Sj gren \200\231s syndrome, APS, SLE Known malignancy Paraneoplastic CD, metastatic disease, AT Heavy metal exposure Lead, mercury, or thallium ataxia Precipitant infection or high protein load Inherited metabolic disorders, VWMD From the examination Extracerebellar \201 ndings Sensory neuropathy Alcoholic CD, paraneoplastic CD, connective tissue disease, Miller Fisher syndrome, vitamin de \201 ciency, heavy metal poisoning, CANVAS, ARCAs (including FRDA, AOA, AT, AVED, ABL) , FXTAS, ADCAs Amyotrophy ARCAs, ADCAs, GM2 gangliosidosis Reduced re \202 exes Miller Fisher syndrome, paraneoplastic CD, ARCAs, SCA2 Ophthalmoplegia MS, Wernicke \200\231s encephalopathy, Miller Fisher syndrome, mitochondrial disease, Whipp le \200\231s disease, AOA1, ADCAs, NPC Oculomotor apraxia AT, ATLD, AOA1, AOA2 Lateralized brainstem signs Vascular causes, posterior fossa tumors, MS Pyramidal features MS, ADEM, super \201 cial siderosis, FRDA, AVED, GM2 gangliosidosis, CTX, ARSACS, mitochon drial disease, AT, AOA2, ADCAs, ALD, MLD, PMD Myoclonus CJD, gluten ataxia, Hashimoto encephalopathy, hypoxia, paraneoplastic CD, SSPE, MSA, PMEs, inborn errors of metabolism, GM2 gangliosidosis, CTX, mitochondrial disease, AT, AOA2, SCA1 4 Extrapyramidal features MSA, ADCAs, FXTAS, GM2 gangliosidosis, CTX, AT, ATLD, AOA1, AOA2, WD, NPC Cognitive impairment/mental retardation Alcoholic CD, CJD, Hashimoto encephalopathy, MS, SSPE, hypothyroidism, ADCAs (DRPLA, SCA17, SCA13), GSS, FXTAS, GM2 gangliosidosis, CTX, mitochondrial disease, AOA1, AOA2, ARSACS, MS S, Gillespie syndrome, inborn errors of metabolism, NPC Psychiatric disturbances Alcoholic CD, paraneoplastic CD, CJD, Hashimoto encephalopathy, ADCAs (DRPLA, SCA17), GM2 g angliosidosis, CTX, mitochondrial disease, hypothyroidism, NPC, MLD Retinitis pigmentosa AVED, ABL, RD, mitochondrial disease Degenerative maculopathy ADCAII (SCA7) Extraneural \201 ndings Short stature Mitochondrial disease, MSS Scoliosis FRDA, AOA1, AOA2, MSS Dysmorphic features PDH de \201 ciency, RD, MSS Pes cavus FRDA, other ARCAs Cataracts MSS, CTX Aniridia Gillespie syndrome Kayser \200\223Fleischer rings WD (Continued) Oxford Textbook of Movement Disorders 286 Table 27.2 (Continued) Clinical feature Telangiectasias Possible diagnosis AT, ACD Skin rash SLE, Lyme disease, Hartnup disease Tendon xanthomas CTX Cervical lipomas Mitochondrial disease Arthritis SLE, Whipple \200\231s disease Cardiomyopathy Alcoholic CD, vascular causes, FRDA, AVED, ABL, RD Hepatomegaly Urea cycle disorders, NPC CD, cerebellar degeneration; ADEM, acute disseminated encephalomyelitis; MS, multiple scler osis; VHL, von Hippel \200\223Lindau disease; FRDA, Friedreich \200\231s ataxia; GAD, gluta mic acid decarboxylase; PMEs, progressive myoclonic epilepsies; ADCA, autosomal dominant ce rebellar ataxia; SCA, spinocerebellar ataxia; DRPLA, dentatorubral \200\223pallidoluysian a trophy; NPC, Niemann \200\223Pick disease type C; EA, episodic ataxia; RD, Refsum \200\231s disease; MSA, multiple system atrophy; FXTAS, fragile X tremor \200\223ataxia syndrome; AP S, antiphospholipid syndrome; SLE, systemic lupus erythematosus; AT, ataxia telangiectasia; VWMD, vanishing white matter disease; CANVAS, cerebellar ataxia with neuropathy and bilate ral vestibular are \202 exia syndrome; ARCAs, autosomal recessive cerebellar ataxias; AOA, ataxia with oculomotor apraxia; AVED, ataxia with vitamin E de \201 ciency; ABL, abetalip oproteinaemia; ATLD, ataxia telangiectasia-like disorder; CTX, cerebrotendinous xanthomatos is; ARSACS, autosomal recessive spastic ataxia of Charlevoix-Saguenay; ALD, adrenoleucodyst rophy; MLD, metachromatic leucodystrophy; PMD, Pelizaeus \200\223Merzbacher disease; CJD, C reutzfeldt \200\223Jakob disease; SSPE, subacute sclerosing panencephalitis; GSS, Gerstmann \200\223Str ussler \200\223Scheinker disease; WD, Wilson disease; MSS: Marinesco \200 \223Sj gren syndrome; PDH, pyruvate dehydrogenase. Investigations Magnetic resonance imaging Th e advent of MRI has revolutionized the diagnos is of cerebel- lar ataxias. A large number of acquired causes can be diagnosed with its ass istance. Th ese include tumors, abscesses, demyelinat- ing lesions, other infl ammatory les ions, infarcts, hemorrhages, or superfi cial siderosis. Gradient-echo T 2 * sequences are p articularly sensitive for picking up superfi cial siderosis. MRI can also assist in the dia gnosis of sporadic degenerative ataxias, such as Creutzfeldt \200\223 Jakob disease (CJD), MSA, and ILOCA, as well as many of the hereditary degenerative ataxias. However, it should be noted that in such cases MRI fi ndings are oft en non-specifi c, consisting of cer- ebel lar and/or brainstem atrophy (25). available, is recommended. Testing for other rarer hereditary ataxias is currently only per formed within research settings. Management Th e treatment of cerebellar