should prompt investigation of chemotherapy-induced ataxia, metastatic cancer, or PCD.

Family history – Genetic ataxias are an important cause of chronic progressive ataxia. Although some genetic variants occur sporadically, many are inherited in an autosomal dominant or autosomal recessive pattern. For affected family members, clinicians should inquire about age of onset, symptom spectrum, and prior genetic testing.

Neurologic examination — The initial focus of the neurologic examination is to determine whether the ataxia is the result of a primary cerebellar abnormality. Typical examination findings arising from midline and hemispheric cerebellar dysfunction are reviewed above. (See 'Clinical syndromes' above.)

It is important to distinguish cerebellar ataxia from peripheral causes of postural instability and loss of balance. Patients with peripheral neuropathy (eg, diabetic neuropathy) leading to proprioceptive loss and those with peripheral vestibular dysfunction (especially bilateral) often present with complaints and signs similar to cerebellar ataxia. Clinical examination with special focus on speech and oculomotor dysfunction, which point to a cerebellar etiology, can often distinguish these conditions. (See "Evaluation of the patient with vertigo".)

Some patients have neurologic signs and symptoms implicating cerebellar pathways as well as other systems (eg, peripheral nervous system, motor pathways, vision, hearing). Such findings may represent additional impairments from unrelated etiologies, or they represent more widespread involvement of a single disease and help narrow the etiologic possibilities. As just one example, ataxia associated with ophthalmoplegia is seen in mitochondrial disorders, progressive supranuclear palsy (PSP), Niemann-Pick disease type C, thiamine deficiency, and Miller Fisher syndrome.

We find it helpful to use a standard assessment scale, such as the Scale for the Assessment and Rating of Ataxia (SARA) [8], to track severity and progression over time.

Imaging and ancillary studies — A tiered approach to testing in patients with subacute or chronic ataxia is summarized here and in the table (table 3).

Imaging – Brain MRI with and without contrast should be obtained in all patients with suspected cerebellar ataxia. CT has poor resolution in the posterior fossa due to bone artifact but is appropriate in the acute setting to rule out hemorrhage and in patients who cannot undergo MRI. Use of contrast will help to identify certain tumors, an inflammatory process involving the leptomeninges (eg, meningoencephalitis, leptomeningeal malignancy), subacute infarction, or a vasculitic process.

In some cases, MRI will identify a specific cause, such as a cerebellar tumor or a pattern of demyelination suggestive of MS. For many subacute and chronic causes of ataxia, however, MRI findings are subtle or nonspecific. Cerebellar atrophy may be evident, especially on sagittal images, although a lack of cerebellar atrophy does not rule out an impairment of cerebellar function. Some degenerative etiologies have characteristic patterns of atrophy involving not only the cerebellum but also the brainstem and cortex.

Laboratories – A variety of laboratory tests can be considered in patients presenting with cerebellar ataxia when the diagnosis is not immediately obvious on clinical and neuroimaging grounds. We obtain a short series of tests on the majority of patients presenting with ataxia to screen for treatable causes of this disorder (table 3). Other laboratory tests are pursued on a case-by-case basis.

A particularly important treatable class of disorders is autoimmune ataxias. Although classified as paraneoplastic disorders, cerebellar ataxia associated with antibodies against cerebellar antigens (eg, GAD65, P/Q calcium channel, and voltage-gated potassium channels [VGKCs], including contactin-associated protein-like 2 [Caspr2]) may be negative for occult malignancy. These disorders can respond to intravenous immune globulin (IVIG), plasma exchange, or oral immunosuppressants [9]. (See "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis".)

Lumbar puncture – In patients with acute or subacute onset of ataxia, an LP is often needed to look for an infectious/inflammatory etiology. The presence of ataxia alone is an indication for neuroimaging prior to LP to evaluate for edema and/or mass effect as causes of elevated intracranial pressure, which is a contraindication for LP because of the possibility of inducing cerebral or cerebellar herniation. When an LP is done to evaluate for infection/inflammation, it is reasonable to collect extra cerebrospinal fluid so that it is available to test for oligoclonal bands and autoantibodies, including paraneoplastic antibodies, if the cerebrospinal fluid cell counts are not indicative of meningitis.

Genetic testing — If the initial workup is negative for obvious and/or reversible causes of ataxia and the condition is most consistent with a progressive degenerative condition of the cerebellum and brainstem, then a genetic evaluation for ataxia is indicated. Determining the mode of inheritance, the age of symptom onset, and key clinical signs can help to narrow the list of likely genetic causes, which can be tested for systematically [10].

Many commercial genetic tests simultaneously screen for a subset of the most frequent known genetic ataxias. However, it is important to realize that many of these commercially available screens evaluate for only a fraction of the known inherited causes of ataxia. Thus, even if a genetic panel for causes of ataxia is negative, retesting for newly described causes of ataxia in the future or use of whole-exome sequencing may yield a diagnosis.

Our approach for patients with a slowly progressive cerebellar ataxia of unknown etiology is as follows:

We screen all patients for the most common inherited causes of cerebellar ataxia that result from nucleotide repeat expansions. Specifically, we evaluate for SCA types 1, 2, 3, 6, 7, and 8 (see "Autosomal dominant spinocerebellar ataxias"), Friedreich ataxia (see "Friedreich ataxia"), and replication factor C subunit 1 (RFC1)-related ataxia [11,12], regardless of family history. In patients with pigmentary retinopathy, we start testing with SCA7. Sometimes it is more practical and cost effective to screen for all of the repeat-associated ataxias simultaneously with an ataxia repeat expansion panel (although RFC1 is not yet included in most such panels). Of note, repeat expansions will not be reliably picked up by most clinical whole-exome or whole-genome sequencing tests unless enhanced bioinformatics or advanced sequencing technologies are used [13].

The yield of this limited genetic testing in patients with ataxia who have been prescreened for secondary causes is approximately 10 percent [14].

If first-line testing is unrevealing, we test older males for fragile X messenger ribonucleoprotein 1 (FMR1) gene premutations associated with fragile X-associated tremor/ataxia syndrome (FXTAS). (See "Autosomal dominant spinocerebellar ataxias", section on 'Fragile X-associated tremor/ataxia syndrome'.)

In remaining cases of cerebellar ataxia with a chronic progressive course and no confirmed etiology, whether familial or sporadic, we then proceed with clinical exome and mitochondrial genome sequencing of all known associated ataxia genes. Several studies demonstrate that the yield of such evaluations is relatively high (upwards of 40 percent) in younger patients and adults [15,16]. (See "Next-generation DNA sequencing (NGS): Principles and clinical applications".)

If whole-exome or whole-genome sequencing is not feasible, we obtain alpha-fetoprotein and cholesterol levels to look for evidence of oculomotor apraxia types 1 and 2, AT, and AT variants in cases where these diagnoses are consistent with the history and examination (see "Ataxia-telangiectasia"). We also check cholestenol levels for evidence of cerebrotendinous xanthomatosis if there are any features of this disorder. (See "Cerebrotendinous xanthomatosis".)

