Acquired diseases causing cerebellar and afferent (sensory) ataxias are shown in Table 4.3. The main causes of acquired cerebellar ataxia are structural lesions of the cerebellum, toxic agents, metabolic diseases, paraneoplastic cerebellar degeneration, autoimmune diseases, infections and superficial siderosis. In the differential diagnosis, it is important to encompass also acquired causes of afferent ataxia, such as vitamin B₁₂ deficiency, Miller-Fisher syndrome (MFS) and sensory Guillain–Barré syndrome. Figure 4.1 illustrates the most frequent causes of acquired ataxias based on speed of onset/progression and age at onset. In adults, acute/subacute onset should suggest a stroke or multiple sclerosis, whereas a viral infection is more likely to cause cerebellar ataxia in childhood.

Wernicke encephalopathy (WE) is an acute life-threatening neuropsychiatric syndrome characterized by ataxia, cognitive or psychiatric changes and oculomotor abnormalities, including nystagmus, abducens palsy and papilloedema. Late-stage, variable abnormalities include hyperthermia, spastic paresis, choreic dyskinesias and coma [10]. Less frequent manifestations include epileptic seizures, hearing loss, hallucinations and behavioural disturbances, cardiac failure, gastrointestinal complaints and polyneuropathy. WE is caused by vitamin B₁ (thiamine) deficiency and its active cofactor thiamine pyrophosphate, an essential coenzyme in the Krebs cycle and the pentose phosphate pathway which plays an important role in cerebral energy use. Thus, thiamine deficiency reduces the metabolism of brain regions with high metabolic requirements and high thiamine turnover, such as the cerebellar vermis [11]. Common causes leading to thiamine deficiency are alcohol abuse and malnutrition, AIDS, cancer and chemotherapeutic treatments, recurrent vomiting or chronic diarrhoea (i.e. hyperemesis gravidarum, pancreatitis, pyloric stenosis), prolonged total parenteral nutrition, gastrointestinal surgical procedures (particularly gastric bypass, gastrectomy, gastrojejunostomy), iatrogenic glucose loading in vulnerable patients, magnesium depletion, intravenous infusion of high-dose nitroglycerine and unbalanced nutrition. Diagnosis of WE is based on clinical features, as there is no specific routine laboratory test available or specific diagnostic abnormality in the blood or cerebrospinal fluid. Blood thiamine concentration lacks specificity, whereas MRI has low sensitivity but high specificity with typical WE lesions described in 58 % of the patients. MRI images may indeed show symmetric increased T2 signal in the paraventricular regions of the thalamus, the hypothalamus, mammillary bodies, the periaqueductal region, the floor of the fourth ventricle and midline cerebellum (Fig. 4.2). An atypical and reversible MRI finding may be bilateral thalamic hyperintensity on T2- and FLAIR-weighted images, a sign previously associated to new variant Creutzfeldt–Jakob disease (CJD) [12]. If not treated, most patients with WE go on to develop Korsakoff syndrome, a disorder characterized by severe anterograde amnesia, disorientation in time, emotional changes and relative preservation of implicit learning and other cognitive domains [13].

Alcoholic and toxic cerebellar degenerations are among the most common forms of chronic cerebellar ataxia due to alcohol-induced degeneration of the cerebellar cortex, particularly in the anterior-superior vermis and adjacent hemispheres (which mainly receive spinal afferents); in addition, chronic thiamine deficiency due to malnutrition may contribute to cerebellar degeneration, as demonstrated by the correlation between low serum thiamine and vermal atrophy on MRI in alcoholics [14]. The prevalence in chronic alcohol users is 11–27 %. Cerebellar ataxia due to chronic alcohol abuse affects gait and lower limbs more than arms and speech and is often associated with signs of peripheral neuropathy.

Cerebellar ataxia can be also be drug induced, most commonly after exposure to lithium, phenytoin, 5-fluorouracil or cytosine arabinoside (Table 4.3) by direct toxicity to the cerebellum or by inactivation of vitamin B₁ (i.e. 5-fluorouracil).