ataxia, both disease-modifying and symptomatic, rem ains poor. Signifi cant advances made on patho- genesis have not yet been translated into s uccessful disease-modifying therapy. However, among numerous cerebellar disorders which are at present untreatable, it is important to identify those ataxias which are amenable to di sease modifi cation. Within the acquired ataxias, these include disorders due to toxic eff ects, vitamin defi - ciencies, vascular pathology, immune-mediated infl ammation and neurod egeneration, tumors or endocrine abnormalities. Among the hereditary ataxias, conditions am enable to modifi cation include some autosomal recessive metabolic disorders, such as ataxi a with vitamin E defi ciency (AVED), Wilson disease (WD), Refsum \200\231s dis- ease (RD), cerebrotendinous xanthomatosis (CTX), ataxia with co- enzyme Q10 defi ciency and Niemann \200\223Pick disease type C (NPC). In the EAs carbonic anhydrase inhibitors can reduce the frequency of attacks and may have an eff ect on disease progression (25). More details on s pecifi c disease-modifying treatments are given in the corresponding paragraphs on diff ere nt ataxias. Th e absence of fi ndings on MRI can also be helpful in the diagno- sis of cerebellar ataxi a, with paraneoplastic CD (in its early stages) and FRDA being characteristic examples. Congenital ataxias, including Chiari malformation, Dandy \200\223 Walker syndrome and Joube rt syndrome, also have characteristic MRI appearances. Other tests including genetic testing A multitude of other diagnostic tests can shed light on the patient with cerebellar ataxia. Th ese include electrophysiological tests (nerve con duction studies, EMG, EEG, visual evoked potentials, somatosensory evoked potentials, and c entral motor conduction time), CSF analysis, and numerous routine and more specialized bloo d tests. Such tests may steer the diagnosis towards more spe- cifi c disorders (Table 27.3) . In the case of FRDA, data implicating oxidative stress in its pathogenesis have led to ther apeutic trials involving antioxidant agents such as vitamin E, co-enzyme Q10, and idebenone . No defi nitive improvement in ataxia was clearly demonstrated in these trials. A potentia lly signifi cant cardioprotective eff ect of idebenone reported initially has not been born e out by more recent larger trials (28, 29). Regarding specifi c genetic testing, guidelines have been recently published by a European task force (27). In the case of ADCAs, testing should include SCA1, 2, 3, 6, and 7. Th ese tests are widely avail able. For episodic ataxias (EAs), testing for EA1 and EA2, available in specialist and research laboratories, is recommended. Concerning ARCAs, testing for FRD A (widely available) should be initially requested. Testing for AT, AOA1 and AOA2 should be done in patients with positive biochemical fi ndings, such as hypoalbu- minaemia, hypercho lesterolaemia or elevated alpha-fetoprotein (AFP). For the X-linked ataxias, testing for FX TAS, which is widely Regarding symptomatic treatment, several approaches have been tried with very limited succe ss. Findings implicating the choliner- gic system in cerebellar ataxia led to trials involv ing physostigmine, choline, and choline derivatives. Overall, results were disappointing (3 0). Attempts at manipulating the serotoninergic and dopaminer- gic systems were also largel y ineff ective. Minor eff ects were reported for buspirone and amantadine (30, 31). Clonaze pam, propranolol, and primidone, used in action tremor, have also been tried in cer- ebella r tremor with limited success (29). Aminopyridines may have some eff ect in cerebellar ocul omotor disturbances (32). CHAPTER 27 Hereditary and acquired cerebellar ataxias 287 Table 27.3 Investigating the patient with cerebellar ataxia (more widely used tests are dis played \201 rst, and blood and CSF tests are grouped together) Investigation Purpose Notes Imaging, electrophysiology, specialist assessment, biopsies Brain MRI Vascular causes, MS, ADEM, in \202 ammatory disease, tumors, infection, trauma, congenital malformations, super \201 cial siderosis, CJD, cerebellar atrophy in hereditary and acqui red degenerative ataxias, molar tooth sign in Joubert syndrome Can exclude common causes of sporadic ataxia Can also assist in hereditary and degenerative ataxias Spinal cord MRI MS, ADEM, in \202 ammatory disease, Chiari malformations, super \201 cial siderosis, vita min de \201 ciency, ARCAs ECG, echocardiography Vascular causes, FRDA, AVED, RD Nerve conduction studies, EMG ACD, paraneoplastic CD, in \202 ammatory disease, MFS, ARCAs, ADCAs, RD, MSA Abnormal anal sphincter EMG in MSA EEG CJD, mitochondrial disease, DRPLA, SCA17, SCA10, SCA14, PMEs, inborn errors of metabolism, SSPE, NPC Ophthalmology, VEP, ERG WD, MS, ADCA II, AVED, mitochondrial diseases, ABL, RD Kayser \200\223Fleischer rings (WD), SCA7 retinal degeneration SSEP MS, ADEM, ARCAs, ADCAs, vitamin de \201 ciency, super \201 cial siderosis TMS MS, ADEM, ARCAs, ADCAs, vitamin de \201 ciency, super \201 cial siderosis Chest and abdominal CT, pelvic US, mammography, testicular US, PET, gallium scan Tumors, paraneoplastic CD, sarcoidosis ENT examination Mitochondrial disease, FRDA, RD, super \201 cial siderosis Autonomic function tests MSA, FXTAS Muscle biopsy Mitochondrial disease Small bowel biopsy Coeliac disease, Whipple \200\231s disease Skin biopsy NPC ( \201 broblast culture), PMEs (Lafora body disease) Blood and urine tests U&E, glucose, LFTs, FBC, ESR Systemic disease, in \202 ammatory disease, infection, ACD, inborn errors of metabolism, A OA1 Low albumin in AOA1 TFTs, anti-thyroid antibodies Hypothyroidism, Hashimoto encephalopathy HbA1c Vascular causes, FRDA, mitochondrial disease, anti-GAD ataxia Arterial blood gasses Inherited metabolic disorders ANA, antiDNA, antiENA, ACL In \202 ammatory disease (SLE, Sj gren \200\231s syndrome, APS) Neurosarcoidosis SACE Serum immunoglobulins In \202 ammatory disease, AT Cholesterol, lipoprotein electrophoresis Vascular causes, ABL, AOA1, AOA2 Viral serology Viral/postviral cerebellitis Tumor markers Tumors, paraneoplastic CD Antigliadin and antiendomysial antibodies Gluten ataxia Not very speci \201 c Antineuronal antibodies Paraneoplastic CD Most commonly with SCLC, breast, ovarian, lymphoma Anti-GAD antibodies Ataxia with anti-GAD antibodies Association with sti \200 person syndrome Anti-GQ1b antibodies MFS Ethanol and drug levels Ethanol and drug toxicity Vitamin E Vitamin B1, B12 Serum alpha-fetoprotein AVED, ABL, other de \201 ciency states ACD, ABL, other de \201 ciency states AT, AOA2, malignancy Serum caeruloplasmin, 24hr urine copper WD Plasma ammonia, lactate and pyruvate Urea cycle disorders, disorders of amino acid and organic acid metabolism, mitochondrial di sease, PDH de \201 ciency Consider in early-onset acute or intermittent phenotypes Genetic testing FRDA, ATXN1,2,3,7, CACNA1A, TBP, FMR1, ATM, APTX, SNTX, KCNA1 FRDA, SCA1,2,3,6,7,17, FXTAS, AT, AOA1, AOA2, EAs Consider also in undiagnosed sporadic ataxias (Continued) Oxford Textbook of Movement Disorders 288 Table 27.3 (Continued) Investigation Serum and urine amino acids, urine organic acids Purpose Disorders of amino acid and organic acid metabolism, PDH de \201 ciency Notes Consider in early-onset acute or intermittent phenotypes Blood \201 lm for acanthocytes ABL Serum cholestanol CXT Serum phytanic acid RD Blood VLCFA Adrenoleucodystrophy White cell enzymes (hexosaminidase A, arylsulfatase A, PDH, chitotriosidase) GM2 gangliosidosis, MLD, PDH de \201 ciency, NPC Serum biotinidase Biotinidase de \201 ciency Serum heavy metals Heavy metal toxicity CSF analysis CSF analysis including OCB Viral cerebellitis, MS, ADEM, paraneoplastic CD, in \202 ammatory disease, MFS, HIV, CJD, RD CSF ACE Neurosarcoidosis CSF antineuronal antibodies Paraneoplastic CD CSF analysis for protein 14 \200\2233-3 CJD MS, multiple sclerosis; ADEM, acute disseminated encephalomyelitis; CJD, Creutzfeldt \200 \223Jakob disease; ARCAs, autosomal recessive cerebellar ataxias; FRDA, Friedreich \200\231 s ataxia; AVED, ataxia with vitamin E de \201 ciency; RD, Refsum \200\231s disease; CD, ce rebellar degeneration; MFS, Miller Fisher syndrome; ADCAs, autosomal dominant cerebellar at axias; MSA, multiple system atrophy; DRPLA, dentatorubral-pallidoluysian atrophy; SCA, spin ocerebellar ataxia; PMEs, progressive myoclonic epilepsies; SSPE, subacute sclerosing panen cephalitis; NPC, Niemann \200\223Pick disease type C; WD, Wilson disease; VEP, visual evoke d potentials; ERG, electroretinogram; ABL, abetalipoproteinaemia; SSEP, somatosensory evoke d potentials; TMS, transcranial magnetic stimulation; FXTAS, fragile X tremor \200\223ataxi a syndrome; AOA, ataxia with oculomotor apraxia; TFTs, thyroid function tests; GAD, glutami c acid decarboxylase; ANA, antinuclear antibodies; ENA, extractable nuclear antigen; ACL, a nticardiolipin antibodies; SLE, systemic lupus erythematosus; APS, antiphospholipid syndrom e; SACE, serum angiotensin-converting enzyme; AT, ataxia telangiectasia; SCLC, small-cell l ung cancer; PDH, pyruvate dehydrogenase; EA, episodic ataxia; CTX, cerebrotendinous xanthom atosis; VLCFA, very long chain fatty acids; MLD, metachromatic leucodystrophy; OCB, oligocl onal bands; ACE, angiotensin-converting enzyme. Chiari malformation Chiari type I malformation is a common condition (prevalence 1 in 1000 in the general population) characterized by cerebellar tonsillar herniation through the for amen magnum. A proportion of children with Chiari type I can present with ataxia (35). Othe r manifesta- tions include suboccipital headache, vertigo, blurred vision, lower cranial ne rve involvement, and long tract signs. Symptom onset is