SUBACUTE ATAXIAS — The onset of subacute ataxias is typically on the order of days to weeks, with progression occurring over weeks to months rather than years. There is significant variability in the time course of these disorders, such that they can sometimes present in an acute or chronic fashion. Etiologies include atypical infections, chronic exposure to toxins or medications, alcohol abuse and vitamin deficiencies, autoimmune disorders, systemic metabolic disorders, paraneoplastic cerebellar degeneration (PCD), and neoplasms.

Atypical infectious agents — Atypical infectious agents that can cause a subacute cerebellar ataxia include progressive multifocal leukoencephalopathy (PML), prion disease, and Whipple disease among others.

Progressive multifocal leukoencephalopathy – PML is caused by reactivation of the JC virus in immunocompromised hosts. Classic PML is progressive and multifocal, with demyelination involving the subcortical white matter and cortex (image 2). Patients with lesions in the cerebellum and/or brainstem may present with progressive limb or gait ataxia. JC virus can also cause infection of cerebellar granule cell neurons (JC virus granule cell neuronopathy), leading to progressive ataxia and cerebellar atrophy. Neuroimaging with MRI classically shows discrete areas of T2 hyperintensity that do not conform to vascular territories and usually do not enhance or have mass effect. Diagnosis of both forms is established by polymerase chain reaction (PCR) detection of JC virus deoxyribonucleic acid (DNA) in the cerebrospinal fluid (CSF) (algorithm 1). (See "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis".)

There is no specific treatment for PML, but management is directed at reversing the immunocompromised state. In patients with human immunodeficiency virus (HIV) who have not been on highly active antiretroviral therapy (HAART), initiation of treatment can be associated with an immune reconstitution inflammatory syndrome that can lead to increased edema and transient worsening of the clinical symptoms. (See "Progressive multifocal leukoencephalopathy (PML): Treatment and prognosis".)

Prion diseases Sporadic Creutzfeldt-Jakob disease (CJD) and other human prion diseases are often associated with cerebellar ataxia. In sporadic CJD, cardinal manifestations include rapidly progressive mental deterioration and myoclonus, commonly accompanied by cerebellar ataxia and extrapyramidal signs such as hypokinesia. MRI shows characteristic signal hyperintensities in the cortical ribbon, putamen, and head of the caudate on T2-weighted, fluid-attenuated inversion recovery (FLAIR), and diffusion-weighted imaging sequences (image 3). Cerebrospinal fluid biomarkers, in particular the real-time quaking-induced conversion assay (RT-QuIC), are useful to support the diagnosis. CJD and other prion diseases are inexorably progressive over the course of weeks to months and are currently without effective treatment. (See "Creutzfeldt-Jakob disease" and "Diseases of the central nervous system caused by prions".)

Whipple disease – Whipple disease is a rare infectious condition caused by the bacillus Tropheryma whipplei and classically associated with arthralgias, weight loss, abdominal pain, and diarrhea. Central nervous system involvement is often asymptomatic; those with symptoms most often present with cognitive change, altered consciousness, and/or a supranuclear gaze palsy, but cerebellar ataxia can occur. Less common but specific findings include oculomasticatory myorhythmia (continuous pendular convergence oscillations of the eyes combined with concurrent contractions of the masticatory muscles) and oculo-facial-skeletal myorhythmia. The diagnostic evaluation includes CSF PCR for T. whipplei and confirmatory small bowel biopsy (algorithm 2). Treatment consists of antibiotics, with dose and duration varying by phase of infection and site of involvement. (See "Whipple's disease".)

Autoimmune disorders — A large number of autoimmune disorders can present with subacute ataxia as a major symptom, including acute disseminated encephalomyelitis (ADEM), celiac disease (gluten enteropathy with ataxia), glutamic acid decarboxylase (GAD) antibody-associated ataxia, Hashimoto thyroiditis/encephalopathy, histiocytosis X, the Miller Fisher variant of Guillain-Barré syndrome (GBS), multiple sclerosis (MS; note overlap with postinfectious cerebellitis as initial presenting symptom), neurosarcoidosis, postinfectious cerebellitis (eg, following varicella-zoster virus or Epstein-Barr virus infections), and vasculitis (including Behçet syndrome, polyarteritis nodosa, and temporal arteritis). Several of these are discussed in greater detail separately.

Multiple sclerosis – MS can have cerebellitis as its first manifestation (as a clinically isolated syndrome), with or without a viral prodrome. Impairment of cerebellar function is also common in patients with relapsing and progressive forms of MS. Onset of symptoms is usually subacute over days and may persist for weeks to months. (See "Manifestations of multiple sclerosis in adults", section on 'Incoordination'.)

Acute disseminated encephalomyelitis – ADEM in its classic form is a monophasic, autoimmune, demyelinating disease that can present with ataxia and encephalopathy, usually with large areas of white matter involvement on MRI. It is more common in children and can follow a viral illness. Immune suppression is the mainstay of treatment. Consideration must be given to whether this represents a first event of MS as discussed above. (See "Acute disseminated encephalomyelitis (ADEM) in adults".)

Miller Fisher syndrome – Miller Fisher syndrome, a variant of GBS, is characterized by the triad of ataxia, ophthalmoplegia, and areflexia. These patients can progress to a more typical form of GBS and are at risk for respiratory failure. The Miller Fisher syndrome is associated with the presence of anti-GQ1b antibodies. As with other variants of GBS, the Miller Fisher syndrome often occurs after viral infections, including HIV seroconversion. The main modalities of therapy for GBS and the Miller Fisher syndrome are plasma exchange and intravenous immune globulin (IVIG). (See "Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis", section on 'GQ1b syndromes' and "Guillain-Barré syndrome in adults: Treatment and prognosis".)

Bickerstaff encephalitis, a related entity, is a brainstem encephalitis characterized by encephalopathy and hyperreflexia with features of Miller Fisher syndrome, such as ophthalmoplegia and ataxia. It is not only clinically linked to Miller Fisher syndrome but is associated with anti-GQ1b antibodies and can respond to IVIG and plasma exchange. Some experts consider Miller Fisher syndrome and Bickerstaff encephalitis to be overlapping expressions of the anti-GQ1b antibody syndrome. (See "Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis", section on 'GQ1b syndromes'.)

GAD antibody-associated ataxia – GAD antibody-associated ataxia is a rare sporadic form of cerebellar ataxia that has been described in patients with onset from age 20 through 70 years [17,18]. Onset can be subacute, but cases of ataxia that slowly progresses over the course of years have been reported. The ataxia is gait predominant, but nystagmus and dysarthria are commonly seen. The majority of affected patients are females, and many also have type 1 diabetes mellitus or other autoimmune diseases such as thyroiditis and pernicious anemia [18,19]. There is some clinical overlap with stiff-person syndrome (see "Stiff-person syndrome"), which can be associated with the same antibody, and approximately 50 percent of patients complain of leg rigidity. The presence of these antibodies has also been associated with refractory epilepsy and myoclonus. Imaging studies can be normal or may show a pure cerebellar atrophy. Cerebrospinal fluid sampling can be normal, but oligoclonal bands are seen in two-thirds of patients. The diagnosis is made by measuring anti-GAD antibodies in the serum in the appropriate clinical setting. Limited retrospective data suggest that some patients have a good clinical response to plasmapheresis, glucocorticoids, IVIG, and azathioprine [17,18,20,21].