Paraneoplastic cerebellar degeneration (PCD) is an immune-mediated degenerative disorder of the cerebellar cortex associated mainly with small-cell lung cancer, breast and ovarian cancer and Hodgkin’s lymphoma. The onset of ataxia in PCD is subacute and of rapid progression, often predating the detection of the underlying malignancy [15] In some patients, other paraneoplastic syndromes of central or peripheral nervous system may coexist, such as limbic encephalitis, sensory neuropathy and Lambert–Eaton syndrome. The most frequent onconeural antibodies associated to PCD are anti-Hu, anti-Yo, anti-Ri and anti-CMV [16]. Cerebellar atrophy is a late finding on MRI. Repeated searches for the primary tumour are highly recommended using CT scan of the chest, abdomen and pelvis and whole-body fluorodeoxyglucose PET.

Anti-GAD ataxia is a slowly progressive cerebellar syndrome due to antibodies to glutamic acid decarboxylase (GAD). It usually affects gait and, less frequently, speech; nystagmus is a frequent feature, and sometimes patients may exhibit focal rigidity in one limb or concurrent myasthenia gravis. Titres of anti-GAD65 antibodies, which are directly pathogenic, may be lower than those found in stiff person syndrome [17]. MRI may show cerebellar atrophy.

Gluten ataxia (GA) is another autoimmune disorder belonging to the spectrum of gluten-related disorders, associated with gluten intake but not necessarily with enteropathy [18]. GA was originally defined as idiopathic sporadic ataxia with positive serological markers for gluten sensitization [19]; however, the relationship between asymptomatic coeliac disease and sporadic ataxia has been debated for a long time. Patients with GA have evidence of gluten sensitivity, defined as a state of heightened immunological responsiveness to gluten in genetically susceptible individuals, as shown by circulating antibodies (IgA and IgG) to gliadin (AGA). Clinical features are gait and limb ataxia, dysarthria and oculomotor abnormalities due to cerebellar involvement; axonal polyneuropathy can occur in ~40 % of patients. Neurological symptoms usually predate the diagnosis of gluten sensitivity and coeliac disease, and gastrointestinal symptoms may be present in only about 10 % of patients, with evidence of enteropathy by duodenal biopsy in less than one third of patients [20]. Brain MRI typically reveals cerebellar atrophy in most patients with GA. Neuropathological studies have shown evidence of immunological damage to the cerebellum, the posterior columns of the spinal cord and the peripheral nerves [19]. However, the pathogenic role of AGA has been questioned as they are also present in ~10 % of ostensibly healthy individuals from the general population. Moreover, mice transgenic for HLA-DR3-DQ2 and immunized with gliadin to achieve high titres of AGA did not develop ataxia and/or cerebellar damage [21]. More recently, identification of IgA deposits against transglutaminase-2 (TG2) in small-bowel biopsies of patients with coeliac disease and, subsequently, of transglutaminase-6 (TG6), an autoantigen primarily expressed in cerebellar neural tissue, has provided a more specific biomarker for neurological manifestations of GRD, since anti-TG6 are detected in 73 % of patients with GA and in only 4 % of healthy controls, and the titres are sensitive to gluten and gluten-free diets [22]. Irrespective of the presence of an enteropathy, patients positive for any of these antibodies with no alternative cause for their ataxia should be offered a strict gluten-free diet. Stabilization or even improvement of the ataxia after 1 year would be a strong indicator that the patient indeed suffers from GA.

Steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT), formerly known as Hashimoto encephalopathy, represents a treatable cause of acquired immune-mediated ataxia [23]. This is a subacute, rapidly progressive form of autoimmune ataxia which responds to steroid treatment and may be misdiagnosed as viral encephalitis or even prion disease [24]; however, insidious onset and slow progression have also been described [25]. The clinical picture is characterized by cognitive impairment and behavioural changes associated with gait ataxia, tremor and transient aphasia. Myoclonus, seizures, sleep impairment and psychotic symptoms may occur. The disease may have a fluctuating course. Concurrent thyroid disease is not required for the diagnosis since it may precede or follow SREAT. Other autoimmune disorders may be present, such as diabetes mellitus type 1, systemic lupus erythematosus, Crohn’s disease and Sjögren’s syndrome. Diagnosis of SREAT relies on the detection of high titres of anti-thyroid peroxidase antibodies (anti-TPO). Recently, serum autoantibodies against the NH2-terminal of α-enolase (anti-NAE) have demonstrated specificity for SREAT, although their application remains limited to research setting [25]. Other laboratory findings in SREAT (which can be demonstrated in most but not all patients) are increased liver enzyme levels, increased thyroid-stimulating hormone levels and increased anti-thyroglobulin antibodies. Thyroid function is usually normal. Cerebrospinal fluid (CSF) analysis may show increased protein and oligoclonal bands, and brain MRI may show diffuse increased signal in the cerebral white matter on T2- and FLAIR-weighted images, which may reverse after steroid treatment [24, 26]. Extensive dural enhancement has been also rarely described.