usually in the second or third deca de. MRI establishes the diag- nosis. Surgical decompression is recommended in symptomatic p atients (36). Rehabilitation measures are particularly important in patients with ataxia to help them mai ntain as good a functional status as possible and cope with activities of daily living. Reg ular physiother- apy, if possible, and occupational therapy are recommended (18). Speech th erapy can be helpful with cerebellar dysarthria. Assistive devices including orthoses, stic ks, or strollers should be used to improve ambulation. Wheelchair and bed-bound patients re quire specifi c care to avoid complications (33). Speci \201 c ataxic disorders In the analysis that follows, non-hereditary and hereditary causes of cerebellar ataxia are discussed separately in order to ensure a more coherent pre sentation. Dandy \200\223Walker syndrome Th is is a relatively common malformation occurring in 1 in 5 000 infants. Th e key components include hypoplasia of the cerebellar vermis and cystic dil atation of the fourth ventricle, diagnosed on MRI. It can be associated with macrocephaly a nd hydrocephalus. Many patients have ataxia and nystagmus as a prominent feature (37). Th e non-hereditary congenital and acquired cerebellar ataxias Congenital non-hereditary at axias Congenital ataxias are due to anomalies present at birth. They are, by definition, re latively non-progressive. Because the cer- ebellar system is functionally incomplete at bir th, they can ini- tially manifest with non-specific hypotonia and developmental delay. More typical ataxic symptoms are usually recognized after the first year of life (34). The demo nstration of non-progression against the background of a child acquiring new motor skills c an be difficult. In general, the combination of severe cerebellar hypoplasia on imaging wit h a child who is not profoundly ataxic can point towards a congenital ataxia (25). Certain congenital ataxias, such as Chiari malformation, can present much later in life. Ataxic cerebral palsy A small percentage of children with cerebral palsy present with \200 \230ataxic cerebral palsy \200\231 (38). It is believed that a signifi cant pro- portion of congenital genetic ataxias may be masked under this umbrella term (25). Acute-onset acquired ataxias with or without intermittent course Vascular causes Cerebellar infarction is a cause of acute-onset ataxia that can be unilateral and is usually associat ed with other brainstem symptoms. CHAPTER 27 Hereditary and acquired cerebellar ataxias 289 Surgical treatment may be necessary in a subset of these patients to avoid brainstem compre ssion (2). Cerebellar hemorrhage, oft en associated with reduced level of consciousness, ma y require emer- gency neurosurgical evacuation (39). dysarthria, vertigo, tinnitus, diplopia, and bilateral paraesthesias, without motor defi ci t. It is more commonly seen in adolescent girls (17). Treatment is as for more typical migr aine. Labyrinthine seda- tive drugs can also be used symptomatically (54). Acute drug toxicity Th e direct toxic eff ect of several drugs, including ethanol, antiepil ep- tics, and lithium, is a common cause of acute cerebellar ataxia (19, 40, 41). Immediate cessation of exposure is oft en therapeutic (1). Conversion reaction Ataxia is a common conversion reaction in children, particularly in the 5 \200\22310-year-old age group. Psychosocial stressors can be identi- fi ed in most cases (55). Acute viral/postviral cerebellitis An acute-onset ataxia can oft en result from viral/postv iral cerebel- litis in childhood. A large number of viruses has been implicated, including varicella, measles, mumps, and rubella (most common), as well as infl uenza, para-infl uenz a, Coxsackie virus, herpes sim- plex virus, cytomegalovirus, Epstein \200\223Barr virus, pa ramyxovirus, and poliovirus (42). Mycoplasma pneumoniae , Borrelia burgdoferi , Bordetella pertussis , Coxiella burnetii , and Salmonella typhi have also been associated with cerebel litis (43). MRI oft en shows diff use increased signal on T 2 images in the cerebellar hemi spheres (44). Antivirals, antibiotics, and steroids are recommended in the man- agement of acute cerebellitis (3). Subacute-onset acquired ataxias Relapsing multiple sclerosis Subacute-onset ataxia can deve lop within the context of a multi- ple sclerosis (MS) attack. Previous episodes of optic ne uritis, oft en undetected, can shed light on the diagnosis. A \200\230pure \200\231 cerebe llar ataxia is the presenting symptom of MS in less than 3% of cases (56). Much more oft en other brainstem or long-tract signs accom- pany the ataxia. Characteristic fi ndings on MR I, delayed visual evoked potentials, and the presence of OCBs in the CSF assist in the diag nosis. Steroids are used to treat the attacks. Tumors Posterior fossa tumors can be a relatively common cause