Ataxia associated with P/Q voltage-gated calcium channel antibodies – Ataxia associated with P/Q voltage-gated calcium channel antibodies can occur with or without symptoms of Lambert-Eaton myasthenic syndrome (LEMS). The P/Q calcium channel is expressed not only at the neuromuscular junction but also in high levels in the cerebellum. Case series, including the original report of LEMS, have described the co-occurrence of LEMS and cerebellar ataxia [22,23], and in some cases ataxia is described in the absence of clear evidence of LEMS [9]. Approximately 50 percent of patients with LEMS/ataxia have an underlying malignancy. Early treatment with immunomodulatory therapy may help improve symptoms in patients with ataxia [9,23]. (See "Lambert-Eaton myasthenic syndrome: Clinical features and diagnosis" and "Lambert-Eaton myasthenic syndrome: Treatment and prognosis" and "Paraneoplastic cerebellar degeneration".)

Celiac disease – Celiac disease, also known as gluten-sensitive enteropathy, is an immune-mediated inflammatory disease of the small intestine caused by sensitivity to dietary gluten and related proteins in genetically predisposed individuals. Classic symptoms are related to malabsorption and include diarrhea, steatorrhea, weight loss, and nutrient or vitamin deficiencies. Neurologic symptoms of celiac disease can include peripheral neuropathy, ataxia, headache, anxiety, depression, and epilepsy. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults" and "Diagnosis of celiac disease in adults".)

Gluten ataxia is defined as an otherwise idiopathic sporadic ataxia with positive antigliadin antibodies or other serologic markers of gluten sensitivity [24-27]. It can occur with or without enteropathy. The most frequent clinical features are gait ataxia, limb ataxia, ocular signs of cerebellar dysfunction, and dysarthria [25,28]. Onset typically occurs in the fifth to sixth decades and is insidious with gradual progression in most, though rapid progression has been observed. Neuroimaging reveals cerebellar atrophy in 60 percent or more [29,30]. The pathogenesis is controversial, but there is some evidence for cross-reactivity of antigliadin antibodies with the cerebellum and a direct autoimmune-mediated process (eg, molecular mimicry). This is supported by studies demonstrating elevated serum levels of antibodies directed against gliadin, tissue transglutaminase type 2, or tissue transglutaminase type 6 in patients with both sporadic [24,26,27,31] and hereditary [31] ataxias. In addition, vitamin deficiencies may contribute to the pathogenesis. Some patients have shown improvement in neurologic symptoms with a gluten-free diet [32]. However, cerebellar degeneration seen with longer disease duration is likely to be irreversible [25,28].

Systemic immune disorders – Systemic immune disorders, such as systemic lupus erythematosus, Behçet syndrome, and Sjögren's disease, occasionally manifest with ataxia as a prominent symptom. Ataxia can also occur uncommonly with many other rheumatologic and systemic vasculitic conditions.

Hashimoto encephalopathy – Hashimoto encephalopathy is a rare, steroid-responsive disorder that can mimic CJD. The presentation is heterogeneous with a fulminant, subacute, or more chronic course of declining mental status that is frequently accompanied by seizures and myoclonus. An associated cerebellar syndrome is reported but is uncommon. The diagnosis of Hashimoto encephalopathy is supported by the presence of elevated antithyroid antibody titers and the exclusion of other causes of encephalopathy. (See "Hashimoto encephalopathy".)

Other autoantibodies – Other autoantibodies associated with cerebellar ataxia have been reported in patients without evidence of a primary cancer as a trigger. Examples include Homer-3 autoantibodies [33,34], contactin-associated protein-like 2 antibodies [35], and anti-M-phase phosphoprotein-1 antibodies [36,37]. If an autoantibody is identified, age-appropriate cancer screening is indicated. Immunomodulatory treatment with glucocorticoids, IVIG, or plasmapheresis may be helpful.

Sarcoidosis – Sarcoidosis is an idiopathic immune-mediated multisystem disorder characterized pathologically by the presence of noncaseating granulomas in affected tissues. The most common organs affected are the lungs, skin, and eyes, but the nervous system is involved in approximately 5 percent of patients, occasionally as an initial manifestation of the disease.

Any part of the central or peripheral nervous system can be affected by sarcoidosis. Common syndromes include a cranial mononeuropathy, neuroendocrine dysfunction, a focal or multifocal encephalopathy, myelopathy, hydrocephalus, aseptic meningitis, peripheral neuropathy, or myopathy. In one small prospective study in patients with neurosarcoidosis, cerebellar ataxia was observed in 13 percent of cases [38]. The diagnosis and treatment of neurosarcoidosis are discussed separately. (See "Neurologic sarcoidosis", section on 'Diagnostic approach' and "Neurologic sarcoidosis", section on 'Treatment'.)

Primary or metastatic tumors — Primary or metastatic tumors in or near the cerebellum can produce ataxia by either local infiltration of cerebellar parenchyma or compression of the cerebellum and its afferent/efferent tracts. In general, primary tumors in the posterior fossa are more common in children than they are in adults. The most frequent types of tumors in or near the cerebellum in adults are metastatic from other organs, most often lung and breast cancers. In addition, benign tumors such as meningiomas can produce symptoms by local compression. Although primary gliomas (usually astrocytomas) in the posterior fossa are more common in childhood, they can also occur in adulthood and present with ataxia as an early symptom.

Cerebellar hemangioblastomas can cause symptoms related to hemorrhage or to pressure on adjacent structure. Hemangioblastomas are the most common lesion associated with von Hippel-Lindau disease and tend to be multiple and infratentorial in location, as discussed elsewhere. (See "Clinical features, diagnosis, and management of von Hippel-Lindau disease".)

Very large vestibular schwannomas can compress the cerebellum producing ataxia. Bilateral vestibular schwannomas are characteristic features of NF2-related schwannomatosis. (See "Vestibular schwannoma (acoustic neuroma)" and "NF2-related schwannomatosis (formerly neurofibromatosis type 2)".)

Paraneoplastic cerebellar degeneration — PCD is an uncommon disorder that can be associated with any cancer; the most frequent are lung cancer (particularly small cell lung cancer), gynecologic cancer, breast cancer, and lymphoma (mainly Hodgkin disease). The neurologic symptoms frequently precede or coincide with the diagnosis of cancer.

Patients with PCD typically present with dizziness, nausea and vomiting, gait instability, and other cerebellar signs progressing over weeks to months. The diagnostic evaluation, including paraneoplastic antibody testing in serum and CSF, is reviewed in detail separately. (See "Paraneoplastic cerebellar degeneration".)

Excessive alcohol and vitamin deficiencies — Excessive consumption of alcohol is a common cause of chronic cerebellar degeneration. Ataxia is usually truncal, reflecting degeneration of the cerebellar vermis, but scanning speech and prominent nystagmus can occur uncommonly. (See "Overview of the chronic neurologic complications of alcohol", section on 'Alcoholic cerebellar degeneration'.)

In addition to the direct toxic effects of alcohol, chronic malnutrition is often seen in individuals with chronic alcohol use disorder and can lead to deficiencies in thiamine, vitamin B12, and vitamin E, which may present acutely or subacutely.