Superficial siderosis is characterized by progressive cerebellar ataxia, hearing loss and pyramidal signs [27]. Ataxia represents the most disabling feature, albeit cognition is frequently impaired. Other manifestations include seizures, visual loss and hyposmia. Symptoms arise from deposition of free iron and haemosiderin along the pial and subpial structures of the brain and spinal cord and subsequent damage to the cerebellar cortex, cochlear nerves, cerebral cortex and spinal cord. Repeated subarachnoid bleeding from various sources (previous neurosurgical procedures of the posterior fossa, remote head injuries, vascular tumours, root lesions and vascular abnormalities) is the primary cause. Brain MRI is diagnostic by revealing the typical linear hypointensity on T2-weighted images on the surface of the brainstem, cerebellum and spinal cord; deposits of haemosiderin may also be seen in the Sylvian fissure, cerebral convexities and interhemispheric fissure [27]. Cerebellar atrophy, more prominent in the superior vermis, is also a frequent finding on MRI (Fig. 4.3). In the majority of patients, spinal MRI shows longitudinally extensive, generally ventrally predominant, intraspinal fluid-filled collections often communicating with the subarachnoid space through a dural defect [28]; it was hypothesized that dural defects related to these ventral intraspinal fluid-filled collections (also reported in spontaneous intracranial hypotension) may be related to the pathogenesis of superficial siderosis [29]. CSF evaluation usually reveals xanthochromia with high red blood cell count.

Infectious causes of cerebellar ataxia can be divided in acute and chronic progressive. Acute ataxia is most commonly a result of viral infections in children. Chronic progressive infection is most prominently represented by neurosyphilis, Whipple’s disease and Creutzfeldt–Jakob disease. Syphilis is an infectious disease caused by the spirochete Treponema pallidum. Neurosyphilis has been divided into early and late forms. Early neurosyphilis develops in the first year of infection and may be asymptomatic or present with meningitis, headache and blurry vision. Tabes dorsalis occurs in late-stage neurosyphilis and is characterized by sensory ataxia due to dorsal column involvement. Argyll-Robertson pupils (i.e. pupil constriction to accommodation but not to light) on examination represent a valuable clue for the presence of neurosyphilis in patients with sensory ataxia. Nevertheless, neurosyphilis might also cause cerebellar ataxia as well as other movement disorders as parkinsonism, myoclonus, chorea and dystonia (for a complete review, see Shah and Lang [30]).

Whipple’s disease is an infectious disease caused by the bacterium Tropheryma whippelii causing diarrhoea, weight loss, abdominal pain and other systemic signs (arthralgia or arthritis, endocarditis). Central nervous system involvement is frequent in Whipple’s disease and includes supranuclear vertical gaze palsy, oculomasticatory myorhythmia [31] (a pathognomonic sign, see also see Chap. 5), cognitive decline, sleep disturbances and ataxia. A retrospective review identified ataxia in 55 % of cases, which was variably associated to memory loss, hypothalamic dysfunction (hypersomnia, insomnia, hypothermia, weight gain or weight loss), supranuclear vertical gaze palsy and oculomasticatory myorhythmia [32]. Brain MRI may disclose increased T2 and FLAIR signal in corticospinal tracts, vermis, cerebellar peduncles and brainstem. Diagnosis of Whipple’s disease is based on: identification of Tropheryma whippelii DNA by PCR in the CSF or in biopsy specimens of involved tissues (small bowel, synovia, brain) [34]; PAS staining of smallbowel biopsy specimens or CSF showing foamy macrophages with positive PAS inclusions on light microscopy. Other non-specific laboratory findings are detection of acute-phase reactants, anaemia, leucocytosis, thrombocytosis and laboratory evidence of malabsorption (including vitamin E malabsorption). In the presence of oculomasticatory myorhythmia, neither CSF nor small-bowel biopsy are required, given its unique presence in this disorder.