of subacute-onset cerebellar ataxia, which is oft en accompanied by headache and vomiting (57). Th ey are more common i n chil- dren. Primary tumors, such as cystic cerebellar astrocytoma, medullo blastoma, and ependymoma, predominate in childhood. Metastatic tumors are more common in adults (58). Cer ebellar haemangioblastomas are vascular, and cystic tumors of the poste- rior fossa oft en found in patients with von Hippel \200\223Lindau disease. Th ese patients require a multidi sciplinary approach to manage- ment (59). Acute disseminated encephalomyelitis Ataxia can be a prominent symptom of acute disseminate d enceph- alomyelitis (ADEM), a postinfectious demyelinating disease most commonly observed in children. Up to 75% of patients report an antecedent infection or vaccination (45). Cha racteristic MRI fi nd- ings and the usual absence of oligoclonal bands (OCBs) in the CSF ca n assist in making the diagnosis (46). Steroids, intravenous immunoglobulin (IVIG), and pla sma exchange are used therapeu- tically (45). Traumatic brain injury/hypoxia/heat stroke Acute ataxia may occasionally develop following traumatic brain injury (47) or acute hypoxia, and sometimes as a component of acute mountai n sickness (48) or as a result of acute heat stroke (49). Management of posterior fossa tra uma is initially directed to stabi- lizing vital functions and controlling intracranial pre ssure. Steroids are not recommended (50). Steroids are used in acute mountain sickness (48) . Vascular malformations Rarely, a vascular anomaly in the posterior fossa, such as a dural f i stula or an arteriovenous malformation, can cause a subacute to chronic cerebellar syndro me. Surgical or endovascular approaches to treatment are recommended when appropriate (60, 61). Paraneoplastic cerebellar degeneration Paraneoplastic cerebellar degeneration (PCD) is an i mmune- mediated disorder characterized by degeneration of the cerebellar cortex, which occu rs most frequently in association with small cell lung cancer, breast and ovarian cancer, a nd Hodgkin \200\231s lymphoma (62). Th e most commonly detected antineuronal antibodies in PCD and their associated tumors are shown in Table 27.4 (62, 63). At presentation, MRI is o ft en unremarkable in patients with PCD, although atrophy develops over time (1). In childr en with an underlying neuroblastoma, cerebellar ataxia may accompany the classic opsoclonus \200\223myoclonus syndrome (64). In general, treat- ment of the underlying tumor and immun osuppressive therapy may be helpful in PCD if given early on. However, more oft en than not the clinical picture is unresponsive to therapy (1). Wernicke \200\231s encephalopathy Acute-onset ataxia is a prominent symptom of Wernicke \200\231s encepha- lopathy, which is characterized by the \200\230classic triad \200\231 o f confusional state, ataxia, and eye signs (nystagmus and ophthalmoplegia). It is caused by thiamine defi ciency, oft en, but not always, associated with alcohol abuse. Intravenous t hiamine should be given without delay to avoid long-term complications (51). Miller Fisher syndrome An acute-onset ataxia is one of the three classic features comprisin g Miller Fisher syndrome (MFS), the other two being ophthalmople- gia and arefl exia (52). Th e presence of anti-GQ1B anti-ganglioside antibodies characterizes MFS, which is thought to be part of a spectrum including Bickerstaff \200\231s encephalitis. Brain MRI is usuall y unremarkable. Treatment is with IVIG or plasma exchange. Th e outcome is usually good (53 ). Infectious causes HIV infection has been associated with cerebellar ataxia, typically resul ting from lesions caused by opportunistic infections such as toxoplasmosis and progressive multifocal leucoencephalopathy. Primary cerebellar degeneration associated with HIV infecti on can also result in a more insidious-onset ataxia (65). Specifi c treatment Basilar migraine Acute ataxia is oft en a prominent symptom of basilar-type migraine, which can also include other brainstem manifestations, such as Oxford Textbook of Movement Disorders 290 Sporadic Creutzfeldt \200\223Jakob disease A subacute-onset ataxia is oft en the fi rst sym ptom of the ataxic var- iant of sporadic Creutzfeldt \200\223Jakob disease (sCJD) (1). As t he dis- ease progresses dementia becomes prominent. Th e EEG may show characteristic period ic discharges (76). MRI reveals basal ganglia hyperintensities and the CSF shows increased concentration of 14-3-3 proteins (77). No eff ective treatments are known at present. Table 27.4 Autoantibodies and associated malignancies in paraneoplastic cerebellar degenera tion Autoantibody Associated malignancy Associated paraneoplastic syndromes Anti-Yo Ovarian, breast Anti-Hu SCLC PEM, sensory neuronopathy Hashimoto encephalopathy Hashimoto encephalopathy is characterized by cognitive changes acc ompanied by