Wernicke encephalopathy – Wernicke encephalopathy results from a deficiency in thiamine and is characterized clinically by the triad of acute or subacute ataxia, delirium, and ophthalmoplegia. It is most often associated with alcoholism but can also occur in other situations including hyperemesis gravidarum, malnutrition from any cause (particularly at the time of refeeding), and in dialysis patients. Wernicke encephalopathy produces petechial hemorrhagic necrosis in midline brain structures and corresponding deficits in mentation, oculomotor function, and gait ataxia. All three of these classic symptoms are present in only one-third of patients. Any one of these, but most often encephalopathy, may be seen in isolation; Wernicke encephalopathy should be considered when one or more occur.

Treatment with parenteral thiamine should immediately follow consideration of the diagnosis of Wernicke encephalopathy. In addition, patients at risk for thiamine deficiency should receive intravenous thiamine prior to intravenous fluids that contain any glucose or other sugars since Wernicke encephalopathy can be precipitated or exacerbated by the administration of intravenous glucose or dextrose in susceptible individuals. (See "Wernicke encephalopathy".)

Vitamin E deficiencyVitamin E deficiency can cause a polyneuropathy and cerebellar ataxia. The disorder is uncommon but can occur with fat malabsorption and steatorrhea associated with primary biliary cholangitis, cholestatic liver disease, cystic fibrosis, small bowel bacterial overgrowth, pancreatic insufficiency, celiac disease, Crohn disease, and following gastric bypass. In addition, there are genetic causes of vitamin E deficiency that are discussed separately. (See "Overview of the hereditary ataxias", section on 'Ataxia with vitamin E deficiency'.)

For patients with cholestatic disease, treatment involves high-dose oral supplementation of vitamin E. (See "Overview of vitamin E".)

Other vitamin deficiencies – Other vitamin deficiencies, including vitamin B12 and copper deficiency, can be associated with a subacute progressive ataxia, usually in the setting of a myeloneuropathy. A primary dietary etiology rarely causes a clinically relevant copper deficiency, but a copper-deficient state can occur after gastric surgery and can be induced by excessive zinc ingestion. (See "Treatment of vitamin B12 and folate deficiencies" and "Copper deficiency myeloneuropathy".)

Systemic disorders — Metabolic abnormalities or organ failure in any of a number of systems can be associated with the development of ataxia over the course of the medical illness. Etiologies include electrolyte abnormalities, hormonal imbalance, and liver failure.

Acquired hepatocerebral degeneration – Acquired hepatocerebral degeneration is a progressive neurologic disorder that occurs in the context of repeated episodes of liver failure or chronic liver cirrhosis, with portosystemic shunting a probable risk factor [39-41]. It is characterized by movement disorders, particularly parkinsonism, ataxia, dystonia, chorea, and orobuccal dyskinesia. Cognitive impairment is frequently present, but unlike hepatic encephalopathy, a reduced level of consciousness is not typical of hepatocerebral degeneration. On brain MRI, there is often increased signal on T1-weighted images involving the pallidum and adjacent basal ganglia, though this finding is nonspecific and may be seen in other forms of chronic liver disease (usually due to manganese). There is no proven treatment for acquired hepatocerebral degeneration, though liver transplantation has been associated with improvement in the neurologic manifestations [41].

Hypothyroidism – Hypothyroidism, especially when severe and untreated, can be associated with ataxia [42-44], which is usually reversible with thyroid hormone replacement therapy. (See "Clinical manifestations of hypothyroidism".)

Hypoparathyroidism – Hypoparathyroidism, either primary or secondary, can be associated with multiple neurologic symptoms including ataxia, weakness, spasticity that can progress to tetany, numbness, neuropsychiatric symptoms, and seizures. Many of these states are related to electrolyte abnormalities, most notably hypocalcemia (see "Clinical manifestations of hypocalcemia") and hypomagnesemia (see "Hypomagnesemia: Clinical manifestations of magnesium depletion"), both of which can trigger ataxia on their own. The ataxia is usually reversible if the hypoparathyroidism can be reversed.

CHRONIC PROGRESSIVE ATAXIAS — Chronic progressive ataxia is the most common presentation of the hereditary forms of cerebellar ataxia and sporadic neurodegenerative causes of cerebellar dysfunction.

Sporadic neurodegenerative disorders — Multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) may present with a slowly progressive ataxia. The diagnosis can only be confirmed with certainty at autopsy, but imaging studies and associated clinical findings can make the diagnosis probable during life [45]. Treatment at this time for these disorders is symptomatic only.

Multiple system atrophy – MSA is the most common cause of sporadic progressive cerebellar degeneration in adults, representing up to one-third of cases [7]. The core clinical features are parkinsonism (bradykinesia plus rigidity and/or tremor), autonomic failure including orthostatic hypotension and urogenital dysfunction, cerebellar ataxia, and pyramidal signs occurring in varying combinations. The motor features of the cerebellar subtype (MSA-C) involve predominant cerebellar dysfunction that manifests as gait ataxia, limb ataxia, ataxic dysarthria, and cerebellar disturbances of eye movements. Diagnosis is based on clinical features and exclusion of alternative etiologies. (See "Multiple system atrophy: Clinical features and diagnosis" and "Multiple system atrophy: Prognosis and treatment".)

Progressive supranuclear palsy – PSP is a neurodegenerative disorder that is characterized by supranuclear ophthalmoplegia, gait disorder and postural instability, dysarthria, dysphagia, rigidity, and frontal cognitive disturbance. Patients typically appear to have a surprised expression on their face and walk in a very upright fashion with extreme imbalance and a propensity to falls early in the course of the illness. PSP is now recognized to encompass a number of phenotypic variants. The two most common are Richardson syndrome (the classic form of PSP) and PSP-parkinsonism. Although ataxia is usually not a prominent symptom, it may be seen and is exacerbated by coexistent parkinsonism and oculomotor palsies. Pathologically, PSP is a tauopathy with the presence of tau-positive neuronal inclusions in affected areas of the brain involving astrocytes, oligodendrocytes, and neurons. Early in the disease course, it can be difficult to differentiate it from Parkinson disease and MSA. (See "Progressive supranuclear palsy (PSP): Clinical features and diagnosis".)

Noncerebellar disorders — Conditions that may mimic cerebellar ataxia include sensory ataxia (eg, from large fiber sensory neuropathy), bilateral vestibulopathy, normal pressure hydrocephalus (NPH), obstructive hydrocephalus, migraine headache with ataxia, and functional ataxia.

Normal pressure hydrocephalus – NPH refers to a condition of pathologically enlarged ventricular size with normal opening pressures on lumbar puncture (LP). NPH is associated with a classic triad of cognitive impairment, gait disturbance, and urinary incontinence. The gait most commonly associated with NPH is characterized by a wide base, hesitancy getting started ("ignition failure"), small steps, and unsteadiness. As described, it can usually be differentiated clinically from the gait ataxia of cerebellar disease. Although not truly an example of ataxia, its potential reversibility by ventriculoperitoneal shunting is an important reason to include it in the differential diagnosis of cerebellar gait ataxia. Shunt-responsive NPH is more likely when the gait disturbance appears early on and is more prominent than the cognitive impairment. (See "Normal pressure hydrocephalus".)