Sporadic Creutzfeldt–Jakob disease (sCJD) is a transmissible spongiform encephalopathy causing rapidly progressive ataxia associated with dementia and myoclonus. The misfolded form of the prion protein (PrP^Sc) self-propagates without nuclear acid genetic material in infected individuals, accumulating in the central nervous system [35]; clinical symptoms appear after a long incubation time. Variant CJD is caused by transmission of bovine spongiform encephalopathy to humans through consumption of prion-contaminated cattle meat. Prion diseases have the unique feature to being either transmitted or inherited (see inherited ataxias). Clinical and histopathological features of sCJD differ depending on whether the patient is homozygous for methionine (MM) or valine (VV) or heterozygous at codon 129 of the prion protein (PRNP) [36]; accordingly, sporadic prion diseases are currently classified in three groups, based on codon 129 polymorphism: (1) cognitive subtype (MM1, MV1, MM2, VV1), (2) ataxic subtype (VV2, MV2) and (3) sporadic prion diseases with non-CJD subtype (sporadic fatal insomnia and variably protease-sensitive prionopathy)[37, 38].

The most common presentation of the cognitive subtype with MM1 or MV1 polymorphism is a rapidly progressive cognitive impairment affecting multiple domains and eventually associated with ataxia, visual blindness and myoclonus. In this subgroup of patients, the disease may present with a clinical picture resembling corticobasal syndrome (see Chap. 1). In this subgroup as well as in the rare sCJD MM2 and sCJD VV1, the sensitivity of brain MRI in demonstrating typical findings associated to sCJD is high. The sCJD MM2 subgroup may present with amnestic aphasia or apraxia and display longer disease duration (median, 14 months) [39]. Finally, the cognitive subtype associated to sCJD VV1 is associated with younger disease onset, more frequent behavioural changes and slow progression.

In the ataxic subtype of sCJD, associated with VV2 and MV2 polymorphism, patients present with prominent truncal ataxia and cognitive impairment [37]. Psychiatric symptoms are very frequent, including hallucinations, restlessness, depression, fear, aggressiveness, paranoia and euphoria [40]. The most frequent misdiagnoses for this subgroup of patients are multiple system atrophy and Alzheimer’s disease [40].

Diagnosis of sCJD relies on EEG, brain MRI and CSF analysis of tau- and 14-3-3 protein. Overall, the most sensitive investigation is brain MRI, which discloses asymmetric cortical hyperintensity on diffusion-weighted imaging (DWI) and basal ganglia hyperintensities in T2- and FLAIR-weighted imaging. DWI appears to be the most sensitive and specific sequence for early diagnosis of sCJD [41] (Fig. 4.4); accordingly, hyperintensity in the striatum or in at least three cortical noncontiguous gyri is highly suggestive of sCJD. Besides hyperintensity in the cerebral cortex and/or basal ganglia, brain MRI in MV2 sCJD patients may also show thalamic hyperintensities [40]. EEG has low sensitivity in the diagnosis of sCJD as the typical periodic or pseudoperiodic sharp wave complexes appear in mid- to late stages and vary according to sCJD subtype (higher sensitivity in MM1/MV1). CSF analysis of 14-3-3 protein is weakened by a specificity as low as 28 % when compared with autopsy examination [42]; the combination of raised tau protein and positive 14-3-3 increases the specificity for the diagnosis of sCJD. More recently, the real-time quaking-induced conversion has been developed; this is an ultrasensitive, multiwell plate-based fluorescence assay involving PrP^Sc-seeded polymerization of recombinant PrP into amyloid fibrils [43]. This test allows detection of PrP^Sc in the CSF with a sensitivity of 91 % and a specificity of 98 % for the diagnosis of sCJD; this technique has also demonstrated PrP^Sc in olfactory epithelium brushings from patients with sCJD with higher sensitivity (97 %) and specificity (100 %) than CSF [44]. Differential diagnosis of ataxic subtypes of sCJD should also encompass vCJD. Since in early disease stages, MRI shows in vCJD the characteristic pulvinar sign (hyperintensity of the pulvinar region of the thalamus relative to that of the anterior putamen) [45]; however, it should be kept in mind that rarely the pulvinar sign has been associated with paraneoplastic limbic encephalitis [46], prolonged status epilepticus and WE [12]. Lately, protein misfolding cyclic amplification (PMCA), another technique to amplify minute quantities of PrP^Sc, has been shown to demonstrate the presence of PrP^Sc in the urine of vCJD but not of sCJD patients or in those with other neurological neurodegenerative or nondegenerative diseases [47]. Finally, palatine tonsil biopsy consistently shows PrP^Sc in vCJD but not in sCJD.