ataxia, tremor, and myoclonus in the presence of anti-thyroid antibodies. It ca n mimic the ataxic variant of sCJD. It responds well to steroid therapy (78). Anti-Ri SCLC, NSCLC, breast Opsoclonus \200\223myoclonus Anti-Tr Hodgkin \200\231s lymphoma Anti-Ma NSCLC, breast, colonic Brain stem dysfunction Anti-CV2/CRMP5 SCLC, thymoma PEM, sensory neuronopathy Anti-Ta/Ma2 Testicular Limbic encephalopathy Insidious-onset acquired ataxias with chronic progression Alcoholic cerebellar degeneration (ACD) ACD is thought to be one of the most common forms of chronic cerebellar ataxia and o ccurs primarily in middle-aged men with a history of chronic alcohol abuse (1). Th e pathog enesis is complex and is thought to involve both the toxic action of alcohol and the sequel ae of thiamine defi ciency (1). MRI characteristically reveals vermal cerebellar atrophy (7 9). Strict abstinence and vitamin B 1 supplementation are recommended and can lead to sympt omatic improvement (1). Anti-VGCC SCLC LEMS Anti-mGluR1 Hodgkin \200\231s lymphoma Anti-ZIC4 SCLC SCLC, small-cell lung cancer; NSCLC, non-small-cell lung cancer; PEM, paraneoplastic enceph alomyelitis; LEMS, Lambert \200\223Eaton myasthenic syndrome. against opportunistic infections and highly active antiretroviral therapy should be institu ted (66). Cerebellar ataxia of subacute onset is a prominent CNS mani- festation in patients with Whi pple \200\231s disease. Systemic symptoms of Whipple \200\231s disease include fever, weigh t loss, arthralgia, nausea, and diarrhea. Other neurological manifestations include altered conscious level, hallucinations, ophthalmoplegia, nystagmus, myo- clonus, and oculomastica tory myorrhythmia (highly characteristic, if not pathognomonic) (67). Patients oft en have multiple enhancing lesions on MRI. Several antibiotic combinations have been used to treat these patients (68). Chronic drug and solvent toxicity/heavy metal poisoning Apart from the acute toxic eff ect of drugs on the cerebellum, an insidious cerebellar syndrome can ensue following chronic us e in certain cases. Such cases include phenytoin (80), lithium (81), amiodarone (82), antic ancer drugs such as 5-fl uorouracil (83), and solvents such as toluene (84). Poisoning with heavy metals includ- ing organo-lead compounds, mercury, and thallium can also cause insid ious cerebellar ataxia (1). Th e most important therapeutic measure for chronic toxicity is immediate discontinuation of expo- sure (1). A cerebellar abscess can also be the cause of a subacute ataxia and will oft en need neurosurgical drainage (69). Subacute sclerosing panencephalitis Cerebellar ataxia can be a prominent symptom in some pa tients with subacute sclerosing panencephalitis (SSPE). SSPE is caused by persistent infect ion of the brain by an aberrant measles virus and is a disorder of childhood. It is extreme ly rare in developed countries with widespread vaccination, but more common in developing c ountries. Th e EEG may show characteristic periodic complexes and MRI, although normal in t he initial stages, may later show diff use T 2 signal increase especially in the periventri cular and subcortical white matter (70). Isoprinosine, alpha-interferon, and ribavirin have been used therapeutically in SSPE but results have overall been disappointing (70). Primary progressive multiple sclerosis Primary progressive multiple sclerosis (PPMS) manife sts in 10 \200\22315% of patients as a chronic progressive ataxic syndrome with prominent c erebellar features (85). Such a presentation is seen in only about 1% of MS patients. Given the oft en scarce MRI fi nd- ings in PPMS, positive OCB can be central to the diagnosis. P PMS responds poorly to disease-modifying treatment (85). Vitamin B and E de \201 ciency An insidious-onset cerebellar ataxia can occur following de fi ciency in vitamin E (86), thiamine (87), or cobalamin (88), oft en within the context of malabsorption in gastrointestinal disease. Vitamin sup- plementation can arrest or even im prove the neurological picture. In \202 ammatory diseases/vasculitides Cerebellar ataxia has been reported as a rare fi nd ing in patients with systemic lupus erythematosus (SLE) (71), primary Sj gren \200\231s syndrome (72), and antiphospholipid syndrome (73). Multifocal lesions are usually present o n MRI (73). Ataxia is also a com- mon symptom in patients with neurosarcoidosis (74). Patie nts with CNS vasculitides, such as Beh et \200\231s disease, may also feature cerebellar ataxia as a prominent symptom (75). Corticosteroids and other immunosuppressive drugs have been used with good response. Super \201 cial siderosis of the CNS Superfi cial siderosis of the CNS is caused by deposi tion of haemo- siderin in the leptomeninges and subpial layers of the brain and spinal cord . Th e clinical syndrome is characterized by insidious onset cerebellar ataxia, sensorineur