Sensory ataxia – Sensory ataxia due to large fiber sensory neuropathy or myelopathy can usually be distinguished by findings on neurologic examination. Neuropathy affecting large myelinated fiber tracts produces depressed reflexes and loss of proprioception and vibratory sense. Myelopathy affecting posterior columns, as occurs with tabes dorsalis and vitamin B12 deficiency (and copper), can present with similar findings. Both anatomic sites should be considered when planning a diagnostic workup, depending on individual circumstances. (See "Approach to the patient with sensory loss", section on 'Neuropathy'.)

Bilateral vestibulopathy – Bilateral vestibulopathy manifests with unsteadiness when walking or standing along with movement-induced blurry vision or oscillopsia and/or worsening unsteadiness in darkness or uneven ground [46]. Patients usually do not have vertigo, but nonspecific dizziness is common. Concomitant hearing loss may or may not be present. The most common causes are ototoxicity (due to antibiotics, chemotherapy, loop diuretics, or other exposures), Meniere disease, and meningitis, but the cause cannot be identified in approximately half of patients [47]. The diagnosis is supported by head impulse and vestibulo-ocular reflex testing. (See "Evaluation of the patient with vertigo", section on 'Head impulse test'.)

Migraine headache with brainstem aura – Migraine headache with brainstem aura (previously called basilar-type migraine) is a rare syndrome that can be associated with episodic ataxia. Usually these patients have headache that occurs either with the ataxia or immediately afterwards; there is often a family history of migraines without ataxia. Of note, patients with genetic forms of episodic ataxia (EA1 and EA2) also often have headaches, which may or may not be temporally contiguous with their ataxic episodes, and this diagnosis should be considered in patients with headache and ataxia. (See "Migraine with brainstem aura".)

Genetic ataxias — Genetic conditions account for the majority of chronic ataxia syndromes in children and one-third to one-half of adult-onset ataxia syndromes. Classification by mode of inheritance is a useful way of organizing the genetic ataxias for both clinical and research purposes, and this approach will be used in this review. These topics are covered in detail elsewhere.

Autosomal dominant ataxias — Many genetic disorders causing ataxia have an autosomal pattern of inheritance, including the spinocerebellar ataxias (SCAs), dentatorubral pallidoluysian atrophy (DRPLA), the episodic ataxias, and adult-onset leukodystrophy.

The spinocerebellar ataxias – The SCAs are a genetically and clinically heterogeneous group of disorders characterized by a slowly progressive cerebellar syndrome in association with various oculomotor, retinal, pyramidal, extrapyramidal, sensory, and cognitive/behavioral symptoms that vary with the underlying affected gene (table 4). Most SCAs are adult-onset, and all feature prominent ataxia. The SCAs are reviewed in detail separately. (See "Autosomal dominant spinocerebellar ataxias".)

Dentatorubral pallidoluysian atrophy – DRPLA is an autosomal dominant progressive ataxia syndrome caused by cytosine-adenine-guanine (CAG) repeat expansion in the atrophin 1 (ATN1) gene. It is seen most commonly in Japan. In addition to ataxia, patients may have rigidity, choreoathetosis, myoclonic epilepsy, and dementia. (See "Autosomal dominant spinocerebellar ataxias", section on 'Dentatorubral pallidoluysian atrophy'.)

The episodic ataxias – The episodic ataxias are a heterogeneous group of dominantly inherited, paroxysmal disorders that typically present in childhood, though some may present in early adulthood. There are seven varieties of dominantly inherited episodic ataxias, called EA1 through EA7. Of these, EA1 and EA2 account for the majority of cases. Diagnosis and treatment are reviewed separately. (See "Overview of the hereditary ataxias", section on 'Episodic ataxias'.)

Autosomal recessive ataxias — Cerebellar ataxia is a prominent feature of a large number of autosomal recessive disorders (table 1 and table 5 and table 6 and table 7 and table 8 and table 9 and table 10) [10]. The most common of these are Friedreich ataxia, ataxia with and without ocular motor apraxia, and ataxia-telangiectasia (AT).

Friedreich ataxia – Friedreich ataxia is the most common hereditary ataxia, caused in most cases by homozygous trinucleotide repeat expansions in both alleles of the frataxin (FXN) gene on chromosome 19q13. The principal neurologic feature is progressive gait and limb ataxia. Additional neurologic manifestations can include optic atrophy, swallowing dysfunction, upper motor neuron weakness, loss of position and vibration sense, and peripheral neuropathy. Cardiomyopathy and diabetes are found in many patients. Disease onset is usually before age 25 years, but some patients have a later disease onset. Patients who present in adulthood are more likely to have a milder phenotype and slower disease progression. (See "Friedreich ataxia".)

Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) – CANVAS is an adult-onset disorder characterized by the association of bilateral vestibulopathy with cerebellar ataxia and sensory neuronopathy [48-52]. The phenotypic spectrum also includes late-onset ataxia without vestibulopathy or neuropathy and ataxia with chronic cough [11,12,53].

Most familial and sporadic forms are caused by homozygous AAGGG repeat expansion within intron 2 of the RFC1 gene, which encodes a large subunit of replication factor C and is involved in DNA synthesis and repair. Interestingly, this repeat is not only expanded but is a different sequence from the major alleles (AAAAG or AAAGG). As the allele frequency of the AAGGG repeat variant is quite common (approximately 0.7 to 4 percent), RFC1 is likely an underrecognized cause of ataxia. In rare patients with a typical CANVAS phenotype and only monoallelic repeat expansion of RFC1, sequencing has identified truncating pathogenic variants in the coding region of the other RFC1 allele [54].

Clinical features of CANVAS include gait imbalance in all, and variable presence of dysesthesia, oscillopsia, impaired vibratory sensation, and loss of ankle reflexes. Up to half of patients have motor system involvement with upper and/or lower motor neuron signs or, less commonly, parkinsonism [52]. All patients have impairment of the oculocephalic reflex (doll's eyes or visually enhanced vestibulo-ocular reflex), which is tested in conscious patients by turning the head quickly from side to side while the patient fixates on an immobile target; the abnormal response is that the eyes fall short of the target due to a hypoactive vestibulo-ocular reflex and make a compensatory saccade ("catch-up" saccade to reach the target). In addition, symptoms of autonomic dysfunction are common [55].

Brain MRI frequently reveals atrophy of the anterior and dorsal cerebellar vermis. Electrodiagnostic testing shows loss of sensory nerve action potentials with or without motor neuron involvement [52,56]. Neuropathologic changes involve a dorsal root ganglionopathy with secondary spinal cord degeneration in the posterior columns, atrophy of cranial sensory ganglia, and cerebellar atrophy with loss of Purkinje cells, mainly in the vermis [51].

Ataxias associated with defective DNA repair – Ataxias associated with defective DNA repair include AT, ataxia-telangiectasia-like disorder (ATLD), and Nijmegen breakage syndrome (NBS). These conditions are associated with wide-ranging defects in organ systems most vulnerable to genomic instability. Some patients with these disorders have a predisposition to malignancy.