Subacute combined degeneration (SCD) [48] is a neurological complication of vitamin B₁₂ deficiency characterized by demyelination of the cervical and thoracic dorsal and lateral columns of the spinal cord and occasional demyelination of cranial and peripheral nerves and white matter in the brain [49]. Development and initial myelination of the central nervous system as well as for the maintenance of its normal function relies on vitamin B₁₂ (cobalamin, Cbl), which is a cofactor for methionine synthase and l-methyl-malonyl-coenzyme A mutase. Absorption and utilization of Cbl requires the cellular uptake of dietary Cbl in the ileal enterocytes and the cellular uptake of circulating Cbl across cell membranes. At gastric level, Cbl is released from food protein through peptic digestion in the stomach at low pH and then is bonded to R-protein. At duodenal and jejunal level, R-protein is degraded by pancreatic proteases, and Cbl is bonded to intrinsic factor (IF). The Cbl-IF complex is carried to its site of absorption in the ileum, where it attaches to specific membrane receptors and Cbl is transported across enterocyte. These notions on Cbl absorption are essential to understand the main causes of SCD [50, 51]: (a) severe malabsorption due to pernicious anaemia (autoimmune gastritis), total or partial gastrectomy, gastric bypass or other bariatric surgery, ileal resection or organ reconstructive surgery, inflammatory bowel disease, tropical sprue, congenital malabsorption of Cbl (mutations of its ileal receptor or mutations of IF); (b) mild malabsorption due to protein-bound vitamin B₁₂ malabsorption, mild atrophic gastritis, use of metformin or antiacid drugs; (c) dietary deficiency (vegan or vegetarian diet, or diet low in meat and dairy products); (d) recreational or occupational abuse of nitrous oxide; and (e) nitrous oxide anaesthesia in occult pernicious anaemia.

In SCD patients, the neurological disturbances are combined with symptoms of macrocytic anaemia, although ~30 % of subjects do not show any evidence of it [52]. Neurological manifestations include gait impairment due to afferent ataxia, dysaesthesia, disturbance of position and vibration sense and spastic paraparesis or tetraparesis; additional manifestations described are segmental cutaneous sensory level and pseudoathetosis of the upper limbs [53], dysautonomia (postural hypotension, incontinence, impotence), polyneuropathy, cognitive disturbances and depression. Laboratory investigations include measurement of Cbl (decreased), methylmalonic acid and homocysteine (both increased). High methylmalonic acid is more sensitive and specific for the diagnosis than the other measurements. Demyelination of lateral columns of the spinal cord is demonstrated by MRI which shows symmetrical hyperintense signals, most commonly confined to posterior and lateral columns in the cervical and thoracic spinal cord on T2-weighted axial images (‘inverted V’ or ‘inverted rabbit ear’ sign) [54].

Miller-Fisher syndrome (MFS), a variant of the Guillain–Barré syndrome, is a rare cause of acquired immune-mediated afferent ataxia associated to ophthalmoplegia and areflexia [55]. Usually MFS is preceded by an infection and is associated with the presence of antiganglioside anti-GQ1b antibodies in over 80 % of the patients, in whom the antibody titre correlates with disease severity. Diagnosis is based on anti-GQ1b detection and evidence of reduced sensory nerve action potentials and absent H reflexes on nerve conduction studies; evidence of cranial nerve dysfunction in MSF may also be revealed by blink reflex studies, which show increased latency of both R1 and R2 (ipsilateral and contralateral) response [56]. CSF analysis reveals albuminocytologic dissociation, although this may be a late finding.

Hereditary cerebellar ataxias are a group of disorders clinically and genetically heterogeneous characterized by slowly progressive gait, speech and coordination disturbances. Genotype–phenotype correlation is difficult because of overlapping clinical features among different genetic diseases, either in the group classified as cerebellar ataxia or as hereditary spastic paraplegia. Cerebellar atrophy is a frequent feature of cerebellar ataxia, although few diseases such as Friedreich ataxia may lack this finding. A classification based on pattern of inheritance distinguishes three major groups (Table 4.4): autosomal dominant spinocerebellar ataxias (SCA) usually of adult onset (Table 4.5), autosomal recessive ataxias usually of childhood-onset and X-linked ataxias. In this chapter, congenital ataxias due to cerebellar a-/hypoplasia (Joubert syndrome-related disorders and malformations), where a major component of motor and mental retardation is present, will not be discussed here.