al deafness, and pyramidal tract signs (89). Th e underlying cause is repeated subarachnoid bleed- ing from various sources (90). Characteristic rim hyperintensities on T 2 * imaging are seen on MRI. Th e CSF is usually xanthocromic CHAPTER 27 Hereditary and acquired cerebellar ataxias 291 with a high protein content. If the cause of chronic bleeding can be identifi ed and surgic ally removed, patients may stabilize (89). following the exclusion of acquired and inherited causes of ataxia. MRI shows cerebellar at rophy without associated brainstem atrophy (98). Treatment, as in all degenerative ataxias, is disappointing. Ataxia associated with anti-GAD antibodies A cerebellar ataxia of insidious onset, suggesti ng a degenerative process, has been reported in patients with anti-glutamic acid decarboxyl ase (anti-GAD) antibodies. It is associated with cerebel- lar atrophy on MRI in half of the cases (91). Many of these patients also have type 1 diabetes (92). IVIG and other immunosu ppressive regimes have been tried in anti-GAD ataxia with variable results (1, 92). Th e hereditary cerebellar ataxias Congenital hereditary ataxias Rare developmental anomali es associated with vermal or cerebellar agenesis or hypoplasia may give rise to congenital ataxia. Most of them are now thought to be genetic and follow autosomal reces- sive inherit ance. Two of the most widely recognized are the Joubert and Gillespie syndromes (99). Other s include the pontocerebellar hypoplasias and congenital disorders of glycosylation. Gluten ataxia A cerebellar ataxia of insidious onset, occasionally associated with myoclonu s, has been reported to be the most common neurologi- cal manifestation in patients with co eliac disease. Th is association has been termed \200\230gluten ataxia \200\231 and is oft en found in patients with antigliadin antibodies and silent enteropathy (93). Patients als o have one or more types of transglutaminase antibody. Sixty% of patients have cerebellar a trophy on MRI (94). A gluten-free diet should be started without delay, but response depend s on the dura- tion of ataxia. IVIG has also been used to treat gluten ataxia in con- junct ion with dietary measures (94). Joubert syndrome Joubert syndrome is a rare genetically heterogeneous inherited con- genita l ataxia. It is characterized by hypotonia evolving into ataxia and developmental delay, ne onatal respiratory disturbances, and oculomotor abnormalities. It is defi ned by the presen ce of a char- acteristic MRI fi nding in the posterior fossa known as the \200\230molar to oth \200\231 sign (100). Gillespie syndrome Gillespie syndrome is a rare inherited congenital ataxia character- ized by the triad of ataxia, aniridia, and mental retardation. Th e genetic causes have not bee n fully elucidated. MRI reveals cerebel- lar, and especially vermal, hypoplasia (101). Hypothyroidism Hypothyroidism has long been recognized as a subacute to chronic cause of ce rebellar ataxia. Th yroxine treatment can reverse the symptoms (95). Acute-onset hereditary ataxias with or without intermittent course Episodic ataxias (EAs) T h e EAs are an expanding group of dominantly inherited disorders characterized by intermitt ent episodes of acute cerebellar dysfunc- tion, with more subtle residual neurological dysf unction between episodes. Th ey belong to the large family of hereditary channelopa- thies. Seven EAs have been recognized to date with four genes iden- tifi ed (Table 27.5), but the main forms are EA1 and EA2 (6, 102). Cerebellar ataxia with neuropathy and bilateral vestibular are \202 exia syndrome (CANVAS) CANVAS is a late-onset ataxia characterized by the triad of insidious-onset cerebellar dys function, bilateral vestibulopathy, and sensory neuronopathy. Initially described in the ea rly 1990s, it was recognized as a distinct syndrome in 2004. Patients charac- teristically have an impaired visually enhanced vestibulo-ocular refl ex. Brain MRI shows cerebellar atr ophy in most cases. Th e iden- tifi cation of two aff ected sibling pairs has raised the po ssibility of a late-onset recessive disorder (96). Episodic ataxia 1 EA1 is an autosomal dominant potassium channelopathy caused by mutations in the KCNA1 gene. It is characterized by brief attacks of ataxia (lasting seconds to minut es), oft en triggered by emotional stress, fatigue, postural changes or startle, and interi ctal myokymia. Onset is in childhood. It may respond to antiepileptic medications or acetaz olamide (103). Multiple system atrophy (see also Chapter 13) Multiple system atrophy (MSA) is a late-onset (usually sixth dec- ade) progressive neurodegenerative disease characterized by severe dys autonomia, parkinsonism, and cerebellar ataxia. In around 20% of European patients the cere bellar component is initially predominant (MSA-C), and the other manifestations only become