Ataxia-telangiectasia – AT is caused by homozygous or compound heterozygous pathogenic variants in the ataxia-telangiectasia mutated (ATM) gene, which lead to defective DNA repair mechanisms and genome instability. AT is a multisystem disease manifested by progressive cerebellar ataxia, abnormal eye movements, other neurologic abnormalities, oculocutaneous telangiectasias, and immune deficiency. Many patients are diagnosed at birth through newborn screening for hereditary immunodeficiency; in other cases, patients present in mid-childhood with progressive neurologic symptoms and characteristic telangiectasia. (See "Ataxia-telangiectasia".)

Nijmegen breakage syndrome and ataxia-telangiectasia-like disorder – NBS and ATLD, two related conditions, present with a somewhat later onset than AT and with a slower progression and no telangiectasias. These related disorders result from deficiencies of other proteins (NBS1 and MUR11, respectively) that are involved in the same DNA repair pathway as ATM. (See "Nijmegen breakage syndrome" and "Ataxia-telangiectasia", section on 'Differential diagnosis'.)

Xeroderma pigmentosum (XP) – XP is a genetically heterogeneous group of rare disorders caused by mutations in DNA excision repair enzymes. Approximately 25 percent of patients with XP have neurologic abnormalities, which may be mild or severe. These include progressive cognitive impairment, ataxia, choreoathetosis, sensorineural hearing loss, spasticity, seizures, and peripheral neuropathy. (See "Neuropathies associated with hereditary disorders", section on 'Xeroderma pigmentosum'.)

Cockayne syndrome – Cockayne syndrome is a rare disorder with ataxia and deafness similar to XP, but it is also characterized by retinal degeneration and accelerated aging without an increased incidence of malignancies. Cockayne is caused by a defect in transcription-related DNA repair. (See "Neuropathies associated with hereditary disorders", section on 'Cockayne syndrome'.)

Ataxia with oculomotor apraxia (AOA) – AOA types 1, 2, and 4 are a group of disorders that present as early-onset autosomal recessive or sporadic cerebellar ataxias with oculomotor apraxia, chorea, facial and limb dystonias, sensorimotor polyneuropathy, and cognitive impairment [57]. They represent up to 20 percent of cases of autosomal recessive cerebellar ataxia [57,58]. Like AT, they all involve a defect in DNA repair and/or transcriptional deficiencies [59].

AOA type 1 – AOA1, also known as "early-onset AOA," usually presents in the first decade of life, although onset has been reported as late as age 25 years. It is associated with hypercholesterolemia and hypoalbuminemia. It results from a mutation in the APTX gene that encodes aprataxin, a protein that may be involved in repair of single-stranded DNA breaks [57]. (See "Ataxia-telangiectasia".)

AOA type 2 – AOA2 is more common than type 1 and has a later age of onset, from the third to sixth decades of life. It is less frequently associated with cognitive impairment, and oculomotor apraxia is a feature in only approximately 50 percent of cases [58]. It is associated with elevated levels of alpha-fetoprotein [59]. AOA2 results from mutations in the SETX gene, which encodes senataxin, a DNA and ribonucleic acid (RNA) helicase [60]. There is no known treatment for either form of AOA, though a subset of patients with AOA1 have a deficiency in coenzyme Q10 and may respond to dietary supplementation [61]. (See "Ataxia-telangiectasia", section on 'Differential diagnosis'.)

AOA type 4 – AOA4 usually presents in the first decade of life with early and severe oculomotor apraxia, although a late-onset case (50 years of age) has been reported [62-64]. Alpha-fetoprotein levels may be mildly increased (1.5 to 4 times normal), and some patients have hypercholesterolemia, hypoalbuminemia, and increased creatine kinase [59]. AOA4 is due to mutations in the polynucleotide kinase 3'-phosphatase (PNKP) gene, which plays a key role in DNA damage repair.

Wilson disease – Wilson disease (hepatolenticular degeneration) is an autosomal recessive disorder of copper metabolism caused by mutations of the ATPase copper transporting beta (ATP7B) gene (see "Wilson disease: Epidemiology and pathogenesis" and "Wilson disease: Clinical manifestations, diagnosis, and natural history", section on 'Clinical features'). Impaired biliary copper excretion leads to accumulation of copper in several organs, most notably the liver, brain, and cornea. Over time, the liver is progressively damaged and eventually becomes cirrhotic. A minority of patients develop acute liver failure, most often in the setting of advanced fibrosis of the liver. In addition, patients may develop neurologic complications, which can be severe. Although ataxia can be present at the time of diagnosis, there is usually but not always evidence of compensated liver failure by the time neurologic symptoms become apparent. In addition to ataxia, Wilson disease is associated with a wide array of movement disorders including tremor, choreoathetosis, and bradykinesia, as well as psychiatric symptoms of depression, paranoia, or delusions. Nearly all patients with Wilson disease with neurologic manifestations have Kayser-Fleischer rings. The diagnosis, management, and prognosis of Wilson disease are reviewed in detail elsewhere. (See "Wilson disease: Clinical manifestations, diagnosis, and natural history" and "Wilson disease: Management".)

Aceruloplasminemia – Aceruloplasminemia is a rare disorder resulting from mutations in the ceruloplasmin gene, which is important for iron transport. It is one of several phenotypically overlapping conditions that make up the syndrome of neurodegeneration with brain iron accumulation. Affected patients present with anemia, pancreatic and liver failure secondary to iron overload, and neurologic symptoms of retinal degeneration, ataxia, and dementia. Treatment with iron chelators is helpful with the liver toxicity but is less effective in treating the neurologic syndrome [65]. (See "Bradykinetic movement disorders in children", section on 'Neurodegeneration with brain iron accumulation'.)

Hereditary vitamin E deficiency – Hereditary vitamin E deficiency can result either from a mutation in the alpha-tocopherol transfer protein causing ataxia with isolated vitamin E deficiency (AVED) or from abetalipoproteinemia (Bassen-Kornzweig disease), which leads to abnormal absorption of the fat-soluble vitamins including vitamin E. These are both autosomal recessive disorders and present with a slowly progressive gait-predominant ataxia in the late teens or early adulthood. Abetalipoproteinemia is also associated with retinal degeneration and peripheral neuropathy as a result of malabsorption of vitamin A and other fat-soluble vitamins. In both of these diseases, early supplementation with high-dose vitamin E is associated with better outcome. (See "Overview of the hereditary ataxias", section on 'Ataxia with vitamin E deficiency'.)

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) – ARSACS is a rare, early-onset disorder with a classic triad of early spasticity, cerebellar ataxia, and sensorimotor peripheral neuropathy [66-69]. ARSACS results from mutations in the SACS gene that encodes the protein sacsin, whose function is unknown, although it has homology to a number of heat-shock proteins. Mutations lead to absent or severely reduced sacsin levels, which appear to correlate with clinical disease severity [70]. This disorder was initially described in families from Quebec, but pathogenic mutations in SACS have now been identified around the world. Although children are usually symptomatic by one year of age, the disease is slowly progressive, and most affected individuals are able to ambulate into their third or fourth decade before requiring a wheelchair in later life. Most patients have preserved cognition until late in the disease course. The phenotypic expression of the disease includes patients who lack one or more of the features that constitute the classic triad (spasticity, cerebellar ataxia, and peripheral neuropathy), or have pure neuropathy, or have atypical features such as autonomic involvement or supranuclear gaze palsy [66,67]. Brain MRI characteristically shows abnormalities involving the pons, including linear hypointensities on T2-weighted sequences, bilateral hyperintensities on fluid-attenuated inversion recovery (FLAIR) sequences involving the lateral pons, and thickening of the middle cerebral peduncle [66,71-73]. Pathologically, patients have atrophy of the cerebellar vermis and almost complete absence of Purkinje cells. Treatment is symptomatic.