obvious with time (1). MSA represents around 30% of adult-on- set cerebellar ataxias (26). It is associated with severe brainstem and cerebellar atrophy, as well as pontine and midd le cerebellar peduncle hyperintensity (1). Consensus criteria that assist in the diagnosis of MSA have recently been published by an international task force (97). Treatment of the c erebellar component of MSA is disappointing (21). Episodic ataxia 2 EA2, the most common EA, is an autosomal dominant calcium channelopathy c aused by mutations in the CACNA1A gene. It is characterized by more prolonged attacks of at axia (lasting hours to days), oft en triggered by exercise, emotional stress, caff eine, or alcohol, and interictal residual ataxia with nystagmus. Onset, as in EA1, is in childhood. Acute attacks respond well to acetazolamide. EA2 is allelic to familial hemiplegic migrain e (FHM) and SCA6 (104). Idiopathic late-onset ataxia Idiopathic late-onset ataxia (ILOCA) is the most common late-o n- set cerebellar ataxia (5). As with MSA, onset is in the sixth decade. However, although slowly progressive, it is a more benign condi- tion and the lasting absence of dysautonomia diff erentiates it from MSA-C. It is characterized by a relatively pure cerebellar ataxia with mild sensory and pyramidal signs (1). Diagnosis can only be made Inborn errors of metabolism Inborn errors of metabolism can present with acute or intermitt ent ataxia oft en due to metabolic decompensation in response to diet- ary intake or interc urrent illness. Inheritance is usually autosomal recessive. An early-onset ataxia with inte rmittent course, associated Oxford Textbook of Movement Disorders 292 Table 27.5 Th e hereditary episodic ataxias (all autosomal dominant) Duration of Episodic a ttacks ataxia Seconds to minutes EA1 Gene/locus Frequency Other manifestations Interictal manifestations Myokymia Clinical notes KCNA1 /12q13 CACNA1A /19p13 Relatively common None EA2 Most common Hours to days Vertigo, nausea, vomiting, headache Ataxia, nystagmus Progressive ataxia EA3 1q42 Rare Minutes to hours Vertigo, tinnitus, myokymia None EA4 NK Rare Brief Vertigo, diplopia Ataxia, nystagmus Later onset, progressive ataxia EA5 CACNB4beta / 2q22 \200\22323 Rare Hours Vertigo Ataxia, nystagmus, seizures Progressive ataxia EA6 SLC1A3 /p13 19q13 Rare Hours Cognitive impairment Ataxia, seizures Progressive ataxia EA7 Rare Hours to days Vertigo, dysarthria None EA, episodic ataxia; NK, not known encephalopathy, seizures, and developmental delay should raise the possibility of inherited metabolic ataxia, especially urea cycle disorders (including ornithine transcarbamylase de fi ciency, which is X-linked), amino acidopathies (including Hartnup and maple syrup urine disease), organic acidopathies (including biotinidase defi ciency), and pyruvate dehydrogen ase defi ciency. Screening for these disorders might include a full blood count, liver func tion tests, arterial blood gasses, blood ammonia, lactate, pyruvate, and ketone, plasma and urinary amino acids, urinary organic acids, and serum biotinidase (Table 27.3) (105). Th e rapeutic management includes dietary restrictions and vitamin administration, such as bioti n in the case of biotinidase defi ciency (106). MRI may show some cord but no cerebellar atrophy. Th e disease is caused by a triplet GAA e xpansion in the FRDA gene coding for frataxin (12). Antioxidants, such as vitamin E, co-enz yme Q10, and idebenone have been used in FRDA with very limited therapeutic success (12). Ataxia with vitamin E de \201 ciency (AVED) Th e clinical phenotype of AVED is very simila r to FRDA. However, cardiomyopathy and diabetes are much more common in FRDA, whereas titub ation and dystonia appear to be specifi c for AVED. Very low levels of vitamin E are charac teristically found in AVED, and this allows the correct diagnosis. Administration of vitami n E supplements can arrest disease progression. Th e disease is caused by a mutation in the ATPP gene coding for alpha-tocopherol trans- fer protein, but genetic diagnosis is usually unnecessary (108). Insidious-onset hereditary ataxias with chronic progression Autosomal recessive cerebellar ataxias Most ARCAs are early-onset disorders, although exceptions to this rule are well doc umented. Th ey are characterized by spinocerebel- lar ataxia, involving both the cerebellum and the dorsal columns, with associated peripheral neuropathy, oft en leading to arefl exi a, and common involvement outside the nervous system (12). Th e prototype and most common A RCA is FRDA. MRI can help dis- tinguish between the ARCAs by revealing the presence or abse nce of cerebellar atrophy. FRDA, AVED, abetalipoproteinaemia (ABL), and RD are characterize d by the absence of cerebellar atrophy. Th e remaining ARCAs show cerebellar atrophy (12). Table 27.6 sum- marizes the most widely recognized ARCAs.