Autosomal recessive cerebellar ataxia type 1 – Autosomal recessive cerebellar ataxia type 1, also known as SCAR8- or SYNE1-related autosomal recessive cerebellar ataxia, is a neurodegenerative disorder with a phenotypic spectrum that ranges from a relatively pure, slowly progressive cerebellar ataxia to (more frequently) a multisystem disorder with features that include upper and lower motor neuron disease, respiratory dysfunction, and intellectual disability [74-76]. The mean age of onset is in the third decade (range age 6 to 46 years) [76,77]. Imaging studies reveal marked cerebellar atrophy. The prevalence of the disorder worldwide is unknown, but it appears to be the most common inherited cause of cerebellar ataxia in Quebec, where it was first identified. It is also a relatively common cause of early-onset (age <40 years) ataxia with autosomal recessive inheritance in Europe after exclusion of Friedreich ataxia [76]. The disorder results from truncation mutations in the spectrin repeat containing nuclear envelope protein 1 (SYNE1) gene on chromosome 6. SYNE1 encodes a large protein related to the spectrin family of proteins that link organelles to the actin cytoskeleton, but its specific function is unknown [74-76].

Autosomal recessive cerebellar ataxia type 3 – Autosomal recessive cerebellar ataxia type 3 is characterized by slowly progressive ataxia with cerebellar atrophy [78]. The disorder is caused by mutations in the anoctamin 10 (ANO10) gene [79,80]. The age of onset varies from early childhood to middle age (mean age 33 years). Common additional features include corticospinal tract signs such as spasticity, hyperreflexia, and extensor plantar responses. In a report from France of 186 unrelated subjects with sporadic or recessive progressive cerebellar ataxia of unknown etiology, mutations in the ANO10 gene were found in 5 percent, suggesting that this disorder is a relatively common cause of recessive cerebellar ataxia [78].

Refsum disease – Refsum disease is a rare autosomal recessive peroxisomal disorder characterized by retinitis pigmentosa, ichthyosis, sensorimotor polyneuropathy, and cerebellar ataxia. In addition, electrocardiographic (ECG) changes and sensorineural hearing loss are also seen. The disease usually presents in adolescence but can present in early adulthood. Patients with classic Refsum disease are unable to degrade phytanic acid due to deficient activity of phytanoyl-CoA hydroxylase (PhyH) caused by mutations in the PHYH gene. Strict reduction in dietary phytanic acid intake may be associated with a significant improvement in both the peripheral neuropathy and ataxia. (See "Peroxisomal disorders", section on 'Refsum disease'.)

Cerebrotendinous xanthomatosis – Cerebrotendinous xanthomatosis is a rare autosomal recessive disorder of bile acid synthesis caused by a genetic defect in the cytochrome P450 family 27 subfamily A member 1 (CYP27A1) gene. Neonatal cholestatic jaundice and infantile diarrhea are early signs in some patients but are rarely identified as symptoms of the disorder until other manifestations appear in late childhood or early adulthood; these include premature cataracts and atherosclerosis, tendon xanthomas, cerebellar gait ataxia, upper motor neuron weakness, pseudobulbar affect, and progressive cognitive deficits. Laboratory studies showing elevated levels of serum cholestanol and serum and urine bile alcohols are supportive of the diagnosis, and genetic testing can confirm the diagnosis. Early initiation of therapy with chenodeoxycholic acid is effective at preventing further deterioration. (See "Cerebrotendinous xanthomatosis".)

Aminoacidurias – Aminoacidurias, such as intermittent branched-chain ketoaciduria and isovaleric acidemia, can cause ataxia in children. This is often combined with seizures, episodic vomiting, and lethargy, similar to that seen in children with urea cycle deficits. The urine usually has a characteristic odor. Hartnup disease results from a defect in renal and intestinal transport of neutral amino acids rather than a metabolic defect. This disorder also is associated with niacin deficiency, often leading to symptoms of pellagra (such as rash and confusion). Hartnup disease results from mutations in the solute carrier family 6 member 19 (SLC6A19) gene, which encodes for a sodium-dependent neutral amino acid transporter that is primarily expressed in the kidney and intestine. (See "Overview of the hereditary ataxias", section on 'Aminoacidurias'.)

X-linked ataxias — Among the X-linked causes of ataxia are adrenomyeloneuropathy, fragile X-associated tremor/ataxia syndrome (FXTAS), ornithine transcarbamylase deficiency, pyruvate dehydrogenase deficiency, X-linked adrenoleukodystrophy, and X-linked sideroblastic anemia with ataxia (table 1).

Fragile X-associated tremor/ataxia syndrome – FXTAS occurs mainly in older males and some females who are carriers of a premutation in the fragile X messenger ribonucleoprotein 1 (FMR1) gene. Patients present with progressive ataxia and a prominent intention tremor, typically beginning after the age of 50 years, frequently associated with cognitive decline, parkinsonism, autonomic dysfunction, peripheral neuropathy, and proximal muscle weakness. Clinical features and diagnosis are reviewed in more detail separately. (See "Autosomal dominant spinocerebellar ataxias", section on 'Fragile X-associated tremor/ataxia syndrome'.)

X-linked sideroblastic anemia with ataxia – X-linked sideroblastic anemia with ataxia is a recessive disorder characterized by relatively mild anemia, unresponsiveness to pyridoxine, and nonprogressive cerebellar ataxia with onset usually in early childhood. The recessive mutation on the X chromosome occurs in an ATP binding cassette subfamily B member 7 (ABC7) gene that leads to mitochondrial accumulation of iron. (See "Overview of the hereditary ataxias", section on 'X-linked sideroblastic anemia with ataxia'.)

Mitochondrial ataxias — Ataxia is a frequent manifestation of mitochondrial disorders, which are a heterogeneous group of conditions caused by mutations in proteins involved in mitochondrial oxidative phosphorylation (see "Mitochondrial regulation and functions"). Some mitochondrial disorders result from mitochondrial DNA mutations, in which case inheritance follows a maternal pattern. Others result from nuclear genome mutations; these may be inherited in an autosomal dominant, autosomal recessive, or X-linked pattern.

Mitochondrial disorders can cause a cerebellar or spinocerebellar syndrome, or sensory ataxia, usually in the context of a multisystem disease [81,82]. Other common manifestations include exercise intolerance, ptosis, progressive external ophthalmoplegia, myopathy, muscle cramps and pain, cognitive or neuropsychiatric difficulties, and seizures. The symptoms may be slowly progressive or fluctuate, and disease onset can occur from infancy to late adulthood. The clinical expression of mitochondrial disorders is extremely variable. A large number of mitochondrial disorders display a cluster of clinical features that fall into a discrete clinical syndrome, but many others have a phenotype that does not match a recognized or named syndrome [83].

In a review of the literature through early 2009, mitochondrial disorders were evaluated for their association with ataxia related to involvement of the cerebellum (cerebellar ataxia) or the spinal cord or peripheral nervous system (sensory ataxia) [82]. The following observations were made:

Ataxia was more frequent in nonsyndromic compared with syndromic mitochondrial disorders

Among syndromic disorders associated with mitochondrial DNA mutations, ataxia was frequently present in the following [82]:

Myoclonic epilepsy with ragged red fibers (MERRF)

Neurogenic weakness with ataxia and retinitis pigmentosa (NARP)

Maternally inherited Leigh syndrome (MILS)

Kearns-Sayre syndrome (KSS)

Ataxia was less frequently present in other syndromic mitochondrial DNA disorders [82]:

Mitochondrial encephalomyelopathy with lactic acidosis and stroke-like episodes (MELAS)

Leber hereditary optic neuropathy (LHON)

Pearson syndrome (PS)

Multiple symmetric lipomatosis (MSL)

Maternally inherited diabetes and deafness (MIDD)

Among syndromic mitochondrial disorders associated with nuclear DNA mutations, ataxia was a frequent sign in the following [82]:

Leigh syndrome (LS)

Sensory ataxic neuropathy with dysarthria and ophthalmoparesis (SANDO)

Spinocerebellar ataxia and epilepsy (SCAE)

Alpers-Huttenlocher disease (AHS)

Infantile-onset spinocerebellar ataxia (IOSCA)

Mitochondrial recessive ataxia syndrome (MIRAS)

Myoclonus, epilepsy, myopathy, and sensory ataxia (MEMSA)

Leukoencephalopathy with brainstem and spinal cord involvement and lactic acidosis (LBSL)

Ataxia was less frequent in other syndromic mitochondrial disorders associated with nuclear DNA mutations [82]:

Chronic progressive external ophthalmoplegia (CPEO)

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)

Coenzyme Q10 deficiency

Autosomal dominant optic atrophy and deafness syndrome (ADOAD)

Dilated cardiomyopathy with ataxia (DCMA)

Pyruvate dehydrogenase complex deficiency

In most of these mitochondrial conditions, the ataxia is predominantly cerebellar, but sensory ataxia is often significant in NARP, MIDD, SANDO, SCAE, AHS, IOSCA, MIRAS, and CPEO [82].

Congenital ataxias — Congenital ataxias are present at birth and are generally static in nature. This category includes cerebellar aplasia, cerebellar hypoplasia, and congenital structural abnormalities such as Chiari malformations (brain malformations with downward displacement of the cerebellar tonsils through the foramen magnum), Joubert syndrome (congenital cerebellar vermis hypoplasia), and Dandy-Walker syndrome (partial or complete absence of the cerebellar vermis with associated enlargement of the fourth ventricle). Some of these defects are amenable to surgical intervention. (See "Chiari malformations".)

MANAGEMENT — Most of the initial workup for cerebellar ataxia is aimed at finding a treatable cause. Unfortunately, numerous causes of cerebellar ataxia are currently without effective therapies. For many of these conditions, there are ongoing clinical trials and support groups or organizations for patients that can provide information and assist in the process of developing new therapeutics.

Supportive therapies, including physical and occupational therapy, are indicated for all patients with cerebellar ataxia and can be of substantial physical and psychological help. Limited data suggest that intensive coordination training improves motor dysfunction in ataxia and slows apparent clinical decline [84]. Many patients benefit from a home evaluation to improve the physical environment by installing handicap aids. Early involvement of speech language pathologists can improve communication and prevent aspiration events [85].

Other symptomatic management options are largely dependent on comorbid aspects of the primary cerebellar process. As an example, patients with marked spasticity may benefit from baclofen or related agents. Novel supportive therapies are under investigation, such as cerebellospinal transcranial direct current stimulation (tDCS) [86].

In the case of the inherited ataxias, genetic counseling should be provided both before and after any genetic testing is conducted to ensure optimal communication and to help patients understand important ethical and practical aspects, such as insurability and implications for other family members. Achieving a definitive genetic diagnosis is often required for involvement in clinical trials and other research studies, and confirmed diagnoses also aid in providing accurate prognosis and family planning.

SUMMARY AND RECOMMENDATIONS

Clinical syndromes – Cerebellar syndromes can be divided into signs arising from either the midline or the cerebellar hemispheres, although there is significant clinical overlap. (See 'Clinical syndromes' above.)

Midline – Damage to the midline of the cerebellum tends to produce gait ataxia and imbalance, truncal ataxia, dysmetria, ocular findings, head tremor, and vertigo. (See 'Midline cerebellar dysfunction' above.)

Hemispheric – Damage to one cerebellar hemisphere leads to symptoms that are most notable in the ipsilateral limbs. The clinical signs most commonly seen include dysdiadochokinesis, dysmetria, limb ataxia, intention tremor, and scanning speech. (See 'Hemispheric cerebellar dysfunction' above.)

Mimics – Neurologic disorders causing cerebellar signs (gait ataxia and limb ataxia) without involvement of the cerebellum include bilateral vestibular loss and impaired proprioception on a peripheral nerve or spinal basis. (See 'Noncerebellar causes of ataxia' above.)

Etiologic evaluation – There are many different etiologies for cerebellar disease (table 1 and table 2). The urgency and scope of the evaluation depend largely on the temporal onset of symptoms. (See 'Etiologic evaluation' above.)

Acute ataxia (medical emergency) – Patients with acute cerebellar ataxia (evolving over minutes to hours) require prompt evaluation that includes head CT and/or brain MRI as well as drug and toxin screen. The most common causes of acute ataxia are stroke, hemorrhage, toxins, medications, and infections. (See 'Urgent neuroimaging' above and 'Important causes' above.)

Subacute or chronic ataxia – Subacute and chronic ataxias have a broad range of potential etiologies, and there is significant clinical variability and overlap. Findings from the history, neurologic examination, and brain MRI guide additional studies in patients without an obvious etiology. First-tier laboratories in all of these patients aim to identify treatable causes (table 3). (See 'Approach to subacute and chronic presentations' above.)

Subacute ataxias – Important causes of subacute cerebellar ataxia include (see 'Subacute ataxias' above):

Atypical infections, such as progressive multifocal leukoencephalopathy (PML), prion disease, and Whipple disease

Autoimmune disorders, such as multiple sclerosis (MS), antibody-mediated encephalopathies, and celiac disease

Primary or metastatic tumors

Paraneoplastic cerebellar degeneration (PCD)

Excessive alcohol and vitamin deficiencies (vitamin E, B12)

Systemic metabolic disorders

Chronic progressive ataxias – While genetic and neurodegenerative etiologies are responsible for a significant proportion of patients with chronic progressive ataxia, all such cases should still be evaluated for common reversible causes of ataxia (table 3). In those without a treatable cause, features of dysautonomia (as in multiple system atrophy [MSA]) or supranuclear gaze palsy (as in progressive supranuclear palsy [PSP]) can lead to a diagnosis that precludes the need for genetic evaluation.

For most other cases, the increasing availability of genetic testing in clinical practice is significantly shortening the time between symptom onset and diagnosis, even for rare causes of disease. (See 'Chronic progressive ataxias' above and 'Genetic testing' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges J. Paul Taylor, MD, PhD, who contributed to an earlier version of this topic review.

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Topic 14134 Version 30.0

References

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